1. General Concepts in QSAR for Using theQSAR Application Toolbox

2. Part IIiForming Chemical Categories
3. What do we mean by a chemical category?
A chemical category is a group of chemicals with attributes in common:
Structuree.g., common substructure or electronic properties
Propertye.g., similar physicochemical, topological, geometrical, or surface properties
Behaviore.g., toxicological response underpinned by common toxicity mechanisms
Functione.g., preservatives, solvents, detergents, fragrances, lubricants , heat transfer, etc.
4. Annex IX of REACH
Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or category of substances.
Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for a reference substance within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint.
5. Source:OECD Manual for Investigation of High Production Volume (HPV) Chemicals. OECD Paris.
OECD Definition of Category
A chemical category is a group of chemicals whose physicochemical and toxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity
These structural similarities may create a predictable pattern in any or all of the following parameters: physicochemical properties, environmental fate and environmental effects, and human health effects
6. Forming Chemical Categories
Chemical categories are being grouped based on attributes important to toxicological behavior
Literature and other data sources are used to organize available data for common assessment endpoints
Read-across and trend analysis are used to extrapolate the data from tested chemicals to untested chemicals
In many cases, the analysis of trends (our examples in this lecture) is used to designate the boundaries for similarity in each of the categories
7. General Concepts in QSAR for Using theQSAR Application Toolbox
8. Part IVQSAR and the OECD Toolbox
Integrating Methods for Convenience, Consistency and Documentation
9. Why Do We Need the QSAR Toolbox?
Defining category boundaries requires the calculation of complex attributes of chemicals to determine which attributes best explain available data
In many cases, metabolic simulators are needed to provide metabolic maps and active metabolites
To do trend analysis, hundreds of available data must be compiled and flexibly analyzed for trends
10. QSAR Application Toolbox
Filling data gaps using available test data
and principles of predictive toxicology
Developed for OECD and ECHA by the Laboratory of
Mathematical Chemistry, Bourgas, Bulgaria
Professor Ovanes Mekenyan, Head
11. 12. General Objectives:
-ENV/JM(2006)47
QSAR Application Toolbox
Improve accessibility of (Q)SAR methods and databases
Facilitate selection of chemical analogues and categories
Integrate metabolism/mechanisms with categories and QSAR
Assist in the estimation of missing values for chemicals
13. Typical queries with theQSAR Application Toolbox
Is the chemical included in regulatory inventories or existing chemical categories?
Has the chemical already been assessed by other agencies/organizations?
Would you like to search for available data on assessment endpoints for each chemical?
14. Typical queries with theQSAR Application Toolbox
Explore a chemical list for possible analogues using predefined, mechanistic, empiric and custom-built categorization schemes?
Group chemicals based on common chemical/toxic mechanism and/or metabolism?
Design a data matrix of a chemical category?
15. QSAR Toolbox Workflow
The first version of the QSAR Toolbox is designed to
facilitate the work of hazard assessors in filling data gaps
for untested chemicals through the use of chemical categories
16. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
17. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
User Alternatives for Chemical ID:
A. Single target chemical

Name 18. CAS# 19. SMILES/InChi 20. Draw Chemical Structure 21. Select from User List/Inventory

B. Group of chemicals

User List 22. Inventory 23. Specialized Databases

Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
General characterization schemes:

Substance information 24. Predefined 25. Mechanistic 26. Empirical 27. Custom 28. Metabolism

Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
Compiling Endpoint Data (SIDS plus)

Aquatic Toxicity (complete AQUIRE) 29. Ecotoxicology (complete ECOTOX) 30. Bioaccumulation 31. Mutagenicity 32. Skin Sensitization 33. Carcinogenicity 34. Rodent Repeat Dose 35. Documented QSAR Estimates

Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
Forming and Pruning Categories:

Predefined 36. Mechanistic 37. Empirical 38. Custom 39. Metabolism

Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
Forming and Pruning Categories:

Predefined 40. OECD categorization 41. US EPA categorization 42. Inventory affiliation 43. Database affiliation 44. Substance type

Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
Accepted Approaches

Read-across 45. Trend analysis 46. QSAR models

Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Category
Definition
Filling
Data
Gaps
Report
Hazard
Endpoints
Report the results:

Estimate Reporting Formats (QMRF) 47. IUCLID 5 Harmonized Templates 48. SIDS Data Dossiers 49. Complete Session History 50. User-Defined Reports

Summary
Explore a chemical list for possible analogues using predefined, mechanistic, empiric and custom-built categorization schemes?
Group chemicals based on common chemical/toxic mechanism and/or metabolism?
Design a data matrix of a chemical category?