VCI Overview on “Endocrine Active Substances” Status: 21 August 2017 Introduction Endocrine active (hormone active) substances are given considerable attention by the scientific community, public authorities, industry, and non-governmental organizations. For more than two decades much effort has been put into research in this area, however without consensus regarding the relevance and existence of new hazards. In respect of regulation, there is a stronger focus on endocrine disrupting substances in the EU Regulatory Framework. For this purpose, criteria how to identify endocrine disruptors are needed. At present criteria and a guidance document are being developed and discussed. The German Chemical Industry is actively involved in the onging scientific and political debate about endocrine disruptors. The VCI overview on “endocrine active substances” provides a concise picture of the topic from the VCI’s perspective. The document starts off with basic concepts and definitions. Furthermore test methods and the current situation are explained as well as proposed criteria and guidance for regulation. The VCI overview on “endocrine active substances” was first published for wider audiences in 2002 and has been regularly updated ever since. This document serves as a scientific backbone to various short communications by VCI on specific issues. 21. August 2017 1 Content 1. Endocrine effects..................................................................................................... 5 1.1. What is the endocrine system? ......................................................................... 5 1.2. Definitions: difference between endocrine active substances and “endocrine disruptors” ................................................................................................................... 6 1.3. Basic principles of the evaluation of endocrine active substances and Weight of Evidence ................................................................................................................. 9 1.4. What hormone systems are discussed in relation to endocrine activity? ......... 11 2. Example: estrogenic activity .................................................................................. 12 2.1. What are estrogens? ....................................................................................... 12 2.2. What substances have estrogen-like activity? ................................................. 12 2.3. How potent are substances with estrogen-like activity? .................................. 13 3. Endocrine effects – human aspects ...................................................................... 14 3.1. What is the main concern for human health? .................................................. 14 3.2. What is the current estimate of the possible risk to humans from endocrine active substances? ................................................................................................... 20 3.3. What information about hormone-like acting substances can be derived from studies examining classical toxicological endpoints ? ............................................... 21 3.4. (Screening) methods to detect endocrine effects ............................................ 23 3.5 Early concept for assessment: Hygiene-based margin of safety (HBMOS) evaluation model from a VCI/UBA joint research project .......................................... 28 4. Endocrine effects – environmental aspects ........................................................... 29 4.1. Endocrine systems in animals ......................................................................... 29 4.2. Adverse effects observed in the environment ................................................. 30 4.3. The aquatic environment ................................................................................. 32 4.3.1. Central-European rivers – a well-documented “case” ............................... 32 4.3.2. The sex ratio of freshwater fish – VCI-funded field biology research project 33 4.3.3. Evaluation of findings from field studies .................................................... 35 4.3.4. Informative significance of the biomarker vitellogenin ............................... 36 4.3.5. Informative significance of the Gonadosomatic Index (GSI), gonad histology, and sex ratio .......................................................................................... 37 4.4. Informative significance of experimental laboratory studies ............................ 39 4.5. Test strategy for detecting endocrine effects ................................................... 40 5. Specific discussions on the subject of endocrine activity ...................................... 45 21. August 2017 2 5.1. Combination effects ......................................................................................... 45 5.2. Do endocrine active substances have adverse effects at low doses and is it possible to determine thresholds and limit values for hormone active substances? . 48 5.2.1. Existence of thresholds of adversity in the context of the REACH Authorisation: ........................................................................................................ 50 5.2.2. History of the “low dose debate”: .............................................................. 51 5.2.3. Further discussion-points: ......................................................................... 52 5.3. Non Monotonic Dose response Relationship (NMDRC) .................................. 57 5.4. Potency of industrial chemicals in comparison with naturally occurring substances ................................................................................................................ 58 5.4.1. Possible implications of the criteria-options proposed by the Commission for natural substances – a case study ................................................................... 60 5.5. Validity and quality of scientific studies and Weight of Evidence Approach .... 60 6. Endocrine effects – regulatory significance ........................................................... 62 6.1. Definitions, risk assessment ............................................................................ 62 6.2. Is a separate hazard category required? ......................................................... 64 6.3. The political context: EU Community Strategy on endocrine disruptors and current developments at EU-level ............................................................................. 65 6.3.1. Community Strategy for Endocrine Disruptors and its revisions ............... 65 6.3.2. European Parliament Initiative Report on ED ........................................... 65 6.3.4. EFSA Opinion on ED ................................................................................ 66 6.3.5. JRC Report ............................................................................................... 67 6.3.6. ROADMAP Defining criteria for identifying Endocrine Disruptors in the context of the implementation of the Plant Protection Product Regulation and Biocidal Products Regulation ................................................................................ 67 6.3.7. Impact Assessment .................................................................................. 67 6.4. Draft proposal for criteria to identify endocrine disruptors and guidance document .................................................................................................................. 69 6.5. ECETOC Seven Steps for the Identification of Endocrine Disrupting Properties (Technical Report 130) ............................................................................................. 70 6.6. Background information - starting points for the development of criteria ......... 71 6.6.1. German contributions ............................................................................... 71 6.6.2. Cefic/Industry Proposal for criteria for identification of endocrine disruptors 72 6.7. Endocrine disrupters in different European regulations ................................... 72 21. August 2017 3 6.7.1. Plant Protection Products Regulation 1107/2009 ..................................... 73 6.7.2. Biocides Product Regulation (BPR) .......................................................... 74 6.7.3. Regulation on Cosmetic Products (1223/2009) ........................................ 74 6.7.4. Water Framework Directive (2000/60/EC) ................................................ 75 6.7.5. Endocrine disrupters in the authorisation procedure of the REACH Regulation (EC) No 1907/2006 ............................................................................. 75 7. Excecutive summary of the VCI overview ............................................................. 78 References ................................................................................................................... 79 Appendices ................................................................................................................. 104 21. August 2017 4 1. Endocrine effects 1.1. What is the endocrine system? Alongside the nervous system, the endocrine system is the “management system” of multicellular organisms, responsible for the coordination and integration of the functions of various organs and tissues. The endocrine system permits flexible adaptation of the organism (e.g. to prevailing external influences) and makes use of the circulation to bridge larger distances within the body. Hormones are the chemical messengers