.[. Soc. Cosmetic Chemists 20 487-499 (1969) •_• 1969 Society o[' Cosmetic Chemists of Great Britaht Skin penetration C. W. BARRETT* Presented at the symposium on "Skin", organised by the Society of Cosmetic Chemists of Great Britain, at Eastbourne, Sussex, on 20th November 1968. Synopsis--The types of adverse reaction, both local and systemic due to penetration of the skin are summarised, and more recent views on pathways and mechanics of absorption discussed. Those factors influencing penetration are reviewed with particular reference to the physico-chemical properties of the penerrant, the vehicle, and the penerrant vehicle relation- ship. The usefulness of excised skin in diffusion cells as a method of determining penetration is described. INTRODUCTION Naturally occurring substances have been applied to the skin since the beginning of time, for belligerent and religious purposes as well as cosmetic and medicinal. That these substances might penetrate through the skin to produce serious toxic effects was not considered until the work of Schwenkenbecher in 1904 (1). He concluded from his experiments that the skin was permeable to lipid-soluble substances and gases, but practically impermeable to electrolytes and water. The rapid development of sensitive analytical techniques in the last 50 years has enabled research workers to monitor the passage of substances into, and through, the skin and learn something of the factors which either hinder or enhance their progress. Chemicals are being synthesised today in ever increasing numbers, for the dermatologist to treat skin conditions, for the cosmetic chemist to prepare a wider range of commercially available preparations and for an * The I,ondon Hospital, lx)ndon, E.1. 487

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