NEW POLYOXYALKYLENE NON-IONICS FOR COSMETICS 305 A particularly desirable feature of the flake non-ionic is that it does not become gummy after being ex- posed to the air at room tempera- ture for at least three months under ambient conditions. Taste. A unique property of this product, Pluronic F68, concerns taste. All other non-ionics tested in our laboratories have a bitter, penetrating taste that persists for several hours. The three liquid prod- ucts of this series have considerably less taste than other non-ionics, while the F68 is practically taste- less. In a test conducted in our laboratory on 24: people, 15 reported a bland, not-unpleasant taste and 8 reported no test at all. One sub- ject reported an unpleasant taste. ToxicITY Another property of considerable interest to the cosmetic and phar- maceutical industries is the un- usually low order of toxicity of these products. Toxicity studies com- pleted to date (2, 3, 4, 7) are sum- marized in Tables 3 and 4. The first of these is for acute oral toxicity. Comparative data from the literature for other surface- active agents are also presented where available (5, 6, 8, 10). L44, L62, and L64 thus have about the same order of acute tox- icity as the other non-ionic surfac- rant listed, the alkylaryl ether. The non-ionics are somewhat less toxic than the synthetic anionics, the alkylaryl sulfonate and the sodium lauryl sulfate. The F68, bowever, has a much lower acute oral toxicity. Except with mice, it was not physically possible to give sufficiently large doses to the sub- jects to cause death. This ap- parent low level of oral toxicity in F68 was investigated further by chronic feeding studies. After six months of daily doses of 0.1 and 0.05 gm./kg. dogs showed no gross synTptoms of toxicity. Groups of rats fed 3 and 5 per cent F68 for six months likewise did not, as a group, show evidence of toxicity, nor was there any apparent difference in weight gain as compared with con- trol animals. There were no sig- nificant biochemical or hematolog- ical changes in the blood of these animals. Table 4 offers a com- parison with other surface-ac- tive agents (10). The data indicate that F68 has a much lower chronic toxicity than alkylaryl sulfonates and sodium alcohol sul- fates. TABLE 3--AcuTE ORAL TOXICITY o• SUKFACTANTS Composition Type Subject LD50, Gin./100 Gin. Pluronic L44, L62, L64 Non-ionic Rat 0.5 Pluronic F68 Non-ionic Mice 1.5 Pluronic F68 Non-ionic Rat, rabbit, dog No acutely toxic effects Alkylaryl sulfonate Anionic Rat 0.14 Sodium lauryl sulfate Anionic Rat 0.27 Alkylaryl ether Non-ionic Mice 0.35 Soap Anionic Rat 1.6 Polyglycol oleate Non-ionic Mice 2.5

306 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS TABLE 4--REPEATED Dose TOXXCXTXES oF SOME SUR. FACTANT$ Composition Subject Level Duration Effect Pluronic F68 Dog 0.1, 0.05 6 months No symptoms of toxicity gm./kg./day Rat 1.0% of food Rat 5.0% of food Rat 0.25-4% of food Guinea 0.2% of food pig Sodium alkyl sulfate Sodium alkyl sulfate Sodium alkyl sulfate Arylalkyl ether 160 days 67% mortality '5 days Died 30 days Minor damage, no death 180 days No damage The recent controversy concern- ing the eye-irritating properties of surface-active agents in shampoos emphasized the importance of this property. The liquid products, L44, L62, and L64 were tested on the eyes of rabbits by the method sug- gested by Draize. In no case, even when the non-ionics were used at 100 per cent active agent concen- tration, was there any permanent damage. The irritating effect was found to be of about the same order for L44, L62, and L64 and, as expected, proportional to the con- centration. Irritation is negligible at common use concentrations. These results indicate that L44, L62, and L64 may be used safely in formulations for shampoos so far as eye irritation is concerned. F68 was not studied in this man-- ner, but 5 and 10 per cent solutions were applied to the conjunctival sac of rabbits. No irritation could be detected grossly or by histological examination. Other data in the literature on surface-active agents are for more dilute solutions, so that direct comparison is not pos- sible. Hopper, et al. (6) have shown that a relationship appears to exist between acute oral toxicity in mice and irritation produced in the rabbit's eye. Further studies on irritation ef- fects showed that: 1. Five and 10 per cent aqueous solutions and a heavy paste of F68 applied to the gums of rabbits and dogs produced no hyperemia or irritation. 2. A 50 per cent aqueous solution of F68 applied to skin wounds on the abdomen of rabbits did not significantly influence healing time. 3. Skin sensitivity studies of F68 on dogs, rabbits, guinea pigs, and man showed no evidence of skin irritation or of hyper- sensitivity reaction. 4. Patch tests on L44, L62, and L64 made on human beings in our laboratories indicated no evidence of irritation or sen- sitizing effect. Preliminary work was done by the prophetic test method (8) with 5 and 85 per cent solutions of Pluronic L44, L62, and L64 applied to 12 men and 12 women. No irrita- tion was observed. Thirteen days later similar patches were placed in the same place on 19 of the 24 subjects available.