Chemical Category Formation: Toxicology and REACH

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