FLUOROCARBON TOXIC1TV 339 influence, chemical stability is not a reliable or predictive determinant of toxicity. As data became available, however, a general principle of toxicity could be ascertained, and the data assembled in Table I illus- trate this principle: a lower degree of toxicity corresponds with an in- creasing number of fluorine atoms in the molecule. All three groups, A, B, and C of Table I, reveal this, with possibly the most striking example evident in comparing CC14 with CF4 of group B. The influence of fluo- rine and its interactions with other atoms in the molecule are also appar- ent in this compilation. As shown by the contrasting toxicities of CHCla and CHC12F (group A), the inclusion of even a single F atom effects a marked lowering of toxicity, explained possibly by the increased stability of neighboring C1 atoms (fostered by the C-F linkage) and subsequent intractability to enzymatic dehalogenation. Addition of further F atoms to this molecule produces continued reduction of toxicity. Group B provides similar evidence of this stabilizing force of F as compared to C1 in the methane series. Group C adumbrates yet another feature relating to the principle under discussion, namely, the interplay of hydro- gen, fluorine, and chlorine. The substitution of C1 for H appears, in some instances, to lower toxicity, as may be seen by comparing CHaC1 with CH2CI= and the replacement of H in CH=CI= and CHCi2F with F to give CHC12F and CC12F=, respectively, also eventuates in lowered tox- icity. Thus, while it is sometimes true that increasing the C1 comple- ment tends to decrease toxicity, fluorine is far more effective than chlo- rine, as illustrated by the lower toxicity of CH=F= compared with that of CH=CI=. Henne (.5) in 1937 reported no toxic effects in guinea pigs in- haling 20% CH=F2 for hours, whereas 2% CH2CI= was fatal in two hours. The intermediate compound, CH2C1F, assumes a mid-position so that the order of toxicity would be: CH.•C12 CH2C1F CH,,.F2 This stabilizing attribute of F may also be noted in connection with bromine. The data of Table II indicate the following toxicity trend: CBr=F= CBrC1F•. CBrFa. From this sequence it may be concluded that the brominated compounds are more toxic than the chlorinated ones and the highly fluorinated are least toxic. It should not be inferred that the fluorination blocks the escape of a toxophoric halogen (Br or C1). It is not the fugitive halogen atom which is offensive but the ensuing active residue. The dehalogenation of CHaBr to form the alkylating CHa-active group is illustrative. The CHa-fragment reacts in vivo with sulfur-containing compounds, thereby producing biologically active corn-

340 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table II Acute Inhalation Toxicity of Fluoromethanes Containing Bromine Exposure Time Compound Animal (min) CBr•.F2 Rat 15 CBrC1F2 Rat 15 CBrF3 Rat 15 Lethal Concentration" (vol. %) 5.5 32 83 Vapor mixed with air. Table Acute Inhalation Toxicity of Several Fluoroethanes Approximate Lethal Concentration Exposure Structure Vol. (%) (hours) Animal CCI•.F--CChF 1.5 4 Rat CC1F2--CC13 1.5 4 Rat CChF--CC1F210 4 Rat CC1F•.--CC1F• 20 8 Guinea pig CH CI2CFa 3.5" 4 Rat CC1F2--CHF•. 20 2 Guinea pig CC1F•.--CFs 80 •' 4 Rat CHF2--CF,• 10 4 Rat CFs--CF3 80 ø 4 Rat '* LC.•o. 0 80% fluorocarbon and 20% O•.. Table IV Comparison of Bromine and Chlorine in the Acute Inhalation Toxicity of Fluoroethanes Compound 1. CH2C1--CFa 2. CH•.C1--CHF2 3. CH•.Br--CFa 4. CH,,Br--CHF2 Lethal Concentration '* (vol. %) 25.0 7.5 11.7 4.6 Mice exposed for ten minutes.