Validation with in vitro test systems of the quantitative structure activity relationships (QSARA) used for the prediction of toxicology of new fire retardants

Abstract

Selection of the chemicals for development as new fire retardants required an assessment of their potential toxicity. Conventional in vivo toxicological studies were proscribed under the terms of this project. Consequently, toxicological predictions were based on SARs and QSARs and selected in vitro biological tests. The TOPKAT programme was used to provide estimates of: rat acute oral toxicity (LD 50), rat maximum tolerated dose (MTD), mouse inhalational toxicity (24 h LC 50), eye and skin irritation, mutagenesis, carcinogenesis, teratogenesis, aerobic biodegradation, fish 96 h LC 50, and Daphnia magna 48 h LC 50. The toxicological activity of all the chemicals was also evaluated using Microtox ™, Mutatox ™. Some evidence of mutagenic and carcinogenic potential was detected. Good correlation was shown between the prediction of some of the experimental parameters of toxicity. TOPKAT predicted bis(aminophenyl)methyl phosphine oxide to be very toxic. Expert judgement contradicted this finding. Experimentally it did not inhibit acetylcholinesterase which supported the hypothesis that the P=O moiety was hindered and hence inactive as an anticholinesterase.