FLUOROCARBON TOXICITY 349 are needed. The following format of investigation is suggested which is designed to bring together rdevant toxicological facts and mechanism of action. III. IV. I. Prdiminary Toxicity Tests (a) Designed to determine single dose toxicity for several routes of administration employing different mammalian species (b) Observations of clinical response and tissue change should be included (e) Objective of this phase is to characterize the toxicity and to discern target organs or systems II. Repeated Dose Studies (a) Designed to ascertain cumulative effects (b) Duration, routes, and species should be sufficient to provide adequate information for intended use (c) Clinical observations and pathology should be included Mechanism Studies (a) Designed to determine major routes of excretion and excretory products for mammals (b) Determination of in vivo handling (intermediary metabolism) (c) Determination of the mode of action (d) Conduct of appropriate human metabolism studies Chronic Toxicity (a) Designed to ascertain lifetime effects, utilizing several species of animals (b) Design based on use pattern in terms of duration and kinds of contact (c) Observations included in lifetime studies should be based on knowledge derived from mechanism experiments. Objective is to determine any alteration in mechanism of action during the various phases of the life cycle It is not the intention of this schema to impose undue strictures on the investigator nor to provide a regimen to be followed religiously by the amateur. Parts III and IV should be weighted differently depend- ing upon usage of a product. Part III would seem to take priority, however, if intdligent extrapolations are to be made with reference to public health. While mechanism studies may be minimized in the face of a clear necessity to conduct prolonged and involved chronic studies,

35O JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS they should not be completely by-passed. The present status of the toxicology of the fluorocarbons definitely places mechanism studies in first rank in future investigations. (Received September 21, 1966) (11) (12) (13) (14) (15) REFERENCES (1) Peters, R. A., Lethal synthesis (Croonian Lecture), Proc. Roy. Soc., London, B139, 143 (1952). (2) Le Beau, P., and Damiens, A., Chimie Minerale sur le Tetrafluorure de Carbone, Cornpt. Rend., 182, 1340 (1926). (3) Lehmann, F., Uber Konstitution and Wirkung. Untersuchungen an aromatischen Fluorverbindungen, Arch. Exptl. Pathol. Pharmakol., 130,259 (1928). (4) Cook, W. A., Maximum allowable concentrations of industrial atmospheric contami- nants, Industr. Med., 14,936 (1945). (5) Henne, A. L., Fluorinated derivatives of methane, J. Am. Chem. Soc., 59, 1400 (1937). (6) Quevauviller, A., Hygiene and safety of propellants in medicated aerosols, Prod. Pharm., 20, 14 (1965). (7) Odou, B. L., Personal communication (1963). (8) Downing, R. C., and Madinabeitia, D., The toxicity of fluorinated hydrocarbon aerosol propellants, Aerosol Age, 5, 25 (1960). (9) Quevauviller, A., Schrenzel, M., and Vu Ngoc Huyen, Local tolerance of skin, mucous membranes, sores, and burns of animals to chlorofluorinated hydrocarbons, Thetapie, 19, 247 (1964). (10) Clayton, J. W., The Mammalian Toxicology of Organic Compounds Containing Fluorine, Chapter 9 in Ixrandbuch der Experimentellen Pharmakologie, New Series, edited by Eichler, O., Farah, A., Herken, H., and Welch, A.D., Vol. XX/1, Springer-Verlag, New York, 1966. Clayton, J. W., Delaplane, M. A., and Hood, D. B., Toxicity studies with octafluoro- cyclobutane, Am. Ind. Hyg. Assoc..L, 21,382 (1960). Siegel, J., Personal communication from U.S. Navy Toxicology Unit (1964). Chenoweth, M. B., and McCarty, L. P., On the mechanism of the pharmacophoric effect of halogenation, Pharmacol. Rev., 15, 673 (1963). Pauling, L., A Molecular theory of general anesthesia, Science, 134, 15 (1961). Dishart, K. T., The Synthesis and Evaluation of Some New Fluorinated Inhalation Anesthetics, presented at the Meeting of the American Chemical Society, Chicago, 1961