5-Amino-o-cresol is used as an oxidative dye coupler (secondary intermediate) or oxidative (permanent) in hair dye formulations. It was nominated for study by the National Cancer Institute because it is a widely used genotoxic hair dye component for which no cancer studies have been reported. Male and female F344/NTac rats and B6C3F1/N mice were administered 5-amino-o-cresol (greater than 99% pure) dermally for 3 months. Genetic toxicology studies were conducted in Salmonella typhimurium, peripheral blood erythrocytes of male and female mice, and bone marrow of male mice.
Groups of 10 male and 10 female core study rats were dermally administered 0, 2, 4, 8, 16, or 32 mg 5-amino-o-cresol/kg body weight in 95% ethanol, 5 days per week for 14 weeks; additional groups of 10 male and 10 female clinical pathology study rats were administered the same doses for 23 days. Groups of 10 male and 10 female mice were administered 0, 8, 16, 32, 64, or 128 mg/kg for 14 weeks.
All rats survived to the end of the study. Mean body weights of all dosed groups of rats were similar to those of the vehicle control groups. There were no biologically significant differences between dosed and vehicle control groups in hematology or clinical chemistry parameters or in organ weights. Administration of 8, 16, or 32 mg/kg did not result in significant changes/differences in reproductive organ histopathology, sperm parameters of male rats, or the estrous cyclicity of female rats when compared to the vehicle controls. There were no gross or microscopic lesions that were considered biologically relevant or treatment related.
All male mice survived to the end of the study; one 32 mg/kg female mouse died spontaneously on day 73. Mean body weights of all dosed groups of mice were similar to those of the vehicle control groups. There were no statistically significant differences between dosed and vehicle control groups in hematology parameters or in organ weights. Administration of 32, 64, or 128 mg/kg did not result in significant changes/differences in reproductive organ histopathology, sperm parameters of male mice, or the estrous cyclicity of female mice when compared to the vehicle controls. There were no gross or microscopic lesions that were considered treatment related.
5-Amino-o-cresol was tested for mutagenicity in four strains of S. typhimurium (TA97, TA98, TA100, and TA1535) with and without 10% induced rat or hamster liver S9 enzymes; it was strongly positive in TA97, TA98, and TA100 in the presence of either species of S9. No mutagenicity was observed for 5-amino-o-cresol in strain TA1535, with or without S9. The strongest mutagenic response (based on fold-increase and the lowest effective dose) was seen in strain TA98, which mutates via frame shifting. In vivo, no increases in micronucleated erythrocytes were observed in peripheral blood of male or female B6C3F1/N mice in the current study. Likewise, no significant dose-related increases in the frequencies of micronucleated reticulocytes were seen in peripheral blood or bone marrow of male B6C3F1/N mice administered 50 to 400 mg/kg 5-amino-o-cresol by gavage once daily for 3 days. No significant changes were seen in the percentage of reticulocytes in any of the micronucleus studies, suggesting that 5-amino-o-cresol did not induce bone marrow toxicity.