APPRAISAL OF METHODS FOR DETECTING PRIMARY SKIN IRRITANTS 745 Since invariably animals are used in initial investigations for irritants, it would appear profitable for some basic studies to be carried out to ascer- tain whether or not any simple correlations do exist between animal and human predictive tests (1, 49). The existence of such a correlation was strongly doubted by Rieger and Battista (5) who also drew attention to the poor correlation of the results of human patch tests and 'in-use' investiga- tions. It has often been stressed that the use of animals for detecting primary irritants is likely to yield information only of a relative kind, i.e. compound A is more irritant than compound B and less than compound C. Such information could be of considerable value if substances of known degrees of irritancy to human skin were included in the animal testing (12-14, 25). The adoption of this principle, together with attention to the other factors described above, would greatly increase the value of animal skin testing. The relative merits of various animal species in tests for primary irritants have been reviewed previously (50, 51). The rabbit has been shown to be the most suitable species for detecting substances likely to irritate human skin, but it was considered advisable to use additional species. On the evidence available, rats, mice and guinea-pigs are satisfactory as secondary species. The difficulty in obtaining consistent results using the rabbit is well illustrated in a large scale collaborative study reported by Weil and Scala (52). If difficulty is encountered when using only one species, the use of additional species may further complicate the evaluation unless care is taken to ensure that the information sought is particularly relevant. Tests in man The patch test, as described by Draize (10, 53), for use in human studies is similar in detail to that used in rabbits. Occlusive patches are applied to suitable areas of skin on the forearm or back of subjects and the reactions are scored in a similar manner. Although an exposure period of 24 h was recommended for use in animal tests (10), Rostenberg (4) suggested that a test period of 48 h would be more suitable to detect obvious irritants in human tests. A modification of the Draize test was suggested by Lanman (24). It involves not just a single application of a test compound followed by a scoring of the skin reaction, but repeated application at daily intervals until such time as the skin shows some change in appearance. In this test, the

746 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS irritancy of a test substance would be based, not on a score, but on the average time taken for a visual skin reaction to be produced. In this way, a severe irritant would be detected after 1 or 2 days, whereas a mild irritant might require up to 10 or 20 days before being detected. The authors believed that the technique considerably reduced errors due to subjective assessment which are bound to occur when skin reactions are scored after single exposures of 24 h. The technique might prove misleading, however, in distinguishing between primary irritants and substances likely to bring about skin fatigue. To distinguish primary irritants from agents which cause skin fatigue, two groups of volunteers could be used (54). One group might be given the standard Draize test with the cutaneous responses being scored after 24 or 48 h exposure, whereas the other group would be treated repeatedly for 1 or 2 weeks by Lanman's test (24). In this type of investigation two controls are required, namely a known primary irritant and a skin fatigue inducing substance. An agent which fails to give a response by the Draize test but gives a reaction by Lanman's test after 10-20 days would be regarded as a mild irritant or skin fatigue inducing agent. As a definitive test in man, substances are tested under conditions which are more closely related to the product in its intended conditions of use (33, 55). One such test designed to incorporate features of the patch testing procedure and the recommended use of the final product, was suggested by Rieger and Battista (5). This test takes the form of daily applications of the test compound to the skin for 30 consecutive days, followed by a rest period of 7 days. Then the substance is applied under its exact conditions of use for an unspecified period. During the initial period, the skin reactions are examined daily whereas in the latter stage, reactions are noted as and when they occur. The results given by such a test might be misleading since the test is likely to also show up agents producing contact sensitization. Fisher (55) suggested a test in which substances are rubbed into areas of the arm or back three times daily for 3 consecutive days. A test frequently employed in the safety testing of detergents takes the form of repeated daily immersion of the arms and hands of volunteers in suitable solution of the test substances, for periods which may vary from a few days to several weeks (48, 56-58). In this test the arms and hands would be ex- amined daily and scores allocated for any reactions present. Satisfactory safety data obtained from these confirmatory tests might be accepted as being indicative of the suitability of a product for marketing. However, in order to be satisfied that a new product is without harmful