International dimension of 3Rs acceptance

…… challenges for industries and regulators EPAA 5-11-2007 Betty Hakkert (personal view)

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Content

• REACH

• REACH testing strategies

• Examples

• Challenges

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REACH Context

• 1….. This Regulation should ensure a high level of protection of Human Health (HH) and Environment (ENV) as well as….. …… This regulation should also promote the development of alternative methods for the assessment of hazards of substances

• 16 …..The Regulation is based on the principle that industry should manufacture, import or use substances or place them on the market with such responsibility and care as may be required to ensure that….HH and ENV are not adversely affected.

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REACH Context: Information Requirements

• Annex VI Guidance on fulfilling requirements of Annexes VII-XIGather and assessment information

• Annex VII to X:Information Requirements is tonnage dependent (number substances):

≥ 1 tonne/y: Annex VII in vitro (20,000)

≥ 10 tonnes/y: Annex VIII base set (5,000)

≥ 100 tonnes/y: Annex IX additional testing (2500)

≥ 1000 tonnes/y: Annex X additional testing (2700)

• Annex XIGeneral rules for adaptation of the standard testing

Annex XI(1): Testing does not appear scientifically necessaryAnnex XI(2): Testing is technically not possibleAnnex XI(3): Exposure-driven waiving/testing

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REACH Context

Annex XI (1) testing does not appear scientifically necessary- Use of existing information, weight of evidence, (Q)SARs, in vitro

methods, grouping/read across

Can be used if:- Suitable methods are used

- Results are adequate for the purpose of Classification and Labelling and/or Risk Assessment

- Adequate and reliable documentation is given

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REACH Context: Information Requirements

Adequate for Classification and Labelling

Important driver under REACH and several other

legislations (e.g. consumer products, transport)

Adequate for Risk Assessment

Information suited to derive a (semi)quantitative dose descriptor

Adequate for PBT, vPvB assessment

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REACH Implementation Projects (RIPs)

RIP 3.3 on information requirements provides guidance for industries how to comply with Annexes VI-XI of the Regulation

This guidance was prepared by experts from Industries, Member States and Commission. Joined action!

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Lessons from RIPs 3.3 (not exhaustive)

• Importance of close collaboration between Industries and Member States/Regulators

• Realisation there are few, if any, alternative methods that could be used as stand alone replacement for C&L, RA and/or PBT assessment

• Further development should focus on regulatory needs and uses

• A method stated to be scientifically validated is not necessarily applicable for a given regulatory purpose

• There is a need for further development and evaluation of integrated testing strategies and refinement of methods (e.g. EU-project OSIRIS)

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Lessons RIPs 3.3: example Three in vitro methods for embryotoxicity that have been considered scientifically valid(ated)*

However, these methods are no replacement of OECD 414 and are (as yet) not suited for (certain) regulatory purposes because:

• They do (as yet) not provide a dose descriptor suited for RA

• They do not include a metabolic system

• The evaluations is based on a limited chemical domain

• There is a need for further refinement for discrimination between non, weak and strong embryotoxicants

• Etc

For use in testing strategies more experience/guidance is needed

• By ECVAM advisory committee ESAC

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Challenges Regulators and Industries

• Regulators should be involved throughout the process of method/testing strategy development in order to assure the methods comply with the regulatory needs

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Anticipated animal use under REACH

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Van der Jagt et al., ECB 2004

70% of experimental animals is required for reproductive toxicity testing in REACH

OECD416

OECD414

OECD421

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Retrospective analyses of existing dataCan hazard assessment be simplified by changing the testing strategy?

• Impact of the second generation in the 2-generation study

(Janer, Hakkert, Slob, Vermiere, Piersma Reprod. Toxicol. 24: 97-102 (2007))

• Comparison of NOELs and critical end points in subchronic versus 2-generation study in the rat

(Janer Hakkert, Piersma, Vermiere, Slob, Reprod. Toxicol. 24: 103-113 (2007))

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Toxicological tests and reproductive toxicity

• Subacute toxicity test

• Subchronic toxicity test

• Chronic toxicity test

• Reproductive/Developmental toxicity screening tests

• Rat two-generation reproductive toxicity test

• Rat developmental toxicity test

• Rabbit developmental toxicity test

What is the impact on C&L and on NOAEL of the rat two-generation study when a subchronic study is available ?

What is the added value of the 2nd generation

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Subchronic study: C&L

The subchronic study did not always detect toxicity to fertility the two-generation studies had an impact on

C&L

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Two-generation vs. Subchronic study: NOAEL

Classified for reproductive toxicity

(n = 47)

Not classified for reproductive toxicity

(n = 75)

The two generation and the subchronic toxicity tests led to similar overall NOAELs

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What is the impact on C&L and on NOAEL of omitting the second generation in a two-generation reproductive toxicity study ?

• Rat two-generation reproductive toxicity test

P0 (parental animals) F1 (first generation) F2 (second generation)

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Impact on Classification and Labelling (n=176)

In general no impact on C&L was observed for the second generation

Impact on NOAELs (n=176)

In general no impact on overall NOAEL

Impact leaving out F1 adults (n=176)

Not maintaining F1 until adulthood could lead to “missing” of effects relevant for C&L and for NOAEL

Note: leaving out 2nd generation saves 1200 animals/study

Main findings added value 2nd generation

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CONCLUSIONS present repro-analyses not exhaustive

• Data base analysis provides important input in refinement/revision of test guidelines/strategies

- Subchronic study is (as yet) insufficient for C&L- 2-gen reproduction study may not be needed to define an overall NOAEL- Omitting the second generation in a 2-gen-reproduction study may go without consequences

for C&L and NOAEL- Not maintaining F1 until adulthood may miss effects relevant for C&L and NOAEL

• The findings support the proposal of an extended 1-generation study (Cooper et al., 2006; Critical Reviews in Toxicology, pg 69-98)

• It is important that additional (confidential) data of industry are made available to further substantiate these conclusions and increase the chemical domain

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These analyses have been brought into the OECD Test Guideline Programme in the project on the extended F1-generation reproduction study (MS, IND, other stakeholders). Importance of mutual acceptance of the revised method because of the high number of animals involved

Need for more information to increase data base a.o. to obtain clear alerts when to conduct 2nd generation

Work in progress by industries/regulatory bodies on conduct of extended F1-generation study

Further work repro-analyses

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Challenges Regulators and Industries 1

Methods should be developed in order to fulfil the regulatory requirements

Regulators/industries should be involved/consulted in all stages of the development of alternative methods/testing strategies (regulatory needs/capacity building)

Development of high quality data basses is essential for Refinement in vivo methods (e.g. example repro) Validation/evaluation alternative methods (e.g. in vitro, “omics”, integrated

methods) Development of models Application of category approaches/reading across

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Challenge to find (acceptable) ways to get/use confidential information from industries to develop/refine methods/testing strategies

In view of the reduction of animals use it is important that methods are widely accepted (e.g mutual acceptance of data of OECD TGs)

Validation/evaluation process should be Transparent and Review Groups should include experts from various field (incl. regulatory knowledge).

Challenges Regulators and Industries (2)

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THANK YOU!