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OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters As a Basis for Regulation of Substances with Endocrine Disrupting Properties

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OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters As a Basis for Regulation of Substances with Endocrine Disrupting Properties OECDOECD ConceptualConceptual FrameworkFramework for forTesting Testing and and Assessment Assessment of Endocrineof EndocrineDisrupters Disruptersas a basis asfor aregulation basis of forsubstances regulation with of substances endocrine disrupting with endocrineproperties disrupting properties Ulla Hass, Majken Dalgaard, Kirsten Jarfelt and Thuri S.A. Kledal Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, Denmark TemaNord 2004:555 OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters as a basis for regulation of substances with endocrine disrupting properties TemaNord 2004:555 © Nordic Council of Ministers, Copenhagen 2004 ISBN 92-893-1073-1 ISSN 0908-6692 Nordic Council of Ministers Nordic Council Store Strandstræde 18 Store Strandstræde 18 DK-1255 Copenhagen K DK-1255 Copenhagen K Phone (+45) 3396 0200 Phone (+45) 3396 0400 Fax (+45) 3396 0202 Fax (+45) 3311 1870 www.norden.org Nordic Environmental Co-operation Environmental co-operation is aimed at contributing to the improvement of the environment and forestall problems in the Nordic countries as well as on the international scene. The co- operation is conducted by the Nordic Committee of Senior Officials for Environmental Affairs. The co-operation endeavours to advance joint aims for Action Plans and joint projects, exchange of information and assistance, e.g. to Eastern Europe, through the Nordic Environmental Finance Corporation (NEFCO). The Nordic Council of Ministers was established in 1971. It submits proposals on co-operation between the governments of the five Nordic countries to the Nordic Council, implements the Council's recommendations and reports on results, while directing the work carried out in the targeted areas. The Prime Ministers of the five Nordic countries assume overall responsibility for the co-operation measures, which are co-ordinated by the ministers for co-operation and the Nordic Co-operation committee. The composition of the Council of Ministers varies, depending on the nature of the issue to be treated. The Nordic Council was formed in 1952 to promote co-operation between the parliaments and governments of Denmark, Iceland, Norway and Sweden. Finland joined in 1955. At the sessions held by the Council, representatives from the Faroe Islands and Greenland form part of the Danish delegation, while Åland is represented on the Finnish delegation. The Council consists of 87 elected members - all of whom are members of parliament. The Nordic Council takes initiatives, acts in a consultative capacity and monitors co-operation measures. The Council operates via its institutions: the Plenary Assembly, the Presidium and standing committees. Contents Contents ............................................................................................................5 Preface...............................................................................................................7 List of abbreviations.........................................................................................9 Executive Summary........................................................................................11 Sammenfatning...............................................................................................17 1 Introduction..............................................................................................23 1.1 Background and definition ..........................................................................23 1.2 OECD for the Testing and Assessment of Endocrine Disrupting Chemicals.........................................................................................................23 1.3 EU Chemicals Policy .....................................................................................26 1.4 Globally Harmonised System of classification and labelling of chemicals (GHS).............................................................................................27 1.5 Aim of the project...........................................................................................27 2 Conceptual Framework – with specific focus on level 2-5 with regard to toxicity testing ....................................................................................29 2.1 Introduction .....................................................................................................29 2.2 Level 2, in vitro assays providing mechanistic data ............................30 2.2.1 Introduction......................................................................................................30 2.2.2 Discussion .......................................................................................................31 2.2.2 Conclusions at level 2....................................................................................35 2.3 Level 3, Short terms in vivo assays providing data about single endocrine mechanisms and effects..........................................................35 2.3.1 Uterotrophic assay .........................................................................................36 2.3.2 Hershberger assay.........................................................................................38 2.3.3 Non-receptor mediated hormone function..................................................40 2.3.4 Assays to detect chemicals with effects on the thyroid............................43 2.3.5 Conclusions at level 3....................................................................................44 2.4 Level 4, male and female pubertal assays, intact male assay, and enhanced OECD TG 407 (28-day toxicity study) providing in vivo data about multiple endocrine mechanisms and effects ....................44 5 2.4.1 Introduction......................................................................................................44 2.4.2 Description of tests.........................................................................................47 2.4.3 Endpoints.........................................................................................................48 2.4.4 Discussion .......................................................................................................51 2.4.5 Conclusions at level 4....................................................................................53 2.5 Level 5, in vivo assays providing adverse effect data from endocrine and other mechanisms.............................................................53 2.5.1 Introduction......................................................................................................53 2.5.2 Reproductive toxicity tests ............................................................................53 2.5.3 Endpoints.........................................................................................................57 2.5.4 Discussion .......................................................................................................61 2.5.5 Conclusions at level 5....................................................................................64 3 Specific chemicals and observed ED-effects........................................65 3.1 Comparison of LO(A)ELs in EDC assays ................................................71 3.2 Discussion and conclusions.......................................................................73 4 Discussion and conclusions ..................................................................75 4.1 Summary on the assays at level 2 to 5 and regulatory proposals ...75 4.2 Enhancement of existing OECD TG..........................................................80 4.3 Hazard classification for EDC effects and authorisation ....................81 5 References ...................................................................................................87 6 Appendix ......................................................................................................97 6 Preface There is a concern that exposure to endocrine disrupting chemicals (EDCs) may be harmful to humans and the environment. Therefore, it is important that EDCs will be covered properly by the chemicals legislation in force. The existing chemicals legislation is changing these years. A new EU chemicals legislation, Registration, Evaluation and Authorisation of Chemicals (REACH), is under way as well as a Globally Harmonised System of hazard classification and labelling of chemicals (GHS). The existing chemical legislation only covers some of the effects caused by endocrine disruption. In the proposal for the new REACH system, endocrine disrupters are covered by the authorisation procedure based on a case-by-case assessment, but no indication of criteria for the assessment is given. The OECD Task force on Endocrine Disrupter Testing and Assessment (EDTA) has agreed upon a revised Conceptual Framework (CF) for Testing and Assessment of potential endocrine disrupting substances in June 2002. Several toxicological and ecotoxicological screening tests for predicting endocrine disrupting properties of a chemical are now under development and international validation, but it will probably take several years before the full range of validated testing methods and criteria are developed. In the meantime there is a need for guidance on how to interpret test results from existing test methods and how to identify a substance as an endocrine disrupter. Regulatory instruments that can be used towards endocrine disrupters should also be considered in this interim period. Therefore, the Nordic
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