Final Report on the Safety Assessment of N-Phenyl-p-Phenylenediamine, N-Phenyl-p-Phenylenediamine Hydrochloride, and N-Pheny 1-p-Phenylenediamine Sulfate

Abstract

N-Phenyl-p-Phenylenediamine and its sulfate and hydrochloride salts are aromatic amines. Whereas N-Phenyl-p-Phenylenediamine Sulfate is not currently reported to be used in cosmetics, N-Phenyl-p-Phenylenediamine and N-Phenyl-p-Phenylenediamine Hydrochloride are used as colorants in hair dyes/colors. Data evaluated are for N-Phenyl-p-Phenylenediamine and are extended to the sulfate and hydrochloride salts. The oral median lethal dose (LD50) in rats ranged from 464 mg/kg to 1,000 mg/kg. Acute oral toxicity studies in cats showed increased methemoglobin and Heinz body formation ≥25 mg/kg. Dose-dependent weight reductions were seen in rats fed ≥2,200 ppm for 90 days. Mice fed 14,700 ppm showed a similar response. CNS damage was observed in mice fed ≥5,000 ppm for 91 weeks. Irritation and sensitization were both observed in guinea pigs, but no ocular irritation was seen in rabbits. Oral administration to female rats showed no developmental toxicity in one study, but showed maternal and fetal toxicity and an increase in skeletal malformations in another. Dermal application of a hair dye formulation containing 2.0% N-Phenyl-p-Phenylenediamine to female rats and mice showed no developmental toxicity of any sort. No evidence of carcinogenicity was found in either male or female rats fed N-Phenyl-p-Phenylenediamine for 78 weeks, or in female mice fed up to 10,000 ppm for 48 weeks. Male mice, however, showed a non-dose-dependent increased incidence of hepatocellular neoplasms. In another study, dermal application of a hair dye formulation containing 2.0% N-Phenyl-p-Phenylenediamine to male and female mice once a week for 23 months resulted in no increase in neoplasms compared to controls. Clinical data indicate that N-Phenyl-p-Phenylenediamine is a skin irritant and can be a sensitizer. Sensitization reactions were more common among dermatitis patients who work as hairdressers. Products containing these ingredients are exempt from the principal adulteration provision of the Federal Food, Drug, and Cosmetic Act when the label bears a caution statement and instructions to perform a patch test to ascertain if the user is sensitive to them. Because this ingredient is a sensitizer, users should be screened with a patch test. On the basis of the information in this report, it is concluded that N-Phenyl-p-Phenylenediamine, N-Phenyl-p-Phenylenediamine Sulfate, and N-Phenyl-p-Phenylenediamine Hydrochloride are safe for use in hair dyes at concentrations up to 1.7% (as the free base).