J. Soc. Cosmet. Chem. 23 739-772 (1972) ¸ 1972 Society of Cosmetic Chernists of Great Britain An appraisal of methods for detecting primary skin irritants A. B. G. LANSDOWN* Synopsis--Problems involved in the safety testing of cosmetic chemicals for SKIN IRRITANCY are discussed with reference to ANIMAL and HUMAN STUDIES. A survey of the literature shows that no single test is adequate to detect all skin irritants to man but that the PATCH TEST PROCEDURE firstly in animals and subsequently in man is the most suitable screening method. Test compounds should be applied to areas of intact and abraded skin under open and occlusive conditions. HISTOLOGICAL EXAMINATION of treated skin is advisable in animal studies to detect changes not visible to the naked eye. TAPE STRIPPING may be useful in human studies where histology is not possible. DYE EXTRAVASATION techniques for tissue injury are insufficiently sensitive. Although some methods for demonstration of the function of skin APPENDAGES were considered, they have not been used sufficiently to establish their value for use in routine studies. Information acquired from patch tests may serve as a basis for conducting secondary tests including biochemical, electrical and mechanical studies IN VIVO or IN VITRO. These tests are not, on available evidence, superior to the patch test and no direct interpretation of the results in terms of tissue damage exists. Tests for materials used in cosmetics should resemble closely the intended 'in-use' applica- tion of the final product and the conditions of test should simulate consumer usage. Definitive tests of this type are followed in practice by pre-marketing trials in which a product is tested as reconm•ended on the label. INTRODUCTION In a safety testing programme for substances intended for inclusion in cosmetic or toilet preparations, it is desirable to employ test conditions that typify the recommended use of the final product as closely as possible (1). * British Industrial Biological Research Association, Woodmansterne Road, Carshalton, Surrey. 739

74O JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS To be suitable, the tests should take into account the actual part of the human body to which the cosmetic will be applied, the maximum concentra- tion of the substance likely to be present in the cosmetic, and the greatest frequency at which the preparation might be used by an individual. As in most toxicological studies, initial safety evaluation tests are carried outusing an animal species and only the confirmatory tests are conducted in man. Substances which irritate the skin are of three types, namely: (a) Primary irritants. (b) Skin fatigue inducing agents. (c) Contact sensitizing agents. A primary irritant, as defined by Fisher (2) is a substance which produces inflammatory changes in the skin as a result of a direct damaging effect. An alternative definition is that it is a substance capable of producing damage without the mediation of an antibody system (3). The response is an extreme reaction of the tissue to injury, which is not physiological and is characterized by the presence of inflammation, vesiculation and necrotic changes at the contact site. Some substances may not produce visible damage in the skin after a single application but, when administered repeatedly, irritation is produced. Such an agent brings about a state of 'skin fatigue', a condition which is characterized by hyperirritability, local hardening and thickening of the skin (2). Contact sensitizing agents are distinguished from the two classes of irritants mentioned above, in that they produce epidermal damage which is mediated by allergic changes in the tissues (3). Often the cutaneous response occurs some time after the original contact and at a site remote from the point of application of the sensitizor. This response is known as 'delayed hypersensitivity'. Since this type of reaction is not relevant to this review, it will not be discussed further. In cosmetics, strong irritants are rarely a problem since they are readily detected by animal tests and consequently would be rejected without further consideration. However, weak irritants present a greater problem, since they may not be detected either in the initial animal tests or in sub- sequent clinical trials. Once a product has been marketed, information on minor reactions is difficult to obtain since users tend to revert to using an alternative preparation, without making a complaint to the manufacturer. Cosmetics and toilet preparations were classified by Rostenberg (3) under the headings--hair and eye cosmetics face powders, creams and lipsticks nail cosmetics antiperspirants and deodorants depilatories