p-Hydroxyanisole is used as an antioxidant in cosmetic products at concentrations of up to 1.0 percent. The acute oral LD50 of p-Hydroxyanisole in rats was estimated as 1630 mg/kg. Undiluted p-Hydroxyanisole is a severe skin and ocular irritant in rabbits but produced minimal eye irritation at 0.1 percent and minimal rabbit skin irritation at 5 percent. Skin sensitization to p-Hydroxyanisole occurred when guinea pigs were treated at 0.5 M. p-Hydroxyanisole is a skin-depigmenting agent at concentrations approximating those used in cosmetic products. p-Hydroxyanisole was nonmutagenic in the Ames assay. No local toxic changes or tumors were observed following long-term application of 5 and 10 percent p-Hydroxyanisole. The antioxidant was inactive as a tumor promoter. Solutions of p-Hydroxyanisole produced embryotoxicity but not teratogenicity.
The function of p-Hydroxyanisole in cosmetics is that of an antioxidant; it is not intended for use as a skin lightener or skin-depigmenting agent. Because of the depigmenting action of p-Hydroxyanisole in black guinea pigs at reported concentrations approaching those used in cosmetics, it is concluded that p-Hydroxyanisole is unsafe for use as a cosmetic ingredient.
References
1.
1. Estrin, N.F., Crosley, P.A., and Haynes, C.R. (1982). CTFA Cosmetic Ingredient Dictionary, 3rd ed.Washington, DC: Cosmetic, Toiletry and Fragrance Association, p. 127.
2.
2. Hawley, G.G. (1971). The Condensed Chemical Dictionary, 8th ed.New York: Van Nostrand Reinhold.
3.
3. Weast, R.C. (1978). CRC Handbook of Chemistry and Physics, 59th ed.Boca Raton, FL: CRC Press.
4.
4. Sax, N.I. (1979). Dangerous Properties of Industrial Materials, 5th ed.New York: Van Nostrand Reinhold, p. 732.
5.
5. COSMETIC, TOILETRY AND FRAGRANCE ASSOCIATION (CTFA). (January 11, 1978). Submission of unpublished data by CTFA. Cosmetic ingredient chemical description: p-Hydroxyanisole.*
6.
6. Hake, C.L., and Rowe, V.K. (1963). Hydroquinone ethers, in: F.A. Patty (ed.). Industrial Hygiene and Toxicology, 2nd ed.New York: Interscience, Vol. 2, pp. 1686–90.
7.
7. Demerseman, P., Platzer, N., Bachelet, J.P., Cheutin, A., and Royer, R. (1971). Relations of the structure and the physicochemical properties of alkylated benzene-type phenols. Bull. Soc. Chim. Fr.1971(1), 201–10.
8.
8. Hodge, H.C., Sterner, J.H., Maynard, E.A., and Thomas, J. (1949). Short-term toxicity tests on the mono-and di-methyl ethers of hydroquinone. J. Ind. Hyg. Toxicol.31(2), 79–92.
10. Habboush, A.E., and Amarin, A.M. (1974). Separation of monosubstituted phenols by gas-liquid chromatography. Talanta21(9), 927–32.
11.
11. AMERICAN CONFERENCE OF GOVERNMENTAL INDUSTRIAL HYGIENISTS, INC. (ACGIH). (1980). Documentation of the Threshold Limit Values, 4th ed. Cincinnati, OH, p. 259.
12.
12. Verma, K.K., Tripathi, R.P., Bajaj, I., Prakash, O., and Parihar, D.B. (1970). Studies on the synthesis of butylated hydroxyanisole. J. Chromatogr.52(3), 507–11.
13.
13. Gakh, I.G., and Gaidai, N.S. (1970). Determination of the vapor pressures of p-methoxyphenol, butyl-hydroxyanisole, and 2,5-dibutylhydroxyanisole. Zh. Prikl. Khim. Leningrad43(1), 212.
14.
14. Aihara, A. (1960). Estimation of the energy of hydrogen bonds formed in crystals. II. Phenols. Bull. Chem. Soc. Jpn.33(2), 194–200.
15.
15. Ghosh, A., and Palit, S.R. (1974). Relative activities of phenols in aprotic solvents. Indian J. Chem.12(4), 382–6.
16.
16. Hansch, C., Kiehs, K., and Lawrence, G.L. (1965). The role of substituents in the hydrophobic bonding of phenols by serum and mitochondrial proteins. J. Am. Chem. Soc.87(24), 5770–3.
17.
17. Wada, S., Tomioka, S., and Moriguchi, I. (1969). Protein bindings. VI. Binding of phenols to bovine serum albumin. Chem. Pharm. Bull.17(2), 320–3.
18.
18. Kulic, J., and Vecera, M. (1974). Kinetics of reaction of p-substituted phenols with bromine in water. Collect. Czech. Chem. Commun.39(1), 171–6.
19.
19. Argauer, R.J. (1968). Rapid procedure for the chloroacetylation of microgram quantities of phenols and detection by electron-capture gas chromatography. Anal. Chem.40(1), 122–4.
20.
20. Coppola, G. (1971). Gas-chromatographic method for determining hydroquinone monomethyl ether. Nuova Chim.47(1), 49–50.
21.
21. Louwerse, H.L. (1968). Gas-liquid chromatographic separation of methyl-and methoxysubstituted benzenes, phenols, phenylacetates, and acetophenols. J. Gas Chromatogr.6(11), 563–6.
22.
22. Vahessaar, V., Klesment, I., and Eisen, O. (1968). Comparative chromatography of phenols and their ethers. Eesti NSV Tead. Akad. Toim. Keem. Geol.17(2), 124–32.
23.
23. Soczewinski, E., and Szumilo, H. (1973). Investigations on the mechanism and selectivity of chromatography on thin layers of polyamide. I. Systems of the type cyclohexane + polar solvent-polyamide. J. Chromatogr.81(1), 99–107.
24.
24. Smith, R.V., Rosazza, J.P., and Nelson, R.A. (1974). Thin-layer chromatographic determination of simple phenols in microbial extracts. J. Chromatogr.95(2), j247–9.
25.
25. Toul, J., and Moukova, N. (1972). Purity control of some o-hydroxy-substituted thiazolylazo dyes by thin-layer chromatography. J. Chromatogr.67(2), 355–42.
26.
26. Brook, A.J.W., and Housley, S. (1969). The interaction of phenols with Sephadex gels. J. Chromatogr.41(2), 200–4.
27.
27. Hendrickson, J.G. (1968). Basic gel permeation chromatography studies. II. Benzene results with small molecules. J. Chromatogr.32(3), 543–58.
28.
28. Lapitskaya, S.K., Kokhanovskaya, M.G., and Khomyakova, L.K. (1974). Polarographic determination of hydroquinone methyl ethers. Obshch. Prikl. Khim.6, 63–4.
29.
29. Karpov, O.N., Gakh, I.G., and Lysyak, V.Y. (1967). Quantitative oxidimetric determination of hydroquinone and its monomethyl ether when present together. Zh. Anal. Khim.22(3), 472–3.
30.
30. FOOD AND DRUG ADMINISTRATION (FDA). (Dec. 22, 1981). Cosmetic product formulation data: Ingredient used in each product category. Computer printout. Washington, DC.
31.
31. FDA. (Jan. 5, 1982). (a) Frequency of trade name ingredients in the cosmetic product file and (b) frequency of common, usual, or chemical names in the cosmetic product file. Computer printout. Washington, DC.
32.
32. CODE OF FEDERAL REGULATIONS. (Revised as of April 1, 1983). Title 21 Part 720.4. Voluntary Filing of Cosmetic Product Ingredient and Cosmetic Raw Material Composition Statement. Information Requested about Cosmetic Products.
33.
33. Pathak, M.A. (November 27, 1983). Submission of unpublished data by CTFA. In vitro and in vivo effects of para-hydroxyanisole (PHA): A report on the acute and chronic toxicity studies of PHA on pigmented skin of guinea pigs and on melanocytes in culture.*
34.
34. Pathak, M.A., Wick, M., Farinelli, W., and Fitzpatrick, T.B. (1979). Evaluation of azelaic acid on normal skin pigmentation and on the B-16 mouse melanoma. Paper presented at the Society for Dermato-logical Research Joint Meeting, RAI Congress Centre, Amsterdam, The Netherlands, June 10–14, 1979 (abstr.). J. Invest. Dermatol.72, 266–90.
35.
35. Gellin, G.A., Maibach, H.I., Misiaszek, M.H., and Ring, M. (1979). Detection of environmental depigmenting substances. Contact Dermatitis5(4), 201–13.
36.
36. Brun, R. (1959). Contribution a l'etude de la depigmentation experimentale (1st communication). Resultats preliminaries. Dermatologica118, 202–7.
37.
37. Brun, R. (1960). Zur experimentellen depigmentierung. J. Soc. Cosmet. Chem.11, 571–80.
38.
38. Brun, R. (1961). Contribution a l'etude, de la depigmentation experimentale. Bull. Inst. Genevois61, 3–89.
39.
39. Riley, P.A. (1969). Hydroxyanisole depigmentation: In vivo studies. J. Pathol.97(2), 185–91.
40.
40. Durmishev, A. (1973). Experimental leukoderma induced by the monomethyl ether of hydroquinone. Dermatol. Venerol. (Bulg.)12(3), 172–7. English translation.
41.
41. Riley, P.A., and Seal, P. (1974). The role of substituted anisoles in epidermal micro-invasion. J. Pathol.114(1), 1–7.
42.
42. Wohlrab, W., and Zaumseil, R.P. (1976). Experimental depigmentation of the skin. Part II. Epidermal reaction by external application of depigmenting substances. Dermatol. Monatsschr.162(12), 980–5.
43.
43. Durmischev, A.L., and Davidoff, M.S. (1976). Depigmentation effect of hydroquinone monomethyl ether. Dermatol. Monatsschr.162(4), 306–11. English translation.
44.
44. Riley, P.A., Sawyer, B., and Wolff, M.A. (1975). The melanocytotoxic action of 4-hydroxyanisole. J. Invest. Dermatol.64(2), 86–9.
45.
45. Riley, P.A. (1969). Hydroxyanisole depigmentation: In vitro studies. J. Pathol.97(2), 193–206.
46.
46. Riley, P.A. (1970). Mechanism of pigment-cell toxicity produced by hydroxyanisole. J. Pathol.101(2), 163–9.
47.
47. Morgan, B.D., O'neill, T., Dewey, D.L., Galpine, A.R., and Riley, P.A. (1981). Treatment of malignant melanoma by intravascular 4-hydroxyanisole. Clin. Oncol.7(3), 227–34.
48.
48. Seal, P., Riley, P.A., and Inman, D.R. (1969). Basal cell encroachment into the dermis caused by applications of hydroxyanisole. J. Invest. Dermatol.52(3), 264–7.
49.
49. Riley, P.A., and Seal, P. (1968). Microinvasion of epidermis caused by substituted anisoles. Nature220(5170), 922–3.
50.
50. Riley, P.A., and Seal, P. (1969). Intranuclear fibers produced by 4-hydroxyanisole. Exp. Mol. Pathol.10(1), 63–7.
51.
51. Woods, D.A., and Smith, C.J. (1969). The effects of 4-hydroxyanisole on hamster cheek pouch. Exp. Mol. Pathol.10(2), 107–14.
52.
52. Grasso, P., and Rostron, C.C. (1970). Microinvasion of epidermis caused by substituted anisoles. Nature225(5228), 188–9.
53.
53. Breathnach, A.S., Diala, E.B., Gallagher, S.M., Porro, M.N., and Passi, S. (1981). Ultrastruc-tural observations on the effect of 4-hydroxyanisole on normal human melanocytes in tissue culture. J. Invest. Dermatol.77(3), 292–6.
54.
54. Breathnach, A., Robins, E., Ethridge, L., Bhasin, Y., Gallagher, S., Passi, S., and Nazzaro-Porro, M. (1983). Ultrastructural and biochemical observations on the effect of 4-hydroxyanisole plus tyrosinase on normal human melanocytes and keratocytes in tissue culture. Br. J. Cancer47(6), 813–22.
55.
55. Bleehen, S.S. (1976). Selective lethal effect of substituted phenols on cell cultures of malignant melanocytes. Pigm. Cell2(1), 108–15.
56.
56. Dewey, D.L., Butcher, F.W., and Galpine, A.R. (1977). Hydroxyanisole-induced regression of the Harding-Passey melanoma in mice. J. Pathol.122(3), 117–27.
57.
57. Webster, D.J., Whitehead, R.H., and Hughes, L.E. (1981). Effect of 4HOA on melanoma. Br. J. Cancer43(5), 729. Meeting abstract.
58.
58. Wattenberg, L.W., Coccia, J.B., and Lam, L.K.T. (1980). Inhibitory effect of phenolic compounds on benzo(a)pyrene-induced neoplasia. Cancer Res.40 (8 Part 1), 2820–23.
59.
59. Wattenberg, L.W., Borchert, P., and Coccia, J. (1982). Effects of p-methoxyphenol and dietary alteration on beta-propiolactone (BPL)-induced neoplasia of the mouse forestomach. Proc. Am. Assoc. Cancer Res.23, 342.
60.
60. Wattenberg, L.W., Borchert, P., Destafney, C.M., and Coccia, J.B. (1983). Effects of p-methoxyphenol and diet on carcinogen-induced neoplasia of the mouse forestomach. Cancer Res.43(10), 4747–51.
61.
61. Sparnins, V.L., and Wattenberg, L.W. (1981). Enhancement of glutathione S-transferase activity of the mouse forestomach by inhibitors of benzo(a)pyrene-induced neoplasia of the forestomach. J. Natl. Cancer Inst.66(4), 769–71.
62.
62. Sparnins, V.L., Chuan, J., and Wattenberg, L.W. (1982). Enhancement of glutathione S-transferase activity of the esophagus by phenols, lactones, and benzyl isothiocyanate. Cancer Res.42(4), 1205–7.
63.
63. Rahimtula, A.D., Jernstrom, B., Dock, L., and Moldeus, P. (1982). Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxyanisole and other phenols on hepatic enzyme activities in mice. Br. J. Cancer45(6), 935–44.
64.
64. Kozumbo, W.J., Seed, J.L., and Kensler, T.W. (1983). Inhibition by 2(3)-tert-butyl-4-hydroxyanisole and other antioxidants of epidermal ornithine decarboxylase activity induced by 12-O-tetradecanoylphor-bol-13-acetate. Cancer Res.43(6), 2555–9.
65.
65. Gilbert, D., Golberg, L., and Gangolli, S.D. (1967). Induction of liver microsomal processing enzymes by substituted phenols. Biochem. J.103(1), 11P–12P.
66.
66. Machleidt, H., Roth, S., and Seeman, P. (1972). The hydrophobic expansion of erythrocyte membranes by the phenol anesthetics. Biochim. Biophys. Acta255(1), 178–89.
67.
67. Roth, S., and Seeman, P. (1972). The membrane concentrations of neutral and positive anesthetics (alcohols, chlorpromazine, morphine) fit the Meyer-Overton rule of anesthesia; negative narcotics do not. Biochim. Biophys. Acta255(1), 207–19.
68.
68. Burton, D.E., Clarke, K., and Gray, G.W. (1964). The mechanism of the antibacterial action of phenols and salicylaldehydes. II. Substituted phenols. J. Chem. Soc.1964, 1314–8.
69.
69. Owen, R.G. (1953). Studies on the nature of fungicidal action. II. Chemical constitution of benzenoid and quinonoid compounds in relation to fungitoxicity and inhibition of amino-and sulfhydryl-dependent enzymes. Contrib. Boyce Thompson Inst.17, 273–82.
70.
70. Gootjes, J., Zwart Voorspuij, A.J., and Nauta, W. Th. (1953). Investigation into the tuberculostatic activity of some aromatic hydroxy compounds. Antonie van Leeuwenhoek. J. Microbiol. Serol.19(3), 237–44.
71.
71. Kramer, P.E., Robbins, M.L., and Smith, P.K. (1955). Phenolic compounds as chemotherapeutic agents against poliomyelitis virus tissue culture. J. Pharmacol. Exp. Ther.113, 262–71.
72.
72. Rosen, F., Millman, N., and Homm, R. (1955). Anti-gonadotropic activities of quinones and related compounds. Endocrinology57, 466–71.
73.
73. Pilotti, A., Ancker, K., Arrhenius, E., and Enzell, C. (1975). Effects of tobacco and tobacco smoke constituents on cell multiplication in vitro. Toxicology5(1), 49–62.
74.
74. Wynn, J., and Fore, W.F. (1965). The effect of hindered phenols on mitochondrial oxidative phosphorylation. J. Biol. Chem.240(4), 1766–71.
75.
75. Levan, A., and Tjio, J.H. (1948). Induction of chromosome fragmentation by phenols. Hereditas34, 453–84.
76.
76. Kaul, B.L. (1979). Cytogenic activity of some common antioxidants and their interaction with x-rays. Mutation Res.67(3), 239–48.
77.
77. Levine, L., Gordon, J.A., and Jencks, W.P. (1963). The relationship of structure to the effectiveness of denaturing agents for deoxyribonucleic acid. Biochemistry2, 168–75.
78.
78. Bray, H.G., Craddock, V.M., and Thorpe, W.V. (1955). Metabolism of ethers in the rabbit. II. Nuclear-substituted anisoles. Biochem. J.60, 225–32.
79.
79. Astill, B.D., Fasset, D.W., and Roudabush, R.L. (1960). The metabolism of phenolic antioxidants. 2. The metabolism of butylated hydroxyanisole in the rat. Biochem. J.75, 543.
80.
80. DOW CHEMICAL CO. (1959). Letter dated February 14, 1979 from Dr. K.J. Olson (Toxicology Research Laboratory, Midland, MI) to Mr. Ralph C. Wands (Director, Cosmetic Ingredient Review, Washington, DC) regarding studies conducted on p-Hydroxyanisole in 1959.
81.
81. Hagan, E.C. (1959). Acute toxicity: Appraisal of the safety of chemicals in foods, drugs and cosmetics. Compiled by the staff of the Div. of Pharmacology, Food and Drug Administration-Dept. of Health, Education and Welfare, pp. 17–25.
82.
82. Weil, C. (1952). Tables for convenient calculation of median-effective dose (LD50 or ED50) and instructions in their use. Biometrics8(3), 249.
83.
83. CTFA. (No date). Submission of unpublished data by CTFA. Reference 1. Raw Material FCR/1006A. Acute oral toxicity; acute eye irritation; human patch test; human repeated insult patch test.*
84.
84. CTFA. (No date). Submission of unpublished data by CTFA. Reference 2a. Moisturizing lotion containing 0.1 percent p-Hydroxyanisole. Code No. FCR-5/1006B. Acute oral toxicity; acute eye irritation; animal patch test; human patch test.*
85.
85. CTFA. (No date). Submission of unpublished data by CTFA. Reference 2b. Moisturizing cream containing 0.05 percent p-Hydroxyanisole. Code No. FCR-5/1006E. Acute oral toxicity; acute eye irritation; animal patch test; human patch test.*
86.
86. CTFA. (No date). Submission of unpublished data by CTFA. Reference 2c. Blusher containing 0.1 percent p-Hydroxyanisole. Code No. FCR 6/100F. Acute oral toxicity; acute eye irritation; animal patch test; human patch test.*
87.
87. Plzak, V., and Doull, J. (February 1969). A further survey of compounds for radiation protection. USAF School of Aerospace Medicine. Aerospace Medical Division. Brooks Air Force Base, Texas. NTIS Document No. AD691–490.
88.
88. Stanley, H.R., Bowen, R.L., and Folio, J. (1979). Compatibility of various materials with oral tissues. II. Pulp responses to composite ingredients. J. Dent. Res.58(5), 1507–17.
89.
89. Draize, J.H. (1959). Appraisal of the safety of chemicals in foods, drugs and cosmetics. Compiled by the staff of the Div. of Pharmacology, Food and Drug Administration-Dept. of Health, Education and Welfare, pp. 46–59.
90.
90. EASTMAN KODAK. (1950). Letter dated February 13, 1979 from Dr. C.J. Terharr (Eastman Kodak: Toxicology Section, Health Safety and Human Factors Laboratory, Rochester, NY) to Mr. Ralph C. Wands (Director, Cosmetic Ingredient Review, Washington, DC) regarding unpublished studies conducted on p-Hy-droxyanisole in 1950.
91.
91. Van Der Walle, H.B., Klecak, G., Geleick, H., and Bensink, T. (1982). Sensitizing potential of 14 monomethacrylates in the guinea pig. Contact Dermatitis8(4), 223–35.
92.
92. Van Der Walle, H.B., Delbressine, L.P.C., and Seutter, E. (1982). Concomitant sensitization to hy-droquinone and p-methoxyphenol in the guinea pig: inhibitors in acrylic monomers. Contact Dermatitis8(3), 147–54.
93.
93. CTFA. (1984). Submission of unpublished data by CTFA. p-Hydroxyanisole: Photocontact sensitization in guinea pigs.*
94.
94. Akhabadze, A.F., Koroleva, N.B., and Kovanova, E.K. (1981). Experimental study of substances used in cosmetics containing paragroups, applied to the skin. Vestn. Dermatol. Venerol.6, 23–7. English translation.
95.
95. Florin, I., Rutberg, L., Curvall, M., and Enzell, C.R. (1980). Screening of tobacco smoke constituents for mutagenicity using the Ames Test. Toxicology18, 219–32.
96.
96. Bartsch, H., Malaveille, C., Camus, A.M., Martel-Planche, G., Brun, G., Hautefeuill, A., Sabadie, N., Barbin, A., Kuroki, T., Drevon, C., Piccoli, C., and Montesano, R. (1980). Validation and comparative studies on 180 chemicals with 5. typhimurium strains and V79 Chinese hamster cells in the presence of various metabolizing systems. Mutation Res.76, 1–50.
97.
97. Boutwell, R.K., and Bosch, D.K. (1959). The tumor-promoting action of phenol and related compounds for mouse skin. Cancer Res.19, 413–24.
98.
98. Stenback, F. (1977). Local and systemic effects of commonly used cutaneous agents: Lifetime studies of 16 compounds in mice and rabbits. Acta Pharmacol. Toxicol.41, 417–31.
99.
99. Colomb, D. (1982). Confetti depigmentation following application of Leucodinine B on a chloasma (1982). Ann. Dermatol. Venereol.109(10), 899–900. English translation.
100.
100. Higashi, N., and Matsumura, M. (1982). Three cases of occupational skin hazards. Skin Res.24(4), 561–6. English translation.
101.
101. Chivers, C.P. (1972). Two cases of occupational leucoderma following contact with hydroquinone monomethyl ether. Br. J. Ind. Med.29(1), 105–7.
102.
102. O'Sullivan, J.J., and Stevenson, C.J. (1981). Screening for occupational vitiligo in workers exposed to hydroquinone monomethyl ether and to paratertiary-amyl-phenol. Br. J. Ind. Med.38(4), 381–4.
103.
103. CTFA. (October 4, 1979). Submission of unpublished data by CTFA. Eight week progressive exposure for depigmentation. Two percent p-Hydroxyanisole in petrolatum and sweet almond oil. Code Nos. FE 1–67/A and FE 1/67B.*
104.
104. CTFA. (1979). Submission of unpublished data by CTFA. Raw material FCR-6/1007A. Skin depigmentation study on 80 human subjects. Two percent p-Hydroxyanisole in sweet almond oil.*
105.
105. CTFA. (No date). Submission of unpublished data by CTFA. p-Hydroxyanisole: Summary of unpublished safety data.*
106.
106. Fisher, A.A. (1973). Contact Dermatitis, 2nd ed.Philadelphia: Lea & Febiger. *Available upon request: Administrator, Cosmetic Ingredient Review, Suite 810, 1110 Vermont Avenue, N.W., Washington, DC 20005.
