# EUR-Lex - 52012DC0252 - EN

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# 52012DC0252

**COMMUNICATION FROM THE COMMISSION TO THE COUNCIL The combination effects of chemicals Chemical mixtures /* COM/2012/0252 final */**

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COMMUNICATION FROM THE COMMISSION TO
THE COUNCIL

The combination effects of chemicals

Chemical mixtures

1.           introduction

In recent years there has been an
increasing focus on the effects on human health and on the environment arising
from exposure to many different chemicals. These effects are variously referred
to as combination effects, mixture effects or cocktail effects. The European
Parliament has consistently drawn attention to the need to take account, in the
context of EU chemicals' legislation, of the combined effects of different
chemicals on human health and the environment. On 22nd December
2009, the Council, based in part on concerns arising from the Danish toddler
study (Box 1), adopted a set of conclusions on the "combination effects of
chemicals"[1].

Box 1.
Mixtures to which human populations are exposed

In 2009,
The Danish authorities published the results of a study[2] in which the
exposure of toddlers (2 year old children) to chemical mixtures in the form of multiple
endocrine disruptors from several sources were examined. The study examined
exposure through the food chain, through indoor air and dust, through clothes
and shoes, through contact with toys, through the application of health care
and hygiene products and through contact with articles such as changing mats
and bath mats. On the basis of the predicted concentration of the various
substances the study concluded that there was a need to reduce exposure to
anti-androgen and oestrogen substances from food, indoor air and consumer products.

The Council in particular, invited the
Commission, "... to assess how and whether relevant existing Community
legislation adequately addresses risks from exposure to multiple chemicals from
different sources and pathways, and on this basis to consider appropriate modifications,
guidelines and assessment methods, and report back to
the Council by early 2012 at the latest."

The purpose of the present Communication is
to respond formally to the invitation from the Council and in particular to
assess whether the current EU legislation which is built predominantly on the
assessment of single substances and single sources, guarantees the high level
of protection required by the Treaty. The challenge of dealing with chemical
mixtures will also be taken-up in the context of preparing the future
priorities for environmental policy. Actions taken to reduce exposure to
potentially harmful chemical mixtures will also contribute to the achievement
of the objectives in the Health for Growth programme[3]

The present document draws heavily upon the
joint opinion of three scientific Committees[4]
(hereinafter "the Scientific Committees") and also takes into account
a major study "State of the Art Report on Mixture Toxicity" financed
by the Commission[5]
.

2.           Mixtures[6] in the context
of EU Chemicals Legislation

In the EU as in other parts of the world, chemicals'
legislation is built on the foundation of assessments carried out on individual
chemical substances. These assessments are frequently used as the basis for
decisions related directly to the individual substances. However, in addition
to the rules governing the assessment and management of individual substances,
there is also an extensive body of EU legislation dealing with various types of
mixtures.

2.1 Intentional Mixtures

In the case of intentional mixtures, the
composition of the mixtures is well known and the assessments are based on the
properties of the constituents supplemented, where appropriate, by tests
carried out on the entire product. Examples of this type of legislation include
rules for the classification, labelling and packaging of mixtures[7], rules for the authorisation of
plant protection products[8],
the rules governing the composition of cosmetics[9],
rules governing the approval of medicinal products for human use[10] and rules governing the
approval of veterinary medicinal products[11].

2.2 Mixtures originating from a single
source.

Discharges to the environment during the
production, transport, use or disposal of goods, often contain a mixture of
chemical substances. Where the composition is known or the components can be
identified by analytical methods, assessments can be made based on knowledge of
the constituents. Where the composition is unknown an assessment would need to
be based on tests carried out on the whole mixture. There are very few examples
of EU legislation specifically requiring the assessment or testing of whole
mixtures. However, the requirement set down in the Water Framework Directive[12] for water bodies to achieve
good ecological status as well as good chemical status entails a focus not only
on the concentrations of individual chemicals but also on their effects in
combination.

2.3 Mixture of
Chemicals originating from multiple sources and through multiple pathways.

In relation to the assessment of multiple
substances from multiple sources, which represents the main focus of the
concern raised by the Council, there are only a limited number of examples in
EU legislation. In the context of REACH[13]
guidance has been developed concerning the assessment of multiple sources of
exposure to a single substance and in specific cases to the assessment of
several closely related and similarly acting substances (e.g. different salts of
the same metal or a number of closely related derivatives of organic substances[14]. In the workplace, employers
are required to carry out an assessment of hazardous chemicals including an
obligation to assess the risks presented by all such chemical agents in
combination[15]
In relation to the establishment of maximum levels for pesticide residues in,
or on, food and feed of plant and animal origin[16] the panel on Plant Protection
Products of the European Food Safety Authority (EFSA), developed approaches for
taking account of cumulative and synergistic effects when setting maximum residue
levels (MRLs) for pesticides with similar modes of action[17]. EFSA is also developing
methodology for pesticides with a dissimilar mode of action for occupational
exposure[18]

2.4 Conclusion

In conclusion, where
chemical mixtures are assessed and regulated under EU legislation this is
predominantly in relation to chemical products of known composition. Some
complex mixtures discharged/emitted to the environment from a single source
(factory, facility, etc), are also subject to controls. There are a few examples
of assessments and controls being carried out in relation to several substances
originating from different sources and through different pathways but these are
limited in their scope. Currently, within the framework of EU legislation,
there is no mechanism for a systematic, comprehensive and integrated assessment
of mixture effects taking into account different routes of exposure and
different product types. Thus the recent study carried out in Denmark (see Box
1) highlighting the concerns associated with the exposure of toddlers to
different endocrine disruptors could not, at present, trigger a comprehensive
assessment within the context of EU legislation.

3.           Can exposure to small
concentrations of different substances have negative effects?

We have seen in section 2 that there exists
a very extensive corpus of legislation designed to ensure that the
concentrations of chemical substances to which human beings or animals and
plants, are exposed are within safe limits. On condition that the legal
requirements are respected, this means that although we (also animals and
plants) are exposed to small concentrations of many different chemicals none of
these chemicals should be present above their individual safe limits. This
being the case and in order to respond to concerns expressed by the Council, we
need to examine whether or not a mixture of chemical substances, originating
from different sources and through different pathways, in which each of the
substances is present at very low concentrations , could have negative effects
on human health or the environment.

The Scientific Committees indicated that,
under certain conditions, chemicals present in a mixture will act jointly in a
way that the overall level of toxicity is influenced. In particular, chemicals with
common modes of action[19]
may act jointly to produce combination effects that are larger than the effects
of each of the mixture components applied singly. However, in the case of
substances with different modes of action (independently acting[20].), the Scientific Committees
concluded that there is no robust evidence available to indicate that exposure
to a mixture of such chemicals is of health concern if the individual chemicals
are present at or below their zero effect levels. As to whether the possibility
of exposure to mixtures of chemical substances is a potential cause for concern
(in relation to human health), the Scientific Committees concluded that " if
the intended level of protection is achieved for each individual substance, the
level of concern for mixtures of dissimilarly acting substances should be
assumed to be negligible".

However, in relation to ecological effects,
the situation is less clear and the Scientific Committees concluded that "In summary, for ecological effects, the exposure to mixtures of
dissimilarly acting substances at low, but potentially relevant concentrations
should be considered as a possible concern, even if all substances are below
the individual Predicted
No Effects Concentrations (PNECs).
Consequently there is a need for improving the current knowledge and
methodologies, and developing holistic approaches for the ecological risk
assessment of chemicals under realistic conditions."

4.           The Scientific Challenge

4.1.        Identifying priorities

As indicated in the previous section,
exposure to mixtures of chemicals even when these chemicals are present at low
(real-world) concentrations may give rise to concerns. However, the number of
potential combinations of the tens of thousands of substances currently in
commerce is astronomical and the attention of the risk assessors should be
focussed on those situations where the potential for negative impacts is
highest. The Scientific Committees have provided clear indications concerning
the criteria and methodologies that could be applied to identify chemical
combinations/mixtures that are priorities for further assessment (see Box 2).

Box 2. Extract
from detailed recommendations of the Scientific Committees in relation to
setting priorities

In view
of the almost infinite number of possible combinations of chemicals to which
humans and environmental species are exposed some form of initial filter to
allow a focus on mixtures of potential concern is necessary. The following
criteria are proposed for consideration:

1) Human
and/or environmental exposure at significant levels.

2) Chemicals
that are produced and/or marketed as multi-constituent substances or commercial
mixtures with several components and/or active ingredients and/or substances of
concern.

3) Potential
serious adverse effects of one or more chemicals at the likely exposure levels.

4) Likelihood
of frequent or large scale exposure of the human population or the environment.

5)
Persistence of chemicals in the body and/or in the environment.

6) Known
information of potential interaction at levels of human and environmental
exposure.

7) Predictive
information that chemicals act similarly.

8) Particular
attention should be paid to mixtures for which one or more components are
assumed to have no threshold for its effects.

4.2.        The scientific assessment
of chemical combinations/mixtures

When a particular chemical mixture is
identified as a priority for further assessment the Scientific Committees has
also provided detailed advice concerning the methods that are currently
available for assessing/predicting the toxicity of such chemical mixtures (see
Box 3).

Box 3. Extract
from detailed recommendation from the Scientific Committees in relation to assessment

In view
of the huge variety of human exposures to chemical mixtures, the default
assumption in human risk assessment had been that the chemicals generally acted
by dissimilar modes of action. In cases, however, where
information is available to indicate a similar mode of action, a
dose/concentration addition approach is appropriate. A dose/concentration
addition approach, if applied to chemical mixture components with unknown modes
of action, may result in an over-prediction of toxicity; using the independent
action approach may however underestimate toxicity. Therefore, in the case of
unknown modes of action, the dose/concentration addition approach is also
preferable to ensure an adequate level of protection.

In ecotoxicology, any approach should be referred to specific
endpoints and to defined taxonomic groups of organisms. [...]A significant
limitation of component-based approaches is that they are only applicable to
mixtures of which the major components are known.

4.3.        Knowledge/Data gaps

While providing extensive guidance
regarding the identification of chemical mixtures of highest concern and the
methodologies for assessing such mixtures, the Committees also drew attention
to the many data and knowledge gaps that impede a more systematic and effective
application of these methodologies (see Box 4).

Box 4.
Extract from detailed Recommendations from the Scientific Committees in
relation to knowledge gaps

With
regard to the assessment of chemical mixtures a major knowledge gap at the
present time is the lack of knowledge on where, how often and to what extent
humans and the environment are exposed to certain chemical mixtures and how
exposure may change over time. There is a need
to better understand human and environmental exposures, both through the use of
monitoring and modeling.

For many
chemicals, there is no good information on mode of action. Currently there is
neither an agreed inventory of modes of action, nor a defined set of criteria
on how to characterise or predict a mode of action for data-poor chemicals or
how to group chemicals into assessment groups.

Interactions[21] of chemicals in mixtures are difficult to foresee, particularly for
long-term effects. Research is needed to define
criteria that predict potentiation or synergy.

In
ecotoxicology, the problem is even more complex. A knowledge of all possible
modes of action that may occur in the different types of organisms of a complex
biological community is difficult (if not impossible) to be attained. On the
other hand, it must be considered that ecologically relevant endpoints are
generally broader and not so specific (e.g. toxicity on specific organs, etc.)
as in human toxicology. A full review of the literature should be made to
prepare a state-of-the-art on mixtures biodegradation modelling.

The
Committees also indicated that "the REACH Regulation is generating the
largest database on chemicals in history and that this information could be
used to reduce some of the current uncertainties........."

4.4.        Can the assessment of
chemical mixtures be carried out in a more systematic way in the context of EU
legislation?

On the basis of the opinion from the
Scientific Committees it appears that having identified a particular chemical
mixture as a priority for further assessment, the scientific methodology is
available for carrying out such assessments although there are currently many knowledge/data
gaps that might act as a barrier to actually applying these methods. The
question therefore remains as to whether the current state of knowledge is
sufficiently robust to support a more systematic assessment of chemical
mixtures in the context of EU legislation. The Scientific Committees also
provided clear recommendations with regard to this matter (see Box 5).

Box 5.
Extract from the Recommendation of the Scientific Committee in relation to the
possibility to undertake assessment of mixtures in a more systematic way in the
context of EU legislation

In many
cases, knowledge is insufficient for a robust scientific analysis. If
toxicologically significant interactions can be excluded, the components of a
mixture are identified and known mode of action information is available,
either a dose addition or independent action model should be applied. This set
of information, in human toxicology, is, however, rarely available and, in most
cases, very cost- and labour-intensive to generate.

In
ecotoxicology, the mode of action should be known for all the relevant
taxonomic groups of aquatic and terrestrial ecosystems. Thus, the availability
of information is even more limited; in addition, modes of actions considered
dissimilar at the individual level may affect the same population relevant
endpoint, and therefore, the dose/concentration addition model may be more
appropriate for predicting effects at the population level.

In order
to prioritize chemical mixtures for possible assessment it is first necessary
to consider whether there is significant human or environmental exposure to the
mixture or its components. Unless there are indications of a significant
interaction, a dose/concentration addition model could be used if the
components of the mixture exert their biological effects via an identical or
similar mode/mechanism of action. If the mixture components act dissimilarly,
the independent action model would be applied. It further appears justifiable
that a dose/concentration addition approach should be used as default approach
in cases where neither mode of action nor dose-response information is
available to ensure adequate conservatism in the assessment.

In addition to the recommendations referred
to in Box 5, the Scientific Committees also provided a decision tree that could
be applied when dealing with chemical mixtures (for further details see Scientific
Committees' opinion).

5.           Conclusions

5.1.        In relation to the current
situation

(1)
Current EU legislation does not provide for a
comprehensive and integrated assessment of cumulative effects of different
chemicals taking into account different routes of exposure. In the case where a
mixture of concern is identified and where such a mixture contains chemical
substances regulated under different pieces of EU legislation, no mechanism
currently exists for promoting an integrated and co-ordinated assessment across
the different pieces of legislation.

(2)
In the case of chemicals with independent modes
of action, the establishment of "safe levels" based on the assessment
of individual substances appears, in relation to human health, to provide a
sufficient safeguard against possible negative effects from
mixtures/combinations.

(3)
However, where chemicals have similar modes of
action there is a potential for cumulative effects when such chemicals are
present together in a mixture (even when the concentration of each substance is
below its "safe level") and then, the concentration/dose addition
approach is preferred in order to assure an adequate level of protection.

(4)
In relation to the effects on wild species and
ecosystems, the situation is less clear and the possibility of
combination/mixture effects should be considered both in the case of
independently acting chemicals as well as for chemicals with similar modes of
action.

(5)
Methodologies for the identification of chemical
mixtures of potential concern as well as for the assessment of chemical
mixtures are available. However, there are extensive knowledge and data gaps
(mainly related to the mode of action and exposure data) that limit the extent
to which mixtures can be properly assessed. Information being collected in the
context of EU legislation, in particular the REACH Regulation, will contribute
to reducing current uncertainties.

(6)
Notwithstanding the knowledge and data gaps it
is possible to assess mixture toxicity in a more systematic manner in the
context of EU legislation. When information regarding the mode of action and
dose/response is not available, or inconclusive, a default assumption of
dose/concentration addition provides a higher level of protection but may also
overestimate negative effects. This limitation and the additional costs it
might imply shall be taken into account in the case where possible management
measures are being considered

(7)
While not specifically addressed in the opinion
from the Scientific Committees, the assessment of chemical mixtures must be
carried out in respect of the principle of reducing, refining and replacing
testing on vertebrate animals.

5.2.        In
terms of operational follow-up

In the light of the above conclusions the
Commission will:

(1)
Establish an ad hoc working group of relevant
services and associated Agencies and Authorities (EFSA, ECHA, EMEA and EEA) to
strengthen co-ordination across the different pieces of legislation and to
promote the integrated assessment of priority mixtures, taking into account the
risks of human and environmental exposure. The ad-hoc working group will
co-ordinate the work of bringing together the data and oversee the integrated
assessment of priority mixtures. Any follow-up action would be taken in the
frame of the legislation under which each substance is currently regulated.

(2)
Develop, by June 2014, and taking account of the
opinion of the Scientific Committees, technical guidelines to promote a consistent
approach to the assessment of priority mixtures across the different pieces of
EU legislation. Such guidelines shall not replace existing rules where such
exist nor shall they impose additional obligations or burdens on economic
operators. The development of these guidelines will be co-ordinated by the
ad-hoc working group referred to in point (1) above.

(3)
Support improved understanding of the chemical
mixtures to which human populations and the natural environment are actually exposed
by :

(a)
reviewing, in consultation with the associated
Agencies, the monitoring data which is currently collected under EU legislation
or generated in the context of EU funded research projects[22];

(b)
promoting a more coherent approach to the
generation, collection, storage and use of chemical monitoring data in relation
to humans and the environment, through the creation of a platform for chemical
monitoring data. This would help identify links between exposure and epidemiological
data in order to explore potential biological effects and lead to improved health
outcomes.

(4)
Examine the opportunities for addressing some of
the other knowledge gaps, in particular relating to (i) the mode of action of
chemicals, (ii) grouping chemicals into categories or assessment groups; (iii) predicting
interactions and (iv) identifying chemical substances that are the main drivers
of mixture toxicity. These actions may in part be supported through Horizon 2020,
the future EU framework programme for research and innovation.

(5)
Promote consistent and science-based approaches
to the risk assessment of chemical mixtures at a global level by participating
in relevant international activities This will help protect health and the environment
as well as promoting the competitiveness of European industry.

(6)
Publish a report on the assessment of chemical
mixtures by the end of June 2015, reviewing the progress and experience
associated with the actions identified under points 1 to 5 above.

In carrying out the actions set out under
points 1-5 above the Commission will collaborate with the Member States and
other stakeholders. The modalities of this collaboration will need to be
defined and will, wherever possible, make use of existing structures.

[1]               Council conclusions on combination effects of
chemicals. 2988th Environment Council meeting Brussels, 22 December
2009.

[2]               Survey and Health Assessment of the exposure of 2
year olds to chemical substances in consumer products. Danish Ministry of the
Environment, Environment Protection Agency, (2009)

[3]               Proposal for a Regulation of the European Parliament
and of the Council on establishing a Health for Growth Prpgramme, the third
multi-annual programme of EU action in the field of health for the period
2014-2020. COM(2011) 709 final.

[4]               Toxicity and Assessment of Chemical Mixtures.
Scientific Committee on Health and Environmental Risks (SCHER), Scientific
Committee on Emerging and Newly Identified Health Risks (SCENHIR) and
Scientific Committee on Consumer Safety (SCCS). Joint Opinion adopted on 14th
December 2011. http://ec.europa.eu/health/scientific_committees/environmental_risks/opinions/index_en.htm

[5]               Web site of DG ENV of the European Commission.
http://ec.europa.eu/environment/chemicals/effects.htm

[6]               The terms "chemical mixtures", "chemical
cocktails" and the "combination effects of chemicals" are often
used interchangeably. For reasons of clarity, the term "chemical mixtures"
will be used in the present document.

[7]               Regulation (EC) No 1272/2008 of the European Parliament
and of the Council of 16 December 2008 on classification, labelling and
packaging of substances and mixtures. OJ L 353,
31.12.2008, p. 1.

[8]               Regulation EC No 1107/2009 of the European Parliament
and of the Council of 21 October 2009 concerning the placing of plant
protection products on the market. OJ L 309, 24.11.2009,
p. 1.

[9]               Regulation (EC) No 1223/2009 of the European
Parliament and of the Council of 30th November 2009 on cosmetic
products. OJ L 342, 22.12.2009, p. 59.

[10]             Directive 2001/83/EC of the European Parliament and of
the Council of 6 November 2001 on the Community code relating to medicinal
products for human use. OJ L 311, 28.11.2001, p. 67

[11]             Directive 2001/82/EC of the European Parliament and of
the Council of 6 November 2001 on the Community code relating to veterinary
medicinal products. OJ L 311, 28.11.2001, p. 1

[12]             Directive 2000/60/EC of the European Parliament and of
the Council of 23 October 2000, establishing a framework for Community action
in the field of water policy. OJ L 327, 22.12.2000, p. 1.

[13]             Regulation (EC) No 1907/2006 of the European Parliament
and of the Council of 18th December 2006 concerning the
Registration, Authorisation and Restriction of Chemicals-REACH. OJ L 136, 29.5.2007, p. 1.

[14]             http://echa.europa.eu/documents/10162/13632/information_requirements_part_e_en.pdf

[15]             Council Directive 98/24/EC of 7th April 1998
on the protection of the health of workers from the risks related to chemical
agents at work. OJ. L131, 5.5.1998, p11

[16]             Regulation (EC) No 396/2005. OJ. L70, 16.5.2005, p1

[17]             EFSA Journal 2008; 704: 1-85
http://www.efsa.europa.eu/en/efsajournal/doc/705.pdf and EFSA Journal 2009; 7:
1167. http://www.efsa.europa.eu/en/efsajournal/pub/1167.htm

[18]             http:www.efsa.europa.eu/en/supporting/pub/232e.htm

[19]             According to the Scientific Committees a Mode Of action
is a plausible hypothesis about measurable key events by which a chemical
exerts its biological effects. A common mode of action is defined by EFSA as
"involving the same key events leading to an adverse health effect following
interaction of the compound with its biological target[s]

[20]             According to the Scientific Committees, Independent
Action occurs where the modes of action and possibly, but not necessarily, the
nature and sites of toxic effects differ between the chemicals in a mixture and
one chemical does not influence the toxicity of another.

[21]             The Scientific Committees indicated that the term
interaction describes the combined effect of two or more chemicals when it is
stronger (synergistic, potentiating or supra-additive) or weaker (antagonistic,
inhibitive, sub-additive) than would be expected on the basis of
dose/concentration addition.

[22]             Taking into account the actions of the European
Environment and Health Action Plan {SEC(2004)729} /* COM/2004 416 final