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.
A Review of the Role of Neurotensin and Its Receptors in Colorectal Cancer
