J. Soc. Cosmetic Chemists, 18,333-350 (May 27, 1967) Fluorocarbon Toxicity' Past, Present, Future J. WESLEY CLAYTON, JR., Ph.D* Presented September 20-21, 1966, Seminar, New York City Synopsis--The history of the development of fluorocarbons and their toxicity is reviewed. It is shown that the toxicity of fluorocarbons is related to the strength of the C-F bond. Animal data on the acute inhalation, topical, and oral toxicity of a variety of fluorocarbons are described. Chronic toxicity data are more sketchy but allow greater insight into the biological activity of these compounds. Finally, some recommendations are made for further toxicological testing of fluorocarbons. INTRODUCTION Mankind has attained dominance on this planet essentially be- cause he was--and is--dissatisfied with the prevailing state of affairs. His early fires enabled him to keep warm and, at the same time, control part of a hostile environment. As he grew in knowledge new combina- tions of elements he wrested from the material world supported increas- ingly complex human societies and, where cleverness was combined with knowledge, dominant groups attained hegemony. The history of technology has been to hurdle obstacles which in preceding periods blocked progress. The development of the field of organic chemistry is a striking example of man's intrusion into a naturally stable and at one time inviolable domain. The chemist's success in combining carbon and fluorine underscores man's continuing triumph over nature in view of the rarity of the C-F bond on earth and its strength. Thus, the story of the fiuorocarbons is one of purely human technology and organic fluorine * E. I. du Pont de Neonours and Company, Haskell Laboratory for Toxicology and Indus- trial Medicine, Wilmington, Del. 19898. 333

334 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS compounds, therefore, are in a way not organic in the sense that they are unnatural. On this basis, it is not surprising that a cardinal property of organic fluorine compounds is their extraordinary stability, related to the high bond strength and short interatomic distance between carbon and fluorine. Fluorine is like hydrogen in that it is not just another substituent for carbon rather, it forms a whole system of carbon compounds now gener- ally called fluorocarbons. Both hydrogen and fluorine are univalent and while fluorine is somewhat larger than hydrogen it is small enough to occupy simultaneously all four valence positions of carbon. This is a feat which is accomplished only with difficulty in the case of other more bulky halogens. Nevertheless, the fluorocarbons are significantly dif- ferent from the hydrocarbons. The greater volume of fluorine, as com- pared to hydrogen, and the greater bond strength of the C-F union (rup- ture energy = 114 kcal), contrasted with that of C-H (rupture energy = 93 kcal), provide a protective integument to the carbon-carbon skeleton, resulting in highly stable compounds among the various fluoro- carbons. The perfluorinated alkanes highlight this attribute. Chemicals such as CF4, F3C--CF3, F3C--CF2--CF2--CF3, and CF2--CF2--CF2--CF• L ] are nonflammable and have virtually no useful synthetic properties. Their durability does, however, make them important commodities of commerce. Attachment of functional groups or other atoms to a fluorocarbon structure yields classes of compounds, the properties of which may be profoundly influenced by as little fluorine as 1 F atom per molecule. It is notable that the C-F link is more stable than the C-C1 bond (rupture energy = 72 kcal) however, in chlorofluorocarbon, the F atom stabi- lizes vicihal C-C1 bonds and relieves the steric strain imposed on the molecule by relatively voluminous C1 atoms. The relative greater sta- bility of CC13F over that of CHClo is illustrative of the settling influence of 1 F atom. It is natural to relate the foregoing chemical features of the C-F compounds to their biological properties. When this is done it is patent that the high order of stability of fluorocarbons is the dominant biological feature. Chemical stability explains a specific biologic action, or, in con- trast, it may be the reason for lack of biological action. Illustrating the first case is the now classical lethal synthesis (1) in which the C-F bond of w-fluoroacetate is refractory to enzymatic dehalogenation. It conse- quently enters the tricarboxylic acid cycle intact and passes unscathed