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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?.

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chemical category formation toxicology and reach

Chemical Category Formation: Toxicology and REACH

Dr Steven Enoch

Liverpool John Moores University

14th May 2009

slide2

Is Regulatory Toxicology Important?

  • Number of stories about the toxicity of chemicals
slide3

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
reach and intelligent testing strategies
REACH and Intelligent Testing Strategies

In chemico

In silico

Risk Assessment

In vitro

In vivo

slide5

In-silico Category Formation

  • Structural
  • Mechanistic
  • Toxicological
  • Qualitative and quantitative predictions
slide6

In-silico Category Formation

  • Structural
  • Mechanistic
  • Toxicological
  • Qualitative and quantitative predictions
slide8

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

slide9

Mechanism for Michael Addition

X = electron withdrawing substituent e.g. CO, CHO, NO2, CO2R.

slide11

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

slide12

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

slide13

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

slide15
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

slide16

Qualitative Read-Across

Read-across prediction (atom environment similarity): D / X

Actual classification: D

slide17

Qualitative Read-Across

Read-across prediction (fingerprint similarity): B

Actual classification: B

slide18

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/

slide19

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
the future intelligent testing strategies
The Future – Intelligent Testing Strategies

In chemico

In silico

?

Risk Assessment

In vitro

In vivo

slide21

Acknowledgements

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