Final report on the safety assessment of 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Chloro-2-Aminophenol. 2004


Each of these ingredients function as hair colorants. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol are identified as oxidative hair dyes, that is, they are combined with an oxidizing agent before being applied to the hair. 6-Amino-m-Cresol, 6-Amino-o-Cresol, 4-Amino-m-Cresol, and 5-Amino-4-Chloro-o-Cresol are used in oxidative hair dyes, but it is not known if they are also used in nonoxidative (semipermanent) hair dyes. No toxicologically significant impurities are present with these two ingredients. To supplement the safety test data on these ingredients, available data on related ingredients (4-amino-2-hydroxytoluene and p-,m-, and o-aminophenol) previously found safe as used by the Cosmetic Ingredient Review (CIR) Expert Panel were summarized. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol do not absorb significant ultraviolet radiation in the UVB region and none in the UVA region, although 4-Amino-m-Cresol had a symmetrical UV absorption peak at 300 nm. Percutaneous penetration of 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol alone was significant, but when combined with oxidative developer, skin absorption was extremely low. Both of these dyes are excreted rapidly via the urine. Repeated exposure of animal skin to 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol failed to produce any cumulative irritation and single exposures up to 10%were not irritating to animal skin. 5-Amino-4-Chloro-o-Cresol and 5-Amino-6-Chloro-o-Cresol combined with oxidizer were not sensitizers in guinea pig maximization tests. Ocular irritation resulted from exposure of animals to undiluted 5-Amino-4-Chloro-o-Cresol, but not to a 5%solution. Only minor irritation was observed with 5%5-Amino-6-Chloro-o-Cresol. Subchronic toxicity testing in animals using 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, and 4-Amino-m-Cresol did not yield any adverse reactions. 6-Amino-m-Cresol and 4-Amino-m-Cresol were generally not mutagenic in in vitro and in vivo tests. Exposure to 5-Amino-4-Chloro-o-Cresol, 5-Amino-6-Chloro-o-Cresol, 6-Amino-m-Cresol and 4-Amino-m-Cresol from cosmetics were several orders of magnitude below developmental toxicity no-observed-adverse effect levels (NOAELs). Although irritation data on several ingredients are absent, products containing these ingredients must include a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure would identify individuals who would have an adverse reaction and allow them to avoid significant exposures. These compounds, when tested alone, are moderate skin sensitizers, but when combined with the developer, these ingredients are not sensitizers in animal tests. This information, coupled with the available animal test data, supports the safety of these ingredients in oxidative hair dyes. In the absence of systemic toxicity data, however, the available data are insufficient to support the safety of 6-Amino-o-Cresol and 4-Chloro-2-Aminophenol in semipermanent hair dyes. The types of data required for these two ingredients for this use include (1) physical and chemical properties, including the octanol/water partition coefficient; (2) impurities data, especially regarding the presence of m-cresol, other organic molecules, and heavy metals; (3) data demonstrating that the metabolism is similar to that of 4-amino-2-hydroxytoluene and/or p-,m-, and o-aminophenol, or 28-day dermal toxicity with histopathology, dermal reproductive toxicity data, and an in vitro genotoxicity study for 6-Amino-o-Cresol and one genotoxicity study in a mammalian system; if positive, a 2-year dermal carcinogenicity study using National Toxicology Program methods may be needed.

UI MeSH Term Description Entries
D007509 Irritants Drugs that act locally on cutaneous or mucosal surfaces to produce inflammation; those that cause redness due to hyperemia are rubefacients; those that raise blisters are vesicants and those that penetrate sebaceous glands and cause abscesses are pustulants; tear gases and mustard gases are also irritants. Counterirritant,Counterirritants,Irritant,Pustulant,Pustulants,Rubefacient,Rubefacients,Vesicant,Vesicants
D002733 Chlorophenols Phenols substituted with one or more chlorine atoms in any position. Chlorophenol,Hydroxychlorobenzenes
D003257 Consumer Product Safety The sum total of measures taken and regulatory policies enacted to ensure the safe use of consumer products. Safety, Consumer Product,Product Approval,Product Approvals,Product Safety, Consumer
D003408 Cresols Any of three isomeric crystalline aromatic methylphenols, also known as hydroxytoluenes.
D006202 Hair Dyes Dyes used as cosmetics to change hair color either permanently or temporarily. Coloring Agents, Hair,Dyes, Hair,Hair Colorants,Hair Dye,Agents, Hair Coloring,Colorants, Hair,Dye, Hair,Hair Coloring Agents
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012869 Skin Absorption Uptake of substances through the SKIN. Absorption, Skin,Intracutaneous Absorption,Intradermal Absorption,Percutaneous Absorption,Transcutaneous Absorption,Transdermal Absorption,Absorption, Intracutaneous,Absorption, Intradermal,Absorption, Percutaneous,Absorption, Transcutaneous,Absorption, Transdermal,Absorptions, Intracutaneous,Absorptions, Intradermal,Absorptions, Percutaneous,Absorptions, Skin,Absorptions, Transcutaneous,Absorptions, Transdermal,Intracutaneous Absorptions,Intradermal Absorptions,Percutaneous Absorptions,Skin Absorptions,Transcutaneous Absorptions,Transdermal Absorptions
D018570 Risk Assessment The qualitative or quantitative estimation of the likelihood of adverse effects that may result from exposure to specified health hazards or from the absence of beneficial influences. (Last, Dictionary of Epidemiology, 1988) Assessment, Risk,Benefit-Risk Assessment,Risk Analysis,Risk-Benefit Assessment,Health Risk Assessment,Risks and Benefits,Analysis, Risk,Assessment, Benefit-Risk,Assessment, Health Risk,Assessment, Risk-Benefit,Benefit Risk Assessment,Benefit-Risk Assessments,Benefits and Risks,Health Risk Assessments,Risk Analyses,Risk Assessment, Health,Risk Assessments,Risk Benefit Assessment,Risk-Benefit Assessments
D019055 No-Observed-Adverse-Effect Level The highest dosage administered that does not produce toxic effects. NOAEL,No-Observed-Effect Level,Acceptable Daily Intake,Tolerable Daily Intake,Acceptable Daily Intakes,Daily Intake, Acceptable,Daily Intake, Tolerable,Daily Intakes, Acceptable,Daily Intakes, Tolerable,Intake, Acceptable Daily,Intake, Tolerable Daily,Intakes, Acceptable Daily,Intakes, Tolerable Daily,Level, No-Observed-Adverse-Effect,Level, No-Observed-Effect,Levels, No-Observed-Adverse-Effect,Levels, No-Observed-Effect,No Observed Adverse Effect Level,No Observed Effect Level,No-Observed-Adverse-Effect Levels,No-Observed-Effect Levels,Tolerable Daily Intakes

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