EN    EN 
 
 
 EUROPEAN  
COMMISSION   
Brussels, XXX   
C(2016) 3752 projet  
ANNEX 1  
  
DRAFT  
ANNEX  
to the  
COMMISSION DELEGATED REGULATION (EU) …/...  
setting out scientific criteria for the determination of endocrine -disrupting properties 
pursuant to Regulation (EU) No 528/2012  
  EN 2   EN ANNEX  
An active substance  shall be considered  as having endocrine disrupting properties  with 
respect to  humans or non -target organisms,  where it meets the criteria set out in section A or 
section B.  
Section A - Endocrine disrupting properties with respe ct to humans  
1. An active substance shall be  identified as having  endocrine disrupt ing properties with 
respect to humans  if it is a substance that meets  all of  the following criteria:  
(1) it is known to cause an adverse effect relevant for human health, wh ich 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 stre ss, or an increase in susceptibility to other 
influences;  
(2) it has an endocrine mode of action;  
(3) the adverse effect relevant for human health is a consequence of the endocrine 
mode of action . 
2. The identification of an active substance as having  endocrine disrupt ing properties in  
accord ance with point 1 shall be based on all of the following : 
(1) all available relevant scientific evidence : 
(a) primarily performed according to international ly agreed study protocols 
(in vivo studies or adequately vali dated alternative test systems predictive 
of adverse effects in humans or animals; as well as in vivo, in vitro and 
mechanistic studies informing about endocrine modes of action) and on 
Guidance on the implementation of Regulation (EU) No 528/2012, 
issued by the European Chemicals Agency . 
(b) apply ing a systematic review methodology to analyse other relevant 
scientific information . 
(2) a compar ison of the weight of the scientific evidence on endocrine mediated 
adverse effects with the criteria set out in po int 1 , considering whether or not 
the effect s are adverse , the mode of action, together with the biological 
plausibility of the causal link between the adverse effect and the endocrine 
mode of action.  
(3) In applying the weight  of evidence determination  referred in point 2 , using 
expert judgement and internation ally agreed guidelines, all of the following 
elements shall be considered:  
(a) the assessment of quality, reliability, reproducibility  and consistency of 
the scientific evidence shall, in particular , consider  all of the following 
factors:  
(i) Both positive and negative results shall be considered together in a 
single weight of evidence determination . 
(ii) The weight of evidence should consider the relevance of the study 
designs for the assessment of adverse  effects and for the evaluation 
of mechanistic information. For the assessment of adverse effects, 
generally adequate reliable and representative data on humans shall EN 3   EN have precedence over other data; but positive results from well -
conducted animal s tudies are not necessarily negated by the lack of 
positive human experience.  
(iii) The biological plausibility of the link between the adverse effects 
and the endocrine mode of action . 
(iv) The quality and consistency of the data shall be given appropriate  
weight, considering the pattern and coherence of the results within 
and between studies of a similar design and across different 
species . 
(v) The route of exposure, toxicokinetic and metabolism studies are 
assumed to be relevant to humans, unless convinci ng evidence 
exists to explain the differences between test animals and humans . 
(vi) The concept of the limit dose, and international guidelines on 
maximum recommended doses and for assessing confounding 
effects of excessive toxicity . 
(b) adverse effects or  endocrine modes of action that are non -specific 
secondary consequences of other toxic effects shall not be considered for 
the identification of the substance as endocrine disruptor . 
(c) where there is information demonstrating that the adverse effects are  
clearly not relevant for humans the substance should not be considered a 
human endocrine disruptor .  
Section B - Endocrine disrupt ing properties with respect to non -target organisms  
1. An active substance shall be  identified as having endocrine disrupting  properties with 
respect to non -target organisms if it is a substance that meets all of following criteria:  
(1) it is known to cause  an adverse effect for non -target organisms, which is a 
change in the morphology, physiology, growth, development, reproduct ion, 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, considered relevant  at the population level;  
(2) it has an endocrine mode of action;  
(3) the adverse effect relevant for the non -target organism at the population level is 
a consequence of the endocrine mode of action . 
2. The identification of  an active substance as having  endocrine disrupting properties in 
accordance with point 1 shall be based on all of the following : 
(1) all available relevant scientific evidence :  
(a) primarily performed according to international ly agreed study protocols 
(in vivo studies or adequately validated alternative test systems predictive 
of adverse effects in humans or animals; as well as in vivo, in vitro and 
mechanistic studies informing about endocrine modes of action) and on 
Guidance on the implementation of Regulation (EU) No 528/2012, 
issued by the European Chemicals Agency ; 
(b) apply ing a systematic review methodology  to analyse other relevant 
scientific information . EN 4   EN (2) a compar ison of the weight of the scientific evidence on endocrine mediated 
adverse effects with the criteria set out i n point 1 , considering whether or not 
the effect s are adverse , the mode of action, together with the biological 
plausibility of the causal link between the adverse effect and the endocrine 
mode of action.  
(3) in applying the weight of evidence determinati on referred in point 2 (2), using 
expert judgement and internationally agreed guidelines, all of the following 
elements shall be considered:  
(a) the assessment of quality, reliability, reproducibility  and consistency of 
the scientific evidence shall conside r all of the following factors:  
(i) both positive and negative results shall be considered together in a 
single weight of evidence determination, discriminating between 
taxonomic groups (e.g. mammals, birds, fish)  where relevant . 
(ii) the weight of evidenc e should consider the relevance of the study 
designs for the relevance of the adverse  effects at the population 
level and for the evaluation of mechanistic information. Generally , 
evidence from field studies shall have precedence over other data . 
Neverthel ess positive results from well -conducted laboratory 
studies shall be considered even in the case lack of positive results 
in field studies.  
(iii) the adverse consequences on reproduction and 
growth/development, as these are the effects most likely to impa ct 
on population s. Adequate, reliable and representative higher tier 
experimental studies and/or results from reliable population models 
shall be considered wh ere available for assessing the relevance of 
the adverse effect at the population level.  
(iv) the biological plausibility of the link between the adverse effects 
and the endocrine mode of action, and its relevance for populat ions 
of non -target organisms.   
(v) the quality and consistency of the data shall be given appropriate 
weight, considering the pa ttern and coherence of the results at 
different doses or exposure levels within and between studies of a 
similar design and across different taxonomic groups . 
(vi) the concept of the limit dose and international guidelines on 
maximum recommended doses and for assessing confounding 
effects of excessive toxicity . 
(b) adverse effects or endocrine modes of action that are non -specific 
secondary consequences of other toxic effects shall not be considered for 
the identification of the substance as endocrine disru ptor with respect to 
non-target organisms . 
(c) where there is information demonstrating that the adverse effects are 
clearly not relevant at the population level for non -target organisms, the 
substance  should not be considered a endocrine disruptor  with r espect to 
non-target organisms .