FLUOROCARBON TOXICITY 345 Trichlorotrifiuoroethane is also low in toxicity, as judged by skin contact studies with rabbits. Application of CC1F2--CC12F to the skin of rabbits gave an ALD greater than 11,000 mg/kg. The only effect was local irritation of the skin at the site of application, and histology disclosed alterations in the dermis and adjacent connective tissues. There were no systemic changes attributable to treatment. Applica- tions of CC12F--CC1F2 at the very high dose of 5000 mg/kg each day for five days resulted in fluctuations in weight and damage to the skin which were evident grossly and histologically. Slight liver changes were ob- served microscopically, but no other systemic changes were disclosed. When instilled undiluted into the eyes of three rabbits and washed out with water twenty seconds later, CC1F2--CC12F produced mild, transient conjunctivitis in one rabbit only, and the others showed no reaction. Instillation into rabbit eyes without water washing produced minimal corneal dullness in only one rabbit, which subsided in forty-eight hours. Similar results from eye studies on dichlorodifiuoromethane were reported by Downing and Madinabeitia (8) citing work conducted at Haskell Laboratory. In this study a 50% solution of CC12Fs in refined mineral oil was sprayed into rabbits' eyes from a distance of about 15 cm. Controls consisted of rabbits receiving mineral oil alone. The animals receiving the fiuorocarbon with mineral oil in the eye showed the same eye reaction as the controls did. In both groups, slight conjunctival irritation developed, but this disappeared in twenty-four hours. Quevauviller et al. (9) and Quevauviller (6) have investigated the effects of various fiuoroalkanes on the skin, tongue, soft palate, and auditory canal of rats the eye of the rabbit and the speed of healing of wounds and burns in the rat. Five materials were evaluated by these tests: CClaF CCleFs CClaF and CCleFs mixed CClaF and CHC1Fe mixed and CC1Fe--CC1F2. The animals were treated once or twice daily, five days a week for five or six weeks. In the case of wounds and burns the treatment was continued until healing was complete. The compounds or mixtures were released from pressurized containers for five or ten seconds from a distance of 10-20 cm onto the experimental site. The skin of the rats became irritated, evincing an edema and slight inflammatory reaction. The reactions were most marked with the CClaF/CHC1Fe mixture and CC1Fe--CC1Fe. Older rats were more severely affected than younger rats. The application of the five test substances to the tongue, soft palate, and auditory canal of rats produced no significant abnormalities. In one
346 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS rat treated with CC1F2---CC1F2 the auditory canal showed desquamation of the epithelium and inflammation. The rabbit eye reacted to the five materials with hyperemia and lacrimation. There was an inflammatory reaction of the eyelid noted in rabbits exposed to CC13F and CC1F2--CC1Fs. There were no other histologic alterations. The healing of wounds and burns made experimentally on the skin of rats was retarded, compared to controls. There appeared to be little if any difference in this retardation among these five compounds or mixtures evaluated. CHRONIC TOXICITY Experiments to evaluate the chronic toxicity have not been extensive, nor do they approach the refinement achieved in the investigation of food additives. Clayton (10) has reviewed the situation with respect to chronic effects of fluoroalkanes, and it appears that experimental designs for evaluating this aspect of toxicity are now capable of arriving at an evaluation of safety for particular uses. Prior to 1960, chronic toxicity studies were concerned primarily with effects of repeated inhalation. This was natural because the majority of fluoroalkanes in use were gases at ambient temperature, and the applications involved an inhalation hazard (10). In 1960, however, the food additive problem was broached by I3uPont's introduction of octa- fluorocyclobutane (OFCB) as a food propellant (11). In this instance, because of the compound's extremely low solubility' in body fluids and the technical irapracticability of "feeding a gas," it was agreed by the Food and Drug Administration that repeated inhalation exposures employing a variety of mammals six hours a day for 90 exposures at 100,000 ppm would suffice to demonstrate the safety of OFCB as a food propellant. Single and short term repeated exposures had demonstrated the "inertness" of OFCB (Table VI). The 99 exposures disclosed no effects, clinically or pathologically, on the animals inhaling OFCB. A similar problem was faced when chloropentafluoroethane (CPFE) was proposed as a food propellant. As with OFCB, a 90 exposure 100,000 ppm test revealed the compound's biologic inactivity. How- ever, CPFE was also administered in cottonseed oil solution to male rats daily for ten days (see below). No evidence of toxicity was discerned from this experiment, which added to the assurance of safety gained by the inhalation phase of the investigation.
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