Regulatory Guidance

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Residue metabolites may differ from their parent a. s. in terms of toxicokinetics, toxicodynamics and overall toxicity profiles. Since some metabolites occur at low levels or not at all in vivo, their intrinsic hazards may not be fully covered by toxicity studies on the parental a.s.. In the absence of experimental data on such a.s. metabolites, their toxicological relevance can be assessed by (Q)SAR and read-across analyses [2,6], providing a rapid and practical alternative to toxicity testing.

In line with current guidance, we will present an example of a hazard assessment for a relevant metabolite using read-across comprising (Q)SAR predictions and a grouping approach, drawing on our extensive experience as consultants in this area. Lines of evidence are integrated and evaluated based on a weight of evidence approach, assessing structural similarity to determine the accuracy of the read-across. Typically, groups consist of a limited number of substances (analogue approach) and the respective assessment follows the Read-Across Assessment Framework and its scenarios [7]. The simplest scenario involves using data from the parent a.s. for predicting metabolite toxicity. If metabolites or a group of metabolites are/is found to be dissimilar to the source substance(s), further assessment can be conducted by identifying suitable external analogues. When prioritising testing, especially in cases where toxicity concerns have been identified for the parent a.s., a ranking can be established based on grouping considerations. This ranking assumes that the likelihood of bearing the same toxicological property diminishes with “distance” of the metabolites to the parent a.s. Based on all available information, a case is established incorporating common assessment elements and if necessary, a testing proposal is provided.

In summary, grouping and read-across serve as effective alternatives to experimental testing in regulatory  assessment of residues.

References:

[1] EFSA PPR Panel 2012, Scientific Opinion on Evaluation of the Toxicological Relevance of Pesticide Metabolites for Dietary Risk Assessment, EFSA Journal 2012;10(07):2799 187pp.
doi:10.2903/j.efsa.2012.2799

[2] ECHA 2023, Guidance document on the impact of water treatment processed on residues of active substances or their metabolites in water abstracted for the production of drinking water, EFSA Journal 2023;21(8):8194 https://doi.org/10.2903/j.efsa.2023.8194

[3] 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

[4] OECD 2009, Guidance Document on the Definition of Residue, Second Edition, Series on Pesticides and Biocides, OECD Publishing, https://doi.org/10.1787/66ca5caa-en

[5] EFSA 2025, Draft Guidance on the use of read-across for chemical safety assessment in food and feed, www.efsa.europa.eu

[6] 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

[7] ECHA 2017, Read-Across Assessment Framework (RAAF), ECHA-17-R-01-EN doi: 10.2823/619212 

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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. 

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