488 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS enormous variety of other purposes. In all cases though they have to be handled, and there is then a possibility that they will come in contact with the skin. It is impoitant therefore not just to the dermatologist and cos- metic chemist but to all those handling chemicals that the ability of a chemical to pass into, or through, the skin and produce toxic symptoms can be quickly and accurately assessed. ADVERSE REACTIONS DUE TO PENETRATION OF THE SKIN The toxicity of substances entering the skin has been reviewed by Malkinson and Rothman (2), Suskind (3), and Idson (4). Some substances will pass through the skin without eliciting an untoward reaction whilst others will produce skin reactions by penetrating only the upper layers of the stratum corneum. Primary irritant reactions are caused by substances which directly damage or kill epidermal cells. Relatively strong acids and alkalis, and substances which are readily oxidised or reduced may act as primary irritants. The severity of the reaction may depend on the concentration applied, the frequency of reapplication, contact time, and the type of vehicle in which the substance is incorporated. Occasionally the skin may recover from the effects of a primary irritant and become resistant to further irritation (5). Substances producing sensitivity reactions must penetrate the skin sufficiently to stimulate the formation of antibodies. This almost certainly means that they penetrate through the stratum corneum and into the Malpighian layer. Many substances have been shown to produce sensitivity reactions of those which have been used in cosmetic preparations the p-phenylenediamine oxidation type hair dyes, eosin type lipstick colorants, the easily oxidisable aidehyde and ketone containing perfumes and lanolin may be mentioned and of the topically applied drugs, sulphonamides, penicillins, the antihistamines, local anaesthetics, and the hydroxybenzoic acid esters. Many substances, however, produce serious systemic effects after penetrating through the skin and into the bloodstream. Piquet and Hem- meler (6) reported the occurrence of fatal poisoning from the percutaneous absorption of tetraethyl lead contained in petrol. Abrams, Hamblin and Marchand (7) reported 198 cases of poisoning due to organophosphorus insecticides absorbed partly through the skin during the first five years of their use in the U.S.A. The compounds are relatively volatile, possess good

SKIN PENETRATION 489 lipid solubility and slight water solubility which enables them to pass rapidly through the skin to produce cholinergic side effects. Fitzpatrick, Griswold and Hicks (8) reported five instances of increased weight and ankle oedema in patients applying 0.2% fluorohydrocortisone acetate lotion for the treatment of eczematous dermatosis. The fluoro- hydrocortisone had penetrated the skin sufficiently to produce systemic mineralocorticoid effects. Boric acid, although now deleted from official pharmacopoeial prepara- tions, has been widely used as a topical antiseptic for many years yet Meyler (9) describes several cases of fatal poisoning due to its penetration through the skin. This is a substance which does not penetrate normal skin in significant amounts but will penetrate inflamed or abraded skin to produce serious systemic toxic effects. Occlusion with plastic film is now widely used to promote the absorption into the skin of topically applied anti-inflammatory corticosteroids. Plastic film dressings, however, must be used with care where the drug applied may produce toxic systemic effects. Vickers and Fritsch (10) reported six cases of toxic reactions after the application of naphazoline to the skin under polyethylene film. PATHWAYS AND MECHANISMS OF PENETRATION A substance may penetrate the skin either transepidermally or trans- appendageally. Palmar skin has been shown to be less permeable than other skin sites in man, even though it contains three times as many sweat glands per unit area. It seeIns unlikely, therefore, that the sweat glands represent a significant pathway of penetration. In rodents, the number of hair follicles and therefore the relative area of invaginated epithelium within hair follicles per unit area of skin is greater than in man. Yet it has been shown for many substances that penetration of rodent skin is not correspondingly higher. Autoradiographic techniques have shown that substances do penetrate down the hair follicles {11). This suggests that penetration of the epithelium within the hair follicles is similar to that surrounding them. Tregear (12) showed that tri-n-butyl phosphate penetrated pig skin equally well, whether it contained hair follicles or not. As the stratified system constitutes the major area of the epidermis in man this is undoubtedly the major route of penetration. With the exception of sodium ions and water which may be actively pulled into the skin(13) most substances are thought to penetrate the skin