Report to the Department for Environment, Food and Rural Affairs

Review of the Scientific Basis for Dealing with Endocrine Disrupting Chemicals within the EC Reach Regulations

Report to the Department for Environment, Food and Rural Affairs

REVIEW OF THE SCIENTIFIC BASIS FOR DEALING WITH ENDOCRINE DISRUPTING CHEMICALS WITHIN THE EC REACH REGULATIONS

Report to the Department for Environment, Food and Rural Affairs

Any enquiries relating to this report should be referred to the Contract Manager at the following address:

WRc plc, Frankland Road, Blagrove, Swindon, Wiltshire, SN5 8YF
Telephone: + 44 (0) 1793 865000 Fax: + 44 (0) 1793 865001

This report has the following distribution:

External: Clients

Internal: Authors

Report No:

Date: December 2005

Authors: I Johnson

Contract Manager: I Johnson

Contract No: 14130-0

DEFRA Reference No: CPEC 39

Contract Duration: January – December 2005

.

Page

CONTENTS Page

LIST OF TABLES ii

LIST OF FIGURES ii

executive SUMMARY 3

1. introduction 11

2. How do the current REACH Regulations plan to deal with chemicals with endocrine disrupting properties? 15

2.1 Current proposals for dealing with chemicals with endocrine disrupting properties within the REACH Regulations 15

2.2 Collation and interpretation of data on chemicals with endocrine disrupting properties under REACH 22

3. What is the current state of knowledge on endocrine disruption? 23

3.1 Approach 23

3.2 Information sources 24

3.3 Conclusions 25

3.4 Key conclusions on current knowledge of the endocrine disrupting properties of chemicals which relates to their control under REACH 31

4. Are any modifications needed to the procedure for dealing with chemicals with chemicals with endocrine disrupting properties based on the current state of knowledge of endocrine disrupters? 35

4.1 Registration stage of the REACH Regulation 35

4.2 Authorisation stage of the REACH Regulation 40

5. Recommendations 55

REFERENCES 57

APPENDICES 61

A – BACKGROUND ON REACH 61

B – EVALUATION OF ISSUES ASSOCIATED WITH THE EFFECTIVE MANAGEMENT OF ENDOCRINE DISRUPTING CHEMICALS UNDER THE REACH SYSTEM 77

C – PRIORITISATION PROCEDURE PROPOSED BY THE UNITED KINGDOM ADVISORY COMMITTEE FOR HAZARDOUS SUBSTANCES (ACHS) FOR SUBSTANCES OF AN EQUIVALENT LEVEL OF CONCERN 131

LIST OF TABLES

Table 1.1 Scope of the Defra funded study on the review of the scientific basis for dealing with chemicals with endocrine disrupting properties under REACH 12

Table 2.1 Criteria for the identification of persistent, bioaccumulative and toxic (PBT) substances and very persistent and very bioaccumulative (vPvB) substances 20

Table 3.1 Issues to be addressed as identified by Defra 23

Table 3.2 Web sites accessed and the type of information obtained 25

Table 3.3 Issues to be addressed as identified by Defra 26

Table 4.1 Potential issues associated with the inclusion of data on chemicals with endocrine disrupting properties in the derivation of DNELs and PNECs 38

Table 4.2 The type of substances which will not be captured for authorisation by the existing CMR criteria 46

Table 4.3 Categories proposed for endocrine disrupting chemicals in WWF (2002) 48

Table 4.4 Scope of the assessment that should be required at the authorisation stage of REACH 52

LIST OF FIGURES

Figure 2.1 Proposed procedure for substance identification and establishment of Annex XIII of the REACH Regulation 17

Figure 4.1 Outline approach to the identification of substances with endocrine disrupting properties which should be considered for authorisation 51

ii

executive Summary

Background

The European Commission has long recognised that the use of chemicals by Member States to facilitate a robust economy has to be balanced by effective assessment and control mechanisms to ensure risks to humans and wildlife are minimised. This is evident from the range of Directives and Regulations that have been implemented to provide the current European Union (EU) legislative framework for chemical substances. However, it has now also been recognised that this system has not provided sufficient information on the effects on human health and wildlife of the majority of the universe of chemicals. As a result the identification and assessment of the risks to humans and wildlife has been hampered as has the introduction of appropriate risk management systems.

In October 2003 the European Commission published proposals for a Regulation of the European Parliament and of the Council concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency and amending Directive 1999/45/EC and Regulation (EC) {on Persistent Organic Pollutants}.

Subsequently the Council of Ministers and the European Parliament have been debating the exact details of the Regulations with a view to having the finalised form ready for the beginning of 2007. The objective of the current activity is to achieve a compromise in the nature of the Regulation that better promotes the health of humans and the environment as well as competitiveness and innovation. A review of the REACH process proposed in the Regulation is given in Appendix A along with recent modifications that are relevant to the assessment of the endocrine disrupting properties of chemicals.

As part of this activity the Department for Environment, Food and Rural Affairs (Defra) has identified a requirement to review the current scientific basis for dealing with chemicals with endocrine disrupting properties under the REACH Regulation. This report has been prepared as part of a Defra funded project to consider how the potential risks posed to humans (consumers and workers) and wildlife by chemicals with endocrine disrupting properties can be evaluated in a pragmatic and scientifically robust manner within REACH. The work will make appropriate recommendations for the most effective management of chemicals with endocrine disrupting properties under the system including what test systems and resulting data need to be applied at specific stages of the process.

Objectives of the study

The objective of the work as stated in the tender specification is “to review the current scientific framework for the regulation of endocrine disrupting chemicals (EDCs) and make appropriate recommendations for their more effective management under REACH”.

Approach

This report constitutes Report 1 of the project and will make appropriate recommendations for the most effective management of endocrine disrupting chemicals under the REACH system. A separate report (Report 2 of the project) has reviewed the proposed inclusion of methodologies for assessing the endocrine disrupting properties of chemicals within the overall testing strategies for different endpoints.

The approach adopted in this report has involved:

1. Reviewing the mechanisms by which the REACH Regulation proposes to consider chemicals with endocrine disrupting properties within the wider human health and environmental assessments.
2. Reviewing the current status of knowledge on endocrine disruption (see Appendix B) by considering a number of issues, which have been agreed with Defra, relating to:

·  Interpretation of data on endocrine disruption in humans and wildlife.

·  Development of appropriate test methods for assessing endocrine disruption in humans and wildlife.

·  Development of a conceptual framework for addressing chemicals with endocrine disrupting properties under REACH.

1. Considering whether any modifications to the proposed procedure for dealing with chemicals with endocrine disrupting properties are needed based on the current state of knowledge of endocrine disrupters?

Key conclusions on current knowledge of the endocrine disrupting properties of chemicals which relates to their control under REACH

The following conclusions are deemed to be particularly relevant to the control of chemicals with endocrine disrupting chemicals under REACH:

1. In humans potential endocrine-mediated effects have been associated with increased incidences of cancers in males and females, alterations in the normal patterns of development and reproduction, but also with changes in behaviour during development and adulthood and modifications of the function of the immune system. In the environment exposure to chemicals considered to be endocrine disrupters has been associated with adverse effects on the development and/or reproduction of a wide range of wildlife groups, including molluscs, crustaceans, fish, amphibians, reptiles, birds and mammals. Clearly, endocrine mediated changes in individuals of a given wildlife species have the greatest significance where they can be translated into population level effects. As a result a broad range of information for different endpoints is needed to adequately assess the implications of endocrine disrupting properties of chemicals. For example effects on behavioural, neurological, and immunological endpoints need to be considered in addition to those for carcinogenicity, mutagenicity, reproduction and development.
2. Despite the wide range of adverse endocrine mediated effects that have been observed in humans and wildlife there are a number of common characteristics, including that:

·  The effects exerted by a chemical may be lifestage specific such that effects observed in early life stages (embryos, larvae, foetuses, and new-borns) differ from those in adult organisms.

·  In many cases, the effects may not (or not only) be seen in the parent generation exposed to them, but rather in its progeny.

·  There are particular ‘critical’ periods when organisms are sensitive to these chemicals and outside these windows of sensitivity, the chemicals may have no effect on the developing organisms.

·  Any adverse effects may be delayed and though the organism is exposed in very early life stages, adverse effects may not become visible until adulthood.

These characteristics mean that traditional endpoints do not readily apply to substances with, for example, reversible and trans-generational effects caused by exposure during a critical time window of sensitivity and resulting through various mechanisms in outcomes which may be multi-dimensional and subtle and not detected using traditional (eco)toxicological methods.

1. It needs to be recognised that, at present, a wide range of international regulatory bodies have expressed the view that endocrine disruption should not be considered as an endpoint per se but rather as a mechanism of action that can result in adverse health effects.
2. In any risk assessment it is important to define whether the critical toxic mechanism for a particular substance is endocrine-mediated. Indeed CSTEE (2000) have stated that “Only in situations where the endocrine-disrupting effects are critical (i.e., the most potent) in comparison to other toxic hazards, should the endocrine disruption be considered for hazard and risk assessments. Little importance should be assigned to situations where the no-observed effect level for endocrine disruption is substantially higher than that for other adverse effects caused by a chemical.”
3. At present there is considerable debate regarding the type and magnitude of changes observed in humans and wildlife that constitute adverse endocrine-mediated effects. Whilst it would be desirable to define guidelines for such effects in terms of the hazard and risk assessment process, the reality is that this will require discussions between relevant regulatory bodies and stakeholders for each chemical of concern.
4. In recent years there has been considerable debate in the scientific community with regard to the evidence on low-dose effects and non-monotonic dose-response relationships (U shaped or inverted U shaped) for endocrine disrupting chemicals in non-mammalian and/or mammalian species. Research into low-dose effects is continuing but since this issue remains contentious it is essential that any data generated from, for example tests carried out using wider dose or concentration ranges, is robust and reproducible. If further evidence of adverse in vivo effects of endocrine disrupting chemicals at low doses becomes evident there will be a greater requirement for the development of appropriate models that can derive appropriate ‘safe’ levels for the assessment of the risks posed to target groups of humans and/or wildlife species.
5. Current regulatory risk assessments focus on individual substances, though in most exposure situations, target groups of humans and wildlife are exposed to several substances (mixtures) simultaneously. Therefore, one of the prominent requirements in elucidating the effects of environmental chemicals on endocrine functions is to attempt to understand the effects resulting from exposure to several contaminants simultaneously. This is particularly important given that the overall effect of the mixture may not be easily inferred on the basis of information on the effects of individual substances. The REACH Regulation states that for preparations additivity of effects should be assumed in the absence of other data. This approach is consistent with recent data generated in the European Commission funded Analysing Combination Effects of Mixtures of Estrogenic Chemicals in Marine and Freshwater Organisms (ACE) project[1] on vitellogenin induction in freshwater fish following exposure to mixtures of oestrogenic substances. Clearly it would never be realistic to test the potential effects of all possible combinations of chemicals with endocrine disrupting properties to which target groups of humans and/or wildlife could be exposed. Instead, it is necessary develop robust predictive models that allow the effects of interactions of mixtures of chemicals with endocrine disrupting properties with similar or different mechanisms of action to be evaluated. Available data suggests that the concentration-addition model adequately describes the effects of mixtures of endocrine disrupting chemicals with similar modes of action.

These issues have also been highlighted in the recent Prague Declaration on Endocrine Disruption, which was prepared as an output from an international workshop in Prague (Czech Republic) on 10-12 May 2005. The Prague Declaration (www.edenreserach.info) details research updates for human health and wildlife, highlights shortcomings of current regulatory frameworks dealing with chemicals and proposes actions to be taken to improve the situation.

Conclusions on modification to the procedure for dealing with chemicals with endocrine disrupting properties based on the current state of knowledge of endocrine disrupters

The following key conclusions have been drawn in the project:

1.  For the vast majority of substances that will be subject to registration and, possibly authorisation, information will not be available from the new or modified OECD test methods designed to assess endocrine disruption. Therefore, a weight of evidence approach using expert judgement will be needed in which all the available data is evaluated for evidence of endocrine disruption and decisions are made regarding the need for further testing. This approach clearly would be aided by the development of objective criteria to indicate whether a substance causes endocrine mediated effects in humans and/or wildlife.

2.  Certain issues associated with the nature of endocrine-mediated health effects and wildlife mean that modifications to the traditional hazard and risk assessment approaches are likely to be needed.

3.  In considering the modified terminology used in Article 54f (and any implicit criteria) it should be recognised that chemicals with endocrine disrupting properties can result in effects on endpoints other than carcinogenicity, mutagenicity and reproductive toxicity (CMR) for humans and growth inhibition and developmental or reproductive toxicity (as T of PBT) in wildlife species. These effects could, for example, be manifest through behavioural, immunological or neurological changes.