J. Soc. Cosmet. Chem., 28, 667-679 (November 1977) Reduction of topical irritation ROBERT L. GOLDEMBERG, Rakuma Laboratories, Inc., P.O. Box 2083, South Hackensack, N•J 07606 and LEOPOLD SAFRIN, 264 So. Harrison St., East Orange, N•J 07018. Received November 23, 1976. Presented SCC St. Louis Chapter Meeting, September 20, 1976 and SCC New York Chapter Meeting, October 6, 1976. Synopsis ANTIIRRITANT effects noted since 1965 are reviewed and grouped into two major chemical categories: IMIDAZOLE and HYDROXY compounds. Several miscellaneous types are also noted: PVP (Polyvinyl py- rollidone), quaternary ammonium complexes, and amido sulfosuccinate surfactants. The "no tears" antiirritancy effect, which results from a combination of AMPHOTERIC surfactants with lauryl sulfates is postulated as resulting from a possible difference in sorption rates which allows the am- photeric to "occupy" the cornea's available binding sites before the anionic can do so, thus preventing "denaturing" damage to the eye by the lauryl sulfate. INTRODUCTION Some 12 years ago Goldemberg (1) presented a paper to the Third IFSCC Congress on the use of antiirritants in cosmetic formulations. Its major thesis was that the topical ir- ritation potential of cosmetic ingredients depends as much on their extrinsic "formula- tion environment" as on intrinsic properties of the ingredients themselves. That initial paper, plus several subsequent ones touching peripherally on this subject, proposed three possible mechanisms of action by which antiirritants may function: (1) via complexation of the irritant (2) by blocking otherwise chemically reactive sites of skin keratin and (3) by preventing complete physical contact with the skin. We have no reason to change this overall view today, and in fact, we provide in this paper a considerable expansion of the original reference section of that 1965 paper, thus bringing the subject to date. We have now had time to explore many of these phenomena in depth. Many clear cut accomplishments have been achieved in this area during the past decade--including a number of newly issued patents covering antiir- ritant activity of various compounds. The "desensitization" (of perfume components) via nonimmunologic processes is now also being actively explored (23, 59). It is the purpose of this paper to summarize such recent developments in the field of antiirritancy, and to offer theoretical considerations linking together as many of them as possible. 667

668 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS GENERAL The basic concept first enunciated in 1965 still holds: it is possible to change the irrita- tion potential of topically applied raw materials by varying their "formula environ- ment." Materials, which per se are soothing to the skin, occasionally reverse their roles and increase topical or eye irritation levels in certain types of formulations. On the other hand, strong irritants can frequently be rendered totally innocuous by combining them with precise (usually small) percentages of other ingredients. It is such other in- gredients which we herein define as "antiirritants." There are several probable mechanisms by which some compounds are able to reduce topical or eye irritation of other ingredients. Some of these processes are more or less mechanical, depending primarily on physical factors for their "activity" in this respect. However, we must not confuse such physical effects with specific antiirritancy of a chemical nature. To avoid later confusion between these two phenomena, we shall first briefly review recently noted physical effects, to preclude them from later discussion of antiirritancy operating via mechanisms of chemical reactivity. PHYSICAL ANTIIRRITANCY The simplest physical effect is diminution of skin contact by the irritant--applying oily substances to the skin prior to application of aqueous irritants (such as greasing the forehead and temples before applying caustic hair straighteners) and gelling (or otherwise thickening) products to reduce intimate skin contact. Gelled shampoos and bubble baths frequently are not irritants when tested "as is." Once diluted to the point where they flow readily, however, they often become primary skin and eye irritants (56). Perhaps related to viscosity and consequent skin penetration are the well known phenomena that light mineral oils (40 visc. and under) are irritants, medium weight (70 visc.) oils are neutral, and heavy mineral oils are antiirritants. The rate of sorption of surfactants onto keratin surfaces has been shown by Garrett (2) to relate directly to their irritation potential. Another rather purely physico-chemical factor affecting irritation response is the loosening of hydrophobic bonds, discussed at length recently by both Dominguez (3) and Hall (4) at the Ninth IFSCC meeting. At this same meeting, Suzuki pointed (5) to the correlation between skin irritancy and rate of penetration (into sebaceous glands by isopropyl myristate, glyceryl trioleate, etc.). The partition coefficient between pharmaceutical vehicles and skin fat has been dis- cussed by both Rabinowitz (6) and Goldemberg (7) as a probable factor determining substantivity and the associated irritation potential of certain active ingredients. Various proteins and partially degraded collagens have been cited for their "protective colloid" and other inactivating effects (8,9,10,11,12,13,20), while partially depolymerized chitin and/or pulverized egg shells appear to promote wound healing (14,15,16,47), perhaps simply by acting as foci for epithelial granulation. Note that Chitin contains D-Glucosamine as a major constituent. Reduction of pH is probably the sole reason that addition of ammonium carbonate reduces irritation of thioglycolate permanent waves (17). Several authors have also pointed out (18,19) that climatic influences should not be ignored when judging the results of human irritation testing, especially large scale tests such as the Food and