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).

Keywords

N-Phenyl-p-Phenyl-enediamine N-Phenyl-p-Phenylenediamine Hydrochloride N-Phenyl-p-Phenylenediamine Sulfate Safety Cosmetic use Hair dye Rat Mouse Hurnan Chemistry Toxicity Carcinogenicity

References

Adams R.M. , Maibach H.I. , Clendenning W.E. , et al. (1985) A five-year study of cosmetic reactions. J Am Acad Dermatol 13:1062–9.

Angelini G. , Vena G.A. , Giglie G. , Fiordalisi F. , Memghini CL. (1985) Contact dermatitis due to cosmetics. J Appl Cosmetol 3:223-36. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

Bayer AG. (1988) p-Aminodiphenylamin: DIN Sicherheitsdatenblatt. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

Bayer AG. ( Bayer AG. (1982a) Institut für Toxikologie, p-Aminodiphenylamin dest. in Stücken, Prüfun auf primäre Hautreizwirkung, unpublished report. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

Bayer AG. (1982b) Institut für Toxikologie, p-Aminodiphenylamin dest. in Stücken, Prüfun auf Schleimhautreizwirkung, unpublished report. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: SpringerVerlag, 45–63.

Bayer AG. (1985) Institut für Toxikologie, p-Aminodiphenylamin rein, dest., Untersuchungen zur akuten oralen Toxizität an der Katze, unpublished report. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

Broeckx W. , Blondeel A. , Dooms-Goossens A. , Achten G. (1987) Cosmetic intolerance. Contact Dermatitis 16:189–94.

Burnett C.M. , Goldenthal EI. (1988) Mutigeneration reproduction and carcinogenicity studies in Sprague-Dawley rats exposed topically to oxidative hair-coloring formulations containing p-phenylenediamine and other aromatic amines. Food Chem Toxicol 26:467–74.

Burnett C. , Goldenthal E.I. , Harris S.B. , et al. (1976) Teratology and percutaneous toxicity studies on hair dyes. J Toxicol Environ Health 1:1027–40.

10.

Burnett C. , Jacobs M.M. , Seppala A. , Shubik P. (1980) Evaluation of the toxicity and carcinogenicity of hair dyes. J Toxicol Environ Health 6:247–57.

11.

Corbett J.F. , Menkart J. (1973) Hair coloring. Cutis 12:190–7.

12.

Cosmetic, Toiletry, and Fragrance Association. (1993) Personal correspondence from G. N. McEwen. (Dated: 12/6/93).

13.

Eastman Kodak Company. (1979) Eastman Organic Chemicals, Catalog No. 50. Rochester, NY. p. 172.

14.

Eiermann H.J. , Larsen W. , Maibach H.I. , et al. (1982) Prospective study of cosmetic reactions: 1977-1980. J Am Acad Dermatol 6:909–17.

15.

Elder RL , ed. (1985) Final report on the safety assessment of p-Phenylenediamine. J Am Coll Toxicol 4:203–66.

16.

Federal Register. (October 16, 1979) Cosmetic Product Warning Statements; coal tar hair dyes containing 4-methoxy-m-phenylenediamine (2,4-diaminoanisole) of 4-methoxy-m-phenylenediamine sulfate (2,4-diaminoanisole sulfate). 44(201):59509–10.

17.

Food and Drug Administration (FDA). (1993) Cosmetic product formulation data. FDA computer printout. Washington, DC: FDA.

18.

Freeman H.S. , Esancy J.F. , Esancy M.K. , Mills K.P. , Whaley W.M. , Dabney BJ. (1987) An approach to the design of non-mutagenic azo dyes: 1. The identification of non-mutagenic precursors and potential metabolites. Dyes and Pigments. 8:417–30. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45-63.

19.

Guerra L. , Tosti A. , Bardazzi F. , et al. (1992a) Contact dermatitis in hairdressers: the Italian experience. Contact Dermatitis 26:101–7.

20.

Guerra L. , Bardazzi F. , Tosti A. (1992b) Contact dermatitis in hairdressers' clients. Contact Dermatitis 26:108–11.

21.

International Agency for Research on Cancer (IARC). (1993) IARC Monographs on the evaluation of carcinogenic risks to humans. Vol. 57. Occupational exposures of hairdressers and barbers and personal use of hair colourants; some hair dyes, cosmetic colourants, industrial dyestuffs and aromatic amines. Lyon, France, 43-118.

22.

Ishihara M. , Nogami T. , Itoh M. , Nishimura M. (1985) Sensitization potency of dye intermediates and modifiers in guinea pigs. Skin Res 27:585–90.

23.

Joshi A. , Tewari P. , Khanna S.K. , Singh GB. (1987) A simple test to monitor aromatic amine clearance in occupational workers. Int J Environ Anal Chem 28:297–307.

24.

Khanna S.K. , Tewari P.T. , Joshi A. , Singh GB. (1987) Studies on the skin uptake and efflux kinetics of N-Phenyl-p-Phenylenediamine: an aromatic amine intermediate. Int J Cosmet Sci 9:137–47. In: BG CHEMIE (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45-63.

25.

Landthaler M. , Burg G. , Zirbs S. (1981) Farbstoff- und Nickelallergie im Friseurgewerbe. Der Hautarzt 32:281–4. In: BG CHEMIE (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45-63.

26.

Litton Bionetic Inc. (1973) Progress report for contract no. NIH-NCI-E-C-72-3252 (1973). In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

27.

McCann J. , Choi E. , Yamasaki E. , Ames BN. (1975) Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals. Proc Nat Acad Sci 72:5135–9. In: BG CHEMIE (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45-63.

28.

Monsanto Company. (1989) Monsanto material safety data sheet. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

29.

Mortelmans K. , Haworth S. , Lawlor T. , Speck W. , Tainer B. , Zeiger E. (1986) Salmonella mutagenicity tests: II. Results from testing of 270 chemicals. Environ Mol Mutagen 8:1–119.

30.

National Cancer Institute (NCI). (1978) Bioassay of N-Phenyl-p-Phenylenediamine for possible carcinogenicity. NTIS No. PB-285 856.

31.

National Toxicology Program (NTP). (1988) Mutagenicity results. In: BG Chemie (1993) Toxicology evaluation 5: Potential health hazards of existing chemicals. New York: Springer-Verlag, 45–63.

32.

Nikitakis J.M. , McEwen G.N. , Wenninger JA. (1991) CTFA International Cosmetic Ingredient Dictionary, 4th ed., Washington, DC: The Cosmetic, Toiletry, and Fragrance Association, Inc., 437–8.

33.

North American Contact Dermatitis Group (1980) Patch testing in allergic contact dermatitis. Evanston, IL: American Academy of Dermatology.

34.

Picciano J.C. , Schnetzinger R.W. , Morris W.E. , Wolf B.A. , Todwell DE. (1984) Evaluation of the teratogenic potential of the oxidative dye N-Phenyl-p-Phenylenediamine. Drug Chem Toxicol 7:167–76.

35.

Raza H. , Khanna S.K. , Singh G.B. , Murti CRK. (1982) Interaction of p-aminodiphenylamine with rat gut mucosal epithelium. Indian J Exp Biol 20:773–5.

36.

Raza H. , Khanna S.K. , Singh S.B. , Murti CRK. (1983) Transport of metanil yellow in rat plasma and interaction of its metabolite, p-aminodiphenylamine with serum proteins. Toxicol Environ Chem 6:179–89.

37.

Schäfer U., Metz J., Pevny I., Rockl H. (1978) Sensibilisierungsversuche an Meerschweinchen mit funf parasubstituierten Benzolderivaten. In: BG CHEMIE (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals.

38.

Schonning L. (1969). Sensitizing properties of p-aminodiphenylamine. Acta Derm Venereol 49:501-2. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.

39.

Schroeder R.E., Daly IW. (1989) A developmental toxicity study in rats with (4-ADPA) 4-aminodiphenyl amine with attached appendices and cover letters dated 031589. NTIS Nos. OTS0516609-1 and OTS0526843.

40.

Singh R.L. , Khanna S.K. , Shanker R. , Singh GB. (1986) Acute and short-term toxicity studies on p-aminodiphenylamine. Vet Hum Toxicol 28:219–23.

41.

Singh R.L. , Khanna S.K. , Singh GB. (1992) p-Aminodiphenylamine induced biochemical changes in sex organs of male albino rats. Indian J Exp Biol 30:110–13.

42.

Srivastava L.P. , Khanna S.K. , Singh G.B. , Murti CRK. (1982a) In vitro studies on the biotransformation of metanil yellow. Environ Res 27:185–9.

43.

Srivastava L.P. , Khanna S.K. , Singh G.B. , Murti CRK. (1982b) Studies on the protein binding mechanism of p-aminodiphenylamine: a hair dye constituent. Chemosphere 11:175–83.

44.

Tewari P. , Das M. , Khanna SK. (1989) N-Phenyl-p-Phenylenediamine uptake onto reconstituted collagen fibrils. Toxicol In Vitro 3:323–8.

45.

Tosti A. , Varotti C. , Minghetti G. , et al. (1986) Immunologic characterization of infiltrating cells in flare-up reactions. Contact Dermatitis 14:62.

46.

Weast RC , ed. (1982) CRC handbook of chemistry and physics. Boca Raton, FL: CRC Press, C-445.

47.

Yoshikawa K. , Uchino H. , Kurata H. (1976) Studies on the mutagenicity of hair dye. Eisei Shikensho Hokok94:28-32. In: BG Chemie (1993) Toxicological Evaluations 5: Potential Health Hazards of Existing Chemicals. New York: Springer-Verlag, 45–63.