Ref. Ares(2015)1661894 - 20/04/2015

EUROPEAN COMMISSION
DIRECTORATE-GENERAL FOR HEALTH AND FOOD SAFETY

Acting Director General

Brussels,
SANTE/E3/LF/np

Subject: Request for information

In your letter dated 16 March 2015 you ask me to send you a copy of a "non-published
EU report" on endocrine disrupters, which was referred to in an article in the journal The
Guardian.
We have no clear indication what "non-published EU report" the newspaper article refers
to. To date, the Commission (as College) has not adopted any paper in this respect. We
can only assume that the newspaper article refers to drafts prepared by individual
Commission departments for internal discussions.
DG SANTE is only aware of one such draft which is available on CIRCABC
('https://circabc.europa.eu/sd/a/7c338c57-2b2a-4324-a8c0Ь71:074Ь51а54/02 Revised%20version%20of%20elements%20for%20criteria(O).pdf)
and which is also attached as an annex to this letter for 7
'

For the Director General absent,
Martin SfcYCHELL
.. -.:yy Director General

Commission européenne/Europese Commissie, 1049 Bruxelles/Brussel, BELGIQUE/BELGIË - Tel. +32 22991111
Office: Fl 01-04/52 - Tel. direct line +32 229-56713 - Fax +32 229-91856

Ref. Ares(2015)1661894 - 20/04/2015

EUROPEAN COMMISSION
DIRECTORATE-GENERAL
ENVIRONMENT
Directorate D - Water, Marine Environment & Chemicals
ENV.D.3 – Chemicals, Biocides and Nanomaterials

Brussels, 19 February 2013
ED-AD-HOC-6/2013/02

THE COMMUNITY STRATEGY FOR ENDOCRINE DISRUPTORS
6TH AD HOC MEETING OF
COMMISSION SERVICES, EU AGENCIES AND MEMBER STATES

Centre de Conférence A. Borschette, room 1A, rue Froissart 36, Brussels
20 February 2013 (09:30 – 17:30)
Concerns:

Brainstorming and discussion on the criteria for Endocrine
Disruptors

Agenda Point:

5

Action Requested:

A paper setting out possible elements for the definition,
identification and categorisation of endocrine disruptors was
developed by DG ENV at the end of 2012 and presented to the 4 th
meeting of the expert advisory group and to the 5th ad hoc meeting
of Commission Services, EU agencies and member states (meeting
document ED-AD-HOC-5/2012/04). The members of both groups
were asked to provide written comments by 7 January 2013.
A draft final report of ED expert advisory group on criteria for
EDs was discussed at their meeting on 4-5 February 2013.
This document contains a revised version of possible elements for
criteria for identification of endocrine disruptors based on the
comments received and the draft report of ED expert advisory
group.
During the ad-hoc meeting the revised version of possible elements
for ED criteria as currently considered by DG ENV will be
presented and the ad-hoc group may wish to provide comments.
The participants to the meeting are invited to:
- take note of this document and provide comments

Revised version of possible elements for criteria for identification of
endocrine disruptors (clean version)

1. 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. (WHO/IPCS)

2. Categories of Endocrine Disruptors
For the purpose of categorisation for endocrine disruption, substances are allocated to one of two
categories based on strength of evidence and additional considerations in weight of evidence.
Categories for endocrine disruptors


Category 1: Endocrine disruptors



Category 2: Suspected endocrine disruptors

3. Criteria for Placing Substances in Categories
Category 1 –Endocrine disruptors
Substances are placed in category 1 when they are known to have caused endocrine mediated
adverse effects in humans or population relevant effects on animal species living in the environment
or when there is evidence from experimental studies, possibly supplemented with other information
(e.g. in vitro, in silico, read across), to provide a strong presumption that the substance has the
capacity to cause endocrine mediated adverse effects in humans or population relevant effects on
animal species living in the environment.
The experimental studies shall provide clear evidence of endocrine-mediated adverse effects in the
absence of other toxic effects, or if occurring together with other toxic effects, the endocrinemediated adverse effects should be considered not to be a secondary non-specific consequence of
other toxic effects.
However, when there is (e.g. mechanistic) information demonstrating that the effects are clearly not
relevant for humans and population of animal species living in the environment, category 2 may be
more appropriate.
Substances can be allocated to the category 1 based on:


Evidence from humans or from animal species living in the environment where it is plausible
that the observed adverse effect is endocrine-mediated, or



Experimental studies where it is plausible that the observed adverse effects are caused by an
endocrine mode of action, or

2



Experimental animal studies showing an endocrine activity in vivo which is clearly linked to
adverse effects in vivo (e.g. through read-across).

Category 2 – Suspected endocrine disruptors
Substances are placed in category 2 when there is some evidence for endocrine mediated adverse
effects from humans, animal species living in the environment or experimental animals, and where
the evidence is not sufficiently strong to place the substance in category 1. If, for example, limitations
in the study (or studies) make the quality of evidence less convincing, category 2 could be more
appropriate.
These endocrine disrupting effects should be observed in the absence of other toxic effects, or if
occurring together with other toxic effects, the endocrine mediated effect should be considered not
to be a secondary non-specific consequence of other toxic effects.
Substances can be allocated to this category based on:


Evidence from humans or from animal species living in the environment where it is
suspected that the observed adverse effect is endocrine-mediated, or



Experimental studies where it is plausible that the observed adverse effects are caused by an
endocrine mode of action but that specific weaknesses in study design or execution weaken
this conclusion, or



Experimental studies where it is suspected that the observed adverse effects are caused by
an ED mode of action, or



Experimental animal studies showing endocrine activity in vivo which is suspected to be
linked to adverse affects in vivo (e.g. through read-across), or



in vitro studies showing endocrine activity, combined with toxicokinetic in vivo data which is
suspected to be linked to adverse effects in vivo (e.g. through read-across, chemical
categorisation and QSAR predictions).

4. Additional considerations
4.1 Endocrine system


No need for defining the endocrine system
o Scientific terms are usually not defined;
o Very little is known about endocrine system of invertebrates and thus difficult to
develop a good definition;



If the definition would be desired, then one suitable definition might be: ‘The endocrine
system is a system regulating all biological processes in the body by synthesising chemical
messengers (hormones) in one tissue which are transported (by the circulatory system) to
other tissues in which they produce their physiological effects’

4.2 Route of exposure
3



No need for specifying route of exposure here, but might be useful to address it in the
guidance document; (for determination of endocrine activity all route of exposure are used,
while for determination of adverse effects physiological route of exposure is used)

4.3 Adversity



It might be useful to define the adversity in the definition section
WHO/IPCS 2009 definition seems to be suitable: A change in the morphology, physiology,
growth, reproduction, development or lifespan of an organism, system or (sub)population
that results in an impairment of functional capacity, an impairment of capacity to
compensate for additional stress or an increase in susceptibility to other influences.

4.4 Mode of action





It might be useful to define the mode of action, however, there is no readily available
definition;
One possibly suitable defines MoA as: The biologically plausible sequence of key events,
starting with the interaction of an agent with a cell, through functional and anatomical
changes leading to an observed effect.
Authors of this paper need additional considerations on whether and how to incorporate it in
the criteria

4.5 Proof of causality


It should be addressed but no need for additional elaboration as it is already covered in the
criteria

4.6 Data


It seems to be useful to describe in general terms data to be used for the assessment;
Possible description is as follow: Categorisation of a substance for endocrine disruption is
made on the basis of evidence from reliable and acceptable studies. The evaluations shall be
based on all existing data, peer-reviewed published studies and additional acceptable data.

4.7 Potency


No potency consideration
o
o

It is not relevant for the hazard identification;
Potency on its own does not inform for high/low concern; potency makes sense only
if combined with exposure information and information on uncertainties;
o A risk from low potent chemical can be higher than from high potent chemical if
exposure to low potent is higher than to high potent chemical;
o There is no scientific way how to define the cut-off threshold; it is always decision
based on impacts;
o Impossible to extrapolate potency cut offs across species;
o No potency consideration for CMRs classes;
o It has been argued that majority of effects seen for endocrine disruptors would be
also identified as carcinogenicity or toxic to reproduction; if a threshold would be

4

established for endocrine disruption, then it could happen that a substance would
not be identified as an endocrine disruptor even if it is a carcinogen or toxic to
reproduction and the endocrine mode of action is well known.

4.8 Lead toxicity


It should not be considered as it is not important for hazard identification whether a
substance is also causing other effect at lower concentration level;

4.9 Severity


It should not be considered; all adverse effects are relevant;

4.10 Irreversibility


It should not be considered; all adverse effects are relevant;

4.11 Specificity



It should be considered
It is incorporated in the criteria

4.12 Step by step procedure
1. Gather all available data
2. Consider adversity and mode of action in parallel
3. Assess the data quality, reliability, reproducibility and consistency
4. Evaluate specificity
5. Evaluate human and wildlife relevance
6. Final (eco)toxicological evaluation and categorisation

5

Revised version of possible elements for criteria for identification of
endocrine disruptors (changes tracked)

1. 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. (WHO/IPCS)
A suspected endocrine disruptor is an exogenous substance or mixture that may alter function(s) of
the endocrine system and consequently may cause adverse health effects in an intact organism, or its
progeny, or (sub)populations. (DK)
A potential endocrine disruptor is an exogenous substance or mixture that possesses properties that
might be expected to lead to endocrine disruption in an intact organism, or its progeny, or
(sub)populations. (WHO/IPCS)

2. Categories of Endocrine Disruptors
For the purpose of categorisation of endocrine disruptors for endocrine disruption, substances are
allocated to one of three two categories based on [weight of evidence] / [level of evidence]strength
of evidence and additional considerations in weight of evidence.
Categories for endocrine disruptors


Category 1: Known or presumed Endocrine disruptors
o

Category 1a: Known endocrine disruptors

o

Category 1b: Presumed endocrine disruptors



Category 2: Suspected endocrine disruptors



Category 3: Potential endocrine disruptors

3. Criteria for Placing Substances in Categories
Category 1 – Known or presumed Endocrine disruptors
Substances are placed in category 1 when they are known to have caused endocrine ED mediated
adverse effects in humans or [animal species living in the environment] / [population relevant effects
on animal species living in the environment ] / [ecosystem relevant adverse effects] or when there is
evidence from [animal studies] / [experimental animal studies], possibly supplemented with other
information (e.g. in vitro, in silico, read across), to provide a strong presumption that the substance
has the capacity to cause ED endocrine mediated adverse effects in humans or [animals living in the
environment] / [population relevant effects on animal species living in the environment] /
[ecosystem relevant adverse effects].

6

The [animal studies] / [experimental animal studies] shall provide clear evidence of endocrineEDmediated adverse effects in the absence of other toxic effects, or if occurring together with other
toxic effects, the endocrineED-mediated adverse effects should be considered not to be a secondary
non-specific consequence of other toxic effects.
However, when there is (e.g. mechanistic) information demonstrating that the effects are clearly not
relevant raises doubt about the relevance of the effect for humans or and [animal species living in
the environment] / [population of animal species living in the environment], category 2 may be more
appropriate.
Category 1 is further divided into two sub-categories on the basis of whether the evidence for
classification is primarily from human data or data from [animals living in the environment] / [field
studies] (Category 1A – Known Endocrine Disruptors) or from [laboratory animal studies] /
[experimental animal studies] (Category 1B – Presumed Endocrine Disruptors).
Substances can be allocated to the sub-category 1A based on evidence from humans or from [animal
species living in the environment] / [field studies] where it is plausible that the observed adverse
effect is endocrineED-mediated.
Substances can be allocated to the sub-category 1B based on:


Evidence from humans or from [animal species living in the environment] / [field studies]
where it is plausible that the observed adverse effect is endocrine-mediated, or



[Animal studies] / [Experimental animal studies] where it is plausible that the observed
adverse effects are caused by an endocrine ED mode of action, or



[Animal studies] / [Experimental animal studies] showing an ED endocrine activity in vivo
which is clearly linked to adverse effects in vivo (e.g. through read-across).

Category 2 – Suspected endocrine disruptors
Substances are placed in category 2 when there is some evidence for ED endocrine mediated adverse
effects from humans, animal species living in the environment or experimental animals, and where
the evidence is not sufficiently convincing strong to place the substance in category 1. If, for example,
limitations in the study (or studies) make the quality of evidence less convincing, category 2 could be
more appropriate.
These endocrine disrupting Such effects should be observed in the absence of other toxic effects, or
if occurring together with other toxic effects, the ED endocrine mediated effect should be considered
not to be a secondary non-specific consequence of other toxic effects.
Substances can be allocated to this category based on:


Evidence from humans or from animal species living in the environment where it is
suspected that the observed adverse effect is endocrine-mediated, or



Experimental studies where it is plausible that the observed adverse effects are caused by an
endocrine mode of action but that specific weaknesses in study design or execution weaken
this conclusion, or

7



Experimental animal studies where it is suspected that the observed adverse effects are
caused by an ED mode of action, or



Experimental animal studies showing endocrine activity in vivo which is suspected to be
linked to adverse affects in vivo (e.g. through read-across), or



in vitro studies showing endocrine activity, combined with toxicokinetic in vivo data which is
suspected to be linked to adverse effects in vivo (e.g. through read-across, chemical
categorisation and QSAR predictions).

Category 3 – Potential endocrine disruptors
Substances are placed in Category 3 when there is some in vitro/in silico evidence indicating a
potential for endocrine disruption mediated adverse effects in intact organisms and where the
evidence is not sufficiently convincing to place the substance in category 1 or 2.
The evidence could also be observed effects in vivo where there is general but not specific evidence
relating those to ED mediated adverse effects (i.e. that may, or may not, be ED-mediated).

4. Additional considerations
4.1 Endocrine system


No need for defining the endocrine system
o Scientific terms are usually not defined;
o Very little is known about endocrine system of invertebrates and thus difficult to
develop a good definition;



If the definition would be desired, then one suitable definition might be: ‘The endocrine
system is a system regulating all biological processes in the body by synthesising chemical
messengers (hormones) in one tissue which are transported (by the circulatory system) to
other tissues in which they produce their physiological effects’

4.2 Route of exposure


No need for specifying route of exposure here, but might be useful to address it in the
guidance document; (for determination of endocrine activity all route of exposure are used,
while for determination of adverse effects physiological route of exposure is used)

4.3 Adversity



It might be useful to define the adversity in the definition section
WHO/IPCS 2009 definition seems to be suitable: A change in the morphology, physiology,
growth, reproduction, development or lifespan of an organism, system or (sub)population
that results in an impairment of functional capacity, an impairment of capacity to
compensate for additional stress or an increase in susceptibility to other influences.

4.4 Mode of action
8






It might be useful to define the mode of action, however, there is no readily available
definition;
One possibly suitable defines MoA as: The biologically plausible sequence of key events,
starting with the interaction of an agent with a cell, through functional and anatomical
changes leading to an observed effect.
Authors of this paper need additional considerations on whether and how to incorporate it in
the criteria

4.5 Proof of causality


It should be addressed but no need for additional elaboration as it is already covered in the
criteria

4.6 Data


It seems to be useful to describe in general terms data to be used for the assessment;
Possible description is as follow: Categorisation of a substance for endocrine disruption is
made on the basis of evidence from reliable and acceptable studies. The evaluations shall be
based on all existing data, peer-reviewed published studies and additional acceptable data.

4.7 Potency


No potency consideration
o
o

It is not relevant for the hazard identification;
Potency on its own does not inform for high/low concern; potency makes sense only
if combined with exposure information and information on uncertainties;
o A risk from low potent chemical can be higher than from high potent chemical if
exposure to low potent is higher than to high potent chemical;
o There is no scientific way how to define the cut-off threshold; it is always decision
based on impacts;
o Impossible to extrapolate potency cut offs across species;
o No potency consideration for CMRs classes;
o It has been argued that majority of effects seen for endocrine disruptors would be
also identified as carcinogenicity or toxic to reproduction; if a threshold would be
established for endocrine disruption, then it could happen that a substance would
not be identified as an endocrine disruptor even if it is a carcinogen or toxic to
reproduction and the endocrine mode of action is well known.

4.8 Lead toxicity


It should not be considered as it is not important for hazard identification whether a
substance is also causing other effect at lower concentration level;

4.9 Severity


It should not be considered; all adverse effects are relevant;

4.10 Irreversibility
9



It should not be considered; all adverse effects are relevant;

4.11 Specificity



It should be considered
It is incorporated in the criteria

4.12 Step by step procedure
7. Gather all available data
8. Consider adversity and mode of action in parallel
9. Assess the data quality, reliability, reproducibility and consistency
10. Evaluate specificity
9.11.

Evaluate human and wildlife relevance

10.12.

Final (eco)toxicological evaluation and categorisation

10