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    Acute Lethal Toxicity Quantitative Structure-Activity Relationships for Electrophiles and Pro-Electrophiles: Mechanistic and Toxicokinetic Principles

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    Published data on acute lethal toxicity of aniline and nitrobenzene derivatives to fish can be correlated with an electrophilic reactivity descriptor based on substituent constants (proposed to relate to electrophilicity of the corresponding C-nitroso compounds, the aniline and nitrobenzene derivatives being regarded as pro-electrophiles). Likewise, published data on acute lethal toxicity of reactive halogen compounds can be correlated with an electrophilic reactivity parameter based on measured rate constants for reaction with a reference nucleophile, 4-nitrobenzylpyridine. In both cases, incorporation of a lipophilicity descriptor does not improve the quantitative structure-activity relationship (QSAR). A toxicokinetic model is proposed, whereby the electrophilic reaction leading to the toxic effect is assumed to take place in an aqueous biological medium separated from the external aqueous environment by a lipid barrier. Based on consideration of whether environment-lipid partition, lipid-aqueous biological medium partition, or reaction with biological nucleophiles is likely to be the rate-determining step, outlying behavior of some of the compounds can be rationalized, and the QSARs can, with justification, be improved by elimination of these compounds.


    aquatic toxicity, structure-activity relationships, aniline derivatives, nitrobenzene derivative, reactive halogen compounds, electrophiles, pro-electrophiles, aquatic, toxicology

    Author Information:

    Roberts, DW
    Scientist, Unilever Research Port Sunlight Laboratory, Bebington, Wirral, Merseyside,

    Committee/Subcommittee: E47.01

    DOI: 10.1520/STP10309S