© copyright 2015cwresearchltd€¦ · animal testing for k-reach; practical how-to for negotiating...

vTo hear about evolving approaches to testing andassessment including the concept of 3R best practice;

vTo understand key points of read-across: definitions,approaches, regulatory use, acceptance, guidance and tools,


approaches, regulatory use, acceptance, guidance and tools,biological similarity and Echa’s read across assessmentframework;

vTo review the overlap between the EU and South Korea’schemical regulatory space; data sharing provisions; practicalhow-to for negotiating access to EU REACH data via EUConsortia; and K-REACH IT system.

, Humane SocietyInternational/Korea; EHWA UniversityCollege of Pharmacy, South Korea

, Liverpool


John Moores University, UK

, Chemtopia, South Korea

Chair: Chemical Watch

152 154 Curtain Road, Shoreditch (EC2A 3AT152 154 Curtain Road, Shoreditch (EC2A 3ATAdvancing 3R best practices for152-154 Curtain Road, Shoreditch (EC2A 3AT152-154 Curtain Road, Shoreditch (EC2A 3ATg pREACH in the EU and Korea

Chemical Watch Webinar | 4 August 2016K-REACH: Read-Across and Data Sharing

Prof Lim Kyung-Min Troy SeidleKorea Science Policy Advisor Director of Research & [email protected] [email protected]

mailto:[email protected]


² Expert team: toxicology, ecotoxicology,pharmacology, biochemistry, neuroscience,endocrinology, law, regulatory science, etc.

² Present on the ground in the EuropeanUnion, S. Korea, China, Japan, Viet Nam, India, United States, Canada, Mexico, Brazil

About HSIHSI is the leading

international NGO

working to advance

non-animal safetyand Latin America, Australia, S. Africa and beyond

² Working cooperatively with industry,regulators, research institutes and otherstakeholders

non-animal safety

testing and bioscience

research worldwide.

² Significant progress in development andvalidation of 3R testing tools (cell andcomputer models), as well as non-testingapproaches (waivers, read-across)

² Deployed according to integrated testingstrategies using weight-of-evidence

Evolving approaches to testing and assessment

² Ongoing paradigm shift based on expanding knowledge of “adverse outcomepathways” (AOPs)

² Regular updates to regulatory datarequirements needed across productsectors (chemicals, pesticides, drugs, etc.)to keep pace with scientific progress

Concept of “3R best practices”² Strategies to Replace, Reduce or Refine animal use in toxicology, including:

ª Removal of redundant in vivo study requirements, e.g., multiple exposure routes(acute oral/dermal/inhalation) and/or species

ª Uptake of all applicable OECD 3R guideline methods and other scientifically supported alternativetesting (and non-testing) strategies

ª Endp int mbi i ( in viª Endpoint-combining (e.g., in vivomicronucleus as part of 28 daystudy)

ª Adopting more efficientstudy designs (e.g.,extended 1-gen repro)

ª Classification by calculationfor mixtures/formulations

Endpoint Test methods OECD guideline (year)

Skin corrosion /irritation

Reconstructed Human Epithelium (RHE), CORROSITEX

431 (2004), 435 (2006), 439(2013)

Eye corrosion /irritation

BCOP, ICE, IRE, Fluorescein Leakage,EpiOcular

437 & 438 (2013), 460(2014), 491, 492 (2015)

Skin sensitization DPRA, KeratinoSens (ARE-nrf2luciferase), h CLAT

442C & 442D (2015), 442E(2016)

OECD guideline tests with replacement potential

luciferase), h-CLAT (2016)Skin absorption Human post-surgical skin; RHE

models428 (2004)

Phototoxicity 3T3 Neutral Red Uptake (NRU) 432 (2004)

Mutagenicity Ames, Chromosomal Aberration,Micronucleus, etc.

471, 473, 476 & 479 (1986),487 (2010), 490 (2015)

Acute fish toxicity Fish embryo test 236 (2013)

3R-based revisions to EU REACH data requirementsNew

² The European Chemicals Agency database contains toxicity data for14,247 unique substances, with an additional 25,000 substancesexpected to be registered by 2018ª Many of these substances are also marketed in South Korea, thus data

sharing agreements could prevent substantial amounts of new, duplicativeanimal testing for K-REACH; practical how-to for negotiating access to EU

Today’s webinar » data sharing & read-across

REACH data via consortia; K-REACH IT system

² ‘Chemical grouping’ and ‘read-across’ are the most commonly usedalternative approaches for data gap filling in registrations submittedunder REACH in the EUª Overview of groupings already accepted in the EU/US/OECD and their

scientific basis; ECHA read-across guidance and regulatory boundaries; andadvantage in acceptance of read/across

Thank you for your attention& enjoy the webinar!

Prof Lim Kyung-Min Borami SeoKorea Science Advisor Korea Policy Advisor [email protected] [email protected]

Troy Seidle Jarlath HynesDirector, Research & Toxicology Dept. EU Science Policy [email protected] [email protected]





Chemical Grouping and Read-Across

Mark CroninLiverpool John Moores University

England

What I am Going to Say…• Definitions of grouping and read-across• Read-across approaches, tools and use• Acceptance of read-across• Biological similarity to increase confidence in • Biological similarity to increase confidence in

read-across• ECHA’s Read-Across Assessment Framework

(RAAF)These are my views and others may wish to

dissociate themselves from them

Key Point 1: Definitions• Category formation, or grouping, identifies

molecules with similar chemical structures• Effects, such as toxicity, may be read across

from a compound with data to fill a gap for a compound with no data

Forming Categories by Chemical Grouping

Br

Br

O

Br

Br

Br

Br

O

Br

Br

Cl

ClCl

Cl

H3C

Cl

CH3

Br

BrBr

O

Br

Br

Br

ClCl

H3C

Cl

CH3

Br Br

Br

Br

Br

Br

Br

Br

BrBr

O

Br

Br

BrBr

Br

O

Br

Br

Br

BrBr

Br

ClClCl

ClCl

ClCl

H3C

Cl

Cl

Cl

Cl

Cl

Cl Cl

Cl

CH3

Cl

Cl

H3C

Cl

Cl

Cl

ClCl

ClCl

Cl

H3C

Br

Br

Br

H

N

O H

H

H

H

HH

N

O

NH

O

H H

H

N

H

O

H H

H H

H

N

H

OH

H

H

H

HH

O

NH

O

HH

H

H

O

HH

HH

H


Br

Br

O

Br

Br

Br

BrBr

O

Br

Br

Br

Br

O

Br

Br Cl

ClCl

Cl

H3C

Cl

CH3

Br

BrBr

O

Br

Br

Br

Cl

ClClCl

Cl

H3C

Cl

CH3

ClCl

ClCl

H3C

Cl

Cl

BrBr

BrBr

Br

O

Br

Br

Br

BrBr

Br

ClCl Cl

Cl

Cl

Cl

Cl Cl

Cl

CH3

Cl

Cl

H3C

Cl

Cl

Cl

ClCl

ClCl

Cl

H3C


Br

Br

O

Br

Br

Br

BrBr

O

Br

Br

Br

Br

O

Br

Br Cl

ClCl

Cl

H3C

Cl

CH3

Br

BrBr

O

Br

Br

Br

Cl

ClClCl

Cl

H3C

Cl

CH3

ClCl

ClCl

H3C

Cl

Cl

BrBr

BrBr

Br

O

Br

Br

Br

BrBr

Br

ClCl Cl

Cl

Cl

Cl

Cl Cl

Cl

CH3

Cl

Cl

H3C

Cl

Cl

Cl

ClCl

ClCl

Cl

H3C

Br

Br

Br

Br

Br

Br

Br

Br

Br

Br

H

N

O H

H

H

H

HH

N

O

NH

O

H H

H

N

H

O

H H

H H

H

N

H

OH

H

H

H

HH

O

NH

O

HH

H

H

O

HH

HH

H

?

Read-across uses information from members of a groupwith known activity to predict activity of unknown(s)

Category Formation for Read Across

Chemical Phys-ChemProperty

Tox

Known 1 1.2 11Known 2 2.3 14Known 3 3.2 18Known 4 4.8 26

Unknown 4.0 ?

Known 1

Known 3

Known 2

Known 4

Unknown?

Good Reasons for Using Read-Across• Potential savings in costs, time to market,

animals etc• It is simple and transparent• Allows for mechanistic interpretation and

rational use of toxicity data and information• Several chemicals can be assessed at the same

time, with few data• It has regulatory acceptance (if done correctly)• Provides solutions to problems

Example of a Category: Long-Chain Alcohols

Veenstra G et al (2009) Ecotox Environ Saf 72: 1016-1030.

Key Point 2: Approaches

• There are many approaches to define twomolecules are being “similar”

Guide to Grouping Chemicals

OH OH OH

Structural Analogues

OH

OH OH OH


Mechanistic Analogues

OH


O O

OOH N O

OH OH OH


Mechanistic Analogues

OH


Mode of Action AnaloguesO O

OOH N O

OH

OH

OH

OH

OH

• Identifying compounds that are metabolisedto a common molecule

• Identifying compounds that are degraded

Other Options for Grouping Chemicals

rapidly to common products

• Using metrics of molecular similarity e.g.Tanimoto indices

Key Point 3: Regulatory Use

• Read-across is increasingly being used• It has been applied for many regulatory

purposes e.g. REACH in the EU

Growth in Publications

Web of Science literature search using key words “Read-Across” and “Toxic” performed 28 July 2016

Where Read-Across is UsedCurrent Roles

• Prioritisation, Classification &Labelling and risk assessment

• EU – emphasis on REACH• Interest for cosmetics• Various other roles in USA,

Canada, Japan, Korea, China,Australia etc

• Transitioning from chemicalsimilarity to biologicalsimilarity

Where Read-Across is UsedCurrent Roles

• Prioritisation, Classification &Labelling and risk assessment

• EU – emphasis on REACH• Interest for cosmetics• Various other roles in USA,

Future Roles• More robust and larger

categories• Better assessment for low / no

toxicity• Development through IATA

Canada, Japan, Korea, China,Australia etc

• Transitioning from chemicalsimilarity to biologicalsimilarity

• Integration of chemical andbiological similarity

• Intelligent testing to definedomains of categories

• Translation topharmaceuticals,nanomaterials etc….

Like it or Not… The Use of Read-Across is a Reality

Toxicity toreproduction (1 882 dossiers covering

phase–in substances100-1 000 tpa)

Developmentaltoxicity (1 882

dossiers)

Full Report Published 2 June 2014 available at:http://echa.europa.eu/documents/10162/13639/alternatives_test_animals_2014_en.pdf

http://echa.europa.eu/documents/10162/13639/alternatives_test_animals_2014_en.pdf

Like it or Not… The Use of Read-Across is a Reality

Toxicity toreproduction (1 882 dossiers covering

phase–in substances100-1 000 tpa)

or Not… The Use of Read-Across

dossiers cophase–in substances

100-1 000

However theacceptance of read-across predictions is

Developmentaltoxicity (1 882

dossiers)

Full Report Published 2 June 2014 available at:http://echa.europa.eu/documents/10162/13639/alternatives_test_animals_2014_en.pdf

toxicit

Published

across predictions isnot fully known

http://echa.europa.eu/documents/10162/13639/alternatives_test_animals_2014_en.pdf

Key Point 4: Acceptance

• Acceptance of a read-across prediction is notguaranteed

• Acceptance relies on thoroughdocumentation, robust justification anddocumentation, robust justification andsupporting evidence

Example of a Category: Terephthalic Acid and Esters

Ball GL et al (2012) Crit Rev Toxicol 42: 28-67.

QUESTION:Can We Fill These Data Gaps?


Can We Fill These Data Gaps?

Probably…. If we have….

• High quality “source” data• Consistency within the data for the category


• Consistency within the data for the category• We are interpolating• There is a good reason and justification for

data gap filling• We can demonstrate similarity

Well Known, and Worrying, Activity Cliffs Exist WhichDemonstrate Problem of Identifying Similar Compounds

Teratogen Sedative

Whilst Read-Across Predictions have been Accepted,There are a Number of Reasons for Rejection

• Unclear substance identity, not possible toascertain structural similarity

• Lack of sufficient evidence to substantiateassumptions made within read-acrossassumptions made within read acrossjustifications

• Read-across to inappropriate data• Lack of scientific plausibility

Ball N et al (2016) Towards Good Read-Across Practice (GRAP) Guidance. Altex 33: 149-166.

Key Issues with Read-Across

• How can we support a read-across prediction?– i.e. provide further (biological) evidence that

chemicals belong to a group (see Key Point 6)

• When do read-across predictions becomeacceptable to replace an animal test?

Key Point 5: Guidance and Tools

• There is much guidance from regulatoryagencies and in scientific literature

• There are many tools (free and commercial) togroup chemicals or find similar structuresgroup chemicals or find similar structures

• There are databases (free and commercial) toprovide toxicological information

• There are increasing numbers of case studies

Current Guidance•Many sources•Need for consistent approach to reporting and assessing read-across

•Adoption of ECHA’s Read Across Assessment Framework

Several Other InitiativesSeveral Other Initiatives

•Adoption of ECHA s Read-Across Assessment Framework(RAAF) and ensure effectiveness

Tools and Databases – Not An Exhaustive ListTool Grouping Tox

DataADME Mechanism Free

Tox/TrackYes PartialYes Some Yes

DrugMatrix

Yes Few Some

Yes Few No

Yes Yes




DrugMatrix• Many bespoke tools for grouping and read-across• May need further guidance / illustrated case studies

Yes Few Some

Yes Few No

Yes Yes

YesYY Few SomeSomeSome

YesYY Few No

YesYY YesYY

May need further guidance / illustrated case studies




DrugMatrix

ToTT x/TrackYesYY PartialYesYY Some YesYY

Yes Few Some

Yes Few No

Yes Yes

YesYY Few No

YesYY YesYY

• Many data sources support read-across• Always opportunities for further data sharing




DrugMatrix


DrugMatrix

Yes Few Some

Yes Few No

Yes YesYesYY YesYY

YesYY Few SomeSomeSome• (Quantitative) metabolite and PK property prediction requires

development and better integration into read-across




DrugMatrix


DrugMatrix

Yes Few Some

Yes Few No

Yes Yes

YesYY Few SomeSomeSome

YesYY Few No• A mechanistic basis to read-across is desirable• AOPs may support read-across in a number of ways

Four repeat dose RAcase studies

Four repeat dose RAcase studies

Case Studies•Many examples•Need for more to addressissues such as RAAF,uncertainty, reporting,biological profiling etc

Ten safety assessments using RA

Several Other Initiatives

TenTT safety assessments using RA

Several Other Initiatives

Key Point 6: Biological Similarity• The future of read-across is more than

chemical similarity (see Key Point 2)• Weight of evidence is required with

supporting information on e.g. mechanism ofaction, toxicokinetics, metabolism etcaction, toxicokinetics, metabolism etc

• Information may be “non-standard” or “non-traditional” e.g. in vitro, high throughput/content screening, or –omics etc.

Application of New Approach Methodologies(NAMs) to Support Read-Across

• Broadly considered to include:– In silico approaches– In chemico and in vitro assays– Information on exposure of chemicals

N t ting tools g. “high th hput eenin ”– New testing tools e.g. “high-throughput screening”and “high-content methods” e.g. genomics,proteomics, metabolomics

– Other methods to improve toxicokinetic ortoxicodynamic knowledge

• Consideration of biological information increasesconfidence

• Proceedings will be published Autumn 2016• Presentations and details of case studies

available from ECHA Website

Key Point 7: RAAF

• RAAF has the potential to bea very important documentto help evaluate read-acrossfor regulatory acceptance

• Demonstrate how NAM canimprove read-acrossargument

The ECHA Read-Across AssessmentFramework (RAAF) Approach

Scientific assessment of a read-across argument according toscenarios defined by 3 key features:

# of substances considered:• Analogue approach – one source and one target• Category approach – multiple source(s) and target(s) (group)

41

Effect (predicted property) caused by:• common substance for source(s) and target(s)• different substances for source(s) and target(s)

For a category, the predicted property:• Follows a regular pattern (trend) across source structures• Does not change across source structures

6 possible read-across scenariosSlide from Andrea-Nicole

Richarz, EC JRC

The RAAF: Assessment Elements andAssessment Options

Set of Assessment Elements (AEs) per scenario• Describing ‘crucial scientific aspects to judge validity and reliability

of read-across for the scenario’• For each AE multiple considerations to be included in justification

42Slide from Andrea-Nicole

Richarz, EC JRC

Assessment Options (AOs):• Reflect the conclusion on adequacy and scientific robustness of the

information provided for the AE• Scores from 5 to 1

• 3 : information provided is acceptable with (3) sufficient, (4) medium, (5) high confidence

• 2 : information provided is (1) not acceptable, (2) not in acceptable in its current form

SEURAT-1 Case Study Considered with the RAAFAE AO

w/oNAM

AOwithNAM

NAMadded info

C.1 Subst. characterisation N/A N/A

C.2 Structural similarity 4 4

C.3 Link structures and regular pattern 4 5 ex vivo perfused liver data link vinyl moiety and effect

C.4 Consistency effects in data matrix;clustering 3 4 in chemico/in silico data show clustering of

potency

C.5 Reliability/adequacy sourcestudy(ies) 3 3

Compounds the organism is exposed ex vivo/in silico: metabolites toxicants,

43

4.1 Compounds the organism is exposedto, transformation 4 5

,not tertiary alcohols;also by hepatic organoids

4.2 Common mechanism, qualitativeaspects 4 5

in chemico/in silico/in vitro data strengthenmechanism evidence, HSC activation markersthe MoA to fibrosis

4.3 Common mechanism, quantitativeaspects 3 4 in chemico data: only quant. info. on potency

differences supported by in silico/in vitro

4.4 Exposure to other compounds 4 4

4.5 Occurrence of other effects 4 4

C.6 Bias influencing prediction 4 4

Slide from Dr Andrea-Nicole Richarz, EC JRC

Conclusions• Read-across provides a means to fill data gaps

when information is available for “similar”chemicals

• Read-across is used widely for regulatorypurposes

• Acceptance of read-across can be complex– Documentation and justification required!– Guidance and case studies on-going

• ECHA’s RAAF may help in developing andassessing read-across arguments and predictions

Date:08/04/2016Speaker:NickChoi(Chemtopia,S.Korea)Email:[email protected]

OverlapbetweenEU/KoreaChemical regulatory space;Datasharingprovisions; Practicalhow-to fornegotiatingaccess toEU-REACHdatavia EUConsortium;andK-REACHIT system


1 Overlap between EU/Korea chemical regulatory space2 Data sharing provisions3 Practical how-to for negotiating access to EU-REACH data via EU Consortium4 K-REACH IT System

Agenda

COPYRIGHT© 2016 Chemtopia Co., Ltd. ALL RIGHTS RESERVED.

Timeline of K-REACH and EU-REACH Registration

2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025

Enforcement of K-REACH

First batch & RegistrationSecond batch ?

Third batch ?

Pre-registration06/01/2008~11/30/2008

07/01/15 ~ 06/30/2018

Registration 1000 ton/yr

Registration of 100 ton/yr

Registration of 1 ton/yr

K-REACH

EU-REACH

• All new chemicals need registration (No tonnage cut-off)• CSR required for

• Existing chemical announced as priority existing need registration

New chemical registration

• New and existing chemicals 1 ton/year• CSR required for

New chemical registration


Timeline of 1st Batch of 510 Existing Chemical Subject to Registration

K-REACH

• 1st batch of 510 existing chemical subject to registration was announced on 6/1/2015

• Once existing chemical subject to registration is published, there is 3 years of grace period.

• As of 8/1/2016, lead registrants have been selected for 239 existing chemical subject to registration

http://www.chemnavi.or.kr/main.do

List of 239 LR for PEC substance

CAS No Chemical name Lead registrant

BASF KOREA

http://www.chemnavi.or.kr/main.do


K-REACH and EU-REACH Comparison Table

Korea REACH EU REACHPre-registration None

Inquiry (Optional)

RegistrationAll new chemical without cut-off tonnage and

PEC(Priority existing chemical) New and existing chemicals more than1 ton/year

Polymer Not exempt from registration Exempt from registration but its monomer needs to be registered

Data requirements

Higher volume, more data <1 (only for new chemical), 1-10, 10-100, 100-

1000, >1000 ton

(grace period, 5 years)

Higher volume, more data 1-10, 10-100, 100-1000, >1000 ton

Joint submissionOnly representative


Existing Chemical Subject to Registration , most of them registered in EU REACH

c.f. The number of existing chemical subject to registration will be around 2,500 in total and the first batch of 510 chemicals were chosen and published last year(~300 substances are already registered in EU REACH)

Existing chemical subject to registration (Article 2 and Article 9)

- An existing chemical is subject to registration for its hazard assessment or risk assessment. - An existing chemical that is subject to registration will be designated and announced with respect to its amount and

hazard/exposure information following the deliberation of the assessment committee


Data Sharing Provision under K-REACHK-REACH Act Article 17 (Special Cases Concerning Vertebrate Animal Test Data)

Where there are existing data of tests on a vertebrate by a testing institution under each Subparagraph of Article 14 (hereinafter referred to as "vertebrate animal test data"), a person who intends to apply for the registration under Article 10 shall utilize, for his/her own application for registration,such vertebrate animal test data with the consent of the owner thereof in order to minimize further animal testing: Provided, that if vertebrate animal test data were submitted as the materials for registration application and was registered more than 15 years ago, said data may be utilized without the owner's consent.

Notwithstanding paragraph, if the owner of the vertebrate animal test data refuses to give consent, a person who intends to apply for registration may not submit the materials for registration application after obtaining the confirmation of the Minister of Environment: Provided, that where it is deemed necessary for vertebrate animal test data to be submitted due to difficulty in judging a hazard of chemical substances without such data, the Minister of Environment may order the production and submission of such data within the period determined by the Decree of the Ministry of Environment.

A person who is requested to give consent to use of vertebrate animal test data subject to paragraph shall comply with such request unless there is a justifiable reason as determined by Presidential Decree to not do so.

A person who refuses to give consent to use vertebrate animal test data without a justifiable reason under paragraph may not submit such vertebrate animal test data for the purpose of applying for registration.

Matters necessary for the consent to use vertebrate animal test data other than those set forth in Subparagraphs 1 through 4 shall be prescribed by the Decree of the Ministry of Environment.

• Registrant needs to utilize the existing vertebrae animal test data by getting consent from the data owner• If consent is refused by the owner, the registrant can submit the registration dossier with such data after getting the

confirmation from MOE• Data owner who refuses to give consent to use vertebrate animal test data without a justifiable reason may not use

such data


Data Sharing Provision under K-REACH

Act Article 16 (Shared Use of Existing Materials for Registration Application)

A person who intends to apply for the registration under Article 10 may utilize, for his/her own application for registration, the materials for registration application determined by the Decree of the Ministry of Environment, from among the materials that have been submitted by other registrants under Article 14 , with the consent of the owner thereof: Provided, that the materials for registration application were registered more than 15 years ago, may be utilized without the consent of the owner.

A person who intends to apply for registration under Article 10 may, in order to utilize existing materials for registration application, inquire with the Minister of Environment whether the same chemical substance has been registered. In such a case, the Minister of Environment shall notifythe inquirer of the outcome of the inquiry, as prescribed by the Decree of the Ministry of Environment.

Matters necessary for the shared use of the materials for registration application other than those set forth in paragraphs and shall be prescribed by the Decree of the Ministry of Environment.

• Potential registrant can utilize existing data submitted by the previous registrant• For this, the potential registrant can send inquiry to NIER whether the substance is registered


Enforcement rule Article 19 (Previous registration application data, etc. for a joint application)

"Registration application data prescribed by the Decree of the Ministry of Environment" of Article 16, Paragraph 1 of the Actrefer to following.1. Data on the physicochemical properties of a chemical substance according to Article 14, Paragraph 1, Subparagraph 5 of theAct2. Data on hazard of chemical substance according to Article 14, Paragraph 1, Subparagraph 6 of the Act

Those who intend to use the data in Subparagraph 1 for the purpose of registration according to Article 10, Paragraph 3, shall submit data owner's approval for use according to Article 16, Paragraph 1, with the application to the head of the National Institute of Environmental Research.


• Enforcement rule Article 19 defines the data that can be utilized• The registrant also need to submit the approval application in case the registrant is using the existing data from data

owner


K-REACH Enforcement rule Article 16 (Joint Submission of Registration Data)

Data requirementsJoint

submissionIndividual

submission

Company information ( Company name, lead registrant information, member companyinformation, if applicable)

Chemical information(CAS No, purity, impurity etc.)

Use

Classification and labelling

Physico-chemical property

Toxicological data

CSR (>10 ton)

Method of Safe Handling (Protective equipment, emergency measures for explosion, fire orrelease)

Test plan report




A guidance on sharing of registration documents and cost (Feb 2015)

• Joint registrants need to utilize existing data owner the joint registrants and open data source for the data defined in the K-REACH Enforcement rule Article 16 (Joint Submission of Registration Data)

• The risk assessment method (NIER public notice 2014-48) appendix 2 states where to look for the open data source such as risk assessment reports from OECD, UNEP, WHO, data base from ECHA, EPA, and Japan NITE, etc.

• Cost calculation and sharing is between interested parties, not legally determined, but this guidance recommends transparent and fair sharing of registration cost

• This guidance introduce cost sharing method (Sharing data cost by tonnage band or by exact tonnage)

Sharing data cost by tonnageband

Shared cost of an individual firm = (Test costs+administration costs) x

Sharing data cost by exact tonnage

Shared cost of an individual firm = ( ) X ( )

Tonnage of an individual firm

Total tonnage of a person who are going to do registration

Test expenses according to tonnage

Total tonnage of persons who are going to do registration

Administration cost

The number of persons who are going to do registration


Test data for submission- The provision of preparation of registration dossier and hazard evaluation

(NIER Public notice. 2014-44, Dec 31, 2014)- Should be written in Korea. Translation of test report is required if it is not provided

in English or Korean.

Brief summary Specify the type of test materials including particulars about test materials, estimated data,abstract from literatures or database, full texts or summary, detailed source, testing laboratories,characteristics of programs used, and country where its test laboratories located and etc.

Testing methods Include test guidelines to produce the testing materials, name of a test item, chemical name and purity oftesting substance, types and contents of impurities and by-products in testing substance, name of positiveand negative control, methods of administration, species of test animals or plants, and testing conditions.

Results of the test Include the values and ranges of test results, determination as positive and negative, severity of responseor effects, general conclusions of test results and severity, summary of symptoms on major target organs,predictability of programs used and etc.



Enforcement rule Article 25 (Order to submit data required for hazard evaluation)

The head of National Institute of Environmental Research can order for applicant of registration or modification to submit data required for hazard evaluation before deadline for submission following an order of submission using Attached form No. 18 pursuant to Article 18, Paragraph 2 of the Act in case which falls into any of the following. In this case, the deadline for submission shall be accepted as valid by the head of National Institute of Environmental Research in consideration of the period required for producing the data.1. Upon review of the data which were submitted for the application for registration pursuant to Article 10, Paragraph 3 of the Act or modification pursuant to Article 12 of the Act , data is needed to be added or supplemented….. 5. When the chemical substance registered according to Article 10 of the Act is used to kill, disturb, or deter all harmful organisms or lives except humans and animals 6. When the accumulated amount of manufacturing and importing new chemical relevant to Article 13, Subparagraph 1 of the Act exceeds 1 ton7. When full text of test data which describes the procedures for producing the data on physiochemical properties and hazard of chemical substance required according to Article 5, Paragraph 1, Subparagraph 1


• NIER can request additional data for hazard evaluation in case it is necessary• Especially when robust summary is not adequate


Data composition of EU-REACH

In case of EU-REACH data, literature, read-across, and study reports are used simultaneously.And some cases with multiple study reports and supporting documents.

Only 5% of the total registration dossiers submitted is being reviewed and it is ongoing process.

IUCLID data = CSR data (data is consistent)*multiple data in the system

Data composition required in K-REACH

In case of K-REACH, the toxicity and environmental toxicity, NIER is asking for GLP studies with clear test guideline. The highest reliability as possible (1~2 range).

For publication and read-across, there are some uncertainty associated with the evaluation of registration dossier.

Registration dossier evaluation will be done in one year once dossier is submitted.

K-REACH IT System CSR data*One key data is allowed to input into systemtechnically ( expected to be fixed soon)

Conservative approach

Data Sharing: Data Format


Things considered when doing data gap analysis1. Selection of Keydata2. Reliability (1~2)3. Reference type (Study report / Read-across / Publication)4. GLP, Test guideline5. National Institute of Environmental Research (NIER) exemption criteria6. Data availability as open data (ex. Japan NITE, publication etc.)

Case Study 1: Data Gap Analysis

For data gap analysis, search for open data for existing chemical information

For this search, ECHA, TOXNET, NITE, and SIDS report can be looked into


Chemtopia has submitted the FIRST joint registration dossier to NIER under K-REACH on 07/12/2016.

This submission was accomplished after reducing data productions and purchases by utilizing read-across and existing open data (literatures)

Reduced $600k

Case Study 2: Joint Registration Experience from HBr

Physio-chemical data was submitted by using handbook and literature

Applied exemptions for tests as needed (HBr is corrosive gas)

Read across using PBr3 and other halogen substances etc.with expert' scientific judgement

Data is purchased at the rate of 50% of testing regardless of no. of members

Used other open data along with EU data DNEL of exposure part in CSR is different compared to EU CSR by reflecting additional toxicity data other than EU data


MOE owns some of the PEC substances toxicity data.

Case Study 3: Korea Ministry of Environment’s data for sale

These data is up on the MOE’s website and for sale for data access for the joint registration.

Price of data accessAt the level of SIEF: 30% of the data productionAt the level of individual registrant: 5% of data production (3% for small business)

MOE also published the average Korean GLP test price for reference

Type Test Price(converted to USD$

Toxi

city

Tes

t

Acute oral tox $2,500

Acute dermal tox $2,800

Skin sensitization $11,000

Eye irritation $2,700

Ames test $2,700

In Vitro Mammalian ChromosomalAberration Test

$4,000

In Vivo Micronucleous Test $8,500

Repeated Dose Toxicity (28 Days) $66,000

Envi

ronm

enta

lTo

xici

ty T

est Acute Daphnid Toxicity $6,300

Acute Fish Toxicity $6,500

Acute Algae Toxicity $6,600

Ready Biodegradability $4,600

Study reports available after the first half of 201639 substances, 139 study reports

Study reports available after the second half of 201638 substances, 308 study reports

Study in progress in 201631 substances, 212 study reports


Check Points

Identity of substances (SIP)

Purchasing data access

Public consensus on Pricing at 30~50% of Korean GLP lab price

Purchasing at the level of SIEF or at individual registrant

Full study or robust summary (full study report when NIER requests)

Read across / QSAR are associated with uncertainty with NIER (Scientific judgment from expert is essential)

Producing new toxicity data could influence the registration elsewhere (Different result)

Does the substance fall under Substance evaluation-CoRAP(Community rolling action plan), Y2018 registration in EU REACH ?

need to check any ongoing tests or future plan on performing tests?

Reimbursement in case NIER rejects the test studies

What to Consider in Data Sharing Negotiation


Intro K-REACH IT system

K-REACH IT System

Web-based registration submissionAll the information is directly input into the site for submission and some of the information is attached and uploaded

https://kreach.me.go.kr/regweb/regMain.do

Chemical Name

Product Name

Molecular Eq

Purity

General Information Part

Registration tonnage range



Intro K-REACH IT system

K-REACH IT System

Web-based registration submissionAll the information is directly input into the site for submission and some of the information is attached and uploaded


Lead registrant

Co-registrant



For Joint registration

K-REACH IT System

Lead registrant has to put down all of the co-registrants into the IT system for LR registration dossier submission.After lead registrant get the registration result after one month, the rest of the co-registrants can submit their registration dossier.

There has to be some kind of notification tool/method for the co-registrants so that the co-registrants can use it for their registration*** Token No? notice?

Data exchange from IUCLID 6

K-REACH IT System (Web-based)

XML

Direct xml data exchange not possible as K-REACH IT System is not xml compatible

X


K-REACH IT System

Registration System and CSR tool

K-REACH IT System (Web-based)

EU-REACH K-REACH

Importing of substance data directly from IUCLID6

Chemical safety assessment/report tool

Currently chemical safety report is attached and upload to IT registration system directly

cf. Korean CSR tool is currently under development


Any questions orconcerns,please contactme @

Nick ChoiEmail: [email protected]: +82-70-4361-3019

Chemtopia provides

Only representativeReporting serviceRegistration dossier preparationConsortium managementRisk assessmentGLP test arrangementWeb based K-REACH supporting systemWeb based GHS creator(Q)SAR

mailto:Email:[email protected]

What did you think about thewebinar? Please take part in ouremail survey (in your inbox now)

A downloadable recording of thispresentation (with slides) will beavailable h l


available shortly.If you have any questions, please contactLorna ([email protected])

5-6 September 2016, Hong Kong

, 7-8 September 2016, Hong Kong

© copyright 2015cwresearchltd€¦ · animal testing for k-reach; practical how-to for negotiating...

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