The new bird and mammal guidance (EFSA 2023): toxicity endpoints and residue decline refinements

Given that the guidance is now >10 years old, EFSA received a mandate from the European Commission to revisit this guidance and revise it according to current science and understanding. A draft of this new guidance was released in 2021 for public consultation, and the resulting final version was recently published in February 2023 (EFSA 2023).

The new bird and mammal guidance (EFSA 2023) has not yet been noted in the EU, and therefore is not yet in force for PPP authorisations. The timetable for voting and implementation is currently unknown. In the meantime, it is useful to consider the potential implications of the new guidance on future bird and mammal risk assessments. There are a number of areas that have changed in the new guidance compared to the 2009 version, so to avoid a very lengthy news article, we have initially selected two areas that we have started to familiarize ourselves with: toxicity endpoints and time-weighted average factors (fTWA). Below are some key points to be aware of, should EFSA (2023) be implemented in the future:

Toxicity endpoints

• Under EFSA (2009) we have traditionally used NOAEL endpoints for birds and mammals. EFSA (2023) now requires the calculation of a 10% response level using benchmark dose modelling (BMD10) – see EFSA (2023) Chapter 5.2.7. This is in line with the general trend to calculate 10% effect levels for all wildlife groups, as per the data requirements under Regulation (EC) 1107/2009. It is noted that the draft new guidance (EFSA 2021) proposed using the lower confidence limit of the 10% response level (i.e. BMDL10), whereas the final guidance uses the median 10% response level (BMD10). In some instances, the BMD10 may be higher than the NOAEL, but in other cases the BMD10 will be lower, both of which may impact the outcome of the risk assessment.
• It is recommended in EFSA (2023) to use the newly released Bayesian BMD model when calculating BMD10 values, which is available on the EFSA R4EU platform.
• The ecological relevance of effects observed in the avian and mammalian studies should be assessed when deriving the NOAEL/BMD10 for use in the reproductive risk assessments – see EFSA (2023) Chapter 5.2.6.4 and 5.2.6.5. This is also possible under EFSA (2009), but further guidance is now provided in EFSA (2023) regarding what is and isn’t considered to be ecologically relevant, aiming to harmonise the approach.

Time-weighted average factors (fTWA)

• Under EFSA (2009), it was possible to include a default fTWA of 0.53 (equivalent to a DT50 of 10 days on food items) in reproductive risk assessments for birds and mammals for foliar applications, providing there was no evidence that long-term effects could arise from short-term exposure. This will no longer be possible under EFSA (2023) – see EFSA (2023) Chapter 6.1.4. Instead, an assessment must be made whether it is appropriate or not to use an fTWA in conjunction with the lowest ecologically relevant endpoint (NOAEL or BMD10) based on an evaluation of the available toxicity data.
• If an fTWA is deemed to be inappropriate for mammals, it is then not possible to use an fTWA for birds, with only rare exceptions where sufficient data on birds are available to allow the applicant to clearly justify use of the fTWA for birds. No additional data should be generated to address this aspect of the risk assessment.
• In cases where an fTWA is deemed to be appropriate for the lowest ecologically relevant endpoints for birds and/or mammals, it must be checked whether an fTWA would not be appropriate for a higher ecologically relevant endpoint (within 3x of the lowest endpoint) and, if so, the risk assessment should be presented using both endpoints i.e. risk assessment #1: lowest ecologically relevant NOAEL or BMD10 with fTWA; risk assessment #2: higher ecologically relevant NOAEL or BMD10 without fTWA.
• If an fTWA is not considered appropriate, the default fTWA of 0.53 cannot be used and no other residue decline refinements are possible. This can have a significant impact on the outcome of bird and mammal risk assessments, with TER values effectively being reduced by half in those scenarios where the default fTWA cannot be used.
• For some active substances, the default DT50 of 10 days is conservative, as their residue decline is actually much faster. However, if the fTWA assessment does not pass for these actives, there will now be a need to develop alternative refinement options to pass the risk assessment; otherwise it will result in the loss of crop uses if this is not feasible.

With both of these aspects of the risk assessment (toxicity and fTWA), the final decision on what should be used in the risk assessment (i.e. which endpoint and yes/no to fTWA) will be made by regulatory authorities and/or EFSA after the risk assessment has been constructed around these parameters and the dossier has been submitted. Higher-tier risk assessment refinements may not have been developed if the risk assessment passed with the proposed endpoint, but may be required if the endpoint is lowered during EU review (which often happened under EFSA 2009). Significant investment in residue decline datasets may have been made, but may end up being redundant if the use of an fTWA is later rejected. It will therefore be critical to present robust argumentations for both the toxicity endpoints and fTWA assessments for birds and mammals, and preferentially have discussed these prior to submission with the RMS (and other regulators/EFSA where possible).

CEA have been deriving ecologically relevant endpoints under EFSA (2009) for many years now, and have also begun to do this under EFSA (2023). We have also now prepared fTWA assessments for several actives under EFSA (2023).

We have presented our experiences to date at conferences and in a journal article, all of which you can find as free downloads in the CEA library.

We will also be presenting posters on both of these topics at the upcoming SETAC Dublin conference in April/May 2023 – hopefully we’ll see you there!

If you would like any further information on any of the points raised here, including investigating the impact on your active substances, please feel free to contact us to discuss further.