QSAR Analyses of the Toxicity of Aliphatic Carboxylic Acids and Salts to Tetrahymena Pyriformis

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Abstract
Carboxylic acids have been conspicuously absent from the quantitative structure activity relationship (QSAR) literature. This study investigated the aquatic toxicity (log(IGC−1 50)) of selected mono- and di-carboxylic acids and their sodium, or disodium salts, tested in the Tetrahymena population growth assay. The relationship between log(IGC−1 50) and hydrophobicity as described by the 1-octanol/water partition coefficient (log K ow ) revealed a distinct sub-class. The relationship [log(IGC−1 50) = 0.27(log K ow ) – 0.68; n = 16, r 2 = 0.943. s = 0.07, F = 233, Pr> F = 0.0001] was derived for mono-carboxylic acids. The QSAR [log(IGC−1 50) = 0.19(log K ow ) – 0.66; n = 9, r 2 = 0.951, s = 0.08, f = 135, Pr < F = 0.0001] was generated for the di-carboxylic acids. Regression analysis of data for the monosodium carboxylic acid salts yielded the model, log(IGC−1 50) = 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 unoccupied molecular orbital (E LUMO ) do not vary within the sub-class for saturated acids. Moreover, pK u and E LUMO did not describe differences in toxicity between sub-classes of saturated aliphatic carboxylic acids and salts. However, these descriptors did vary for unsaturated acids. Inclusion of unsaturated acids afforded the derivation of a global response-surface for all aliphatic carboxylic acids, log(IGC−1 50) = 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 attacked and other more large, hydrophobic molecules.