NOTOX B.V.NOTOX B.V.

REACH (Registration and Evaluation)REACH (Registration and Evaluation)

SOCMA Corporate Excellence Conference 16 May 2008

Savannaha, Georgia

Core business of NOTOX B.V.Core business of NOTOX B.V.

Regulatory support for the notification of industrial, crop protection and biocidal products

Performance of studies for the registration of industrial and agrochemicals

Conduct of pre-clinical studies on APIs in support of new drug development

Track Record Regulatory SupportTrack Record Regulatory Support

Industrial and specialty chemicals: HPV OECD/ICCA

– > 50 substances HPV US-EPA Test plans and gap-filling

– > 150 substances Notification dossiers EU

– > 1,000 substances– consortia experience

REACH ProvisionsREACH Provisions

REACH objectives:– Protection of human health and environment– Development of hazards, use conditions and exposure information for existing substances– Compulsory sharing of information to ensure

competitiveness of EU chemical industries Reduce animal testing (in vitro, QSAR, read-across) Responsibility for hazard information shifts from

the government to the industry Sustain REACH-IT portal for communication

among registrants

REACH RegulationREACH Regulation

Evaluate existing (EINECS) substances (30,000) 2010 - 2018

Compile registration technical dossiers on EINECS substances – IUCLID 5

Reduction of testing requirements for new chemicals 1 – 10 tons

QSAR and alternatives for animal studies accepted, also using read-across

REACH: phase-in substancesREACH: phase-in substances

Tiered approach for registration1. 2,600 substances > 1,000 MT + CMR2. 2,900 substances 100 – 1,000 MT3. 4,600 substances 10 – 100 MT

20,000 substances 1 – 10 MTThere will be one pre-registration and consortiabuilding opportunity (SIEF formation) before data

collection starts.

REACH: REACH: ExemptionsExemptions Substances under PPORD are exempted

for 5 – 10 years medicinal products including intermediates waste foodstuffs pesticides radioactive substances substances in transit - customs supervision cosmetics Polymers are exempted (for the moment).

REACH: Time schedule REACH: Time schedule

NEW chemical guideline(67/548/EEC) amended

1 June2007

Set- up Agency

Ent

ry in

to fo

rce

(EC

190

7/20

06)

1 June2008

Pre -registration

1 Dec.2008

Phase- in substances> 1000 t/y

> 100 t/y + R50/53> 1 t/y + CMR

Phase- in substances

100 – 1000 t/y

Phase- in substances

1 – 10 t/y10 – 100 t/y

1 Dec.2010

1June2013

1June2018

Registration Phase - in substances

Data requirements for Data requirements for phase-in substancesphase-in substances

Tonnage > 1,000 100 – 1,000 10 – 100 1 – 10

Data –Annex

VII & VIII* VII & VIII* VII & VIII VII

CSR Yes Yes Yes No

Time path 3.5 years 6 years 11 years 11 years

CMRs 1&2 + PBT + vPvB

3.5 years 3.5 years 3.5 years 3.5 years

* Requires a test plan submitted to ECHA for any additional studies from Annex IX or X

CSR: Chemical Safety Report

Who is responsibleWho is responsible

Manufacturer of chemicals in the EU Importers of chemicals, products and

articles Only representatives (OR) for non-EU

manufacturersOther players:- Third party representatives- Downstream users

1- 10 MT/y (Annex VII)1- 10 MT/y (Annex VII)

Physico-chemical properties Acute toxicity Environmental toxicity and

biodegradation

Rough costs: € 50,000 - € 65,000 or minimum $75,000

10 – 100 MT/y (Annex VIII)10 – 100 MT/y (Annex VIII)

Additional acute toxicity Repeated dose toxicity Reproductive toxicity Additional environmental toxicity and

behaviour

Rough costs: € 180,000 - € 220,000 or minimum $270,000

100 – 1,000 t/y (Annex IX)100 – 1,000 t/y (Annex IX)

Additional physico-chemical Further repeated dose toxicity Long-term aquatic toxicity Degradation and e-fate behaviour Terrestrial toxicity

Rough costs: € 550,000 – € 1,000,000 minimum $825,000

> 1,000 MT/y (Annex X)> 1,000 MT/y (Annex X)

Only after approval by authorities: Additional long-term toxicity Additional long-term aquatic toxicity Additional terrestrial toxicity

Rough costs: € 1,300,000 mimimum $2,000,000

Pre-registration ApproachesPre-registration Approaches

To be done between 1 June and 1 December 2008

What is needed to What is needed to pre-register a substancepre-register a substance::Registration number (EINECS/CAS)Chemical name (IUCLID or CAS)Registrant/Contact informationRegistration deadline and tonnageInformation on similar substances

for QSAR and potential read-acrossMust submit via REACH-IT portal

Prepare for SIEF activitiesPrepare for SIEF activities

Determine value of data you ownDecide on required role in consortia

(lead, active or passive member)Decide on sharing company

confidential information (composition data, use information)

Advise downstream users of REACH conformance

Test plan:Test plan:

Data gaps based on volume needs (Annex VII + VIII)

Data needs based on scientific or use considerations for Annex IX + X end-points

Data needs based on the outcome of the CSA/CSR

What can be waived using Annex XI

After Pre-registrationAfter Pre-registration

Companies who have pre-registered a substance will automatically become listed on the pre-SIEF page (REACH-IT) of this substance.

To initiate discussions after pre-registration, a pre-registrant can volunteer on the pre-SIEF page to become SIEF formation facilitator

. ECHA will publish by 1 January 2009, a list of pre-registered

substances on its website. The list will comprise of all substances that have been pre-registered by 1 December 2008. For each substance the following information is displayed:

Substance identification: EINECS number, CAS number and names of the substance

Substance identification of the similar substances, if applicable

The first envisaged registration deadline

Registration Technical Dossier:Registration Technical Dossier:

Annex VII: ± € 3,500 Annex VIII: ± € 15,000 Annex IX: ± € 30,000 Annex X: ± € 39,000

Based on setting the economic values and making robust summaries of one study per endpoint. The estimated time for a substance imported/produced in Europe above 100 MT, is a worst case estimate as only data from Annex VII

and VIII are compulsory to report .

Annex XI: what’s in it?Annex XI: what’s in it?

Testing does not appear scientifically necessary– Use existing (non-GLP) data– Use historical human data– Weight of evidence– (Q)SAR possibilities– In vitro methods– Grouping and read-across

Testing is technically not possible Substance-tailored exposure-driven testing

REACH and new chemicalsREACH and new chemicals(non-phase-in substances)(non-phase-in substances)Changing of notification levels

– < 1 ton: exempt– 1-10 tons: limited testing (Annex VII)

– > 10 tons: full package (Annex VII + VIII) plus a test plan if > 100 tons

Introduction of in-vitro testingIntroduction of computer modelsIntroduction of read-across

Important websitesImportant websites

http://echa.europa.eu/pre-registrationhttp:// echa.europa.eu/reachithttp:// echa.europa.eu/iuclid

Any Questions ??Any Questions ??

Contact:Robert B. Foster, Senior Scientific AdvisorNOTOX (USA)Tel: 508-830-6708E-mail: notoxusa@aol.comWebsite: www.notox.nl

Data packages for Data packages for Annex VII-XAnnex VII-X

Existing and New Substances

Test Package 1 – 10 t/a (Annex VII)Test Package 1 – 10 t/a (Annex VII)Physico-chemical propertiesPhysico-chemical properties

- Melting point- Boiling point- Relative density- Vapour pressure- Surface tension- Water solubility- Partition coefficient

- Flash point- Flammability- Explosive properties- Self-ignition

temperature- Oxidising properties- Granulometry

Test Package 1 – 10 t/a (Annex VII)Test Package 1 – 10 t/a (Annex VII)Toxicological informationToxicological information

- Acute oral toxicity- In vitro skin

corrosion and/or in vitro skin irritation

- In vitro eye irritation- Sensitisation (LLNA)

- In vitro mutagenicity (Ames test)

- Aquatic toxicity – Daphnia acute test

- Algae growth inhibition

- Biodegradation

- All other available data

Test Package 10 – 100 t/a Test Package 10 – 100 t/a (Annex VIII) This is in addition to Annex VII(Annex VIII) This is in addition to Annex VII

Toxicity data:- In vivo skin irritation *- In vivo eye irritation *- In vitro cytogenicity in

mammalian cells and/or

- In vitro gene mutation in mammalian cells

* Depending on Annex VII result

- Acute dermal or inhalation

- 28-day repeated dose- Reproductive toxicity

- Developmental screen (OECD 421 or 422)

- Toxicokinetic assessment

Test Package 10 – 100 t/a Test Package 10 – 100 t/a (Annex VIII) This is in addition to Annex VII(Annex VIII) This is in addition to Annex VII

Aquatic toxicology:

- Acute toxicity with fish- Active sludge respiration inhibition test- Hydrolysis as function of pH (abiotic)- Adsorption/desorption screening study- Further degradation testing if needed

Test Package 100 – 1000 t/a Test Package 100 – 1000 t/a (Annex IX) This in addition to Annex VII+VIII(Annex IX) This in addition to Annex VII+VIII

Physico-chemicalproperties:

- Stability in organic solvents

- Dissociation constant- Viscosity

Toxicological Information:

- 90-day repeated dose- Teratogenicity - 2-generation study

Test Package 100 – 1000 t/a Test Package 100 – 1000 t/a (Annex IX) This in addition to Annex VII+VIII(Annex IX) This in addition to Annex VII+VIII

Aquatic toxicology:- Long-term study on

Daphnia- Long-term study on fish

One of the following:- Fish ELS or- Fish embryo and sac-fry stages- Fish juvenile growth

Degradation:- further biotic studies- Soil or sediment simulation testing- identification of degradation productsE-fate/behaviour:- fish bioconcentration- further adsorption / desorption studies

Test Package 100 – 1000 t/a Test Package 100 – 1000 t/a (Annex IX) This in addition to Annex VII+VIII(Annex IX) This in addition to Annex VII+VIII

Further e-fate testing:

Effects on terrestrial organisms:- Acute toxicity on earthworms- Effects on soil micro-organisms- Acute toxicity to plants

Test Package > 1000 t/a Test Package > 1000 t/a (Annex X) (Annex X) This in addition to Annex VII+VIII+IXThis in addition to Annex VII+VIII+IX

Further toxicity testing only in agreement with authorities.

Further aquatic testing only in agreement with authorities.

Additional terrestrial studies:- Long-term testing on earthworms- Long-term testing on soil invertebrates- Long-term testing on plants- Long-term testing to sediment organisms

(proposal)- Long-term or reproductive study on birds