Conclusions by EFSA of a critical assessment of the endocrine disrupting properties of a series of pesticides

Introduction

The European Union introduced in 2009 new criteria for the approval of the active substances in pesticides, including some that look at the endocrine disrupting potential of a substance to decide if it represents a hazard and consequently, needs to be banned from use¹. This Regulation (1107/2009) specifies the criteria for substances that have properties that can cause Cancer or Mutations, or that can be toxic for Reproduction (those classified as “CMR substances”), and for substances that are Persistent Organic Pollutants (POPs) or that are Persistent, Bioaccumulable and Toxic (PBTs), including those very Persistent and very Bioaccumulable (vPvB).

But the Regulation also calls for setting specific scientific criteria for the determination of endocrine disrupting properties. The Regulation enacts a number of so-called ‘interim criteria’, pending adoption of final criteria, based on classification considerations and ‘toxic effects on the endocrine organs’.

¹Regulation EC) No 1107/2009

What is the purpose of this specific report of EFSA ?

EFSA was required to give a Conclusion in the light of current scientific and technical knowledge on the properties of active pesticide substances and whether these can be expected to meet the approval criteria, covering hazard-based criteria and the risk to human health, animal health and the environment according to the so-called “Uniform Principles” for assessing pesticide active substances and products.

For an explanation of the distinction between “hazard” and “risk”, you can see this GreenFacts video: www.youtube.com/watch?v=PZmNZi8bon8 

Based on the available data, this report presents an overview and the EFSA Conclusions, which explicitly summarise the assessment of potential endocrine effects on 41 active substances, 15 are new and 26 are submitted for renewal of applications. Out of the 41 evaluated, for 24 active substances including 3 microbial pesticide, the available information has not led to the detection of specific concerns and no classification was required. In the case of two substances EFSA has not detected concerns but has recommended additional studies to confirm this conclusion. ²

What were the sources of information available to EFSA to make these assessments and their conclusions?

The assessment is a scientific evaluation of all available information, which covers regulatory guideline studies, scientific peer-review publications and complementary information sources. The information available to EFSA and used for their scientific assessments combines basically:

• the dossier prepared by the applicant;
• the draft risk assessment prepared by the rapporteur Member State;
• additional information, which includes a public consultation and several commenting rounds with the risk assessors experts in the Member States and collected during the EFSA peer-review process;
• the complementary information networks, which includes general scientific knowledge, relevant information from previous assessments by EFSA and other risk assessment bodies, related grants and procurements including systematic literature reviews, etc., made available to EFSA and the Member States’.

These different information sources include both regulatory studies performed for the registration dossier and mostly conducted under the guidelines of “Good Laboratory Practices”, and scientific peer-review publications.

The outcome of the scientific assessment is compared with hazard-based criteria and then used in the hazard characterisation and risk assessment.

What are the specific requirements for the assessment of an endocrine disruption potential?

Regarding effects on the endocrine system, following the scientific assessment methodology, EFSA evaluates the available evidence during the peer-review, focusing on observed adverse effects, which are plausibly linked to endocrine modes of action, and evidence from in vitro mechanistic studies, as well as other information sources such as evidence from closely structurally related substances.

The scientific assessment is conducted in line with the Opinion of the EFSA Scientific Committee (EFSA SC, 2013) and the OECD developments following the Conceptual Framework for Testing and Assessment of Endocrine Disrupting Chemicals (OECD, 2012).

The outcome of the scientific assessment is then compared with the hazard-based criteria, in particular regarding the assessment of ‘toxic effects on endocrine organs’. The two interim criteria that are defined in the regulations are that should be considered as having an endocrine effect:

• First: substances that are classified as causing some cancers and having a toxic effect on reproduction,
• Second: substances that have a toxic effect on reproduction and on endocrine organ.

This assessment approach is also used in the hazard characterisation and the risk assessment to identify critical areas of concern as well as issues that could not be finalised. When such additional information is needed, the identification of these data gaps is also presented.

Where and how are ‘hazard-based concerns’ and ‘critical areas of concern’ identified?

The hazard-based concerns are based in all cases on the classification for reproductive and carcinogenic effects according to the regulatory interim criteria. These criteria are applied by covering both the actual classification as well as proposed classifications issued from the EFSA peer-review. In some but not all cases, these criteria are complemented by the identification of adverse effects for which plausible endocrine-mediated mechanisms were identified.

‘Critical areas of concern’ are identified where hazard or risk based concerns were identified from the available information, with regard to the approval criteria and in line with the EC Regulation of 2009 regarding the placing of plant protection products on the market.

‘Issues not finalised’ are concerns that are identified but where the available information does not allow to rule out an endocrine mediated mode of action. In this case there is insufficient information to establish a conclusion and the lacking information is then identified as a ‘data gap’.

Other issues include minor deficiencies and less relevant data gaps, and are also presented in the Conclusion but not highlighted as concerns.

This approach has been established by EFSA, following a discussion with the European Commission and the Member States, in order to offer risk managers, stakeholders, and the public a clear communication of the risks and concerns identified for each pesticide active substance.

The EFSA conclusions consider independently both interim criteria, informing risk managers, stakeholders and citizens on observations related to toxic effects on endocrine organs even when the first criterion is met.

What are the conclusions of the present overview ?

In the conclusions, EFSA has considered the current harmonised classification under the European « Classification Labelling and Packaging Regulation (1272/2008) » and its own assessment regarding the substances that “have to be classified”. When available, the opinion of the Committee for Risk Assessment of the European Chemicals Agency (ECHA) was also considered.

Even if the number of substances assessed to date was insufficient to conduct a statistical analysis and if for some substances the interim criteria were not met, a wide range of options is already evident. EFSA highlighted the evidence suggesting possible concerns and recommended the need for additional studies to finalise the assessment of the potential endocrine mediated adverse effects of these substances.

For a number of further EFSA Conclusions under Regulation (EC) No 1107/2009, the assessment was limited in scope to either applications for amendment to the conditions of approval or to specific mandates under the Regulation. These conclusions do not provide an assessment of endocrine effects and the substances have been listed only for completeness.

The EFSA Conclusions include specific sections where health or environmental concerns are listed, in order to facilitate communication of the assessment to risk managers, stakeholders and the public.

Some Conclusions adopted under the previous legal framework and not requiring the specific assessment of endocrine effects as approval criteria, have not been included in this report.

Summaries of the assessment of endocrine disrupting properties for the relevant EFSA Conclusions for the substances assessed are given in appendices of the report, and an overview of the outcome of the assessments of the interim criteria and the concerns identified regarding endocrine disrupting properties is presented below (?).

Active substances assessed in the EFSA Conclusions for their endocrine disrupting properties

No concerns and no data gaps were identified		Concerns and/or data gaps were identified	Other EFSA conclusions with no reference to endocrine effects.	Other EFSA Conclusions
Cerevisane,     Isaria fumosorosea strain Apopka 97, Sulfoxaflor, Sulfosulfuron, Fenhexamid, Pyridate, Cyantraniliprole, Prosulfuron, COS-OGA, Esfenvalerate, Halauxifen-methyl, Flumetralin, 3-decen-2-one, Cyhalofop,	Metsulfuron-methyl Ferric phosphate Pepino mosaic, virus strain CH2 isolate 1906 Florasulam Metalaxyl-M Pyraflufen-ethyl Rescalure Trichoderma atroviride strain SC1 Mandestrobin, Famoxadone.	Iprovalicarb, Bentazone, Lambda-cyhalothrin, Acibenzolar-S-methyl, Flumioxazin, Amitrole, Flutianil, 2,4-D, Terpenoid blend QRD-460, Pymetrozine, Flupyrsulfuron (variant evaluated flupyrsulfuron-methyl-sodium), Tricyclazole, Benzovindiflupyr, Thifensulfuron- methyl, Isoproturon.	Fluazifop-P, Fenazaquin, Acrinathrin, Fenpyroximate, Imidacloprid, Neonicotinoids (clothianidin), Neonicotinoids (thiamethoxam), Neonicotinoids (imidacloprid).	Tebuconazole, Chlorpyrifos.

For instance, in the case of flupyrsulfuron, the first interim criterion is met due to the proposed classification, but the information suggested the substance to be unlikely an endocrine disruptor in mammals.

Regarding the second criteria, the term “toxic effects on endocrine organs” has been interpreted in line with the current scientific knowledge, to include adverse structural or functional alterations observed in organs involved in hormonal control resulting in adverse alterations in the regulation of endocrine systems.

It is important to mention that in all cases where the second interim criteria is met according to the EFSA evaluation, the complementary scientific assessment indicates that endocrine mediated mechanisms cannot be ruled out regarding some adverse effects.

In addition, for several substances the interim criteria were not met, but EFSA highlighted evidence extracted from the regulatory studies or scientific publications suggesting possible concerns, and therefore recommended the need for additional studies to finalise the assessment of the endocrine effects.

With this approach, the EFSA Conclusions offer risk managers, stakeholders and citizens a transparent assessment of the available evidence, thus providing information that can be used to support the decision making process.