Under the EU regulation for authorising plant protection products (Regulation (EC) 1107/2009), the potential risks to wild mammals must be assessed. The default approach for wild mammal risk assessments is to use the worst-case no observed adverse effect level (NOAEL) that was concluded from the toxicology package for the human health risk assessment. However, there are lots of parameters that are measured in toxicology studies, some of which are relevant for individual humans but not for wild mammal populations. The current bird and mammal guidance (EFSA 2009) theoretically allows the derivation of an ‘ecologically relevant’ wild mammal toxicity endpoint that only takes into account those effects relevant for wild mammal populations. It was later recommended by EFSA in 2015 that the assessment of ecological relevance should be made at the active substance level. Five years has now passed since this recommendation was made, so what has happened since?
The aim of this poster was to review active substances that have been approved in the EU since 2015. Due to the work involved in this review, only those actives that had completed the authorisation process were included, with any incomplete or rejected actives not being reviewed. Key documents (EFSA conclusion, RAR, PRAPeR reports) were reviewed for each active substance with several key questions in mind:
- Was the wild mammal reproductive NOAEL refined?
- If so, at what stage?
- How was it refined?
- What impact did the refinement have on the risk assessment outcome?
In total, 117 active substances were reviewed. The majority of active substances still used the same NOAEL as for the human risk assessment, but the proportion of refined NOAELs has increased since 2015.
Only 13% of NOAEL refinements were proposed within the submitted dossiers, whereas nearly 50% of refinements occurred during the expert meeting stage. This means that there would have been little time for Notifiers to prepare rebuttals or develop alternative refinements, thus resulting in unresolved wild mammal risk assessments at the active substance level.
For active substances where refinement of the NOAEL was attempted, an ecorelevance argument was attempted in 63% of cases. Other lines of argumentation attempted were reinterpreting the exposure doses during the toxicology expert meeting, benchmark dose modelling, etc.
Final NOAELs for wild mammals were predominately reliant on rat multi-generation studies, though several were reliant on rabbit developmental studies and a few reliant on other studies e.g. rat development study, rat neurotoxicity study.
The type of effects that were used to determine the final NOAEL were variable between active substances, including parameters with an obvious link to population-level effects, such as offspring viability and litter size, and those with a less obvious link such as delayed ossification and kidney effects. There was some inconsistency in the assessment of the relevance of effect types on wild mammal populations, with effects on body weight gain, delayed ossification, skeletal variations and kidney effects being considered ecologically relevant for some active substances but specifically stated as non-relevant for others.
The magnitude of effect that determined the final NOAEL was also variable between active substances, and also between the types of effects which drove the NOAEL. For example, bodyweight effects of both more than and less than 10% were considered relevant for defining the NOAEL for wild mammals.
The underlying reasons for these apparent inconsistencies in the type and magnitude of effect used to define the NOAEL are currently being further investigated by CEA, and this news article will be updated in due course to report on these findings.
The final NOAEL concluded for the active substance resulted in ~50% of wild mammal reproductive risk assessments failing that previously passed, and ~13% of risk assessments passing that previously failed; the risk assessment outcome was unchanged for the remaining active substances.
Based on this review of active substances that have been authorised in the EU over the last 5 years we have made a number of conclusions and recommendations:
- More collaboration between toxicologists and ecotoxicologists may help avoid changes in NOAEL at a late stage of the EU review process e.g. co-authorship of the derivation of an eco-relevant NOAEL for wild mammals between tox/ecotox experts; it may be beneficial to have a combined tox/ecotox PRAPER meeting, clearly discussing effects observed and their eco-relevance
- Regulators to more clearly communicate the evaluation process when defining the wild mammal NOAEL, describing any concerns raised and the associated reasons for these concerns; ideally, regulators would follow a formalised framework for their evaluation e.g. Lewis et al.
- More guidance needed for regulatory ecotoxicologists regarding what types of effects and what magnitudes of difference to the control are eco-relevant and more understanding of the toxicology data package – this is highlighted by all stakeholders in public consultation comments on EFSA (2009)
- It appears that less evidence/argumentation is required to decrease a NOAEL (by regulators/EFSA) compared to potentially increasing it
- The final NOAEL conclusion is sometimes influenced by the impact on the risk assessment conclusion – if it passes, sometimes a more conservative endpoint is accepted; this can be problematic for future national authorisations with different GAPs
- Reporting of discussion regarding deriving eco-relevant endpoint within dossiers is currently inconsistent – can be found in the MCA, MCP or Vol 1 sections of the dossier – this should be agreed at EU level (MCA wild mammal section seems most relevant); should include the reasons why the NOAEL was selected rather than referring to the PRAPeR report etc.
- Multi-generation rat studies were predominantly used to define the NOAEL – BMD modelling may have been a useful refinement for some of these actives now that the approach is supported by EFSA, though further work is required to define acceptable levels of response for each type of effect e.g. is a 10% change in bodyweight acceptable?
To find out more about this work, please download our poster: “Deriving ecologically relevant endpoints for wild mammal risk assessments – 5 years on, what is the state of play?”. For further information, please contact Amy.Brooks@cea-res.co.uk.
In addition to this topic, CEA also presented 4 other posters at the SETAC virtual conference (SETAC SciCon, 3-7 May 2020). These are available for download here.
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