EN    EN 
 
 
 EUROPEAN  
COMMISSION   
Brussels, XXX   
C(2016) 3751 projet  
ANNEX 1  
  
DRAFT  
ANNEX  
to the  
COMMISSION REGULATION (EU) .../...  
setting out scientific criteria for the determination of endocrine disrupting properties 
and amending Annex II to Regulation (EC) 1107/2009   EN 2   EN ANNEX  
 
Annex II to Regulation (EC) No 1107/2009 is amended as follows:  
(1) Point 3.6.5. is replaced by the following:  
"3.6.5 . Endocrine disrupting properties  
3.6.5.1. An active substance, safener or synergist shall only be approved if, on the basis of the 
assessment of Community  or internationally agreed test guidelines or other available data and 
informati on, including a review of the  scientific literature, reviewed by the Authority, it is not 
considered to have endocrine disrupting properties  that may cause adverse effect in humans, 
unless the exposure of humans to that active substance, safener or  synergi st in a plant 
protection product, under realistic proposed conditions of use, is negligible, that is, the  
product is used in closed systems or in other conditions excluding contact with humans and 
where residues of  the active substance, safener or synergis t concerned on food and feed do not 
exceed the default value set in  accordance with point (b) of Article 18(1) of Regulation (EC) 
No 396/2005.   
By 14 December 2013, the Commission shall present to the Standing Committee on the Food 
Chain and Animal  Health a draft of the measures concerning specific scientific criteria for the 
determination of endocrine disrupting  properties to be adopted in accordance with the 
regulatory procedure with scrutiny referred to in Article 79(4).   
Pending the adoption of these cr iteria, substances that are or have to be classified, in 
accordance with the  provisions of Regulation (EC) No 1272 /2008, as carcinogenic category  2 
and toxic for reproduction category  2, shall be considered to have endocrine disrupting 
properties.   
In addition, substances such as those that are or have to be classified, in accordance with the 
provisions of  Regulation (EC) No 1272/2008, as toxic for reproduction category 2 and which 
have toxic effects on the  endocrine organs, may be considered to have su ch endocrine 
disrupting properties.   
3.6.5.2. From [date of EIF] , the following shall apply instead of the first, the third and the 
fourth paragraph of point 3.6.5.1.  
1. An active substance, safener or synergist shall only be approved if, on the basis of t he 
assessment of the available evidence carried out in accordance with the data requirements for 
the active substances, safeners or synergists and other available data and information, it is not 
identified as having endocrine disrupting properties with res pect to humans according to the 
criteria specified in point 3.6.5.2 , unless the risk to humans from exposure to that active 
substance, safener or synergist in a plant protection product, under realistic worst case 
proposed conditions of use, is negligible,  in particular where the product is used in closed 
systems or in other conditions which aim at excluding contact with humans, and where 
maximum residue levels of the active substance, safener or synergist concerned in or on food 
and feed can, taking accoun t of the latest opinion of the Authority with respect to that active 
substance, synergist, safener, be set in accordance with Regulation (EC) No 396/2005, which 
ensure a high level of consumer protection.  
2. An active substance, safener or synergist shall be considered  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, which is a 
change in the morphology, physiology, growth, development, reproduction, or, EN 3   EN 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;  
(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 . 
3. The identificat ion of an active substance, safener or synergist as having endocrine 
disrupt ing properties in  accord ance with point 1 shall be based on all of the following : 
(1) all availab le relevant scientific evidence,  
(a) primarily performed according to international ly agree d 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) , in 
particular, on those  internationally agreed study protocols listed in the 
Commission Communications in the framework of setting out the data 
requirements for active substances and plant protection products, in 
accordance with Regulation (EC) No 1107/2009 , 
(b) apply ing a systematic review methodology, in particular following 
guidance listed in the Commission Communications in the framework of 
setting out the data requirements for active substances and plant 
protection products, in accordance with Regulation (EC) No 1107 /2009, 
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 point 1 , considering whether or not 
the effect s are adverse , the mode of actio n, 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, using expert judgement and 
internationally agreed guidelines, the following elem ents 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, 
genera lly adequate reliable and representative data on humans shall 
have precedence over other data; but positive results from well -
conducted animal studies 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 . EN 4   EN 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 a cross different 
species . 
v. The route of exposure, toxicokinetic and metabolism studies are 
assumed to be relevant to humans, unless convincing evidence 
exists to explain the differences between test animals and humans . 
vi. The concept of the limit dose, a nd 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 f or 
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 ." 
(2) Point 3.8.2 . is replac ed by  the following :  
"3.8.2 .  Endocrine disrupting properties  
1. As of [Date of EIF] , an active substance, safener or synergist shall be  identified as 
having endocrine disrupt ing properties  with respect to non -target organisms if it is a 
substance that meets all of the 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, reproduction, or, 
life span of an organism, system, or (su b)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 mo de 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 , safener or synergist 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) , in 
particular, on those internationally agreed stu dy protocols listed in the 
Commission Communications in the framework of setting out the data 
requirements for active substances and plant protection products, in 
accordance with Regulation (EC) No 1107/2009 , 
(b) apply ing a systematic review methodology, in pa rticular following 
guidance listed in the Commission Communications in the framework of EN 5   EN setting out the data requirements for active substances and plant 
protection products, in accordance with Regulation (EC) No 1107/2009, 
to analyse other relevant scient ific information . 
(2) a compar ison of the weight of the scientific evidence on endocrine mediated 
adverse effects with the criteria set out in point 1 , considering whether or not 
the effect s are adverse , the mode of action, together with the biological 
plausib ility 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 internationally agreed guidelines, all of the following 
elements shall b e considered:  
(a) The assessment of quality, reliability, reproducibility  and consistency of 
the scientific evidence shall consider 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 evidence should consider the relevance of the study 
designs, for relevance of  the adverse  effects at the population level, 
and for the eval uation of mechanistic information. Generally, 
evidence from field studies shall have precedence over other data . 
Nevertheless positive results from well -conducted laboratory 
studies shall be considered even in the case of lack of positive 
results in field studies.  
iii. The adverse consequences on reproduction and 
growth/development, as these are the effects most likely to impact 
on population s. Adequate, reliable and representative higher tier 
experimental studies and/or results from reliable population mo dels 
shall be considered whe re 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 pattern and coherence of the results within 
and between studies of a similar design and across different 
taxonomic groups . 
vi. The concep t 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 shal l not be considered for 
the identification of the substance as endocrine disruptor  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 organ isms, the EN 6   EN substance should not be considered a endocrine disruptor  with respect to 
non-target organisms . 
3. An active substance, safener or synergist shall only be approved if it is not 
identified as having  endocrine  disrupting properties according to the criteria 
specified above, unless the risk from exposure of the non -target organisms to that 
active substance, safener or synergist in a plant protection product, under realistic 
worst case proposed conditions of use, is negligible."