APPENDIX IV OECD GUIDELINES FOR TESTING OF CHEMICALS 1- The OECD Test Guidelines submission and adoption process The OECD Test Guidelines Programme provides the mechanism for developing new Test Guidelines, and/or updating existing Guidelines. OECD Test Guidelines are broadly accepted by the international scientific community and by appropriate regulatory authorities of OECD Member countries and a number of Non-Member countries. The Joint Meeting of the Chemicals Committee and Working Party on Chemicals, Pesticides and Biotechnology (the Joint Meeting) is the OECD policy body that oversees the implementation of the Test Guidelines Programme. The Joint Meeting reviews and endorses draft Test Guidelines, and builds consensus to overcome policy differences that would otherwise jeopardise progress in Test Guideline development. A pivotal role in this Programme has been assigned to the Working Group of National Co-ordinators of the Test Guidelines Programme (WNT). The European Commission (EC) participates in this group, along with the National Co-ordinators from Member countries as appointed by their respective National Delegations to the Joint Meeting. Other invited experts also participate, as agreed by the Joint Meeting. The WNT considers proposals for new and updated Guidelines for the work programme and prioritises such proposals. The WNT meets yearly, usually in late May or early June. Any proposal to develop a new, or update an existing, Test Guideline should include a critical appraisal concerning its scientific justification, its sensitivity, and its reproducibility. New methods, and existing Test Guidelines for which major revisions are proposed, should be validated as appropriate prior to their adoption. The process of validation is flexible, but transparency is essential. Proposals to develop new or updated Test Guidelines should be supported by valid arguments, which explain that there is a need for such a new or updated, supported by regulatory arguments. These should include at least one of the following; That the proposal will achieve further progress in international harmonization of datarequirements; That scientific arguments indicate the importance of the or the modifications; That the proposal addresses issues and/or endpoints which are of major human health or environmental concern. That there are animal welfare advantages to the proposed /procedure with respect to the 3R s(replacement, reduction and refinement) without loss of essential information; That the proposed /procedure will result in reduced cost without loss of essential information. When there is a recognised need for new or updated Test Guidelines, the development/update of these Test Guidelines, as part of the overall work programme approved by the Joint Meeting, can be realised in one of two ways: (i), by beginning with a Detailed Review Paper of the area concerned or, when a particular method has not yet emerged as the preferred one, (ii) by drafting a Test Guideline proposal
When a new/revised is developed sufficiently to be proposed as an OECD Test Guideline, submission to the OECD Secretariat may be done by any of the following processes: a Member country, or the European Commission, through its National Co-ordinator; industry, trade unions, environmental citizen organisations, and animal protection organisations through their representative invited experts on the WNT Detailed information about the basis for the and its performance should be documented and available for review, including the validation study reports, any specific data requested by the validation management group, and the peer review report. Details of the process for adopting a method as an OECD Test Guideline are provided in a separate Guidance Document (OECD (1995), which is currently under review. If the draft Test Guideline proposal meets the OECD criteria, it is submitted to the National Coordinators for their review. Through the WNT, National Experts review the proposals for technical content and policy issues such as animal welfare, cost effectiveness and consistency with national regulatory requirements. National Co-ordinators consider the comments from their National Experts and submit National Positions on the proposals. After consensus is reached among Member countries, draft Test Guideline proposals are approved by the WNT, either at the WNT meeting or by written procedure. These proposals are forwarded to the Joint Meeting for their review and endorsement. The Joint Meeting is held about every eight months. A draft Test Guideline rejected by the Joint Meeting will be referred back to the WNT for their reconsideration, together with the reason for its rejection. After the Joint Meeting endorses a new or revised Test Guideline, the Secretariat submits the Test Guideline proposal to the Environment Policy Committee (EPOC). As part of this process, EPOC is invited to review the draft Test Guidelines proposal, within an agreed timeframe (which should be at least six weeks after submission), and, if appropriate, agree to its submission to the Council for formal adoption. The Secretariat can respond to comments from EPOC in a number of ways, ranging from making straight-forward edits and corrections to the proposal, through to referring the comments to the WNT, in which case the modified proposal will again be submitted to the Joint Meeting and EPOC for their approval and endorsement. When any EPOC issues have been resolved, the Secretariat submits the draft Test Guideline Proposal, together with a summary of its rationale and political/social implications for Member countries, to the Council with the request to adopt the Test Guideline under the written procedure. Test Guidelines adopted by the Council become effective from the date of Council adoption. The Secretariat then arranges for publication at the earliest possible date. The total time period from submission of a draft Test Guideline proposal to the formal adoption by Council of a new or updated Test Guideline varies. In cases where well-written draft proposals fulfil the general OECD requirements for a new or updated Test Guideline, and are accompanied by the necessary background documentation (including documented validation study, independent peer review), the period from submission to adoption can be within 18 months. Proposals that are less well developed and supported take a longer the time period, dependent upon the number of iterations required by the WNT and/or Joint Meeting, and the complexity of the issues to be resolved.
2- Overview of currently available and draft guidelines of Section 4- Health Effects Original adoption date and the most recent updates together with improvements considering the 3R: reduction, refinement and replacement. The list also covers the la drafts and their status and is divided into two sections; short and long-term toxicology ing and genetic toxicology ing. OECD Guidelines on Short and Long Term Toxicology Testing TG No. Title Original A d o p t i o n Most Recently Updated 401 Acute Oral Toxicity 12 May 1981 Date of Deletion: 20 December 2002 402 Acute Dermal Toxicity 12 May 1981 24 February 1987: Animal (Reduction method) compared to the original TG from 1981, lowering of the dose level 403 Acute Inhalation Toxicity 12 May 1981 Animal 404 Acute Dermal Irritation/Corrosion 405 Acute Eye Irritation/Corrosion 12 May 1981 24 April 2002: Animal (Refinement/reduction tiered ing strategy regarding the original OECD TG), including in vitro screens 12 May 1981 24 April 2002: Animal ; (Refinement/reduction tiered ing strategy regarding the original OECD TG),including in vitro screens, 406 Skin Sensitisation 12 May 1981 17 July 1992: : Animal (Reduction method by 50% compared to original OECD TG) 407 Repeated Dose 28-Day Oral Toxicity Study in Rodents 408 Repeated Dose 90-Day Oral Toxicity Study in Rodents 409 Repeated Dose 90-Day Oral Toxicity Study in Non- 12 May 1981 27 July 1995: Animal (Refinement method compared to original OECD TG)more information on best dosing practice, more information from the same animal. 12 May 1981 21 September 1998: Animal 12 May 1981 21 September 1998: Animal
Rodents 410 Repeated Dose Dermal Toxicity: 28-Day 411 Subchronic Dermal Toxicity: 90-Day 412 Repeated Dose Inhalation Toxicity: 28/14-Day 413 Subchronic Inhalation Toxicity: 90-Day 414 Prenatal Developmental Toxicity Study 12 May 1981 Animal 12 May 1981 Animal 12 May 1981 Animal 12 May 1981 Animal 12 May 1981 22 January 2001: Animal (Reduction method regarding the original OECD TG) [use (-20% animals), more information from the same animal] 26 May 1983 Animal 415 One-Generation Reproduction Toxicity 416 Two-generation 26 May 1983 22 January 2001: Reproduction Toxicity Study Animal 417 Toxicokinetics 4 April 1984 Animal 418 Delayed Neurotoxicity of 4 April 1984 27 July 1995: Animal Organophosphorus Substances Following Acute Exposure 419 Delayed Neurotoxicity of Organophosphorus Substances:28-Day Repeated Dose Study 420 Acute Oral toxicity Fixed Dose Procedure (FDP) 421 Reproduction/Developmental Toxicity Screening Test 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test 4 April 1984 27 July 1995: Animal 17 July 1992 17 December 2001: Animal (Reduction, refinement method regarding the conventional TG 401). Less suffering, smaller number of animals 27 July 1995 Animal (reduction method compared to original TGs) New Screening provides essential information with a minimum number of animals. 22 March 1996 Animal (reduction method compared to the individual TGs). Combines the new screening on reproduction toxicity with TG 407 and
423 Acute Oral Toxicity Acute Toxic Class Method (ATC) 424 Neurotoxicity Study in Rodents 425 Acute Oral Toxicity: Up-and- Down Procedure 426 Developmental Neurotoxicity Study 427 Skin Absorption: In vivo method 428 Skin absorption: In vitro method 429 Skin Sensitisation: Local Lymph Node Assay 430 In Vitro Skin Corrosion: Transcutaneous Electrical Resistance Test (TER) 431 In Vitro Skin Corrosion: Human Skin Model Test further reduces the number of animals to an absolute minimum for these combined endpoints. 22 March 1996 17 December 2001 Animal (Reduction method regarding the conventional TG 401). Much smaller number of animals (10% of TG 401) 21 July 1997 Animal 21 September1998 Draft New Guideline (April 2004) (April 2004) 17 December 2001: Animal (Reduction method regarding the conventional TG 401). Smaller number of animals, provides a closer estimate of the LD50 than TG s 420 and 423 Animal Submitted to Council for adoption. Animal Submitted to Council for adoption. True alternative to the in vivo method. Full replacement over the TG 427 24 April 2002 Animal (Reduction / refinement method regarding TG 406) allowing more information and less suffering. (April 2004) (April 2004) Submitted to Council for adoption. Nonanimal (Replacement method over the corrosion part of TG 404) Submitted to Council for adoption. Nonanimal (Replacement method over the corrosion
part of TG 404) 432 In Vitro 3T3 NRU phototoxicity (April 2004) Submitted to Council for adoption. Nonanimal. Full replacement (no OECD TG existed for animal ) 433 Acute Inhalation Toxicity: Fixed Dose Procedure (FDP) Draft New Guideline Animal (Reduction, refinement method regarding TG 403). Uses fewer animals and less suffering. 434 Acute Dermal Toxicity: Fixed Dose Procedure (FDP) Draft New Guideline Animal (Reduction, refinement regarding TG 404). Uses fewer animals and less suffering. 435 In Vitro Skin Corrosivity Draft New Guideline Non-animal (replacement method for the corrosion part of TG 404, for specific applications - only applicable to acids & bases) 451 Carcinogenicity Studies 12 May 1981 Animal 452 Chronic Toxicity Studies 12 May 1981 Animal 453 Combined Chronic toxicity/carcinogenicity Studies 12 May 1981 Animal (the combined TG 453 could offer Reduction compared to individual TG 452 + TG 471 Bacterial Reverse Mutation Test 472 Genetic Toxicology: Escherichia coli, Reverse Assay 473 In Vitro Mammalian Chromosome Aberration Test 474 Mammalian Erythrocyte Micronucleus Test 453) 26 May 1983 21 July 1997: In vitro for point mutations *. Non animal (part of strategy) 26 May 1983 Date of deletion: 21 July 1997 (Method merged with TG 471) 26 May 1983 21 July 1997: True alternative to the in vivo. Non animal (part of battery, it does not fully replace the in vivo ) 26 May 1983 21 July 1997: Animal (Reduction
475 Mammalian Bone Marrow Chromosome Aberration Test 476 In Vitro Mammalian Cell Gene Mutation Test 477 Genetic Toxicology: Sex- Linked Recessive Lethal Test in Drosophilia melanogaster 478 Genetic Toxicology: Rodent dominant Lethal Test 479 Genetic Toxicology: In Vitro Sister Chromatid Exchange assay in Mammalian Cells 480 Genetic Toxicology: Saccharomyces cerevisiae, Gene Mutation Assay 481 Genetic Toxicology: Saccharomyces cerevisiae, Mitotic Recombination Assay 482 Genetic Toxicology: DNA Damage and Repair, Unscheduled DNA Synthesis in Mammalian Cells In Vitro 483 Mammalian Spermatagonial Chromosome Aberration Test 484 Genetic Toxicology: Mouse Spot Test 485 Genetic Toxicology: Mouse Heritable Translocation Assay method compared to 1983 version using a smaller number of animals. 4 April 1984 21 July 1997: Animal 4 April 1984 21 July 1997: In vitro for gene mutations (genetic toxicity)*. Non animal (part of strategy) 4 April 1984 Non-animal (flies= non vertebrates) Note: 86/609 defines animals as any live non-human vertebrates 4 April 1984 Animal In vitro for DNA exchanges between sister chromatids (genetic toxicity) *. Non animal (part of strategy) In vitro for gene mutations in Saccharomyces (genetic toxicity*. Non animal (part of strategy) In vitro for mitotic recombination in Saccharomyces (genetic toxicity*. Non animal (part of strategy) True alternative to the in vivo method for DNA damage. Non animal (part of battery, it does not fully replace thein vivo ) 21 July 1997: Animal Animal Animal
486 Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells In Vivo 21 July 1997 Animal All in vitro s on Genetic Toxicology Testing are part of a ing strategy which progresses to animal ing only if necessary (in case of equivocal results)