264 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The observed submicellar composition and concentration are evidence of non-ideal so- lution behavior. These results support the conclusion that small submicellar aggregates of surfactants exist above the CMC. The author speculates that aggregates may in fact account for the increase in irritation and barrier damage observed at doses greater than the CMC. Similar conclusions were reached by Lod•n (34) from her penetration studies with SLS. She concluded that monomer activity of SLS was not constant above the CMC but increases as the concentration of micelies increase. However, above the CMC the penetration rate was considerably slower. One may hypothesize that micelies themselves may in fact interact with skin but that it is unlikely that (a) such a large structure can penetrate into the barrier and (b) micelies in their thermodynamically preferred state will collapse upon contact with skin surface, releasing their surfactant molecules to interactive sites on the skin. Thus the hypothesis of miceliar aggregates as interactive species seems reasonable. SURFACTANT INTERACTIONS THAT COUNTER IRRITATION Recent information suggests that surfactants do not react with skin in an additive fashion to produce their various effects. In fact, addition of a mild surfactant to an irritating one often results in lower reactivity than is elicited by the irritating surfactant alone. This occurs despite the higher total concentration of the system after the second surfactant is added. Rhein eta/. (17) explored the effects of mixing ethoxylated alcohol sulfates and amphoterics with SLS on the swelling of isolated stratum corneum (Table III). Clearly, the swelling induced by the mixed systems was considerably lower than that caused by 1% SLS alone, despite the higher level of actives in the mixed system. The same effect was confirmed in an in vivo patch test for SLS and AEOS-6EO (17). The reduction in surfactant activity can possibly be caused by either of two mechanisms. The surfactants may interact in solution, reducing the CMC and forming mixed micelies that sequester the irritating surfactant, lowering its free monomer concentration and Table III Effects of Ethoxylated Alcohol Sulfates and Amphoterics on SLS-Induced Stratum Corneum Swelling Treatment Experiment (6-h incubation) Stratum corneum swelling (% increase from hydrated length) 1% SLS 1% SLS + 1% AEOS-3EO a 1% SLS + 1% AEOS-6EO a 1% SLS 1% SLS + 1% LDAO • 1% SLS + 0.5% LDAO • 1% SLS + 1% betaine • 1% SLS + 0.5% betaine • 46.1 + 3.62 21.6 + 1.29 19.1 + 3.60 46.8 + 4.08 7.7 + 1.72 25.8 + 8.44 21.0 + 4.45 34.5 + 4.25 a Values are means + SD. AEOS-3EO, (laureth-3 sulfate), AEOS-6EO (laureth-6 sulfate), LDAO (lauryl dimethyl amine oxide, and cocamidopropyl betaine when tested alone at 1% (w/w) all produced small or negligible increases in swelling above the hydrated lengths (i.e., equal to or less than 5% increase in 6 h). All treatments caused a significant reduction in swelling compared to 1% SLS treatment alone (p 0.01). SLS, sodium lauryl suli•te. From ref. 17.

SURFACTANTS AND STRATUM CORNEUM 265 preventing its interaction with the skin (33). This is discussed in more detail in the section on the role of the CMC. Alternatively, the mild surfactant may compete with the irritating surfactant for binding sites on the skin's surface. If tested at saturating levels, this would result in a reduced response. Dominguez et al. (35) showed that mixtures of cocoamidopropyl betaine and SLS elicited less ocular irritation than did either surfactant alone. They ascribed this synergism to interactions between the surfactants in solution, reducing the amount of either species available to elicit irritation. This could also explain the effect seen in Table III with laury! dimethyl amine oxide, i.e., a cationically charged surfactant interacts or associates strongly with the anionic surfactant, reducing the amount of either species available to cause irritation. Similarly, Faucher and Goddard (3) demonstrated a reduction in SLS adsorption to human hair keratin when a nonionic surfactant, Tergitol 15-S-9 (which is a 15-carbon alcohol containing 9 ethoxylate units), was added to the system, even though the total concentration of the system increased with the added nonionic surfac- rant. As very little noaionic surfactant was adsorbed to the hair, the authors suggest that the Tergitol and SLS are interacting in solution, preventing SLS binding. Inclusion of the nonionic in the system will lower the CMC, thus reducing the amount of free SLS monomer available to interact with skin (see section on role of CMC). Surfactants in mixtures can also compete for binding sites on the skin. In an earlier study, Dominguez et al. (36) showed competition between betaine and SLS in their binding to skin callus. This competition was affected by the pH and alkyl chain length of the betaine. Additional research is needed to identify more precisely the major factors controlling interactions to reduce the skin response. Dillarstone and Paye (37) examined various surfactant solutions in human patch testing to verify that one milder surfactant can counter the irritation of an irritating surfactant. Combinations of SLS with either AEOS-2EO (a C12 alkyl ether sulfate with 2 ethoxylate units), cocodiethanolamide (cocamide DEA), or cocoamidopropyl betaine, each contain- ing 20% SLS and •0% added mild surfactant were patched on the upper arm for up to 72 hours along with 20% SLS alone. Results showed a highly significant amelioration of the irritancy of SLS even though the total surfactant concentration was substantially higher. Similar results were found for LAS in combination with AEOS-2EO and a nonionic ethoxylated (8EO) alcohol (a C•5 alcohol with 8 ethoxylate units). Such strategies can be used quite nicely to formulate mild skin cleansing products. This strategy of countering irritation potential using surfactant mixtures was investi- gated in more detail (29). The hypothesis offered was that by mixing surfactants, one of which has a high CMC and the other a low CMC, one can control the composition and amount of the surfactant monomer and small aggregates that are the skin-interactive species. To study this, the researchers (one of whom was the present author) used SLS with a CMC of 7.8 mM and AEOS-6EO (a C•2 alkyl sulfate with 6 ethoxylate units) with a CMC of 0.4 mM. We performed 21-day cumulative irritation studies on mixtures of these two surfactants (Table IV). SLS was maintained at a constant dose of 8.8 mM and 34.7 mM, and three different amounts of AEOS-6EO were added to each dose of the SLS. Results show that as more AEOS is added, irritation is lowered, even though the total surfactant concentration is increasing substantially. This suggested that the effective monomer concentration of SLS is being reduced considerably. We investigated this further by determining the new CMC of various mole fractions of the surfactant mixture.