128 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS The irritant reaction of HCP in animals was much higher in intensity 4 or 5 days than in 1 or 2 days after topical application. This result was obtained from animal experiments macroscopically and histologically. Microscopic ex- amination of the specimen taken 3 days after the application revealed that the epidermis was hardly affected, but that erythrocytes showed an extravascular outflow and the vascular walls were degenerated. Although the came of these specific reactions has not been clarified, the experimental result suggests that it may be necessary to observe the site of reaction for a considerably longer time after topical application of HCP. Stott (22) presented the negative data for phototoxicity of HCP from his experiment on the ear of the guinea pig. In our experiment, the intensity of positive irritant reaction was always higher at the sites of HCP application followed by the irradiation than at the sites applied with HCP alone. How- ever, the increase in intensity of irritant reaction to HCP influenced by the exposure of ultraviolet ray was remarkably low. Therefore, further examina- tion for the presence or absence of phototoxicity of HCP should be performed before any conclusion is drawn on this problem. Negative results of contact and photocontact sensitization of HCP in guinea pigs were obtained in our experiments. On the other hand, Harber et al. (18) obtained positive results from their experiment on 24 guinea pigs, observing 1 case of contact sensitization and t3 cases of photocontact sensitization. Although a positive reaction was induced by the challenge with 0.1% of HCP in 4 of 20 sensitized animals and in 13 of 20 photosensitized animals in our experiments, it was finally judged that neither contact nor photocontact sensitization had taken place, since a primary irritant reaction could be in- duced by application with 0.1% HCP solution, and no positive reaction oc- curred when challenge had been made by a concentration of HCP not higher than 0.05%. In short, when such a substance as HCP which induces an irritant reaction at a low concentration is applied, it seems necessary to study the concentration of the substance used for challenge. SD"IVIMARY Hexachlorophene (HCP) had a more potent primary irritancy effect upon experimental animals than any other halogenated compound studied. The influence of vehicle for HCP was found to be significant in the primary irri- tant rcaction to this chemical in experimental animals. The irritant reaction of HCP was more readily produced when acetone was used as vehicle than when polyethylene glycol 400 was used. A 50-fold difference in primary irri- tant threshold was noted between these two vehicles. There was no difference in the primary irritant reaction of HCP in experi- mental animals between open and closed patch test. When examined by the closed patch test on human skin, a primary irritant reaction was produced by

SKIN SAFETY OF HEXACHLOROPHENE 129 HCP dissolved in propylene glycol at a lower concentration than HCP dis- solved or suspended in any other vehicle tested. The irritant reaction to HCP was compared between humans and experi- mental animals. When propylene glycol was used as vehicle for HCP, irrita- tion was induced in human beings at a slightly lower concentration than in experimental animals. When any other vehicles were used, the irritant reac- tion to HCP was much more readily induced in experirnental animals than in human beings. The most intense primary irritant reaction to HCP was observed macro- scopically in experimental animals 4 to 5 days after topical application. When histological examination was carried out on the site of primary irritant reac- tion to HCP in experimental animals, some disturbances of the vascular wall and extravasation of erythrocytes were observed. Exposure to ultraviolet rays slightly intensified the primary irritant reac- tions of HCP. Neither contact sensitization nor photocontact sensitization of HCP was observed in any experimental animals. (Received December 13, 1972) REFERENCES (1) Jillson, O. F., and Baughman, R. D., Contact photodermatitis from bithionol, Arch. Dermatol., 88, 409 (1963). (2) Baughman, R. D., Contact photodermatitis from bithionol, Ibid., 90, 153 (1964). (3) Epstein, S., Photocontact dermatitis from bithiono], Ibid., 92, 591 (1965). (4) Harber, L. C., Harris, H., and Baer, R. L., Photoallergic contact dermatitis due to halogenated salicylanilides and related compounds, Ibid., 94, 255 (1966). (5) O'Quinn, S. E., Kennedy, C. B., and Isbell, K. tI., Contact photodermatitis due to bithionol and related compounds, J. Amer. Med. Ass., 199, 89 (1967). (6) Barry, J. N., Cross sensitivity between fenticlor and bithiono], Arch. Dermatol, 97, 497 (1968). (7) Morikawa, F., Metabolism of hapten in skin tissue, Jap. J. Clin. Dermatol., 25, 273 (1971). (8) Masuda, T., Honda, S., Nakauchi, Y., Ito, H., and Mizoguchi, M., Photocontact dermatitis due to bithionol, TBS, diaphene and hexachlorophene, Jap. J. Dermatol., 81, 566 (1971). (9) Fukuhara, N., Ishikawa, S., Nakayama, Y., Nagura, T., Fukuda, M., Yano, K., and Morikawa, F., Experimental studies on photosensitivity of halogenated phenol com- pounds, Skin Allergy News, 2, 26 (1971). (10) Nakayama, Y., Fukuda, M., Yano, K., and Morikawa, F., Experimental study on photosensitivity of 3,4',5-tribromosalicylanilide, Jap. J. Dermatol. 81, 538 (1971). (11) Gump, W. S., Toxicological properties of hexachlorophene, J. Soc. Cosmet. Chem., 20, 173 (1969). (12) Epstein, S., Hexachlorophene (G-11) in the treatment of eczematous dermatoses., AMA Arch. Dermatol., 71, 692 (1955). (13) K]igman, A.M., The identification of contact allergens by human assay. II. Factors influencing the induction and measurement of allergic contact dermatitis, J. Invest. Dermatol., 47, 375 (1966). (14) Kligman, A.M., The identification of contact allergens by human assay. III. The maximization test: A procedure for screening and rating contact sensitizers, Ibid., 47, 393 (1966).