Acute toxicity of substituted phenols to Rana japonica tadpoles and mechanism-based quantitative structure-activity relationship (QSAR) study

Acute 12 h and 24 h lethal toxicity (12 h-LC50 and 24 h-LC50) of 31 substituted phenols to Rana japonica tadpoles was determined. Results indicate that toxicity of phenols to tadpoles varied only slightly with length of exposure and the 12-h test could serve as surrogate of the 24-h test. A mechanism-based quantitative structure-activity relationship (QSAR) method was employed and 1-octanol/water partition coefficient (log K-OW)-dependent models were developed to study different modes of toxic action. Most phenols elicited their response via a polar narcotic mechanism and an excellent log K-OW-dependent model was obtained. Soft electrophilicity and pro-electrophilicity were observed for some phenols and a good log K,,-dependent model was also achieved. Additionally, the significant dissociation of carboxyl on benzoic acid derivatives sharply reduced their toxicity. A statistically robust QSAR model was developed for all studied compounds with the combined application of logK(OW), energy of lowest unoccupied orbital (E-lumo), heat of formation (HOF) and the first-order path molecular connectivity dices ((1)chi (p)). (C) 2001 Elsevier Science Ltd. All rights reserved.