International dimension of 3Rs acceptance

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• 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-XI
• Gather 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 XI
• General rules for adaptation of the standard
  testing
• Annex XI(1) Testing does not appear
  scientifically necessary
• Annex XI(2) Testing is technically not possible
• Annex 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 CL, 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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OECD416
OECD414
OECD421
70 of experimental animals is required for
reproductive toxicity testing in REACH
Van der Jagt et al., ECB 2004
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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 CL 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 CL
The subchronic study did not always detect
toxicity to fertility ? the two-generation
studies had an impact on CL
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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 CL 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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Main findings added value 2nd generation
Impact on Classification and Labelling
(n176) In general no impact on CL was observed
for the second generation Impact on NOAELs
(n176) In general no impact on overall NOAEL
Impact leaving out F1 adults (n176) Not
maintaining F1 until adulthood could lead to
missing of effects relevant for CL and for
NOAEL Note leaving out 2nd generation saves
1200 animals/study
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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 CL
• 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 CL and NOAEL
• Not maintaining F1 until adulthood may miss
  effects relevant for CL 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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Further work repro-analyses
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
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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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Challenges Regulators and Industries (2)
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).
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• THANK YOU!