FLUOROCARBON TOXICITV through to fiuorocitric acid. At this point, steric hindrance precludes the action of the enzyme aconitase so that the next step in the chain, con- version to aconitic acid, is blocked. A major part of the toxicity of c0-fiuoroacetate, and compounds degraded thereto, is the result of a metabolic blockade caused by a highly stable interloper. On the other hand, lack of biologic activity is demonstrated by the fiuoroanalogues of the chloromustards: H•C- -S CH,_, CH•--C1 H2C --S--CH,, CH• F tt•C- S--CHs--CH• C1 H2•-- S CH2 CH•--F 1 The chlorocompound (I) is a potent vesicant owing to removal of la- bile C1 which releases a highly active residue. It is the latter which is biologically active, not the fugitive halogen. The fluoroanalogue (II), on the other hand, is inoffensive due to firm C-F bonds and concomitant shielding of otherwise active loci on the molecule. In the same vein, C-F cohesion is undoubtedly the reason for the low toxicity of the fluoroalkanes. This class is probably the most important group at present in view of its wide use in commerce. Fluoroalkanes are used as refrigerants, propdlants, didectric agents, fire extinguishing com- pounds, solvents, and freezing agents. Yet while C-F firmness insures stability and favors low toxicity, it does not imply complete lack of biological activity. Trifluoroiodometh- ane, tagged with I TM, may be safdy used to trace the circulatory paths of the brain, thereby demonstrating that, while the compound undergoes no detectable biological degradation, it is biologically active in penetrating the blood-brain barrier. Similar considerations apply to fluorinated an- esthetics in which metabolic degradation is not a sine qua non for the narcotic activity. The story is muct• the same for other fluoroalkanes- low in toxicity but active in the organism to varying degrees and for different reasons. COMMERCIAL HISTORY OF FLUOROCARBONS Because of their commercial importance in cosmetics the fiuoro- alkanes are of interest to cosmetic chemists and naturally the general public. Historically, three devdopments reflect the increasing impor- tance of knowledge of the toxicity of the fluorocarbons and particularly the fluoroalkanes. The first was the advent in the 1920's of mechanical refrigeration. Early refrigerants were unsatisfactory. Ethylene was flammable SO2 and NH.• were corrosive and toxic. It was about the

336 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS same time that Le Beau and Damiens (2) prepared CF4, the simplest perfiuorocarbon. Shortly thereafter, CCI•F• was prepared specifically for refrigerant use. This compound provided not only the requisite temperature-pressure relationships but also nonflammability and low degree inhalation toxicity. So convinced of the low toxicity of CCI•Fe was Thomas Midgley that at the 1930 American Chemical Society Meet- ing, to demonstrate nonflammability, he inhaled CCI•Fs and on exhala- tion extinguished a burning candle. The second historical development is indicated by the publication in 1928 by F. Lehmann (3) of experiments on the pharmacological action and influence of the trifiuoromethyl group. This was the first in the development of a number of fiuorinated compounds which possessed pharmacological activity. Thirdly, and probably eclipsing the first two, was the synthesis of a number of derivatives of w-fiuoroacetates emerging from chemical war- fare research during World War II. Wartime security obscured the development of other fiuorocarbons but during this period, the first fiuoropolymer, a tetrafiuoroethylene resin, was developed by Du Pont. This resin, because of its resistance to the most aggressive chemical agents, was largely committed to the atomic energy programs of that era. Post-war commercial development of fiuorocarbons saw a decline of the toxic fiuoroacetate compounds (except as pesticides) and a rapid rise of polyfiuorinated organic compounds because of their high stability and low toxicity. The major fiuorocarbons in this extensive market penetra- tion have been the fiuoroalkanes. Prominent among the uses cited above is the aerosol propellant mar- ket. Nonfood aerosols have shown a phenomenal growth, doubling since 1960 to about 1.45 billion units in 1965. Food aerosols are not as large in volume (60-70 million units yearly), but applications in this area are increasing. For example, chloropento-fiuoroethane and octafiuoro- cyclobutane, the fiuoroalkanes, Freoff • 11 •5 and Freon © C-318, are ap- proved by FDA for food propellants. ACUTE INHALATION TOXICITY Because of rapid developments on the marketplace and the increasing likelihood of consumer exposure, the need for toxicological information has grown. Midgley's dramatic demonstration fortunately did not set a precedent for the conduct of toxicity experiments, although it did focus attention on the inhalation hazard as primary in the early studies on the fluoroalkanes used in refrigeration units and also as fire extinguishing