The Commission Delegated Regulation (EU) 2017/2100 [1] specifying the scientific criteria for the determination of endocrine-disrupting properties (ED criteria) under Regulation (EU) No 528/2012[2] (BPR) establishes that the ED criteria becomes applicable by 7 June 2018.

According to the Endocrine disruption criteria a substance shall be considered as having endocrine disrupting properties if it meets all of the following criteria:

a) it shows an adverse effect in [an intact organism or its progeny]/[non-target organisms], which is a change in the morphology, physiology, growth, development, reproduction or life span of an organism, system or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;

b) it has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system;

c) the adverse effect is a consequence of the endocrine mode of action.

A note agreed by Member States’ Competent Authorities for Biocidal and Products presents a proposal for the practical implementation of the ED criteria in the context of active substances and product authorization (see CIRCABC). It proposes a specific way forward, depending on whether the applications for authorization are still under evaluation by the evaluating body referred to in Annex VI to the BPR, or whether they are in a later stage of the procedure (but before the product authorization is granted). It also addresses how to deal with already authorized biocidal products. The objective of this draft note is to discuss the proposed way forward with Member States’ competent authorities and stakeholders in order to find an agreement.

It should be noted though that Articles 26(3), 30(2), 34(4)[3] and 44(1)[4] of the BPR establish the legal deadlines by which the evaluating body[5] must conclude its assessment of an application for product authorization. Moreover, Article 89(3) provides that, following the approval of a particular active substance, Member States shall ensure that authorizations for biocidal products are granted, modified or cancelled within three years of the date of approval.

Paragraph 8(a) of Annex VI to the BPR establishes that the evaluating body must, when evaluating a biocidal product, take into consideration other relevant technical or scientific information which is reasonably available to him with regard to the properties of a biocidal product, its components, metabolites or residues. Therefore, the evaluating body must consider the ED properties of a biocidal product in any procedure that is still under the evaluation phase. This involves considering the ED criteria for both:

  • the active substance(s) included in the product; and
  • the non-active substances in the product (so-called ‘co-formulants’).

A biocidal product will be considered to have ED properties if it contains:

  • active substance(s) and/or non-active substance(s) having ED properties on the basis of the scientific criteria established by Article 5(3) of the BPR and/or,
  • active substance(s) and/or non-active substance(s) having ED properties in accordance with Article 57(f) and 59(l) of Regulation (EC) No 1907/2006, and/or,
  • active substance(s) with an intended biocidal mode of action that consists of controlling target organisms via their endocrine system(s). Such an active substance will have an intended biocidal mode of action consisting of controlling target organisms via their endocrine system(s), for which the information has been submitted in the application for approval as required by point 6.5 of Annex II of the BPR, and for which it is showed that the intended biocidal mode of action is sufficiently effective.

Assessment

ECHA and EFSA  developed a scientific guidance to implement the scientific criteria (EFSA journal, published on 7 June 2018).

This guidance document was written to provide guidance to applicants and assessors of competent regulatory authorities on how to identify endocrine disruptors in accordance with the ED criteria laid down in Commission Delegated Regulation (EU) No 2017/21003 and Commission Regulation (EU) No 2018/6054 for biocidal products (BP) and plant protection products (PPP), respectively. The guidance document describes how to gather, evaluate and consider all relevant information for the assessment, conduct a mode of action (MoA) analysis, and apply a weight of evidence (WoE) approach, in order to establish whether the ED criteria are fulfilled.

All relevant information on endocrine disruption should be reported. Such information can come from regulatory guideline studies, non-guideline investigative studies, public literature, QSAR models, read-across approaches, databases (see Appendix D of the Guidance), epidemiological data, field studies, monitoring data and population modelling.

Part of the Guidance document is an Excel template on how the available information can be reported and analyzed. It is recommended that applicant use this template to gather the relevant information from the available studies. Applicants are asked to submit the filled in template in their substance dossier. The Excel template can be found under ' Supporting Information'.

The conclusions on endocrine disruption should answer the two problem formulations identified within the guidance document:

  • Is there a biologically plausible link between endocrine activity and observed adverse effect(s) that are relevant for humans?
  • Is there a biologically plausible link between endocrine activity and observed adverse effect(s) that are relevant for non-target organisms at population level?

A conclusion should always be drawn for both humans and non-target organisms.

When concluding on ED properties it is important to take the following points into consideration:

a. It is sufficient that the substance meets the ED criteria for one group of non-target organisms in order to be identified as ED.

b. Where, based on a sufficient dataset, no ‘EATS-mediated’ adversity was observed or where endocrine activity was found negative, it is possible to by-pass the MoA analysis and to conclude that the criteria are not met.

c. Where a MoA is based on ‘EATS-mediated’ adversity the ED criteria are considered met; unless an alternative non-endocrine MoA is demonstrated and in a comparative analysis found to be the most likely explanation.

d. Where a MoA is based on ‘sensitive to but not diagnostic of EATS’ adversity and the MoA  supports the biological plausibility of the link between the observed adverse effects and endocrine activity for at least one postulated MoA(s), the substance is considered to meet the ED criteria, unless an alternative non endocrine MoA is demonstrated and in a comparative analysis found to be the most likely explanation.

e. Where the available information is sufficient to postulate a non-EATS endocrine MoA, it is possible that, the supporting available information would be not sufficient to develop the MoA. In these situations, an analysis of the available testing methodologies should be carried out by the applicant in order to justify that the generation of further scientific information suitable for the identification of a non-’EATS mediated’ endocrine MoA is not feasible based on the available scientific knowledge and that the biological plausibility is highly uncertain, and therefore, a conclusion is currently not possible.

f. There may be cases where data are not provided for performing the ED assessment according to this Guidance and this is not considered justifiable. For example, failure to perform the MoA analysis as required, failure to generate the information needed to sufficiently investigate endocrine activity and/or endocrine related adversity (despite the fact that appropriate test methods are available), and failure to provide adequate scientific justifications for omission of information. In all those cases, the assessors shall clearly indicate which missing information should have been provided by the applicant when following the present Guidance and to which extent this information is critical to allow a conclusion to be reached on the ED properties of a substance.

The conclusion on the ED criteria needs to be transparently documented, including the remaining uncertainties. A conclusion on whether the ED criteria are met should always be drawn with respect to both humans and non-target organisms. Additional regulatory provisions for endocrine disruptors are covered under REACH , the Regulation on cosmetics and under EU legislation on food contact materials.

The same active substance may be used in biocidal products and plant protection products. Information on EDs submitted for the approval of an active substance under the Plant Protection Products Regulation[1] can also be used by the eCA in the assessments if it would not benefit the applicant, as any available information can be used to reach a conclusion on the properties of biocidal active substances.  This is consistent with point 8 of Annex VI (common principles for the evaluation of dossiers for biocidal products) of the BPR stating that the evaluating body shall take into consideration other relevant technical or scientific information which is reasonably available to them with regard to the properties of the biocidal product, its components, metabolites, or residues. The ECHA and the European Food Safety Authority (EFSA) should apply the established procedures in the Memorandum of Understanding of 20 May 2009 to enable ED data submitted to the EFSA on the same substance to be used in evaluating a biocidal active substance and vice versa. While EFSA information can be used as additional information during the evaluation by the eCA and ECHA, it must not be used to replace data (and therefore fill a data gap) which the applicant has an obligation to provide.

This approach of using data or information submitted by an applicant under other EU rules is consistent with the data protection rules in Article 59 of the BPR and Article 59 of the Regulation (EC) No 1107/2009 (plant protection products) as these rules clarify that the data protection applies only to the use of data for the benefit of other applicants under these regulations.

Summary for applicants:

  • Review the active substances in your products and portfolio in light of the new criteria.
  • Be prepared to provide more information on the possible endocrine-disrupting properties of your active substance in your application.
  • Consult the national authority responsible for the evaluation of your active substance before starting to test it to support the identification and assessment of possible endocrine disrupting properties.
  • If your substance has already been approved at EU-level, note that the European Commission and national authorities are in talks on whether and on what level already approved substances should undergo assessment for endocrine-disrupting properties.
  • Note that the criteria will also apply to co-formulants, not only active substances.
  • Stay up-to-date - talk to your national industry association and follow ECHA’s news.

Footnotes

[1] Commission Delegated Regulation (EU) 2017/2100 was published on 17 November 2017 and is applicable as of 7 June 2018.

[2] Regulation (EU) No 528/2012 of the European Parliament and of the Council of 22 May 2012 concerning the making available on the market and use of biocidal products (OJ L 167, 27.6.2012, p. 1).

[3] For procedures of mutual recognition in parallel, before the reference MS sends its assessment report and the summary of biocidal product characteristics (SPC) to the MSs concerned.

[4] For Union authorisation procedures, before the evaluating CA sends the assessment report and the conclusions of its evaluation to the Agency.

[5] I.e. the CA responsible for the evaluation of the application referred to in Articles 26(1), 30(1), 34(1) or 44(1) of the BPR.

[6] Regulation (EC) No 1107/2009 of the European Parliament and of the Council of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directive 79/117/EEC and 91/114/EEC.