REACH, risk assessment and the need for a change in mind set Kees van Leeuwen TNO Quality of Life The Netherlands

REACH, risk assessment and the need for a change in mind set

Kees van LeeuwenTNO Quality of Life

The Netherlands

http://www.tno.nl/ [email protected]

CONTENTS

I. Key elements of REACHII. Risk assessment will changeIII. REACH data requirements and hazard

assessment optionsIV. Why a change in mind set is neededV. Concluding remarks

I. Key elements of REACH

See also:

• http://ec.europa.eu/echa/

• McKim-I and II• Van Leeuwen, C.J., B.G. Hansen and J.H.M. de Bruijn. 2007. Management of

industrial chemicals in the European Union (REACH). 2007. In: Risk Assessment of Chemicals. An Introduction (2nd edition). Van Leeuwen, C.J. and T.G. Vermeire, eds. Springer Publishers, Dordrecht, The Netherlands, pp

511-551.

The REACH legislation

• Final version published in OJ L136, volume 50, on 29 May 2007 (Corrigendum to Regulation 1907/2006)

• 141 articles• In 15 Titles• With 17 annexes• ≈ 850 pages (including annexes)

OJ = Official Journal of the European Union

Although it is European legislation, it coversimports and so it will have global implications

A new REACH language• CMR = Carcinogenic, Mutagenic, Reprotoxic• CSA/CSR= Chemical Safety Assessment / Report• DU = Downstream User• ERA/HRA = Environmental/Human Risk Assessment• M/I = Manufacturer/Importer• PBT = Persistent Bioaccumulating & Toxic• PPROD = Product and Process Oriented Research and Development• QSAR = Quantitative Structure Activity Relationship• RIP = REACH Implementation Project• RMM = Risk Management Measure• SIEF = Substance Information Exchange Forum• vPvB = very Persistent & very Bioaccumulating

Main features of REACH

• Single Coherent System for new (non phase-in) and existing (phase-in) substances

• Responsibility for all manufacturers and importers • Registration of substances produced/imported above 1

tonne/year• Evaluation by the Agency and Member States• Authorization for substances of very high concern• Restrictions - the safety net• Agency to manage the system

Registration under REACH• Aim: to ensure that industry adequately manages the risk arising from its

substances (starting at 1 tonne/y)

• Method:– Manufacturer/importer obtains adequate data– Provides a registration dossier which includes a chemical safety report

for substances above 10 tonnes/y– Submits to authorities (enforcement, transparency)– Increased info requirements according to tonnage (testing proposal)– Reduced requirements for polymers and intermediates

Registration timelines

1 June2007

1 June20081 December

2008

Non-phase-in substances

Pre-registration

30 November

2010

31 May2013

31 May2018

> 1000 t/yCMRs (> 1 t/y)Very aquatic toxic (R50/53) > 100 t/y)

100 - 1000 t/y

1 - 100 t/y

Entry into force

Authorization under REACH• Deals with CMR (category 1 or 2), PBT, vPvB, and substances

of “equivalent concern”• Focus on PBT or vPvB properties, wide dispersive use and high

volumes• Prioritized by the Agency with input from the Member States• Considerations:

– The risks and adequate control of these risks– Social and economic benefits/implications of a refusal to authorize– The analysis of alternatives submitted– Available information on risks of any alternative substances or

technologies• Commission decision based on Agency opinion

Core tools under REACH

• The Chemical Safety Assessment (CSA) is the tool used to determine

• The Chemical Safety Report (CSR) is the tool used to record/document

• The Safety Data Sheet (SDS) is the tool used to communicate

Guidance on Annex XV for C&L

Guidance onevaluation

Guidance on Identification

of SVHC

Guidance on Annex XIV inclusion

Guidance on Annex XV

for restrictions

Guidance mainly for authorities≈ 650 pages Guidance on SEA

-Restrictions

readynot ready

Guidance on registration

Guidance on SEA-Authorisation

Guidance for authorisation

application

Guidance on pre-registration

Guidance for articles

Guidance on C&L notification Guidance on

PPRODR

Guidance on intermediates

Guidance on polymers

Guidance on data sharingGuidance mainly

for industry≈ 800 pages

Guidance for Downstream users

readynot ready

Guidance on substance

identification

Guidance onCPL

Guidance on IUCLID

Guidance on priority setting

Guidance on REACH methods

≈ 4400 pages Guidance on information requirements

ready

not ready

Comprehensive guidance and tools

The total package of REACH (legislation and guidance) comesclose to 7000 pages and:

• Some guidance documents still not available• Not all guidance is comprehensive and concise• Many methodologies still not harmonized

So: Implementation will be a long processA process of “learning by doing” Quality and acceptance take time

Conclusions I. Lessons from the past

• Science is like life in general: a continuous forgetting and rediscovering old thruths (Brody, 1945)

• Legislation is important but implementation is key (De Bruijn, Hansen and van Leeuwen, 2000)

• Legislation is only as strong as its implementation and enforcement (US comments on REACH, 2006)

PEC/PNEC

Emission rates

Distribution

PEC

Data set

Single speciestoxicity data

Extrapolation

PNEC

Exposure assessment Effects assessment

Risk characterization

Data evaluation

II. Risk assessment will change

TGD

EUSES

REACH: safe use of chemicals

Hazard information Exposure information

Safe use?

Exposure scenarios under REACH are:an integral approach to control risks

Formal definition: the set of conditions, including operational conditions and risk management measures, that describe how the substance is manufactured or used during its life-cycle and how the manufacturer or importer controls, or recommends downstream users to control, exposures of humans and the environment. These exposure scenarios may cover one specific process or use or several processes or uses as appropriate.

Building Exposure Scenarios

Initial ES• Short title

• Operational conditions

• Risk management measures

If risk not demonstrated to be controlled

Decisions by M/I• Refine hazard assessment

• Refine exposure assessment

• Modify RMM or OC

• Advise against use

Final ES• Short title• Operational conditions• Risk management measures

REACH and the use of test animals

• Testing on vertebrate animals shall be undertaken only as a last resort (art. 25)

• Information may be generated by other means than tests, in particular through in vitro methods, (Q)SARs and read-across (art. 13)

Legislative text + guidance should limit use of animals and prevent box-ticking

Conclusions II1. RMMs are the start of a RA. The focus is on exposure2. It requires multidisciplinary and integrative thinking & expertise right from the

start3. Dialogue up and down the supply chain between actors in the supply chain is

key to success!4. It requires paradigm shifts:

• effects-based → exposure-driven• risk assessment → risk management

5. It requires detailed information on use and exposure of substances (in products) which is generally not available to the authorities (Haigh and Bailly, 1992!)

6. Expertise in and outside industry is scarce (aging population)7. Animal welfare considerations and resources (time, cost and laboratory

capacities) require other approaches to hazard assessment

Annex VII (≥ 1 tonne per year) • Physicochemical properties • Human health: in vitro irritation, sensitization, mutagenicity, acute toxicity (one route)• Environmental: acute aquatic toxicity (daphnia, algae), biodegradationAnnex VIII (≥ 10 tonnes per year) • Human health: including in vivo irritation, and 28-day repeat dose studies• Environmental: acute toxicity fish, fate studies (hydrolysis, adsorption / desorption)Annex IX ( ≥ 100 tonnes per year) • Long term, repeat dose, chronic toxicity, fate etcAnnex X (≥ 1000 tonnes per year) • Further long term, repeat dose, chronic toxicity, fate etc

III. REACH data requirements and hazard assessment options

REACH data requirements: a phased approach

1-10 t

Annex VII

10-100 tAnnex VIII

> 1000 t

Annex X

100-1000 t

Annex IX

Estimated costs per dossier

Estimated number of substances

400-875 k€

2,900

70-330 k€ 4,600

30 k€ 20,000

400k-2 M€

2,600

2008…..2010……………..2013……………………………………………….2018

Estimated test animal need (van der Jagt et al., 2004) Test animal need for different endpoints

(% of total test animals needed)

0 5 10 15 20 25 30 35 40

Long-term bird

In vivo skin irritation

In vivo eye irritation

Acute oral tox

Acute dermal tox

Acute inhalation tox

Short-term fish

Long-term repeated tox

Sub-chronic tox

Carcinogenicity

Short-term repeated dose

Accumulation

Developm. tox screening

Long-term fish tox

Skin sensitisation

Further mutagenicity

Developm. tox study

Two-generation reprotox

%

2030

Ani

mal

use

Dec 2008Pre-registration

Dec 2010Registration Annex X (2.600 substances)

+ CMR (cat 1+2) > 1 tonne/y (? substances)+ very toxic (R50/53) > 100 tonnes/y (? substances)

June 2013Registration Annex IX (2.900 substances)

June 2018Registration Annex VII & VIII (24.600 substances)

2008 2010 2020

REACH ambition: reduction of animal use

Full replacement of animal testing (SCCNFP, 2004) Human health effects Foreseeable time involved for full replacement

Acute toxicity >2014

Skin irritation >2014

Skin corrosion <2004

Eye irritation >2010

Skin sensitisation >2019

Skin absorption/penetration >2006

Subacute/subchronic toxicity >>2014 (not foreseeable)

Genotoxicty/mutagenicity >2016

UV-induced effects >>2019 (not foreseeable)

Toxicokinetics and biotransformation >>2014 (not foreseeable)

Carcinogenicity >>2014 (not foreseeable)

Reproductive toxicity >>2014 (not foreseeable)

U.S. NRC Toxicity Testing in the 21st Century (2007)

Compounds

Metabolite(s)

AssessBiological

Perturbation

AffectedPathway

Measures ofdose in vitro

Dose ResponseAnalysis for Perturbations

of Toxicity Pathways

Calibrating in vitro and human

Dosimetry

Human ExposureData

Population BasedStudies

ExposureGuideline

Mode of ActionChemicalCharacterization

Dose Response Assessment

Hazard Characterization

Risk Characterization

Exposure Assessment

U.S. NRC Toxicity Testing in the 21st Century

Dose ResponseAnalysis for Perturbations

of Toxicity Pathways

Toxicity Pathway: A cellular response pathway that, when sufficiently perturbed, is expected to result in adverse health effects

U.S. NRC (2007) New Paradigm:

Early CellularChanges

Exposure

Tissue dose

Biological interaction

Pertubation

Biological inputs

Cellinjury

Morbidity and mortality

Normal BiologicFunction

Adaptive Stress Responses

Activation of Toxicity Pathways

Options for Future Toxicity Testing Strategies (Modified after the US NRC 2007)

Option Iin vivo

Option IItiered in vivo

Option IIIin vitro / in vivo

Option IVin vitro

Focus Animal biology

Animal biology Primarily human biology

Primarily human biology

Doses High High Broad range Broad range Throughput Low Improved High & medium High Cost High Less  Less  Less Time cons. High Less  Less  LessAnimal nrs. Relative large Fewer Substantially fewer Virtually no animals

Endpoints Apical Mode of toxic action

Pertubations of toxicity pathways

Pertubations of toxicity pathways

Techniques Animal tests Some in silico andin vitro screens

In silico screens possible

In silico screens

Regulatory acceptance

High Medium Low Low

National Academy of Sciences Report (2007)Toxicity Testing in the Twenty-first Century: A Vision and a Strategy

Science: Feb 15, 2008

Options for Future Toxicity Testing Strategies• Complete replacement with in vitro or (Q)SAR methodologies is not

possible for the most relevant endpoints (SCCNFP, 2004)

• The USNRC described a vision and a strategy but the expectations to replace animal tests seem to be running ahead of scientific reality

• Industry concern: new technologies can only be used to replace traditional testing approaches unless relevance for safety assessment has been demonstrated

• Dose / exposure information is the critical component in hazard and risk assessment independent of the technology used

• So, what do we do in the next 20 years? Focus on effects only or also on exposure? And what can we learn from current regulatory programs?

Current regulatory toxicology testing paradigm

To generate in vivo animal data for all possible outcomes to determine which of all possible effects are relevant

Mortality • Systemic Toxicity• Disease• Cancer

Reproductive fitness • Viable Offspring• Fertility

Developmental impairment • Terato• Prenatal Deficits

BATTERY of Animal Testing

(Jones and Bradbury, USEPA, 2005)

Current regulatory testing strategiesData rich chemicals(pesticides)

Data poor chemicals(industrial chemicals)

Most of the animal data are not used as only a few toxicological endpoints play a role in RA

To generate in vivo animal data for all chemicals (box ticking) is not feasible

Waste of resources: time, money and animals

Efficient, focused animaltesting is needed

Targeted testing seems to be the way forward

In the very near future category approaches appear to be the most effective option

Molecular Interactions Biochemical Responses

Cellular Responses

Tissue/Organ Function

CHEMICAL INVENTORIES

C2Cl3

ClClC

C2Cl3

ClClC

C2Cl3

ClClC

Cl

ClClCl

Cl

Cl

ClCl

ClCl

Cl

Cl

ClClCl

Cl

Cl

ClCl

ClClCl

Cl

ClOHOH

OH

Existing data Read-acrossCategories

QSARsTTC

in vitro

Adverse OutcomesEFFICIENT, FOCUSSED

ANIMAL TESTING

Prioritization/Screening

(Jones and Bradbury, USEPA, 2005)

Future testing paradigm

A paradigm shift is needed

In the context of regulatory programs, the challenge is to move in a scientifically credible and transparent manner from a paradigm that requires extensive hazard testing to one in which a hypothesis- and risk-driven approach can be used to identify the most relevant in vivo information

(Bradbury, Feytel and Van Leeuwen, 2004)

Intelligent Testing Strategies (ITS)

The most efficient way to carry out hazard and risk assessments of large numbers of chemicals, while reducing costs to industry and minimising animal testing, is to obtain the necessary information by means of intelligent testing strategies (ITS).

Intelligent testing strategies are integrated approaches comprising of multiple elements aimed at speeding up the risk assessment process while reducing costs and animal tests

(Bradbury, Feytel and Van Leeuwen, 2004)

INTELLIGENT TESTING STRATEGIES

In vitro(Q)SAR

Grouping Exposure

Experiences from the US HPV Challenge Program

Experiences from the US HPV Challenge Program

• Until now 2200 chemicals have been evaluated

• For the human health data 88% of the missing data was estimated using read-across.

• For the environmental data 83% of the missing data was estimated using either QSAR or read-across.

Testing costs: € 800-1130 millionNumber of animals: 1.3-1.9 million

The most likely scenario for REACH according to the JRC: 2.6 million vertebrate animals and € 1.5 billion for testing (http://ecb.jrc.it/ )

Expectations in Europe: REACH saving potential of ITS (Van der Jagt et al., 2004; EUR report 21405)

Towards a 7-R strategy implementing ITS1. Risks Focus on risks (include exposure)2. Repetitive A tiered approach should be applied, going from

simple, to refined or comprehensive, if necessary, to quickly assess chemicals of low concern and to prevent animal testing.

3. Relatives The focus should be on families or categories of chemicals (a group-wise approach) using read-across, QSARs and exposure categories: move away from the chemical-by-chemical approach.

4. Restriction of testing (waiving of testing) where possible and carry out in-vivo testing where needed in order to prevent damage to human health and/or the environment. The strategy should also encompass the current 3-R strategy of:

5. Replacement (substitution)6. Refinement (reduce suffering and distress)7. Reduction

OECD TOOLBOX Tracks and Workflow

Problems and Challenges

“A major focus for the future of computational toxicology will be integration and analysis of large data sets. The current state of toxicity databases is something of a mess. There are a number of databases, each with differing content, architecture, and searchability, that makes the task of integration extremely difficult.” (Jacobs and Marnett, 2007)

New toxicity data models provide the means, and the data entry tools provide the mechanism, for migrating previously inaccessible data and new data into a standardized, relational format (Richard, Yang and Judson, 2008)

Conclusions III

1. ITS / innovative toxicology is on the political agenda, partnerships with industry have been set up and has a great animal-saving and cost-saving potential

2. A paradigm shift is needed from extensive animal testing to efficient, focussed animal testing applying the 7-R approach

3. Expectations to replace animal tests seem to be running ahead of scientific reality (CSTEE & SCCNFP, 2004 and Greim et al. 2006)

4. A long-term commitment for further scientific work is needed for the next two decades

5. Timeline driven regulatory programs such as REACH cannot wait. Tools and approaches are urgently needed in the next few years. The OECD Toolbox is a major step to fulfil the needs for category approaches

6. The availability and accessibility of high quality in vivo data can be a limiting factor both for the development of in silico and in vitro methodologies

7. Industry involvement and leadership is key and so is the change in mind set for all stakeholders

IV. Why a change in mind set is needed(three scenarios for implementation)

1) The past

2) The present (REACH as planned)

3) The future (REACH as needed)

Public Availability of Data on HPVCs(Allanou, Hansen and van Der Bilt, 1999)

• 14 %:base set data

• 65%: less than base set

• 21%: no data86%

Priority list

Draft RAR

Agreed RAR

Agreed risk reduction strategy

Tour de EU Implementation of EU

measures

1-? y

SETAC BRIGHTON CONFERENCE (2000) JdB, BH, KvL

Scenario 1 The past (legislation from the past)

Achieved or planned

141 HPVCs have been evaluated in the last 14 years

Change in mind set Not applicable

Uncertainty Very high. Most chemicals have not been assessed and most (> 90%) chemicals lack basic information

Consequences Full evaluation of all 2700 HPVCs is estimated to take another 250 years. All other chemicals cannot be assessed

Qualification We were doing the things right, but not the right things. Penny wise, pound foolish

Scenario 2 The present (REACH as planned)

Achieved or planned 30,000 chemicals are planned to be evaluated in the next 11 years

Change in mind set No: focus on individual chemicals (chemical by chemical) remains. Business as usual

Uncertainty Even a 10-fold increase in the assessment rate of chemicals as compared to the past will reduce the total uncertainty only marginally

Consequences Full implementation may take at least 10 times more time as currently predicted or the system may even collapse

Qualification No changes. We may get some more pennies wiser, but basically it is business as usual

Scenario 3 The future (REACH as needed)

Achieved or planned 30,000 chemicals have been evaluated in a cost-effective manner in the next 11 years

Change in mind set Yes: focus on groups of chemicals and reducing uncertainty for the entire group of chemicals in a pragmatic manner.

Uncertainty Uncertainty almost fully reduced, i.e. knowledge on hazard and risks of 30,000 industrial chemicals is reduced largely compared to the legislation of the past.

Consequences Timely and cost-effective implementation of REACH while enhancing the competitiveness and innovative capacity of the chemical industry.

Qualification Doing the right things will make us pound wise and penny foolish. It will bring us a significant step further towards sustainable development

Conclusions IV

Stakeholders should be aware of the uncertainty paradox. The focus should be on the reduction of the overall uncertainties of 30,000 chemicals in the context of REACH (doing the right things) rather than on doing the things right (a perfect scientific analysis of the risks of only a few chemicals).

V. CONCLUDING REMARKS:Trends and paradigm shifts are needed

1. From focus on legislation to implementation 2. From public authorities to industry (burden of proof)3. From reactive to proactive (attitude)4. From full testing to selective testing (ITS 7-R)5. From effects-oriented to exposure-driven6. From focus on RA to RMM

PERSONAL OBSERVATIONS1. In the last 14 years 141 priority chemicals were evaluated: high quality

but slow process: most chemicals have not been assessed.2. Uncertainty paradox: The past focus on less than 1% of the 30,000

chemicals implies that the other 99% are not assessed. We were doing the things right but not the right things (penny wise and pound foolish).

3. In order to reduce the overall uncertainty of 30,000 chemicals under REACH we should move away from chemical-by-chemical approaches to more pragmatic approaches (Exposure: use and exposure categories and Hazards: toxicological categories).

4. “It is often necessary to make a decision on the basis of knowledge sufficient for action but insufficient to satisfy the intellect” (Jens Steensberg, 1989).

5. Industry and other stakeholders need to drastically simplify the REACH guidance (≈ 6000 pages) to facilitate implementation.

6. We need a change in mind set and address the uncertainty paradox in order to become pound wise and penny foolish, otherwise REACH implementation will take much more time than currently predicted

FACT SHEET OF THE BOOK• Main contributors: European Commission & RIVM• Second edition (first edition published in 1995)• Kees van Leeuwen and Theo Vermeire (eds.)• Team work: 14 organizations (writing) / 36 (total)• Including industry (ECETOC) and scientific community• 2 years of work• Publisher: Springer.com• 16 Chapters• 37 Authors• 39 Reviewers• 700 pages• 2 kg

Allanou R, Hansen BG, Van Der Bilt Y. 1999. Public availability of data on EU high production volume chemicals. Report EUR 18996 EN, European Commission, Joint Research Centre, Ispra, Italy.

Bradbury S, Feijtel T, Van Leeuwen K. 2004. Meeting the scientific needs of ecological risk assessment in a regulatory context. Environ Sci Technol 38/23, 463-470a.

Commission of the European Communities. 2007. Corrigendum to Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC (OJ L 396, 30.12.2006). OJ L136, volume 50, 29 May 2007.

Greim, H. et al. 2006. Toxicological comments to the discussion about REACH. Arch Toxicol 80:121-124

Haigh N Baillie A. 1992. Final report on chemicals control in the European Community in the 1990s. Institute for European Environmental Policy, London, UK.

Hansen BG, van Haelst AG, van Leeuwen K, van der Zandt P. 1999. Priority setting for existing chemicals: European Union risk ranking method. Environ Toxicol Chem 18, 772-779.

References

Jones, J. 2006. National Pesticide program. A new toxicological testing paradigm: meeting common needs. Presentation to the National Research Council Committee on toxicity testing and assessment of environmental agents on January 19. Irvine, CA. USEPA-OPP, Washington DC.

Steensberg J. 1989. Environmental health decision making. The politics of disease prevention. Thesis. Supplementum 42 to the Scandinavian Journal of Social Medicine, Almqvist & Wiksell International, Copenhagen, Denmark

Van der Jagt K, Munn S, Tørsløv J, De Bruijn J. 2004. Alternative approaches can reduce the use of test animals under REACH. Addendum to the report “Assessment of additional testing needs under REACH. Effects of (Q)SARs, risk based testing and voluntary industry initiatives”. Report EUR 21405. European Commission, Joint Research Centre, Ispra, Italy.

Van der Poel, P, Brooke, D and Van Leeuwen, C.J. 2007. Emissions of chemicals. In: Risk assessment of chemicals. In: Risk Assessment of Chemicals. An Introduction (2nd edition). Van Leeuwen, C.J. and T. G. Vermeire, eds. Springer Publishers, Dordrecht, The Netherlands, pp 37-72.

Van Leeuwen CJ, Bro-Rasmussen F, Feijtel TCJ, Arndt R, Bussian BM, Calamari D, Glynn P, Grandy NJ, Hansen B, Van Hemmen JJ, Hurst P, King N, Koch R, Müller M, Solbé JF, Speijers GAB, Vermeire T. 1996. Risk assessment and management of new and existing chemicals. Environ Toxicol Pharmacol 2: 243-299

U.S. NRC. Toxicity testing in the 21st century: a vision and a strategy. Committee on toxicity testing and assessment of environmental agents. National Research Council, USA.

Van Leeuwen, C.J., B.G. Hansen and J.H.M. de Bruijn. 2007. Management of industrial chemicals in the European Union (REACH). 2007. In: Risk Assessment of Chemicals. An Introduction (2nd edition). Van Leeuwen, C.J. and T.G. Vermeire, eds. Springer Publishers, Dordrecht, The Netherlands, pp 511-551. Greim, H. et al. 2006. Toxicological comments to the discussion about REACH. Arch Toxicol 80:121-124

Van Leeuwen, C.J., G. Y. Patlewicz and A. P. Worth. 2007. Intelligent Testing Strategies. In: Risk assessment of chemicals. In: Risk Assessment of Chemicals. An Introduction (2nd edition). Van Leeuwen, C.J. and T.G. Vermeire, eds. Springer Publishers, Dordrecht, The Netherlands, pp 467-509.

Relevant websites

Website of the European Chemicals Bureau: http://ecb.jrc.it/reach/ Website of the European Chemicals Agency:

http://ec.europa.eu/echa/home_en.html Websites of the European Commission

http://ec.europa.eu/environment/chemicals/reach/reach_intro.htmhttp://ec.europa.eu/enterprise/reach/index_en.htm

http://ecb.jrc.it/DOCUMENTS/REACH/REACH_in_brief_0207.pdf Helpdesks of the EU member states, i.e.:

http://www.reachright.ie http://www.senternovem.nl/reach