176 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS (10). However, in another test (7), dogs survived doses from 100 to 160 mg/kg. Higher toxicity was reported by Delak et al. (11) when they conducted tests on a small number of dogs. Doses of 10 to 20 mg/kg were tolerated without toxic symptoms. Administration of 30 mg was toxic doses of 40 to 50 mg/kg caused death of most of the animals. Since Hirschler (12) reported on the anthelmintic property of hexa- chlorophene against liver flukes, many papers have been published on this subject, and besides reports on the efficacy of the drug, data on its oral toxicity for cattle and sheep are usually presented. While space does not permit referring to all toxicity studies, it would appear that these animals are more susceptible to hexachlorophene than rodents. Doses of 20 mg/kg are well tolerated by cattle, doses of 30 and 40 mg give toxic symptoms, and death may occur at the higher level (3, 9). Sheep tolerate somewhat higher doses of hexachlorophene. Guilhon and Graber (13) reported that, in most cases, the animals did not exhibit toxic symptoms at single doses of 100 mg/kg on the other hand, Curalp et al. (14) stated that all 8 sheep given 70 or 80 mg/kg showed signs of toxicosis, and 4 of them died. Factors such as breed, pregnancy, condition of animals, climate, and mode of administration, whether suspension in water or solution in oil, influence the toxicity of hexachlorophene for cattle and sheep. SUBACUTE ORAL TOXICITY Not much had been done in regard to subacute oral toxicity. A study (15) in six rats each at a dose level of 0.02 and 0.04% of hexachlorophene in their diet over a period of 30 days showed that the lower dose was mildly toxic, the animals gaining less weight, and that the higher dose was definitely toxic, showing pathological changes in the liver and kidney of the sacrificed animals. SYSTEMIC TOXICITY Concerning systemic toxicity, Price and Bonnett (16) reported in 1948 that hexachlorophene was toxic when injected intravenously. As little as 85 mg in 0.01N sodium hydroxide solution caused death in dogs weighing 7 or 8 kg within a few minutes. Convulsions, sudden respiratory failure, and widespread intravascular clotting of blood were the characteristic symptoms. Tests in rats (17) given a solution of hexachlorophene in propylene glycol intravenously showed a LD•0 of 9.1 mg/kg (range 7.8 to 10.6 rag) and in a preliminary study in rabbits (18) the LDs0 appeared to be 8.5 mg/kg. Vitez (19) studied the toxicity of hexachlorophene when injected intraperitoneally into mice. Those animals which received 12.5

TOXICOLOGY OF HEXACHLOROPHENE 177 and 25 mg/kg remained well during the two-week test period. More than 25 mg/kg caused death within 30 minutes amidst convulsions and respiratory paralysis. REACTIONS IN HUMANS Oral toxicity in humans does not present a great problem as long as hexachlorophene is not ingested accidentally. Cases of poisoning, caused by improper use of hexachlorophene-containing preparations, have been reported. Wear et al. (20) described 10 preoperative patients who swal- lowed an emulsion with 3 •o hexachlorophene (pHisoilex©) '• which was mistaken for milk of magnesia. The major toxic symptoms were anorexia, nausea, vomiting, abdominal cramps, and diarrhea. Dehydration was some- times severe and adequate fluid and electrolyte replacement was essential. Lustig (21) reported a case where a girl, aged 6 years, died 9 hours after the ingestion of about 4 or 5 oz. of pHisoilex, or approximately 250 mg/kg of body weight. The autopsy revealed congestion of organs and severe inflammation of the stomach. No specific antidote to hexachlorophene is known. Another case of hexachlorophcne intoxication after continued oral admin- istration of pHisoilex to an infant was reported by Pilapil (22). The infant received approximately 37 mg/kg per day for one week. He recovered completely with no known residual effect from the poisoning. A case of poisoning in an infant where a 3 c/o hexachlorophcne emulsion was put on the skin after a bath and left there was cited by Herter (23). After four days of these applications, slight twitchings of arms, legs, and face were observed which progressed to convulsions. As the skin of the buttocks and the face became severely cxcoriated, the toxic symptoms were caused by absorption of the hexachlorophene through the broken skin. Carrol et al. (24) showed that the absorption of radioactive hexachloro- phene-C x4 in pHisoilex through lacerated or burned rat tails is much greater than the penetration through the intact, normal skin. In view of these observations, hexachlorophene-containing preparations should not be left on damaged skin, and especially on large denuded areas of burns where systemic toxicity may lead to convulsions. If products with hexachlorophene are being used on burns to protect against the spread of infection, they must be washed off thoroughly after a short period of contact. To our knowledge, hexachlorophene has not been employed orally for therapeutic purposes, except in China. In that country, a group of in- * Winthrop Laboratories, New York, N.Y.