482 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS therapeutic effects could be obtained after cutaneous application of such substances as belladonna, mercury, pilocarpine and cod liver oil. This author also noted the presence of salicylic acid and phenol in the urine after their topical application to the skin. Toxic effects, often serious and sometimes fatal, have been reported from substances applied percutaneously. Macht (4) reported deaths in experimental animals following the percutaneous absorption of a number of essential oils and Sannicandaro (5), and Gottlieb and Storey (6), reported deaths in humans from the absorption of salicylic acid and phenol through the intact skin. In recent years several examples of poisoning with organo- phosphorus compounds from percutaneous absorption have been reported both in humans following accidental contamination of the skin (7, 8), and in animals used in experimental studies (9). A number of other compounds have been reported to have caused toxicity in humans through percutaneous absorption. These include the chlorinated hydrocarbon insecticides, carbon tetrachloride, aromatic amines, dinitrophenol and hydrogen cyanide gas (10). These observations have created an awareness that compounds present in many consumer products including toilet preparations, cosmetics and household materials, could produce untoward systemic effects by virtue of percutaneous absorption. Examples of this sort are the biologically active substances, intended for use in cosmetics, that are reported from time to time in the literature. One may recall here the mercaptans used in 'cold- hair wave processes' (11), steroid hormones intended to beautify the skin (12) and antibacterial agents (13). The recent reports indicating that hexachloro- phene, added to a variety of toiletry preparations as an antibacterial agent, is absorbed percutaneously in amounts considered to be of toxicological hazard for babies (14) underlies the importance of keeping under review the risks that may arise from the inclusion of biologicall3, active substances in cosmetic and toiletry preparations. Awareness of the possible toxic effects that may arise from these sources has led to the discovery that some cyclo- siloxanes, originally developed for inclusion into cosmetic creams, are potent gonadotoxic and embryotoxic compounds (15). This was done during preliminary toxicological investigations on animals involving per- cutaneous absorption tests. In order to assess potential toxicological hazard from this route it is important to have an understanding of the principles underlying the methods of testing and of the factors which influence percutaneous absorption. Both these fields have been extensively reviewed over the past two decades, but most reviewers tend to emphasize certain specialized aspects of the problem

PERCUTANEOUS ABSORPTION 483 (1, 4, 10, 16-37). The object of the present review is to deal with the principles of percutaneous absorption from a broader view point, bearing in mind the needs of those involved in the biological testing of these compounds. In attempting to delineate these principles we have taken into account lessons learnt from experimental results with a number of compounds of importance to the cosmetic chemist. These include alcohols, soaps, deter- gents and emollients. Although these are not absorbed from the site of topical application to any meaningful extent, they may produce profound local changes which affect the permeability of the skin to other, possibly toxic, compounds. In addition to the experience gained from this source, we have drawn upon the extensive experience of work done in the field of pharmaceuticals, pesticides and basic research, wherever appropriate. THE CUTANEOUS BARRIER Nature of the barrier The passage of water and other substances into or out of the organism is limited by the skin which in mammals consists basically of an acellular layer of keratin and one or more layers of viable cells underneath. This 'barrier' function resides almost entirely in the stratum corneum (38, 39), a thin membranous layer (in the human 600 [tm in the palms and soles, 10-15 pm in other parts) which is mechanically strong and is capable of resisting chemical attack (38). The importance of this layer in maintaining an adequate barrier was demonstrated by Blank (40, 41). He developed a method for stripping the stratum corneum in successive layers and showed that the rate of water loss, under standardized experimental conditions increased from 0.5 mg cm -ø' h -• to 8 mg cm -ø' h -• after complete stripping of the stratum corneum. Removal of the outer layers had little effect on the rate of water loss indicating that the main barrier occurs at the deeper layer which histologically is the stratum lucidum. The stratum lucidum is an equally effective barrier against the penetration of substances from the outside and its stripping considerably increases the penetration of topically applied substances. This was demonstrated by Blank, Griesemer and Gould (42) in their studies on the percutaneous absorption of the organo- phosphorus insecticide 'satin' from the skin. The absorption of satin after six strippings did not differ from that of controls, but after 12 strippings there was a hundred-fold increase. Damage to this layer also results in increased permeability to a variety of chemical agents (43-45).