QSAR for acute toxicity of saturated and unsaturated halogenated aliphatic compounds

Training-set of 19 compounds — 11 haloalkanes and 8 haloalkenes — was selected from a group of 58 halogenated aliphatic hydrocarbons using statistical experimental design. Strictly defined method was used for preparation of water solutions and toxicity measurements of volatile and poorly water-soluble halogenated aliphatic substances. The acute toxicity expressed as the effective concentrations (EC50) was determined for the compounds in the training set using the Microtox test. The quantitative structure-activity relationships (QSAR) models for haloaliphatic compounds were constructed using the Projection of latent structures method. Size of the molecules was the most important parameter for toxicity of saturated haloaliphatic compounds. This characteristics can be related to accumulation of the haloalkanes in biological membranes or binding to biomacromolecules. Toxicity of 2-chlorobutane was significantly higher than expected from its size. This compound, as the only representative of sB-substituted chloroderivatives in the data set, has probably different mode of action than terminally substituted compounds. Three unsaturated compounds — cis-1,2-dichloroethylene, trans- 1,4-dichlorobutene, and cis-1,4-dichlorobutene — displayed similar mode of action to that observed for haloalkanes, while another two haloalkenes — 3-chloropropylene, and 2,3-dibromopropylene displayed different - reactive - type of toxicity. The steric parameters had to be complemented by four electronic descriptors for explanation of their high toxicity.