J. Soc. Cosmetic Chemists 15 385-394 (1964) ¸ 1964 society of Cosmeti• Ckemists of Great Britai• TESTING DRUGS FOR DERMAL TOXICITY G. F. SOMERS, D.Sc., Ph.D., F.P.S.* Presented at the Symposium on "Toxicology of Cosmetic Materials", at Leamington, Warwicks., on 20th November 1963. Methods for determining local toxicity on the skin and mucous mem- branes, and for assessing systemic dermal toxicity (acute and chronic), are descri•. Chemical substances in contact with the skin may have toxic effects. These can occur locally, the compound causing irritation and damage to the skin or the compound may be absorbed into the general circulation, leading to systemic toxic effects. In addition, particularly in humans, the skin may become sensitized showing allergic reactions upon repeated exposure. As in all toxicological work, initial studies of derreal toxicity should be carried out in animals. The results obtained must be interpreted with caution, and can only be a guide to the possible dangers in man. There are considerable structural and physiological differences between animal and human skin. Tests on animal skin will detect really toxic and irritant substances, and therefore provide a valuable first line of defence. Results obtained with minor irritants tend to be misleading, and sensitization studies can only really be made on human skin. Finally, it should be recognized that medicinal substances are often applied to damaged and diseased skin where the absorption characteristics may be completely changed. LOCAL TOXICITY Skin A primary irritation of the skin occurs when a compound first comes into contact with it. In animals it is usually determined on the skin of the rabbit or guineapig. It has been suggested that the pig should be the animal of choice, because its skin is most similar to human skin, but they are difficult animals to handle. Most workers use a method similar to that described by Draize (1). Lilly Research Laboratories Ltd., Liverpool 24, Lancs. Now at Reckitt & Sons, Ltd., Hull, Yorks. 38,5

386 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The hair is first removed over an area of the back, using electric clippers. 'This may be followed by chemical depilation with barium sulphide paste, but there is a danger of a damaging keratolytic effect. Acute effects are determined from a single application, chronic effects from repeated application of the compound. Acute effects The compound is applied to the skin and covered with a piece of gauze held in place with adhesive piaster. Solids may be applied direct or in solution. Formulated preparations, such as ointments, creams and lotions, may be lightly rubbed in. The trunk of the animal is then wrapped in a plaster of Paris bandage to keep the test patch in position. The skin is examined after 24 and 72 hours, and the reactions scored according to an arbitrary scale which records the degree of damage. Mildly irritant substances produce no more than a slight erythema, moderate irritants a severe erythema, and severe irritants a marked necrotic effect with scab formation. In addition to tests on intact skin, the substance may be applied to abraded skin. Chronic effects These are determined following repeated application of the compound to the skin over a period of 10 to 14 days. Again the damage may be scored at the completion of the test. Some observers keep the skin covered throughout the test, others do not. Covering does prevent the animal from removing the compound, and it is not difficult to apply the substance under the piaster of Paris bandage. Covering does not in itself produce damage, but there is some evidence that covered skin is more sensitive than uncovered skin. A more sensitive method for assessing primary skin irritation is to inject a single dose of the compound intradermally into the skin of the guineapig or the rabbit. Again the hair is removed from an area on the back or flanks. A solution of the compound is injected intradermaliy using a volume of 0.05 to 0.25 m!. Several injection sites can be included in the same area, so that direct comparisons can be made in the same animal of different compounds. The injection sites are observed at intervals, over 7 days, and scored accord- ing to an arbitrary scale for the amount of damage produced. For inter- pretation of the results it is desirable to make comparisons with substances of known irritancy. Mucous membranes It is necessary to determine the effects of compounds on mucous mere-