Guidance for the generation of information on hazards 3rd ...eeas.europa.eu/archives/delegations/india/documents/eu_india/... · 16/09/2008 · 2 QOrganisation for Economic Co-operation

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Guidance for the generation of Guidance for the generation of information on hazards information on hazards

33rdrd IndiaIndia--EU Environment ForumEU Environment Forum

Mumbai, 16 September 2008Mumbai, 16 September 2008

Laurence MussetEnvironment, Health and Safety Division

Environment Directorate

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Organisation for Economic Co-operation and Development

Mutual Acceptance of Data (MAD)- Good Laboratory Practice Principles- Test Guidelines

In vitro test methods

(Quantitative) Structure Activity Relationships (Q)SARs

UCLID5

Introduction

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Organisation for Economic Co-operation and Development

Intergovernmental organisation to:– Discuss issues of mutual concern– Work together to respond to international problems– Co-ordinate and harmonise policies and tools (avoid

duplication of work)– Adopt legal instruments

(All stakeholders are involved: members, selected non members, industry, trade unions, Environmental NGOs, Animal welfare NGOs)

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AustriaBelgiumCzech Republic DenmarkFinlandFranceGermanyGreeceHungaryIrelandItalyLuxembourgNetherlands

PolandPortugalSlovak RepublicSpainSwedenUnited Kingdom

CanadaMexicoUnited states

OECD Member Countries

EU NAFTA

EUROPEAN NON-EU

IcelandNorway SwitzerlandTurkey

ASIA - PACIFIC

AustraliaJapanNew ZealandKorea

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OECD enlargement and engagement with non members

Accession talks with Chile, Estonia, Israel, Russian Federation, Slovenia

Co-operation (enhanced engagement) with India, China, Indonesia, Brazil, South Africa

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Test Guidelines

Mutual Acceptance of DataLegally binding on OECD Member countries

MAD Council Decision open to selected non-members

Good LaboratoryPractice

Mutual Acceptance of Data (MAD)

→Avoids duplication of testing by industry: US $50-60 million saved each year→Reduces use of animals

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1981 “MAD” Decision OECD Council Decision on Mutual Acceptance

of Data in an Assessment of Chemicals including PesticidesC(81)30(Final)

“Decides that the data generated in the testing of chemicals in an OECD Member country in accordance with OECD Test Guidelines and OECD Principles of Good Laboratory Practice shall be accepted in other Member countries for purposes of assessment and other uses relating to the protection of man and the environment.”*

*MAD is not the harmonization of requirements for testing

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1997 “MAD” Decision

OECD Council Decision on the Adherence of Non-Member countries to the Council Acts related to the Mutual Acceptance of Data in the Assessment of Chemicals

C(97)114Final

Sets out a step-wise procedure for non-OECD countries with a significant chemical industry input to take part as full members in this systemSouth Africa, Slovenia and Israel are now full members of that part of the Chemicals Programme involving MAD with the same rights and obligations as member countiesIndia, Singapore, Brazil, Argentina and Malaysia are provisional members

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Good Laboratory Practice (1)

Objective of GLP is to ensure the generation of high quality and reliable non clinical test data related to the safety of chemicals

The 1989 Council Decision-Recommendation on Compliance with Good Laboratory Practice

- requires the establishment of national compliance monitoring programmes based on laboratory inspections and study audits, and

- recommends the use of the Guides for Compliance Monitoring Procedures for Good Laboratory Practice and the Guidance for the conduct of Laboratory Inspection and Study Audits

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Working Group on Good Laboratory Practice (Heads of compliance monitoring programmes in member and adhering non member countries)

Main activities of the Working GroupPublication of advisory and consensus documentsPeriodical on-site evaluation visits: 4 to 5 countries visited each year by a team from the Working GroupTraining courses for inspectors (next in 2009)Work with non members

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Examples of Consensus Documents: - The application of the Principles of GLP to Computerised

Systems (1995)- The Application of the OECD Principles of GLP to the

Organisation and Management of Multi-Site Studies (2002)

Example of Advisory Documents: The Application of the Principles of GLP to in vitro Studies (2004)

Website: http://www.oecd.org/env/glp

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Test Guidelines Programme

Managed by the Working Group of the National co-ordinators (WNT) Projects: Test Guidelines and related documents

Projects Work Plan

Standard Project Submission Form Focus on priorities and needs of member countries

A significant number of projects are related to endocrine disrupters

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Composition of the Working Group of the National Coordinators of the Test

Guidelines Programme (WNT)National Coordinators (NCs) from the 30 OECD member countries + European Commission

NCs from non member countries that are part of MAD: South Africa, Slovenia, Israel

NCs Observers from countries that adhere to MAD provisionally: India, Singapore, Brazil, Argentina

Ad Hoc observers from other countries on a case by case basis, e.g., China

Invited experts from industry and NGOs (animal welfare)

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Steps for Development of TGs

Background Document or Detailed Review Paper (not always necessary)

Proposal for a test method

Validation of the test method (reliability and relevance) according to Guidance Document 34

– (validation may be coordinated by OECD)

Peer review (GD 34)

Test Guideline

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Procedures for development and adoption of Test Guidelines (TGs)

Project for the development of a TG and/or related document submitted to the WNT (Standard Project Submission Form)

Inclusion of the project in the work plan

National Experts in all countries discuss the proposal (Expert Group Meetings in most cases)

NCs and representatives from industry and NGOs send expert comments and national positions on successive versions of the TGs until approval by NCs, generally at a WNT meeting

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TG Adoption OECD Council

Working Group of National Coordinators of the Test Guidelines Programme

Environment Policy Committee

Chemicals Committee

Ad hoc Expert Groups for nearly each project of the work plan

Endocrine Disrupters Testing and AssessmentAG

Validation Management Groups (i) for Mammalian Testing and (ii) for Ecotoxicity Testing

Validation Management Group for Non Animal Testing

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Main Guidance Documents (GDs) for the development of TGs

GD for the Development of OECD Guidelines for the Testing of Chemicals (GD 1)

GD on the Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment (GD 34)

includes 8 main principles/criteria for test method validation

GD on the Recognition, Assessment, and Use of Clinical Signs as Humane Endpoints for Experimental Animals Used in Safety Evaluation (GD 19)

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Objectives of new and updated TGs

New and updated TGs are developed to:

Meet regulatory needs of countries

Reflect scientific progress

Address animal welfare aspects

Improve cost-effectiveness of test methods

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Existing Guidelines for the Testing of chemicals and related documents

Original publication (1981): 51 Test GuidelinesLast update:2007 - Next update expected in October 2008> 115 new or updated Guidelines

Available free of charge since January 2007www.sourceoecd.org

Detailed Review Documents, Guidance documents, validation reports (no MAD)

www.oecd.org/env/testguidelines

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Sections of the Guidelines for the Testing of Chemicals

Section 1: Physical Chemical Properties (22)

Section 2: Effects on Biotic Systems (24)

Section 3: Degradation and Accumulation (14)

Section 4: Health Effects (51)

Section 5: Other TGs (Pesticide Residue Chemistry (5), TGs for in vitro test methods covering both health effects and effects on biotic systems, biocide efficacy?, specific effects of nanomaterals?)

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Different types of OECD Test GuidelinesIn vivo methodsMethods using a reduced number of animals– Incorporating testing strategy e.g. TG 404 (Acute

Dermal Irritation/Corrosion)– Incorporating modules (project on reproductive

toxicity)In vitro methods

- OECD Test Guidelines apply to all types of chemicals (e.g., industrial chemicals, pesticides, cosmetics, others) - substances (and mixtures) - non clinical health safety studies (For pharmaceutical, ICH methods are more currently used) - All Test Guidelines are now developed or updated with consideration of the 3Rs

70 projects in the work plan

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In vitro Test Methods (1): most recently adopted Test Guidelines

TG 428 Skin Absorption: In Vitro Method (2004)

TG 432 In vitro 3T3 NRU Phototoxicity Test (2004)

TG 430 In vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (2004)

TG 431 In vitro Skin Corrosion: Human Skin Model Test (2004)

TG 435 In Vitro Membrane Barrier Test Method for Skin Corrosion (2006)

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In vitro Test Methods (2): Test Guidelines approved by the WNT provisionally)

Stably Transfected Transcriptional Activation Assay for Detecting Estrogenic Activity of Chemicals (JPN)

Mutagenicity: TG 487 In vitro Micronucleus Test (GBR)

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In vitro test methods (3): Test Guidelines under WNT discussion

- In Vitro Skin Irritation Assay (EC)

- In Vitro Method for Identifying Ocular Corrosives and Severe Irritants: Bovine Corneal Opacity and Permeability Test Method (USA)

- In Vitro Method for Identifying Ocular Corrosives and Severe Irritants: Isolated Chicken Eye Test Method (USA)

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In vitro test methods (4): Projects included in the work plan

Cell Transformation assays:

– In vitro SHE Cell Transformation Assay (FRA)

– Cell Transformation Assay using Balb/c 3T3 cell line (JPN)

Genotoxicity

- Comet Assay in Genotoxicity Testing (JPN)

Molecular screening (high throughput) (USA)

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In vitro test methods (4): projects included in the work plan (continued)

Detection of endocrine disrupters:- STTA Assay for the Detection of Estrogen Receptors Agonist and Antagonists (LUMI-CELL) (USA)- Human Recombinant Estrogen Receptor Alpha Binding Assays (2 protocols) (USA+EC+DEU+JPN)- H295R Cell-based Steroidogenesis Assay (USA)- STTA Assay for the Detection of Androgenic and Anti-androgenic Activity of Chemicals (JPN)- STTA Assay for the Detection of Anti-estrogenic activity of Chemicals (JPN)

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In vitro Test Methods (5)- Other Available Documents related to in vitro

test methodsDetailed Review Paper on Cell Transformation Assays for Detection of Chemicals Carcinogens (2007)

Detailed Review Paper on Non-Animal Assays for Metabolism Assessment (final stage)

Detailed Review Paper on Availability of In Vitro receptor assays in Fish for Screening of endocrine modulating activities of Environmental Chemicals (under development)

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Conclusions

A large number of projects are underway in the OECD Test Guidelines Programme

These are conducted to meet the regulatory needs of the member countries/region and to bring a high level of harmonization in testing approaches

All countries are committed to the 3Rs but European legislation is the most stringent in terms of reducing animal use

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Test Guidelines: one of the tools available for Hazard Assessment

In vivo tests

In vitro tests

Toxicogenomics

(Quantitative) Structure/Activity Relationships: Read Across, Categories and (Q)SARs Toolbox)

Data bases (eChemportal)

Integrated approaches

Test Guidelines andMutual Acceptance of Data

Future development of TGs

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(Q)SARs

« Non-testing » information for hazard assessment based on structure alerts/equations

Case study report: Good overview of country uses of predictive methods (2006)

OECD Principles for the Validation, for Regulatory Purposes, of (Q)SAR Models (2004)

Guidance Document on the Validation of (Q)SAR Models (2007) EC lead

(Q)SAR Application Toolbox

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(Q)SARs Application Toolbox (1)

Decision system for governments and industry (mostly funded by the EC) – available since March 2008

Provides direct information in databases, and

Allows the user to built his own predictive model by chemical grouping using:

- the « analogue approach » via read across (few chemicals)

- the « category approach » via read across, trend analysis and QSAR equations (more chemicals)

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The toolbox can be used to:

Fill data gaps in a chemical category using read-across, trend analysis or QSAR modelsExplore a chemical list for possible analogues for each chemicalGroup chemicals based on molecular similarity and reactivity analysisIdentify chemicals with anomalous metabolic pathways or toxicity mechanismsGroup chemicals based on common metabolites

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The different steps:

Chemical input: enter the structureProfiling: find existing information (inclusion in data base, mechanistic information, DNA or protein binding)Endpoints: experimental test results available in the toolboxCategory definition: grouping, i.e., looking for similar structures or mechanismsFilling data gapReport: all steps printed

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User Alternatives for Chemical ID:A. Single target chemical• Name• CAS# • SMILES/InChi• Draw Chemical Structure• Select from User List/InventoryB. Group of chemicals• User List/Inventory• Specialized Databases

Chemicalinput

Profiling CategoryDefinition

Fillingdata gap

ReportEndpoints

Logical sequence of components usage

Toolbox Inventories:US EPA TSCACanadian DSLOECD HPVCs, US EPA HPVCsEU EINECSJapanese MITIDANISH EPA

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General characterization of chemical• Inventory Affiliation: HPVC, LPVC, TSCA, DSL, etc.• Chemical Type: polymers, mixtures, discrete,

inorganic/organic • Chemical Class: aldehyde, phenol, esters, acids etc.• In Existing Category? (OECD, US EPA etc)• Previous Hazard/Risk Assessment Report?• Hazard Indentification:

•Protein/DNA binding•Structural Alerts (BioByte parent analogue)•Cramer Classification (ToxTree)

Chemicalinput


Fillingdata gap

ReportEndpoints


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Chemicalinput


Fillingdata gap

Report

Finding Data for SIDS and Other Endpoints• Selecting Data Base(s):

Toolbox databasesPublicly availableProprietary databases

• Selecting type of extracting data:Measured DataEstimated DataBoth

Endpoints


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Forming Categories:• OECD Categories• Other Established Categories (EPA)• Searches for Analogues (AIM-EPA)• Fragments:

DNA binding alertsProtein binding alertsBioByte SuperfragmentsAtom-centered fragments

Pruning Categories-Subcategory Formation• Mechanisms boundaries• Metabolism boundaries

Chemicalinput


Fillingdata gap

ReportEndpoints


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Data gaps filling approaches• Read-across• Trend analysis• QSAR models

Chemicalinput


Fillingdata gap

ReportEndpoints


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Report the results• QMRF/QPRF/TERF• Harmonized Templates• SIDS Dossiers (Data matrix)

Chemicalinput


Fillingdata gap

ReportEndpoints


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Phase 2: 2008-2011– Other functionalities– Expansion of categorisation mechanisms– Addition of databases– Addition of QSARs– Communication with other tools– Long-term maintenance– Training material

www.oecd.org/env/existingchemicals/qsar

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Conclusion:

the Toolbox integrate existing data, expert knowledge and computational methods to facilitate hazard assessments

The concept makes many QSAR methods readily accessible

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IUCLID 5 (1)

The International Uniform Chemical Information Database on intrinsec and hazard properties of chemical substances is a software tool to manage data set, i.e.,

- create new data sets

- import existing data sets

- merge data sets

- store data sets

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IUCLID 5 (2)

Used by industry to enter, store information, generate and submit dossiers on chemical substances to the EC, OECD and other governments

IUCLID 5 data comply with the REACH legislation requirements, and with requirements of OECD HPV chemicals programme, US HPV Challenge programme, Japan Challenge programme

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IUCLID 5 (3)

Implement the OECD harmonized templates: standards data format for reporting results of studies (e.g., all endpoints covered by OECD Test Guidelines) or (Q)SARs

Allows exchange of data electronically between different programmes on chemicals (e.g., REACH and OECD)

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IUCLID 5 (4)

A IUCLID data set can be prepared for a substance or complex mixture

IUCLID 5 is downloadable free of charge at: http://iuclid.eu

Frequently Asked QuestionsManuals / Video tutorials