QSARs for monosubstituted anilines eliciting the polar narcosis mechanism of action.

The relative toxicities (log IGC50(-1] of a fairly heterogeneous series of 66 anilines that were monosubstituted in the 2-, 3-, and 4-positions have been evaluated in the 48 h static Tetrahymena population growth impairment system. Quantitative structure-activity relationships (QSARs) were examined using the 1-octanol/water partition coefficient (log KOW) and the summation of the Hammett sigma electronic substituent constant (sigma sigma) as orthogonal independent predictors. Four chemicals, 4-decylaniline, 4-dodecylaniline, 4-tritylaniline and 4-aminophenethyl alcohol, did not elicit the measured response at saturation. Five chemicals, 2-aminophenol, 2-phenylenediamine, 4-aminophenol, 4-phenylenediamine and 4-nitroaniline, had an altered HPLC spectrum with time. As previously reported, the parent compound, aniline, as well as the 4-position halogen derivatives have been shown to be aberrantly more toxic than expected. None of these chemicals were included in QSAR development which employed linear regression analysis. Log IGC50(-1) = 0.599(log KOW) - 0.905 (n = 52, r2 = 0.885, s = 0.265, f = 383.65, Pr greater than f = 0.0001) was found to be a good predictor of relative toxicity of these monosubstituted anilines. The addition of sigma sigma as a second predictor did not improve the predictability of this QSAR. Abiotic loss over the duration of the assay varied markedly with derivative; however, chemical persistence was not considered to be a factor with this model. The above equation was strikingly similar to log IGC50(-1) = 0.595(log KOW) - 0.996 (n = 67, r2 = 0.866, s = 0.254, f = 421.64, Pr greater than f = 0.0001), a previously developed QSAR from data on a heterogeneous set of monosubstituted phenols. The data for these two equations were combined and subsequent regression analysis resulted in log IGC50(-1) = 0.588(log KOW) - 0.939 (n = 119, r2 = 0.873, s = 0.261, f = 806.49, Pr greater than f = 0.0001). The authors feel that this represents the log KOW-dependent QSAR in the Tetrahymena population growth assay for the polar narcosis mechanism of toxic action.