To facilitate practical application of (Q)SAR approaches in regulatory contexts by governments and industry and to improve their regulatory acceptance, the OECD (Q)SAR project has developed various outcomes such as the principles for the validation of (Q)SAR models, guidance documents as well as the QSAR Toolbox. The Toolbox is a software application intended for governments, the chemical industry and other stakeholders in filling gaps in (eco)toxicity data needed for assessing the hazards of chemicals. It has been developed in close collaboration with the European Chemicals Agency. The Toolbox incorporates information and tools from various sources into a logical workflow. Crucial to this workflow is grouping chemicals into chemical categories.
Quantitative Structure-Activity Relationships Project
(Quantitative) Structure-Activity Relationships [(Q)SARs] are methods for estimating properties of a chemical from its molecular structure and have the potential to provide information on hazards of chemicals, while reducing time, monetary cost and animal testing currently needed.
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Grouping of Chemicals: Chemical Categories and Read-Across
A chemical category is a group of chemicals whose physicochemical and human health and/or ecotoxicological properties and/or environmental fate properties are likely to be similar or follow a regular pattern, usually as a result of structural similarity.
The similarities may be based on the following:
- a common functional group (e.g. aldehyde, epoxide, ester, specific metal ion);
- common constituents or chemical classes, similar carbon range numbers;
- an incremental and constant change across the category (e.g. a chain-length category);
- the likelihood of common precursors and/or breakdown products, via physical or biological processes, which result in structurally similar chemicals (e.g. the metabolic pathway approach of examining related chemicals such as acid/ester/salt).
As a result of these similarities, data gap filling in a chemical category can be carried out by applying one or more of the following procedures: read-across, trend analysis, and (external) (Q)SARs.
A chemical category can be represented graphically as a two-dimensional matrix in which different category members occupy different columns, and the different category endpoints occupy different rows, as illustrated in the following figure.
Graphical illustration of a chemical category
In the read-across approach, endpoint information for one chemical (the source chemical) is used to predict the same endpoint for another chemical (the target chemical), which is considered to be "similar" in some way (usually on the basis of structural similarity or on the basis of the same mode or mechanisms of action). In principle, read-across can be used to assess physicochemical properties, toxicity, environmental fate and ecotoxicity. For any of these endpoints, it may be performed in a qualitative or quantitative manner.
Qualitative read-across is similar to the use of a SAR, and the process involves:
- the identification of a chemical substructure or mode or mechanism of action that is common to two substances (which are considered to be analogues); and
- the assumption that the presence (or absence) of a property/activity for a substance can be inferred from the presence (or absence) of the same property/activity for the analogous substance.
The main application of qualitative read-across is in hazard identification.
Quantitative read-across involves:
- the identification of a chemical substructure or mode or mechanism of action that is common to two substances (which are considered to be analogues); and
- the assumption that the known value of a property for one substance can be used to estimate the unknown value of the same property for another substance.
In both cases, expert judgement is needed and some justification should be provided.
Guidance on chemical categories and read-across
The following guidance documents have been developed by OECD on chemical categories:
Guidance on Grouping of Chemicals, second edition Series on Testing and Assessment No. 194, 2014
Guidance Document for using the OECD (Q)SAR Application Toolbox to develop Chemical Categories according to the OECD Guidance on Grouping of Chemicals, Series on Testing and Assessment No. 102, 2009
Validation of (Q)SAR Models
Although a variety of (Q)SAR models have been developed, and some models have been used in assessment of chemicals in some countries for many years, transparent validation process and objective determination of the reliability of (Q)SAR models are crucial in order to further enhance the regulatory acceptance of (Q)SAR models.
In November 2004, the OECD member countries agreed on the principles for validating (Q)SAR models for their use in regulatory assessment of chemical safety. The agreed principles provide member countries with basis for evaluating regulatory applicability of (Q)SAR models and will contribute to their enhanced use for more efficient assessment of chemical safety.
OECD principles for the Varidation, for Regulatory Purpose, of (Q)SAR Models
A full report from the OECD Expert Group on (Q)SARs was also published in 2004: The report from the Expert Group on (Q)SARs on the validation of (Q)SARs
In February 2007, the OECD published a "Guidance Document on the Validation of (Q)SAR Models" with the aim of providing guidance on how specific (Q)SAR models can be evaluated with respect to the OECD principles. A checklist for the validation, a reporting format for the validation and validation case studies are attached as annexes: