1. General Concepts in QSAR for Using the QSAR Application Toolbox

2. Part IIi Forming Chemical Categories

3. What do we mean by a chemical category?
A chemical category is a group of chemicals with attributes in common:
Structure e.g., common substructure or electronic properties
Property e.g., similar physicochemical, topological, geometrical, or surface properties
Behavior e.g., toxicological response underpinned by common toxicity mechanisms
Function e.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. 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
Source: OECD Manual for Investigation of High Production Volume (HPV) Chemicals. OECD Paris.

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 the QSAR Application Toolbox

8. Part IV QSAR 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

12. QSAR Application Toolbox
General Objectives:
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
-ENV/JM(2006)47

13. Typical queries with the QSAR 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 the QSAR 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
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report 16

17. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
User Alternatives for Chemical ID:
A. Single target chemical
Name
CAS#
SMILES/InChi
Draw Chemical Structure
Select from User List/Inventory
B. Group of chemicals
User List
Inventory
Specialized Databases 17

18. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
General characterization schemes:
Substance information
Predefined
Mechanistic
Empirical
Custom
Metabolism 18

19. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
Compiling Endpoint Data (SIDS plus)
Aquatic Toxicity (complete AQUIRE)
Ecotoxicology (complete ECOTOX)
Bioaccumulation
Mutagenicity
Skin Sensitization
Carcinogenicity
Rodent Repeat Dose
Documented QSAR Estimates 19

20. Forming and Pruning Categories:
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
Forming and Pruning Categories:
Predefined
Mechanistic
Empirical
Custom
Metabolism 20

21. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
Forming and Pruning Categories:
Predefined
OECD categorization
US EPA categorization
Inventory affiliation
Database affiliation
Substance type 21

22. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
Accepted Approaches
Read-across
Trend analysis
QSAR models 22

23. Logical sequence of Using Toolbox components
Chemical
Input
Chemical
Profiling
Hazard
Endpoints
Category
Definition
Filling
Data
Gaps
Report
Report the results:
Estimate Reporting Formats (QMRF)
IUCLID 5 Harmonized Templates
SIDS Data Dossiers
Complete Session History
User-Defined Reports 23

24. 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?