Benzophenones-1 to 12 are substituted derivatives of 2-hydroxybenzophe-none. They are used as photostabilizers in cosmetics and have a photoprotective effect on the skin.
When ingested and absorbed, Benzophenones were primarily conjugated and excreted in the urine. Benzophenones were practically nontoxic when chronically administered orally to rats, and Benzophenones-3 and 4 were nontoxic when applied to the skin of rabbits at doses of > 5 g/kg. Subchronic oral ingestion of Benzophenone-3 at 1 % was nontoxic to rats; however, another study showed Benzophenone-3 at 0.5% was toxic. Benzophenone-1 elicited toxic effects in rats at 0.6 g/kg.
Benzophenones were nonirritating or mildly irritating to rabbit skin at concentrations of up to 100% and practically nonirritating to the eyes of rabbits. A subchronic skin irritation test indicated that Benzophenone-4 was capable of causing minimal irritation in rabbits at a concentration of 10%. Benzophenone-3 was reported to be nonsensitizing and nonphototoxic in guinea pigs and rabbits.
Benzophenones-1, 3, 4, 5, and 9 were nonmutagenic both with and without metabolic activation in the Ames test.
Skin irritation and sensitization in humans indicated that Benzophenones were mildly irritating and sensitizing at concentrations greater than those used in cosmetics.
On the basis of the available animal data and clinical human experience, it is concluded that Benzophenone-1, 3, 4, 5, 9, and 11 are safe for topical application to humans in the present practices of use and concentration in cosmetics.
References
1.
1. Saharia, C.S. and Sharman, B.R. (1957). Hydroxy ketones. III. Fries reaction of the esters of o- and m-methoxybenzoic acids and a study of the mechanism. J. Sci. Ind. Res. (India)16B, 125–8.
2.
2. Grover, P.K., Shah, G. D., and Shah, R.C. (1955). Xanthones. IV. A new synthesis of hydroxyxan-thones and hydroxybenzophenones. J. Soc. Cosmet. Chem. 3982-5.
3.
3. COSMETIC, TOILETRY AND FRAGRANCE ASSOCIATION (CTFA). (1979). Cosmetic Ingredient Chemical Description: Benzophenones.*
4.
4. Hayashi, M. Benzophenone derivatives. (1929). J. Prakt. Chem.123, 289–312.
5.
5. Stecher, H. (1958). Ultraviolet-absorptive additives in adhesives, lacquers, and plastics. Adhesion2(1), 243–4.
6.
6. Nurmukhametov, R., Shigorin, D., and Mileshina, L. (1967). Mechanism of inhibition of polymeric photochemical degradation with hydroxy benzophenone stabilizers. Vysokomol. Soedin.9(1), 26–31.
7.
7. Pivovarov, A.P., Ershov, A., and Lukovnikov, A.F. (1966). Mechanism of light stabilizing of polypropylene by various additives. Plast. Massy10, 7–9.
8.
8. Kysel, O. (1969). Acid-base equilibriums in the ground and excited state of photo-stabilizers. Benzophenone derivatives. Kinet. Mech. Polyreactions, Int. Symp. Macromol. Chem., Prepr.5, 263–70.
9.
9. Makhkamov, K., Virnik, A.D., and Rogovin, Z.A. (1965). Effect of chemical structure of some stabilizers on the light stability of cellulose acetate fabrics. Tekstil'n. Prom.25(1), 28–30.
10.
10. Holm, T. and Crossland, I. (1971). Mechanism of the Grignard addition reaction. VIII. Reaction rates and product distribution for the reactions of teributyi-magnesium chloride and methylmagnesium bromide with substituted Benzophenones. Acta Chem. Scand.25, 59–69.
11.
11. Pitts, Jr., J.N., Johnson, H.W., and Kuwana, T. (1962). Structural effects in the photochemical processes of ketones in solution. J. Phys. Chem.66, 2456–61.
12.
12. Otterstedt, J.E.A. (1973). Photostabiiity and molecular structure. J. Chem. Phys.58, 5716–25.
13.
13. Kamocawa, H. (1969). Responsive polymers. V. Preparation of some polymeric phenolic ultraviolet absorbers. Kogyo Gijursuin Sen'i Kogyo Shikensho Kenkyu Hokoku86, 95–6.
14.
14. Uhde, W.J. and Zydek, G. (1968). Thin-layer chromatography of substituted 2-hydroxybenzophenones. Fresenius' Z. Anal. Chem.239(1), 25–6.
15.
15. Simpson, D. and Currel, B.R. (1971). Determination of certain antioxidants, ultra-violet absorbers, and stabilizers in plastics formulations by thin-layer chromatography. Analyst (London)96(1), 515–21.
16.
16. Durisinova, L. and Bellus, D. (1968). Thin-layer chromatography of 2-hydroxybenzophenones. J. Chromatogr.32(1), 584–7.
17.
17. Mazur, H. and Lewandowska, I. (1976). Study of the migration of benzophenone derivative UV (light) stabilizers. Rocz. Panstw. Zakl. Hig.27, 611–9.
18.
18. Dobies, R.S. (1968). Thin-layer chromatographic method for determining ultraviolet absorbers in paraffin wax. J. Chromatogr.35(1), 370–5.*
19.
19. Su, H.C. and Cameron, J.L. (1967). Gas-chromatographic method for evaluation of ultraviolet absorbers in polymeric materials. Anal. Chem.39(1), 949–53.
20.
20. Poelmans, M. (1968). Analysis of rigid poly(vinyl chloride) compounds. Ind. Chim. Beige33, 36–9.
21.
21. Mikhailova, N.N. and Vorozheeva, V.P. (1964). Determination of derivatives of hydroxybenzo-phenone by paper chromatography. Zavodsk. Lab.30(1), 802–3.
22.
22. Hrdlovic, P., Schubertova, N., and Pavlocik, R. (1971). Substituent effects on chemical shift of hydroxyl group in 2-hydroxybenzophenone derivatives. Collect. Czech. Chem. Commun.36(1), 1942–7.
23.
23. George, W.O., Hassid, D.V., and Phillips, J. (1971). Mass spectra of chloro-substituted benzophenones. Org. Mass Spectrum5, 605–13.
24.
24. Carrick, A. and Paisley, H.M. (1974). Metastable peaks in a mass spectrum measured automatically under high resolution fast scan conditions. Org. Mass Spectrum8, 229–34.
25.
25. Krenmayr, P., Heller, R., and Varmuza, K. (1974). Mass spectrometry investigation of benzophenone and substituted benzophenone. I. Determination of thermodynamic data. Org. Mass. Spectrum9, 998–1005.
26.
26. Kirkbright, G.F., Narayanaswamy, R., and West, T.S. (1970). Fluorescence and phosphorescence characteristics of some antioxidants and ultraviolet absorbers. Anal. Chim. Acta52(1), 237–46.
27.
27. Merrill, J.R. (1961). Measurement of intramolecular hydrogen bonding by nuclear magnetic resonance and infrared spectroscopy. J. Phys. Chem.65, 2023–6.
28.
28. CTFA. (1978). Submission of data. Assay of Benzophenones (Draft).*
29.
29. CTFA. (1981). Submission of data. Supplementary 1R Spectra and chemical property data.*
30.
30. Stephen, H. (1920). A new method for the preparation of 2,4-dihydroxy- and 2,4,4′-trihydroxyben-zophenone and some observations relating to the Hoesch reaction. J. Soc. Cosmet. Chem.117, 1529–34.
31.
31. Zilberman, E.N. and Rybakova, N.A. (1964). New catalysts of the Hoesch reaction. Kinetika i. Kataliz.5(1), 538–40.
32.
32. Shaw, R.C. and Mehta, P. (1936). A new and convenient synthesis of 2,4-dihydroxybenzophenone. J. Ind. Chem. Soc.13, 368–71.
33.
33. Head, F.S.H. (1969). Derivatives of 2,4-dihydroxybenzophenone. J. Soc. Cosmet. Chem.1, 34–7.
34.
34. Daivi, V.J. and Jadhav, G.V. (1957). Derivatives of 2,4-dihydroxy-butyrophenone (resbutyrophenone) and 2,4-dihydroxybenzophenone (resbenzphenone). J. Univ. Bombay25A(1), 19–22.
35.
35. Fertig, J., Goldberg, A.I., and Skoultchi, M. (1966). Ultraviolet-stabilizing monomers and polymers. II. Synthesis and polymerization of acrylate and metacrylated derivatives of 2,4-dihydroxybenzophenone. J. Appl. Polymer Sci.10(1), 663–72.
36.
36. Watanabe, H. and Kunizo, K. (1957). Reactivity of aromatic compounds with diphenylpicrylhydrazyl. Kogyo. Kagako. Zasshi.60, 1476–9.
37.
37. Van Allen, J. and Tinker, J. (1956). Derivatives of Benzoylresorcinol. J. Org. Chem.19, 1243
38.
38. Parrish, J.A., Pathak, M.A., and Fitzpatrick, T.B. (1972). Protection of skin from germicidal ultraviolet radiation in the operating room by topical chemicals. N. Eng. J. Med.284(1), 1257–8.
39.
39. CTFA. (1979). Submission of data. Unpublished data, Appendix 7a.*
41. Weast, R.C. (ed.). (1978). Handbook of Chemistry and Physics, 59th ed.Palm Beach, FL: CRC Press.
42.
42. Temchim, Y.I., Burmistrov, E.F., et at. (1970). Volatility of stabilizers and their compatibility with polymers. Vysokomol Soedin., Ser. A12(1), 1901–8.
43.
43. AMERICAN CYANAMID CO. (ACC). (1979). Submission of data by CTFA. Unpublished data, Chemistry Supplement.*
44.
44. Fand, I. (1972). The protective effect of a sunscreen upon the lysosomes of ultra-violet-irradiated skin. Dermatologica144(1), 237–47.
45.
45. Forbes, Jr., M.A., Brannen, M., and King, C. (1966). Benzophenone as a sunscreen. South Med. J.59(1), 321–4.
46.
46. Van Allen, J.A. (1958). Derivatives of benzoylresorcinol. J. Org. Chem.23, 1679–82.
47.
47. Pinkus, A.G. and Meng, L.Y.C. (1966). Reaction of 5-chloro-2-hydroxybenzophenone and phosphorus pentachloride. Structural studies. J. Org. Chem.31(1), 1038–42.
48.
48. Armstrong, L. (1977). Nitrogen-oxygen donor macrocyclic Hands. I. Cobalt (II) complexes of cyclic diimini ligands derived from salicylaldehyde and 5-chloro-2-hydroxybenzophenone. Inorg. Chem.16(1), 1665–9.
49.
49. ACC. (April 1957). Submission of data by CTFA. Unpublished data on Benzophenones, Appendix 2h.*
50.
50. Kligman, A.M. (Feb. 1976). Submission of data by CTFA. Unpublished data on Benzophenone, Appendices 2d, 2g, 2i.*
51.
51. Ismail, R.M. (1970). Organosilicon compounds. XV. Preparation and ultraviolet absorption of silicon esters and metal-containing benzophenone derivatives. Z. Naturforsch. B.25(1), 14–8.
52.
52. ACC. (1975). Submission of data by CTFA. Unpublished data, Appendix 2g.*
53.
53. Temchim, Y.I., Burmistrov, E.F., and Zalevskii, V.V. (1967). Volatility of stabilizers of polymers. Plast. Massy3, 72–4.
54.
54. Signore, A. and Woodward, F.E. (1958). Ultraviolet light absorbers in cosmetics. J. Soc. Cosmet. Chem.9, 358–68.
55.
55. Smith, E.B., Dickson, J.E., and Knox, J.M. (1973). Protection from sunlight: evaluation of a new screening agent. South. Med. J.66(1), 278–80.
56.
56. Torosian, G. and Lemberger, M.A. (1972). OTC sunscreen and suntan products. J. Am. Pharm. Assoc.12(1), 571–5.
57.
57. Macleod, T.M. and Frain-Bell, W. (1975). A study of chemical light screening agents. Br. J. Dermatol.92(1), 417–25.
58.
58. Dunitriv, R. and Harap, E. (1967). Photoprotective action of a Benzophenone derivative. Derm. Vener.12(1), 435–42.
59.
59. Wolska, H., Langner, A., and Marzulli, F.N. (1974). Hairless mouse as an experimental model for evaluating the effectiveness of sunscreen preparations. J. Soc. Cosmet. Chem.25(1), 639–44.
60.
60. Cripps, D.J. and Hegedus, S. (Feb. 1974). Protection factor of sunscreens to monochromatic radiation. Arch. Dermatol.109(1), 202–4.
61.
61. Lachman, L., Urbanyi, T., Weinstein, S., et al. (1962). Color stability of table formulations. V. Effect of ultraviolet absorbers on the photostability of colored tablets. J. Pharm. Sci.51, 321–6.
62.
62. Wilson, W.W., Quero, R., and Master, K.J. (1966). The search for a practical sunscreen. South Med. J.59(1), 1425–30.
63.
63. Willis, I. and Kligman, A.M. (1969). Evaluation of sunscreens by human assay. J. Soc. Cosmet. Chem.20(1), 639–51.
64.
64. Koehler, F.T. and Legato, G.J. (1970). Benzophenone/resin copolymer for UV-absorbing hair fixatives. Deterg. Spec.7, 48, 50, 56.
65.
65. Thomas, Jr., W.G. (1966). Protection of cosmetic colors by means of UV absorbers. J. Soc. Cosmet. Chem.17(1), 553–70.
66.
66. Russo, M. and Rosa, V.L. (1971). Effects of ultraviolet rays on coloring agents in cosmetics. Riv. Ital. Essenze, Profuni, Piante Offic. Aromi, Saponi, Cosmet. Aerosol.53, 333–9.
67.
67. FOOD AND DRUG ADMINISTRATION (FDA). (Aug. 1976). Cosmetic product formulation data. Computer printout.
68.
68. CTFA. (June 1980). Submission of data. Summary of unpublished data on Benzophenones.*
69.
69. FDA. (Aug. 25, 1978). Report on Sunscreen Drug Products for Over-the-Counter Human Drugs. 32 Fed. Reg. 412.
70.
70. Parrish, J., Pathak, M., and Fitzpatrick, T. (1971). Prevention of unintentional overexposure in topical psoralen treatment of vitiligo. Arch. Dermatol.104(1), 281–3.
71.
71. Korenyi, C. (1969). The effect of Benzophenone sunscreen lotion on chlorpromazine-treated patients. Am. J. Psychiat.7, 971–4.
72.
72. Oleniacz, W.S., Sincer, E.J., Doyle, A.B., and Vinson, L. (1968). Induction of photohemolysis by tetra chlorosalicylanilide. J. Pharm. Sci.57(1), 2136–9.
74. Emmett, E.A., Taphorn, B.R., and Kominsky, J.R. (1977). Phototoxicity occurring during the manufacture of ultraviolet-cured ink. Arch. Dermatol.113(1), 770–5.
75.
75. Mizami, R.M. and Baboo, M.T. (1974). Office management of patients with uriticaria: an analysis of 215 patients. Ann. Allergy33(1), 78–85.
76.
76. FDA. (Jan. 1967). Report on Food Additives. Antioxidants and/or stabilizers for polymers. 32 Fed. Reg. 412.
78. Nickerson, P.R. and Barbehenn, K.R. (1975). Organochlorine residues in starlings-1972. Perstic. Monit. J.8(1), 247–54.
79.
79. Morris, O.N. and Moore, A. (1975). Studies on the protection of insect pathogens from sunlight inac-tivation. Chem. Control Res. Inst.113, 34
80.
80. Baur, J. and Bouey, R. (1974). Ultraviolet and volatility loss of herbicides. Arch. Environ. Contam. Toxicol.2(1), 275–88.
81.
81. Kabivanov, V., Peneva, A., Khadzhidocheva, S., et al. (1965). Light aging and stabilization of plasticized poly(vinyl chloride) suspension. Polim. Sb. Tr. Nauchnoizsled. Inst. Kauch. Plastmasova Prom.2, 55–76.
82.
82. Quackenbos, H.M. and Samuels, H. (1967). Weatherability of plastics. Practical problems of predicting weathering performance. Mod. Plast.44(8), 143.
83.
83. Mulin, Y.A., Yakoviev, A.D., and Sheshukov, A.V. (1967). Effect of stabilizers on properties of polypropylene coatings. Plast. Massy2, 10–1.
85. Marcincin, A. and Pikler, A. (1968). Compatability of light stabilizers with polypropylene. II. Significance of the surface energy values. Plast. Hmoty. Kauc.5(1), 166–8.
86.
86. Uhde, W.J. and Woggon, H. (1976). New results from migration behavior of Benzophenone-based UV absorbents from polyolefins in foods. Nahrung20(1), 185–94.
87.
87. Novikova, I. (1968). Light stabilization of poly(ethylene terephthalate) films. Celiotehknika4, 53–5.
88.
88. Novikova, I., Virnik, A., and Roqovin, Z. (1969). Effect of different light stabilizers on a poly(ethylene terephthalate) film. Geliotekhnika5, 40–3.
89.
89. Chrzczonowicz, S. and Hippe, Z. (1966). Selection of effective sensitizers for photo-induced cross-linking of poly(vinyl butyral). Bull. Acad. Pol. Sci., Ser. Sci. Chim.14(1), 627–30.
90.
90. Popova, Z.V., Yanovskii, D.M., Zil'berman, E.N., et al. (1961). Effect of some phenols on the thermal and light decomposition of poly(vinyl chloride). Zhur. Priklad. Khim.34, 874–81.
91.
91. Giesen, M. (1959). The effect of ultraviolet rays and their absorption by ultraviolet absorbers in synthetic resins and dyes. Farbenchemiker61(1), 13–9.
92.
92. Hawley, G.G. (ed.). (1971). The Condensed Chemical Dictionary, 8th ed.New York, NY: Van Nostrand Reinhold Co.
93.
93. Finnegan, R.A., Merkel, K.E., and Patel, J.K. (1973). Constituents of Mammea americana L. XII. Biological data for xanthones and Benzophenones. J. Pharm. Sci.62(1), 483–5.
94.
94. Patel, Y.M., Levinskas, G.J., and Shaffer, C.B. (1968). Toxicity and metabolism of 2-hydroxy-4-n-octoxybenzophenone. Food Cosmet. Toxicol.6(1), 199–208.
95.
95. HAZELTON LABS. (Nov. 1953). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 2a.*
96.
96. ACC. (April 1959). Submission of data by CTFA. Unpublished data, Appendix 2e, 192f.*
97.
97. Homrowski, S. (1968). Studies on the toxicity of additives applied in the domestic production of plastics. 3. Acute and subacute toxicity of some Benzophenone derivatives. Rocz. Panstw. Zakl. Hig.19(2), 179–87.
98.
98. Lewerenz, H.J., Lewerenz, G., and Plass, R. (1972). Acute and subacute toxicity studies of the UV absorber MOB in rats. Food Cosmet. Toxicol.10(1), 41–50.
99.
99. INDUSTRIAL BIOLOGY AND RESEARCH TESTING LABS (IBRTL). (June 1960). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 1a.*
100.
100. INDUSTRIAL BIOLOGY LABS (IBL). (July 1964). Submission of data by CTFA. Unpublished data, Appendix 1i.*
101.
101. HAZELTON LABS. (Oct. 1953). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 2b.*
102.
102. IBL (April 30, 1962). Submission of data by CTFA. Unpublished data, Appendix 1m.*
103.
103. INDUSTRIAL TOXICOLOGY LABS (ITL). (Jan. 1955). Submission of data by CTFA. Unpublished data, Appendix 1s.*
104.
104. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1p.*
105.
105. IBL. (Aug. 1964). Submission of data by CTFA. Unpublished data, Appendix 1e.*
106.
106. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1k.*
107.
107. IBL. (April 1967). Submission of data by CTFA. Unpublished data, Appendix 1h.*
108.
108. ACC. (1976). Submission of data by CTFA. Unpublished data, Appendix 2c*
109.
109. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1o.*
110.
110. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1f.*
111.
111. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1j.*
112.
112. IBL. (Oct. 1965). Submission of data by CTFA. Unpublished data, Appendix 1r.*
114. Marzulli, F.N. and Maibach, H.I. (1975). The rabbit as a model for evaluating skin irritants: A comparison of results obtained on animals and man using repeated skin exposures. Food Cosmet. Toxicol.13(1), 533–40.
115.
115. IBL. (July 1964). Submission of data by CTFA. Unpublished data, Appendix lb.*
116.
116. IBL. (April 1962). Submission of data by CTFA. Unpublished data, Appendix In.*
117.
117. AVON PRODUCTS. (Feb. 1979). Submission of data by CTFA. Unpublished data on Benzophenones, Appendix 4a.*
118.
118. CTFA. (1980). Submission of data. Supplementary mutagenesis data.*
119.
119. DEFT. OF HEALTH, EDUCATION AND WELFARE (DHEW). (May 1978). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 5b.*
120.
120. DHEW. (Feb. 1979). Submission of data by CTFA. Unpublished data, Appendix 5c*
121.
121. HILL TOP RESEARCH LABS. (June 1979). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 3a.*
122.
122. HILL TOP RESEARCH LABS. (Sept. 1979). Submission of data by CTFA. Unpublished data, Appendix 3b.*
123.
123. LITTON BIONETICS. (1979). Submission of data by CTFA. Supplementary mutagenesis data.*
124.
124. IBRTL. (Aug. 1957). Submission of data by CTFA. Unpublished data, Appendix 1g.*
125.
125. FOOD AND DRUG RESEARCH LABS (FDRL). (Nov. 1978). Submission of data by CTFA. Unpublished data on Benzophenones, Appendix 7e and supplement.*
126.
126. ITL. (Aug. 1952). Submission of data by CTFA. Unpublished data on Benzophenone, Appendix 1c*
127.
127. IBL. (May 1962). Submission of data by CTFA. Unpublished data, Appendix II.*
128.
128. ITL. (Jan. 1954). Submission of data by CTFA. Unpublished data, Appendix 1u.*
129.
129. Fisher, A. (Aug. 1980). Correspondence with CIR.*
