FEDERAL INSTITUTE FOR RISK ASSESSMENT ASSESSING ENDOCRINE DISRUPTING SUBSTANCES Handling of risk assessment under different regulations Andreas Hensel
How EDs may act - sexual hormones as an example Hypothalamus (Releasing factors) Hypophysis (Gonadotrophic hormons FSH, FSH, LH) Feed back mechanisms Gonads (Estrogenes gestagenes androgenes) androgenes) Phase I/I/-II enzymes ED Hormone biosynthesis Binding to transport proteins SHBG Excretion Hormone metabolism Target tissue ER α/β AR Receptor binding (Agonist/antagonist) Signal transduction Seite 2
What is an Endocrine Disruptor?...the world of known chemicals Endocrine active substances (EAS) effects on the endocrine system! Endocrine disruptors (EDs( EDs) effects on the endocrine system induce adverse health effects Seite 3
Definition of Endocrine Disruptors WHO/IPCS 2002 definition An Endocrine Disruptor is an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub) populations. in vitro or in vivo methods in vivo methods Definition of adversity (WHO/IPCS 2004) A change in morphology, physiology, growth, reproduction, development or lifespan of an organism which results in impairment of functional capacity or impairment of capacity to compensate for additional stress or increased susceptibility to the harmful effects of other environmental influences. Seite 4
One substance one toxicological assessment! Plant Plant Protection Protection Products Products 1107/2009) 1107/2009) Biocides (98/8/EC; 528/2012) Food Food additives additives 1333/2008) 1333/2008) REACH REACH 1907/2006) 1907/2006) Plastics Plastics with with food food contact contact (EU (EU 10/2011) 10/2011) Cosmetics Cosmetics 1223/2009) 1223/2009) Food Food and and others others Are Are data data requested requested under under the the regulation regulation sufficient sufficient for for identification? identification? ( ) What What are are the the principle(s) principle(s) ) of of regulation? regulation? Approval Approval procedure procedure Approval Approval (EU lists of approved (EU lists of approved additives: AII/III) additives: AII/III) depending depending on on production production volume volume Registration, Registration, Authorization Authorization ( ) depending depending on on migration migration from from material material ( ) depending depending on on intended intended use use Risk Risk assessment assessment + + Risk Risk assessment assessment authorization authorization + + addition addition to to lists lists of of prohibited prohibited (EU (EU list list of of substances substances (AII) (AII) authorized authorized substances) substances substances with with substances) restrictions restrictions (AIII) (AIII) allowed allowed substances substances (AIV, V, VI) (AIV, V, VI) usually no product specific toxicological data usually no product specific toxicological data from manufacturers for the authorities available from manufacturers for the authorities available Risk assessments Risk assessments General provisions General provisions Avoiding Avoiding disparities disparities in in the the assessment assessment of of toxicological toxicological properties properties es between between the the different different regulations regulations Predictability, Predictability, efficiency, efficiency, consistency consistency Seite 5
Identification of human health related ed properties (joint BfR-CRD proposal 2011) I. I. Evaluation Evaluation of of all all available available toxicological toxicological data data of of the the substance substance yes II. II. Adverse Adverse effects effects potentially potentially related related to to ED ED in in intact intact organisms organisms in in acceptable acceptable studies? studies? yes Does Does the the available available evidence evidence demonstrate that that ED ED mode mode of of action action in in animals animals is is plausible? plausible? yes III. III. Are Are the the effects effects judged judged to to be be relevant relevant to to humans? humans? yes PPP/biocides If no no no no Substance classified/has to be classified as CMR Cat 1A/1B (CLP)? Substance is not deemed an ED of very high regulatory concern: Proceed with standard risk assessment Are Are serious serious ED ED effects effects observed observed at at or or below below the the STOT-RE STOT-RE Cat Cat 1 guidance guidance values values of of the the CLP CLP Regs Regs *? * yes VI. VI. Substance Substance is is an an ED ED of of very very high high regulatory regulatory concern concern no * Only potent EDs can be considered of equivalent concern to CMR 1A or 1B substances, as required by REACH Art 57(f); Seite 6
Decision tree to assess human health related ED properties Regulatory )* Regulatoryconsequence(s consequence(s)* I. Data evaluation Existing Data & non-test information Physical & chemical properties available toxicological data (standardized or non-standardized tests) Read across, QSAR, other in silico predictions, ADME modelling II. Identification of EDCs Weight-of-evidence process Are the adverse toxicological effects potentially related to ED in intact organisms in acceptable in-vivo studies (e.g. OECD CF Level 4/5)? The available data provide convincing evidence or demonstrate an ED mode of action? Are the effects judged to be relevant to humans? III. Categorization/priorization Decision matrix guidance values STOT (Repeated Dose) Category 1 (CLP) severity of effect reversibility of effect others if applicable * Biocides Plant Protection Products Chemicals Cosmetic ingredients Food additives Plastic with food contact Food ED effect suspected (EU) No 528/2012 ) No 1107/2009 ) No 1907/2006 ) No 1223/2009 ) No 1333/2008 ) No 10/2011 ) No 178/2002 Request Requestfor forfurther furthertoxicity toxicitytesting testing No Noapproval approval no authorization no authorization no noplacing placingon onthe themarket market ED 1 Standard StandardRisk RiskAssessment Assessment e.g. e.g.regulation regulationaccording accordingtotothe themost most sensitive toxicological endpoint sensitive toxicological endpoint ED 2 Seite 7
ED classes with relevance to regulation* Decision matrix ED 1 ED 2 Guidance values for specific target organ toxicity after repeated exposure (STOT Repeated Dose Category 1, CLP) below STOT 1 values exceeded Severity of effect(s) severe significant effects Reversibility of effect(s) Other aspects (i)rreversible (if applicable) reversible (if applicable) * ED Categorization: implies direct regulatory consequence (e.g. no approval) * ED Priorization: implies no direct regulatory consequence (e.g. SVHC identification acc. Article 57f/REACH) * based on WHO/IPCS definition (2002) Seite 8
Substances in plastic materials with food contact* A. A. Migration < 0.05 0.05 mg/kg mg/kg of of food: food: Quantification Quantification of of migration migration Genotoxicity Genotoxicityassays: ** bacterial bacterial assay assay (Ames (Ames test) test) ** mammalian mammalian gene gene mutation mutation assay assay ** chromosome chromosome aberration aberration assay assay * EU No 10/2011 (Plastic materials and articles intended to come into contacts with food) EFSA (2008) Note for Guidance (Food Contact Materials) B. B. Migration 0.05 0.05 5 mg/kg mg/kg of of food: food: in in addition addition to to (A) (A) 90d 90d toxicity toxicity study study (oral) (oral) investigation investigation of of bioaccumulation bioaccumulation C. C. Migration 5-605 5-60 mg/kg mg/kg food: food: in in addition addition to to (B): (B): Toxicokinetics Toxicokineticsand and metabolism metabolism Chronic Chronic toxicity toxicity and and carcinogenicity carcinogenicity Developmental Developmental toxicity toxicity Reproductive Reproductive toxicity toxicity Problems: Substances with low migration (<( < 0.05 mg/kg): effects on the endocrine system are not addressed suitable in-vitro studies addressing endocrine effects (e.g. OECD Conceptual Framework Level 1/2) should be mandatory for substances also with low migration! substances with medium migration (<( < 5 mg/kg): only very limited information on endocrine effects might come from the data set substances with migration > 5 mg/kg: endocrine effects are not directly addressed but could be uncovered from the data set in most cases Seite 9
Substances in food Examples: isoflavones (e.g. genistein and daidzein), botanical extracts etc. Food supplements contain often high amounts of certain nutrients/compounds intake often not achievable via normal food items Usually a lot of toxicological data available for single ingredients But often only limited toxicological data available for single products (necessary for case-by-case decisions) Very limited safety evaluations in human studies So far no risk assessment concept or regulatory options for endocrine active substances in food supplements (Regulation ) No 178/2002, Article 14 Food must be safe ) Seite 10
Core messages 1. In the interest of predictability and efficiency, the purpose of this concept is to ensure a consistent high level of protection of human health under different regulations based on a scientific weighting of available data. 2. The decision tree combines a flexible scientific weight of evidence process and a conclusion based on a decision matrix including established toxicological guidance values (STOT RE Category 1 of CLP) which ensures comprehensive decisions assures predictability of legal decisions (e.g. in authorization procedures) 3. The concept was originally designed for substances where a complete set of toxicological data is available. Yet, it provides a common principle for the evaluation and authorisation of ED substances to ensure a harmonised approach e.g. for Biocides under Regulation ) No 528/2012 Plant Protection Products under Regulation ) No 1107/2009 Chemicals Cosmetic ingredients under Regulation ) No 1223/2009 Food additives under Regulation ) No 1333/2008 Plastic with food contact under Regulation ) No 10/2011 Food under Regulation ) No 178/2002 under Regulation ) No 1907/2006 (REACH) Seite 11
BUNDESINSTITUT FÜR RISIKOBEWERTUNG THANK YOU FOR YOUR ATTENTION Andreas Hensel Federal Institute for Risk Assessment Max-Dohrn-Straße 8-10 D-10589 Berlin Tel. +49 030 8412-0 Fax 0 30-84 12-47 41 bfr@bfr.bund.de www.leitung@bfr.bund.de