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Key points from the recent EFSA guidance for PPPs that have stereoisomers

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Key points from the recent EFSA guidance for PPPs that have stereoisomers

EFSA recently published a guidance document on stereoisomer risk assessments for PPPs. The following article highlights some of the key areas for efate and behaviour, ecotoxicology and toxicology.

Background

  • A considerable number of active substances of plant protection products present stereogenic elements in their molecular structure (i.e. single atom, axis or a plane with an asymmetric configuration) that give rise to several potential stereoisomers. When this occurs, such substances are marketed either as a more or less purified stereoisomer or as a mixture of them. The isomeric constituents of the active substance should be taken into consideration when the risk assessment is performed.
  • This is of concern as a number of cases may be found in the scientific literature where the differences on toxicological and environmental properties of stereoisomers have a potential impact on the outcome of the risk assessment.
  • The document provides guidance on the information necessary to perform the risk assessment of plant protection active substances that contain stereoisomers in their composition as active components or impurities.
  • The guidance should also be used for active substances that without containing any stereogenic element may generate transformation products or metabolites that do contain them.
  • In this guidance, the Regulation (EU) 283/2013 on the data requirements for the plant protection active substances is analysed and recommendations are given on how to best address and assess data requirements for active substances containing stereoisomers.

 

Fate and behaviour in the environment

  • Degradation in soil

    • Given that route of degradation studies in soil should permit the soil residue of concern to which non-target species are or may be exposed to, to be defined, for active substances containing stereoisomers it is necessary to determine the composition of the stereoisomers to which non-target organisms are exposed to. Consequently, it is necessary to conduct studies to determine how the isomeric composition changes in soil over time.

    • Both route and rate information on the isomers must be available.

  • Adsorption in soil

    • Whilst enantiomers are not expected to exhibit any differential adsorption in soil, diastereomers sometimes do – consequently, an investigation using the HPLC OECD Test 121 should be carried out to investigate if significant differences are indicated.

    • If significant differences are apparent, then batch adsorption studies would be required.

  • Fate and behaviour in water and sediment

    • Where an active substance or metabolites consists of racemates, then it is not considered necessary to separate enantiomers in the analysis of sterile hydrolysis and sterile aqueous photochemical degradation studies.

    • When the active or metabolites consist of pure or enriched enantiomers, then the separation of enantiomers in the analysis is necessary for sterile hydrolysis and sterile aqueous photochemical degradation studies.

    • For the case where actives or metabolites consist of mixtures of diastereomers, different behaviour in the sterile hydrolysis and sterile aqueous photochemical degradation studies may be expected, and these species would need to be resolved in the analytical method.

    • In the aerobic mineralisation in surface water study, differentiated transformation of stereoisomers and stereoisomer interconversion would need to be investigated (including separated enantiomers).

    • The same is true for water/sediment studies; differentiated transformation of stereoisomers and stereoisomer interconversion would need to be investigated (including separated enantiomers).

  • Fate and behaviour in air

    • For active substances containing stereoisomers, the vapour pressure may need to be reported separately for individual diastereomers. Enantiomers are expected to have the same vapour pressure.

    • Stereoisomerism is not expected to influence the calculated half-lives in the upper atmosphere.

    • Likewise, stereoisomerism is not considered with respect to global warming, ozone depletion potential, photochemical ozone creation potential, accumulation in the troposphere, acidification potential and eutrophication potential.

  • Definition of the residue

    • For active substances containing stereoisomers, the residue definition (for both risk assessment and monitoring) needs to be specified taking into account the exact chemical residues (including stereoisomerism) in the different environmental compartments.

  • Monitoring data

    • For active substances containing stereoisomers, monitoring data corresponding to all related active substances, containing different proportions of the stereoisomers, should be presented if available.

 

Ecotoxicology

  • General issues:

    • Separate risk assessments may be required for each isomer where either their fate into the environment is different, or when the ecotoxicological properties are different (defined as a difference of ≥3 between comparable endpoints being observed).

    • Ecotoxicological studies should take into account the proportion of isomers that non-target organisms would be exposed to.

    • Ecotoxicology studies on invertebrate organisms, algae and plants can be undertaken using the active substance as manufactured and the purified stereoisomer(s) listed in the residue definitions for risk assessment; for vertebrate organisms, testing should be minimised, with all available information on related active substances with the same stereoisomers being taken into account, together with metabolism studies. For aquatic organisms, the most sensitive group of species can be identified and used in the additional testing.

    • Chemical analysis of the test system during the course of higher tier tests is highly recommended, to capture interconversion and/or preferential degradation of isomers in the environment.

    • Ecotoxicological endpoints (ECx, NOEC) should be reported in terms of the specific composition of stereoisomers and the stability of the test item during the study should be demonstrated.

  • Birds and other terrestrial vertebrates

    • The isomeric proportion in the tested substance needs to be checked and reported.

    • Testing of stability in dietary matrix over the course of the test is required unless <10% change is expected between each feeding dose.

    • Acute studies using non-dietary exposure are not considered to be feeding studies and therefore stability testing is not required.

  • Aquatic organisms

    • The isomeric proportion in the tested substance needs to be checked and reported.

    • Stability may not need to be checked in the case of semi-static and flow-through systems if <10% change is expected between renewals.

  • Bees

    • Residues of the active substance in nectar, pollen and water (including guttation) should be investigated taking into account its isomeric variation.

    • Isomer specific ecotoxicological endpoints on bees may be needed if isomer composition changes in/on the relevant matrices to which the bees are exposed to is expected or cannot be excluded.

  • Other wildlife groups

No specific requirements are outlined for the other wildlife groups in the data requirements. It is recommended that the risk assessments for these organisms and processes can be addressed by analogy to similar points considered in the guidance.

  • Ecotoxicological Risk assessment

    • Where separate ecotoxicological endpoints for stereoisomers are not available, to minimise the need for additional testing, the following approaches can be applied:

      • If neither the levels of the stereoisomers nor the relative toxicological potency of them is known, then it will be assumed that the toxicity of the original mixture can be entirely attributed to a single stereoisomer and that the whole residue is constituted by this same stereoisomer.

      • If the levels of the individual stereoisomers in the residue are not known, but the relative toxicological potency of them is known, it will be assumed that the residue is constituted by the most toxic stereoisomer.

      • If the levels of the individual stereoisomers in the residue are known, but the relative toxicological potency of them is not known, it will be assumed that the toxicity of the original mixture can be attributed to the most abundant stereoisomer in the residue.

      • If the risk assessment fails, ecotoxicity tests with the individual isomer(s) may be needed.

    • Appendix B of the guidance outlines how the risk assessment should be undertaken depending on the information available, including case studies.

 

Toxicology and human risk assessment

Specific guidance is given for toxicological assessment of absorption, distribution, metabolism and excretion (ADME), genotoxicity and general toxicity.

  • ADME

  • Stereoisomers may be absorbed, distributed, transported, metabolised or excreted in different ways depending upon the isomerism.
  • In vivo ADME and in vitro metabolism studies used to assess hazard and risk of an active substance will also need to address differential ADME properties of stereoisomers which may occur.
  • Genotoxicity

  • If there are changes in the stereoisomeric mixture, the composition needs to be compared with the material tested in the genotoxicity studies. As long as all of the sterioisomers are present in the tested material, the conclusion on genotoxicity will be applicable to the stereoisomeric mixture.

  • If one or more stereoisomer(s) are not present in the tested material, read across will be required.  This will require consideration of structural alerts and an assessment of potential differences in metabolism and mutagenicity potency.

  • If read-across does not support or enable an assessment to be made, further in vitro testing will be required.

  • General toxicity

  • If there are changes in the stereoisomeric mixture, it should be compared with the specification of the test material used in the toxicity studies.  If there is no significant difference in composition (ie component level differences are < 10%), it can be considered to be substantially equivalent and the toxicity study data can be used for hazard and risk assessment.

  • If the stereoisomeric composition and test material are not substantially equivalent, read-across from available toxicological data would then be required, considering:

  • Toxicological profile of the active substance and its metabolites

  • Metabolism of the active substance and its metabolites

  • Mechanistic data

  • Pesticide and toxicological mode of action

  • Information from other active substances with the same stereoisomers in different proportions

  • Whether differences in potency are likely

  • A weight of evidence approach would then be used to assess all information and make a conclusion on hazard and risk assessment of the stereoisomeric mixture.

  • If hazard cannot be established from read across, it may be possible to conclude acceptable risk if there is negligible exposure to humans. However, if this is not the case, or if residual risk is identified, appropriate data and testing will be required.

If you have any questions relating to this new EFSA guidance on stereoisomers, please contact us.

The full guidance document published by EFSA is available on the EFSA website:

EFSA (European Food Safety Authority), Bura L, Friel A, Magrans JO, Parra-Morte JM and Szentes C, 2019. Guidance of EFSA on risk assessments for active substances of plant protection products that have stereoisomers as components or impurities and for transformation products of active substances that may have stereoisomers. EFSA Journal 2019;17(8):5804, 33 pp.

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