44 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS fully natural moisturizer etc. removed during this washing. Equally, the fact that we have found some surfactants denature keratin or modify the stratum corneum suggests that the skin may be sufficiently altered after one application to behave quite differently during subsequent applications. Although sodium lauryl sulphate has a very low rate of penetration (per- meability constant of 0.065 x 10 -6 cm min -•) it is probable that if the animals had been previously washed with this surfactant prior to application of the radioactive compound, sufficient changes in the stratum corncure may have occurred to allow greater amounts to be absorbed. This has certainly been shown to be true for sodium lauroyl isethionate. Table V gives a permea- bility constant of 0.3 x 10 -6 cm min -•. When additional guinea-pigs were washed three times with this surfactant on the day prior to the penetration study we found that the average value of the permeability coefficient was 0.92 x 10 -6 cm min -•. Thus, frequency of treatment has a direct bearing on observed penetrability. This would suggest that laboratory methods designed to examine individual aspects of the skin's response to surfactants should be designed to resemble normal methods of application of these compounds. Secondly, in the present study we have examined by no means all of the salient parameters of skin-surfactant interaction. Middleton (1) showed that the amount of lipid extracted from stratum corncure was dependent upon the type of surfactant used, and its removal affected the water-binding capacity and the flexibility of the skin. We have not as yet studied lipid removal by model surfactants. It may well be that this aspect is more important than, say, removal of proteins and amino acids from the stratum corneum. Indeed, the stability of the skin's lipid mantle during washing and its subsequent rate of recovery may be a rate-limiting factor. Equally, we have no precise data on substantivity. If a seemingly non-penetrating sur- factant actually tightly binds to the stratum corncure this may in practice leave a large cutaneous pool which gradually penetrates during many hours after a single exposure, and so overall irritation potential would be greater than first thought. Also, we have not considered partition coefficients of the sttrfactants used: it is possible that solubility in the components of the skin (lipids, aqueous phase) is important to overall irritancy. Each of the four approaches dealing with individual aspects of overall skin-surfactant interactions we have described, indicate that the chemical structure of surfactants is very important in determining its effect upon the skin. Head-group polarity determines whether a surfactant can denature protein, extract compounds from the stratum comeurn and penetrate to the living cells. Also, the length of the lipophilic chain imparts properties of

SKIN IRRITATION POTENTIAL OF SURFACTANTS 45 extraction, penetrability and cell-lytic ability. The concentration of sur- factant used is most important, below the critical micelle concentration, when the surfactant behaves as an ideal solution, denaturation and extrac- tion of the corneum is not so important. This suggests that adequate know- ledge of the physical chemistry and solution thermodynamics of surfactants is vital to an understanding of how surfactants may invoke a skin response. The studies reported here suggest that no one experimental procedure can adequately replace that in which surfactants are directly applied to the backs of animals, and the skin's response is assessed by the naked eye. If one wishes to compile a mathematical equation for skin irritancy, this must necessarily be a complex function, and more than just an expression of penetration and cell toxicity. One must also include expressions governing the binding of surfactants to skin, the modification of the stratum corneum which allows greater penetration, the polarity of the surfactants involved, etc. Thus, when one attempts to employ laboratory methods dealing with various parameters of the skin's response to surfactants, one must clearly define the questions being asked by such tests. For example, knowledge of the effect of surfactants upon living cells would have no value in evaluating whether a surfactant formulation had a drying effect upon the stratum corneum, whereas studies on extraction ability would. On the other hand, substantivity and knowledge of penetrability through the skin would be important in deducing whether a compound was able to cause erythema. The data described above do not permit us to state which type of laboratory test would be the most adequate to give an indication of whether a surfactant is potentially irritant to the skin, rather, we have shown that there are many parameters of the response to be considered, each playing a specific part in the overall phenomenon of skin-surfactant interactions. Similar conclusions have been drawn by Brown (17). (Received: 22nd May 1974) REFERENCES (1) Middleton, J. D. The mechanism of action of surfactants on the water binding properties of isolated stratum corneum. J. $oc. Cosmet. Chem. 20 399 (1969). (2) Blank, I. H. Factors which influence the water content of the stratum corneum. J. Invest. Derrnatol. 18 433 (1952). (3) Bettley, F. R. The irritant effect of detergents. Trans. St. John's Hosp. Derrnatol. $oc. 58 65 (1972).