ED assessment of active substances in PPPs came into effect in November 2018 in the EU. Insights from EFSA’s assessment of the first 65 actives shows how guidance is applied and how waivers are being used. Read on to find out how to negotiate the ED assessment process and when to consider derogations for active substances with ED potential.
Endocrine Disruptor definition and assessment in the EU
In June 2018, the European Food Safety Agency (EFSA) and the European Chemicals Agency (ECHA) published guidance on the identification of Endocrine Disruptors (EDs), which has impacted all active substance renewals in plant protection products (PPPs) since November 2018.1 An active substance is classed as an ED if:
- It produces an adverse effect in an intact organism, subpopulation or progeny that results in an impairment of functional capacity or capacity to compensate for additional stress. Or increases susceptibility to other influences.
- It has an endocrine mode of action.
- The adverse effect is a consequence of its endocrine mode of action.
Assessment of ED focuses on the impact of an active substance on the estrogen, androgen, thyroid hormone and steroidogenesis pathways – known as EATS modalities. Table 1 shows the standard information requirements for PPPs under the ECHA/EFSA guidance.
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Regulation 283/2013 further states that where there is evidence that the active substance may have ED properties, additional information shall be required. The data package of most active substances is likely to contain data derived from older versions of OECD studies; however, this data will only be deemed sufficient for assessing EATS-mediated adversity, if all parameters required in the ED guidance are reported. The following ‘best practice’ parameters should be included in new study protocols and reported fully:
- Anogenital distance of each F1 and F2 pups
- Presence and number of nipples/areolae in all male F1 and F2 pups
- Histopathological assessment of the mammary gland in P0 and F1 adult males and females
- Sperm parameters measured always by default (regardless of whether they have also been tested in the 90 days)
The newer versions of the OECD test guidelines have mandatory thyroid hormone (TH) measurement. However, effective TH assessment continues to prove challenging.
Furthermore, where no mode of action analysis is provided, effects observed on many endocrine organs are considered to be EATS mediated. A plausible link between the adverse effect and endocrine activity is important.
The current status of ED assessment of active substances by EFSA
In November 2020, EFSA shared details of the first 65 active ingredient ED assessments.2 This gives valuable insight about the EU approach and the potential issues that registrants may face. Of the 65 ED assessments completed up to November 2020:2
- 37% required additional data for EATS modalities relating to human health.
- 73% required additional data for EATS modalities relating to non-target organisms.
- 23% (eight) active substances were identified as EDs, of which five were related to the thyroid modality.
It is also noteworthy that a proportion of active substances saw ED data requirements waived during the renewal:
- 18.5% of ED assessments relating to human health
- 12.3% of ED assessments relating to non-target organisms
It is the rapporteur Member States that propose the information required to reach an ED conclusion in the draft renewal assessment report. Assessment of most active substances are now in the ‘stop-the-clock’ phase, which allows up to 30 months for registrants to provide missing ED data. Collecting and analyzing data within that timeframe is challenging, especially as studies like EOGRTS are complex to conduct, due to triggered breeding, and require flexible capacity to house extended generations.
ED assessment waivers and when they apply
In some scientifically justified circumstances, EFSA will waive ED assessment.3 The most common rationale for waiving ED assessment relates to the intrinsic physicochemical and the (eco) toxicological properties of the active. If these demonstrate that ED assessment is not scientifically necessary or technically not possible, then they may be waived. EFSA insists that each waiver should be scientifically justified and made on a case-by-case basis. That means summarizing all relevant information, evaluating it in the context of the ED guidance and making a clear scientific argument.3
Based on the first 65 active substances assessed, ED assessment was waived for human health for actives showing potent anti-cholinesterase inhibition, dose-limiting local irritant effects and dose-limiting induction of methemoglobinemia.2,3 The ED assessment waivers granted for non-target organisms related to actives with non-toxic modes of action, inert properties or because the active was consumed as part of a normal diet.2
Derogation for active substances classified as EDs
Even if your active substance is classified as an ED, you may have the option of requesting derogation. During the ‘stop-the-clock’ period, you can request derogation or submit information on the basis that human or non-target organism exposure to an active substance in a PPP, under realistic conditions of use, is negligible. This anticipates that the PPP will be used in a closed system or under other conditions that exclude contact with humans and that the residues do not exceed the default value made in Regulation (EC) No 396/2005. Similarly, its effect on non-target organisms must also be negligible, as stated in Annex II, Points 3.6.5 and 3.8.2.
In addition, applicants should inform the EC of certain serious plant protection dangers that cannot be controlled by any other means. Approval may be granted for a period not exceeding seven years as a candidate of substitution.
According to Regulation 1109/2009, national authorities can also grant derogations under Article 53 for emergency use in special circumstances. Applicants need to apply to individual member states for authorization of products containing candidates of substitution.
Having a good understanding of your active substance’s mode of action and its use in an agricultural context is key to successful derogation arguments. For example, your active substance might qualify for derogation when:
- It is the only active that offers either a contact or a systemic action and that mode of action is critical for controlling the pest.
- It is important for use in a resistance-management program to prevent further development of resistant strains.
- It is the only compatible active substance for use within an integrated pest-management program.
- Compared with other methods of controlling the pest or disease, it is the safer alternative.
This is not an exhaustive list of examples but illustrates how to think about derogation arguments.
Future considerations for ED assessment across all EU legislation
A recent fitness check4of all EU legislation related to ED assessment identified that, although there was no inconsistency in ED identification, risk-management approaches did vary. Consolidation of the principles guiding ED risk management was recommended. Risk management is already built into biocidal product ED assessment and this may be extended to PPPs in future. In addition, the criteria already developed for pesticides and biocides could be further rolled out to other sectors.
The ED assessment mandates the use of animals, with studies like EOGRTS requiring testing on adults and progeny. It is, therefore, not surprising that the fitness check also identified the need to develop ED assessment methods that minimize animal use.
Active substances in PPPs are now undergoing ED assessment in the EU per EFSA guidelines. Having detailed dossiers clearly adhering to the ED guidance enhances the chance of success during active substance renewal. ED assessment waivers may be relevant in some cases for actives with appropriate physicochemical properties and low toxicity profiles. Derogation may be appropriate for active substances which are, or are suspected of being, EDs, if exposure is demonstrated to be negligible or there is a unique plant protection need for the active.
For active substances classified as EDs, approval will be withdrawn and they can no longer be marketed in Europe, unless derogation is approved.
Covance by Labcorp has been keeping abreast of guideline discussions to anticipate requirements, and we are expanding available capacity to enable clients to meet requirements now and in the future.