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Chemical Category Formation: Toxicology and REACH

Chemical Category Formation: Toxicology and REACH. Dr Steven Enoch Liverpool John Moores University 14 th May 2009. Is Regulatory Toxicology Important?. Number of stories about the toxicity of chemicals. Is Regulatory Toxicology Important?. Number of stories about the toxicity of chemicals

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Chemical Category Formation: Toxicology and REACH

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  1. Chemical Category Formation: Toxicology and REACH Dr Steven Enoch Liverpool John Moores University 14th May 2009

  2. Is Regulatory Toxicology Important? • Number of stories about the toxicity of chemicals

  3. Is Regulatory Toxicology Important? • Number of stories about the toxicity of chemicals • Many chemicals have little or no toxicological data • Concerns about the potential toxicity of chemicals • New REACH legislation regarding chemical safety • Applies to excipients, intermediates etc • Cosmetics directive prohibits animal testing

  4. REACH and Intelligent Testing Strategies In chemico In silico Risk Assessment In vitro In vivo

  5. In-silico Category Formation • Structural • Mechanistic • Toxicological • Qualitative and quantitative predictions

  6. In-silico Category Formation • Structural • Mechanistic • Toxicological • Qualitative and quantitative predictions

  7. Mechanistic Category Formation – Skin Sensitisation

  8. Electrophilic Reaction Chemistry • Six key chemical reactions have been defined for protein reactivity1 • All known skin sensitising chemicals can be assigned to one of these mechanisms • SMARTS based rules have been developed2 1Aptula AO and Roberts DW (2006) Chem ResToxicol 19; 1097-1105 2Enoch SJ et al (2008) SAR QSAR Environ Sci 19; 555-578

  9. Mechanism for Michael Addition X = electron withdrawing substituent e.g. CO, CHO, NO2, CO2R.

  10. Mechanistic Category Formation

  11. Read-Across within a Mechanistic Category • Qualitative read-across using only mechanistic assignment • Quantitative read-across using the electrophilicity index () to model protein reactivity within a category3 • Electrophilic index calculated from HOMO and LUMO using DFT 3Enoch SJ et al (2008) Chem Res Toxicol 21; 513-520

  12. Quantitative Electrophilicity (w) Ranking pEC3 = NC, w = 1.10 pEC3 = 0.55, w = 1.49 pEC3 = 1.82, w = 1.55 Increasing electrophilicity (w) Increasing skin sensitising potential (pEC3) pEC3 = 1.25, w = 1.61 pEC3 = 1.64, w = 2.10 pEC3 = 4.04, w = 3.90

  13. Quantitative Read-Across Predictions Chemical A: w = 1.61,EC3 = 5.5, pEC3 = 1.25 Chemical X: w = 1.73 Pred. pEC3 = 1.29 (1.31) Pred. EC3 = 9.87 (9.30) Chemical B: w = 1.80,EC3 = 7.5, pEC3 = 1.30

  14. Toxicological Category Formation - Developmental Toxicity

  15. Mechanistic read-across requires a priori mechanistic knowledge What about category formation when we don’t know about the mechanism of action? Can we use chemical similarity to form categories?4 Read-Across within a Toxicological Category 4Enoch SJ et al (2009) QSAR Comb Sci in-press

  16. Qualitative Read-Across Read-across prediction (atom environment similarity): D / X Actual classification: D

  17. Qualitative Read-Across Read-across prediction (fingerprint similarity): B Actual classification: B

  18. Regulatory QSAR Tools • OECD QSAR Application Toolbox4 • Chemical category formation • Read-across and trend analysis • Regulatory reporting for ECHA • Toxmatch and Toxtree5 • Similarity based category formation • Rule based category formation 4http://www.oecd.org/document/23/0,3343,en_2649_34377_33957015_1_1_1_1,00.html 5http://ecb.jrc.ec.europa.eu/qsar/qsar-tools/

  19. Conclusions • REACH envisages intelligent testing of chemicals • In silico developed chemical categories play a central role • Qualitative and quantitative predictions of toxicity used to fill data gaps • In silico methods must be transparent and simple in order for regulatory acceptance from EChA

  20. The Future – Intelligent Testing Strategies In chemico In silico ? Risk Assessment In vitro In vivo

  21. Acknowledgements • The funding of the European Chemicals Agency (EChA) Service Contract No. ECHA/2008/20/ECA.203 is gratefully acknowledged

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