NOAEL Studies Active Ingredient

Kojic Acid NOAEL Studies

INCI: KOJIC ACID

CAS: 501-30-4

Raw No Observed Adverse Effect Level endpoint records grouped by source. This page does not render calculated Margin of Safety values.

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CIR_vision_codex 20 endpoints

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
CIR_vision_codex	NOAEL	=100	mg/kg	rat	oral	Subchronic	repeated dose toxicity	{"citation":"300; 100; 56","dose":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.","effect":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...","page":7,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_001"}
CIR_vision_codex	NOAEL	=125	mg/kg	rat	dermal	Chronic	NOAEL study	{"citation":"500; 2; 125","dose":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.","effect":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...","page":8,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_002"}
CIR_vision_codex	NOAEL	=150	mg/kg	mouse	oral	3 weeks	repeated dose toxicity	{"citation":"3; 900; 18","dose":"No other effects were observed in the fetuses or weanlings in any dose group.","effect":"se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...","page":11,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_003"}
CIR_vision_codex	NOAEL	=0.5	%	rat	oral	-	oral toxicity	{"citation":"2; 0; 5","dose":"e foci were significantly increased in the liver of the 2.0% dose group.","effect":"e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S","page":18,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_004"}
CIR_vision_codex	NOAEL	=1	%	guinea pig	-	-	NOAEL study	{"citation":"4; 1","dose":"A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.","effect":"appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...","page":26,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_005"}
CIR_vision_codex	NOAEL	=100	mg/kg	rat	oral	Subchronic	repeated dose toxicity	{"citation":"300; 100; 56","dose":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.","effect":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...","page":7,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_001"}
CIR_vision_codex	NOAEL	=125	mg/kg	rat	dermal	Chronic	NOAEL study	{"citation":"500; 2; 125","dose":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.","effect":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...","page":8,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_002"}
CIR_vision_codex	NOAEL	=150	mg/kg	mouse	oral	3 weeks	repeated dose toxicity	{"citation":"3; 900; 18","dose":"No other effects were observed in the fetuses or weanlings in any dose group.","effect":"se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...","page":11,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_003"}
CIR_vision_codex	NOAEL	=0.5	%	rat	oral	-	oral toxicity	{"citation":"2; 0; 5","dose":"e foci were significantly increased in the liver of the 2.0% dose group.","effect":"e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S","page":18,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_004"}
CIR_vision_codex	NOAEL	=1	%	guinea pig	-	-	NOAEL study	{"citation":"4; 1","dose":"A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.","effect":"appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...","page":26,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_005"}
CIR_vision_codex	NOAEL	=100	mg/kg	rat	oral	Subchronic	repeated dose toxicity	{"citation":"300; 100; 56","dose":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.","effect":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...","page":7,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_001"}
CIR_vision_codex	NOAEL	=125	mg/kg	rat	dermal	Chronic	NOAEL study	{"citation":"500; 2; 125","dose":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.","effect":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...","page":8,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_002"}
CIR_vision_codex	NOAEL	=150	mg/kg	mouse	oral	3 weeks	repeated dose toxicity	{"citation":"3; 900; 18","dose":"No other effects were observed in the fetuses or weanlings in any dose group.","effect":"se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...","page":11,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_003"}
CIR_vision_codex	NOAEL	=0.5	%	rat	oral	-	oral toxicity	{"citation":"2; 0; 5","dose":"e foci were significantly increased in the liver of the 2.0% dose group.","effect":"e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S","page":18,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_004"}
CIR_vision_codex	NOAEL	=1	%	guinea pig	-	-	NOAEL study	{"citation":"4; 1","dose":"A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.","effect":"appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...","page":26,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_005"}
CIR_vision_codex	NOAEL	=100	mg/kg	rat	oral	Subchronic	repeated dose toxicity	{"citation":"300; 100; 56","dose":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.","effect":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...","page":7,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_001"}
CIR_vision_codex	NOAEL	=125	mg/kg	rat	dermal	Chronic	NOAEL study	{"citation":"500; 2; 125","dose":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.","effect":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...","page":8,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_002"}
CIR_vision_codex	NOAEL	=150	mg/kg	mouse	oral	3 weeks	repeated dose toxicity	{"citation":"3; 900; 18","dose":"No other effects were observed in the fetuses or weanlings in any dose group.","effect":"se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...","page":11,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_003"}
CIR_vision_codex	NOAEL	=0.5	%	rat	oral	-	oral toxicity	{"citation":"2; 0; 5","dose":"e foci were significantly increased in the liver of the 2.0% dose group.","effect":"e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S","page":18,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_004"}
CIR_vision_codex	NOAEL	=1	%	guinea pig	-	-	NOAEL study	{"citation":"4; 1","dose":"A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.","effect":"appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...","page":26,"pdf":"PRS529.pdf","row_type":"noael_study","study_id":"PRS529_noael_005"}

COSMOS_DB 1 endpoint

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
COSMOS_DB	LOAEL	5.84999990463	mg/kg bw/day	rat	oral	28 day	Short Term Toxicity	SCCP; Tamura T et al. Inhibition of Thyroid Iodine Uptake and Organification in Rats Treatedwith Kojic Acid. Toxicological Sciences47, 170-175

IARC Monographs 1 endpoint

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
IARC Monographs	IARC carcinogenicity classification	3	IARC group	-	-	2000	IARC Monographs	{"additional_info":"volume_publication_year=2001","evaluation_year":2000,"source_table":"iarc_classifications","volume":"79"}

NTP_ICE_cancer 1 endpoint

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
NTP_ICE_cancer	IARC group	3	unitless	-	-	-	WOE; IARC Carcinogenicity	sheet=Data; excel_row=3166; Record_ID=cancer_1714; Data_Type=WOE; Formulation_Name=Kojic acid; Mixture=Chemical; DTXSID=DTXSID2040236; Assay=IARC Carcinogenicity; Endpoint=IARC group; Response=3; Response_Unit=Unitless; URL=http://publications.iarc.fr/97; URL_CompTox=https://comptox.epa.gov/dashboard/chemical/details/DTXSID2040236

SCCS_vision_codex 128 endpoints

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
SCCS_vision_codex	NOAEL	=100	mg/kg/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine","page":20,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_001"}
SCCS_vision_codex	NOAEL	=23.8	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_002"}
SCCS_vision_codex	NOAEL	=5.85	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_003"}
SCCS_vision_codex	NOAEL	=6	mg/kg bw/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_004"}
SCCS_vision_codex	NOAEL	=62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	{"citation":"Ref.: 32 Comment A NOAEL of 62","dose":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","effect":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_005"}
SCCS_vision_codex	NOAEL	=0.03	%	rat	oral	8 weeks	NOAEL study	{"citation":"Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0","dose":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.","effect":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode","page":50,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_006"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw	rat	oral	2 weeks	NOAEL study	{"dose":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:","effect":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic","page":57,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_007"}
SCCS_vision_codex	NOAEL	=150	mg/kg bw/day	rat	-	21 days	reproductive toxicity	{"dose":"A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.","effect":"SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro","page":59,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_008"}
SCCS_vision_codex	NOAEL	=30	mg/kg bw/day	mouse	-	-	reproductive toxicity	{"citation":"Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study","dose":"Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.","effect":"ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","page":61,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_010"}
SCCS_vision_codex	NOAEL	=100	mg/kg bw/day	rat	-	-	NOAEL study	{"citation":"Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment","dose":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.","effect":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%","page":62,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_011"}
SCCS_vision_codex	NOAEL	=0.069	mg/kg	rat	oral	4-week	dermal absorption	{"dose":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","effect":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_014"}
SCCS_vision_codex	NOAEL	=0.104	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_017"}
SCCS_vision_codex	NOAEL	=0.173	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_020"}
SCCS_vision_codex	NOAEL	=0.003	%	rat	oral	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_023"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_024"}
SCCS_vision_codex	NOAEL	=15	mg/kg bw/day	rat	-	4 weeks	NOAEL study	{"dose":"d, when 3% Kojic acid were administered for 4 weeks.","effect":"d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and","page":71,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_026"}
SCCS_vision_codex	NOAEL	=125	mg/kg bw/day	rat	dermal	28 day	NOAEL study	{"dose":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.","effect":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc","page":6,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_003"}
SCCS_vision_codex	NOAEL	=227	mg/kg bw/day	rat	oral	55-week	dermal absorption	{"citation":"(Ref. 5)","dose":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...","effect":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola","page":11,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_010"}
SCCS_vision_codex	NOAEL	=2.38	µg/cm	human	dermal	-	genotoxicity	{"citation":"(Ref. 11)","effect":"roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_013"}
SCCS_vision_codex	NOAEL	=6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	{"citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","effect":"id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_014"}
SCCS_vision_codex	NOAEL	=0.079	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_017"}
SCCS_vision_codex	NOAEL	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_019"}
SCCS_vision_codex	NOAEL	=8.39	µg/cm	rat	oral	28 days	repeated dose toxicity	{"dose":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...","effect":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_020"}
SCCS_vision_codex	NOAEL	=0.12	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_021"}
SCCS_vision_codex	NOAEL	=0.199	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_026"}
SCCS_vision_codex	NOAEL	=1637	-	human	-	-	NOAEL study	{"dose":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_020"}
SCCS_vision_codex	NOAEL	=2600	mg/kg bw	rat	oral	28-day	repeated dose toxicity	{"dose":"Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.","effect":"w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m","page":41,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_021"}
SCCS_vision_codex	NOAEL	=2	%	rat	oral	4 weeks	NOAEL study	{"dose":"Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:","effect":"SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_024"}
SCCS_vision_codex	NOAEL	=40	-	-	-	-	NOAEL study	{"dose":"Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","effect":"Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_028"}
SCCS_vision_codex	NOAEL	=2	-	-	-	-	NOAEL study	{"effect":"Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_029"}
SCCS_vision_codex	NOAEL	=68	-	-	-	-	NOAEL study	{"dose":"Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","effect":"Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_032"}
SCCS_vision_codex	NOAEL	=0.5	%	rat	oral	28 days	NOAEL study	{"dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","page":70,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_036"}
SCCS_vision_codex	NOAEL	=100	mg/kg/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine","page":20,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_001"}
SCCS_vision_codex	NOAEL	=23.8	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_002"}
SCCS_vision_codex	NOAEL	=5.85	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_003"}
SCCS_vision_codex	NOAEL	=6	mg/kg bw/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_004"}
SCCS_vision_codex	NOAEL	=62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	{"citation":"Ref.: 32 Comment A NOAEL of 62","dose":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","effect":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_005"}
SCCS_vision_codex	NOAEL	=0.03	%	rat	oral	8 weeks	NOAEL study	{"citation":"Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0","dose":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.","effect":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode","page":50,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_006"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw	rat	oral	2 weeks	NOAEL study	{"dose":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:","effect":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic","page":57,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_007"}
SCCS_vision_codex	NOAEL	=150	mg/kg bw/day	rat	-	21 days	reproductive toxicity	{"dose":"A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.","effect":"SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro","page":59,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_008"}
SCCS_vision_codex	NOAEL	=30	mg/kg bw/day	mouse	-	-	reproductive toxicity	{"citation":"Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study","dose":"Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.","effect":"ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","page":61,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_010"}
SCCS_vision_codex	NOAEL	=100	mg/kg bw/day	rat	-	-	NOAEL study	{"citation":"Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment","dose":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.","effect":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%","page":62,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_011"}
SCCS_vision_codex	NOAEL	=0.069	mg/kg	rat	oral	4-week	dermal absorption	{"dose":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","effect":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_014"}
SCCS_vision_codex	NOAEL	=0.104	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_017"}
SCCS_vision_codex	NOAEL	=0.173	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_020"}
SCCS_vision_codex	NOAEL	=0.003	%	rat	oral	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_023"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_024"}
SCCS_vision_codex	NOAEL	=15	mg/kg bw/day	rat	-	4 weeks	NOAEL study	{"dose":"d, when 3% Kojic acid were administered for 4 weeks.","effect":"d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and","page":71,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_026"}
SCCS_vision_codex	NOAEL	=100	mg/kg/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine","page":20,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_001"}
SCCS_vision_codex	NOAEL	=23.8	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_002"}
SCCS_vision_codex	NOAEL	=5.85	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_003"}
SCCS_vision_codex	NOAEL	=6	mg/kg bw/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_004"}
SCCS_vision_codex	NOAEL	=62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	{"citation":"Ref.: 32 Comment A NOAEL of 62","dose":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","effect":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_005"}
SCCS_vision_codex	NOAEL	=0.03	%	rat	oral	8 weeks	NOAEL study	{"citation":"Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0","dose":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.","effect":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode","page":50,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_006"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw	rat	oral	2 weeks	NOAEL study	{"dose":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:","effect":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic","page":57,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_007"}
SCCS_vision_codex	NOAEL	=150	mg/kg bw/day	rat	-	21 days	reproductive toxicity	{"dose":"A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.","effect":"SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro","page":59,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_008"}
SCCS_vision_codex	NOAEL	=30	mg/kg bw/day	mouse	-	-	reproductive toxicity	{"citation":"Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study","dose":"Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.","effect":"ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","page":61,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_010"}
SCCS_vision_codex	NOAEL	=100	mg/kg bw/day	rat	-	-	NOAEL study	{"citation":"Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment","dose":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.","effect":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%","page":62,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_011"}
SCCS_vision_codex	NOAEL	=0.069	mg/kg	rat	oral	4-week	dermal absorption	{"dose":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","effect":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_014"}
SCCS_vision_codex	NOAEL	=0.104	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_017"}
SCCS_vision_codex	NOAEL	=0.173	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_020"}
SCCS_vision_codex	NOAEL	=0.003	%	rat	oral	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_023"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_024"}
SCCS_vision_codex	NOAEL	=15	mg/kg bw/day	rat	-	4 weeks	NOAEL study	{"dose":"d, when 3% Kojic acid were administered for 4 weeks.","effect":"d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and","page":71,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_026"}
SCCS_vision_codex	NOAEL	=125	mg/kg bw/day	rat	dermal	28 day	NOAEL study	{"dose":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.","effect":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc","page":6,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_003"}
SCCS_vision_codex	NOAEL	=227	mg/kg bw/day	rat	oral	55-week	dermal absorption	{"citation":"(Ref. 5)","dose":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...","effect":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola","page":11,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_010"}
SCCS_vision_codex	NOAEL	=2.38	µg/cm	human	dermal	-	genotoxicity	{"citation":"(Ref. 11)","effect":"roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_013"}
SCCS_vision_codex	NOAEL	=6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	{"citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","effect":"id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_014"}
SCCS_vision_codex	NOAEL	=0.079	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_017"}
SCCS_vision_codex	NOAEL	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_019"}
SCCS_vision_codex	NOAEL	=8.39	µg/cm	rat	oral	28 days	repeated dose toxicity	{"dose":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...","effect":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_020"}
SCCS_vision_codex	NOAEL	=0.12	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_021"}
SCCS_vision_codex	NOAEL	=0.199	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_026"}
SCCS_vision_codex	NOAEL	=125	mg/kg bw/day	rat	dermal	28 day	NOAEL study	{"dose":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.","effect":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc","page":6,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_003"}
SCCS_vision_codex	NOAEL	=227	mg/kg bw/day	rat	oral	55-week	dermal absorption	{"citation":"(Ref. 5)","dose":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...","effect":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola","page":11,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_010"}
SCCS_vision_codex	NOAEL	=2.38	µg/cm	human	dermal	-	genotoxicity	{"citation":"(Ref. 11)","effect":"roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_013"}
SCCS_vision_codex	NOAEL	=6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	{"citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","effect":"id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_014"}
SCCS_vision_codex	NOAEL	=0.079	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_017"}
SCCS_vision_codex	NOAEL	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_019"}
SCCS_vision_codex	NOAEL	=8.39	µg/cm	rat	oral	28 days	repeated dose toxicity	{"dose":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...","effect":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_020"}
SCCS_vision_codex	NOAEL	=0.12	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_021"}
SCCS_vision_codex	NOAEL	=0.199	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_026"}
SCCS_vision_codex	NOAEL	=1637	-	human	-	-	NOAEL study	{"dose":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_020"}
SCCS_vision_codex	NOAEL	=2600	mg/kg bw	rat	oral	28-day	repeated dose toxicity	{"dose":"Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.","effect":"w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m","page":41,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_021"}
SCCS_vision_codex	NOAEL	=2	%	rat	oral	4 weeks	NOAEL study	{"dose":"Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:","effect":"SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_024"}
SCCS_vision_codex	NOAEL	=40	-	-	-	-	NOAEL study	{"dose":"Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","effect":"Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_028"}
SCCS_vision_codex	NOAEL	=2	-	-	-	-	NOAEL study	{"effect":"Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_029"}
SCCS_vision_codex	NOAEL	=68	-	-	-	-	NOAEL study	{"dose":"Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","effect":"Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_032"}
SCCS_vision_codex	NOAEL	=0.5	%	rat	oral	28 days	NOAEL study	{"dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","page":70,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_036"}
SCCS_vision_codex	NOAEL	=1637	-	human	-	-	NOAEL study	{"dose":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_020"}
SCCS_vision_codex	NOAEL	=2600	mg/kg bw	rat	oral	28-day	repeated dose toxicity	{"dose":"Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.","effect":"w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m","page":41,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_021"}
SCCS_vision_codex	NOAEL	=2	%	rat	oral	4 weeks	NOAEL study	{"dose":"Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:","effect":"SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_024"}
SCCS_vision_codex	NOAEL	=40	-	-	-	-	NOAEL study	{"dose":"Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","effect":"Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_028"}
SCCS_vision_codex	NOAEL	=2	-	-	-	-	NOAEL study	{"effect":"Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_029"}
SCCS_vision_codex	NOAEL	=68	-	-	-	-	NOAEL study	{"dose":"Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","effect":"Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_032"}
SCCS_vision_codex	NOAEL	=0.5	%	rat	oral	28 days	NOAEL study	{"dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","page":70,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_036"}
SCCS_vision_codex	NOAEL	=100	mg/kg/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine","page":20,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_001"}
SCCS_vision_codex	NOAEL	=23.8	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_002"}
SCCS_vision_codex	NOAEL	=5.85	mg/kg bw/day	rat	oral	4 weeks	NOAEL study	{"citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","effect":"imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta","page":21,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_003"}
SCCS_vision_codex	NOAEL	=6	mg/kg bw/day	rat	oral	28 days	NOAEL study	{"citation":"Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_004"}
SCCS_vision_codex	NOAEL	=62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	{"citation":"Ref.: 32 Comment A NOAEL of 62","dose":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","effect":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats","page":22,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_005"}
SCCS_vision_codex	NOAEL	=0.03	%	rat	oral	8 weeks	NOAEL study	{"citation":"Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0","dose":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.","effect":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode","page":50,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_006"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw	rat	oral	2 weeks	NOAEL study	{"dose":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:","effect":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic","page":57,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_007"}
SCCS_vision_codex	NOAEL	=150	mg/kg bw/day	rat	-	21 days	reproductive toxicity	{"dose":"A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.","effect":"SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro","page":59,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_008"}
SCCS_vision_codex	NOAEL	=30	mg/kg bw/day	mouse	-	-	reproductive toxicity	{"citation":"Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study","dose":"Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.","effect":"ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","page":61,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_010"}
SCCS_vision_codex	NOAEL	=100	mg/kg bw/day	rat	-	-	NOAEL study	{"citation":"Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment","dose":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.","effect":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%","page":62,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_011"}
SCCS_vision_codex	NOAEL	=0.069	mg/kg	rat	oral	4-week	dermal absorption	{"dose":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","effect":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_014"}
SCCS_vision_codex	NOAEL	=0.104	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_017"}
SCCS_vision_codex	NOAEL	=0.173	mg/kg	rat	oral	28-days	dermal absorption	{"dose":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","effect":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","page":69,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_020"}
SCCS_vision_codex	NOAEL	=0.003	%	rat	oral	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_023"}
SCCS_vision_codex	NOAEL	=15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	{"dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","effect":"ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin","page":70,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_024"}
SCCS_vision_codex	NOAEL	=15	mg/kg bw/day	rat	-	4 weeks	NOAEL study	{"dose":"d, when 3% Kojic acid were administered for 4 weeks.","effect":"d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and","page":71,"pdf":"sccp_o_148.pdf","row_type":"noael_study","study_id":"sccp_o_148_noael_026"}
SCCS_vision_codex	NOAEL	=125	mg/kg bw/day	rat	dermal	28 day	NOAEL study	{"dose":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.","effect":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc","page":6,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_003"}
SCCS_vision_codex	NOAEL	=227	mg/kg bw/day	rat	oral	55-week	dermal absorption	{"citation":"(Ref. 5)","dose":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...","effect":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola","page":11,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_010"}
SCCS_vision_codex	NOAEL	=2.38	µg/cm	human	dermal	-	genotoxicity	{"citation":"(Ref. 11)","effect":"roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_013"}
SCCS_vision_codex	NOAEL	=6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	{"citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","effect":"id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat","page":14,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_014"}
SCCS_vision_codex	NOAEL	=0.079	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_017"}
SCCS_vision_codex	NOAEL	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	{"dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_019"}
SCCS_vision_codex	NOAEL	=8.39	µg/cm	rat	oral	28 days	repeated dose toxicity	{"dose":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...","effect":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_020"}
SCCS_vision_codex	NOAEL	=0.12	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_021"}
SCCS_vision_codex	NOAEL	=0.199	mg/kg	rat	oral	28 days	repeated dose toxicity	{"dose":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","effect":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","page":15,"pdf":"sccs_o_098.pdf","row_type":"noael_study","study_id":"sccs_o_098_noael_026"}
SCCS_vision_codex	NOAEL	=1637	-	human	-	-	NOAEL study	{"dose":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_020"}
SCCS_vision_codex	NOAEL	=2600	mg/kg bw	rat	oral	28-day	repeated dose toxicity	{"dose":"Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.","effect":"w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m","page":41,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_021"}
SCCS_vision_codex	NOAEL	=2	%	rat	oral	4 weeks	NOAEL study	{"dose":"Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:","effect":"SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_024"}
SCCS_vision_codex	NOAEL	=40	-	-	-	-	NOAEL study	{"dose":"Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","effect":"Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_028"}
SCCS_vision_codex	NOAEL	=2	-	-	-	-	NOAEL study	{"effect":"Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267","page":40,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_029"}
SCCS_vision_codex	NOAEL	=68	-	-	-	-	NOAEL study	{"dose":"Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","effect":"Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","page":68,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_032"}
SCCS_vision_codex	NOAEL	=0.5	%	rat	oral	28 days	NOAEL study	{"dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","page":70,"pdf":"sccs_o_259.pdf","row_type":"noael_study","study_id":"sccs_o_259_noael_036"}

UnifiedCodex:CIR:beta.noael_studies 5 endpoints

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
UnifiedCodex:CIR:beta.noael_studies	-	125	mg/kg	rat	dermal	Chronic	-	SOURCE_SUBDIR=PRS529; REPORT_TITLE=Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics Christina L. Burnett, Wilma F. Bergfeld, MD, FACP, Donald V. Belsito, MD, Ronald A. Hill, PhD, Curtis D. Klaassen, PhD, Daniel C. Liebler, PhD, James G. Marks, Jr., MD; OPINION_NUMBER=PRS529; COMMITTEE=Expert Panel for Cosmetic Ingredient Safety; REPORT_DATE=Category 2009; VALUE_TEXT=125; DOSE=nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.; EFFECT=nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...; CITATION=500; 2; 125; CITATION_NUMBERS=[500,2,125]; REFERENCE=500; 2; 125; DETAILS_JSON={"cas_number":"501-30-4","citation":"500; 2; 125","dose":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group.","duration":"Chronic","effect":"nd relative weights of the adrenal glands were increased in the dose groups receiving 500 and 1000 mg/kg kojic acid; however, the absolute weights of the adrenal glands in the recovery groups were almost the same as that for the control group. In the 1000 mg/kg dose group, 2 rats had vacuolation of anterior cells of the pituitary gland, but the researchers of this study could not be certain this effect was treatment-related. No other treatment-related effects in the tissues were observed. It was concluded that the NOEL of kojic acid in this experiment was 125 mg/kg per d.57 Chronic Toxicity Studies of chronic exposures have been summarized in the Car- cinogenicity section of this safety assessment. Ocular and Dermal Irritation A 3% aqueous solution of kojic acid was tested for ocular irri- tation potential in rabbits (strain not reported).58 In a prelimi- nary study, 0.05 mL of the kojic acid solution was instilled in the right eye of 3 rabbits. The eyes were not rinsed. The rabbit eyes were observed at 1, 3, 6, and 48 hours posttreatment. No changes were observed. For the main st...","endpoint":"","ingredient":"the Safety Assessment of Kojic Acid","loael_value":"","noael_unit":"mg/kg","noael_value":"125","page":8,"route":"dermal","species":"rat","study_id":"PRS529_noael_002"}
UnifiedCodex:CIR:beta.noael_studies	-	1	%	guinea pig	-	-	-	SOURCE_SUBDIR=PRS529; REPORT_TITLE=Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics Christina L. Burnett, Wilma F. Bergfeld, MD, FACP, Donald V. Belsito, MD, Ronald A. Hill, PhD, Curtis D. Klaassen, PhD, Daniel C. Liebler, PhD, James G. Marks, Jr., MD; OPINION_NUMBER=PRS529; COMMITTEE=Expert Panel for Cosmetic Ingredient Safety; REPORT_DATE=Category 2009; VALUE_TEXT=1; DOSE=A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.; EFFECT=appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...; CITATION=4; 1; CITATION_NUMBERS=[4,1]; REFERENCE=4; 1; DETAILS_JSON={"cas_number":"501-30-4","citation":"4; 1","dose":"A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%.","duration":"","effect":"appropriate. A depigmentation study of kojic acid in black guinea pigs, how- ever, found that skin whitening was statistically significantly at a concentration of 4%. In the same study, a kojic acid concen- tration of 1% did not result skin whitening that was different from the vehicle control. Kojic acid did not appear to damage melanocytes, and the skin-whitening effect at 4% likely is attributed to tyrosinase inhibition. While reversible, the Panel considers tyrosinase inhibition to be an adverse effect with a NOEL of 1%. Therefore, the Expert Panel finds that kojic acid should only be used up to a concentration of 1% in cosmetic products. The Panel recognizes that the EWG on its Web site and Health Canada in its product database have reported uses of kojic acid at concentrations greater than 1%. Because these data may include over-the-counter drug uses, it was not possi- ble to determine the extent to which cosmetic products were being sold with concentrations greater than 1%, the limit estab- lished by the Panel. The CIR Expert Panel noted the large number of studies on the e...","endpoint":"","ingredient":"the Safety Assessment of Kojic Acid","loael_value":"","noael_unit":"%","noael_value":"1","page":26,"route":"","species":"guinea pig","study_id":"PRS529_noael_005"}
UnifiedCodex:CIR:beta.noael_studies	oral toxicity	0.5	%	rat	oral	-	oral toxicity	SOURCE_SUBDIR=PRS529; REPORT_TITLE=Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics Christina L. Burnett, Wilma F. Bergfeld, MD, FACP, Donald V. Belsito, MD, Ronald A. Hill, PhD, Curtis D. Klaassen, PhD, Daniel C. Liebler, PhD, James G. Marks, Jr., MD; OPINION_NUMBER=PRS529; COMMITTEE=Expert Panel for Cosmetic Ingredient Safety; REPORT_DATE=Category 2009; VALUE_TEXT=0.5; DOSE=e foci were significantly increased in the liver of the 2.0% dose group.; EFFECT=e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S; CITATION=2; 0; 5; CITATION_NUMBERS=[2,5]; REFERENCE=2; 0; 5; DETAILS_JSON={"cas_number":"501-30-4","citation":"2; 0; 5","dose":"e foci were significantly increased in the liver of the 2.0% dose group.","duration":"","effect":"e foci were significantly increased in the liver of the 2.0% dose group. Incidences of hyaline casts and basophilic tubules were also significantly increased in the 2.0% dose group. Dif- fuse follicular cell hyperplasia was noted in the thyroid glands in both treatment groups, with focal follicular cell hyperplasia, and adenomas and/or carcinomas observed in the 2.0% group. The 2.0% dose group also had increased hypertrophy of corti- cal cells in zona fasciculate in the adrenal glands. The study concluded that the NOAEL of kojic acid was below 0.5% (227 mg/kg body weight/d).93 Carcinogenicity studies are summarized in Table 5. Tumor Promotion The carcinogenesis-modifying action of kojic acid in rat liver using a 2-stage model with initiation by diisopropanolnitrosa- mine (DHPN) was investigated.94 Sixty male F344 rats received either a single subcutaneous injection of 2000 mg/ kg DHPN or the vehicle and then were fed a diet containing Burnett 261S","endpoint":"oral toxicity","ingredient":"the Safety Assessment of Kojic Acid","loael_value":"","noael_unit":"%","noael_value":"0.5","page":18,"route":"oral","species":"rat","study_id":"PRS529_noael_004"}
UnifiedCodex:CIR:beta.noael_studies	repeated dose toxicity	100	mg/kg	rat	oral	Subchronic	repeated dose toxicity	SOURCE_SUBDIR=PRS529; REPORT_TITLE=Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics Christina L. Burnett, Wilma F. Bergfeld, MD, FACP, Donald V. Belsito, MD, Ronald A. Hill, PhD, Curtis D. Klaassen, PhD, Daniel C. Liebler, PhD, James G. Marks, Jr., MD; OPINION_NUMBER=PRS529; COMMITTEE=Expert Panel for Cosmetic Ingredient Safety; REPORT_DATE=Category 2009; VALUE_TEXT=100; DOSE=eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.; EFFECT=eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...; CITATION=300; 100; 56; CITATION_NUMBERS=[300,100,56]; REFERENCE=300; 100; 56; DETAILS_JSON={"cas_number":"501-30-4","citation":"300; 100; 56","dose":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups.","duration":"Subchronic","effect":"eatment period in both males and females in the 300 and 1000 mg/kg per d dose groups. This effect had partially reversed at the end of the treatment-free period in males of the high-dose group. No treatment-related changes were observed in blood chemistry parameters or urinalysis. At necropsy, decreased absolute and relative spleen weights were observed in the high-dose females, but there were no treatment-related findings during the gross or microscopic examinations in any dose group. The study concluded that the no observable effect level (NOEL) was 100 mg/kg per d, although the author noted that observed changes in lympho- cytes and white blood cell counts in the higher dose groups were minimal to mild in severity and the toxicological signifi- cance of this finding was uncertain.56 Subchronic Oral Toxicity. In a subchronic study,8 male SD strain rats received daily oral (by stomach tube) doses of 0, 0.25, 0.5, 1.0, 2.0, or 3.0 g/kg kojic acid suspended in 1.0% carboxy- methylcellulose for 13 weeks. The dose groups included 20 rats each. The administration period was followed b...","endpoint":"repeated dose toxicity","ingredient":"the Safety Assessment of Kojic Acid","loael_value":"","noael_unit":"mg/kg","noael_value":"100","page":7,"route":"oral","species":"rat","study_id":"PRS529_noael_001"}
UnifiedCodex:CIR:beta.noael_studies	repeated dose toxicity	150	mg/kg	mouse	oral	3 weeks	repeated dose toxicity	SOURCE_SUBDIR=PRS529; REPORT_TITLE=Final Report of the Safety Assessment of Kojic Acid as Used in Cosmetics Christina L. Burnett, Wilma F. Bergfeld, MD, FACP, Donald V. Belsito, MD, Ronald A. Hill, PhD, Curtis D. Klaassen, PhD, Daniel C. Liebler, PhD, James G. Marks, Jr., MD; OPINION_NUMBER=PRS529; COMMITTEE=Expert Panel for Cosmetic Ingredient Safety; REPORT_DATE=Category 2009; VALUE_TEXT=150; DOSE=No other effects were observed in the fetuses or weanlings in any dose group.; EFFECT=se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...; CITATION=3; 900; 18; CITATION_NUMBERS=[3,900,18]; REFERENCE=3; 900; 18; DETAILS_JSON={"cas_number":"501-30-4","citation":"3; 900; 18","dose":"No other effects were observed in the fetuses or weanlings in any dose group.","duration":"3 weeks","effect":"se group had significantly increased kidney weights at 3 weeks of age. No other effects were observed in the fetuses or weanlings in any dose group. F1 dams from the 900 mg/kg dose group had significantly decreased heart weights on day 18 of gestation while 13-week males of the 25 and 900 mg/kg dose groups had decreased adrenal and prostate glands, respectively. No other abnormalities were observed in the reproduction of the F1 mice or in the development of the F2 fetuses. The no observa- ble adverse effect level (NOAEL) for maternal toxicity and embryotoxicity in this study was 150 mg/kg per d.69 The effect of kojic acid was investigated on pregnant Slc:ddy mice and F1 offspring.70 The pregnant mice received once daily oral doses of 0, 30, 160, and 800 mg/kg on days 15 of gestation to day 21 postpartum. All dams were allowed spontaneous delivery of the pups and the second generation of mice were subjected to postnatal observations, with litter size adjusted to 4 males and 4 females per litter analyzed on day 4 postpartum and 2 males and 2 females per litter analyzed at weaning fo...","endpoint":"repeated dose toxicity","ingredient":"the Safety Assessment of Kojic Acid","loael_value":"","noael_unit":"mg/kg","noael_value":"150","page":11,"route":"oral","species":"mouse","study_id":"PRS529_noael_003"}

UnifiedCodex:SCCS_SHADOW:beta.noael_studies 98 endpoints

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg/day	rat	oral	28 days	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100; DOSE=SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.; EFFECT=SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine; CITATION=Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs; CITATION_NUMBERS=[19,344,9,1,8,2,3]; REFERENCE=Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test subs","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day.","duration":"28 days","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 20 Conclusion Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. Ref.: 19 Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 9 males/group (Experiment 1) 8 males or 8 females/group (Experiment 2) 8 males/group (Experiment 3) Test substance: Kojic Acid Batch: / Purity: / Dose levels: Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Experiment 2 and 3: 0 or 2% in diet Exposure period: 28 days GLP: / Experiment 1 Groups of nine","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"100","page":20,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_001"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	23.8	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=23.8; DOSE=30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.; EFFECT=control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs; CITATION=Ref.: 30 Comment From this study a NOAEL of approximately 23; CITATION_NUMBERS=[30,23]; REFERENCE=Ref.: 30 Comment From this study a NOAEL of approximately 23; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","duration":"4 weeks","effect":"control levels in both sexes. Serum TSH level started to increase at week 1 and reached a maximum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test subs","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"23.8","page":21,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_002"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	5.85	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=5.85; DOSE=30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.; EFFECT=imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta; CITATION=Ref.: 30 Comment From this study a NOAEL of approximately 23; CITATION_NUMBERS=[30,23]; REFERENCE=Ref.: 30 Comment From this study a NOAEL of approximately 23; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 30 Comment From this study a NOAEL of approximately 23","dose":"30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake.","duration":"4 weeks","effect":"imum at weeks 2-3. Experiment 3 Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. Ref.: 30 Comment From this study a NOAEL of approximately 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of approximately 5.85 mg/kg bw/day with respect to iodine uptake. Rats, oral, diet Guideline: / Species/strain: F344 rats Group size: 8 males/group Test substance: Kojic Acid Batch: / Purity: / Dose levels: 0, 0.008, 0.03, 0.125, 0.5, 2.0% in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day Exposure period: 4 weeks GLP: / Male F344 rats received basal diet containing the test substance or basal diet alone for 4 weeks. After the end of treatment period blood samples were ta","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5.85","page":21,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_003"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw/day	rat	oral	28 days	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=6; DOSE=SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.; EFFECT=SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo; CITATION=Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived; CITATION_NUMBERS=[31,125,6]; REFERENCE=Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived","dose":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","duration":"28 days","effect":"SCCP/11182/08 Opinion on Kojic acid ___________________________________________________________________________________________ 22 to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. Ref.: 31 Comment On the base of histopathological findings and altered 125I uptake a NOAEL of approximately 6 mg/kg bw/day can be derived. Rat, oral, gavage Guideline: / Species/strain: F344 rats Group size: 10 males/group Test substance: Kojic Acid in 0.5% carboxymethylcellulose Batch: / Purity: / Dose levels: 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw Exposure period: 28 days GLP: / Male F344 rats received Kojic acid in doses of 4, 15, 62.5, 250, 1000 mg/kg bw/day at volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Bo","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":22,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_004"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	0.03	%	rat	oral	8 weeks	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=0.03; DOSE=ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.; EFFECT=ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode; CITATION=Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0; CITATION_NUMBERS=[86,344,20]; REFERENCE=Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0","dose":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively.","duration":"8 weeks","effect":"ar cell hyperplasias in the DHPN- initiated groups treated with 0.125, 0.5 and 2% Kojic acid at week 20 were 5/10, 10/10 and 8/8 rats, respectively. At week 20 adenomas were observed in 7/10 rats in the DHPN + 0.5% Kojic acid group and in 8/8 rats in the DHPN + 2.0% Kojic acid group, while carcinomas were developed in 6/8 rats in the DHNP + 2.0% Kojic acid group. In groups without DHPN initiation, only focal follicular cell hyperplasia was observed in 1/9 rates in the highest dose group. It was concluded that the NOAEL for thyroid tumour-promoting effect for Kojic acid is 0.03% or 15.5 mg/kg bw/day under experimental conditions chosen and that the substance possesses weak tumourigenic activity in rats due to continuous serum TSH stimulation by a non-genotoxic mechanism. Ref.: 86 Rats, initiation assay, thyroid, Guideline: / Species: F344 rats Group sizes: 20 males/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 0, 0.02, 0.2 or 2% in the diet, given for 8 weeks GLP: / A two-stage rat thyroid tumorigenesis mode","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"0.03","page":50,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_006"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	15.5	mg/kg bw	rat	oral	2 weeks	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=15.5; DOSE=possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:; EFFECT=possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF:","duration":"2 weeks","effect":"possible 1000, 2000 mg/kg bw single application liver, hepatctotomised Kojic acid 2-AAF: 2 weeks effect on proliferation possible 4 F344 rats m 2 or 4 % in diet 12 weeks thyroid DHPN: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions 5 F344 rats m 2 % in diet 12 weeks thyroid BHP: 2800 mg/kg bw Kojic acid: 12 weeks thyroid proliferative lesions, adenomas 20 weeks thyroid - - hypertrophy 6 F344 rats m 0.002 to 2.0 % in diet 20 weeks thyroid DHPN: 2000 mg/kg Kojic acid: 20 weeks adenomas, carcinomas, NOAEL: 15.5 mg/kg bw 7 F344 rats m 0.02 to 2% in the diet 8 weeks thyroid Kojic acid 0.1% (SDM), 23 weeks hyperplasia, proliferative lesions 8 F1 mice f/m 1.5 or 3 % in diet 20 months thyroid - - hyperplasia and follicular adenomas (f/m) liver - - incidences of hepatomas (f) 9 p53(+/-) CBA mice m 1.5 or 3 % in diet 26 weeks thyroid - - hypertrophy and hyperplasia liver - - adenomas 10 ICR mice m 3 % in diet 4 weeks liver, hepatctotomised Kojic acid phenobarbital: 14 weeks effect on proliferation possible 11 B6/C3/F1 mic","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"15.5","page":57,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_007"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	150	mg/kg bw/day	mouse	-	13-week	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=150; DOSE=nd in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively.; EFFECT=nd in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively. No effect considered to be due to treatment was observed in the reared offspring concerning time point of descending of the testes and opening of the vagina. No effects were noted on the sexual cycle, copulation rate, conception rate and foetal finding (F2) in the reproduction ability test of F1 (each one male and female from a dam) carried out in the 11th week after delivery. Conclusion A NOAEL for maternal toxicity and for embryotoxicity of 150 mg/kg bw/day can be derived from this study. Ref.: A1 Study 4 Guideline: / Species/strain: ddy-SLC mice Group size: 35/group Test substance: Kojic acid in 1% methylcellulose Batch: 1527R; CITATION=Ref.: A1 Study 4 Guideline: / Species/strain: ddy-SLC mice Group size: 35/group Test substance: Kojic acid in 1% methylcellulose Batch: 1527R; CITATION_NUMBERS=[1,4,35,1527]; REFERENCE=Ref.: A1 Study 4 Guideline: / Species/strain: ddy-SLC mice Group size: 35/group Test substance: Kojic acid in 1% methylcellulose Batch: 1527R; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: A1 Study 4 Guideline: / Species/strain: ddy-SLC mice Group size: 35/group Test substance: Kojic acid in 1% methylcellulose Batch: 1527R","dose":"nd in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively.","duration":"13-week","effect":"nd in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively. No effect considered to be due to treatment was observed in the reared offspring concerning time point of descending of the testes and opening of the vagina. No effects were noted on the sexual cycle, copulation rate, conception rate and foetal finding (F2) in the reproduction ability test of F1 (each one male and female from a dam) carried out in the 11th week after delivery. Conclusion A NOAEL for maternal toxicity and for embryotoxicity of 150 mg/kg bw/day can be derived from this study. Ref.: A1 Study 4 Guideline: / Species/strain: ddy-SLC mice Group size: 35/group Test substance: Kojic acid in 1% methylcellulose Batch: 1527R","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"150","page":60,"route":"","species":"mouse","study_id":"sccp_o_148_noael_009"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw/day	rat	-	-	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100; DOSE=uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.; EFFECT=uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%; CITATION=Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment; CITATION_NUMBERS=[38]; REFERENCE=Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment","dose":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group.","duration":"","effect":"uded one heart defect in the 20 mg/kg bw/day group and three effects from two litters in the 100 mg/kg bw/day group. Effects were considered to be unrelated to treatment as in the highest dose group no major malformations were observed. Minor anomalies were significantly increased in the highest dose group, however, effects were considered not to be related to Kojic acid. Ref.: 38 Comment The SCCP considers the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day can be derived for maternal toxicity and for embryotoxicity from this study. Study 2 Guideline: ICH, 1993 Species/strain: Wistar rats Group size: 6 females/group Test substance: Kojic acid (53758) in 0.5% methylcellulose Batch: 8A44 Content: 98 – 102%","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":62,"route":"","species":"rat","study_id":"sccp_o_148_noael_011"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw/day	rat	-	-	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100; DOSE=This finding was not considered to be related to the administration of the test substance as effect was not dose- depending.; EFFECT=s (24.3 versus 0%). This finding was not considered to be related to the administration of the test substance as effect was not dose- depending. The number of foetuses per female was reduced at 300 and 1000 mg/kg bw/day compared to the control group but values were not significant (8.5 and 10.8 versus 12.2, respectively). No post-implantation loss occurred in any group. The test substance did not influence body weight or sex ration of foetuses. No malformations or anomalies were observed. It was concluded that the NOAEL for maternal toxicity, embryo- and foetotoxicity is 100 mg/kg bw/day under the experimental conditions chosen. Ref.: 20 Comment Only six females per group were investigated. Study 3 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 females/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in 0.1 ml propylene glycol Treatment period: day 1 - 5 of gestation GLP: / The test substance was given orally to mated females in 0.1 ml propylene glycol daily at a concentration of 50; CITATION=Ref.: 20 Comment Only six females per group were investigated; CITATION_NUMBERS=[20]; REFERENCE=Ref.: 20 Comment Only six females per group were investigated; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 20 Comment Only six females per group were investigated","dose":"This finding was not considered to be related to the administration of the test substance as effect was not dose- depending.","duration":"","effect":"s (24.3 versus 0%). This finding was not considered to be related to the administration of the test substance as effect was not dose- depending. The number of foetuses per female was reduced at 300 and 1000 mg/kg bw/day compared to the control group but values were not significant (8.5 and 10.8 versus 12.2, respectively). No post-implantation loss occurred in any group. The test substance did not influence body weight or sex ration of foetuses. No malformations or anomalies were observed. It was concluded that the NOAEL for maternal toxicity, embryo- and foetotoxicity is 100 mg/kg bw/day under the experimental conditions chosen. Ref.: 20 Comment Only six females per group were investigated. Study 3 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 females/group Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in 0.1 ml propylene glycol Treatment period: day 1 - 5 of gestation GLP: / The test substance was given orally to mated females in 0.1 ml propylene glycol daily at a concentration of 50","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":63,"route":"","species":"rat","study_id":"sccp_o_148_noael_012"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	15	mg/kg bw/day	rat	-	4 weeks	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=15; DOSE=d, when 3% Kojic acid were administered for 4 weeks.; EFFECT=d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"d, when 3% Kojic acid were administered for 4 weeks.","duration":"4 weeks","effect":"d, when 3% Kojic acid were administered for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic acid for 12 to 20 weeks. In one promotion assay carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice hypertrophy in males as well as hyperplasia and adenomas in females and","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"15","page":71,"route":"","species":"rat","study_id":"sccp_o_148_noael_026"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw	rat	oral	-	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100; DOSE=After oral exposure to 100 mg/kg bw AUC values in the rat were approximately 5000 times higher than for humans exposed dermally to a dose which was 1000 times lower.; EFFECT=n rats after topical application under occlusion was approximately 20% of the respective exposure following oral administration. After oral exposure to 100 mg/kg bw AUC values in the rat were approximately 5000 times higher than for humans exposed dermally to a dose which was 1000 times lower. These data support the conclusion, that skin penetration in rats and humans is considerable. Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw. The NOAEL dose, however, is lower and could be derived at 6 mg/kg bw/day from the studies provided. For these reasons a safety approach based on kinetic data can not be used. In rats repeated exposure resulted in higher blood levels of Kojic acid than after single administration. In humans repeated use of bleaching products may also result in higher systemic exposure than determined after single administration. For bleaching products a mean amount of 1 g formulation containing 1% Kojic acid applied twice daily to the face; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"After oral exposure to 100 mg/kg bw AUC values in the rat were approximately 5000 times higher than for humans exposed dermally to a dose which was 1000 times lower.","duration":"","effect":"n rats after topical application under occlusion was approximately 20% of the respective exposure following oral administration. After oral exposure to 100 mg/kg bw AUC values in the rat were approximately 5000 times higher than for humans exposed dermally to a dose which was 1000 times lower. These data support the conclusion, that skin penetration in rats and humans is considerable. Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw. The NOAEL dose, however, is lower and could be derived at 6 mg/kg bw/day from the studies provided. For these reasons a safety approach based on kinetic data can not be used. In rats repeated exposure resulted in higher blood levels of Kojic acid than after single administration. In humans repeated use of bleaching products may also result in higher systemic exposure than determined after single administration. For bleaching products a mean amount of 1 g formulation containing 1% Kojic acid applied twice daily to the face","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"100","page":73,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_028"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw	rat	oral	28 day	-	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=6; DOSE=Studies with Japanese women were conducted by single application of 500 mg of a 1% Kojic acid formulation resulting in a dose of 5 mg or approximately 0.1 mg/kg bw (50 kg bw estimated for Japanese women).; EFFECT=acid on the face. Studies with Japanese women were conducted by single application of 500 mg of a 1% Kojic acid formulation resulting in a dose of 5 mg or approximately 0.1 mg/kg bw (50 kg bw estimated for Japanese women). It has to be taken into account, that consumers may be exposed to higher doses, especially, when they apply Kojic acid containing bleaching products also to other parts of the skin, e. g. hands and arms, neck and décolleté. For the safety assessment a skin penetration rate of 7.28 µg/cm2 and a NOAEL of 6 mg/kg bw, based on histopathological findings and altered iodine uptake after oral administration in a 28 day study with rats, was used for MOS calculation. 4. CONCLUSION Based on the information provided, margins of safety of respectively 35 (face and hands), 58 (hands) and 88 (face) have been calculated suggesting that the use of Kojic acid at a maximum concentration of 1.0% in skin care formulations poses a risk to the health of the consumer. In addition, other parts of the skin might be exposed to Koj; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Studies with Japanese women were conducted by single application of 500 mg of a 1% Kojic acid formulation resulting in a dose of 5 mg or approximately 0.1 mg/kg bw (50 kg bw estimated for Japanese women).","duration":"28 day","effect":"acid on the face. Studies with Japanese women were conducted by single application of 500 mg of a 1% Kojic acid formulation resulting in a dose of 5 mg or approximately 0.1 mg/kg bw (50 kg bw estimated for Japanese women). It has to be taken into account, that consumers may be exposed to higher doses, especially, when they apply Kojic acid containing bleaching products also to other parts of the skin, e. g. hands and arms, neck and décolleté. For the safety assessment a skin penetration rate of 7.28 µg/cm2 and a NOAEL of 6 mg/kg bw, based on histopathological findings and altered iodine uptake after oral administration in a 28 day study with rats, was used for MOS calculation. 4. CONCLUSION Based on the information provided, margins of safety of respectively 35 (face and hands), 58 (hands) and 88 (face) have been calculated suggesting that the use of Kojic acid at a maximum concentration of 1.0% in skin care formulations poses a risk to the health of the consumer. In addition, other parts of the skin might be exposed to Koj","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"6","page":73,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_029"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	125	mg/kg bw/day	rat	dermal	28 day	-	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=125; DOSE=study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.; EFFECT=study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day.","duration":"28 day","effect":"study, Kojic Acid was administered to Sprague Dawley rats for 26 consecutive weeks at 125, 250, 500 and 1000 mg/kg bw/day. The substance induced some clinical signs (including exophthalmos), kidney and liver related effects. A reduction in body weight gain and increased absolute and relative weights of several organs, including the thyroid gland, were found. The majority of the effects were only observed at the highest dosage levels. No histopathological changes were noted. Based upon the results of this study, a NOEL of 125 mg/kg bw/day was determined. Specific thyroid markers, such as TSH, T3 and T4 levels, were not analysed in this study. A 28 day dermal study in Wistar rats was carried out under GLP. Daily administered doses were 0, 100, 300 and 1000 mg/kg in a 0.5% aqueous methylcellulose solution. No topical effects could be attributed to treatment. Body weight and food consumption were measured once a week. They were similar in control and treated groups and food consumption was unaffected by treatment. Decreased lymphoc","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"125","page":6,"route":"dermal","species":"rat","study_id":"sccs_o_098_noael_003"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	15	mg/kg bw/day	rat	-	4 weeks	-	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=15; DOSE=n 3% Kojic Acid was administered orally for 4 weeks.; EFFECT=n 3% Kojic Acid was administered orally for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic Acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic Acid for 12 to 20 weeks. In one promotion assay, carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice, hypertrophy in males as well as hyperplasia and adenomas in females and males were reported in two feeding studies up to 3 % Kojic Acid for 26 weeks or 20 months, respectively. According to a negative study on DNA-adducts in the; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"n 3% Kojic Acid was administered orally for 4 weeks.","duration":"4 weeks","effect":"n 3% Kojic Acid was administered orally for 4 weeks. Investigations were performed in male mice except for one 20 month feeding study, were incidences of hepatomas were reported for female mice. Liver weights were increased in male and female mice and also in the F1 offspring of Kojic Acid treated dams. Thyroid proliferative lesions, hyperplasia and adenomas were reported when male rats were investigated in feeding studies up to 4 % Kojic Acid for 12 to 20 weeks. In one promotion assay, carcinomas were observed. A NOAEL of 15 mg/kg bw/day was derived from this study. In mice, hypertrophy in males as well as hyperplasia and adenomas in females and males were reported in two feeding studies up to 3 % Kojic Acid for 26 weeks or 20 months, respectively. According to a negative study on DNA-adducts in the","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"15","page":7,"route":"","species":"rat","study_id":"sccs_o_098_noael_005"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw	rat	oral	-	-	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=100; DOSE=Overall, toxicokinetic data in the rat and in humans were available, but at different dose levels.; EFFECT=SCCS-rejected applicant NOAEL: e. g. hands and arms, neck and decollage. In addition, as in rats repeated exposure resulted in higher blood levels of Kojic Acid than after single administration, the SCCP considered that in humans repeated use of bleaching products containing Kojic Acid may also result in higher systemic exposure than determined after single administration. Overall, toxicokinetic data in the rat and in humans were available, but at different dose levels. Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day). Therefore a safety approach based on kinetic data could not be used. 3.1.2 Safety evaluation (including calculation of the MoS) In 2006, the SCCP calculated the following MoS values for Kojic Acid, taking into consideration that the compound is used as a skin whitening agent at a concentration of 1% in leave-on creams, which are generally applied to the faceand hands. For calculation of MoS, an NOAEL of 6 mg/kg bw/day was used, based on thyroid effects after oral administration in ra; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Overall, toxicokinetic data in the rat and in humans were available, but at different dose levels.","duration":"","effect":"SCCS-rejected applicant NOAEL: e. g. hands and arms, neck and decollage. In addition, as in rats repeated exposure resulted in higher blood levels of Kojic Acid than after single administration, the SCCP considered that in humans repeated use of bleaching products containing Kojic Acid may also result in higher systemic exposure than determined after single administration. Overall, toxicokinetic data in the rat and in humans were available, but at different dose levels. Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day). Therefore a safety approach based on kinetic data could not be used. 3.1.2 Safety evaluation (including calculation of the MoS) In 2006, the SCCP calculated the following MoS values for Kojic Acid, taking into consideration that the compound is used as a skin whitening agent at a concentration of 1% in leave-on creams, which are generally applied to the faceand hands. For calculation of MoS, an NOAEL of 6 mg/kg bw/day was used, based on thyroid effects after oral administration in ra","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"100","page":9,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_007"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw/day	rat	oral	28 day	-	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day).; EFFECT=SCCS-rejected applicant NOAEL: e levels. Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day). Therefore a safety approach based on kinetic data could not be used. 3.1.2 Safety evaluation (including calculation of the MoS) In 2006, the SCCP calculated the following MoS values for Kojic Acid, taking into consideration that the compound is used as a skin whitening agent at a concentration of 1% in leave-on creams, which are generally applied to the faceand hands. For calculation of MoS, an NOAEL of 6 mg/kg bw/day was used, based on thyroid effects after oral administration in rats (28 day treatment). For absorption through the skin, the maximum obtained value of 7.28 µg/cm² from the in vitro study with human skin was used. The resulting MoS values were: Face: MoS = 88 Hands: MoS = 58 Face and hands: MoS = 35 3.1.3 Additional discussion points and SCCP conclusion The SCCP pointed out that consumers who want to bleach their skin not only apply the products on hands and face, but also on parts of the a; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day).","duration":"28 day","effect":"SCCS-rejected applicant NOAEL: e levels. Moreover, the rat data concerned a dose level of 100 mg/kg bw, whereas the NOAEL was lower (6 mg/kg bw/day). Therefore a safety approach based on kinetic data could not be used. 3.1.2 Safety evaluation (including calculation of the MoS) In 2006, the SCCP calculated the following MoS values for Kojic Acid, taking into consideration that the compound is used as a skin whitening agent at a concentration of 1% in leave-on creams, which are generally applied to the faceand hands. For calculation of MoS, an NOAEL of 6 mg/kg bw/day was used, based on thyroid effects after oral administration in rats (28 day treatment). For absorption through the skin, the maximum obtained value of 7.28 µg/cm² from the in vitro study with human skin was used. The resulting MoS values were: Face: MoS = 88 Hands: MoS = 58 Face and hands: MoS = 35 3.1.3 Additional discussion points and SCCP conclusion The SCCP pointed out that consumers who want to bleach their skin not only apply the products on hands and face, but also on parts of the a","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":9,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_008"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw	rat	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100; DOSE=Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw.; EFFECT=issues detected were sulphate conjugates of Kojic acid (35.6 – 93.7% of total radioactivity) and glucuronides (6.4 – 39.6% of total radioactivity). In rats repeated exposure resulted in higher blood levels of Kojic acid than after single administration. In humans repeated use of bleaching products may also result in higher systemic exposure than determined after single administration. Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw. The NOAEL dose, however, is lower and could be derived at 6 mg/kg bw/day from the studies provided. For these reasons a safety approach based on kinetic data can not be used.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw.","duration":"","effect":"issues detected were sulphate conjugates of Kojic acid (35.6 – 93.7% of total radioactivity) and glucuronides (6.4 – 39.6% of total radioactivity). In rats repeated exposure resulted in higher blood levels of Kojic acid than after single administration. In humans repeated use of bleaching products may also result in higher systemic exposure than determined after single administration. Additionally, it has to be considered, that data on kinetics of Kojic acid in the rat were obtained with doses of 100 mg/kg bw. The NOAEL dose, however, is lower and could be derived at 6 mg/kg bw/day from the studies provided. For these reasons a safety approach based on kinetic data can not be used.","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"100","page":16,"route":"","species":"rat","study_id":"sccs_o_259_noael_001"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg/day	rat	oral	28-day	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100; DOSE=Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day.; EFFECT=tive nor quantitative changes were observed at the end of the treatment or treatment-free period. Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day. Because there were no histopathological changes observed in the spleen, the significance of the splenic weight changes was uncertain. No treatment-related macroscopic or microscopic post- mortem findings were noted at the end of the treatment period. Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. (Roger, 1999) A 28-day study was described consisting of 3 separate experiments with Kojic acid in the diet of male F344 rats. In the first experiment, groups of nine animals received 0 (control), 0.008; 0.03, 0.125, 0.5 or 2.0% Kojic acid containing diet for 28 days (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). Twenty-four hours before the end of the experiment, four animals in each group received 0.2 ml/100 g bw Na 125I at a concentration of 2.5 x105; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day.","duration":"28-day","effect":"tive nor quantitative changes were observed at the end of the treatment or treatment-free period. Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day. Because there were no histopathological changes observed in the spleen, the significance of the splenic weight changes was uncertain. No treatment-related macroscopic or microscopic post- mortem findings were noted at the end of the treatment period. Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. (Roger, 1999) A 28-day study was described consisting of 3 separate experiments with Kojic acid in the diet of male F344 rats. In the first experiment, groups of nine animals received 0 (control), 0.008; 0.03, 0.125, 0.5 or 2.0% Kojic acid containing diet for 28 days (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). Twenty-four hours before the end of the experiment, four animals in each group received 0.2 ml/100 g bw Na 125I at a concentration of 2.5 x105","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"100","page":25,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_002"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg/day	rat	oral	28-day	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100; DOSE=Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day.; EFFECT=observed at the end of the treatment or treatment-free period. Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day. Because there were no histopathological changes observed in the spleen, the significance of the splenic weight changes was uncertain. No treatment-related macroscopic or microscopic post- mortem findings were noted at the end of the treatment period. Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. (Roger, 1999) A 28-day study was described consisting of 3 separate experiments with Kojic acid in the diet of male F344 rats. In the first experiment, groups of nine animals received 0 (control), 0.008; 0.03, 0.125, 0.5 or 2.0% Kojic acid containing diet for 28 days (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). Twenty-four hours before the end of the experiment, four animals in each group received 0.2 ml/100 g bw Na 125I at a concentration of 2.5 x105 c.p.m./; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day.","duration":"28-day","effect":"observed at the end of the treatment or treatment-free period. Lower absolute and relative spleen weights were observed in females given 1000 mg/kg bw/day. Because there were no histopathological changes observed in the spleen, the significance of the splenic weight changes was uncertain. No treatment-related macroscopic or microscopic post- mortem findings were noted at the end of the treatment period. Based on the changes observed in lymphocytes and white blood cell counts, the No Observed Adverse Effect Level (NOAEL) was established at 100 mg/kg/day. (Roger, 1999) A 28-day study was described consisting of 3 separate experiments with Kojic acid in the diet of male F344 rats. In the first experiment, groups of nine animals received 0 (control), 0.008; 0.03, 0.125, 0.5 or 2.0% Kojic acid containing diet for 28 days (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). Twenty-four hours before the end of the experiment, four animals in each group received 0.2 ml/100 g bw Na 125I at a concentration of 2.5 x105 c.p.m./","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"100","page":25,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_003"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	23.8	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=23.8; DOSE=(Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake.; EFFECT=were then killed and examined as in experiments 1 and 2, except that 125l was injected 12 h before death. Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. (Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake. Over the course of four weeks, male F344 rats (8 animals/group) received a basal diet containing Kojic acid at 0, 0.008, 0.03, 0.125, 0.5, 2.0% (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). At the end of treatment period blood samples were taken from 5 animals for hormone analysis and animals were autopsied. Histopathological examination of thyroid and pituitary ti; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"(Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake.","duration":"4 weeks","effect":"were then killed and examined as in experiments 1 and 2, except that 125l was injected 12 h before death. Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. (Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake. Over the course of four weeks, male F344 rats (8 animals/group) received a basal diet containing Kojic acid at 0, 0.008, 0.03, 0.125, 0.5, 2.0% (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). At the end of treatment period blood samples were taken from 5 animals for hormone analysis and animals were autopsied. Histopathological examination of thyroid and pituitary ti","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"23.8","page":26,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_004"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	5.85	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=5.85; DOSE=(Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake.; EFFECT=jected 12 h before death. Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. (Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake. Over the course of four weeks, male F344 rats (8 animals/group) received a basal diet containing Kojic acid at 0, 0.008, 0.03, 0.125, 0.5, 2.0% (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). At the end of treatment period blood samples were taken from 5 animals for hormone analysis and animals were autopsied. Histopathological examination of thyroid and pituitary tissues was performed. The remaining animals were sacrificed for measurement of 12; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"(Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake.","duration":"4 weeks","effect":"jected 12 h before death. Organic 125I formation returned to normal after 6 hours, 125I uptake per unit thyroid weight rose to 70% of the control level within 24 hours. T3 and T4 were 47 and 34% of control levels after 4 weeks feeding of Kojic acid diet. They increased to normal within 48 hours after return to standard diet, high levels of TSH decreased to normal within 24 hours. (Fujimoto et al., 1999) SCCS comment From this study, a NOAEL of 23.8 mg/kg bw/day can be derived with respect to thyroid weight, and a NOAEL of 5.85 mg/kg bw/day with respect to iodine uptake. Over the course of four weeks, male F344 rats (8 animals/group) received a basal diet containing Kojic acid at 0, 0.008, 0.03, 0.125, 0.5, 2.0% (calculated as 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day). At the end of treatment period blood samples were taken from 5 animals for hormone analysis and animals were autopsied. Histopathological examination of thyroid and pituitary tissues was performed. The remaining animals were sacrificed for measurement of 12","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5.85","page":26,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_005"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw/day	rat	oral	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=In quantitative morphometric analysis the ratio of the area of follicular epithelial cells to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.; EFFECT=ell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis was evident in all rats of the 2% Kojic acid group. In quantitative morphometric analysis the ratio of the area of follicular epithelial cells to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. (Tamura et al., 1999)b SCCS comment Based on the histopathological findings and altered 125I uptake, a NOAEL of 6 mg/kg bw/day can be derived. Male F344 rats (10 animals/group) received Kojic acid in 0.5% carboxymethylcellulose at doses of 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day in volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Body weights, food and water consumption were determined twice a week. Necropsy was performed, thyroid weights were recorded and histopathological examination was performed. The uptake of iodine and the iodination were determined before; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"In quantitative morphometric analysis the ratio of the area of follicular epithelial cells to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above.","duration":"","effect":"ell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis was evident in all rats of the 2% Kojic acid group. In quantitative morphometric analysis the ratio of the area of follicular epithelial cells to the area of the colloids in a unit area was significantly increased in groups treated with 0.03% Kojic acid and above. (Tamura et al., 1999)b SCCS comment Based on the histopathological findings and altered 125I uptake, a NOAEL of 6 mg/kg bw/day can be derived. Male F344 rats (10 animals/group) received Kojic acid in 0.5% carboxymethylcellulose at doses of 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day in volumes of 5 ml/kg bw by gavage for 28 consecutive days. Clinical signs of animals were checked twice daily. Body weights, food and water consumption were determined twice a week. Necropsy was performed, thyroid weights were recorded and histopathological examination was performed. The uptake of iodine and the iodination were determined before","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":26,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_006"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	227	mg/kg bw/day	rat	oral	26 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=227; DOSE=administered orally to male rats over a period of 26 weeks.; EFFECT=administered orally to male rats over a period of 26 weeks. (Chronic toxicity test and recovery, 1980) From SCCP/1481/12 The SCCS added to the Kojic acid opinion of 2012 a published article of a 55-week chronic toxicity study of dietary administered Kojic acid of 0% (control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, Kojic acid induced thyroid follicular cell tumors and liver preneoplastic lesions could be observed. From this study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"administered orally to male rats over a period of 26 weeks.","duration":"26 weeks","effect":"administered orally to male rats over a period of 26 weeks. (Chronic toxicity test and recovery, 1980) From SCCP/1481/12 The SCCS added to the Kojic acid opinion of 2012 a published article of a 55-week chronic toxicity study of dietary administered Kojic acid of 0% (control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, Kojic acid induced thyroid follicular cell tumors and liver preneoplastic lesions could be observed. From this study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats.","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"227","page":28,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_008"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	150	mg/kg bw/day	mouse	oral	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=150; DOSE=Mean foetal weights were decreased only in the 900 mg/kg bw/day group, but differences were not significant.; EFFECT=nificantly lower number of implantations per litter. Post-implantation loss was comparable for all groups. Mean foetal weights were decreased only in the 900 mg/kg bw/day group, but differences were not significant. No major malformations were observed in any group and incidences of minor visceral and skeletal anomalies were essentially comparable for all groups. The SCCP commented that Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity could be derived from this study. (Palmer, 1979a) Kojic acid was administered by oral gavage in 1% methylcellulose to ddy-SLC strain SPF mice from days 6 to 15 of gestation and effects on pregnancy, development of foetuses and live born offspring were studied. The administered dose levels were 0, 25, 150 or 900 mg/kg bw/day (1ml/kg bw). During gestation period, only animals of the 900 mg/kg bw/day group exhibited calmness and ataxia and in some cases coma and d; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Mean foetal weights were decreased only in the 900 mg/kg bw/day group, but differences were not significant.","duration":"","effect":"nificantly lower number of implantations per litter. Post-implantation loss was comparable for all groups. Mean foetal weights were decreased only in the 900 mg/kg bw/day group, but differences were not significant. No major malformations were observed in any group and incidences of minor visceral and skeletal anomalies were essentially comparable for all groups. The SCCP commented that Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity could be derived from this study. (Palmer, 1979a) Kojic acid was administered by oral gavage in 1% methylcellulose to ddy-SLC strain SPF mice from days 6 to 15 of gestation and effects on pregnancy, development of foetuses and live born offspring were studied. The administered dose levels were 0, 25, 150 or 900 mg/kg bw/day (1ml/kg bw). During gestation period, only animals of the 900 mg/kg bw/day group exhibited calmness and ataxia and in some cases coma and d","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"150","page":29,"route":"oral","species":"mouse","study_id":"sccs_o_259_noael_011"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	150	mg/kg bw/day	mouse	-	13-week	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=150; DOSE=the 25 mg/kg bw/day group.; EFFECT=the 25 mg/kg bw/day group. Three week old F1 mice revealed significantly increased kidney weights in both sexes at 900 mg/kg bw/day. In F1 dams heart weight was reduced significantly on day 18 of pregnancy in the highest dose group and in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively. No effect considered to be due to treatment was observed in the reared offspring concerning time point of descending of the testes and opening of the vagina. A NOAEL for maternal toxicity and for embryotoxicity of 150 mg/kg bw/day can be derived from this study. (Anon, 1980) Kojic acid was orally administered in 1% methylcellulose at doses of 0, 30, 160 or 800 mg/kg to ddY-SLC mice (35 per group) once daily from day 15 of pregnancy to day 21 postpartum to assess the effect of treatment on dams and F1 offspring. Spontaneous parturition was allowed for all the dams and the second generation was subjected to postnatal observations. A significant decrease in food consumption and; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"the 25 mg/kg bw/day group.","duration":"13-week","effect":"the 25 mg/kg bw/day group. Three week old F1 mice revealed significantly increased kidney weights in both sexes at 900 mg/kg bw/day. In F1 dams heart weight was reduced significantly on day 18 of pregnancy in the highest dose group and in 13-week old males adrenal prostata gland weights were decreased in the 900 and the 25 mg/kg bw/day group, respectively. No effect considered to be due to treatment was observed in the reared offspring concerning time point of descending of the testes and opening of the vagina. A NOAEL for maternal toxicity and for embryotoxicity of 150 mg/kg bw/day can be derived from this study. (Anon, 1980) Kojic acid was orally administered in 1% methylcellulose at doses of 0, 30, 160 or 800 mg/kg to ddY-SLC mice (35 per group) once daily from day 15 of pregnancy to day 21 postpartum to assess the effect of treatment on dams and F1 offspring. Spontaneous parturition was allowed for all the dams and the second generation was subjected to postnatal observations. A significant decrease in food consumption and","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"150","page":30,"route":"","species":"mouse","study_id":"sccs_o_259_noael_012"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	100	mg/kg bw/day	rat	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100; DOSE=Major malformations observed included one heart defect in the 20 mg/kg bw/d group and three effects from two litters in the 100 mg/kg bw/d group.; EFFECT=SCCS-rejected applicant NOAEL: . Major malformations observed included one heart defect in the 20 mg/kg bw/d group and three effects from two litters in the 100 mg/kg bw/d group. Effects were considered to be unrelated to treatment as the highest dose group did not show major malformations. Minor anomalities were significantly increased in the highest dose group, however not considered treatment related by the authors. The SCCP considered the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day was derived for maternal toxicity and for embryotoxicity. (Palmer, 1979b) In a study in Sprague Dawley rats (7 females/group) Kojic acid at 50 μg/day in 0.1 ml propylene glycol was given orally from day 1 to 5 of pregnancy. Animals of the control group received the vehicle alone. One female of the treated group died before delivery, 2 animals showed nasal and mouth infections. Significant loss in litter size was observed in females treated with Kojic acid. Furthermore reduction in implantation; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Major malformations observed included one heart defect in the 20 mg/kg bw/d group and three effects from two litters in the 100 mg/kg bw/d group.","duration":"","effect":"SCCS-rejected applicant NOAEL: . Major malformations observed included one heart defect in the 20 mg/kg bw/d group and three effects from two litters in the 100 mg/kg bw/d group. Effects were considered to be unrelated to treatment as the highest dose group did not show major malformations. Minor anomalities were significantly increased in the highest dose group, however not considered treatment related by the authors. The SCCP considered the minor anomalies observed in the highest dose group of relevance with respect of Kojic acid treatment. A NOAEL of 100 mg/kg bw/day was derived for maternal toxicity and for embryotoxicity. (Palmer, 1979b) In a study in Sprague Dawley rats (7 females/group) Kojic acid at 50 μg/day in 0.1 ml propylene glycol was given orally from day 1 to 5 of pregnancy. Animals of the control group received the vehicle alone. One female of the treated group died before delivery, 2 animals showed nasal and mouth infections. Significant loss in litter size was observed in females treated with Kojic acid. Furthermore reduction in implantation","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":31,"route":"","species":"rat","study_id":"sccs_o_259_noael_014"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	1637	-	human	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=unclear:SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO; DOSE=SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...; EFFECT=SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199...","duration":"","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"unclear:SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 40 Area of application SED (mg/kg bw/day) Adjusted NOAEL (mg/kg bw/day) MoS Face+neck 0.0075 2 267 Hands 0.0067 2 199 Aggregate (face+neck+hands) 0.0142 2 141 Although it can be assumed that Kojic acid after exposure at a sufficient dose for a sufficient time can potentially also interfere with thyroid hormone homeostasis in humans, there are currently no compound-specific quantitative data available to substantiate this assertion. Therefore a change of the interspecies toxicodynamic default factor of 2.5 has not been applied in the case of Kojic acid. 3.5 DISCUSSIO","page":40,"route":"","species":"human","study_id":"sccs_o_259_noael_020"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	2	%	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2; DOSE=Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:; EFFECT=SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1:","duration":"4 weeks","effect":"SCCS/1637/21 Final version & CORRIGENDUM ANNEX 6, Table 6: Overview of toxicological studies with Kojic acid studying endocrine-related endpoints 1 Study Test compound Guideline Dose Duration Test system/Spe cies Target NOAEL (mg/kg bw/d) Ref Rats, oral, diet 125 l uptake and hormone determination Kojic acid / Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet 4 weeks F344 rats, 9 males / group (Experiment 1) Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted onl","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"2","page":68,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_024"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw/day	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on.; EFFECT=ights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered 125I uptake) (Tamura et al., 1999b); CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on.","duration":"","effect":"ights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered 125I uptake) (Tamura et al., 1999b)","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":69,"route":"","species":"","study_id":"sccs_o_259_noael_025"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	62.5	mg/kg bw/day	rat	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=62.5; DOSE=Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.; EFFECT=he thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 μg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 NOAEL of 62.5 mg/kg bw/day (decreased T3 level) Cmax was 25.07 ± 4.56 μg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 μg eq/ml. (Higa et al., 2000); CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","duration":"","effect":"he thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 μg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 NOAEL of 62.5 mg/kg bw/day (decreased T3 level) Cmax was 25.07 ± 4.56 μg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 μg eq/ml. (Higa et al., 2000)","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"62.5","page":70,"route":"","species":"rat","study_id":"sccs_o_259_noael_026"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	0.03	%	rat	-	20 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=0.03; EFFECT=ek 4 revealed no significant intergroup differences. It was concluded that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanism independent of T4-UDP-GT activity. Rat, promotion Kojic acid / Experiment 1: 0, 0.002, F344 rats - Experiment 20 weeks Overall 4 animals died due to tracheal blockage caused by extremely hyper-throphied thyroids NOAEL of 0.03% or 15.5 (Tamura et al.,; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"","duration":"20 weeks","effect":"ek 4 revealed no significant intergroup differences. It was concluded that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanism independent of T4-UDP-GT activity. Rat, promotion Kojic acid / Experiment 1: 0, 0.002, F344 rats - Experiment 20 weeks Overall 4 animals died due to tracheal blockage caused by extremely hyper-throphied thyroids NOAEL of 0.03% or 15.5 (Tamura et al.,","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"0.03","page":77,"route":"","species":"rat","study_id":"sccs_o_259_noael_027"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	40	-	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=unclear:Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS; DOSE=Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS; EFFECT=Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","duration":"","effect":"Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"unclear:Unlabeled table on page 40: Area of application \| SED (mg/kg bw/day) \| Adjusted NOAEL (mg/kg bw/day) \| MoS","page":40,"route":"","species":"","study_id":"sccs_o_259_noael_028"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	2	-	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2; EFFECT=Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 40: Face+neck \| 0.0075 \| 2 \| 267","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"2","page":40,"route":"","species":"","study_id":"sccs_o_259_noael_029"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	2	-	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2; EFFECT=Unlabeled table on page 40: Hands \| 0.0067 \| 2 \| 199; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 40: Hands \| 0.0067 \| 2 \| 199","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"2","page":40,"route":"","species":"","study_id":"sccs_o_259_noael_030"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	2	-	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2; EFFECT=Unlabeled table on page 40: Aggregate (face+neck+hands) \| 0.0142 \| 2 \| 141; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 40: Aggregate (face+neck+hands) \| 0.0142 \| 2 \| 141","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"2","page":40,"route":"","species":"","study_id":"sccs_o_259_noael_031"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	68	-	-	-	-	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=unclear:Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref; DOSE=Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref; EFFECT=Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","duration":"","effect":"Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"","noael_value":"unclear:Unlabeled table on page 68: Study \| Test compound \| Guideline \| Dose \| Duration \| Test system/Spe cies \| Target \| NOAEL (mg/kg bw/d) \| Ref","page":68,"route":"","species":"","study_id":"sccs_o_259_noael_032"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	23.8	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=23.8; DOSE=0, 0.008, 0.03, 0.125, 0.5, or 2% in diet \| 4 weeks \| F344 rats, 9 males / group (Experiment 1) \| Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner.; EFFECT=Unlabeled table on page 68: Rats, oral, diet 125 l uptake and hormone determination \| Kojic acid \| / \| Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet \| 4 weeks \| F344 rats, 9 males / group (Experiment 1) \| Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted only in the highest dose group. Serum T3, T4 and TSH level were also only affected in the 2.0% group. \| 23.8 mg/kg bw/day (thyroid weight) 5.85 mg/kg bw/day (iodine uptake) \| (Fujimoto et al., 1999); CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"0, 0.008, 0.03, 0.125, 0.5, or 2% in diet \| 4 weeks \| F344 rats, 9 males / group (Experiment 1) \| Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner.","duration":"4 weeks","effect":"Unlabeled table on page 68: Rats, oral, diet 125 l uptake and hormone determination \| Kojic acid \| / \| Experiment 1: 0, 0.008, 0.03, 0.125, 0.5, or 2% in diet \| 4 weeks \| F344 rats, 9 males / group (Experiment 1) \| Diet containing > 0.125% of Kojic acid increased thyroid weight in a dose-dependent manner. The weight in the 2.0% group reached nine times the control value. 125I uptake into the thyroid was more sensitive to Kojic acid treatment, being significantly suppressed at 0.03%. Organic 125I formation was, however, interrupted only in the highest dose group. Serum T3, T4 and TSH level were also only affected in the 2.0% group. \| 23.8 mg/kg bw/day (thyroid weight) 5.85 mg/kg bw/day (iodine uptake) \| (Fujimoto et al., 1999)","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"23.8","page":68,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_033"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	2	%	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2.0; DOSE=0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats;; EFFECT=Unlabeled table on page 69: Rats, oral, diet hormone analysis, Histopathologi cal examination of thyroid and pituitary tissues \| Kojic acid \| / \| 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats; 8 animals/group \| Body weight differences insignificant. Absolute and relative thyroid weights were increased significantly in the groups who received 0.5 and 2% Kojic acid. For pituitary and liver relative weights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis \| NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered...; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats;","duration":"4 weeks","effect":"Unlabeled table on page 69: Rats, oral, diet hormone analysis, Histopathologi cal examination of thyroid and pituitary tissues \| Kojic acid \| / \| 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats; 8 animals/group \| Body weight differences insignificant. Absolute and relative thyroid weights were increased significantly in the groups who received 0.5 and 2% Kojic acid. For pituitary and liver relative weights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis \| NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered...","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"2.0","page":69,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_034"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	6	mg/kg bw/day	rat	oral	4 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats;; EFFECT=Unlabeled table on page 69: Rats, oral, diet hormone analysis, Histopathologi cal examination of thyroid and pituitary tissues \| Kojic acid \| / \| 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats; 8 animals/group \| Body weight differences insignificant. Absolute and relative thyroid weights were increased significantly in the groups who received 0.5 and 2% Kojic acid. For pituitary and liver relative weights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis \| NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered...; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats;","duration":"4 weeks","effect":"Unlabeled table on page 69: Rats, oral, diet hormone analysis, Histopathologi cal examination of thyroid and pituitary tissues \| Kojic acid \| / \| 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet Average daily intake calculated: 0, 5.85, 23.8, 95.3, 393.6, 1387.3 mg/kg bw/day \| 4 weeks \| F344 rats; 8 animals/group \| Body weight differences insignificant. Absolute and relative thyroid weights were increased significantly in the groups who received 0.5 and 2% Kojic acid. For pituitary and liver relative weights differed compared to the control. 125I uptake decreased in a dose- dependent manner from 0.03% Kojic acid on. In addition, significant reduction of organic formation of iodine and serum T3 and T4 levels were observed in the 2% Kojic acid group along with pronounced elevation of TSH. Histopathologically, decreased colloid in the thyroid follicles and follicular cell hyperthrophy in the thyroid were apparent at high incidences in the groups given 0.03% Kojic acid or more. In addition, thyroid capsular fibrosis \| NOAEL of 6 mg/kg bw/day (histopathologi cal findings and altered...","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":69,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_035"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	0.5	%	rat	oral	28 days	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=0.5; DOSE=Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...; EFFECT=Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","duration":"28 days","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"0.5","page":70,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_036"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	62.5	mg/kg bw/day	rat	oral	28 days	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=62.5; DOSE=Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...; EFFECT=Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in moti...","duration":"28 days","effect":"Unlabeled table on page 70: Rat, oral, gavage Clinical and histopathologi cal examination. Recording of iodine uptake and iodination. Hormone analysis in blood \| Kojic acid in 0.5% carboxymethy l cellulose \| / \| 0, 4, 15, 62.5, 250, 1000 mg/kg bw/day or 0, 0.008, 0.03, 0.125, 0.5, 2.0% Kojic acid in diet dosing volumes of 5 ml/kg bw, single oral administration of 14C-Kojic acid (10 μCi/100 g or to 100 mg/kg bw/day) \| 28 days \| F344/ DuCrj rats 10 males/group \| decrease in motility, inhibition of body weight gain, and a decrease in food consumptionat 1000 mg/kg bw. A significant increase in absolute and relative thyroid weight and hypertrophy of epithelial cells of the thyroid gland follicles were observed at every time point investigated. In addition the uptake of radioactive iodine form blood into the thyroid gland was enhanced significantly and the TCA-precipitable radioactive iodine in the thyroid gland increased in those rats. Although serum T4 concentration was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes wer...","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"62.5","page":70,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_037"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	-	0.03	%	rat	-	20 weeks	-	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=0.03; EFFECT=Unlabeled table on page 77: Rat, promotion \| Kojic acid \| / \| Experiment 1: 0, 0.002, \| F344 rats - Experiment \| 20 weeks \| Overall 4 animals died due to tracheal blockage caused by extremely hyper-throphied thyroids \| NOAEL of 0.03% or 15.5 \| (Tamura et al.,; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"","duration":"20 weeks","effect":"Unlabeled table on page 77: Rat, promotion \| Kojic acid \| / \| Experiment 1: 0, 0.002, \| F344 rats - Experiment \| 20 weeks \| Overall 4 animals died due to tracheal blockage caused by extremely hyper-throphied thyroids \| NOAEL of 0.03% or 15.5 \| (Tamura et al.,","endpoint":"","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"0.03","page":77,"route":"","species":"rat","study_id":"sccs_o_259_noael_038"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	6	mg/kg bw/day	rat	oral	4-week	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=6; DOSE=Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.; EFFECT=SCCP/1182/08 Opinion on kojic acid 69 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-da; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","duration":"4-week","effect":"SCCP/1182/08 Opinion on kojic acid 69 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-da","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_013"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=0.069	mg/kg	rat	oral	4-week	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 0.069; DOSE=ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.; EFFECT=ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","duration":"4-week","effect":"ATION OF THE MARGIN OF SAFETY For calculation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.069","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_014"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	4-week	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=ation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.; EFFECT=ation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"ation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref.","duration":"4-week","effect":"ation of MoS, an NOAEL of 6 mg/kg bw/day is used, based on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_015"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	4-week	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=(Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL...; EFFECT=on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal abso; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"(Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL...","duration":"4-week","effect":"on histopathological findings and altered iodine uptake after oral administration in rats (4-week treatment, ref. 41). (Skin care formulation, 1% Kojic acid) Face Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 565 cm2 Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal abso","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_016"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=0.104	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 0.104; DOSE=per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...; EFFECT=per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","duration":"28-days","effect":"per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.104","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_017"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment...; EFFECT=Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment...","duration":"28-days","effect":"Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_018"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human...; EFFECT=dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human...","duration":"28-days","effect":"dose (SED) SAS x A x 0.001/60 = 0.069 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 88 Hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 860 cm2 Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_019"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=0.173	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 0.173; DOSE=ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...; EFFECT=ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) =...","duration":"28-days","effect":"ent SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.173","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_020"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=y weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment...; EFFECT=y weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"y weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment...","duration":"28-days","effect":"y weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_021"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	=6	mg/kg	rat	oral	28-days	dermal absorption	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT== 6; DOSE=SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human...; EFFECT=SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human...","duration":"28-days","effect":"SAS x A x 0.001/60 = 0.104 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 58 Face and hands Maximum absorption through the skin A (μg/cm2) = 7.28 µg/cm² Skin Area surface SAS (cm2) = 1425 cm2 Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.173 mg/kg No observed adverse effect level (mg/kg) NOAEL = 6 mg/kg (28-days, rat, oral) Margin of Safety NOAEL / SED = 35","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 6","page":69,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_022"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	6	mg/kg bw/day	rat	dermal	28-day	dermal absorption	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=The applicant further contested the view of SCCP that a single-dose human dose would underestimate the human risk after repeated exposure as the plasma levels were below the limit of quantification after 24 hours, meaning that accumulation was not expected to occur.; EFFECT=licant, result in a minimal to negligible systemic availability. The applicant further contested the view of SCCP that a single-dose human dose would underestimate the human risk after repeated exposure as the plasma levels were below the limit of quantification after 24 hours, meaning that accumulation was not expected to occur. In addition, the typically used in vitro dermal absorption study also implies a single dose application. Concerning the calculation of the MoS, the applicant argued against the use of the NOAEL value of 6 mg/kg bw/day originating from a 28-day study in the rat and based on thyroid effects as such effects in the rat is known for its potential irrelevance to man. The main reason for this is that thyroxine is rapidly metabolized in rodents due to the absence of freely circulating thyroid-hormone binding globulin that is significantly present in humans. Furthermore, the human thyroid appears to be less sensitive to prolonged TSH stimulation than that of the rat. Therefore, it is also less sensitive to tumour; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"The applicant further contested the view of SCCP that a single-dose human dose would underestimate the human risk after repeated exposure as the plasma levels were below the limit of quantification after 24 hours, meaning that accumulation was not expected to occur.","duration":"28-day","effect":"licant, result in a minimal to negligible systemic availability. The applicant further contested the view of SCCP that a single-dose human dose would underestimate the human risk after repeated exposure as the plasma levels were below the limit of quantification after 24 hours, meaning that accumulation was not expected to occur. In addition, the typically used in vitro dermal absorption study also implies a single dose application. Concerning the calculation of the MoS, the applicant argued against the use of the NOAEL value of 6 mg/kg bw/day originating from a 28-day study in the rat and based on thyroid effects as such effects in the rat is known for its potential irrelevance to man. The main reason for this is that thyroxine is rapidly metabolized in rodents due to the absence of freely circulating thyroid-hormone binding globulin that is significantly present in humans. Furthermore, the human thyroid appears to be less sensitive to prolonged TSH stimulation than that of the rat. Therefore, it is also less sensitive to tumour","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":10,"route":"dermal","species":"rat","study_id":"sccs_o_098_noael_009"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	227	mg/kg bw/day	rat	oral	55-week	dermal absorption	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=227; DOSE=surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...; EFFECT=surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola; CITATION=(Ref. 5); CITATION_NUMBERS=[5]; REFERENCE=(Ref. 5); DETAILS_JSON={"cas_number":"501-30-4","citation":"(Ref. 5)","dose":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) t...","duration":"55-week","effect":"surprising, as the current safety assessment of Kojic Acid concerns the use as a skin whitening agent (by retarding melanin production) at 1%. - The SCCS added to the kojic acid submission a published article of a 55-week chronic toxicity study of dietary administered Kojic Acid of 0%(control), 0.05 % (227mg/kg bw/day) and 2% (968mg/kg bw/day) to male F344 rats. At the highest dosage, induced thyroid follicular cell tumors and liver preneoplastic lesions were observed. From the study it could be concluded that the NOAEL is below 227 mg/kg bw/day in male rats (Ref. 5). 3.2.2 In vitro dermal absorption study Guideline: OECD TG 428: Percutaneous Absorption: In vitro Method (2004), SCCS/1358/10 Date of test: 17-29 September 2010 Test system: Excised, dermatomed (400µm) human skin on a static diffusion cell N° of samples: 12 samples (4 donors, 3 skin samples/donor) per tested concentration Test substance: Leave-on skin care formulation containing 1% of Kojic Acid (full composition stated in appendix 1 to this opinion) Batch: Radiola","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"227","page":11,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_010"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	6	mg/kg bw/day	rat	oral	28-day	dermal absorption	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat.; EFFECT=orption value used in SCCP/1182/08 comes from an explanatory study, using too few skin samples. The mean dermal absorption value was 3.63 µg/cm2 and the maximum value of 7.28 µg/cm², which was used for the calculation of the MoS by the SCCP. The applicant submitted a new in vitro dermal absorption study resulting in a much lower absorption rate (mean value of 0.75 µg/cm²). 2) The applicant considers the observed thyroid effects in the rats with Kojic Acid irrelevant for man and therefore suggests using a different NOAEL value. Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat. With the dermal absorption value of 0.75 µg/cm² instead of 7.28 µg/cm², the MoS values calculated by the applicant are 850 (face), 558 (hands) and 337 (face and hands). 1) Dermal absorption data The dermal absorption value of 0.75 µg/cm² originates from a study in which a formulation is used that may not be representative of the majority of Kojic Acid- containing; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat.","duration":"28-day","effect":"orption value used in SCCP/1182/08 comes from an explanatory study, using too few skin samples. The mean dermal absorption value was 3.63 µg/cm2 and the maximum value of 7.28 µg/cm², which was used for the calculation of the MoS by the SCCP. The applicant submitted a new in vitro dermal absorption study resulting in a much lower absorption rate (mean value of 0.75 µg/cm²). 2) The applicant considers the observed thyroid effects in the rats with Kojic Acid irrelevant for man and therefore suggests using a different NOAEL value. Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat. With the dermal absorption value of 0.75 µg/cm² instead of 7.28 µg/cm², the MoS values calculated by the applicant are 850 (face), 558 (hands) and 337 (face and hands). 1) Dermal absorption data The dermal absorption value of 0.75 µg/cm² originates from a study in which a formulation is used that may not be representative of the majority of Kojic Acid- containing","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":13,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_011"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	dermal absorption	6	mg/kg bw/day	rat	oral	28-day	dermal absorption	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat.; EFFECT=al absorption value was 3.63 µg/cm2 and the maximum value of 7.28 µg/cm², which was used for the calculation of the MoS by the SCCP. The applicant submitted a new in vitro dermal absorption study resulting in a much lower absorption rate (mean value of 0.75 µg/cm²). 2) The applicant considers the observed thyroid effects in the rats with Kojic Acid irrelevant for man and therefore suggests using a different NOAEL value. Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat. With the dermal absorption value of 0.75 µg/cm² instead of 7.28 µg/cm², the MoS values calculated by the applicant are 850 (face), 558 (hands) and 337 (face and hands). 1) Dermal absorption data The dermal absorption value of 0.75 µg/cm² originates from a study in which a formulation is used that may not be representative of the majority of Kojic Acid- containing formulations. As mentioned in chapter 3.2.2, it contains a high amount of silicones, polyols and nylon. In an; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat.","duration":"28-day","effect":"al absorption value was 3.63 µg/cm2 and the maximum value of 7.28 µg/cm², which was used for the calculation of the MoS by the SCCP. The applicant submitted a new in vitro dermal absorption study resulting in a much lower absorption rate (mean value of 0.75 µg/cm²). 2) The applicant considers the observed thyroid effects in the rats with Kojic Acid irrelevant for man and therefore suggests using a different NOAEL value. Nevertheless, in the proposed calculations, the applicant uses the thyroid-based 6 mg/kg bw/day NOAEL value of the 28-day oral study in the rat. With the dermal absorption value of 0.75 µg/cm² instead of 7.28 µg/cm², the MoS values calculated by the applicant are 850 (face), 558 (hands) and 337 (face and hands). 1) Dermal absorption data The dermal absorption value of 0.75 µg/cm² originates from a study in which a formulation is used that may not be representative of the majority of Kojic Acid- containing formulations. As mentioned in chapter 3.2.2, it contains a high amount of silicones, polyols and nylon. In an","endpoint":"dermal absorption","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":13,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_012"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	developmental toxicity	6	mg/kg bw/day	rat	-	developmental	developmental toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=SCCS overall conclusion on ED properties Based on histopathological findings and altered iodine uptake in rats, a NOAEL of 6 mg/kg bw/day remains appropriate for risk assessment of Kojic acid.; EFFECT=SCCS-rejected applicant NOAEL: perts, 1999). Taken together, the SCCS is of the opinion that changes in serum thyroid hormone levels observed in animal studies are evidence of endocrine effects and cannot be disregarded as such. Furthermore, safety assessment and/or regulatory decisions based on the endocrine effects in animals are protective for humans against down-stream (non-cancer) effects, such as developmental neurotoxicity. SCCS overall conclusion on ED properties Based on histopathological findings and altered iodine uptake in rats, a NOAEL of 6 mg/kg bw/day remains appropriate for risk assessment of Kojic acid. Based on the findings of several research groups, it is apparent that differences are being measured between rodents and humans with respect to sensitivity to thyroid toxicity. What this means in quantitative terms is not very clear and therefore the interpretation of the results remains rather speculative. According to the SCCS Notes of Guidance (SCCS/1628/21), in case of different susceptibility to HPT-axis disturbances in rats and humans,; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SCCS overall conclusion on ED properties Based on histopathological findings and altered iodine uptake in rats, a NOAEL of 6 mg/kg bw/day remains appropriate for risk assessment of Kojic acid.","duration":"developmental","effect":"SCCS-rejected applicant NOAEL: perts, 1999). Taken together, the SCCS is of the opinion that changes in serum thyroid hormone levels observed in animal studies are evidence of endocrine effects and cannot be disregarded as such. Furthermore, safety assessment and/or regulatory decisions based on the endocrine effects in animals are protective for humans against down-stream (non-cancer) effects, such as developmental neurotoxicity. SCCS overall conclusion on ED properties Based on histopathological findings and altered iodine uptake in rats, a NOAEL of 6 mg/kg bw/day remains appropriate for risk assessment of Kojic acid. Based on the findings of several research groups, it is apparent that differences are being measured between rodents and humans with respect to sensitivity to thyroid toxicity. What this means in quantitative terms is not very clear and therefore the interpretation of the results remains rather speculative. According to the SCCS Notes of Guidance (SCCS/1628/21), in case of different susceptibility to HPT-axis disturbances in rats and humans,","endpoint":"developmental toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":38,"route":"","species":"rat","study_id":"sccs_o_259_noael_017"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	genotoxicity	100	mg/kg/day	rat	-	4-week	genotoxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=100; DOSE=Acid _________________________________________________________________________________________ 7 counts were observed in male and female rats given 300 or 1000 mg/kg/day at the end of the 4-week treatment period.; EFFECT=Acid _________________________________________________________________________________________ 7 counts were observed in male and female rats given 300 or 1000 mg/kg/day at the end of the 4-week treatment period. These were partially reversed in males at the end of a treatment-free period of 2 weeks. Absolute and relative spleen weights were decreased in females at the highest dosage. No histopathological changes were associated with it. Based on the changes observed in lymphocytes and white blood cell counts a NOEL value of 100 mg/kg/day was established. Mutagenicity/Genotoxicity Overall, the genotoxicity program on Kojic Acid investigated the three endpoints of genotoxicity: gene mutations, structural chromosome aberrations and aneuploidy. Kojic Acid appeared to be mutagenic in the bacterial gene mutation assays, but these findings could neither be confirmed in the gene mutation test in hamster V79 cells (performed without S9-mix only) and in the mouse lymphoma assay at the hprt locus. Kojic Acid was clastogenic in two in; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Acid _________________________________________________________________________________________ 7 counts were observed in male and female rats given 300 or 1000 mg/kg/day at the end of the 4-week treatment period.","duration":"4-week","effect":"Acid _________________________________________________________________________________________ 7 counts were observed in male and female rats given 300 or 1000 mg/kg/day at the end of the 4-week treatment period. These were partially reversed in males at the end of a treatment-free period of 2 weeks. Absolute and relative spleen weights were decreased in females at the highest dosage. No histopathological changes were associated with it. Based on the changes observed in lymphocytes and white blood cell counts a NOEL value of 100 mg/kg/day was established. Mutagenicity/Genotoxicity Overall, the genotoxicity program on Kojic Acid investigated the three endpoints of genotoxicity: gene mutations, structural chromosome aberrations and aneuploidy. Kojic Acid appeared to be mutagenic in the bacterial gene mutation assays, but these findings could neither be confirmed in the gene mutation test in hamster V79 cells (performed without S9-mix only) and in the mouse lymphoma assay at the hprt locus. Kojic Acid was clastogenic in two in","endpoint":"genotoxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"100","page":7,"route":"","species":"rat","study_id":"sccs_o_098_noael_004"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	genotoxicity	2.38	µg/cm	human	dermal	-	genotoxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=2.38; EFFECT=roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c; CITATION=(Ref. 11); CITATION_NUMBERS=[11]; REFERENCE=(Ref. 11); DETAILS_JSON={"cas_number":"501-30-4","citation":"(Ref. 11)","dose":"","duration":"","effect":"roviding an average amount of 3.63 µg/cm² with a SD of 2.38 µg/cm² (highest value was 7.28 µg/cm²). As in the latest version of the Notes of Guidance (7th revision, SCCS/1416/11) it is stated that, when a dermal study has some shortcomings, the mean value plus 2SD should be used, the value taken into account for the calculation of the MoS becomes therefore 8.39 µg/cm² (mean dermal absorption is 3.63 and SD 2.38 µg/cm²) instead of the highest value, used in the earlier opinion (SCCP/1182/08). 2) The choice of the NO(A)EL The SCCS acknowledges that some thyroid effects are known to be rodent-specific. However, to give exclusion that the effects observed in this particular case are irrelevant for men and that Kojic Acid is not a thyroid tumour inducer, the original raw data with respect to genotoxicity/mutagenicity from 2006 are re-examined according to the current standards. In addition, the RIVM report (601516009) (Ref. 11) on the overall assessment of the relevance of thyroid effects observed in rodents for humans is taken into c","endpoint":"genotoxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"µg/cm","noael_value":"2.38","page":14,"route":"dermal","species":"human","study_id":"sccs_o_098_noael_013"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	irritation	100	mg/kg bw/day	rat	dermal	19 weeks	irritation	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100; DOSE=d weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally.; EFFECT=d weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resulting from depression of serum T3 and T4 levels. After dermal exposure for 28 consecutive days a NOAEL of 100 mg/kg bw/day could be derived for rats. A study on dermal toxicity in rabbits can not be evaluated due to bacterial infection of the testing animals. After application of 0.3% Kojic acid to the skin for 19 weeks body weight was significantly reduced in female mice. Irritation/Sensitisation Kojic acid was not irritant to rabbit skin or mucous membranes but slightly photoirritant. In the Guinea pig and in humans, Kojic acid was found to be a sensitizer. The substance was not photosensitising.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"d weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally.","duration":"19 weeks","effect":"d weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resulting from depression of serum T3 and T4 levels. After dermal exposure for 28 consecutive days a NOAEL of 100 mg/kg bw/day could be derived for rats. A study on dermal toxicity in rabbits can not be evaluated due to bacterial infection of the testing animals. After application of 0.3% Kojic acid to the skin for 19 weeks body weight was significantly reduced in female mice. Irritation/Sensitisation Kojic acid was not irritant to rabbit skin or mucous membranes but slightly photoirritant. In the Guinea pig and in humans, Kojic acid was found to be a sensitizer. The substance was not photosensitising.","endpoint":"irritation","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":70,"route":"dermal","species":"rat","study_id":"sccp_o_148_noael_025"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=62.5; DOSE=ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.; EFFECT=ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats; CITATION=Ref.: 32 Comment A NOAEL of 62; CITATION_NUMBERS=[32,62]; REFERENCE=Ref.: 32 Comment A NOAEL of 62; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 32 Comment A NOAEL of 62","dose":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","duration":"Sub-chronic","effect":"ation was low in rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 µg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. Ref.: 32 Comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 µg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 µg eq/ml. 3.3.5.2. Sub-chronic (90 days) oral / dermal / inhalation toxicity Guideline: / Species/strain: SD rats","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"62.5","page":22,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_005"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	0.003	%	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=0.003; DOSE=TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.; EFFECT=fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","duration":"subchronic","effect":"fected are the thyroid and the pituitary gland as well as the liver. An increase in thyroid weight was shown at doses above 0.125% Kojic acid in the diet given to male rats for 28 consecutive days. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"%","noael_value":"0.003","page":70,"route":"oral","species":"rat","study_id":"sccp_o_148_noael_023"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=15.5; DOSE=TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.; EFFECT=ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"TSH levels increased in a dose- and time-dependent manner after Kojic acid administration.","duration":"subchronic","effect":"ere reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% and a NOAEL of approximately 6 mg/kg bw/day can be derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week-feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered to 1.5% Kojic acid orally. Effects were more pronounced in males. It is obvious that thyroid proliferative lesions were induced by Kojic acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resultin","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"15.5","page":70,"route":"","species":"rat","study_id":"sccp_o_148_noael_024"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	23.8	mg/kg bw/day	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=23.8; DOSE=5% (95.3 mg/kg bw/day) Kojic Acid in the diet given to male rats for 28 consecutive days in a study specifically designed to study effects of Kojic Acid on the thyroid function.; EFFECT=5% (95.3 mg/kg bw/day) Kojic Acid in the diet given to male rats for 28 consecutive days in a study specifically designed to study effects of Kojic Acid on the thyroid function. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% (23.8 mg/kg bw/day) and a NOAEL of approximately 6 mg/kg bw/day was derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week- feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered 1.5% Kojic Acid orally. Effects were more pron; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"5% (95.3 mg/kg bw/day) Kojic Acid in the diet given to male rats for 28 consecutive days in a study specifically designed to study effects of Kojic Acid on the thyroid function.","duration":"subchronic","effect":"5% (95.3 mg/kg bw/day) Kojic Acid in the diet given to male rats for 28 consecutive days in a study specifically designed to study effects of Kojic Acid on the thyroid function. Reduced serum level of T3 and T4 were reported in several studies. TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% (23.8 mg/kg bw/day) and a NOAEL of approximately 6 mg/kg bw/day was derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week- feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered 1.5% Kojic Acid orally. Effects were more pron","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"23.8","page":6,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_001"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	15.5	mg/kg bw/day	rat	-	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=15.5; DOSE=TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration.; EFFECT=everal studies. TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% (23.8 mg/kg bw/day) and a NOAEL of approximately 6 mg/kg bw/day was derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week- feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered 1.5% Kojic Acid orally. Effects were more pronounced in males. From the available studies, it is obvious that thyroid proliferative lesions were induced by Kojic Acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituit; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration.","duration":"subchronic","effect":"everal studies. TSH levels increased in a dose- and time-dependent manner after Kojic Acid administration. In male rats the uptakes of 125I, as well as the numbers of colloid in thyroid follicles and follicular cell hypertrophy were significantly changed at 0.003% (23.8 mg/kg bw/day) and a NOAEL of approximately 6 mg/kg bw/day was derived with respect to these effects. These findings were affirmed by additional results from subchronic and chronic toxicity studies. With respect to hyperplasia and thyroid adenomas a NOAEL of 15.5 mg/kg bw/day was derived for male rats from a 20 week- feeding study. Increased thyroid weights as well as diffuse hypertrophy and hyperplasia of the follicular epithelial cells were also reported for female and male mice, administered 1.5% Kojic Acid orally. Effects were more pronounced in males. From the available studies, it is obvious that thyroid proliferative lesions were induced by Kojic Acid administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituit","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"15.5","page":6,"route":"","species":"rat","study_id":"sccs_o_098_noael_002"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.; EFFECT=id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat; CITATION=(Ref. 11); CITATION_NUMBERS=[11]; REFERENCE=(Ref. 11); DETAILS_JSON={"cas_number":"501-30-4","citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","duration":"28-day","effect":"id tumours observed in rats are not relevant for human carcinogenicity risk. In contrast to the risk of carcinogenicity, the disturbance of the hypothalamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for durat","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"6","page":14,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_014"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.; EFFECT=halamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for duration extrapolation (to extrapolate from subacute to subchronic exposure). As the newly introduced dermal absorption study is considered not to be repr; CITATION=(Ref. 11); CITATION_NUMBERS=[11]; REFERENCE=(Ref. 11); DETAILS_JSON={"cas_number":"501-30-4","citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","duration":"28-day","effect":"halamus-pituitary-thyroid (HPT) axis itself is considered to be toxicologically relevant for humans since regulation of thyroid function is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for duration extrapolation (to extrapolate from subacute to subchronic exposure). As the newly introduced dermal absorption study is considered not to be repr","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"6","page":14,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_015"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=6; DOSE=Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.; EFFECT=unction is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for duration extrapolation (to extrapolate from subacute to subchronic exposure). As the newly introduced dermal absorption study is considered not to be representative for the products present on the market (as explained above), the conservative dermal absorption of 8.39 µg/cm2 is take; CITATION=(Ref. 11); CITATION_NUMBERS=[11]; REFERENCE=(Ref. 11); DETAILS_JSON={"cas_number":"501-30-4","citation":"(Ref. 11)","dose":"Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account.","duration":"28-day","effect":"unction is comparable in rats and humans, although the latter are less susceptible to such disturbances. Therefore, disturbance of the HPT-axis is considered to be a hazard indicator for humans and should be taken into account when setting a NOAEL value. Upon expert judgement a reduced interspecies assessment factor could be taken into account (Ref. 11). This means that the conservative NOAEL of Kojic Acid derived from the 28-day oral study in rat still is used. Therefore, in the MOS calculation, the conservative NOAEL value of 6 mg/kg/day as obtained in the 28-day, oral rat study, focussing on the effects on the HPT-axis, is taken into account. As this value is derived from a subacute study, a default assessment factor of 3 is applied to correct for duration extrapolation (to extrapolate from subacute to subchronic exposure). As the newly introduced dermal absorption study is considered not to be representative for the products present on the market (as explained above), the conservative dermal absorption of 8.39 µg/cm2 is take","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg/day","noael_value":"6","page":14,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_016"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=0.079	mg/kg	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 0.079; DOSE=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...; EFFECT=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","duration":"28 days","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.079","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_017"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=6	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 6; DOSE=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...; EFFECT=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat,; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","duration":"28 days","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat,","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_018"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...; EFFECT=SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic ex...","duration":"28 days","effect":"SCCP/1481/12, 22.5.12 Opinion on Kojic Acid _________________________________________________________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_019"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=8.39	µg/cm	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 8.39; DOSE=______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...; EFFECT=______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOA...","duration":"28 days","effect":"______________________________________________ 15 Face Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 565 cm² Dermal absorption per treatment SAS x A x 0.001 = 4.11 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"µg/cm","noael_value":"= 8.39","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_020"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=0.12	mg/kg	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 0.120; DOSE=x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...; EFFECT=x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","duration":"28 days","effect":"x A x 0.001/60 = 0.079 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.120","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_021"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=6	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 6; DOSE=observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per tr...; EFFECT=observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No o; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per tr...","duration":"28 days","effect":"observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No o","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_022"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=6	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 6; DOSE=/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical...; EFFECT=/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to s; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical...","duration":"28 days","effect":"/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to s","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_023"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Syst...; EFFECT=observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchro; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Syst...","duration":"subchronic","effect":"observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchro","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_024"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	6-month	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=ronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adve...; EFFECT=ronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"ronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adve...","duration":"6-month","effect":"ronic study (6-month, rat, oral) Margin of Safety NOAEL / SED = 25.3 Hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 860 cm² Dermal absorption per treatment SAS x A x 0.001 = 6.28 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_025"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=0.199	mg/kg	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 0.199; DOSE=e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...; EFFECT=e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) =...","duration":"28 days","effect":"e (SED) SAS x A x 0.001/60 = 0.120 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg","noael_value":"= 0.199","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_026"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=6	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 6; DOSE=0 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per tr...; EFFECT=0 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"0 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per tr...","duration":"28 days","effect":"0 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_027"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=6	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 6; DOSE=OAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical...; EFFECT=OAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"OAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical...","duration":"28 days","effect":"OAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 6","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_028"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Sys...; EFFECT=, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":", oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Sys...","duration":"subchronic","effect":", oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_029"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=ed to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adv...; EFFECT=ed to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"ed to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adv...","duration":"subchronic","effect":"ed to subchronic study Margin of Safety NOAEL / SED = 16.7 Face and hands Maximum absorption through the skin A (μg/cm²) = 8.39 µg/cm² Skin Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_030"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	=2	mg/kg bw/d	rat	oral	28 days	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT== 2; DOSE=Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchron...; EFFECT=Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchron...","duration":"28 days","effect":"Area surface SAS (cm²) = 1425 cm² Dermal absorption per treatment SAS x A x 0.001 = 10.37 mg Typical body weight of human = 60 kg Systemic exposure dose (SED) SAS x A x 0.001/60 = 0.199 mg/kg No observed adverse effect level NOAEL = 6 mg/kg bw/d (28 days, rat, oral) No observed adverse effect level NOAEL/3 = 2 mg/kg bw/d extrapolated to subchronic study Margin of Safety NOAEL / SED = 10.1 In the MoS calculation (i) A conservative value for the dermal absorption is applied (mean plus 2 SD), (ii) A conservative NOAEL, derived from the disturbance of the HPT-axis in rats, is used, (iii) An extrapolation factor from subacute to subchronic exposure is used","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"= 2","page":15,"route":"oral","species":"rat","study_id":"sccs_o_098_noael_031"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	62.5	mg/kg bw/day	rat	oral	Sub-chronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=62.5; DOSE=n rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.; EFFECT=n rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 μg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24h was calculated to be 101.54 ± 19.35 μg eq/ml. (Higa et al., 2000) SCCS comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 μg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 μg eq/ml. 3.3.4.2 Sub-chronic (90 days) oral / dermal / inhalation toxicity From SCCP/1182/08 13 weeks of consecutive administration of Kojic acid in 1% aqueous solution of carboxymethylcellulose was performed in male SD rats (20 animals/group) by oral gavage at dose levels of 0, 250, 500, 1000, 2000, 3000 mg/kg bw/day, followed by 4 weeks treatment-free. After dose setting and co; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"n rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed.","duration":"Sub-chronic","effect":"n rats treated with 1000 mg/kg bw/day, no changes in TSH concentration were observed. None of these changes were found in the other groups except for a significant decrease in T3 level in week 1 at 250 mg/kg bw/day. Absorption of Kojic acid was rapid. Tmax of blood concentrations of radioactivity was 1.0 ± 0.0 hours with Cmax of 25.07 ± 4.56 μg eq/ml. T1/2 was 4.8 ± 0.3 hours. Elimination was nearly complete within 24 hours. AUC0-24h was calculated to be 101.54 ± 19.35 μg eq/ml. (Higa et al., 2000) SCCS comment A NOAEL of 62.5 mg/kg bw/day can be derived from this study. Cmax was 25.07 ± 4.56 μg eq/ml and AUC0-24 h was calculated to be 101.54 ± 19.35 μg eq/ml. 3.3.4.2 Sub-chronic (90 days) oral / dermal / inhalation toxicity From SCCP/1182/08 13 weeks of consecutive administration of Kojic acid in 1% aqueous solution of carboxymethylcellulose was performed in male SD rats (20 animals/group) by oral gavage at dose levels of 0, 250, 500, 1000, 2000, 3000 mg/kg bw/day, followed by 4 weeks treatment-free. After dose setting and co","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"62.5","page":27,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_007"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	23.8	mg/kg bw/day	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=23.8; DOSE=Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only.; EFFECT=ENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 29 (Ota et al., 2009) SCCS comment No new data was submitted or identified from the open literature. Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only. SCCS overall comment on repeated dose toxicity The SCCS agrees with the former Opinion that the most conservative NOAEL that could be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I and the changed numbers of colloid in thyroid follicles and of follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. 3.3.5 Reproductive toxicity 3.3.5.1 Fertility and reproduction toxicity From SCCP/1182/08 Kojic acid in 1% methylcellulose was administered in dose levels of 25, 150 or 900 mg/kg bw/day by oral gavage in CRL:COBS CD (SD; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only.","duration":"subchronic","effect":"ENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 29 (Ota et al., 2009) SCCS comment No new data was submitted or identified from the open literature. Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only. SCCS overall comment on repeated dose toxicity The SCCS agrees with the former Opinion that the most conservative NOAEL that could be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I and the changed numbers of colloid in thyroid follicles and of follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. 3.3.5 Reproductive toxicity 3.3.5.1 Fertility and reproduction toxicity From SCCP/1182/08 Kojic acid in 1% methylcellulose was administered in dose levels of 25, 150 or 900 mg/kg bw/day by oral gavage in CRL:COBS CD (SD","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"23.8","page":29,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_009"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg bw/day	rat	oral	subchronic	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only.; EFFECT=the open literature. Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only. SCCS overall comment on repeated dose toxicity The SCCS agrees with the former Opinion that the most conservative NOAEL that could be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I and the changed numbers of colloid in thyroid follicles and of follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. 3.3.5 Reproductive toxicity 3.3.5.1 Fertility and reproduction toxicity From SCCP/1182/08 Kojic acid in 1% methylcellulose was administered in dose levels of 25, 150 or 900 mg/kg bw/day by oral gavage in CRL:COBS CD (SD) BR rats (20 per group). The control group received the vehicle alone. At 900 mg/kg bw/day treatment was associated with behaviour changes. Males appeared more affected than females. Brown staining of fur was described as well as dark coloration of urine samples from males dur; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only.","duration":"subchronic","effect":"the open literature. Studies on repeated dose, i.e. subchronic and chronic oral toxicity, were performed with male rats only. SCCS overall comment on repeated dose toxicity The SCCS agrees with the former Opinion that the most conservative NOAEL that could be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I and the changed numbers of colloid in thyroid follicles and of follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. 3.3.5 Reproductive toxicity 3.3.5.1 Fertility and reproduction toxicity From SCCP/1182/08 Kojic acid in 1% methylcellulose was administered in dose levels of 25, 150 or 900 mg/kg bw/day by oral gavage in CRL:COBS CD (SD) BR rats (20 per group). The control group received the vehicle alone. At 900 mg/kg bw/day treatment was associated with behaviour changes. Males appeared more affected than females. Brown staining of fur was described as well as dark coloration of urine samples from males dur","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":29,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_010"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg bw/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=3.4 SAFETY EVALUATION (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY The calculation of the systemic exposure dose (SED) was carried out using data from a clinical percutaneous absorption study, as described in section 3.2.4.; EFFECT=the ability to act as an immunomodulatory agent. (Da Costa et al., 2018) SCCS comment Studies on the immunomodulatory potential of Kojic acid are of limited importance to the overall risk assessment of the substance. 3.4 SAFETY EVALUATION (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY The calculation of the systemic exposure dose (SED) was carried out using data from a clinical percutaneous absorption study, as described in section 3.2.4. As point of departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1). Since the point of departure is based on a subacute 28- day study, an additional assessment factor of 3 was added to the risk assessment to extrapolate to a subchronic 90-day study, in accordance with the SCCS Notes of Guidance (SCCS/1628/21). Furthermore, as Kojic acid is well absorbed after oral exposure, no correction for oral bioavailability is used, resulting in an adjusted NOAEL of 2 mg/kg bw/day. Following MoS c; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"3.4 SAFETY EVALUATION (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY The calculation of the systemic exposure dose (SED) was carried out using data from a clinical percutaneous absorption study, as described in section 3.2.4.","duration":"28-day","effect":"the ability to act as an immunomodulatory agent. (Da Costa et al., 2018) SCCS comment Studies on the immunomodulatory potential of Kojic acid are of limited importance to the overall risk assessment of the substance. 3.4 SAFETY EVALUATION (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY The calculation of the systemic exposure dose (SED) was carried out using data from a clinical percutaneous absorption study, as described in section 3.2.4. As point of departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1). Since the point of departure is based on a subacute 28- day study, an additional assessment factor of 3 was added to the risk assessment to extrapolate to a subchronic 90-day study, in accordance with the SCCS Notes of Guidance (SCCS/1628/21). Furthermore, as Kojic acid is well absorbed after oral exposure, no correction for oral bioavailability is used, resulting in an adjusted NOAEL of 2 mg/kg bw/day. Following MoS c","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":39,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_018"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	2	mg/kg bw/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2; DOSE=f departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1).; EFFECT=f departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1). Since the point of departure is based on a subacute 28- day study, an additional assessment factor of 3 was added to the risk assessment to extrapolate to a subchronic 90-day study, in accordance with the SCCS Notes of Guidance (SCCS/1628/21). Furthermore, as Kojic acid is well absorbed after oral exposure, no correction for oral bioavailability is used, resulting in an adjusted NOAEL of 2 mg/kg bw/day. Following MoS calculations for separate product types and aggregated exposure can be calculated:; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"f departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1).","duration":"28-day","effect":"f departure for risk assessment, a NOAEL of 6 mg/kg bw/day, based on a 28-day oral repeated dose rat study is used (see section 3.3.4.1). Since the point of departure is based on a subacute 28- day study, an additional assessment factor of 3 was added to the risk assessment to extrapolate to a subchronic 90-day study, in accordance with the SCCS Notes of Guidance (SCCS/1628/21). Furthermore, as Kojic acid is well absorbed after oral exposure, no correction for oral bioavailability is used, resulting in an adjusted NOAEL of 2 mg/kg bw/day. Following MoS calculations for separate product types and aggregated exposure can be calculated:","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"2","page":39,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_019"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	2600	mg/kg bw	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=2600; DOSE=Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.; EFFECT=w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure.","duration":"28-day","effect":"w data were submitted or identified. Acute toxicity of Kojic acid is low. Mean LD50 values for oral administration are 1800 or > 2000 mg/kg bw for rats and 5100 mg/kg bw for mice, 2600 or 2700 mg/kg bw after subcutaneous application in rats or mice, respectively and > 2000 mg/kg bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce m","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw","noael_value":"2600","page":41,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_021"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	repeated dose toxicity	6	mg/kg bw/day	rat	oral	28-day	repeated dose toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=6; DOSE=For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice.; EFFECT=bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mi; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice.","duration":"28-day","effect":"bw for rats after dermal exposure. For intraperitoneal administration the mean LD50 is 2400 mg/kg bw for rats and 2600 mg/kg bw for mice. Repeated dose toxicity No new repeated dose data were submitted or identified. The most conservative NOAEL that can be identified from repeated dose studies with Kojic acid is based on the reduced uptake of 125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mi","endpoint":"repeated dose toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"6","page":41,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_022"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	150	mg/kg bw/day	rat	-	21 days	reproductive toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=150; DOSE=A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.; EFFECT=SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study.","duration":"21 days","effect":"SCCP/1182/08 Opinion on kojic acid 59 Sialodacryoadenitis infection was observed among males and females in all groups starting during their acclimatisation periods. A NOAEL of 150 mg/kg bw/day for parental- and embryotoxicity can be derived from this study. Study 2 Guideline: / Species/strain: Sprague Dawley rats Group size: 7 males for control, 8 males for treatment groups Test substance: Kojic acid Batch: / Purity: / Dose levels: 50 µg/day in propylene glycol Treatment period: 21 days GLP: / Male rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 µg/rat/day for 21 days. The control group received pro","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"150","page":59,"route":"","species":"rat","study_id":"sccp_o_148_noael_008"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	30	mg/kg bw/day	mouse	-	-	reproductive toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=30; DOSE=Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.; EFFECT=ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.; CITATION=Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study; CITATION_NUMBERS=[41,30]; REFERENCE=Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study; DETAILS_JSON={"cas_number":"501-30-4","citation":"Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study","dose":"Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day.","duration":"","effect":"ation index and fertility index of the offspring in the reproduction study performed at week 11 after birth (1 male and 1 female F1 mouse per litter) were unaffected in any of the treatment groups. Changes were a smaller number of live male foetuses at 30 mg/kg bw/day and a significant and dose-dependent higher placental weight at 160 and 800 mg/kg bw/day. At 800 mg/kg bw/day F1 dams showed significantly decreased body weights, thymus and liver weights. No changes were observed for F2 foetuses. Ref.: 41 Comment A NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"30","page":61,"route":"","species":"mouse","study_id":"sccp_o_148_noael_010"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	100	mg/kg bw/day	rat	-	1 to day	reproductive toxicity	SOURCE_SUBDIR=sccp_o_148; REPORT_TITLE=OPINION ON Kojic acid; OPINION_NUMBER=SCCP/1182/08; COMMITTEE=Scientific Committee on Consumer Products (SCCP); REPORT_DATE=30 September 2008; VALUE_TEXT=100 to 150; DOSE=NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.; EFFECT=less sensitive than rodents with regard to perturbation of thyroid hormone homeostasis but it is not clear if these species differences are of qualitative or quantitative nature. Despite these comments, a threshold on the basis of hormonal disruption can be assumed. Reproductive toxicity Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 µg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Kinetics and safety assessment Kojic acid is rapid; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.","duration":"1 to day","effect":"less sensitive than rodents with regard to perturbation of thyroid hormone homeostasis but it is not clear if these species differences are of qualitative or quantitative nature. Despite these comments, a threshold on the basis of hormonal disruption can be assumed. Reproductive toxicity Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 µg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Kinetics and safety assessment Kojic acid is rapid","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100 to 150","page":72,"route":"","species":"rat","study_id":"sccp_o_148_noael_027"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	100	mg/kg bw/day	rat	-	1 to day	reproductive toxicity	SOURCE_SUBDIR=sccs_o_098; REPORT_TITLE=OPINION ON Kojic Acid; OPINION_NUMBER=SCCS/1481/12; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=adopted 30 September 2008; VALUE_TEXT=100 to 150; DOSE=NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.; EFFECT=less sensitive than rodents with regard to perturbation of thyroid hormone homeostasis but it is not clear if these species differences are of qualitative or quantitative nature. Despite these comments, a threshold on the basis of hormonal disruption can be assumed. Reproductive toxicity Kojic Acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameters and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 µg Kojic Acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Toxicokinetics Toxicokinetic studies with the rat; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.","duration":"1 to day","effect":"less sensitive than rodents with regard to perturbation of thyroid hormone homeostasis but it is not clear if these species differences are of qualitative or quantitative nature. Despite these comments, a threshold on the basis of hormonal disruption can be assumed. Reproductive toxicity Kojic Acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameters and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 µg Kojic Acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Toxicokinetics Toxicokinetic studies with the rat","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100 to 150","page":8,"route":"","species":"rat","study_id":"sccs_o_098_noael_006"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	30	mg/kg bw/day	rat	-	21 days	reproductive toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=30; DOSE=The SCCP commented that a NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.; EFFECT=SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 31 foetuses. The SCCP commented that a NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study. (Mineshita, 1983) Male Sprague Dawley rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 μg/rat/day for 21 days. The control group (7 males) received propylene glycol alone. Fertility performance of the individual rat was studied from day 16 to day 21 of treatment. Each male (8 per group) was caged separately with two females of proven ferti; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"The SCCP commented that a NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study.","duration":"21 days","effect":"SCCS/1637/21 Final version & CORRIGENDUM Opinion on Kojic acid ___________________________________________________________________________________________ _________________________________________________________________________ 31 foetuses. The SCCP commented that a NOAEL of 30 mg/kg bw/day for maternal toxicity and for embryotoxicity can be derived from this study. (Mineshita, 1983) Male Sprague Dawley rats (150 – 200 g bw) of proven fertility were orally administered a suspension of Kojic acid in propylene glycol at a dose of 50 μg/rat/day for 21 days. The control group (7 males) received propylene glycol alone. Fertility performance of the individual rat was studied from day 16 to day 21 of treatment. Each male (8 per group) was caged separately with two females of proven ferti","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"30","page":31,"route":"","species":"rat","study_id":"sccs_o_259_noael_013"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	100	mg/kg bw/day	rat	-	-	reproductive toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100; DOSE=This finding was not considered test substance related, since the effect was not dose-dependent.; EFFECT=SCCS-rejected applicant NOAEL: implantation loss (24.3 versus 0%). This finding was not considered test substance related, since the effect was not dose-dependent. The number of foetuses per female was reduced at 300 and 1000 mg/kg bw/day compared to the control group but values were not significant (8.5 and 10.8 versus 12.2, respectively). No post-implantation loss occurred in any group. The test substance did furthermore not influence body weight or sex ration of foetuses. No malformations or anomalies were observed. It was concluded that the NOAEL for maternal toxicity, embryo- and foetotoxicity is 100 mg/kg bw/day under the experimental conditions chosen. The SCCP commented that only six females per group were investigated. (Richard, 1998) SCCS comment No new data was submitted or identified from the open literature. SCCS overall comment on reproductive toxicity The SCCS agrees with the former Opinion that Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effec; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"This finding was not considered test substance related, since the effect was not dose-dependent.","duration":"","effect":"SCCS-rejected applicant NOAEL: implantation loss (24.3 versus 0%). This finding was not considered test substance related, since the effect was not dose-dependent. The number of foetuses per female was reduced at 300 and 1000 mg/kg bw/day compared to the control group but values were not significant (8.5 and 10.8 versus 12.2, respectively). No post-implantation loss occurred in any group. The test substance did furthermore not influence body weight or sex ration of foetuses. No malformations or anomalies were observed. It was concluded that the NOAEL for maternal toxicity, embryo- and foetotoxicity is 100 mg/kg bw/day under the experimental conditions chosen. The SCCP commented that only six females per group were investigated. (Richard, 1998) SCCS comment No new data was submitted or identified from the open literature. SCCS overall comment on reproductive toxicity The SCCS agrees with the former Opinion that Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effec","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":32,"route":"","species":"rat","study_id":"sccs_o_259_noael_015"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	100	mg/kg bw/day	rat	-	1 to day	reproductive toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100 to 150; DOSE=NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.; EFFECT=xperimental conditions chosen. The SCCP commented that only six females per group were investigated. (Richard, 1998) SCCS comment No new data was submitted or identified from the open literature. SCCS overall comment on reproductive toxicity The SCCS agrees with the former Opinion that Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour of mothers was reported after delivery in two studies where rats received 50 μg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation (females). This effect, however, was not reported by other authors and its relevance is unclear. 3.3.6 Mutagenicity / genotoxicity 3.3.6; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice.","duration":"1 to day","effect":"xperimental conditions chosen. The SCCP commented that only six females per group were investigated. (Richard, 1998) SCCS comment No new data was submitted or identified from the open literature. SCCS overall comment on reproductive toxicity The SCCS agrees with the former Opinion that Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour of mothers was reported after delivery in two studies where rats received 50 μg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation (females). This effect, however, was not reported by other authors and its relevance is unclear. 3.3.6 Mutagenicity / genotoxicity 3.3.6","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100 to 150","page":32,"route":"","species":"rat","study_id":"sccs_o_259_noael_016"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies	reproductive toxicity	100	mg/kg bw/day	rat	oral	28-day	reproductive toxicity	SOURCE_SUBDIR=sccs_o_259; REPORT_TITLE=OPINION on Kojic acid - CORRIGENDUM -; OPINION_NUMBER=SCCS/1637/21; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=16 March 2022; VALUE_TEXT=100 to 150; DOSE=125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day.; EFFECT=125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 μg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Mutagenicity / genotoxicity/photomutagenicity/pho; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"501-30-4","citation":"","dose":"125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day.","duration":"28-day","effect":"125I, as well as the changed amount of colloid in thyroid follicles and follicular cell hypertrophy at a dose level of 23.8 mg/kg bw/day in rats (28-day, oral), leading to a NOAEL of 6 mg/kg bw/day. Reproductive toxicity No new data were submitted or identified for reproductive toxicity. Kojic acid showed no effects on fertility of rats and mice in various one-generation studies. The test substance did not induce malformations. Effects observed were changes in litter parameter and organ weights in the offspring. NOAEL values for maternal toxicity as well as for embryotoxicity are in the range of 100 to 150 mg/kg bw/day for rats, at 100 mg/kg bw/day for rabbits and at 30 mg/kg bw/day for mice. Cannibalistic behaviour during lactation period was reported in two studies for rats who received 50 μg Kojic acid daily for 21 consecutive days before mating (males) or from day 1 to day 5 of gestation. This effect, however, was not reported by other authors and its relevance is unclear. Mutagenicity / genotoxicity/photomutagenicity/pho","endpoint":"reproductive toxicity","ingredient":"Kojic acid","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100 to 150","page":41,"route":"oral","species":"rat","study_id":"sccs_o_259_noael_023"}

openFDA substances 4 endpoints

Source	Endpoint Type	Value	Unit	Species	Route	Duration	Study Type	Reference
openFDA substances	FDA UNII substance identifier	6K23F1TT52	UNII	-	-	-	chemical	{"approval_status":null,"molecular_formula":"C6H6O4","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"6K23F1TT52"}
openFDA substances	FDA UNII substance identifier	6K23F1TT52	UNII	-	-	-	chemical	{"approval_status":null,"molecular_formula":"C6H6O4","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"6K23F1TT52"}
openFDA substances	FDA UNII substance identifier	6K23F1TT52	UNII	-	-	-	chemical	{"approval_status":null,"molecular_formula":"C6H6O4","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"6K23F1TT52"}
openFDA substances	FDA UNII substance identifier	6K23F1TT52	UNII	-	-	-	chemical	{"approval_status":null,"molecular_formula":"C6H6O4","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"6K23F1TT52"}