(Q)SAR and Read Across Analyses in Regulatory Assessment of Pesticide Metabolites and Impurities in the Light of Current Insights and Demands

Authors: Svenja Termeer de Amanqui, Volker Harder

Consumers can be exposed to pesticide residues potentially containing active substances (a.s.) and concomitantly to impurities and residue metabolites. As these substances may have properties of concern for human health, they need to be evaluated. In contrast to the comprehensive toxicological data set of an a.s., toxicological information on metabolites and impurities is generally scarce or non-existent. Based on legislation there is the possibility to apply New Approach Methodologies to assess the toxicological relevance of a.s. metabolites and impurities. (Quantitative) structure activity relationship ((Q)SAR) and read across (RA) analyses enable rapid and feasible hazard assessments.

Metabolites are evaluated according to the EFSA PPR Guidance (2016) using the EFSA templates (2020) for assessing (Q)SAR reports and for summarizing and integrating the evidence. The forthcoming OECD Guidance on residue definition (2023) is expected to further demand additional RA/grouping. To assess relevance of impurities the Guidance on assessment of equivalence (2012) is followed.

Reflecting all recommendations, robust in silico predictions are generated for genotoxicity and other toxicity endpoints by complementary rule- and statistics-based (Q)SAR software tools. The reliability of the predictions is evaluated based on the prediction’s evidence. Knowledge of the chemistry/biology regarding the endpoint is needed for overall evaluation in a weight of evidence approach. The OECD QSAR Toolbox is additionally used for toxicity screening, assessment of organic functional groups, calculation of physico-chemical properties and similarity to facilitate grouping, selection of appropriate analogues and data gap filling.

Based on all information, a case is established with a rationale, and if needed with a testing proposal, to support the conclusion for dietary risk assessment of metabolites or for the evaluation of the relevance of impurities. State-of-the-art reports describe strategy, methods followed, and results obtained.

In summary, in silico methods are an efficient and accepted tool in the assessment of the toxicological relevance of pesticide metabolites and impurities.

References:
EFSA PPR Panel, 2016, Guidance on the establishment of the residue definition for dietary risk assessment, EFSA Journal 2016;14(12):4549, 129 pp. doi:10.2903/j.efsa.2016.4549
EFSA, 2020, Technical report on the outcome of the pesticides peer review meeting on general recurring issues in mammalian toxicology, EFSA supporting publication 2020:EN-1837. 26 pp. doi:10.2903/sp.efsa.2020.EN-1837
EC, 2012, Guidance document on the assessment of the equivalence of technical materials of substances regulated under regulation (EC) No 1107/2009, SANCO/10597/2003 –rev. 10.1

Key words: impurities, in silico, metabolites, New Approach Methodologies, pesticide active substance.