Phenyl Methyl Pyrazolone (PMP) is a heterocyclic amine that is used in hair colorants. The phenylhydrazine content in PMP is below the limit of detection. Phenyl Methyl Pyrazolone was slightly toxic to rats, with an oral LD50 of 3.5 g/kg. Feeding rats and mice with PMP-treated feed for 7 weeks was uneventful. A compound containing 500 mg/kg of PMP was, at most, a mild ocular irritant. Phenyl Methyl Pyrazolone was slightly irritating to rabbit skin when tested under occlusive patches. It did not produce a sensitization reaction in guinea pigs. Phenyl Methyl Pyrazolone was nonmutagenic in two assays and noncarcinogenic in oral feeding studies. On the basis of the available data presented in this report, it is concluded that Phenyl Methyl Pyrazolone is safe for use as a cosmetic ingredient in the present practices of use and concentration.
References
1.
Anthony, H.M. and Thomas, G.M. (1970). Tumors of the urinary bladder: An analysis of the occupations of 1,030 patients in Leeds, England. J. Natl. Cancer Inst.45:879–898.
2.
Ashby, J. and Tennant, R.W. (1988). Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. Mutat. Res., 204:17–115.
3.
Baty, J.D. and Price Evans, D.A. (1973). Norphenazone, a new metabolite of phenazone in human urine. J. Pharm. Pharmac.25:83–84.
4.
Bottcher, J., Bassmann, H., and Schuppel, R. (1984). Quantitation of norantipyrine sulfate and norantipyrine glucuronide as major metabolites of antipyrine in man and rat. J. Pharm. Pharmacol.36:391–398.
5.
Brusick, D. (1983). Evaluation of chronic rodent bioassays and Ames tests as accurate models for predicting human carcinogens. Environ. Sci. Res.29:153–163.
6.
Clemmesen, J. (1981). Epidemiological studies into the possible carcinogenicity of hair dyes. Mutat. Res.87:65–79.
7.
Code Of Federal Regulations. (April 1, 1982). Title 21, Part 720.4. Voluntary filing of cosmetic product ingredient and cosmetic raw material composition statement. Information requested about cosmetic products.
8.
Cole, P., Hoover, R., and Friedall, C.H. (1972). Occupation and cancer of the lower urinary tract. Cancer29:1250–1260.
9.
Corbett, J.F. and Menkart, J. (1973). Hair coloring. Cutis12:190–197.
10.
Cosmair. (1990). Absorbance spectrum for phenyl methyl pyrazolone. Submission of unpublished data to CTFA.1
11.
Cosmetic, Toiletry, And Fragrance Association (Ctfa). (1983). CTFA List of Japanese Cosmetic Ingredients. Washington, D.C.: CTFA.
12.
Ctfa. (1990). Data received from the supplier of phenyl methyl pyrazolone concerning the boiling point and % purity of phenyl methyl pyrazolone. Submission of unpublished data to CTFA.1
13.
Danhof, M., De Groot-Van Der Vis, E., and Breimer, D.D. (1979). Assay of antipyrine and its primary metabolites in plasma, saliva and urine by high-performance liquid chromatography and some preliminary results in man (Abstr. only). Pharmacology18(4):210–223.
14.
De Vries, J.X., Staiger, C., Wang, N.S., Schlicht, F., and Koroknay, B. (1984). Simultaneous determination of antipyrine and metabolites in human plasma and urine by high-performance liquid chromatography (Abstr. only). J. Chromatogr.309:219–221.
15.
Dunham, L.J., Rabson, A.S., Stewart, H.L., Frank, A.S., and Young, J.L. (1968). Rate, interview, and pathology study of cancer of the urinary bladder in New Orleans, LA. J. Natl. Cancer Inst.41:683–709.
16.
Dunkel, V.C., Zeiger, E., Brusick, D., McCoy, E., McGregor, D., Mortelmans, K., Rosenkranz, H.S., and Simmon, V.F. (1985). Reproducibility of microbial mutagenicity assays: II. Testing of carcinogens and noncarcinogens in Salmonella typhimurium and Escherichia coli. Environ. Mutagen.7(5):1–248.
17.
Eichelbaum, M., Sonntag, B., and Dengler, H.J. (1981). HPLC determination of antipyrine metabolites. Pharmacology23:192–202.
18.
Elder, R.L. (Ed.). (1985a). Final report on the safety assessment of p-phenylenediamine. J. Am. Coll. Toxicol.4(3):203–266.
19.
Elder, R.L. (Ed.). (1985b). Final report on the safety assessment of 2-nitro-p-phenylenediamineand4-nitro-o-phenylenediamine. J. Am. Coll. Toxicol.4(3):161–202.
Estrin, N.F., Crosley, P.A., and Haynes, C.R. (Eds.). (1982). CTFA Cosmetic Ingredient Dictionary. Washington, D.C.: CTFA. p. 232.
22.
European Economic Community (Eec). (1989). The EEC Cosmetic Directive. Updated Version—Incorporating all amendments until 15 March 1989.
23.
Federal Register. (October 16, 1979). Cosmetic Product Warning Statements; Coal Tar Hair Dyes Containing 4-Methoxy-m-Phenylenediamine (2,4-Diaminoanisole) or 4-Methoxy-m-Phenylenediamine Sulfate (2,4-Diaminoanisole Sulfate). 44(201), 59509–10.
24.
Food And Drug Administration (Fda). (1984). Cosmetic product formulation data. FDA computer printout.
25.
Fda. (1987). Frequency of current common usual or chemical ingredients on the product file.
26.
Garfinkel, J., Selvin, S., and Brown, S.M. (1977). Possible increased risk of lung cancer among beauticians. J. Natl. Cancer Inst.58:141–143.
27.
Grasselli, J.G. (Ed.). (1973). Atlas of Spectral Data and Physical Constants for Organic Compounds. Cleveland, OH: CRC Press, p. B-846.
28.
Green, A., Willet, W.C., Colditz, G.A., Stampfer, M.J., Bain, C., Rosner, B., Hennekens, C.H., and Speizer, F.E. (1987). Use of permanent hair dyes and risk of breast cancer. J. Natl. Cancer Inst.79(2):253–257.
29.
Griesemer, R.A. and Cueto, C. (1980). Toward a classification scheme for degrees of experimental evidence for the carcinogenicity of chemicals for animals. Int. Agency Res. Cancer27:259–281.
30.
Hare, R.C. (1974). Chemical and environmental treatments promoting rooting of pine cuttings. Can. J. For. Res.4:101–106.
31.
Hare, R.C. (1981). Improved rooting powder for chrysanthemums. Hort. Sci.16(1):90–91.
32.
Hawley, G.G. (1971). The Condensed Chemical Dictionary, 8th ed. New York: Van Nostrand Reinhold Co., p. 582.
33.
Haworth, S., Lawlor, T., Mortelmans, K., Speck, W., and Zeiger, E. (1983). Salmonella mutagenicity results for 250 chemicals. Environ. Mutagen.5(1):3–142.
34.
Hennekens, C.H., Speizer, F.E., Rosner, B., Bain, C.J., Belanger, C., and Peto, R. (1979). Use of permanent hair dyes and cancer among registered nurses. Lancet1:1390–1393.
35.
Hignite, C.E., Tschanz, C., Huffman, D.H., and Azarnoff, D.L. (1978). Quantitation of N-demethylantipyrine in biological samples and isolation and characterization of its glucuronic acid conjugate. Drug Metab. Disposition6(3):288–295.
36.
Hodge, H.C. and Sterner, J.H. (1949). Tabulation of toxicity classes. Am. Indus. Hyg. A. Quart.10:93–96.
37.
Inaba, T. and Fischer, N.E. (1980). Antipyrine metabolism in man: simultaneous determination of norantipyrine and 4-hydroxyantipyrine in urine by gas chromatography (Abstr. only). Can. J. Physiol. Pharmacol.58(1):17–21.
38.
International Agency For Research On Cancer (Iarc). (1982). Evaluation of Carcinogenic Risk of Chemicals to Humans, Vol. 16. Lyon, France: IARC. pp. 51–62.
39.
Iarc. (1987). The establishment of the risk of chemicals to humans. Overall evaluation of carcinogenicity and updating of IARC monographs. IARC Monogr.1–42 (Suppl. 7):61
40.
Jain, M., Morgan, R.W., and Elinson, L. (1977). Hair dyes and bladder cancer. Can. Med. Assoc. J.117:1131–1133.
41.
Kahn, G.C., Boobis, A.R., Blair, I.A., Brodie, M.J., and Davies, D.S. (1981). A radiometric high-pressure liquid chromatography assay for the simultaneous determination of the three main oxidative metabolites of antipyrine studies in vitro. Analyt. Biochem.113:292–300.
42.
Katritzky, A.R. and Maine, F.W. (1964). Tautomers of hetero-aromatic compounds with five-membered rings. IV. 1-substituted pyrazolin-5-ones. Tetrahedron20:299.
43.
Kinlen, L.J., Harris, R., Garrod, A., and Rodriguez, K. (1977). Use of hair dyes by patients with breast cancer: A case-control study. Br. Med. J.2:366–368.
44.
Koenig, K., Pasternack, B.S., Shore, R.E., and Strat, P. (1991). Hair dye use and breast cancer: A case-controlled study among screening participants. Am. J. Epidemiol.133:985–995.
45.
L'Oreal. (1977a). Determination of the ocular irritation index of phenyl methyl pyrazolone in the rabbit. Unpublished data submitted to CTFA.1
46.
L'Oreal. (1977b). Primary cutaneous irritation index of phenyl methyl pyrazolone. Unpublished data submitted to CTFA.1
47.
L'Oreal. (1981). Evaluation of the sensitizing potential of a test substance (phenyl methyl pyrazolone) by a topical application in the guinea pig. Unpublished data submitted to CTFA.1
48.
L'Oreal. (1985). Determination of the phenylhydrazine content in phenyl methyl pyrazolone by HPLC. Unpublished data submitted to CTFA.1
49.
Marichy, M., Gonnet, C., and Zlatanov, L. (1986). Chromatographic behavior of alkyl-bonded phases: separation of barbiturates and pyrazolones on precoated plates. Chromatographia21(2):105–109.
50.
Markley, B., Meloan, C.E., Lambert, J.L., and Chiang, Y.C. (1987). A sensitive, selective, and rapid colorimetric method to determine cyanide contamination in containers, capsules, and liquids. Anal. Lett.20(8):1225–1236.
51.
Medical Subject Headings (Mesh)—Supplementary Chemical Records. (1985). Bethesda, MD: (U.S.) National Library of Medicine.
52.
Menck, H.R., Pike, M.C., Henderson, B.E., and Jing, J.S. (1977). Lung cancer risk among beauticians and other female workers. J. Natl. Cancer Inst.59:1423–1425.
53.
Mikati, M.A., Szabo, G.K., Pylilo, R.J., Le Duc, B.W., Browne, T.R., and Greenblatt, D.J. (1988). Improved high-performance liquid chromatographic assay of antipyrine, hydroxymethylantipyrine, 4-hydroxyantipyrine, and norantipyrine in urine. J. Chromatogr.433:305–311.
54.
Moncrieff, J. (1986). Simultaneous assay of antipyrine and its major metabolites in urine using high-performance liquid chromatography and on-line solid phase sample clean-up (Abstr. only). J. Chromatogr.383(2):425–431.
55.
Murray, S. (1980). An improved combined gas chromatographic mass spectrometric assay for the estimation of norphenazone in urine. Biomed. Mass Spectrom.7(4):179–182.
56.
Nakagawa, A., Nakamura, K-I., Takashi, I., and Chiba, K. (1982). Automated high-performance liquid chromatographic method for the determination of antipyrine and its metabolites in urine. J. Chromatogr.231:349–360.
57.
Nanda, B., Padmanavan, S., Tripathy, B., and Mittra, A.S. (1975). Heterocyclic fungicides—Part 1. J. Ind. Chem. Soc.52:533–537.
58.
Nasca, P.C., Lawrence, C.E., Greenwald, P., Chorost, S., Arbuckle, J.T., and Paulson, A. (1979). Relationship of hair dye use, benign breast disease, and breast cancer. J. Natl. Cancer Inst.64:23–28.
59.
National Cancer Institute (Nci). (1978). Bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity. DHEW Publication No. (NIH) 78–1396.
60.
Nayak, A., Das, S., Mishra, C.R., and Mittra, A.S. (1977). Heterocyclic fungicides—Part II. J. Ind. Chem. Soc.54:485–487.
Shafer, N. and Shafer, R.W. (1976). Potential of carcinogenic effects of hair dyes. N.Y. State J. Med.76:394–396.
63.
Shelby, M.D. and Stasiewicz, S. (1984). Chemicals showing no evidence of carcinogenicity in long-term, two-species rodent studies: The need for short-term test data. Environ. Mutagen.6:871–878.
64.
Shore, R.E., Pasternack, B.S., Thiessen, E.U., Sadow, M., Forbes, R., and Albert, R.E. (1979). A case-control study of hair dye use and breast cancer. J. Natl. Cancer Inst.62:277–283.
65.
Society Of Dyers And Colourists. (1956). Colour Index. 2nd ed. Vol. 3. Yorkshire, England.
66.
Sweet, D.V. (Ed.). (1987). Registry of Toxic Effects of Chemical Substances (RTECS). 1985–86 ed. Vol. 4. p. 4009.
67.
Tang, B.K., Uchino, H., Inaba, T., and Kalow, W. (1982). Simultaneous determination of antipyrine, 4-hydroxymethylantipyrine, and norantipyrine in urine by gas chromatography chemical ionization mass spectrometry. Biomed. Mass Spectrom.9(10):425–428.
68.
Teunissen, M.W.E., Meerburg-Van Der Torren, J.E., Vermeulen, N.P.E., and Breimer, D.D. (1983). Automated high-performance liquid chromatographic determination of antipyrine and its main metabolites in plasma, saliva, and urine, including 4,4′-dihydroxyantipyrine (Abstr. only). J. Chromatogr.278(2):367–378.
69.
U.S. International Trade Commission. (1977). Synthetic organic chemicals: United States production and sales, 1975. Washington, D.C.: USITC Publication 804, U.S. Government Printing Office.
70.
Weast, R.C. (Ed.). (1982). CRC Handbook of Chemistry and Physics. Boca Raton, FL: CRC Press, Inc., Section C, p. 484.
71.
Weisburger, E.K. (1983). Species differences in response to aromatic amines. Basic Life Sci.24:23–47.
72.
Wynder, E.L. and Goodman, M. (1983). Epidemiology of breast cancer and hair dyes. J. Natl. Cancer Inst.71:481–488.
73.
Wynder, E.L., Onderdonk, J., and Mantel, N. (1963). An epidemiological investigation of cancer of the bladder. Cancer16:1388–1407.
74.
Zeiger, W. (1987). Carcinogenicity of mutagens: Predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res.47:1287–1296.
75.
Zeiger, E., Anderson, B., Haworth, S., Lawlor, T., Mortelmans, K., and Speck, W. (1987). Salmonella mutagenicity tests: III. Results from testing of 255 chemicals. Environ. Mutagen.9(9):1–110.
