Search

Humans and wildlife are exposed to an intractably large number of different combinations of chemicals via food, water, air, consumer products, and other media and sources. This raises concerns about their impact on public and environmental health. The risk assessment of chemicals for regulatory purposes mainly relies on the assessment of individual chemicals. If exposure to multiple chemicals is considered in a legislative framework, it is usually limited to chemicals falling within this framework and co-exposure to chemicals that are covered by a different regulatory framework is often neglected. Methodologies and guidance for assessing risks from combined exposure to multiple chemicals have been developed for different regulatory sectors, however, a harmonised, consistent approach for performing mixture risk assessments and management across different regulatory sectors is lacking. At the time of this publication, several EU research projects are running, funded by the current European Research and Innovation Programme Horizon 2020 or the Seventh Framework Programme. They aim at addressing knowledge gaps and developing methodologies to better assess chemical mixtures, by generating and making available internal and external exposure data, developing models for exposure assessment, developing tools for in silico and in vitro effect assessment to be applied in a tiered framework and for grouping of chemicals, as well as developing joint epidemiological-toxicological approaches for mixture risk assessment and for prioritising mixtures of concern. The projects EDC-MixRisk, EuroMix, EUToxRisk, HBM4EU and SOLUTIONS have started an exchange between the consortia, European Commission Services and EU Agencies, in order to identify where new methodologies have become available and where remaining gaps need to be further addressed. This paper maps how the different projects contribute to the data needs and assessment methodologies and identifies remaining challenges to be further addressed for the assessment of chemical mixtures., Highlights • Mapping EU funded research projects to different aspects of mixture risk assessment. • Overview of current status and methodological developments • Need to further address data and knowledge gaps overarching different chemical sectors

Objectives There is growing evidence that single substances present below their individual thresholds of effect may still contribute to combined effects. In component-based mixture risk assessment (MRA), the risks can be addressed using information on the mixture components. This is, however, often hampered by limited availability of ecotoxicity data. Here, the possible use of ecotoxicological threshold concentrations of no concern (i.e. 5th percentile of statistical distribution of ecotoxicological values) is investigated to fill data gaps in MRA. Methods For chemicals without available aquatic toxicity data, ecotoxicological threshold concentrations of no concern have been derived from Predicted No Effect Concentration (PNEC) distributions and from chemical toxicity distributions, using the EnviroTox tool, with and without considering the chemical mode of action. For exposure, chemical monitoring data from European rivers have been used to illustrate four realistic co-exposure scenarios. Based on those monitoring data and available ecotoxicity data or threshold concentrations when no data were available, Risk Quotients for individual chemicals were calculated, to then derive a mixture Risk Quotient (RQmix). Results A risk was identified in two of the four scenarios. Threshold concentrations contribute from 24 to 95% of the whole RQmix; thus they have a large impact on the predicted mixture risk. Therefore they could only be used for data gap filling for a limited number of chemicals in the mixture. The use of mode of action information to derive more specific threshold values could be a helpful refinement in some cases., Graphical abstract Unlabelled Image, Highlights • The EnviroTox database and tool is a powerful tool to derive environmental threshold concentrations. • The ecoTTC approach can be used for data gap filling. • For mixture assessment, it can be used for a limited number of chemicals only. • In some case the Mode of Action can be used to refine the surrogate value.

Pharmaceutical excipients for topical use may contain impurities, which are often neglected from a toxicity qualification viewpoint. The possible impurities in the most frequently used topical excipients were evaluated in-silico for their toxicity hazard. Acetol, an impurity likely present in different topical pharmaceutical excipients such as propylene glycol and glycerol, was withheld for the evaluation of its health risk after dermal exposure.An ex-vivo in-vitro permeation study using human skin in a Franz Diffusion Cell set-up and GC as quantification methodology showed a significant skin penetration with an overall Kp value of 1.82Ã10â3 cm/h. Using these data, limit specifications after application of a dermal pharmaceutical product were estimated. Based on the TTC approach of Cramer class I substances, i.e. 1800 µg/(dayâperson), the toxicity-qualified specification limits of acetol in topical excipients were calculated to be 90 µg/mL and 180 µg/mL for propylene glycol and glycerol, respectively.It is concluded that setting specification limits for impurities within a quality-by-design approach requires a case-by-case evaluation as demonstrated here with acetol. Keywords: Acetol, Impurity, Excipients, Transdermal penetration, Specification limits