TOXICOLOGY OF HEXACHLOROPHENE 181 might have been produced, each patient was patch-tested again 10 days I _ •-___ All taLCS. z•n the tests were negative, indicating that hexachlorophene was non- irritating to the skin and was not a sensitizer. Similar negative results were obtained by Udinsky (34) with an 8r)•o solution of a bar soap containing 2% hexachlorophene Schwartz (35) also reported that a deodorant soap with 2 % hexachlorophene was not more irritating or sensitizing than ordinary soap. Furthermore, he stated that several million cakes of deodorant soap have been used by the public with no reports of proven cases of sensitization. In our opinion, the widespread use of a product over a long period of time is the best criterion of its safety and is more reliable than artificial methods of testing. Hexachlorophene is used in hundreds of products by a very large number of people in the United States and foreign countries, but remarkably few cases of irritation and allergy have been reported. Epstein (36) found two patients to be allergic to hexachlorophene, but stated that "hexachlorophene sensitivity is rare, and usually a consequence of sensitization to a chemically related and more potent antigen such as bithionol or tetrachlorosalicylanilide." References in the literature which attest to the fact that hexachlorophene is well tolerated by the human skin are too numerous to list here. It should suffice to repeat only Suskind's (37) statement: From the data of animal experiments (38) and "subsequent controlled human application one could conclude that hexachlorophene if used on the skin over long periods of time in nonirritating concentrations had little or no toxic potential. The experience of millions of users over the period of several years has demonstrated that this interpretation was correct." A single application of a patch was considered not to be a stringent enough test, and, for that reason, methods which would be more severe and perhaps resemble more the continuous use of a product were suggested by Shelanski and Shelanski (38) and by Draize (39). The so-called Repeated Insult procedure calls for repeated (10 to 15) applications instead of a single patch. At a time when these modified patch tests were introduced, soaps, emulsions, creams, etc., containing hexa- chlorophene had been widely used without bad effects. Nonetheless, addi- tional information is always of value and a few studies were made. The first one (40) was with a solution of hexachlorophene in 80% aqueous propylene glycol and with the solvent alone. Fifty subjects received 15 primary patches and a challenge application. Aqueous propylene glycol was found to have a mild irritant and fatiguing effect on the skin. More reactions (erythema) were noted with the hexachlorophene solution. No evidence of sensitization was seen in any of the subjects.

182 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS In another study (41), a solution of 5% hexachlorophene in dimethyl phthalate was applied to 50 subjects. Patches were allowed to remain on the skin for 48 hours and 10 such applications were made followed by a challenge test after a two-week rest period. Only one subject showed a continuous reaction in the form of slight erythema. We can give no explanation why hexachlorophene when dissolved in propylene glycol is quite irritating to the human skin but is so to a much lesser degree when dimethyl phthalate is used as a solvent. There were no reports that soaps and cosmetics containing hexachloro- phene have photosensitizing properties up to the time when Wilkinson (42) in 1961 found that 3,3',4',5-tetrachlorosalicylanilide in soap was the agent responsible for outbreaks of contact dermatitis and photodermatitis in Eng- land, and Jillson and Baughman (43) established that bithionol, a bisphenol structurally related to hexachlorophene, is a primary photosensitizer. The question whether hexachlorophene might act similarly was re- examined and a few cases of photocontact dermatitis where hexachlorophene is stated to be the primary photosensitizer have been reported by O'Quinn et al. (44) and by Freeman and Knox (45). However, it cannot be definitely excluded that previous contact with a photosensitizer might have led to the irritation by hexachlorophene. Similarly, the four patients who, according to Epstein et al. (46), gave positive photopatch reactions with hexachlorophene, were also sensitive to other compounds. Persons photo- sensitive to tetrachlorosalicylanilide and bithionol showed cross-sensitivity to hexachlorophene (4:7, 4:8). Sensitivity to both bithionol and hexachloro- phene was also suspected by Gaul (4:9) in one patient and was reported for two patients by Epstein (50). SUMMARY AND CONCLUSIONS The toxicological properties of hexachlorophene have been described. Data on studies on experimental animals and on humans have been presented. The following conclusions may be drawn. The fairly high oral and systemic toxicity of hexachlorophene for animals presents no problems for its topical use by humans as long as misuses are avoided. Such misuses may consist in accidental ingestion of preparations containing hexachlorophene or in the contact of higher concentrations of hexachlorophene with broken skin or denuded areas of burns over longer periods of time. Shaved skin of rabbits and guinea pigs is irritated by hexachlorophcne. However, on human intact skin, it is well tolerated. Its allergic factor is