Final report on the safety assessment of 3-methylamino-4-nitrophenoxyethanol as used in hair dyes.

3-Methylamino-4-Nitrophenoxyethanol is a semipermanent (direct) hair colorant used in 21 hair dyes and colors at use concentrations up to 0.15%. When applied to human skin in vitro, 0.42% of the applied 3-Methylamino-4-Nitrophenoxyethanol was recovered in the receptor fluid. In an acute toxicity study using rats, 3-Methylamino-4-Nitrophenoxyethanol at 1000 mg/kg resulted in hypoactivity, piloerection, dyspnea, and lateral recumbency in animals that later died. The surviving rats exhibited none of these signs. No abnormalities were found at necropsy. Subchronic toxicity tests using rats fed 25, 100, or 400 mg/kg day(-1)3-Methylamino-4-Nitrophenoxyethanol for up to 93 days resulted in yellow urine and tails with all three dose levels and yellow fur occurred in the two high-dose groups. The no observed adverse effect level (NOAEL) for 3-Methyl-amino-4-Nitrophenoxyethanol was 100 mg/kg day(- 1). Two percent 3-Methylamino-4-Nitrophenoxyethanol was a slight ocular irritant but not a dermal irritant using rabbits and it was not a sensitizer using the murine local lymph node Assay. There were no embryotoxic or teratogenic effects observed in doses up to 750 mg/kg day(-1) in rats; the NOAEL was defined as 100 mg/kg. 3-Methylamino-4-Nitrophenoxyethanol was not genotoxic in in vitro assays including multiple strains of Salmonela typhimurium and Escherichia coli, Chinese Hamster ovary cells, and human lymphocyte cultures. No carcinogenicity studies were available, nor were any clinical tests reported. As reviewed by the Cosmetic Ingredient Review (CIR) Expert Panel, there are gaps in the data available for of 3-Methylamino-4-Nitrophenoxyethanol. In particular, there is an absence of data from chronic animal studies. The Expert Panel considered that the low percutaneous absorption and that the available developmental toxicity data and the subchronic toxicity data, both of which resulted in relatively high NOAEL values, alleviate concern about the absence of chronic exposure data. In addition, several studies demonstrated that 3-Methylamino-4-Nitrophenoxyethanol is not genotoxic. Direct hair dyes, of which 3-Methylamino-4-Nitro-phenoxyethanol is one, although not the focus in all investigations, appear to have little evidence of an association with adverse events as reported in hair dye epidemiology studies. The lack of phototoxicity data was not considered to be a concern because this is a direct hair dye ingredient, which has little skin contact and residual color is attached to hair, not normally to skin. No human skin sensitization or irritation data were available. However, hair dyes containing 3-Methylamino-4-Nitrophenoxyethanol, as coal tar hair dye products, are exempt from the principal adulteration provision and from the color additive provisions in sections 601 and 706 of the Federal Food, Drug, and Cosmetic Act, when the label bears a caution statement and patch test instructions for determining whether the product causes skin irritation. The Expert Panel expects that following this procedure will prospectively identify individuals who would have an irritation/sensitization reaction and allow them to avoid significant exposures and concluded that 3-Methylamino-4-Nitrophenoxyethanol is safe as a cosmetic ingredient in the practices of use and use concentrations described in this safety report.