j. Soc. Cosmet. Chem., 28, 197-209 (May 1977) A method for appraising the stinging capacity of topically applied substances PETER J. FROSCH and ALBERT M. KLIGMAN Duhring Laboratories, Department of Dermatology, University of Pennsylvania, 3500 Market Street, Phdadelphia, Pennsylvania ] 9104. Received April 13, 1976. Synopsis ß SUBSTANCES, which cause SUSTAINED STINGING, can be recognized by APPLICATION to the NASOLABIAL FOLDS and CHEEKS during PROFUSE SWEATING, The test was carried out on pre- " selected individuals in whom a susceptibility to stinging had been demonstrated by exposure to 5 per cent '=:' aqueous lactic acid. Stinging proneness is greater in females than in males, and in whites more so than in blacks, and especially in light complexioned persons who tan poorly. Stinging is mainly perceived on the :: face. : :i?i Stinging and irritancy were not strictly correlated. Most primary irritants do not cause stinging. Weak ir- ß ':'• fitants may sting badly. ,- :: INTRODUCTION !: Producers of medicaments, cosmetics, and toiletties are attuned to the necessity of certifying the safety of their products. Generally speaking, adequate test procedures •::" have been developed for assessing the likelihood of toxicity from irritation, contact sensitization, and photosensitization. :i:•!i Nonetheless products which pass these tests and which fulfill the purposes for which they were designed may still be unacceptable. The consumer will reject even effective iS:.,/:!j formulations if disagreeable sensations arise after application. In this paper, we are V concerned with a special type of subjective discomfort, namely, delayed stinging or •:,::" smarting from topical agents applied to the skin. In contrast to substances like alcohol ?: which cause immediate but transient stinging, those that induce delayed and sustained '•'•i stinging are not so easily recognized. This adverse effect may not come to light until •. after the product has been in widespread use. Our focus is on substances which begin to "sting" or "burn" within a minute or two. The discomfort intensifies over the next 5 to 10 min and may become so severe that frenetic attempts are made at removal. Intense stinging generally abates within about 15 min. Signs of irritation--redness, scaling, edema--do not develop. 197

198 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS It is this sustained, crescendo type stinging that we undertook to study. An embarrass. ing experience precipitated our research. Although, it had been previously noted (1) that amyl-dimethyl-p-aminobenzoic acid (ADP)* could cause stinging, our premarket- ing tests of a sunscreen containing this ingredient repeatedly failed to disclose sus- tained stinging even under thermal stress. It was only after widespread sale that com- plaints were made by a small proportion of users. In our opinion, the prevalence of disagreeable stinging from this product is less than that reported by Parrish et al. (2) Were this not so, the extensive field testing, which was done in hot climates, would have revealed this adverse reaction much earlier. We are not the first to become conscious of the need to ascertain undesirable subjec- tive reactions. Armstrong and his coworkers applied test substances to the base ofcan- tharidin blisters in order to appraise their capacity to cause pain (3). This test is not relevant for materials that provoke stinging on normal skin. Laden (4) clearly perceived •. the problem and attempted to develop appropriate methodologies for detecting sting- • ing potentiality. He immersed the abraded tails of rats in test solutions and determined the time re- quired for the rat to flick its tail out of the solution. He emphasized the variability the results though useful information could be secured. For human testing, Laden ap•.:: ß plied test materials to scotch-tape stripped skin, obtaining reasonable agreement with7 the animal data. Again this procedure mainly measures pain (or does not clearly dis51 criminate between pain and stinging) its applicability to stinging from application to normal skin is uncertain. Laden made the important observation that stinging and irri -• tation could not be correlated. For example, substances such as citric and acetic acids :?_ caused intense stinging but scored quite low in tests of primary irritancy. . Recently, Shanaban and Ward (5) described an interesting animal model for estimating 71 i the stinging capacity of shampoos. They injected mice intraperitoneally and scored the ß intensity of the ensuing writhing. The results correlated well with human eye sting"•'::! :. tests. Again, stinging and irritancy were not found to parallel each other. Some sham-:t•} poos which proved to be nonirritating by the Draize rabbit eye test caused stinging. MATERIALS AND METHODS We gradually came to appreciate that only a small proportion of persons would show i'7: a stinging response to ADP. Our first task then was to develop a screen to locate?55 "stingers," persons who had this peculiar susceptibility. The following procedure ii: proved reliable. A volunteer was brought to a state of profuse sweating in an environ•.•'5': mental chamber at 110øF and 80 per cent relative humidity (R.H.). Then a 5 per cent::'. ß -? aqueous solution of lactic acid was rubbed briskly over the nasolabial fold and cheek. *Padimate, Eclipse, G. S. Herbert Co.