APPRAISAL OF METHODS FOR DETECTING PRIMARY SKIN IRRITANTS 765 substance under investigation and the nature of the cosmetic in which it will be included. No single animal species is entirely reliable for predicting the irritancy of all substances to man but a retrospective survey of the literature indicates that the rabbit has a skin which is sensitive to most substances likely to irritate human skin. However, other species should be used in addition to the rabbit in routine studies for primary irritants. Although no single schedule of testing is completely reliable for detecting irritants, the tests most frequently employed in animal and human investiga- tions are similar in detail. They are essentially of two types. The first is the patch test, which is a biological test designed to show whether a substance is irritant and under what conditions. This knowledge may then serve as a basis for conducting secondary tests to ascertain the mechanism by which the substance exerts its irritant action. The patch test as originally described, specified that substances should be tested only under occlusive conditions, with the skin reactions being subjectively evaluated. To be of greater value, tests should be carried out using both open and occlusive conditions and areas of intact and abraded skin. To overcome the difficulty of detecting minor degrees of damage not visible to the naked eye, histology and histochemistry have an obvious advantage, particularly in animal tests. However, in human studies, where this type of investigation is not usually practicable, an examination of successive layers of keratinized cells removed by adhesive tape stripping, is considered to be informative. The value of methods for exaggerating the sensitivity of animal skins by chemical and mechanical means and other modifications of the patch test have been discussed in detail. Following the initial animal tests and the subsequent trials with human volunteers, both with individual chemicals and definitive cosmetic formula- tions as they are intended for marketing, 'in-use' tests with panels of volunteers are essential. These tests cannot be standardized, but should be realistic for the particular cosmetic. The test should take the form of applications of the cosmetic to the skin under its exact recommended con- ditions of use, for a given period. Adverse reactions should be recorded as and when they occur and the results analysed statistically. A number of secondary tests for investigating the action of topically applied substances on the character of the skin, its biochemistry, electrical conductivity, mechanical properties and chemical constitution have been discussed. Also reference has been made to tests designed to investigate the functional capacity of the skin appendages. The conclusion reached

766 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS regarding these secondary tests is that, whereas several are likely to provide interesting information on the effect of a substance on the skin, insufficient experience seems to have been gained from using them to be able to recom- mend their adoption routinely. Since animal tests are essential in the initial screening for primary skin irritants, some basic research into the reactions of animal skin compared with human skin is required. This information is likely to enhance the value of initial predictive tests greatly and to facilitate the extrapolation of the data to man. ACKNOWLEDGMENTS I acknowledge the encouragement and advice given by the Director, Dr. R. F. Crampton, and the assistance of Dr. Joan Hardy, Dr. K. Butter- worth and Dr. P. Grasso in the preparation of the manuscript. (Received: 11th May 1972) (1) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) REFERENCES Carter, R. O and Griffith, J. F. Experimental basis for the realistic assessment of safety of topical agents. Toxicol. Appl. Pharmacol. 7 60 (1965). Fisher, A. A. Contact dermatitis (1968) (Lea & Febiger, Philadelphia). Rostenberg, A. Cutaneous reactions from cosmetics. J. Soc. Cosmet. Chem. 11 170 (1960). Rostenberg, A. Methods for the appraisal of the safety of cosmetics. Drug Cosmet. Ind. 88 592 (1961). Rieger, M. M. and Battista, G. W. Some experiences in the safety testing of cosmetics. J. $oc. Cosmet. Chem. 15 161 (1964). Calnan, C. D. The significance of assay method for the dermatologist. Brit. J. Dermatol. 82 43 (1970). Jadassohn, J. Verh. Deut. Derm. Ges. V. Kongr. 103 (1896). Bloch, B. Experimentelle Studien ueber das Wesen der Jodoformidiosynkrasie. Z. Exp. Path. Therap. 9 509 (1911). Bloch, B. Referate ueber Ekzem Pathogenese. Arch. Dermatol. Syphilol. 145 34 (1924). Draize, J. H., Woodard, G. and Calvary, H. O. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. t'harmacol. Exp. Ther. 82 377 (1944). Kligman A.M. Evaluation of cosmetics for irritancy. Toxicol. Appl. Pharmacol. $uppl. 3 30 (1969). Wolven, A. and Levenstein, I. Techniques for evaluating dermal irritation. J. $oc. Cosmet. Chem. 18 199 (1967). Kligman, A.M. and Wooding, W. M. A method for the measurement and evaluation of irritants on human skin. J. Invest. Dermatol. 49 78 (1967). Wooding, W. M. and Opdyke, D. L. A statistical approach to the evaluation of cutaneous responses to irritants. J. $oc. Cosmet. Chem. 18 809 (1967). Levenstein, I. and Wolven, A. Evaluating the dermal toxicity test of the FDA. Amer. Perfum. Cosmet. 80 64 (1965). Schmid, O. Tierexperimentelle Untersu6hungen zur Hautvertraeglichkeit. J. $oc. Cosmet. Chem. 21 835 (1970).