Joint EFSA/ECHA guidance document for the identification of endocrine disruptors under EU Biocides and Pesticides Regulation

The European Food Safety Authority (EFSA) and the European Chemical Agency (ECHA) jointly published in June 2018 the long-awaited guidance for the identification of endocrine disruptors. While being a well-thought through and worked out guidance for industry and authorities, it remains to be seen how high the hurdles for concluding whether a substance is or is not an endocrine disruptor will be.

Endocrine active substances (EAS) are substances that can interact or interfere with normal hormonal action. When this leads to adverse effects, they are called endocrine disruptors (ED). Humans and animals may be exposed to a wide range of EAS, for example via use of chemical-based products or the environment. They can be naturally occurring (e.g., phytoestrogens in soya) or man-made. Some EAS are intentionally used in medicines because of their endocrine active properties. Scientific knowledge in this area is still growing and, therefore, understanding of what EAS/ED continues to be the subject of scientific debate.

At the EU regulatory level, a first Community strategy for endocrine disruptors has been developed between 1996 and 2000. At this time, the objective was to identify the problem of endocrine disruption, its cause and consequences and to propose appropriate policy action to allow responding quickly and effectively to the problem, thereby alleviating the public concern. The European Commission was called on to identify substances to be prioritised for immediate action. This led, between 2006 and 2012, to the development of European legislation to address and regulate the use of ED in chemicals, pesticides, biocides, and cosmetics. However, while there was Regulation in place, there was neither consensus on how to define an ED nor any regulatory guidance how to identify an ED. It took until June 2018 until the European Food Safety Authority (EFSA) and the European Chemical Agency (ECHA) jointly published their guidance for the identification of endocrine disruptors in the context of the EU Biocides and Pesticides Regulations.

What is the agreed definition of an endocrine disruptor?

According to the EFSA/ECHA guidance, a substance is considered to have endocrine disrupting properties if it meets all of the following criteria:

• It shows an adverse effect in an intact organism or its progeny 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;
• It has an endocrine mode of action, i.e. it alters the function(s) of the endocrine system;
• The adverse effect is a consequence of the endocrine mode of action

 What steps are involved in identifying if a substance has endocrine disrupting properties?

Very topline, the general ED assessment strategy includes the following steps:

1. Gather information
   • Identification and collection of relevant information from standard studies according to internationally agreed protocols (e.g., OECD TG) and other relevant scientific data retrieved with systematic review methodology
   • Evaluation of information for its relevance and reliability
2. Assess the evidence
   • Assembling of information into lines of evidence, integrating information for both adversity and endocrine activity
3. Initial analysis of the evidence
   • Scenario-based analysis; scenarios are driven by the availability of EATS-mediated parameters and/or evidence of endocrine activity
4. MoA analysis
   • If ED properties have been observed in available studies, establish whether there is a biologically plausible link between observed adverse effects and endocrine activity
5. Conclusion on ED criteria
   • Draw conclusion as to whether the ED criteria are met with regard to humans and non-target organisms

Following a very thorough and systematic review of all relevant scientific information, eventually complemented by state-of-the-art structure activity (QSAR) analysis in Step 1, the critical analysis of the data, how they are linked together and whether the weight of evidence supports a mechanistical and biologically plausible link between endocrine activity and adversity of a chemical is conducted in Step 2-5.

The publication of the ED guidance document and its application throughout the different legislation will hopefully alleviate some public concerns around chemicals occurring in consumer products or in the environment and rationalise the discussion. There is a lot of work to be done now. It remains to be seen how high the authorities will finally set the hurdles for drawing the conclusion whether a substance is or is not an endocrine disruptor.