REACH
Data requirements & exposure scenarios

Kees van Leeuwen
TNO Quality of Life
Zeist, The Netherlands

CONTENTS
1.
2.
3.
4.
5.
6.

Introduction
Data requirements
REACH and the use of animals
Exposure scenarios & risk management
Concluding remarks
Further guidance and tools

The data: current situation
141
Priority
Substances
2767 HPVCs> 100.000 EINECS substancesPublic Availability of Data on HPVCs(Allanou, Hansen and van Der Bilt, 1999)! 14 %:base set data
! 65%: less than base set
86%! 21%: no data

What is the aim of a CSA?
The CSA of a chemical substance aims to establish thesafe conditions of manufacture and use of a substancefor all life-cycle stages. Manufacturers, importers anddownstream users of substances on their own or in
preparations have to ensure that these are
manufactured and can be used in such a way thathuman health and the environment are not adversely
affected.

2. Data requirements
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), biodegradation
Annex 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 etc
Annex X (! 1000 tonnes per year)! Further long term, repeat dose, chronic toxicity, fate etc

REACH data requirements
Annex VII

Estimated costs per dossier
Estimated number of substances

General estimates from several sources

Annex VIII
Annex IX

Annex X

~30 k!

170-330 k!

400-875 k!

400k-2 M!

20,000

4,600

2,900

2,600

3. 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 thantests, 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

Use of animal experiments in the EU in 2002
COM(2005) 7 final
Diagnosis of
disease2,12%
Toxicological andother safety
evaluation
9,93%

Education andtraining
3,2%
Other
5,57%

Production andquality control ofveterinary
medicine
2,42%
Production andquality control ofhuman medicine
and dentistry
13,6%

total number in 2002 = 10.7 million

Fundamental
biology studies
34,7%

Research anddevelopment of
products anddevices forhuman medicine
and dentistry andfor veterinary
medicine
28,4%

Purposes of animal experiments in 2002
COM(2005) 7 final

Total number
Safety evaluations
Agricultural chemicals
Industrial chemicals
Cosmetics

10,700,000
1,060,000
123, 000
136,000
2,700

100 %
10 %
1%
1%
0.025%

Estimated test animal need (van der Jagt et al., 2004)
Test animal need for different endpoints(% of total test animals needed)
Two-generation reprotox
Developm. tox study
Further mutagenicity
Skin sensitisation
Long-term fish tox
Developm. tox screening
Accumulation
Short-term repeated dose
Carcinogenicity
Sub-chronic tox
Long-term repeated tox
Short-term fish
Acute inhalation tox
Acute dermal tox
Acute oral tox
In vivo eye irritation
In vivo skin irritation
Long-term bird
0

5

10

15

20

%

25

30

35

40

Three tests determine the costs
Currently no alternatives to animal testing areavailable for the three main contributors to theoverall test animal use and costs:
1. two-generation reprotoxicity
2. developmental toxicity studies
3. further mutagenicity (in vivo) study

These studies contribute with approximately 70% to
the total test animal needs and testing costs.

Cost-saving aspects:
Intelligent Testing Strategies
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 ofintelligent testing strategies (ITS).
Intelligent testing strategies are integrated approaches comprising ofmultiple elements aimed at speeding up the risk assessment process
while reducing costs and animal tests(Bradbury, Feytel and Van Leeuwen, 2004)

REACH: saving potential of ITS(Van der Jagt et al., 2004; EUR report 21405)!Testing costs:!Number of animals:! 800-1130 million
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/ )Intelligent Testing Strategies (ITS)
Read Across(Q)SARs

In-vitro

Endpoint
information
Exposure
Scenarios(Annex VII/VIII)?
TESTING

Existing
information

Current toxicology testing paradigm generates in vivo
animal data for all possible outcomes to determine whichof all possible effects are relevant
Mortality!Systemic Toxicity!Disease!Cancer

Reproductive
fitness

Developmental
impairment!Viable Offspring!Fertility!Terato!Prenatal Deficits

BATTERY of Animal Testing(Jones and Bradbury, USEPA, 2005)

Components of Intelligent Testing Strategies(v) Read-across and chemical categories (USEPA, 2004)

Human health

Environmental
effects

Adequate studies 50%

58%

Estimation via
read-across
Testing

44%

35%

6%

7%

A paradigm shift is needed

In the context of regulatory programs, the challenge is to
move in a scientifically credible and transparent mannerfrom a paradigm that requires extensive hazard testing to
one in which a hypothesis- and risk-driven approach can beused to identify the most relevant in vivo information(Bradbury, Feytel and Van Leeuwen, 2004)

Towards a 7-R strategy implementing ITS
1.
2.
3.

4.

5.
6.
7.

Risks Focus on risks (include exposure)
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.
Relatives The focus should be on families or categories ofchemicals (a group-wise approach) using read-across, QSARs andexposure categories: move away from the chemical-by-chemical
approach.
Restriction of testing (waiving of testing) where possible and carryout in-vivo testing where needed in order to prevent damage tohuman health and/or the environment. The strategy should also
encompass the current 3-R strategy of:
Replacement (substitution)
Refinement (reduce suffering and distress)
Reduction

REACH, registration and ITS! Increased pressure to use/develop alternative methods(Limited impact now but may influence future acceptance of
methods)! Agency in cooperation with MSs and interested parties should
develop appropriate guidance (REACH Recital 38)

Conclusions on ITS
1.

2.
3.
4.
5.

Expectations to replace animal tests with in vitro studies and QSARs seemto be running ahead of scientific reality (see CSTEE & SCCNFP in Van
Leeuwen, Patlewicz, Worth, 2007 and Greim et al. 2006)
A paradigm shift is needed from extensive animal testing to efficient,focussed animal testing applying the 7-R approach
ITS has a great animal-saving and cost-saving potential
Guidance on data requirements (RIP 3.3) is available in draft form (seewebsite of the ECB; 1100 pages!
Further scientific work (2007 onwards) and regulatory implementation isneeded.

4. Exposure scenarios & risk management
The Chemical Safety Assessment (CSA) is the tool used to determine theway chemicals can be used safely
An exposure scenario sets out, for a given use, how the substance can be used in a waythat risks are adequately controlled by describing the conditions for use:
" Process descriptions (incl. quantity used)" Operational conditions (incl. frequency and duration of specified operations)" Risk management measures (process and emission control, personal protective
equipment, good hygiene, etc.)
Exposure scenarios are developed as part of the CSA The Chemical
Safety Assessment (CSA) is the tool used to determine the way chemicals
can be used safely

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 andhow the manufacturer or importer controls, or recommends
downstream users to control, exposures of humans and theenvironment. These exposure scenarios may cover one
specific process or use or several processes or uses asappropriate.

Registration requires:
1. A technical dossier (for all substances ! 1 tonne/y).
2. A chemical safety report (CSR; for substances ! 10 tonnes/y).
If the substance meets the criteria for classification as
dangerous or is assessed to be PBT or vPvB, the CSA
has to include an exposure assessment including one
or more exposure scenario(s), exposure estimation andrisk characterization.

Six steps to develop an exposure scenario
1. Identification of uses and use processes
2. Description of manufacturing or use process
3. Development of a #tentative$ ES
4. Exposure estimation and risk characterisation
5. Defining the #final$ ES
6. Developing the annex to the SDS

Supply chain communication
Supplier

SDS including
Exposure Scenarios(Recommended Risk
Management
Measures)

SafetyData
Sheet

Downstream user(s)Identify use

Types of risk management measures
1.
2.
3.
4.
5.
6.
7.

Product-substance related measures
Limitation of the marketing of a substance/productInstructions to limit the use
Instructions/information/warnings
Technical measures
Organisational measures
Personal protection measures

Source: RIP 3.2 WP1 development of the concept of
Exposure scenarios, 337 pp (Website of ECB)Existingknowledge/data

Hazardidentification

Exposure scenarios
Revise assumed RMM
and/or operational
conditions

Classificationand labelling
Exposure
assessment

Hazardassessment

Risk characterisationNO

Are risks adequately controlled?

NO

YES
ESs with RMM and operational conditions to adequately control the risks, to be:
Documented in the Chemical Safety Report (CSR)
Communicated to users (to downstream users via an SDS annex)

Typical characteristics of an ES
ES characteristics

Examples of parameters(not exhaustive)

Remarks

Life cycle of substance or productto which the ES refers

Manufacture or import, synthesis,
compounding, formulation, use,
service life, waste phase

Identify relevant exposures for all
target groups, supports selectionof suitable broad ES

Process characteristics

Industrial category, use category

Manufacture or use activity

Operational conditions

Type of activity/use
Duration of activity/use
Frequency of activity/use
Temperature, pH, etc.
Containment of process[open/closed]

Determines type of exposure(short term vs. long term) andchoice of PNEC or DNEL

Preparation characteristics

Weight fraction of substance
Migration rate

Determines exposure of humans
and environment for preparations
or products

Used quantity

Use rate [tonnes/year]
Amount handled [kg/day, etc]

Determines the exposure potential
per time

Risk Management Measures(within control)

Local exhaust ventilation
On-site waste (water) treatment
Personal Protective Equipment

RMMs as part of process or under
direct control by DU

Conclusions on ESs and RMMs
1.
2.
3.
4.

5.
6.

RMMs are the start of a RA. The focus is on exposure
It requires multidisciplinary and integrative thinking & expertise rightfrom the start
Dialogue up and down the supply chain between actors in the supply
chain is key to success!
It requires paradigm shifts:! effects-based " exposure-driven! risk assessment" risk management
It requires detailed information on use and exposure of substances(in products) which is generally not available to the authorities (Haighand Bailly, 1992!)
Expertise in and outside industry is scarce (aging population)

5. 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-driven
6. From focus on RA to RMM
7. The Implementation will take much more timethan currently predicted

6. Further guidance and tools" 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.htm
http://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" Haigh N Baillie A. 1992. Final report on chemicals control in the European Community in the 1990s.
Institute for European Environmental Policy, London, UK.
" 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.
" 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. 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.
" 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 assessmentof environmental agents on January 19. Irvine, CA. USEPA-OPP, Washington DC.

Greim, H. et al. 2006. Toxicological comments to the discussion about REACH. Arch Toxicol 80:121-124
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 andRestriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC andrepealing 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.
" Guidance document on data requirements (RIP 3.2). See website ECB" Van Leeuwen, C.J., G.Y. Patlewicz, and A.P. Worth. 2007. Intelligent Testing Strategies 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.
" 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, 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.
" National Research Council, 2007. Toxicity Testing in the Twenty-first Century: A Vision and a Strategy. The National
Academic Press, Washington DC.
""

Data requirements under REACH Annex VII for" 1 TONNE
Skin irritation or skin corrosion
8.2
8.3
8.4.1
8.5.1

Eye irritation
Skin sensitisation
Mutagenicity (gene mutation in bacteria)
Acute toxicity (oral route)

Ecotoxicological information
9.1.1
9.1.2
9.2.1.1

Short-term toxicity invertebrates (Daphnia)
Growth-inhibition plants (algae)
Ready biodegradability

Data requirements under REACH Annex VIII for" 10 TONNES
Toxicological information
8.1.1
8.2.1
8.4.2
8.4.3
8.5.2
8.5.3
8.6.1
8.7.1
8.8.1

Skin irritation (in vivo)
Eye irritation (in vivo)
Cytogenicity in mammalian cells (in vitro)
Gene mutation in mammalian cells (in vitro)
Acute toxicity (inhalation)
Acute toxicity (dermal)
Repeated dose toxicity (28days)
Reproductive/developmental toxicity screening test; OECD 421 or 422)
Toxicokinetics

Ecotoxicological information
9.1.3.
9.1.4.
9.2.2.1
9.3.1

Short-term toxicity fish
Activated sludge respiration inhibition test
Hydrolysis as a function of pH
Adsorption/desorption screening test

Data requirements under REACH Annex IX for "100 TONNES
Toxicological information
8.6.1
8.6.2
8.7.2
8.7.3

Repeated dose toxicity (28 days)
Sub-chronic toxicity (90 days)
Developmental toxicity; OECD 414
Two-generation reproductive toxicity study

Ecotoxicological information
9.1.5
9.1.6.
9.1.6.1
9.1.6.2
9.1.6.3
9.2.1.2
9.2.1.3
9.2.1.4
9.2.3
9.3.2
9.3.3
9.4.1
9.4.2
9.4.3

Long-term toxicity invertebrates (Daphnia)
Long-term toxicity to fish
Fish early-life stage test
Fish short term toxicity embryo and sac fry
Fish juvenile growth test
Ultimate degradation in surface water
Soil simulation testing
Sediment simulation testing
Identification of degradation products
Bioaccumulation in aquatic species (fish)
Further information on adsorption/desorption
Short-term terrestrial toxicity (invertebrates)
Effects on soil micro-organisms
Short-term toxicity to terrestrial plants

Data requirements under REACH Annex X for "1000 TONNES
Toxicological information
8.6.3
8.7.2
8.7.3
8.9.1

Long-term repeated toxicity (%12 months)
Developmental toxicity; OECD 414
Two-generation reproductive toxicity
Carcinogenicity study

Ecotoxicological information
9.3.4
9.4.4
9.4.6
9.5.1
9.6.1

Further fate and behaviour in the environmentof the substance and/or degradation products
Long-term toxicity on invertebrates
Long-term toxicity on plants
Long-term toxicity to sediment organisms
long-term toxicity to birds