FLUOROCARBON TOXICITY g41 pounds. In this regard, CHaC1 is not as active as CH3Br and, as would be anticipated, CH3F is least active of the three. Thus toxicologically the order is: CHaBr CHaC1 CHaF. A correspondence of low toxicity with increasing fluorination is dis- closed by inhalation experiments with fluoroalkanes of longer chain length. Table III summarizes relevant data on fluoroethanes, some with chlorine substituents Table IV depicts the comparative roles of C1 and Br in fluoroethane (compare compound 1 with 3 and 2 with 4). In the latter table, the relation of H and F is evident from a comparison of compound 1 with 2 and of 3 with 4. Table V summarizes the acute in- halation toxicity for several fluoropropanes. Again, the principle of declining toxicity with increasing fluorination is observed. The toxicity of octafluorocyclobutane with its full complement of fluorine would seem to be the epitome of toxicological inertness demonstrated in Table VI. ACUTE ORAL AND TOPICAL TOXICITY In the decade when the fluoroalkanes were employed primarily as refrigerants and fire extinguishing agents, study of their acute inhalation toxicity seemed adequate to evaluate the safety for their intended use. However, expanding applications of these materials in pharmaceuticals, cosmetics, foods, and the aerospace industry necessitated a reappraisal of the basis for toxicological judgment. This, of course, reflects an evolu- tionary trend typical for any chemical or class of materials whenever penetration of the marketplace becomes a potential public health issue. In this way, fluorocarbons participated with other chemicals in society's requirement for a wider base on which to judge safety and health effects. Thus, uses of the fluorocarbons meant new routes of contact, and experi- mental procedures were adapted accordingly. The first experiments at Haskell Laboratory in the 1950's were con- ducted with dichlorodifluoromethane, CCI,,F2, and symmetrical dichloro- tetrafluoroethane, CC1F,, -CC1F2. For both of these the acute oral tox- icity, as judged by single doses of the fluorocarbon in oil, was low. The approximate Lethal Dose (ALD) was CCI,,F= greater than 1000 mg/kg, CC1F=--CC1Fs greater than 2250 mg/kg. In other words, maximum feasible single doses were not sufficient to kill rats. Repeated doses of CCI,,F• at 430 mg/kg and CC1F=--CC1F,, at 1300 mg/kg administered daily for ten days produced no signs of toxicity or pathological change in male rats. Organ weights were within control limits, and histology of major organs, including the liver, was unaffected by these dosages of CCI,,F2 or CC1F,,--CC1F,,. Quevauviller (6) confirmed these observa-

,'342 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table V Toxicity of Several Fluoropropanes for Mice Exposed for Ten Minutes Structure Approx. Anesthetic Lethal Concentration Concentration (%) (%) HCFe--CFs--CC1Fs 10 20 H CF,,--CFo•--CBrF• 4 10 HCF,•--CF.,--CHC1F 2.5 3 H CF,_,--CF•.--CH Cls 0.5 2 CC1F•--CFs--CH•F 10 15 CC1Fe--CFs--CHFo• 10 20 Table VI Toxicity Studies ou Octafiuorocyclobutane (OFCB) Exposure OFCB Concentration Duration No. of (vol. %) (hours) Exposures Animals 8()" 0.25 1 Mice 8() • 4 1 Rats 1.0 6 19 Rats 10 6 4 Rats, mice, guinea pigs, dogs 10 6 90 Rats, mice, rabbits, dogs • 80 •c•/c OFCB q- 2()rf/• oxygen. Toxic Effects __ None None None None None Table Vii Acute Oral Toxicity of Various Fluoroalkanes _ Compound ALD (mg/kg) • CClsF.• 1,00() •' CH CI•CC1F.2 7,500 CCI•FCCi.,F 25,000 CC1F:CCI:• 25,000 CC1Fo•CCI.,F 45,000 (LD:,0 = 43,000 mg/kg) 2,250 mg/kg •' CC1F.,CC1F• "Rats, ten to fourteen day survival period. t' Maximum feasible (lose of fluorocarbon dissolved iu peanut oil.