QSAR analyses of the toxicity of aliphatic carboxylic acids and salts to Tetrahymena pyriformis

Carboxylic acids have been conspicuously absent from the quantitative struc ture activity relationship (QSAR) literature. This study investigated the a quatic toxicity (log(IGC(50)(-1))) of selected mono- and di-carboxylic acid s and their sodium, or disodium salts, tested in the Tetrahymena population growth assay. The relationship between log(IGC(50)(-1)) and hydrophobicity as described by the 1-octanol/water partition coefficient (log K-ow) revea led a distinct sub-class. The relationship [log(IGC(50)(-1)) = 0.27(log K-o w) - 0.68; n = 16, r(2) = 0.943, s = 0.07. F = 233, Pr > F = 0.0001] was de rived for mono-carboxylic acids. The QSAR [log(IGC(50)(-1)) = 0.19(log K-ow ) - 0.66; n = 9, r(2) = 0.951, s = 0.08, F = 135, Pr > F = 0.0001] was gene (ra)(te)d for the di-carboxylic acids. Regression analysis of data for the monosodium carboxylic acid salrs vielded the model, log(IGC(50)(-1)) = 0.60 (log K-ow) + 0.58. n = 4, r(2) = 0.932, s = 0.19, F = 41.2. Pr > F = 0.008 . Values for the ionization constant (pK(a)) and the energy of the lowest u noccupied molecular orbital (E-LUMO) do not vary within the sub-class for s aturated acids. Moreover, pK(a) and E-LUMO did not describe differences in toxicity between sub-classes of saturated aliphatic carboxylic acids and sa lts. However, these descriptors did vary for unsaturated acids. Inclusion o f unsaturated acids afforded the derivation of a global response-surface fo r all aliphatic carboxylic acids, log(IGC(50)(-1)) = 0.25(log K-ow) - 0.13( E-LUMO) - 0.54; n = 34. r(2) = 0.850, s = 0.138, F = 87.9, Pr > F = 0.0001. Outliers to the response-surface included small molecules that provided 2- positions in which the molecule could potentially undergo electrophilic att acked and other more large, hydrophobic molecules.