Überblick über REACH: Anforderungen Annex VII bis X Adaptierungsmöglichkeiten mit Beispielen
DGPT Advanced Course
Ulrike REUTER
Senior Scientific Officer
European Chemicals Agency
09. März 2015
Overview
• ECHA
• REACH Standard Information Requirements
• Testing strategies for skin/eye irritation and sensitisation
• Mutagenicity: new in vivo test methods
• Repeated dose toxicity studies
• Screening tests reproductive toxicity
• Developmental toxicity studies
• Two-generation reproductive toxicity study / EOGRTS
• Dossier Evaluation
• Testing proposals
• Compliance checks
• General Adaptation Possibilities (Annex XI)
• Weight of evidence
• Read across
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ECHA
Evaluation:
E at REACH and ECHA
• Directorate of Evaluation
• Director: Leena Ylä-Mononen
• 3 Evaluation Units
• Heads of Units:
Guilhem de Seze (E1), Claudio Carlon (E2), Ofelia Bercaru (E3)
• 9 Dossier Evaluation Groups (DEGs)
• Co-operation with Directorates A (Communications), B (Legal Affairs and MSC-Secretariat), C (Substance Identity, QSAR), D (Exposure Assessment & Risk Management)
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Stakeholder environment
DGPT Advanced Course 9 March 2015
Registrants Science Community
International Activities
(e.g. OECD TG, GLP)
National Enforcement Authorities
EU Agencies
European Commission
Media
Industry Groups
Non-governmental organizations
LAU SID
Dir E BoA
ECHA
Forum
MSC MSCA
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BoA = Board of Appeal; Dir E = ECHA directorate evaluation; LAU = ECHA legal affairs unit; SID = Substance identity; MSC = Member State Committee;
REACH
Standard
Information
Requirements
(Carcinogenicity)
EOGRTS
2nd PNDT
(EOGRTS)
1st PNDT
Rep. dose 90-d
Rep. dose 28-d
Screening tests
Toxicokinetics
Mutagenicity in vitro / in vivo
Acute tox inhal/derm
Acute tox oral
Mutagenicity, Ames
Skin sensitisation
Skin/eye irritation
or corrosion
Annex VII VIII IX X
tpa 1-10 10-100 100-1000 >1000
REACH standard information requirements
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Testing strategies for skin/eye irritation and sensitisation
•DGPT Advanced Course 9 March 2015
Testing strategies for eye irritation/corrosion
New/revised test methods for eye irritation/corrosion
• Bovine Corneal Opacity and Permeability test Method (BCOP), EU B.47, OECD 437 (revised 2013)
• Isolated Chicken Eye Test (ICE), EU B.48, OECD 438 (revised 2013)
• Fluorescein leakage method, OECD 460 (adopted 2012)
• Short time exposure (STE) method (Draft OECD TG under discussion)
• Cytosensor Microphysiometer (Draft OECD TG under discussion)
• Acute Eye Irritation/Corrosion, EU B.5, OECD 405 (revised 2012)
ECHA instruction how to use those test guidelines within REACH: http://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_eye_irritation_en.pdf
ECHA Guidance on information requirements and Chemical Safety Assessment, Chapter R.7.a, Section R.7.2. ‘Irritation/corrosion’ in the process of update; Latest draft: http://echa.europa.eu/support/guidance/consultation-procedure/ongoing-reach
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Testing strategies for skin irritation/corrosion
New/revised in vitro test methods for skin irritation or corrosion
Irritation
• Reconstructed human epidermis tests, EU B.46, OECD 439 (revised 2013)
Corrosion
• Transcutaneous electrical resistance test (TER), EU B.40, OECD 430, (revised 2013)
• Human skin model test (includes more than one protocol), EU B.40 bis, OECD 431, (revised 2013)
• In vitro membrane barrier test method, OECD 435 (2006)
ECHA instruction how to use those test guidelines within REACH: http://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_skin_irritation_en.pdf
ECHA Guidance on information requirements and Chemical Safety Assessment, Chapter R.7.a, Section R.7.2. ‘Irritation/corrosion’ in the process of update; Latest draft: http://echa.europa.eu/support/guidance/consultation-procedure/ongoing-reach
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Testing strategies for skin sensitisation
New in vitro test methods for skin sensitisation
• In Chemico Skin Sensitisation, OECD 442C (February 2015)
• In Vitro Skin Sensitisation, OECD 442D (February 2015)
ECHA Guidance under development; guidance will be published under the following link: http://echa.europa.eu/support/oecd-eu-test-guidelines
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Mutagenicity in vivo: new test methods
•DGPT Advanced Course 9 March 2015
Mutagenicity in vivo: new tests
New test methods for in vivo genotoxicity
• In Vivo Mammalian Alkaline Comet Assay, OECD 489 (September 2014)
• Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays, EU B.58, OECD 488 (July 2013)
ECHA instruction how to use those test guidelines within REACH: http://echa.europa.eu/documents/10162/21650280/oecd_test_guidelines_genotoxicity_en.pdf
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IN VIVO test method in TG TGR Comet
Route (in TG) any appropriate route any appropriate route
Test system / target tissue or
cells
usually rodent (transgenic) /
any tissue (incl. germ cell)
usually rodent /
any tissue (excl. germ cell)
GENOTOXICITY endpoint Gene mutations DNA damage
EU / OECD guideline B.58 / 488 none / 489
DURATION of treatment 28 + 3 days (up to 28 + 10
weeks)
2 days (up to 90d, if combined to a
90d study)
NUMBER of GROUPS 5 (3 + NC + PC) 5 (3 + NC + PC)
NUMBER of ANIMALS ≥ 25 (≥ 50 if germ cell long sampling;
≥ 20 if proficient lab) ≥ 25
Ability to study mutagenicity /
genotoxicity in GERM cell
YES (TGR, as described in TG 488,
considered appropriate to measure
mutagenicity in mature germ cells)
Not really (comet, as described in
TG489, not considered appropriate to
measure genotoxicity in mature germ
cells)
Ability to study FROZEN tissue YES (TG 488 mentions possibility to
freeze tissues; no major impact on results)
Not really (no OECD agreed protocols;
freezing can have major impact on results)
COST 150-200 k€
(depend on protocol, e.g. nb of
tissues)
15-30 k€
(depend on protocol, e.g. nb of tissues) 15
Repeated Dose Toxicity Studies
•DGPT Advanced Course 9 March 2015
Repeated Dose Toxicity: route of administration (I) REACH Annex IX, 8.6.1./2., column 1
Sub-chronic toxicity study (90- day), one species, rodent, male and female, most appropriate route of administration, having regard to the likely route of human exposure
REACH Annex IX, 8.6.2, column 2
Testing by the inhalation route is appropriate if: — exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size.
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Repeated Dose Toxicity: route of administration (II)
ECHA Guidance Document R.7.5.4.3
Concerning repeated dose toxicity testing the oral route is the preferred one.
However, dependent on the physico-chemical properties of a substance as well as on the most relevant route of human exposure, the dermal or the inhalation route could also be appropriate as specified in REACH Annex VIII and IX.
ECHA Guidance Document R.7.5.4.3
For local effects route-to-route extrapolation is not an alternative (see ECHA Guidance R.8.4.2) and route-specific information is required (see ECHA Guidance R.8.1.2.6) to derive a route-specific (e.g. inhalation) DNEL that address local effects.
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Inhalation-specific effects
Inhalation-specific effects, e.g.,
• Irritation/corrosion
• Lung overload (respirable particles of low water solubility)
• Lung specific toxicity (e.g., some metal/metal oxides, fibres)
• Hydrolysis or metabolism in the respiratory tract to reactive intermediates (e.g., esters, glycol ethers)
• Specific systemic toxicity following inhalation that may or may not be observed following oral administration (e.g., oral first pass effect)
Substances with inhalation-specific effects for which human inhalation exposure is likely, those need to be addressed:
• Route-specific information (inhalation studies) or
• Qualitative assessment (see ECHA Practical Guide 15)
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Screening tests OECD 421 or 422
•DGPT Advanced Course 9 March 2015
Screening tests OECD 421/422
• Standard information requirement at Annex VIII.
• Could be waived at Annex VIII and IX in case a pre-natal developmental toxicity study or a (one-) or two-generation study is available.
Highly recommended not to waive the screening study at Annex VIII or IX if no (one-) or two-generation study is available (see ECHA Guidance R.7.6. under update)!
• Update of the test methods foreseen which will improve the value of this study for post-natal developmental toxicity
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Screening test OECD 422
• preferred over OECD 421 plus 28-day repeated dose toxicity study (statistical power, animal numbers)
• central study for read-across approaches
• might be used as a part of weight of evidence
• useful as a dose-range finding study for a (one-) or two-generation study
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Developmental toxicity studies
•DGPT Advanced Course 9 March 2015
Developmental toxicity studies Annex IX, 8.7.2. Pre-natal developmental toxicity study
• one species [first species; rat or rabbit],
• most appropriate route of administration [for hazard identification], having regard to the likely route of human exposure [default oral]
• (B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414).
• Annex IX, 8.7.2., column 2: [second species in case of concern]
Annex X, 8.7.2. Developmental toxicity study
• one species [second species; rabbit or rat],
• most appropriate route of administration [for hazard identification], having regard to the likely route of human exposure [default oral]
• (OECD 414).
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Two-generation reproductive toxicity study / Extended one-generation reproductive toxicity study (EOGRTS)
•DGPT Advanced Course 9 March 2015
Two-generation reproductive toxicity study / EOGRTS
Change of REACH Annexes (entry info force 13 March 2015)
Replacement of the two-generation reproductive toxicity study by the extended one-generation reproductive toxicity study (EOGRTS)
ECHA Guidance on information requirements and Chemical Safety Assessment, Chapter R.7.6. ‘Reproductive toxicity’ in the process of update; Latest draft : http://echa.europa.eu/support/guidance/consultation-procedure/ongoing-reach
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Extended one-generation reproductive toxicity study (EOGRTS; OECD 443)
Focus of EOGRTS in REACH is on fertility!
Implementation of EOGRTS in REACH with following design:
• 10 week pre-mating (unless data support shorter pre-mating)
• Highest dose to induce systemic toxicity
• Preferred oral route
• 2nd generation triggered
• Cohort neurotoxicity triggered
• Cohort immunotoxicity triggered
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EOGRTS: trigger for 2nd generation
a) “the substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles, and
b) any of the following conditions are met:
• the substance displays genotoxic effects in somatic cell mutagenicity tests in vivo which could lead to classifying it as Mutagen Category 2, or
• there are indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, or
• there are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches.”
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EOGRTS: trigger for neurotox cohort
• existing information on the substance itself derived from relevant available in vivo or non-animal approaches, or
• specific mechanisms/modes of action of the substance with an association to (developmental) neurotoxicity, or
• existing information from studies on effects caused by substances structurally analogous to the substance being studied suggesting such effects or mechanisms/modes of action.
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EOGRTS: trigger for immunotox cohort
• existing information on the substance itself derived from relevant available in vivo or non-animal approaches, or
• specific mechanisms/modes of action of the substance with an association to (developmental) immunotoxicity, or
• existing information from studies on effects caused by substances structurally analogous to the substance being studied suggesting such effects or mechanisms/modes of action. Agreed to be deleted based on the discussion at the PEG meeting
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Dossier Evaluation
Evaluation overview
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Testing proposals (TP)
•DGPT Advanced Course 9 March 2015
Testing proposals
REACH Article 40: ECHA to examine any testing proposal set out in a registration or a downstream user report for provision of the information specified in Annexes IX and X
Testing proposals for human health endpoints:
• Mutagenicity studies in vivo
• 90-day repeated dose toxicity study by oral, inhalation or dermal route
• Developmental toxicity study in first or second species (rats, rabbits)
• Two-generation reproductive toxicity study / EOGRTS
• Carcinogenicity
Note: TP for those test are also required if registration is at lower tonnage (e.g., Annexes VII or VIII)!
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Testing proposals
Deadline for ECHA: 1 December 2012 for registrations received by 1 December 2010
• 557 dossiers (of adequate substance ID) examined
Deadline for ECHA: 1 June 2016 for registrations received by 1 June 2013
• 2014: 228 dossiers (of adequate substance ID) examined
• 2015/16: ca. 250 dossiers to be examined
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Compliance checks (CCH)
•DGPT Advanced Course 9 March 2015
REACH Evaluation Compliance check (CCH)
7
122
268
733
0
100
200
300
400
500
600
700
800
2010 2011 2012 2013
* 989 – 5.0%
1130 – 5.7%
19772 – 100% Checking registration dossiers
for compliance
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Compliance Checks
• To check whether the information requirements in the registration dossiers are fulfilled (compliant)
• To promote the high quality of registrations
• The Agency may perform a compliance check of any registration dossier
• Some priority setting is suggested in the legislation:
• Concern
• Dossiers where information is submitted separately (opting-out of joint submission)
• Substance is on Community Rolling Action Plan (Substance Evaluation)
• Random selection
• Concern-driven vs random selection: ~ 70 : 30 %
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General
adaptation possibilities (Annex XI)
Weight of Evidence (WoE)
•DGPT Advanced Course 9 March 2015
REACH Annex IX, 1.2.
There may be sufficient weight of evidence from several
independent sources of information leading to the
assumption/conclusion that a substance has or has not a
particular dangerous property, while the information from
each single source alone is regarded insufficient to support
this notion.
[…]
In all cases adequate and reliable documentation shall be
provided.
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Requirements for WoE
• Substance-specific
• Endpoint specific e.g., address the key parameters of an endpoint
• Hazard based
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Example for WoE
Elements that were provided to waive the 2-generation reproductive toxicity study:
• [ECHA noted that screening study OECD 421/422 is missing!]
• Repeated dose toxicity study (90-d) with appropriate investigation of reproductive organs: very low systemic toxicity
• Developmental toxicity: no maternal or developmental toxicity
• QSAR toolbox: no alerts for reproductive toxicity
• 2-Generation studies with chemically related substances: no systemic or reproductive toxicity
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Read Across
•DGPT Advanced Course 9 March 2015
Annex IX, 1.5.: Read Across
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.
Application of the group concept requires 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).
45
Example read-across
Target (registered) substance Source (analogue) substance
• Acute toxicity studies • Acute toxicity studies
• Skin/eye irritation/corrosion • Skin/eye irritation/corrosion
• Sensitisation study • Sensitisation study
• in vitro mutagenicity studies • in vitro mutagenicity studies
• OECD 422 screening test • OECD 422 screening test
read-across • Repeated dose toxicity study (90d)
read-across • Testing proposal for developmental toxicity study
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Read-across hypothesis and justification
• Substance identity of source and target substances:
• composition,
• main constituents and
• impurities with identifiers (e.g., CAS number)
• Structural similarity:
• functional groups,
• common breakdown products
• Physicochemical properties for target and source
• Toxicokinetics of target and source substances
• oral, dermal, inhalation absorption
• hydrolysis products with information on hydrolysis time .
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Read-across hypothesis and justification
• Toxicity data of target and source substances (IUCLID): similar toxicity profile
• Toxicity data of the hydrolysis products (IUCLID)
• Classification and labelling of target and source substances
• Conclusion
• Data matrix
• References
ECHA webpage for read-across support: http://echa.europa.eu/support/grouping-of-substances-and-read-across
ECHA read-across illustrative example: http://echa.europa.eu/documents/10162/13628/read_across_example_1_en.pdf
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The
Annual
Evaluation
Progress
Report:
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http://echa.europa.eu/documents/10162/13628/evaluation_report_2014_en.pdf
www.echa.europa.eu
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