NOAEL Studies
Active Ingredient
Alpha-Arbutin NOAEL Studies
INCI: ALPHA-ARBUTIN
CAS: 84380-01-8
Raw No Observed Adverse Effect Level endpoint records grouped by source. This page does not render calculated Margin of Safety values.
SCCS_vision_codex 88 endpoints
| Source | Endpoint Type | Value | Unit | Species | Route | Duration | Study Type | Reference |
|---|---|---|---|---|---|---|---|---|
| SCCS_vision_codex | NOAEL | =29 | - | - | oral | 14 days | repeated dose toxicity | {"citation":"Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_001"} |
| SCCS_vision_codex | NOAEL | =3.3 | - | guinea pig | oral | Sub-chronic | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_002"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg/day | rat | oral | 28d | NOAEL study | {"dose":"3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","effect":"ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","page":37,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_003"} |
| SCCS_vision_codex | NOAEL | =74 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_004"} |
| SCCS_vision_codex | NOAEL | =25 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_005"} |
| SCCS_vision_codex | NOAEL | =75 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_006"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_007"} |
| SCCS_vision_codex | NOAEL | =56 | - | - | dermal | 14-day | repeated dose toxicity | {"dose":"56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:","effect":"exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_008"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.","effect":"k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_009"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_010"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_012"} |
| SCCS_vision_codex | NOAEL | >250 | mg/kg bw | rat | oral | 14-day | repeated dose toxicity | {"dose":"Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","effect":"SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the","page":42,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_013"} |
| SCCS_vision_codex | NOAEL | =20 | % | guinea pig | dermal | 14-day | irritation | {"effect":"SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.","page":43,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_015"} |
| SCCS_vision_codex | NOAEL | =150 | mg/kg/day | rat | - | - | reproductive toxicity | {"dose":"NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_021"} |
| SCCS_vision_codex | NOAEL | =9 | - | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9)","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_022"} |
| SCCS_vision_codex | NOAEL | =2 | % | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_024"} |
| SCCS_vision_codex | NOAEL | =344 | - | rat | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_025"} |
| SCCS_vision_codex | NOAEL | =1550 | - | rat | oral | 28-day | repeated dose toxicity | {"dose":"SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.","effect":"SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_001"} |
| SCCS_vision_codex | NOAEL | =1000 | mg/kg bw/day | rat | oral | 28-day | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...","effect":"ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_002"} |
| SCCS_vision_codex | NOAEL | =100 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","effect":". 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.","page":42,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_003"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_005"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_006"} |
| SCCS_vision_codex | NOAEL | =29 | - | - | oral | 14 days | repeated dose toxicity | {"citation":"Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_001"} |
| SCCS_vision_codex | NOAEL | =3.3 | - | guinea pig | oral | Sub-chronic | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_002"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg/day | rat | oral | 28d | NOAEL study | {"dose":"3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","effect":"ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","page":37,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_003"} |
| SCCS_vision_codex | NOAEL | =74 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_004"} |
| SCCS_vision_codex | NOAEL | =25 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_005"} |
| SCCS_vision_codex | NOAEL | =75 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_006"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_007"} |
| SCCS_vision_codex | NOAEL | =56 | - | - | dermal | 14-day | repeated dose toxicity | {"dose":"56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:","effect":"exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_008"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.","effect":"k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_009"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_010"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_012"} |
| SCCS_vision_codex | NOAEL | >250 | mg/kg bw | rat | oral | 14-day | repeated dose toxicity | {"dose":"Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","effect":"SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the","page":42,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_013"} |
| SCCS_vision_codex | NOAEL | =20 | % | guinea pig | dermal | 14-day | irritation | {"effect":"SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.","page":43,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_015"} |
| SCCS_vision_codex | NOAEL | =150 | mg/kg/day | rat | - | - | reproductive toxicity | {"dose":"NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_021"} |
| SCCS_vision_codex | NOAEL | =9 | - | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9)","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_022"} |
| SCCS_vision_codex | NOAEL | =2 | % | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_024"} |
| SCCS_vision_codex | NOAEL | =344 | - | rat | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_025"} |
| SCCS_vision_codex | NOAEL | =29 | - | - | oral | 14 days | repeated dose toxicity | {"citation":"Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_001"} |
| SCCS_vision_codex | NOAEL | =3.3 | - | guinea pig | oral | Sub-chronic | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_002"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg/day | rat | oral | 28d | NOAEL study | {"dose":"3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","effect":"ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","page":37,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_003"} |
| SCCS_vision_codex | NOAEL | =74 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_004"} |
| SCCS_vision_codex | NOAEL | =25 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_005"} |
| SCCS_vision_codex | NOAEL | =75 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_006"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_007"} |
| SCCS_vision_codex | NOAEL | =56 | - | - | dermal | 14-day | repeated dose toxicity | {"dose":"56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:","effect":"exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_008"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.","effect":"k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_009"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_010"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_012"} |
| SCCS_vision_codex | NOAEL | >250 | mg/kg bw | rat | oral | 14-day | repeated dose toxicity | {"dose":"Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","effect":"SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the","page":42,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_013"} |
| SCCS_vision_codex | NOAEL | =20 | % | guinea pig | dermal | 14-day | irritation | {"effect":"SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.","page":43,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_015"} |
| SCCS_vision_codex | NOAEL | =150 | mg/kg/day | rat | - | - | reproductive toxicity | {"dose":"NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_021"} |
| SCCS_vision_codex | NOAEL | =9 | - | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9)","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_022"} |
| SCCS_vision_codex | NOAEL | =2 | % | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_024"} |
| SCCS_vision_codex | NOAEL | =344 | - | rat | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_025"} |
| SCCS_vision_codex | NOAEL | =1550 | - | rat | oral | 28-day | repeated dose toxicity | {"dose":"SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.","effect":"SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_001"} |
| SCCS_vision_codex | NOAEL | =1000 | mg/kg bw/day | rat | oral | 28-day | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...","effect":"ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_002"} |
| SCCS_vision_codex | NOAEL | =100 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","effect":". 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.","page":42,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_003"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_005"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_006"} |
| SCCS_vision_codex | NOAEL | =1550 | - | rat | oral | 28-day | repeated dose toxicity | {"dose":"SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.","effect":"SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_001"} |
| SCCS_vision_codex | NOAEL | =1000 | mg/kg bw/day | rat | oral | 28-day | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...","effect":"ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_002"} |
| SCCS_vision_codex | NOAEL | =100 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","effect":". 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.","page":42,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_003"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_005"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_006"} |
| SCCS_vision_codex | NOAEL | =29 | - | - | oral | 14 days | repeated dose toxicity | {"citation":"Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_001"} |
| SCCS_vision_codex | NOAEL | =3.3 | - | guinea pig | oral | Sub-chronic | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","effect":"on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","page":29,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_002"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg/day | rat | oral | 28d | NOAEL study | {"dose":"3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","effect":"ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","page":37,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_003"} |
| SCCS_vision_codex | NOAEL | =74 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_004"} |
| SCCS_vision_codex | NOAEL | =25 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_005"} |
| SCCS_vision_codex | NOAEL | =75 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_006"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg/day | rat | oral | 28d | reproductive toxicity | {"dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_007"} |
| SCCS_vision_codex | NOAEL | =56 | - | - | dermal | 14-day | repeated dose toxicity | {"dose":"56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:","effect":"exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_008"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.","effect":"k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain","page":40,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_009"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_010"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw | - | oral | - | carcinogenicity | {"dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","effect":"and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application","page":41,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_012"} |
| SCCS_vision_codex | NOAEL | >250 | mg/kg bw | rat | oral | 14-day | repeated dose toxicity | {"dose":"Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","effect":"SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the","page":42,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_013"} |
| SCCS_vision_codex | NOAEL | =20 | % | guinea pig | dermal | 14-day | irritation | {"effect":"SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.","page":43,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_015"} |
| SCCS_vision_codex | NOAEL | =150 | mg/kg/day | rat | - | - | reproductive toxicity | {"dose":"NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_021"} |
| SCCS_vision_codex | NOAEL | =9 | - | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9)","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_022"} |
| SCCS_vision_codex | NOAEL | =2 | % | - | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_024"} |
| SCCS_vision_codex | NOAEL | =344 | - | rat | - | - | NOAEL study | {"effect":"Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the","page":38,"pdf":"sccs_o_176.pdf","row_type":"noael_study","study_id":"sccs_o_176_noael_025"} |
| SCCS_vision_codex | NOAEL | =1550 | - | rat | oral | 28-day | repeated dose toxicity | {"dose":"SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.","effect":"SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_001"} |
| SCCS_vision_codex | NOAEL | =1000 | mg/kg bw/day | rat | oral | 28-day | repeated dose toxicity | {"dose":"Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...","effect":"ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l","page":37,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_002"} |
| SCCS_vision_codex | NOAEL | =100 | mg/kg bw/day | - | dermal | - | NOAEL study | {"dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","effect":". 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.","page":42,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_003"} |
| SCCS_vision_codex | NOAEL | =20 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_005"} |
| SCCS_vision_codex | NOAEL | =15 | mg/kg bw/d | - | - | - | repeated dose toxicity | {"dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","effect":"Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","page":43,"pdf":"sccs_o_264.pdf","row_type":"noael_study","study_id":"sccs_o_264_noael_006"} |
UnifiedCodex:SCCS_SHADOW:beta.noael_studies 31 endpoints
| Source | Endpoint Type | Value | Unit | Species | Route | Duration | Study Type | Reference |
|---|---|---|---|---|---|---|---|---|
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | =20 | mg/kg/day | rat | oral | 28d | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 20; DOSE=3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day; EFFECT=ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","duration":"28d","effect":"ggest that the α-glycosidic linkage plays an important role in the inhibitory effect (13, 17). The effect of alpha-Arbutin on reduced skin pigmentation seems not to be due to inhibition of cell growth or decreased tyrosinase gene transcription, but rather to the inhibition of the enzyme at protein level (16). 3.3.13 Information on the toxicity of hydroquinone Taken in part from the SCCP/1158/08 Opinion and updated in SCCS/1550/2015 LD50-oral-rat = 298 mg/kg Slightly irritating to the eye Sensitising to the skin NOEL (28d/90d-oral-rat) = 20 mg/kg/day","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 20","page":37,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_003"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 20 | mg/kg bw/day | - | dermal | - | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=20; DOSE=624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.; EFFECT=k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived.","duration":"","effect":"k assessment requires compound-specific toxicity data” when applying the TTC decision tree. Alternatively, it can be hypothesized that the systemic toxicity of alpha-arbutin is mainly due to hydroquinone formation in the body. Based on the worst-case assumption of complete cleavage, based on the SED of max. 624 µg/person/day corrected for molecular weight (624 µg alpha-arbutin x 110.11 / 272.25 = 252 µg hydroquinone) and a body weight of 60 kg a dose of 4.2 µg/kg bw/day hydroquinone can be derived. Compared to the NOEL of hydroquinone of 20 mg/kg bw/day a margin of safety of 4800 is calculated. Further safety considerations will focus on ingredient-related topical exposure to hydroquinone, taking into account information on the stability and metabolic fate of alpha- arbutin in and on skin, to estimate hydroquinone release. Safety evaluation for hydroquinone Background information on the toxicity of hydroquinone is provided in section 3.3.13 of this opinion. Exposure to hydroquinone (HQ) from application of alpha-arbutin contain","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"20","page":40,"route":"dermal","species":"","study_id":"sccs_o_176_noael_009"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | =20 | mg/kg/day | rat | oral | 28d | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 20; DOSE=NOEL (28d/90d-oral-rat) = 20 mg/kg/day; EFFECT=Unlabeled table on page 37: NOEL (28d/90d-oral-rat) = 20 mg/kg/day; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOEL (28d/90d-oral-rat) = 20 mg/kg/day","duration":"28d","effect":"Unlabeled table on page 37: NOEL (28d/90d-oral-rat) = 20 mg/kg/day","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 20","page":37,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_016"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | =74 | mg/kg/day | rat | dermal | 28d | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 74; DOSE=NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day; EFFECT=Unlabeled table on page 38: NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day","duration":"28d","effect":"Unlabeled table on page 38: NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 74","page":38,"route":"dermal","species":"rat","study_id":"sccs_o_176_noael_017"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | =15 | mg/kg/day | rat | - | - | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 15; DOSE=NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity).; EFFECT=Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity).; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity).","duration":"","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity).","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 15","page":38,"route":"","species":"rat","study_id":"sccs_o_176_noael_020"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 9 | - | - | - | - | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=Positive in the in vitro chromosome aberration test (+S9); EFFECT=Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9); CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 38: Positive in the in vitro chromosome aberration test (+S9)","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"","noael_value":"Positive in the in vitro chromosome aberration test (+S9)","page":38,"route":"","species":"","study_id":"sccs_o_176_noael_022"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 2 | % | - | - | - | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=2; EFFECT=Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 38: Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"%","noael_value":"2","page":38,"route":"","species":"","study_id":"sccs_o_176_noael_024"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 344 | - | rat | - | - | - | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=sensitive strain of animals (male F344 rat) has been postulated to be involved in the; EFFECT=Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"","duration":"","effect":"Unlabeled table on page 38: sensitive strain of animals (male F344 rat) has been postulated to be involved in the","endpoint":"","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"","noael_value":"sensitive strain of animals (male F344 rat) has been postulated to be involved in the","page":38,"route":"","species":"rat","study_id":"sccs_o_176_noael_025"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 100 | mg/kg bw/day | - | dermal | - | - | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=100; DOSE=In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).; EFFECT=. 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","duration":"","effect":". 3.4.2.2. SCCS comments on the safety evaluation of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin.","endpoint":"","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":42,"route":"dermal","species":"","study_id":"sccs_o_264_noael_003"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | - | 100 | mg/kg bw/day | - | dermal | - | - | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=100; DOSE=In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).; EFFECT=on of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin. The exposure to hydroquinone from each of these; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015).","duration":"","effect":"on of beta-arbutin by the applicant after the commenting period As no new data have been submitted by the applicant for beta-arbutin, calculations can only be done for beta-arbutin and for aggregate exposure of both arbutins, using for beta-arbutin the numbers as present in the SCCS opinion 2015. The maximum exposure to beta-arbutin is 6.8 μg/kg bw/day (SCCS 2015). In the reproduction toxicity study with subcutaneous administration of beta-arbutin, the conservative NOAEL was 100 mg/kg bw/day (SCCS 2015). If this NOAEL is applied, the MoS is 14700. 3.4.3 Hydroquinone 3.4.3.1. Safety evaluation of hydroquinone submitted by applicant during the commenting period ALPHA-ARBUTIN The exposure to hydroquinone via alpha- and/or beta-arbutin can occur via: 1. Cleavage of alpha- or beta-arbutin to hydroquinone in skin upon dermal penetration; 2. Hydroquinone as an impurity of alpha- or beta-arbutin; 3. Formation of hydroquinone from alpha- or beta-arbutin by skin microbiome on the skin. The exposure to hydroquinone from each of these","endpoint":"","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":42,"route":"dermal","species":"","study_id":"sccs_o_264_noael_004"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | carcinogenicity | 20 | mg/kg bw | - | oral | - | carcinogenicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=20; DOSE=Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:; EFFECT=an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","duration":"","effect":"an add 135 µg HQ (external amount) and use 50% dermal absorption for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with product","endpoint":"carcinogenicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw","noael_value":"20","page":41,"route":"oral","species":"","study_id":"sccs_o_176_noael_010"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | carcinogenicity | 20 | mg/kg bw | - | oral | - | carcinogenicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=20; DOSE=Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:; EFFECT=n for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may c; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","duration":"","effect":"n for HQ, resulting in an extra 68 µg HQ per day. Below the exposure to hydroquinone from application of alpha-arbutin containing products (sum of a) and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may c","endpoint":"carcinogenicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw","noael_value":"20","page":41,"route":"oral","species":"","study_id":"sccs_o_176_noael_011"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | carcinogenicity | 15 | mg/kg bw | - | oral | - | carcinogenicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=15; DOSE=Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:; EFFECT=and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test:","duration":"","effect":"and b) above) is assessed and compared to risks related to 1.) repeated toxicity, 2.) induction of ochronosis and 3.) carcinogenicity. Internal exposure of 190 µg HQ-equivalents per person/day divided by 60 kg results in an SED of 3.166 µg/kg bw/day or 0.00317 mg/kg bodyweight 1.) HQ repeated toxicity NOEL from repeated oral toxicity test: 20 mg/kg bw MOS 6309 NOEL from 2-generation reprotoxicity test: 15 mg/kg bw MOS 4731 2.) HQ induction of ochronosis HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established for exogenous ochronosis (EO), the lowest effect level described in a case report was used to calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as the minimum exposure level of HQ causing EO since no publication available suggests EO with products formulated with 1% or less HQ. Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day [1 x 0.8 x 1000 x 2 x 50 / 100 x 100] – lowest concentration in product 1% – maximum quantity of application","endpoint":"carcinogenicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw","noael_value":"15","page":41,"route":"oral","species":"","study_id":"sccs_o_176_noael_012"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | carcinogenicity | 25 | mg/kg/day | - | - | - | carcinogenicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=25; DOSE=Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day.; EFFECT=Unlabeled table on page 38: Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day.","duration":"","effect":"Unlabeled table on page 38: Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day.","endpoint":"carcinogenicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"25","page":38,"route":"","species":"","study_id":"sccs_o_176_noael_023"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | developmental toxicity | =25 | mg/kg/day | rabbit | - | developmental | developmental toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 25; DOSE=NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams); EFFECT=Unlabeled table on page 38: NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams); CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams)","duration":"developmental","effect":"Unlabeled table on page 38: NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams)","endpoint":"developmental toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 25","page":38,"route":"","species":"rabbit","study_id":"sccs_o_176_noael_018"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | developmental toxicity | =75 | mg/kg/day | rabbit | - | developmental | developmental toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 75; DOSE=NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; EFFECT=Unlabeled table on page 38: NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","duration":"developmental","effect":"Unlabeled table on page 38: NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","endpoint":"developmental toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 75","page":38,"route":"","species":"rabbit","study_id":"sccs_o_176_noael_019"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | irritation | 20 | % | guinea pig | dermal | 14-day | irritation | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=20; EFFECT=SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"","duration":"14-day","effect":"SCCS-rejected applicant NOAEL: lightening agent and analysis of parent compound and hydroquinone in skin biopsies (as conducted for beta-arbutin), the SCCS considers that 20% of the absorbed alpha-arbutin fraction in skin is present as hydroquinone. Systemic toxicity No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL.","endpoint":"irritation","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"%","noael_value":"20","page":43,"route":"dermal","species":"guinea pig","study_id":"sccs_o_176_noael_015"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 29 | - | - | oral | 14 days | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=unclear:__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due; DOSE=Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.; EFFECT=__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due; CITATION=Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS; CITATION_NUMBERS=[26]; REFERENCE=Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS; DETAILS_JSON={"cas_number":"84380-01-8","citation":"Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","duration":"14 days","effect":"__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"","noael_value":"unclear:__________ 29 Skin erythema was noted at the dosed site of only one animal during each of the 14 days of the study. The control sites did not show signs of irritation. The scores (and a maximum weekly irritation index of 0.03*), showed that the test substance is non-irritating with daily dosing repeated for 14 days. Conclusion This study is designed to give mainly dermal irritation information and has very limited reliability for demonstrating more subtle and meaningful systemic effects to support definition of a NOAEL. Ref.: (26) SCCS comment *Maximum weekly irritation index is not a category used by SCCS. Yet, the results are in line with the acute skin irritation study (section 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due","page":29,"route":"oral","species":"","study_id":"sccs_o_176_noael_001"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 3.3 | - | guinea pig | oral | Sub-chronic | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=unclear:on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te; DOSE=Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.; EFFECT=on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available.","duration":"Sub-chronic","effect":"on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"","noael_value":"unclear:on 3.3.2.1) and the conclusion that alpha- arbutin is not irritating to skin. 3.3.5.2 Sub-chronic (90 days) toxicity (oral) 3.3.5.3 Chronic (> 12 months) toxicity No chronic toxicity study with alpha-Arbutin is available. Overall conclusion on repeated dose toxicity Only one study with repeated dermal application of alpha-arbutin is available. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. The data base for toxicity of alpha-arbutin is insufficient to calculate a MOS; yet the ban on animal studies, effective of 2013 in the EU, precludes requests for a repeated toxicity study. 3.3.6 Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation assay Guideline: OECD 471 (1997) Species/strain: Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2uvrA– Replicates: Triplicates per test concentration in 2 independent experiments Te","page":29,"route":"oral","species":"guinea pig","study_id":"sccs_o_176_noael_002"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 56 | - | - | dermal | 14-day | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=unclear:exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre; DOSE=56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:; EFFECT=exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose:","duration":"14-day","effect":"exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"","noael_value":"unclear:exposure scenarios: External amount: 56 (max 80) + 39.1 = (range) 96 - 129 mg/person/day External dose: 0.933 (max 1.334) + 0.65 = 1.583 (max 1.984) mg/kg bw/day Internal dose (SED): 0.005 (max 0.007) + 0.0034 = 0.0084 (max 0.0104) mg/kg bw/day SED expressed in µg/person/day: 300 (or max 420) + 204 = (range) 504 - 624 * (area body – area face and hand) Estimation of Margin of Safety Without a repeated dose toxicity study with alpha-Arbutin (only a 14-day dermal irritation study) there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. The applicant has suggested using the TTC approach2. Without a justification the applicant assigned Cramer class I (safe dose: 1800 µg/person/day) for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is pre","page":40,"route":"dermal","species":"","study_id":"sccs_o_176_noael_008"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | >250 | mg/kg bw | rat | oral | 14-day | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=>250; DOSE=Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).; EFFECT=SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","duration":"14-day","effect":"SCCS-rejected applicant NOAEL: /kg body weight. Two acute oral toxicity tests in rats with either a 5% or 10% alpha-Arbutin cream formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw","noael_value":">250","page":42,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_013"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | >250 | mg/kg bw | guinea pig | oral | 14-day | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT=>250; DOSE=eam formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).; EFFECT=SCCS-rejected applicant NOAEL: eam formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is predicted as a Cramer Class III subs; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"eam formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient).","duration":"14-day","effect":"SCCS-rejected applicant NOAEL: eam formulation did not reveal lethality after single gavage doses at 2000 mg formulation/kg bw (or >125 and >250 mg/kg bw active ingredient). No toxicity studies with repeated dosing has been carried out, except for a 14-day study in guinea pigs with dermal application. However, due to its focus on irritation and the low number of animals, this study is not suitable for conclusions on systemic effects or derivation of a NOAEL. Without a repeated dose toxicity study with alpha-Arbutin there is no basis to derive a NOAEL for a classical MOS calculation for systemic safety by topical exposures. Thus, the applicant has suggested using the TTC approach, and assigned (without any justification) Cramer class I for alpha-arbutin applied topically under the assumption that the molecule remains intact as applied. However, the SCCS considers that hydroquinone can be released when alpha-arbutin is applied to the skin and can also be present in the formulation as an impurity. Furthermore, alpha-arbutin is predicted as a Cramer Class III subs","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg bw","noael_value":">250","page":42,"route":"oral","species":"guinea pig","study_id":"sccs_o_176_noael_014"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 1550 | - | rat | oral | 28-day | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=unclear:SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st; DOSE=SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.; EFFECT=SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available.","duration":"28-day","effect":"SCCS-rejected applicant NOAEL: SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"","noael_value":"unclear:SCCS/1550/15) 3.3.4 Repeated dose toxicity Alpha-arbutin: no conclusive data was available in the SCCS/1552/15 Opinion; no new data was submitted, and no open literature data are available. Overall conclusion on repeated dose toxicity for alpha-arbutin Only one study with repeated dermal application of alpha-arbutin was available in SCCS/1552/15. Due to its focus on irritation and the limited number of animals (3 guinea pigs of each sex), it is not suitable for conclusions on systemic effects or derivation of a NOAEL. No new data are available, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these st","page":37,"route":"oral","species":"rat","study_id":"sccs_o_264_noael_001"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 1000 | mg/kg bw/day | rat | oral | 28-day | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=1000; DOSE=Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...; EFFECT=ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the...","duration":"28-day","effect":"ble, therefore a MoS for alpha-arbutin cannot be calculated. (SCCS/1552/15) Beta-arbutin: In SCCS/1550/15 only limited data was present; no new data was submitted, and no open literature data is available. Overall conclusion on repeated dose toxicity for beta-arbutin As no new data is available and only a repeated dose 28-day oral study and 90-day dermal study with the rat revealed some sporadic observations that could not be related to beta- arbutin, the highest dosage tested of these studies was designated as NOEL, i.e.1000 mg/kg bw/day for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal study. (SCCS/1550/15) 3.3.5 genotoxicity/mutagenicity Alpha-arbutin The genotoxicity of alpha-arbutin has been investigated in genotoxicity tests for gene mutations in bacteria and for structural and numerical chromosomal aberrations in an in vivo micronucleus test. Alpha-arbutin did not induce gene mutations in bacteria nor an increase in cells with micronuclei in bone marrow cells of mice. Based on this l","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"1000","page":37,"route":"oral","species":"rat","study_id":"sccs_o_264_noael_002"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 20 | mg/kg bw/d | - | - | - | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=20; DOSE=SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...; EFFECT=RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","duration":"","effect":"RBUTIN upon absorption) 1.23 μg/kg bw/day 2 (impurity of ALPHA-ARBUTIN) 0.00175 μg/kg bw/day 3 (formation from ALPHA-ARBUTIN via skin microbiome) 0.883 μg/kg bw/day Total 2.11 μg/kg bw/day BETA-ARBUTIN No new data are available for Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"20","page":43,"route":"","species":"","study_id":"sccs_o_264_noael_005"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | repeated dose toxicity | 15 | mg/kg bw/d | - | - | - | repeated dose toxicity | SOURCE_SUBDIR=sccs_o_264; REPORT_TITLE=Final Opinion Scientific Committee on Consumer Safety SCCS OPINION on the safety of alpha-arbutin and beta-arbutin in cosmetic products; OPINION_NUMBER=SCCS/1642/22; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=final version of 31 January 2023; VALUE_TEXT=15; DOSE=SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...; EFFECT=Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate de...","duration":"","effect":"Beta-Arbutin, and therefore the exposure to hydroquinone is taken from the SCCS 2015 opinion. SED hydroquinone from beta-arbutin exposure is 45.8 μg /day or 0.763 μg /kg bw/day for a 60-kg person MoS calculations HQ-SED MoS SED conservative MoS conservativ e Repeated dose toxicity NOAEL 20 mg/kg bw/d Alpha-arbutin 0.00211 20/0.00211 =9500* 0.00211 9500* Beta-arbutin 0.000763 (2015opinion) 26200* 0.003853 (+microbiom e) 5200* Aggregate deterministic exposure 0.00287 7000* 0.005963 3300* Reproduction toxicity NOAEL 15 mg/kg bw/d Alpha-arbutin 0.00211 15/0.00211 =7100* 0.00211 9500* Beta-arbutin 0.000763 19700* 0.003853 3900*","endpoint":"repeated dose toxicity","ingredient":"Alpha-Arbutin","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"15","page":43,"route":"","species":"","study_id":"sccs_o_264_noael_006"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | reproductive toxicity | =74 | mg/kg/day | rat | oral | 28d | reproductive toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 74; DOSE=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; EFFECT=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","duration":"28d","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in","endpoint":"reproductive toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 74","page":38,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_004"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | reproductive toxicity | =25 | mg/kg/day | rat | oral | 28d | reproductive toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 25; DOSE=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; EFFECT=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","duration":"28d","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage le","endpoint":"reproductive toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 25","page":38,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_005"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | reproductive toxicity | =75 | mg/kg/day | rat | oral | 28d | reproductive toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 75; DOSE=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; EFFECT=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","duration":"28d","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many y","endpoint":"reproductive toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 75","page":38,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_006"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | reproductive toxicity | =15 | mg/kg/day | rat | oral | 28d | reproductive toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 15; DOSE=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).; EFFECT=SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects).","duration":"28d","effect":"SCCS/1552/15 Opinion on α-arbutin, ___________________________________________________________________________________________ 38 NOAEL (28d/90d-dermal-rat) = 74 mg/kg/day NOEL (developmental toxicity-rabbit) = 25 mg/kg/day (dams) NOEL (developmental toxicity-rabbit) = 75 mg/kg/day (teratogenic effects). NOEL (1-generation reproduction toxicity-rat) = 15 mg/kg/day (general toxicity). NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity). Negative in the Ames test, the dominant lethal assay and the mouse spot test. Positive in the in vitro chromosome aberration test (+S9) Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test. Equivocal conclusions on potential carcinogenic effects at dosage levels 25 mg/kg/day. [HQ Refs. A, B] Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It does not directly bleach the ski","endpoint":"reproductive toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 15","page":38,"route":"oral","species":"rat","study_id":"sccs_o_176_noael_007"} |
| UnifiedCodex:SCCS_SHADOW:beta.noael_studies | reproductive toxicity | =150 | mg/kg/day | rat | - | - | reproductive toxicity | SOURCE_SUBDIR=sccs_o_176; REPORT_TITLE=OPINION ON α-arbutin; OPINION_NUMBER=SCCS/1552/15; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=27 May 2015; VALUE_TEXT== 150; DOSE=NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).; EFFECT=Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"84380-01-8","citation":"","dose":"NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","duration":"","effect":"Unlabeled table on page 38: NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).","endpoint":"reproductive toxicity","ingredient":"Alpha-Arbutin (CAS 84380-01-8; EC 283-934-3) with the chemical","loael_value":"","noael_unit":"mg/kg/day","noael_value":"= 150","page":38,"route":"","species":"rat","study_id":"sccs_o_176_noael_021"} |
openFDA substances 3 endpoints
| Source | Endpoint Type | Value | Unit | Species | Route | Duration | Study Type | Reference |
|---|---|---|---|---|---|---|---|---|
| openFDA substances | FDA UNII substance identifier | 72VUP07IT5 | UNII | - | - | - | chemical | {"approval_status":null,"molecular_formula":"C12H16O7","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"72VUP07IT5"} |
| openFDA substances | FDA UNII substance identifier | 72VUP07IT5 | UNII | - | - | - | chemical | {"approval_status":null,"molecular_formula":"C12H16O7","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"72VUP07IT5"} |
| openFDA substances | FDA UNII substance identifier | 72VUP07IT5 | UNII | - | - | - | chemical | {"approval_status":null,"molecular_formula":"C12H16O7","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"72VUP07IT5"} |