Structure–toxicity relationships for selected halogenated aliphatic chemicals

Abstract

Toxicity to the ciliate Tetrahymena pyriformis (log (IGC 50 −1)) for 39 halogen-substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log (IGC 50 −1) along with the hydrophobic term, log K ow (1-octanol/water partition coefficient) and the electrophilic parameter, E lumo (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure–activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohols. The relationship for the haloalkanes [log (IGC 50 −1)=0.92 (log K ow)−2.58; n=4, r 2=0.993, s=0.063, f=276, Pr> f=0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log (IGC 50 −1)=0.63(log K ow)−1.18; n=19, r 2=0.860, s=0.274, f=104, Pr> f=0.0001] was observed for the haloalcohols. No hydrophobicity-dependent model ( r 2=0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log (IGC 50 −1)=−1.245( E lumo)+0.73; n=15, r 2=0.588, s=0.764, F=18.6, Pr> f=0.0009] was developed for the halonitriles. Additional analysis designed to examine surface-response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log (IGC 50 −1)=0.60(log K ow)−0.747( E lumo)−0.37; n=34, r 2=0.915, s=0.297, F=162, Pr> F=0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure–toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character.