Scoping paper

Workshop on a pragmatic approach to regulatory measures addressing the risk from combined exposure to chemicals – REACH as an example


Summary. 1

Terminology. 2

Introduction to the scoping paper. 2

1.      Background. 4

1.1         Policy instruments. 4

1.2         Profiling the problem of unintentional mixtures of substances in humans and the environment  5

2.      Possible approach to assess risks of unintentional mixtures. 6

2.1         Taking a helicopter view.. 6

2.2         Tiered approach. 8

2.3         Proposed approach for implementation under REACH.. 9

References. 9


The EU Commission in 2012 communicated that the 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, and identified the need to do so in case of chemicals that have similar modes of action (human health) or all cases (environment). This call was repeated in 2019. REACH contributes to the systematic underestimation of these EU wide risks by not taking combined exposure to substances into account. Detailed risk assessment of combined exposure under REACH would require a more extensive information requirement, huge additional costs for testing and logistical challenges of communicating uses and exposures of substances that could possibly occur in numerous combinations of chemicals. To avoid these drawbacks, a pragmatic approach is proposed as intermediate regulatory measure.  It is proposed to adopt an assessment factor under REACH Annex I, as part of the mandatory DNEL or PNEC derivation for substances to account for the fact that any registered substance under REACH may eventually contribute to the combined daily exposure of humans and the environment. The workshop aims to reflect on and discuss this approach, and all participants are invited to propose alternative approaches for discussion that are compatible with REACH while considering feasibility, practicality of implementation, maintaining a level playing field and avoiding additional data requirements.


The terminology used is in line with what is laid down in OECD (2018):

  • single substance, all routes/aggregated exposure: exposure to the same substance from multiple sources and by multiple routes
  • combined exposure: exposure to multiple substances by a single route and from multiple substances by multiple routes, from one or multiple sources of release and/or use(s). Co-exposure is used as synonym
  • combined hazard: hazard from multiple substances by a single route or from multiple substances by multiple routes, from one or multiple sources of release and/or use(s)
  • risks from combined exposure: risk from exposure to multiple substances by a single route and risk from exposure to multiple substances by multiple routes, from one or multiple sources of release and/or use(s)
  • risk assessment of combined exposure: risk assessment of exposure to multiple substances by a single route and risk assessment of exposure to multiple substances by multiple routes, from one or multiple sources of release and/or use(s)

OECD (2018) further specifies the following terms to describe different “combined exposures” to multiple substances:

  • mixtures: co-existing set of two or more substances in which they do not react
  • intentional mixtures: manufactured formulations e.g. commercial mixtures of industrial chemicals; technical mixtures; product formulations
  • coincidental mixture: substances from different sources, occurring in a medium e.g. combination of substances applied dermally from use of two or more product formulations
  • environmental mixtures: substance combinations in one environmental compartment e.g. substances found in soil from various exposure sources (application of product formulation, deposition from air, water run-off, etc.)

In this scoping paper:

  • unintentional mixtures: the sum of aggregated and combined exposures to substances, such as surface water contamination or the total of exogeneous chemicals present in a urine sample. This term includes both coincidental mixtures and environmental mixtures.  

Introduction to the scoping paper

In 2012, the Communication from the Commission on Combination effects of Chemicals (Chemical mixtures) (COM 2012) stated that exposure to chemical mixtures gives rise to risks for human health (HH) and the environment (ENV) that are higher than the risks accepted for single substances, and that the combined risks are rarely addressed in current European laws. Further development of existing legislation was called for to properly address this issue. Since then, several initiatives started focusing at regulating risks from intentional mixtures. Less attention was given to addressing the combined exposure to coincidentally formed and variable combinations of substances from one or several sources and via multiple routes that humans and the environment are exposed to on a daily basis (OECD, 2018). Anno 2019, risks from combined exposure to chemicals are still not properly addressed (COM, 2019).

The REACH Regulation provides the basic information on hazard and exposure of over 22,000 single substances brought on the market in quantities over 1 ton/annum to allow for their safe use on their own, in mixtures and in articles. REACH, however does not take combined exposure into account. This contributes to a systematic, EU-wide lack of adequate protection of the general population, the environment and workers (COM, 2012; COM, 2019). This is exemplified by the recent restriction on four phthalates in articles (REACH Annex XVII, entry 51)[1].

To address this issue, the Dutch Ministry of Infrastructure and Water Management (Competent Authority on REACH) and the Swedish Chemicals Agency (KemI) will host a series of two workshops. This scoping paper aims to facilitate further reflection and discussion at the first workshop.

It focuses on exploring a possible regulatory approach to addressing the potential risk from combined exposure to substances (unintentional mixtures) for humans and the environment under the REACH Regulation. Having defined this limited scope, safeguarding humans and the environment against possible risks from unintentional mixtures may require specific adaptations within and between all regulatory frameworks dealing with the safe use of chemicals, and like REACH, each of these legislations may require specific procedures for implementing an amendment/provision to such effect.

This scoping paper:

  • Summarizes the state of knowledge regarding risks of unintentional mixtures and the regulatory measures in place to safeguard humans and the environment;
  • Explores a possible approach to address risk from combined exposure to substances from unintentional mixtures for humans and the environment, and
  • Acts as a background document outlining some identified approaches but is not comprehensive and thus does not exclude that there may be other relevant approaches.

Hence, all participants are invited to propose alternative approaches for discussion to take account of combined effects that are compatible with REACH while considering feasibility, practicality of implementation, maintaining a level playing field and avoiding additional data requirements.

Aim of the first workshop

The first workshop aims to reach a common understanding on possible approaches to deal with the overarching challenge observed for both human health and environment that current combined exposure to chemicals can lead to unacceptable risks for humans and the environment. At the end of the workshop there should be:

  • A strategy outlining possible approaches under REACH to address the risk from combined exposure to substances from unintentional mixtures for humans and the environment;
  • Insight in the support for the proposed approach(es);
  • Identification of outstanding issues and the need for further fine-tuning of the proposed approach(es), including the likely need for and aim of a second (follow up) workshop.


Scientific literature clearly shows that risks from exposure to multiple chemicals are much larger than the risks accepted for single substances. As the current EU regulation is mainly on single-substance basis, this leads to higher aggregated and combined exposure and therefore to possible unacceptable risks to health and environment (COM, 2012; Gustavsson, 2017; Kortenkamp and Faust, 2018; EU fitness check, 2019). This issue is further highlighted in the EU-Council (ENVI) conclusions “Towards a Sustainable Chemicals Policy Strategy of the Union” (10713/19), the Green Deal (COM, 2019) and the results from recently concluded EU-research projects (Drakvik et al., 2020). Following the EU-Commissions’ Communication in 2012, important progress has been made on the assessment of these so-called ‘cocktail effects’ of mixtures with known composition, both in terms of methodology development (OECD 2018) and in terms of regulatory developments (see Section 1.1). However, a serious regulatory gap remains to address the cocktail effects of unintentional mixtures of chemicals that humans and the environment are exposed to on a daily basis. The general lack of data on chemical composition and exposure characteristics of unintentional mixtures is the main reason why designing adequate regulation has not been taken up until now . Acknowledging the need for further data, recent key EU-research projects (i.e. EDC-MixRisk,  EuroMix, HBM4EU, SOLUTIONS, EU-ToxRisk), an EU Workshop on Combination effects of Chemicals held in May 2018 and an EU workshop held in March 2019[2] highlight that intermediate regulatory measures should be considered, and already can be considered, while awaiting further data generation that may facilitate more targeted future measures (Kortenkamp and Faust, 2018; Ruden, 2019; Drakvik et al., 2020).

1.1Policy instruments

Kienzler et al. (2016) give a comprehensive overview of the way risks from combined exposure to substances are taken into account in the different chemicals legislations. Most of these legislations recognize that combined exposure to chemicals is an area of possible concern. Prospective risk assessment on intentional mixtures on the European market is performed for products such as  biocides, pesticides, food or feed additives, pharmaceuticals and cosmetics on the basis of their (known) chemical composition for their intended use. However, when several products are used in combination, or when different sources or routes of exposure occur in parallel, the resulting risk is generally not assessed.

Examples of regulations that to some extent do address the risks of such unintentional mixtures in their legal body text are the Plant Protection Product Regulation (PPPR), the Occupational Safety and Health Directive (OSH), the Toy Safety Directive (TSD), the Water Framework Directive (WFD) and the Marine Water Strategy Framework Directive (MSFD) (Kienzler et al., 2016)[3]. Among these, the PPPR clearly includes general requirements for the risk assessment of unintentional mixtures for human health concerning maximum residue levels for known pesticides in foods under EFSA’s remit[4] based on a recently published guidance document (EFSA, 2019). The other regulatory frameworks most often address risks from unintentional mixtures retrospectively on an ad hoc basis. Examples of such ad hoc measure are the requirement to group-wise (risk) assess certain substances like is done under e.g. the Industrial Emissions Directive (2010/75/EU; IED) and the Food Contaminants Regulation (315/95/EEC)[5], and most recently under the WFD[6]. Taking retrospective action instead of prospective action is mainly due to a lack of prospective information on the chemical composition of any unintentional mixture (which may be highly variable over time and space), the (combined) health hazard and the causal relationship between contaminants and biological effects. Limited prospective assessment is obligatory for tank mixtures of plant protection products (under the PPPR) and effluents of industrial activity (under the IED).

Provisions under the REACH Regulation

Under REACH, provisions for multi-constituent substances, substances of unknown or highly variable composition or biological materials (UVCBs) and intentional mixtures are explicated in the Regulation and Guidance material. As stated previously, there are no standard provisions in the REACH Regulation to assess the hazard and risk of unintentional mixtures. On an ad hoc basis, regulatory measures may be introduced for specific (groups of) substances under the process of Authorisation and Restriction. First examples of addressing intentional and unintentional mixtures under REACH have been introduced as part of the recent restrictions on the four phthalates in articles[7] and PFOA[8], and the identification of GenX as substance of very high concern[9].

1.2Profiling the problem of unintentional mixtures of substances in humans and the environment

Various human biomonitoring studies have shown that people in Europe are exposed on a daily basis to a great number of anthropogenic chemicals (Knudsen and Merlo, 2012; Bornehag et al., 2019). For the environment, first results from the FP7 Solutions project[10] suggest that the quality of approximately 65% of all European fresh water bodies would be classified as “insufficiently protected” [11] from combined effects[12] (Posthuma et al., 2019).

Risk management of environmental chemicals remains a major challenge because the available data for adverse health effects are mostly generated by examining one substance at a time, whereas in real life, organisms are exposed to mixtures of substances. Substances, mixtures and articles may have been assessed as safe or not exceeding the safe levels in a mixture as single substance, but they have not been assessed for their combined exposure (or various potential combinations of exposures in space and time).

A holistic approach to address possible effects from the total daily load of chemicals exposure is yet lacking. Where the different legislations are suited to assess specific substances, mixtures and articles, they are often not able to deal with the large number of possible exposure scenarios that take place in real life. Neither are they equipped to provide the necessary information to assess the possible risk of substances and uses across regulatory frameworks.

In 2018, the OECD (OECD, 2018) published an overview of different methodologies available to assess combined effects of chemicals. Which methodology to apply depends on the aim of the assessment and the information available. Typically, chemicals may impact the same target organ by the same mode-of-action, by a different mode-of-action, or impact different organs, and hence different chemicals combinations may require different assessment methodologies. Depending on their exact combination and concentrations, different chemicals can act together by ’simply’ adding on to each other’s effect (additivity), by exceeding the expectations of additivity and independence in reinforcing each other’s effect (synergism) or by reducing each other’s effect (antagonism).

These interactions seem to occur without a threshold to a combined effect, meaning that all combined exposures will lead to some form of combined effect, which may already become apparent below the no observed effect concentrations (NOEC) or no observed adverse effect levels (NOAEL) of the individual substance in the mixture (e.g. Carvalho et al. 2014; Kortenkamp, 2014; Bal-Price, 2019; Bopp, 2018).  

Detailed quantitative assessment of the overall toxicity of a mixture for human health or the environment requires detailed knowledge on the chemicals involved, their concentration and toxicity, including toxicokinetics, and their possible interaction. The REACH Regulation defines the information requirements for all industrial chemicals. These requirements do not include toxicokinetic data, and REACH only requests information on the so-called higher endpoints for substances that are brought onto the market in yearly volumes higher than 100 tonnes and only on a substance-by-substance basis. This means that that the information available on toxicity will most often be insufficient to perform a quantitative combined hazard assessment on unintentional mixtures. In addition, the information on use and exposure under REACH only has to be provided for substances identified as hazardous in the aggregated form of the so-called use and exposure categories, and does not involve any requirements for information on unintended uses and exposures. Hence, in many instances information available on individual substances is insufficient to enable proper combined exposure assessment for unintentional mixtures. Consequently, data gaps on both hazard and exposure are hampering a conclusive (quantitative) assessment of the overall risks of unintentional mixtures to health and environment under REACH.[13]

2.Possible approach to assess risks of unintentional mixtures

A detailed assessment of risks of all possible unintentional mixtures under REACH would require a significant increase of information requirements, which would lead to huge additional costs for testing and would build an additional logistical challenge of communicating uses and exposures of substances through their value-chain. To avoid these, intermediate measures under REACH should be pragmatic and feasible given the information that is typically available on substances, and should be based on what is known from current available science and a more general trend analyses.

2.1Taking a helicopter view

According to e.g. Gustavsson et al. (2017), the actual composition of environmental mixtures may vary strongly per location and time. The overall toxic pressure of environmental mixtures is well reproduced by assuming that the effects of all chemicals can be considered dose-additive (Kortenkamp, 2009). Analysis shows that of all chemicals present, typically only a few (on the order of 2 to 10, which may be different ones from location to location) dominate the overall risk, which shows up as a heavily tailed waterfall-like overall toxicity profile of relative per-chemical contributions (Harbers et al., 2006; Zijp et al., 2014; Gustavsson et al., 2017; Backhaus and Karlsson, 2014; Vallotton and Price, 2016; Posthuma et al., 2016). An example of such a plot is shown in Figure 1 for an environmental mixture of pesticide active substances, but similarly shaped waterfall-like patterns are found for pharmaceuticals and industrial chemicals.

Figure 1 from Gustavsson et al. (2017), cumulative sum of risk coefficients (RQ) for 27 pesticides for an environmental mixture (red) and for the simulated case of taking single-chemical risk management measures (green) reducing each individual chemical concentration in the mixture to 95% of its Swedish Water Quality Objective (WQO).

Building on to this work, Van Broekhuizen et al. (2017), Kortenkamp and Faust (2018), Ruden (2019) and Drakvik et al. (2020) have suggested as a generic intermediate approach the application of a safety factor (named Mixture Assessment Factor (MAF), Mixture Allocation Factor or Assessment Factor (AF) in these different publications) in the chemical risk assessment of individual chemicals to account for the fact that the few chemicals that do dominate the overall toxicity of every unintentional mixture share the same ’toxic space’ or ’risk cup’. Taking the single substance risk assessment as point of departure and the Risk Characterization Ratio (RCR; exposure level / safe level)[14]  as the indicator to identify a risk for humans or the environment (RCR>1 indicates a risk; RCR<1 indicates no risk), the toxic space available for chemicals reaches up to an RCR of 1. For multiple chemicals contributing to the overall toxicity, and assuming full dose additivity, it should consequently hold that the sum of all single substance RCRs remains below 1.

Considering the accountability of different actors, van Broekhuizen et al. (2017) postulated that all chemicals have a fundamental and equal right to the toxic space available. There is no convincing argument to why a not so very toxic chemical, or a chemical brought onto the market in low volumes should be entitled to more toxic space than a more toxic chemical or a chemical brought onto the market in higher yearly tonnages, each expressed as an RCR. This led van Broekhuizen et al. (2017) to propose a uniform MAF for all substances on the European market, irrespective of their individual impact and reason for concern. This is in line with both the REACH principle of equal market treatment and with the fact that at any given specific location, the chemical mix may be different and thus other chemicals may dominate the overall toxic pressure.

Gennings et al. (2018) developed a statistical model, based on human epidemiology data, that may be used to suggest data-driven assessment factors to account for the human exposure to environmental mixtures in the single-substance risk assessment, which is similarity to a MAF. Application of this method showed that the regulatory guideline values derived for single-substance risk assessment, are insufficiently protective against combined exposures to multiple substances, and should hence be lower when a similar level of protection is aimed for. This is clearly illustrated by recent results from the SELMA[15] study as part of the EDC-MixRisk project, where effects from real-life combined exposure in humans were compared to effects from real-life simulation combined exposure in vivo. SELMA studied the chemicals present in blood and urine of over 2000 pregnant women, assessed the anogenital distance (AGD) of the baby boys that were born (as an indicator of impaired sexual development) and compared the effect to that of simulated real-life combined exposures in vivo (Bornehag et al., 2019). It was shown that the real-life simulating phthalate mixtures dose led to a 13% increased risk of pregnant women for giving birth to baby boys with shortened AGD, whereas for that same mixtures dose in silico additivity modelling only predicted a 3% increased risk, and a substance-by-substance approach for risk assessment suggested an even lower 1.6% increased risk. The real-life simulating phthalate mixtures dose in SELMA approximated the combined exposure observed in humans with a focusing on possible endocrine effects, but involved many more chemicals. And this may again only be a subset of the total combined exposure. The total combined exposure in humans likely is composed of more chemicals than the known, identified ones included in analyses.

2.2Tiered approach

Possible regulatory measures may range from more reactive to more proactive[16], and from local or national to EU (or even world) wide. Though first regulatory measures are being implemented, including under REACH (see Section 1.1), it is clear from the recent Commission Communication (COM, 2019) that while substances are all regulated in their own right, their possible risks in combination are still not or insufficiently considered.[17] These risks should be proactively addressed under REACH before substances are placed on the market. Given the complexity of the problem of combined exposures from unintentional mixtures, one may envisage that a possible proactive and pragmatic approach may consist of a tiered approach with the following elements:

  • Tier 1 generic mixture assessment factor to be implemented under REACH for both human health and the environment to account for the fact that combined exposure to chemicals leads to an average excess risk across Europe that is higher than deemed acceptable, and
  • An additional Tier 2, which can be a more specific assessment for any additional concern on top of the EU-average excess risk, e.g. to be applied more locally in regions of higher chemical activity than the EU average via other forms of regulatory action, e.g. via the industrial emission permits, or e.g. for specific combinations of chemicals for which knowledge is available that synergism can be expected.

2.3Proposed approach for implementation under REACH

Under REACH, there are several places in the legislation where safety of substances is addressed and which could be expanded to address risks due to combined exposure:

  1. above 10 tonnes/annum production volume per year for hazardous substances, a chemical safety report (CSR) is required that outlines the exposure scenarios under which safe use is possible,
  2. Registrants are obliged to derive safe exposure levels (Derived No-Effect Levels, DNELs, for human health, and Predicted No-Effect Concentrations, PNECs, for environmental health), and
  3. under Authorisation and Restriction, limitations on production and use can be defined to safeguard human and environmental health[18].

We suggest to adopt a mixture assessment factor (MAF) under the REACH Regulation Annex I, as part of the mandatory DNEL or PNEC derivation for substances to account for the fact that any registered substance under REACH may eventually become part of an unintentional mixture to which humans and the environment will be exposed. An alternative suggestion is to introduce such assessment factor on the RCRs derived in the CSR or in the process of authorisation or restriction as indicative for safe use .

The magnitude of the MAF is proposed to be set to correct for the average excess toxic pressure in Europe, in order to reduce that pressure to acceptable levels. The aim would be to minimize over-regulation of areas of low toxic pressure, and to leave space to implement additional risk reduction measures when needed in areas of higher toxic pressure, or areas with more specific combinations of chemicals where detailed knowledge (on combination toxicity and exposure) is available. Within such a system, still several choices are to be made like the magnitude of the MAF and which substances to apply the MAF to.


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Bal-Price A., 2019. Non-neurotoxic concentrations of single environmental chemicals become neurotoxic in mixture: developmental neurotoxicity (DNT) evaluation using human in vitro model. Reproductive Toxicology, Volume 88, September 2019. Doi: 10.1016/j.reprotox.2019.07.030.

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[1] While the use of each single phthalate in single articles is considered safe, this is not the case for exposure to multiple articles and multiple phthalates.

[2] The EDC-MixRisk and EuroMix Joint Stakeholder Workshop, The Chemical Cocktail Challenge took place on March 26th 2019 at the Thon Hotel EU in Brussels, Belgium. The presentations from the workshop can be accessed from link). The EuroMix Stakeholder Workshop, Harmonisation and Usability of the EuroMix tools took place on March 27th 2019 at the Thon Hotel EU in Brussels, Belgium. The presentations from the workshop can be accessed from link).

[3] The Chemical Agents Directive under OSH prescribes the assessment of occupational risks from combined exposure to multiple substances. This may be further detailed in national implementation of this legislation. The Toy Safety Directive stipulates that the exposure to chemicals from toys may contribute to no more than 10% of the overall per-substance acceptable daily intake (ADI). The WFD and the MSFD recognize the importance of mixture effects, but do not provide specific details on how this should be assessed. The assessment remains limited to a list of so-called priority substances, with the exception of the WFD that recently identified a priority group of substances to be assessed.

[4] link)

[5] For e.g. Dioxins, Furans and Poly Aromatic Hydrocarbons

[6] For a group of poly- and perfluoro alkylated substances, PFAS

[7] Annex XVII, entry 51

[8] Annex XVII, entry 68

[9] GenX (2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propionic acid), a substance belonging to the group of PFAS, its salts and its acyl halides adopted in 2019; ECHA, Candidate list of Substances or Very High Concern, link)

[10] link)

[11] “Sufficiently protected” is judged based on the 95% protection goal under the Water Framework Directive for environmental species remaining unaffected by their chemicals exposure.

[12] Results are based on toxicity impact modelling for a representative set of over 1700 chemicals (industrial chemicals, pesticides and pharmaceuticals) and comparison to environmental monitoring data on biodiversity.

[13] The phthalates subject of restriction entry 51 in Annex XVII of REACH, are a rather exceptional case, with relatively abundant data on hazard and exposure for the different substances involved.

[14] RCR is the quotient of the concentration of a certain chemical and its no observed effect concentration (NOEC) or derived no effect level (DNEL)

[15] SELMA: Swedish Environmental Longitudinal Mother and child, Asthma and allergy

[16] The term reactive measures is used here to indicate measures that are put in place in reaction to an observed risk related to a concrete chemical or group of chemicals. The term proactive measures is used here to indicate measures that are put in place for substances meeting certain characteristics in anticipation of a possible risk and to prevent this risk from manifesting itself.

[17] To illustrate: the phthalates restriction entry 51, Annex XVII, though limited in scope (the restriction only aimed at four phthalates (so not all phthalates), and focussing only at phthalates in articles for use by the general population (so for instance not at phthalates in food, or at production or occupational exposure)), illustrates that whereas single phthalates in single articles do not pose a risk, there is clearly a risk when combining four phthalates and multiple articles. And the actual risk will be even higher if also other sources (e.g. food) and other populations (e.g. workers) would be additionally taken into account.

[18] These regulatory measures are already being employed on an ad hoc basis.