J. Soc. Cosmet. Chem. 26, 173-187 (1975) ¸ 1975 Society of Cosmetic Chemists of Great Britain Exaggerated exposure in topical irritancy and sensitization testing N.J. VAN ABBI•,* P. NICHOLASI and ELIZABETH BOON* Presented on 26-30th August 1974 in London at the IFSCC Vlllth International Congress on 'Cosmetics--Quality and Safety' organ fled by the Society of Cosmetic Chemists of Great Britain. Synopsis--The concept of a 'safety margin' provides a convenient expression for the hazard of adverse reaction following topical administration. Exaggeration of exposure conditions in PREDICTIVE TESTING helps to establish the safety margin, but reliability of any prediction depends on limiting the effects of exaggeration to quantitative rather than qualitative enhance- ment of responses. Gross exaggeration often leads to qualitative changes defying interpretation in terms of hazard during normal use. Techniques for safety evaluation based upon causing only threshold effects and comparison of an unknown with a well-established 'control' preparation of similar type are suggested as most suitable for relatively innocuous cosmetics. Human tolerance tests would probably be ideal for the purpose but extremely time-consuming. If animal tests are used to screen for skin and EYE IRRITANCY, there should not be any need for grossly exaggerated exposure since the species mostly used approximate quite closely to man in their susceptibility to skin and eye irritants. The prediction of sensitizing potential by exaggerating exposure is unsatisfactory owing to insufficiency of data on DOSE-RESPONSE behaviour for mild SENSITIZERS. Experience in normal use of a cosmetic by gradually increasing numbers of individuals would seem to be the only available way to establish SENSITIZING POTENTIAL for cosmetic formulations, although a GUINEA-PIG TEST may be useful for screening new raw materials. INTRODUCTION The possible hazard of adverse reaction in response to topical administration needs to be assessed by means of suitable predictive tests. The extent of such a hazard is conveniently expressed in terms of the margin * Beecham Products Research Dept., Leatherhead, England. •' Present address: Toxicol Laboratories Ltd, Ledbury, Herefordshire. 173

174 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS between probable exposure of the skin or mucous membranes during normal use and the level of exposure which would produce an adverse reaction. In order to err on the side of safety, broad margins of safety are sought by exaggerating the levels and conditions of exposure in the test procedures. However, injury may result from grossly excessive direct con- tact of many tissues with even the most innocuous environmental chemicals and so a rational approach to exaggeration is essential. The degree of chemical insult that the skin or mucous membranes might be expected to tolerate is somewhat problematical. The extensive testing carried out on the safety of ingested materials, such as food additives, offers little guidance as such investigations are principally aimed at demonstrating toxic effects after systemic absorption. The aspect of safety evaluation for ingested substances corresponding to topical administration is the direct effect, if any, of the test materials on the gastro-intestinal lining. Severe irritation of the lining would indeed be observed under conditions of gross exposure to many universally-accepted food materials and especially con- diments such as vinegar and mustard. In other words, although there should be a wide margin of tolerance once a test material has been diluted in the body fluids following absorption, a narrower margin is to be expected in the case of a tissue in direct contact with the test material. Whilst acknowledging that there are likely to be considerable differences between direct exposure and exposure after absorption, it might be instruc- tive to consider the postulates on which the safety evaluation of food additives is based. A hundredfold safety factor (1) is commonly quoted this may be deemed to offer a tenfold allowance for the greater suscepti- bility to systemic toxicants of man compared to laboratory animals, to- gether with a further tenfold allowance for variation in susceptibility between individuals. In terms of systemic toxicity, such a tenfold allowance for inter-species differences in metabolic transformation and excretion seems reasonable. Effects on the skin and mucous membranes, however, are not primarily dependent on species-specific metabolic pathways. Indeed, the skin of those martahals most often used for irritancy testing approximates quite closely to human skin in its susceptibility to irritation or even shows greater sensitivity to some irritants (2, 3). The epidermal horny layer of the skin is an important barrier to the absorption of foreign chemicals (4) and provides the first line of defence against irritants. Thickness of the horny layer varies across the human skin and in some regions it is thinner than the horny layer of other mammals. However, human epidermis overall is much thicker (5) than in most