SURFACTANTS AS ANTIMICROBIAL AGENTS 739 basic compounds, whether aliphatic or aromatic and when active, will show effect on gram (-) organisms. To summarize, acidic or neutral compounds (amides, aminimides or esters) are active against gram (+) and yeast organisms while amine compounds characteristically enjoy wide spectrum biocidal activity. ANTIMICROBIAL ACTIVITY VS. HUMAN TOXICITY The aspect of toxicity and irritation and surfactant biological activity while representing two separate functional properties are today of great concern, especially to the cos- metic chemist. Regardless of the practicality of the zero-risk concept, regulatory agencies have challenged the cosmetic chemist to seek better and safer alternative chemicals. Because all cells (microorganisms) are not alike, it may be possible to design compounds which are effective against microorganisms but not man. All cells are unique and they should be expected to react differently, quantitatively if not qualita- tively, to chemical agents. This uniqueness resides primarily in the cellular walls and/or membranes. Indeed it may be the membrane (wall) that not only gives the cell its unique character but also controls its metabolic function. The above argument needs no supporting references for acceptance. Despite this recognition, most drugs have been designed to affect the interior of the cell rather than the membrane. It is my hypothesis that drugs, and surfactants in particular, can be made to act more selectively if their action is directed to certain cells or classes of cells. This hypothesis, conceived during my work with aliphatic surfactants, has now reached fruition. The best example of this can be found in our study of unsaturated fatty acids. Oleic acid is considered a growth factor for mammalian cells (19). Jenkin et al. (20) found that while Aa 18:1 was inhibitory for kidney cells and the A 2, A7 and A8 18:1 isomers were growth stimulators, Kabara et al. (! 3) reported these latter isomers to be lethal against group A Streptococcus. This is the first example that ! am aware of where a compound such as the A2 C•8: • derivative can be a growth stimulator for a mammalian cell and an inhibitory agent for a microorganism. Such specificity can only stimulate• the imagina- tion to look for other examples. Among the surfactants there is a distinct trend towards higher toxicity for aromatic compounds as compared to lipophilic groups, which are aliphatic and natural in origin. Aliphatic surfactants offer germicidal activity which are reasonably high and safe since their biotransformation products--water, carbon dioxide and ammonia or trimethyl amine--are rather innocuous. From a toxicity point of view, the cationic surfactants, while representing the most active biocides, are also the most toxic. The oral LD•0 toxicity of these basic compounds is between 50-500 mg/kg, the amide and aminimides between 1-3 g/kg, anionic compounds 2-8 g/kg, while the nonionic surfactants, the least toxic, have values between 5-50 g/kg. The above generalization on agent toxicity suggests that nonionic surfactants de- serve greater attention in the future as compared to the past. Past experience, how- ever, has suggested that nonionics have little antimicrobial activity. Our research has demonstrated that this conclusion was based on nonionic compounds composed of mixed acids and representing mixed esters. Our laboratory data with purified surfactants reveal that mono-esters of polyhydric alcohols and esterified with lauric

740 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS acid are biologically active (15). The most active of these mono-esters is monolaurin (Lauricidin, 90% mono-ester), which is considered GRAS material. While the parent compound has useful but limited antimicrobial activity, monolaurin has been successfully compounded with other food-grade materials to yield products with wide spectrum activity and a short killing time (16). I'm sure other successful nontoxic formulations will be developed in the future. The other toxicological aspect of surfactants of particular concern to the cosmetic formulator is skin irritation (contact dermititis). Lipophilic chains (Cs and C•0) in satu- rated soaps are highly irritating while C • chain length is less irritating and C •4 to C •8 are the blandest. Thus, among soaps, short chains and high alkalinity are conducive to irritation. Commonly, long, straight chain surfactants are less irritating than short, branched chain products. Again, as with toxicity, the quaternaries are, in general, much more irritating than the anionics or nonionics. The nonquaternary amine salts tend to be at least as irritating as the quaternaries and possibly even more hazardous. In terms of eye irritation, the U.S. Food and Drug Administration laboratories have found a wide variation among individual surfactants and surfactant mixtures. As a general statement, the nonionics are least injurious, the cationics the most injurious and the anionics as intermediate. SUMMARY I have, thus, presented some structure-function associations which relate to cationic, artionic, amphoteric and nonionic surfactants as biocides. Of the large number of fatty acid surfactants used, the nonionics appear to be the most attractive. Based on their low index of toxicity and irritability and derived from renewable resources, nonionic surfactants offer real advantages to the cosmetic chemist. Contrary to the art for other nonionics, the high antimicrobial properties of the lauryl monoesters are unusual in that they can impart "medicated" or preservative quality to cosmetic formulations without added toxicity. With the current rage of "returning to nature," these fatty acid derivatives can rightly claim to be composed of "all natural ingredients." Current research indicates their use- fulness as food-grade preservatives, anticariogenic agents and in topical antimicrobial products (15, 16). As petro chemicals become less available and toxicology, rather than high germicidal property, becomes a greater consideration, I predict a wider and more diversified use for nonionic surfactants, particularly lauryl derivatives, as antimicrobial agents in foods, cosmetics and toiletry formulations. REFERENCES (1) F. Hawking andJ. S. Lawrence, "The Sulphonamides," Lewis Press, London, 1950. (2) H. N. Glassman, Surface-active agents and their application in bacteriology, Bact. Rev., 12, 105-148 (1949). (3) A.M. Schwartz, J. W. Perry and J. Berch, "Surface Active Agents and Detergents," R. E. Krieger Pub- lishing Company, Huntington, New York, 1977, pp 204-241. (4) J. Ferguson, The use of chemical potentials as indices of toxicology, Proc. Roy. Soc. (London), 127B, 387-404 (1939). (5) A.M. Schwartz et al., op cit., pp 230.