Überblick über reach: anforderungen annex vii bis x ......• fluorescein leakage method, oecd 460...

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

2

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)

5

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

6

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

8

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

10

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

11

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

12

Mutagenicity in vivo: new test methods


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


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.

17

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.

18

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)

19

Screening tests OECD 421 or 422


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

21

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

22

Developmental toxicity studies


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).

24

Two-generation reproductive toxicity study / Extended one-generation reproductive toxicity study (EOGRTS)


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

26

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

27

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.”

28

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.

29

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

30

Dossier Evaluation

Evaluation overview

32

Testing proposals (TP)


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)!

34

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

35

Compliance checks (CCH)


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

37

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 %

38

General

adaptation possibilities (Annex XI)

Weight of Evidence (WoE)


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.

41

Requirements for WoE

• Substance-specific

• Endpoint specific e.g., address the key parameters of an endpoint

• Hazard based

42

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

43

Read Across


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

46

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 .

47

http://echa.europa.eu/documents/10162/13628/read_across_example_1_en.pdf

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

48

The

Annual

Evaluation

Progress

Report:

49

http://echa.europa.eu/documents/10162/13628/evaluation_report_2014_en.pdf

www.echa.europa.eu

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Überblick über reach: anforderungen annex vii bis x ......• fluorescein leakage method, oecd 460...

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