j. Soc. Cosmet. Chem., 48, 307-317 (November/December 1997) The skin irritation potential of quaternaries M. M. RIEGER, Morris Plains, NJ 07950. Accepted for publication November 7, 1997. Synopsis It is frequently reported that the relative skin irritancy of surfactants depends on the ionic species formed by the surfactant. Thus the irritation potential of surfactants is widely assumed to follow the pattern below in which quaternaries are the most irritating: quaternaries amphoterics anionics nonionics. The basis of this relative rating is examined below, with the conclusion that it requires modification for topically used quaternaries and surfactants in general. INTRODUCTION The evidence for the relative skin irritancy rating of surfactants--quaternaries am- photerics anionics nonionics--dates back to the period following World War II when eye and skin irritancy were assessed via the well-known Draize animal procedures [as detailed in 1959 in ref. (1)]. In addition, the potential of any surfactant to cause skin irritation can be established by a variety of alternative toxicological test procedures, as reviewed by Drobeck (2). It is the objective of this review to examine the pertinence of these and related tests for the assessment of skin irritation that may result from acci- dental or deliberate contact with quaternary surfactants. In order to complete this effort, it will be necessary to include some details of the testing of irritancy of other groups of surfactants. DEFINITION OF SKIN IRRITATION Skin irritation is defined simply as a transitory adverse response of skin to contact with the irritating species. Irritation may result from any corrosive or toxic substance, i.e., one that attacks the integument. Skin exposure to such a substance under normal cosmetic use may lead to changes in transepidermal water loss, dryness, tautness, scaling, and even erythema. The early investigators were limited to relying on erythema as the marker for skin irritation since they had no other means of assessing damage. Thus much of the data refers to the rate and level of reddening and the effect of concentration of the eliciting substance. It must be clearly recognized that erythema is a late effect of irritation, requiring that the applied substance itself reaches the dermal vasculature or that the 307

308 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS substance triggers the release or formation of a compound within the skin that upon further permeation (or via feedback) causes the hyperemia. Erythema-•even in the absence of urticaria--is also a sign of sensitization, but this is a reaction that is distinct from that of irritation. The elicitation of immune responses can be the result of the presence of epidermal immunocompetent cells or may take place only after systemic processing of the allergen. Immune responses to the application of qua- ternaries to the skin will not be discussed since they are evidently rare. Skin irritation in this review is, therefore, defined as a dermal reaction to topical administration. It is unrelated to dermal manifestations resulting from systemic administration of an irritant or to systemic toxicity. DEFINITION OF QUATERNARY In this review a quaternary is defined as a compound in which a nitrogen atom is covalently bound to four alkyl groups reg,•rd/ess ofpH and, therefore, carries a positive charge reg,•rd/ess of pH. Thus amines and amphoterics, in which the charge on the nitrogen atom varies as a function of pH, are excluded. Despite this limitation, the number of cosmetically useful quaternaries is well over 500. For clarification, the de- fining quaternary structure is shown below: R• I R 2-N +-R 3 I R 4 Up to three of the covalently bonded R groups may be part of the same cyclic or aromatic system, as, e.g., in the well-known pyridinium salts. The hydrophobicity of quaternaries can be modified by the inclusion of a (poly)oxyethylene group in one or more of the substituent R groups. The counterion to the positively charged N- atom can be a halogen, a sulfate (ethosoulfate), a carboxylic acid, or, in fact, any species that can form an anion. In some cases, the anion-forming group may be part of one of the alkyl groups. A typical example of this is a betaine in which a zwitterionic species can be formed over a limited pH range. Quaternary molecules are not unusual in nature. The N- atom in phosphatidylcholine is a true quaternary, and lecithin is a ubiquitous constituent of animal and plant tissue. Even though it is a quaternary, it is not regarded as toxic or irritant. The safety of lecithin leads to its use in parenteral nutrition. On the other hand, most of the cos- metically or pharmaceutically useful quaternaries are synthetic substances. Their inges- tion or injection into mammals has elicited some toxic responses, especially at the dosages commonly employed by toxicologists. The purity of synthetic quaternary substances is almost never described in the toxico- logical literature. In the early toxicological literature, identification was by (commercial) trade name (3). In retrospect, it is likely that most substances tested during this period included some amines and remnants of the alkylating agents. Unfortunately, details of this type are irretrievably lost, even though their significance to any skin irritation potential could be important.