FLUOROCARBON TOXICITY 343 tions on CC1F2--CC1F2 by showing that a daily dose of 2000 mg/kg was not toxic for rats receiving the dosage for twenty-three to thirty-three days. In work by Haskell Laboratory, chloropentafluoroethane, CC1F2-- CFa, dissolved in cottonseed oil, was administered orally to rats five times a week for two weeks. Five milliliters of test solution was given at each treatment, and the individual daily doses were in the range of 140-172 mg/kg. A group of control rats received the oil alone. During the treatment period, there were no differences between the test and control rats with respect to appearance and rate of weight gain. This was also true of a recovery period of two weeks. Test and control rats were killed four hours or fourteen days after the tenth dose. Gross and microscopic examination of major tissues revealed no change attributable to CC1F2-- CFa. Therefore, under the conditions of this experiment, there was no evidence of cumulative toxic effects exerted by CC1Fs--CFa. This work demonstrated a low order of toxicity via the oral route of administration both for acute and short-term repeated dosing. Hepatoxic chlorinated materials, CC14 and CHCla, would produce liver cell injury at comparable dosage. Table VII summarizes the acute oral toxicity of several other fluoroalkanes. Points of contact other than oral are a subject of consideration, and toxicity data on the symmetric and asymmetric isomers of tetrachlorodi- fluoroethane and of 1,1,2-trichlorotrifluoroethane illustrate what may be required to establish a safe use of these fluoroalkanes as solvents. Data on isomers of tetrachlorodifluoroethane are shown in Table VIII. The two isomers were shown by this work to have a low order of acute oral, dermal, and inhalation toxicity. The Approximate Lethal Dose for rats by the oral route is greater than 25,000 mg/kg for both isomers. On skin application, rabbits exhibited local irritation but did not succumb nor exhibit any systemic response to either isomer, although a maximum feasible dose was applied. These were greater than 7500 mg/kg of CClsF--CC12F and greater than 11,000 mg/kg of CC1F2--CCla. Application of the symmetric isomer, CC12F--CClsF, to the skin of guinea pigs produced mild irritation but no skin sensitization. It was mildly irritating to the rabbit eye without damaging the cornea or iris. Washing the eye with water reduced the duration of irritation. These experiments demonstrated that the biological action of the two isomers was similar at the same dose levels. Orally, the two compounds acted on the gastrointestinal tract and produced a mild liver reaction at high doses without histological injury. Repeated oral doses of both isomers,

344 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table VIII Comparison of the Toxicity of the Symmetric and Asymmetric Isomers of Tetrachlorodifluoroethane Symmetric Isomer (CC12F--CC12F) Asymmetric Isomer (CC1F2--CCI•) Oral Toxicity Approximate lethal dose (rat) 25,000 mg/kg Diarrhea, weight loss at 11,000 mg/kg and above Liver and major organs normal histologically Ten-day repeated (rat) 5000 mg/kg daily Mortality: 1/5 diarrhea initial body weight loss tremor inactivity slight in- crease in liver weight, slight reversible histological change in liver 25,000 mg/kg Diarrhea, weight loss at 11,000 mg/kg and above Slight increase in liver weight at 25,000 rag/ kg Liver and kidney normal histologically 5,000 mg/kg daily Mortality: 0/6 diarrhea initial body weight loss tremor inactivity slight increase in liver weight liver normal his- tologically Dermal Toxicity Approximate lethal dose (rabbit) 7500 mg/kg 11,000 mg/kg Skin erythema no signs of systemic toxicity Severe skin irritation in ethanol weight no histological changes in major organs loss histological change in skin muscu- lature, none in major organs Inhalation Toxicity Approximate lethal concentration (rat) 15,000 ppm (vol.) 15,000 ppm (vol.) Respiratory and CNS effects slight liver Respiratory and CNS effects, slight to change histologically moderate liver changes histologically 5000 mg/kg daily for 10 days, also act similarly: These resulted in a slight reversible liver response, as judged histologically. Trichlorotrifluoroethane, CC12F--CC1F2, as indicated by rat studies, has a low order of oral toxicity with an Lb50 of 43,000 mg/kg. Odou (7) has administered a massive oral dose to a female dog lightly anesthetized with sodium pentobarbital. The total dose given was 92,000 mg/kg, and death occurred in one and one-half hours. Some dogs have survived oral doses of this magnitude, and Odou (7) reported that a human under anesthesia accidentally received about 1 1 of cold CC12F--CC1Fs in the stomach. This produced vomiting and transient cyanosis. The indi- vidual survived and reported only severe rectal irritation and diarrhea for three days thereafter.