NOAEL Studies Active Ingredient

Melatonin NOAEL Studies

INCI: MELATONIN

CAS: 73-31-4

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

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NTP_ICE_adme_parameters 2 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
NTP_ICE_adme_parameters Clint 0 uL/min/10^6 cells Human - - Measured; httk, Human Hepatic Intrinsic Clearance sheet=Data; excel_row=505; Record_ID=adme_parameters_610; Data_Type=Measured; DTXSID=DTXSID1022421; Assay=httk, Human Hepatic Intrinsic Clearance; Endpoint=Clint; Response=0.0; Response_Unit=ul/min/10^6 cells; Species=Human; Reference=httk2.3.1, Wambaugh 2019; URL=https://cran.r-project.org/web/packages/httk/index.html; URL_CompTox=https://comptox.epa.gov/dashboard/chemical/details/DTXSID1022421; URL_CEBS=https://doi.org/10.22427/NTP-DATA-DTXSID1022421
NTP_ICE_adme_parameters Fu 0.498 fraction Human - - Measured; httk, Human Plasma Fraction Unbound sheet=Data; excel_row=504; Record_ID=adme_parameters_610; Data_Type=Measured; DTXSID=DTXSID1022421; Assay=httk, Human Plasma Fraction Unbound; Endpoint=Fu; Response=0.498; Response_Unit=Unitless Fraction; Species=Human; Reference=httk2.3.1, Wambaugh 2019; URL=https://cran.r-project.org/web/packages/httk/index.html; URL_CompTox=https://comptox.epa.gov/dashboard/chemical/details/DTXSID1022421; URL_CEBS=https://doi.org/10.22427/NTP-DATA-DTXSID1022421
NTP_ICE_endocrine 1 endpoint
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
NTP_ICE_endocrine Model Score 0 unitless - - - ARPathway2016; AR Pathway Model, Antagonist sheet=Integrated_approaches; excel_row=11200; RecordID=ARPathway2016_1520; DatasetName=ARPathway2016; DTXSID=DTXSID1022421; Assay=AR Pathway Model, Antagonist; Endpoint=Model Score; Response=0; Response_Unit=Unitless; URL_CompTox=https://comptox.epa.gov/dashboard/chemical/details/DTXSID1022421; URL_CEBS=https://doi.org/10.22427/NTP-DATA-DTXSID1022421
SCCS_vision_codex 32 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
SCCS_vision_codex NOAEL =0.3 % rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_003"}
SCCS_vision_codex NOAEL =0.3 % rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_003"}
SCCS_vision_codex NOAEL =0.3 % rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_003"}
SCCS_vision_codex NOAEL =0.3 % rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_003"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/day rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_002"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw rat dermal 28 days dermal absorption {"citation":"Ref.: 41 3","dose":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","effect":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","page":27,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_009"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/d human dermal - dermal absorption {"dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_016"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/day rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_002"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw rat dermal 28 days dermal absorption {"citation":"Ref.: 41 3","dose":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","effect":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","page":27,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_009"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/d human dermal - dermal absorption {"dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_016"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/day rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_002"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw rat dermal 28 days dermal absorption {"citation":"Ref.: 41 3","dose":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","effect":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","page":27,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_009"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/d human dermal - dermal absorption {"dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_016"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/day rat oral Sub-chronic repeated dose toxicity {"citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_002"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw rat dermal 28 days dermal absorption {"citation":"Ref.: 41 3","dose":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","effect":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","page":27,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_009"}
SCCS_vision_codex NOAEL =0.5 mg/kg bw/d human dermal - dermal absorption {"dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_016"}
SCCS_vision_codex NOAEL =5 mg/kg bw/day rat - - NOAEL study {"citation":"Ref.: 14","dose":"Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.","effect":"ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_004"}
SCCS_vision_codex NOAEL =5 mg/kg bw/day rat - - NOAEL study {"citation":"Ref.: 14","dose":"Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.","effect":"ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_004"}
SCCS_vision_codex NOAEL =5 mg/kg bw/day rat - - NOAEL study {"citation":"Ref.: 14","dose":"Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.","effect":"ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_004"}
SCCS_vision_codex NOAEL =5 mg/kg bw/day rat - - NOAEL study {"citation":"Ref.: 14","dose":"Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.","effect":"ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","page":16,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_004"}
SCCS_vision_codex NOAEL =100 mg/kg bw/day rat intravenous prenatal developmental toxicity {"citation":"Ref.: 19","dose":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.","effect":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","page":20,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_007"}
SCCS_vision_codex NOAEL =100 mg/kg bw/day rat intravenous prenatal developmental toxicity {"citation":"Ref.: 19","dose":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.","effect":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","page":20,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_007"}
SCCS_vision_codex NOAEL =100 mg/kg bw/day rat intravenous prenatal developmental toxicity {"citation":"Ref.: 19","dose":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.","effect":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","page":20,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_007"}
SCCS_vision_codex NOAEL =100 mg/kg bw/day rat intravenous prenatal developmental toxicity {"citation":"Ref.: 19","dose":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.","effect":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","page":20,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_007"}
SCCS_vision_codex NOAEL =200 mg/kg/day rat oral subacute repeated dose toxicity {"citation":"Ref.: 6 3","dose":"Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.","effect":"l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7","page":15,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_001"}
SCCS_vision_codex NOAEL =200 mg/kg bw/day - - developmental reproductive toxicity {"dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","effect":"lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_019"}
SCCS_vision_codex NOAEL =200 mg/kg/day rat oral subacute repeated dose toxicity {"citation":"Ref.: 6 3","dose":"Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.","effect":"l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7","page":15,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_001"}
SCCS_vision_codex NOAEL =200 mg/kg bw/day - - developmental reproductive toxicity {"dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","effect":"lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_019"}
SCCS_vision_codex NOAEL =200 mg/kg/day rat oral subacute repeated dose toxicity {"citation":"Ref.: 6 3","dose":"Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.","effect":"l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7","page":15,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_001"}
SCCS_vision_codex NOAEL =200 mg/kg bw/day - - developmental reproductive toxicity {"dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","effect":"lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_019"}
SCCS_vision_codex NOAEL =200 mg/kg/day rat oral subacute repeated dose toxicity {"citation":"Ref.: 6 3","dose":"Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.","effect":"l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7","page":15,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_001"}
SCCS_vision_codex NOAEL =200 mg/kg bw/day - - developmental reproductive toxicity {"dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","effect":"lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs","page":29,"pdf":"sccs_o_022.pdf","row_type":"noael_study","study_id":"sccs_o_022_noael_019"}
ToxValDB_ECOTOX 3 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
ToxValDB_ECOTOX LOEL =3 mg/kg bw/day Rat injection subchronic; 43 days subchronic LONG_REF=Toxicology195(1): 69-75 Baltaci,A.K., R. Mogulkoc, A. Kul, C.S. Bediz, and A. Ugur Opposite Effects of Zinc and Melatonin on Thyroid Hormones in Rats 2004; TITLE=Opposite Effects of Zinc and Melatonin on Thyroid Hormones in Rats; AUTHOR=Baltaci,A.K., R. Mogulkoc, A. Kul, C.S. Bediz, and A. Ugur; DOI=10.1016/j.tox.2003.09.001; QUALITY=Control type: Concurrent control; EXTERNAL_SOURCE_ID=85833; EXTERNAL_SOURCE_ID_DESC=ECOTOX Reference Number; STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/6759bce8e4b0a7c65d37bc5f; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://cfpub.epa.gov/ecotox/; YEAR=2004; ORIGINAL_YEAR=2004; TOXICOLOGICAL_EFFECT=Accumulation: Residue|Biochemistry: Zinc content|Hormone(s): Thyrotropin|Hormone(s): Thyroxine|Hormone(s): Triiodothyronine; TOXICOLOGICAL_EFFECT_CATEGORY=clinical chemistry|other; STUDY_GROUP=ECOTOX:15596825:M:--; QC_CATEGORY=Data source QC'd by data provider prior to ECOTOX import; QC_STATUS=not determined; SOURCE_HASH=8b837f803621ba94706571df4b2f85c7
ToxValDB_ECOTOX NOEL =0.5 mg/kg bw/day Rat oral short-term; 28 days short-term LONG_REF=Asian Pac. J. Trop. Biomed.2(8): 645-650 Umosen,A.J., S.F. Ambali, J.O. Ayo, B. Mohammed, and C. Uchendu Alleviating Effects of Melatonin on Oxidative Changes in the Testes and Pituitary Glands Evoked by Subacute Chlorpyrifos Administration in Wistar Rats 2012; TITLE=Alleviating Effects of Melatonin on Oxidative Changes in the Testes and Pituitary Glands Evoked by Subacute Chlorpyrifos Administration in Wistar Rats; AUTHOR=Umosen,A.J., S.F. Ambali, J.O. Ayo, B. Mohammed, and C. Uchendu; QUALITY=Control type: Concurrent control; EXTERNAL_SOURCE_ID=160416; EXTERNAL_SOURCE_ID_DESC=ECOTOX Reference Number; STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/6759bce8e4b0a7c65d37bc5f; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://cfpub.epa.gov/ecotox/; YEAR=2012; ORIGINAL_YEAR=2012; TOXICOLOGICAL_EFFECT=Biochemistry: Malondialdehyde|Enzyme(s): Superoxide dismutase (SOD) enzyme activity; TOXICOLOGICAL_EFFECT_CATEGORY=enzyme activity|other; STUDY_GROUP=ECOTOX:15598461:M:--; QC_CATEGORY=Data source QC'd by data provider prior to ECOTOX import; QC_STATUS=not determined; SOURCE_HASH=cf4c51ae274fbf2df3299fc1548d69ee
ToxValDB_ECOTOX NOEL =10 mg/kg bw/day Rat oral short-term; 28 days short-term LONG_REF=Indian J. Biochem. Biophys.45(4): 278-281 Suke,S.G., R. Pathak, R.S. Ahmed, A.K. Tripathi, and B.D. Banerjee Melatonin Treatment Prevents Modulation of Cell-Mediated Immune Response Induced by Propoxur in Rats 2008; TITLE=Melatonin Treatment Prevents Modulation of Cell-Mediated Immune Response Induced by Propoxur in Rats; AUTHOR=Suke,S.G., R. Pathak, R.S. Ahmed, A.K. Tripathi, and B.D. Banerjee; QUALITY=Control type: Carrier or solvent control; EXTERNAL_SOURCE_ID=111928; EXTERNAL_SOURCE_ID_DESC=ECOTOX Reference Number; STORED_SOURCE_RECORD=https://clowder.edap-cluster.com/files/6759bce8e4b0a7c65d37bc5f; RECORD_SOURCE_LEVEL=Extraction document; SOURCE_URL=https://cfpub.epa.gov/ecotox/; YEAR=2008; ORIGINAL_YEAR=2008; TOXICOLOGICAL_EFFECT=Physiology: Cell Migration Inhibition (Immune Response Activity); TOXICOLOGICAL_EFFECT_CATEGORY=other; STUDY_GROUP=ECOTOX_dup_EPA ORD_15604425_15607071:M:--; QC_CATEGORY=Data source QC'd by data provider prior to ECOTOX import; QC_STATUS=not determined; SOURCE_HASH=2a735dc77c9402d8958d3a86c6746c4e
UnifiedCodex:SCCS_SHADOW:beta.noael_studies 19 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
UnifiedCodex:SCCS_SHADOW:beta.noael_studies - 5 mg/kg bw/day rat - - - SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=5; DOSE=Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.; EFFECT=ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14; CITATION=Ref.: 14; CITATION_NUMBERS=[14]; REFERENCE=Ref.: 14; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 14","dose":"Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group.","duration":"","effect":"ared as not clinically significant, since no concurrent effects on thyroid histopathology were observed. Cystic uterine endometrial hyperplasia was observed in a number of treated Long-Evans female rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","endpoint":"","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5","page":16,"route":"","species":"rat","study_id":"sccs_o_022_noael_004"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies - 5 mg/kg bw/day rat - - - SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=5; DOSE=Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy.; EFFECT=rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14; CITATION=Ref.: 14; CITATION_NUMBERS=[14]; REFERENCE=Ref.: 14; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 14","dose":"Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy.","duration":"","effect":"rats, but also in their respective control group. Finally, one treatment- related finding in a 50 mg/kg bw/day treated Long-Evans female was a dilated uterus at necropsy. Conclusion In light of the poor description of the test and given the fact that the raw data cannot be consulted, it is very difficult to establish a NOAEL value based on this study. An additional issue is that there is a large gap between the dosages of 0.05 and 5 mg/kg bw/day. Without full description of the test and without the raw data, the NOAEL value can be temporarily set on 5 mg/kg bw/day (based upon the significant treatment-related adverse effects, being the coloured faces and the dilated uterus). Ref.: 14","endpoint":"","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5","page":16,"route":"","species":"rat","study_id":"sccs_o_022_noael_005"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies - 5 mg/kg bw/day rat oral 14 days - SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=5; DOSE=eated dose toxicity study of Prevo et al.; EFFECT=eated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"eated dose toxicity study of Prevo et al.","duration":"14 days","effect":"eated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.","endpoint":"","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5","page":28,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_015"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies dermal absorption =0.5 mg/kg bw rat dermal 28 days dermal absorption SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT== 0.5; DOSE=ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.; EFFECT=ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294; CITATION=Ref.: 41 3; CITATION_NUMBERS=[41,3]; REFERENCE=Ref.: 41 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 41 3","dose":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","duration":"28 days","effect":"ding to the parameters analysed, there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","endpoint":"dermal absorption","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw","noael_value":"= 0.5","page":27,"route":"dermal","species":"rat","study_id":"sccs_o_022_noael_009"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies dermal absorption =0.5 mg/kg bw rat dermal 28 days dermal absorption SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT== 0.5; DOSE=there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.; EFFECT=there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294; CITATION=Ref.: 41 3; CITATION_NUMBERS=[41,3]; REFERENCE=Ref.: 41 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 41 3","dose":"there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study.","duration":"28 days","effect":"there is no toxicological effect that might compromise the use of melatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","endpoint":"dermal absorption","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw","noael_value":"= 0.5","page":27,"route":"dermal","species":"rat","study_id":"sccs_o_022_noael_010"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies dermal absorption =0.5 mg/kg bw rat dermal 28 days dermal absorption SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT== 0.5; DOSE=elatonin at a dose of 10 mg for a period of 28 days in this study.; EFFECT=elatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294; CITATION=Ref.: 41 3; CITATION_NUMBERS=[41,3]; REFERENCE=Ref.: 41 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 41 3","dose":"elatonin at a dose of 10 mg for a period of 28 days in this study.","duration":"28 days","effect":"elatonin at a dose of 10 mg for a period of 28 days in this study. Ref.: 41 3.3.12. Special investigations No documents submitted 3.3.13. Safety evaluation (including calculation of the MoS) CALCULATION OF THE MARGIN OF SAFETY Melatonin Applied dose of 0.1 mg was considered as 100% absorbed Dermal absorption per treatment = 0.1 mg Typical body weight of human = 60 kg Systemic exposure dose SED = 1.7 µg/kg bw No observed adverse effect level NOAEL = 0.5 mg/kg bw (28-day, rat, subcutaneous) Margin of Safety NOAEL / SED = 294","endpoint":"dermal absorption","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw","noael_value":"= 0.5","page":27,"route":"dermal","species":"rat","study_id":"sccs_o_022_noael_011"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies dermal absorption 0.5 mg/kg bw/d human dermal - dermal absorption SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.5; DOSE=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.; EFFECT=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","duration":"","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 29 Since no reliable data is available for quantification of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even i","endpoint":"dermal absorption","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"0.5","page":29,"route":"dermal","species":"human","study_id":"sccs_o_022_noael_016"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies dermal absorption 0.5 mg/kg bw/d human oral - dermal absorption SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.5; DOSE=on of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.; EFFECT=on of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even if average day time plasma levels of the population are exceeded by up to 20 ng/l, no adverse neurophysiological effects e.g. such influencing the fitness to drive, are expected. An oral application of 0.1 to 0.3 mg Melatonin at midday has been shown to only increase the duration of sleep at night (D; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"on of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin.","duration":"","effect":"on of dermal absorption, SCCS assumed a worst case scenario, i.e. that the total applied dose of 0.1 mg is absorbed through the skin. This equals a dose of 1.67 µg/kg bw/d (60 kg bw). Comparing this dose with the lowest NOAEL of 0.5 mg/kg bw/d observed in rodents (see below), would then result in a MOS of 294. The NOAEL of 0.5 mg/kg bw/d can be used for the interpretation of the increase of Melatonin plasma levels caused by topical application of 0.1 mg Melatonin. Serum levels of Melatonin in the dose group at the NOAEL were 1 to 2 orders of magnitude higher than the physiological levels of Melatonin in humans. In contrast, after topical application of 0.1 mg Melatonin the plasma levels remained well within physiological levels. Even if average day time plasma levels of the population are exceeded by up to 20 ng/l, no adverse neurophysiological effects e.g. such influencing the fitness to drive, are expected. An oral application of 0.1 to 0.3 mg Melatonin at midday has been shown to only increase the duration of sleep at night (D","endpoint":"dermal absorption","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/d","noael_value":"0.5","page":29,"route":"oral","species":"human","study_id":"sccs_o_022_noael_017"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies developmental toxicity 100 mg/kg bw/day rat intravenous prenatal developmental toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=100; DOSE=o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.; EFFECT=o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et; CITATION=Ref.: 19; CITATION_NUMBERS=[19]; REFERENCE=Ref.: 19; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 19","dose":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day.","duration":"prenatal","effect":"o treatment, reduced maternal weight gain) was noted at ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","endpoint":"developmental toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":20,"route":"intravenous","species":"rat","study_id":"sccs_o_022_noael_007"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies developmental toxicity 100 mg/kg bw/day rat intravenous prenatal developmental toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=100; DOSE=t ≥ 100 mg/kg bw/day.; EFFECT=t ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et; CITATION=Ref.: 19; CITATION_NUMBERS=[19]; REFERENCE=Ref.: 19; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 19","dose":"t ≥ 100 mg/kg bw/day.","duration":"prenatal","effect":"t ≥ 100 mg/kg bw/day. In the definitive study, no maternal deaths occurred, and clinical signs associated with Melatonin exposure were minimal. Aversion to treatment was noted at ≥ 50 mg/kg bw/day, and mild sedation, reduced maternal food intake, and reduced body weight gain were found during initial treatment with 200 mg/kg bw/day. Melatonin had no effect on prenatal survival, foetal body weight, or incidence of foetal malformations/variations. Conclusion The NOAEL for maternal toxicity was 100 mg/kg bw/day. The NOAEL for developmental toxicity was 200 mg/kg bw/day (the highest dose tested). Ref.: 19; 20 3.3.9. Toxicokinetics Melatonin administered intravenously Intravenous administration of Melatonin to the rat has shown to result in a rapid distribution into plasma and all tissues of the animal, including cerebrospinal fluid and brain [Kopin et","endpoint":"developmental toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":20,"route":"intravenous","species":"rat","study_id":"sccs_o_022_noael_008"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 0.3 % rat oral Sub-chronic repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.3; DOSE=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...; EFFECT=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin; CITATION=Ref.: 35 3; CITATION_NUMBERS=[35,3]; REFERENCE=Ref.: 35 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","duration":"Sub-chronic","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.00 - 50 - 200 mg/kg bw/day Administration: gavage GLP: / Date of study: Published in 2003 In a 90-day toxicity study, Melatonin","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"%","noael_value":"0.3","page":16,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_003"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 0.5 mg/kg bw/day rat oral Sub-chronic repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.50; DOSE=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...; EFFECT=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.; CITATION=Ref.: 35 3; CITATION_NUMBERS=[35,3]; REFERENCE=Ref.: 35 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 35 3","dose":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes...","duration":"Sub-chronic","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 16 Although the authors do not define a clear NOAEL value, one can propose the value of 0.50 mg/kg bw/day (corresponds to the 0.3% Melatonin solution in the male rats) as the NOAEL for Melatonin based on decreased testes weights and testicular degenerative changes. Ref.: 35 3.3.5.3. Sub-chronic (90 days) oral Guideline: / Species/strain: Long-Evans and Fischer 344 rats Group size: 10 males and 10 females per dosage group Observation period: 90 days Test substance: Melatonin (in methylcellulose 0.5% containing ethanol 0.25%) Dosage levels: 0.0 - 0.005 - 0.050 - 5.","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"0.50","page":16,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_002"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 0.5 mg/kg bw/day - - Chronic repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.5; DOSE=Chronic (> 12 months) toxicity No data submitted General comment on repeated dose toxicity The repeated dose toxicity studies suffer from inadequate design (Batelle, 2003) or poor description and documentation (Gerken et al., 2003).; EFFECT=SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 17 3.3.5.3. Chronic (> 12 months) toxicity No data submitted General comment on repeated dose toxicity The repeated dose toxicity studies suffer from inadequate design (Batelle, 2003) or poor description and documentation (Gerken et al., 2003). So there is only one study (Prevo et al., 2000) from which a NOAEL can be derived. The NOAEL of 0.5 mg/kg bw/day is based on decreased testes weights and testicular degenerative changes. 3.3.6. Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation test In order to determine the mutagenic potential of Melatonin and its major metabolite 6- hydroxymelatonin, a Bacterial reverse mutation test tests were performed using three strains of Salmonella typhimurium (TA 97, TA 98 and TA 100) without and with metabolic activation (Arochlor 125; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"Chronic (> 12 months) toxicity No data submitted General comment on repeated dose toxicity The repeated dose toxicity studies suffer from inadequate design (Batelle, 2003) or poor description and documentation (Gerken et al., 2003).","duration":"Chronic","effect":"SCCS/1315/10, 24.3.10 Opinion on Melatonin __________________________________________________________________________________ 17 3.3.5.3. Chronic (> 12 months) toxicity No data submitted General comment on repeated dose toxicity The repeated dose toxicity studies suffer from inadequate design (Batelle, 2003) or poor description and documentation (Gerken et al., 2003). So there is only one study (Prevo et al., 2000) from which a NOAEL can be derived. The NOAEL of 0.5 mg/kg bw/day is based on decreased testes weights and testicular degenerative changes. 3.3.6. Mutagenicity / Genotoxicity 3.3.6.1 Mutagenicity / Genotoxicity in vitro Bacterial reverse mutation test In order to determine the mutagenic potential of Melatonin and its major metabolite 6- hydroxymelatonin, a Bacterial reverse mutation test tests were performed using three strains of Salmonella typhimurium (TA 97, TA 98 and TA 100) without and with metabolic activation (Arochlor 125","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"0.5","page":17,"route":"","species":"","study_id":"sccs_o_022_noael_006"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 0.5 mg/kg bw/day rat oral 28 days repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=0.5; DOSE=General toxicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful.; EFFECT=n on the scalp remained within the range of physiological levels. General toxicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"General toxicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful.","duration":"28 days","effect":"n on the scalp remained within the range of physiological levels. General toxicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"0.5","page":28,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_012"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 5 mg/kg bw/day rat oral 28 days repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=5; DOSE=The 28 days repeated dose toxicity study of Prevo et al.; EFFECT=utely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"The 28 days repeated dose toxicity study of Prevo et al.","duration":"28 days","effect":"utely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"5","page":28,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_014"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 200 mg/kg/day rat oral subacute repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=200; DOSE=Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.; EFFECT=l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7; CITATION=Ref.: 6 3; CITATION_NUMBERS=[6,3]; REFERENCE=Ref.: 6 3; DETAILS_JSON={"cas_number":"73-31-4","citation":"Ref.: 6 3","dose":"Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day.","duration":"subacute","effect":"l signs, no early deaths, no substance-related body weight changes, no organ weight changes, no gross lesions or histopathological findings were noted in this study. Administration of Melatonin did not result in dose-response related differences in retinal outer nuclear layer thickness means in any sex, strain, and lighting treatment groups up to the highest tested dose of 200 mg/kg bw/day. Conclusion Although not designed as a classical subacute toxicity study, and despite of the brief description of the test, a NOAEL of 200 mg/kg/day can be established for the specific effects measured in this 14-day oral study with Melatonin in the rat. Ref.: 6 3.3.5.1. Repeated Dose (28 days) subcutaneous toxicity 28-Day subcutaneous study in the rat Guideline: / Species/strain: Sprague Dawley rat Group size: 19 males and 19 females per dosage group Observation period: 28 days Test substance: Melatonin (obtained from Regis Technologies, Morton Grove, USA) Dosage levels: 0.0, 0.050, 0.50 and 4.8 mg/kg bw/day (males) 0.0, 0.074, 0.75 and 7","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg/day","noael_value":"200","page":15,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_001"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies repeated dose toxicity 200 mg/kg bw/day rat oral 28 days repeated dose toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=200; DOSE=xicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful.; EFFECT=xicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"xicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful.","duration":"28 days","effect":"xicity With an acute oral LD50-value of > 3200 mg/kg bw, Melatonin is considered as acutely non- harmful. The 28 days repeated dose toxicity study of Prevo et al. (2000) was chosen as the critical one, as this study showed adverse effects at the lowest doses and other studies had significant shortcomings. Subcutaneous administration of Melatonin lead to decreased testis weights and testicular degenerative changes at doses higher than the NOAEL of 0.5 mg/kg bw/day in rats. In a 14 days study (oral administration) a NOAEL of 200 mg/kg bw/day was observed. An oral 90-day study in the rat resulted in a NOAEL value of 5 mg/kg bw/day. The NOAEL value of 0.5 mg/kg bw/d (from the 28 day study of Prevo et al. 2000) was used in the calculation of the MoS.","endpoint":"repeated dose toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"200","page":28,"route":"oral","species":"rat","study_id":"sccs_o_022_noael_013"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies reproductive toxicity 100 mg/kg bw/day - - developmental reproductive toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=100; DOSE=A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.; EFFECT=ic toxicity or carcinogenicity animal studies are available. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain sc; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","duration":"developmental","effect":"ic toxicity or carcinogenicity animal studies are available. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain sc","endpoint":"reproductive toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"100","page":29,"route":"","species":"","study_id":"sccs_o_022_noael_018"}
UnifiedCodex:SCCS_SHADOW:beta.noael_studies reproductive toxicity 200 mg/kg bw/day - - developmental reproductive toxicity SOURCE_SUBDIR=sccs_o_022; REPORT_TITLE=OPINION ON Melatonin; OPINION_NUMBER=SCCS/1315/10; COMMITTEE=Scientific Committee on Consumer Safety (SCCS); REPORT_DATE=24 March 2010; VALUE_TEXT=200; DOSE=A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.; EFFECT=lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs; CITATION_NUMBERS=[]; DETAILS_JSON={"cas_number":"73-31-4","citation":"","dose":"A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity.","duration":"developmental","effect":"lable. With regard to risk from teratogenicity and reproduction toxicity, the applicant provided an expert statement based on an extensive discussion of the available literature. In conclusion, at the proposed maximum amount of 0.1 mg Melatonin to be applied daily, and considering the fact that resulting plasma concentrations are within physiological levels, effects on reproductive function are highly unlikely to occur. A separate teratogenicity study reveals a NOAEL of 100 mg/kg bw/day for maternal toxicity and a NOAEL of ≥ 200 mg/kg bw/day for developmental toxicity. Mutagenicity/ Genotoxicity Melatonin was found to be negative in the bacterial reverse mutation test, in the WP2 Mutoxitest, in the COMET assay and in the micronucleus test. Its anticlastogenic activity was shown in experimental studies where Melatonin reduced the frequencies of chromosomal aberrations and micronuclei induced by genotoxic agents. Although the documentation provided consists of public domain scientific publications that clearly suffer from the abs","endpoint":"reproductive toxicity","ingredient":"melatonin in cosmetic products.","loael_value":"","noael_unit":"mg/kg bw/day","noael_value":"200","page":29,"route":"","species":"","study_id":"sccs_o_022_noael_019"}
openFDA substances 4 endpoints
Source Endpoint Type Value Unit Species Route Duration Study Type Reference
openFDA substances FDA UNII substance identifier JL5DK93RCL UNII - - - chemical {"approval_status":null,"molecular_formula":"C13H16N2O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"JL5DK93RCL"}
openFDA substances FDA UNII substance identifier JL5DK93RCL UNII - - - chemical {"approval_status":null,"molecular_formula":"C13H16N2O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"JL5DK93RCL"}
openFDA substances FDA UNII substance identifier JL5DK93RCL UNII - - - chemical {"approval_status":null,"molecular_formula":"C13H16N2O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"JL5DK93RCL"}
openFDA substances FDA UNII substance identifier JL5DK93RCL UNII - - - chemical {"approval_status":null,"molecular_formula":"C13H16N2O2","source_table":"substance_identifiers_fda","substance_class":"chemical","unii_code":"JL5DK93RCL"}