use of read-across & categories under reach...read_across_and_categories_tatiana_netzeva_echa...

Use of Read-across & Categoriesunder REACH

Webinar on Information Requirements

10 December 2009

Outline

• Basic principles of category building and read-across

• Step-wise approach for analogue search and filling of data gaps

• Example on how to report category in IUCLID

Approaches to generate non-test hazard information:

• Grouping of substances

• Read-across from substance or category

• Trend analysis (internal models)

• “Global” QSARs/expert systems (external models)

�� For filling data gaps, prioritization and testing strategies,

in weight of evidence, to avoid unnecessary testing!

Non-test information

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.

Similarities may be based on:

• common functional group

• common precursor or break-down products

• a constant pattern in changing of potency

• common constituents or chemical classes

Grouping of substances

• Common behaviour or consistent trends are generally

associated with a common mechanism/mode of action

• The use of a category approach provides a basis on

which to identify possible trends in properties across

the category

• A substance can belong to more than one category

• Category would ideally include all potential members

when first developed

Chemical categories

• Results are adequate for the purpose of classification

and labelling and/or risk assessment

• Adequate and reliable coverage of the key parameters

are addressed in the corresponding test methods

• An exposure duration comparable to or longer than the

corresponding test method is covered, if the exposure

duration is relevant parameter

• Adequate and reliable documentation of the applied

method is provided

Conditions set in Annex XI

Annex XI of the REACH stipulates that:

Physicochemical properties, human health effects and

environmental effects or environmental fate may be

predicted from data for reference substance(s) 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.

Read-across approach

• One-to-oneOne analogue -> estimation for single chemical

• One-to-manyOne analogue -> estimation for single chemical

• Many-to-oneTwo or more analogues -> estimation for single chemical

• Many-to-ManyTwo or more analogues -> estimations for more chemicals

Qualitative or quantitative

Types of read-across

Step 0

Check if the chemical is already a member of a suitable

existing category (e.g.: OECD HPV categories)

NOTE: in case of new data, reassessment of the category

may be needed

How to develop category?

• Identify similar substances/analogues to form a category - use online search engines (e.g. eChemPortal)- designed tools (eg. OECD QSAR Toolbox)

• Build category hypothesis & definition

Consider functional groups, structural similarities,

metabolic pathways, mechanism/mode of action

• Link data for members by chemical similarities

Step 1


eChemPortal

QSAR Application Toolbox

Step 2 Gather data from each category member

• Perform extensive search to retrieve data that can also be available in the public domain

• Bare in mind:

– purity and impurity profiles

– details on molecular structure

– data on physicochemical properties

– environmental fate parameters

– (eco)toxicological and toxicokinetic data


Step 3Evaluate available data for adequacyE.g. do the data fulfill REACH information requirements either individually or as Weight of Evidence and are adequate for risk assessment and/or C/L?

Step 4Construct a matrix of data availabilityIUCLID 5 can help to build this matrix and can later be used for data gap filling, see (manual under development)


Step 5Perform a preliminary evaluation of the category and fill data gaps

• Verify initial hypothesis of the category

• Analyse trends

• Verify that sufficient, relevant and reliable information is

available for category members

• Justify the category (common endpoints)

• Address each endpoint for data gap filling and its

adequacy for REACH requirements


Step 6Propose and perform testing if necessary

• Additional testing may be necessary for the members

of the category and/or their metabolites

• Testing does not necessarily mean animal testing

– in vitro testing could be useful

– toxicokinetics usually essential for robust categories

• Testing proposals for Annex IX and X endpoints for

substances to be registered under REACH


Step 7Further assessment of the category • If new test data are generated assess the category again

Step 8Document the finalised category and its rationale• Include detailed justification to explain how the

REACH Annex XI criteria for Categories (Grouping of Substances) are metE.g. structural similarities, metabolic pathways, trend analysis, Mode of Action


NOTE: Important aspects to consider

• Analyse & report the impact of different functional groups

• Address constituents, impurities, common precursors and/or transformation products, etc.

• Report impact of toxicokinetic parameters in the acceptance of read-across within the category

• Describe applicability (or not) for all routes of exposure (oral, dermal, inhalation)

MAKE A GOOD CASE


Example how to fill IUCLID

1. Create a category dataset

Remember that a substance has to beregistered, NOT the category. Thecategory dataset will be included in Registration Dossier of the substanceto be registered.

2. Describe the category hypothesis and assign the category members

Make sure that the category members are similar and full and detailed justification is included in the registration dossier regarding fulfilling similarity rules.


3. Select the endpoints applicable to your category

A category does not necessarily meanthat all endpoints and routes of exposure can be covered using read across from one member to another.


4. Provide all necessary justification(s) and report(s)

Detailed justification is required to include adequate informationon structural similarities, commonbreakdown products, mode of action and/or trend analysis.


5. Generate the matrix (high level view on data available)


The matrix could contain more than one value for endpoints. However, it does not provide a justification for why the value is included. A data gap should be filled possibly by interpolation than by extrapolation.

6. When ready, a REACH submission dossier can be created, containingthe category data

Include all available information retrieved (also from public domain)to increase the robustness of the category


• Guidance on information requirements and chemical safety assessment: R6: QSARs and grouping of chemicals

• OECD Guidance on grouping of chemicalshttp://www.oecd.org/env/existingchemicals/qsar

• OECD QSAR Toolbox websitehttp://www.oecd.org/env/existingchemicals/qsar

• JRC Computational toxicology websitehttp://ecb.jrc.ec.europa.eu/qsar/

Useful links

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