730 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS said to be no more effective skin lighteners than ammoniated mercury. Inhibition of melanogenesis and freedom from adverse side effects are attributed to the action of hydroquinone at the 2•o level. Although skin irritation was reported after higher dosage sensitization did not occur. Lightening took place gradually within 3-6 months and from biopsy material these authors concluded that hydroquinone caused a reduction in melanin synthesis. The mode of action of the p-hydroxyphenyl derivatives of hydroquinone is still obscure. p-Hydroxypropiophenone presumably interferes with the first step in melanin synthesis and the monobenzyl ether is probably converted to hydroquinone in the skin (19). Whilst mercuric compounds cause appreciable skin lightening (20) in part due to exfoliation it is likely that mercury will replace copper necessary for tyrosinase activity and thereby inactivate this enzyme. Melanin may be kept in its reduced and light coloured form by ascorbic acid in elevated levels (21). Ascorbic acid can also inhibit melanogenesis by preventing oxidation of the intermediate dopa-quinone. Systemic effects can be anticipated following extensive and prolonged topical application of skin lightening products based on hydro- quinone or its derivatives. Application to guinea pig skin causes cortical hyperplasia in the adrenal glands, focal fibrosis in the myocardium and fatty dystrophy in kidneys and liver and a diminution of circulating lymphocytes (22). Surprisingly no cumulative actions were reported by Carlson and Brewer (23) following their studies involving rats. Skalka's (24) observation that hydroquinone interferes with spermiogenesis is interesting and raises the question whether certain skin lightening products may pose a mutagenic hazard. Although there seem to be no reports in the literature of skin tumours due to hydroquinone Boutwell and Bosch (25) studied the ability of substituted phenols, including hydroquinone, to promote skin tumours in mice after an initiating dose of dimethyl-benzanthracene and the results were negative for hydroquinone. Little is known about the metabolism of the latter except that it is oxidized to the more toxic quinone. This can depress the medullary centres of the brain and there is a report that quinone is carcinogenic (26). COMPOUNDS OF QUINONE STRUCTURE AS ALLERGENS Compounds of low molecular weight are sometimes referred to as incomplete antigens or haptens they are unable to sensitize unless attached to a carrier of high molecular weight and only then do they acquire full antigenicity. Quinone derivatives possess avidity for combination (27) and

EFFECTS OF SKIN LIGHTENING COMPOUNDS 731 the polymerization of substituted quinones leads to compounds of high molecular weight. Proteins are readily attached to quinones (28) and it is likely that this is the basis for their ability to act as sensitizers. Depigrnenta- tion at sites distant from those where compounds touch the skin has been reported (8) and it has been suggested that antibody-antigen interaction may be the basis for this phenomenon (29). The search for compounds capable of lightening mammalian skin led Bleehen, Pathak, Hori and Fitzpatrick (30) to investigate biological effects of catechols and substituted catechols. 4-Iso-propyl catechol is most effective, causing a reduction in the number of epidermal melanocytes and it is anticipated that change of this nature will affect control mechanisms concerned with homeostatic regulation of skin components (31). Depigmentation is an uncommon form of occupa- tional disease, occurring mainly as a sequel to thermal or chemical burns however, it has been reported that 4-tertiarybutyl catechol may cause de- pigmentation in man (32). Although the subject of chemically mediated changes in hair colour lies outside the scope of this article and has been reviewed recently (33) it is interesting to note that 4-isopropylcatechol does not affect hair colour (34) implying selective interference with epidermal melanocytes. Similar selective changes are caused by certain mercapto- ethylamines (35, 37) and 8-hydroxyquinoline (36). Recent studies stress the selective nature of the mode of action of certain depigmenting compounds. Frenk and Fritz (38) have reported that the toxicity of the monoethyl ether of hydroquinone on pigment cells is limited to those normally producing black pigment, red hair, albino melanocytes and melanoma cells being unaffected and Potten (39) suggested changes in pigmentation due to application of actinomycin D may be due to inhibition of DNA dependent RNA synthesis by the prevention of transcription. Future developments may involve use of naturally occurring inhibitors of melanogenesis compounds of this nature have recently been found in the skin (40-42) and studies indicate that these are peptides (43). (Received: 11th February 1973) REFERENCES (1) Ottel, H. Die Hydrochinonvergiftung. Arch. Exp. Pathol. Pharmakol. 183 319 (1936). (2) Martin, G. L. and Ansbacher, S. Confirmatory evidence of the chromotrichial activity of p-Aminobenzoic acid. J. Biol. Chern. 138 441 (1941). (3) Mishima, Y. and Chavin, W. The role of the pituitary in the maintenance and proliferation of melanophores in the goldfish. Anat. Rec. 137 382 (1960).