NOTOX B.V. REACH (Registration and Evaluation) SOCMA Corporate Excellence Conference 16 May 2008 Savannaha, Georgia

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 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 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 Regulation  Evaluate existing (EINECS) substances (30,000)  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 substances Tiered approach for registration 1.2,600 substances > 1,000 MT + CMR 2.2,900 substances 100 – 1,000 MT 3.4,600 substances 10 – 100 MT 20,000 substances 1 – 10 MT There will be one pre-registration and consortia building opportunity (SIEF formation) before data collection starts.

REACH: Exemptions  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 NEW chemical guideline (67/548/EEC) amended 1 June 2007 Set - up Agency Entry into force (EC 1907/2006) 1 June 2008 Pre-registration 1 Dec 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/y 10–100 t/y 1 Dec June June 2018 Registration Phase-in substances

Data requirements for phase-in substances Tonnage> 1, – 1,00010 – 1001 – 10 Data – Annex VII & VIII* VII & VIIIVII CSRYes No Time path3.5 years6 years11 years CMRs 1&2 + PBT + vPvB 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 responsible  Manufacturer of chemicals in the EU  Importers of chemicals, products and articles  Only representatives (OR) for non-EU manufacturers Other players: -Third party representatives -Downstream users

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)  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)  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) 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 Approaches To be done between 1 June and 1 December 2008

What is needed to pre-register a substance :  Registration number (EINECS/CAS)  Chemical name (IUCLID or CAS)  Registrant/Contact information  Registration deadline and tonnage  Information on similar substances for QSAR and potential read-across  Must submit via REACH-IT portal

Prepare for SIEF activities  Determine value of data you own  Decide 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:  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-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 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:  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?  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 chemicals (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 testing  Introduction of computer models  Introduction of read-across

Important websites echa.europa.eu/reachit echa.europa.eu/iuclid

Any Questions ?? Contact: Robert B. Foster, Senior Scientific Advisor NOTOX (USA) Tel: Website:

Data packages for Annex VII-X Existing and New Substances

Test Package 1 – 10 t/a (Annex VII) Physico-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) Toxicological 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 (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 day repeated dose - -Reproductive toxicity - Developmental screen (OECD 421 or 422) - -Toxicokinetic assessment

Test Package 10 – 100 t/a (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 (Annex IX) This in addition to Annex VII+VIII Physico-chemical properties: -Stability in organic solvents -Dissociation constant -Viscosity Toxicological Information: day repeated dose - -Teratogenicity - -2-generation study

Test Package 100 – 1000 t/a (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 products E-fate/behaviour: - fish bioconcentration - further adsorption / desorption studies

Test Package 100 – 1000 t/a (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 (Annex X) This 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