Evaluation of CADASTER QSAR Models for the Aquatic Toxicity of (Benzo)triazoles and Prioritisation by Consensus Prediction

Stefano Cassani, Simona Kovarich, Ester Papa, Partha Pratim Roy, Magnus Rahmberg, Sara Nilsson, Ullrika Sahlin, Nina Jeliazkova, Nikolay Kochev, Ognyan Pukalov, Igor V. Tetko, Stefan Brandmaier, Mojca Kos Durjava, Boris Kolar, Willie Peijnenburg, and Paola Gramatica

QSAR regression models of the toxicity of triazoles and benzotriazoles ([B]TAZs) to an alga (Pseudokirchneriella subcapitata), Daphnia magna and a fish (Onchorhynchus mykiss), were developed by five partners in the FP7-EU Project, CADASTER. The models were developed by different methods — Ordinary Least Squares (OLS), Partial Least Squares (PLS), Bayesian regularised regression and Associative Neural Network (ASNN) — by using various molecular descriptors (DRAGON, PaDEL-Descriptor and QSPRTHESAURUS web). In addition, different procedures were used for variable selection, validation and applicability domain inspection. The predictions of the models developed, as well as those obtained in a consensus approach by averaging the data predicted from each model, were compared with the results of experimental tests that were performed by two CADASTER partners. The individual and consensus models were able to correctly predict the toxicity classes of the chemicals tested in the CADASTER project, confirming the utility of the QSAR approach. The models were also used for the prediction of aquatic toxicity of over 300 (B)TAZs, many of which are included in the REACH pre-registration list, and were without experimental
data. This highlights the importance of QSAR models for the screening and prioritisation of untested chemicals, in order to reduce and focus experimental testing.
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Experimental Assessment of the Environmental Fate and Effects of Triazoles and Benzotriazole

Mojca Kos Durjava, Boris Kolar, Lovro Arnus, Ester Papa, Simona Kovarich, Ullrika Sahlin
and Willie Peijnenburg4,5

The environmental fate and effects of triazoles and benzotriazoles are of concern within the
context of chemical regulation. As part of an intelligent testing strategy, experimental tests were performed on endpoints that are relevant for risk assessment. The experimental tests included the assessment of ecotoxicity to an alga, a daphnid and zebrafish embryos, and the assessment of ready biodegradability. Triazole and benzotriazole compounds were selected for testing, based on existing toxicity data for vertebrate and invertebrate species, as well as on the principal component analysis of molecular descriptors aimed at selecting the minimum number of test compounds in order to maximise the chemical domain spanned for both compound classes. The experimental results show that variation in the toxicities of triazoles and benzotriazole across species was relatively minor; in general, the largest factor was approximately 20. The study conducted indicated that triazoles are not readily biodegradable.
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