Exposure informed testing under REACH

Transcription

1 Exposure informed testing under REACH SETAC Europe Special Science Symposium REACH, October Theo Vermeire (RIVM), Marja van de Bovenkamp (RIVM), Hans Marquart (TNO) 1

2 2 Outline Background Exposure and ITS Legal aspects Justification Examples Methodology Conclusions

3 3 REACH goals High level of protectionof human health and the environment including promotion of alternative methods for assessment of hazards Free circulation of substances on the internal Market while enhancing competitiveness and innovation

4 4 Alternatives and ITS (Q)SAR omics read across categories in vitro Exposure/TTC optimized in vivo

5 5 Exposure and ITS Exposure based waiving Exposure is low -> low probability that the acquisition of additional effects information will lead to an improvement in the ability to manage the risk. Exposure based triggering Exposure high enough to justify testing above the requirements laid down in Annexes VI-X.

6 6 Legal aspects Exposure Based Waiving (EBW), endpoint specific Mentioned in Column 2 of Annexes VIII-X Exposure Based Triggering (EBT), endpoint specific If CSA shows risks indicating the need further research Annex XI(3) mentions the conditions for SUBSTANCE- TAILORED EXPOSURE-DRIVEN TESTING Requires exposure assessment and Exposure Scenario, according to Annex 1(5). Testing in accordance with sections 8.6 (repeated dose tox) and 8.7 (reproductive tox) of Annex VIII, and testing according to Annex IX and Annex X may be omitted, based on exposure scenario(s) Below predefined limits in preparations: no CSA (0.1% w/w, 0.02% v/v)

7 7 Column 2 Human tox testing: Implementation of appropriate RMMs for genotoxic substances Exclusion of exposure routes Environmental testing: No emission (bacterial inhibition) Ready biodegradability (simulation testing) Absence of exposure (soil toxicity, bioaccumulation)

8 8 Situation for EBW Justification Certain needed uses are excluded: Specific use or limited emissions substance is a solid and no dusts are formed). Testing or risk assessment? EBW/EBT risk and Exposure Scenario based Justification: Qualitative: Specific operational or use conditions Explanation o no consumer application o no professional application Emissions to certain environmental compartments are excluded (e.g., air emissions are irrelevant because the Low exposure, due to e.g. small amounts used in total or low emissions/ exposure to the substance, for instance due to a combination of substance properties (low vapour pressure, solids etc.) and negligible emissions due to low emission rates and/or tonnage, low frequency of use etc. Use is in (semi) closed systems, leading to limited or negligible exposure that should be argued in a qualitative or semi-quantitative way Use in strictly controlled systems with extensive PPE due to the toxicity of the substance Intensity of use (duration, frequency) Substance properties Infrequent use due to the function of the substance such as specialty products for highly specific occupational situations with a low frequency and duration Physico-chemical properties of the preparation or article. For instance when a substance is covalently bound to a matrix, e.g. plastic additives)

9 9 Justification Testing or risk assessment? Justification: Qualitative: Quantative: exposure < no-further action level* PEC < PNEC: PNEC can often be derived by extrapolation, even to other compartments, If not, use a toxicological threshold value? Exposure < DNEL or DMEL: DNEL/DMELcannot be derived from data on other endpoints. Is there a role for some sort of toxicological threshold value? * REACH: limited / no / no significant / low / not relevant exposure

10 10 EBW possibilities limited All life cycle stages The whole supply chain All exposure routes Not for Annex VII Annex XI EBW: repeated dose and reproductive toxicity tests in Annex VIII, Tests in Annex IX and X. Column 2 environment for simulation tests, bioaccumulation test, toxicity soil organisms, bacterial inhibition

11 11 TTC in RA paradigm (Kroes et al., 2005)

12 12 TTC in RA paradigm (Kroes et al., 2005) Criticisms: Are exposures below TTC/ETNC without risk? What is applicability domain? TTC/ETNC not available for all routes, compartments, endpoints TTCs for humans based on bw of 60 kg ETNC only for direct effects on aquatic organisms ETNC does not take biodegradation/metabolism into account..

13 13 Exposure estimate Model criteria: Should be able to estimate low exposures with resolution in the lower range Should be valid in the lower exposure range Input parameters can be estimated with sufficient validity It is indicated where data fit in the distribution of exposure levels Specific important parameters included? Duration, frequency of use/emission Amount of substance used Emission potential (e.g., dustiness/volatility)

14 14 Exposure estimate Model criteria (continued): Particle size Evaporation from skin Aerosol formation Coating RMM, PPE Criteria for measured data Should obey strict reliability criteria Representative for Exposure Scenarios considered LOQ < No-Further-Action-Level

15 15 Model analysis EUSES Stoffenmanager RISKOFDERM ECETOC Web Tool ECETOC TRA https// CONSEXPO

16 16 Probability density To waive or not to waive I EBW A B NO EBW log PEC (exposure/nfal) / PNEC

17 17 Probability density exposure Cumulative density effect To waive or not to waive II exposure adverse effect Expected risk 9% Dose

18 18 Conclusions REACH only allows EBW in a limited number of cases. EBW/EBT requires a very thorough exposure assessment No-Further-Action-Level needs further research. EBW possible if exposure distribution clearly below a no-further action level If a conservative deterministic exposure estimate is not clearly below NFAL: either testing or a higher tier exposure/uncertainty assessment is needed Probabilistic (skewed) distributions of measured or modelled exposure: wat is acceptability criterion for deciding exposure is below NFAL? Criteria for models and measurements can be specified

19 19 Further work Describe improvements of models for use within EBW Gather probability density functions for use in uncertainty analysis Uncertainty analysis using probabilistic techniques Integration of EBW/EBT in ITS for different human and environmental endpoints

20 20 Acknowledgements Thanks to: Joost Bakker, Jos Bessems, ZhiChao Dang, Jacqueline van Engelen, Sjöfn Gunnarsdottir, Betty Hakkert, Werner Hagens, Cees de Heer, Elbert Hogendoorn, Ingrid Links, Richard Luit, Janneke Mikkers, Theo Traas, Maaike van Zijverden, This work was supported by the EU 6 th Framework Integrated Project OSIRIS (contract no. GOCE-ET ) ( the Netherlands Ministries of Housing, Spatial Planning and the Environment and Social Affairs and Employment, and RIVM Reference: Vermeire TG et al Exposure informed testing under REACH. RIVM report /2008, TNO-report V RIVM, Bilthoven and TNO, Zeist, The Netherlands