REACH 2018 Steps to a Successful Registration. Thursday, October 8, 2015

Transcription

1 REACH 2018 Steps to a Successful Registration Thursday, October 8, 2015

2 Today s Speakers Steps to a Successful REACH 2018 Registration Sandra Meijer, The REACH Centre REACH Overview with Special Considerations for REACH 2018 Rosalinda Gioia, The REACH Centre Registration Process and Logistics Steps to the REACH Registration Timelines and costs Actions for a successful Registration Jiaru Zhang, Gradient Technical Issues 2 Copyright Gradient 2015

3 REACH Overview with Special Considerations for REACH 2018 Dr Sandra Meijer 8 October 2015

4 REACH Overview REACH Registration no data, no market Industry needs to demonstrate that the risks associated with the use of the substance are adequately controlled Manufacturers and importers of chemicals (substances on their own or in mixtures) > 1 tpa need to register the substance(s) with the European Chemicals Agency (ECHA) Both new and existing substances

5 Exempt from Registration Specific substances for defence purposes Polymers (but not monomers used in them!) Certain named substances (Annex IV) Certain groups of substances (Annex V) Certain uses (medicinal, veterinary, food and foodstuffs) R & D and PPORD Recovered materials Re-imports REACH Overview

6 REACH Overview Registration Timelines Pre-registration (phasein substances only) Registration of : 1 tonne/year CMRs 100 tonnes/year very toxic to the aquatic environment 1000 tonnes/year 100 tonnes/year 1 tonne/year New substances; before manufacturing, importing or placing on the market

7 REACH Overview Impact of REACH on US companies REACH requirements placed on EU companies mean that often full product composition is needed in order to determine compliance obligations This creates CBI issues for US companies wishing to sell into Europe US companies can take on registration obligations in order to safeguard CBI (via Only Representative) The OR carries out the REACH duties of an importer (but not the commercial activities of an importer such as customs clearance etc) The OR will submit the pre-registration and registration and will be the contact with the ECHA

8 REACH Overview Only Representative vs. Importer Non-EU manufacturer A Non-EU EU Take home: Be well aware of the supply chain and communicate with your EU client to ensure business continuity Trader EU manufacturer EU company Non-EU manufacturer B Only Rep

9 REACH Overview Late pre-registration It is possible to make a late pre-registration but only for new activities A late pre-registration must be made within 6 months of the activity commencing but cannot be made within 12 months of an applicable phase-in registration deadline (i.e. not after 1st June 2017 for registration deadline of 1 st June 2018) Phase-in substances which have not been pre-registered require immediate registration following the submission of an Inquiry to ECHA This can delay access to the EU market as processing of Inquiry dossiers by ECHA can be very slow! Take home: even if volumes are currently low (< 1t), consider a late pre-registration now in order to avoid delays later on

10 REACH Overview Inquiry Process Non phase-in substances and substances that have not been pre-registered require submission of an Inquiry to ECHA (Article 26); Inquiry dossier includes full characterisation which is assessed by ECHA before approving substance identity (so that correct SIEF can be identified) Inquiry dossiers often fail due to insufficient substance identity information No time limit on ECHA s assessment period Lengthy process compared to pre-registration Take home: Inquiry process can act as a barrier to EU market access

11 REACH 2018 Get ready for The final registration deadline is 31 May 2018 Tonnage bands: 1 10 tpa tpa ECHA is expecting up to 70,000 registrations More SMEs More niche chemicals this time Confidentiality issues OR solution Less data available Larger portfolios more time needed! Take home: Start now

12 Thank you Dr. Sandra Meijer twitter.com/thereachcentre

13 Registration Process and Logistics Dr Rosalinda Gioia 8 October 2015

14 Registration Process Main steps to a successful registration 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date

15 Registration Process Step 1: Know your portfolio 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date Registrants responsible for safe manufacture and use 1. Identify number of substances: How many do we need to register by 2018? 2. Identify your tonnage band: Are your tonnage band still valid? 3. Establish substance identity: Are these substances what we think they are? Point (3) and is the basis for all other activities

16 Registration Process Step 2. Find your co-registrants 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date Every company that has pre-registered a substance is automatically part of the pre-sief. Agree on substance sameness No need to apply to join a SIEF (& no cost attached) It is possible to change SIEFs e,g. if you realise your substance is different from what you thought or when SIEFs are split or merged

17 Registration Process Step 2. Find your co-registrants Substance NOT YET registered by industry Has anyone offered to take the lead? NO Do we want to take the lead? NO WAIT? < 1 TPA? REPLACE? OR Substance ALREADY registered by industry YES YES BUSINESS DECISION! Submit a Joint Registration Prepare and submit a Lead dossier; Act as Lead Registrant

18 Registration Process Step 2. Agree on Datasharing If your substance is already registered: Letter of Access costs need to be fair, equitable and nondiscriminatory Varies widely from 500 EUROS to 250,000 EUROS Cost divided by number of registrants (so # of registrants has big impact!) You can t negotiate a special price You shouldn t have to pay again for data you already own Most LRs envisage a refund possibility after 2018 (more registrants expected to come on board between now and 2018) Cost sharing SIEF members must reach an agreement on how to share the cost of data and the cost of SIEF administration [ ] Under REACH, the cost needs to be shared in a fair, transparent and non-discriminatory way

19 Registration Process STEP 2. Lead Registrant role If you are taking the LR role: Perform literature search and data gap assessment Plan to fill data gaps Prepare a SIEF agreement. Use model agreements and templates prepared by industry associations like CEFIC. Reach a general agreement on how to share the cost of data and the cost of SIEF administration (fair, transparent, non-discriminatory). Do you have the expertise to complete registration? For Lead Registration Time, Preparation and Expertise are important factors.

20 Registration Process Fleisher Costs Data Costs Fleischer 1-10t t t 1000t+ Cost (EUR) Annex VII phys/chem $19,126 Annex VII tox endpoints $40,892 Annex VIII $322,266 Annex IX $690,690 Annex X $1,198,932 Total $2,271,906 Fleischer, M (2007) Testing Costs and Testing Capacity According to the REACH Requirements - Results of a Survey of Independent and Corporate GLP Laboratories in the EU and Switzerland, 4(3), Journal of Business Chemistry, p In practice, a number of studies may not need to be performed Read across Data waiving Literature data available

21 Timelines for LR (1-10 tonnes) Registration Process Week Substance Characterisation Data Gap Analysis + ITS Quotes Physchem Human Toxicology (Phase 1) Human Toxicology (Phase 2) Ecotoxicology Dossier preparation and submission Shorter timeframe if not all tests are required

22 Registration Process STEP 3. Prepare and submit your dossier in IUCLID 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date IUCLID stands for International Uniform ChemicaL Information Database A database system for the storage and retrieval of detailed hazard information concerning chemical substances. Compliant with OECD Harmonised Data Formats and compatible with other pieces of legislation (e.g. the Biocidal Products Regulation) Can be installed as stand-alone or network systems Contains 9,000 data fields

23 Registration Process Step 3. Submit your dossier If you are a lead registrant Create the joint submission object in REACH-IT; Communicate the joint submission name and token generated by REACH-IT to the members; Submit the lead registration dossier in REACH-IT. ECHA will check if it can process your dossier (business rules). Only after this check, will members be able to submit their own dossiers. You are strongly advised to submit your lead dossier well before the end of May

24 Registration Process Step 3. Submit your dossier If you are a member registrant After receiving the joint submission token from your lead, confirm your membership in the joint submission in REACH- IT; Check in REACH-IT that the joint registration dossier submitted by the lead registrant has been accepted; Submit your IUCLID registration dossier in REACH-IT. ECHA will check if it can process your dossier (business rules). This is the check you need to pass by 31 May

25 Registration Process Step 4. Keep your registration up-to-date 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date What happens next? ECHA may examine any registration to verify if the information submitted by registrants is compliant with the legal requirements. The selection for compliance check is either random or concern-based (targeted).

26 Step 4: Changes requiring dossier update It is a legal requirement to keep your registration up-to-date For Lead Registrants this could include: New hazard data New uses (e.g. if new members join) New harmonised classification and labelling Also check ECHA's annual evaluation reports. Pro-actively improving your dossier may help to avoid a dossier evaluation. For Joint (and Lead) registrants this could include: Company size Tonnage band New uses Registration Process

27 Registration Process Take-home messages Identify number of substances to register and their identities- Start as early as possible. Establish if LR or JR - Business decision Consider time and costs required for studies. Start as early as possible to allow a sequential testing scheme-cost Minimization If you are a JR complete the relevant sections in IUCLID as soon as you receive the information from the LR

28 Thank you Dr Rosalinda Gioia twitter.com/thereachcentre

29 Steps to a Successful REACH 2018 Registration Technical Considerations Jiaru Zhang, MPH Gradient October 8 th, 2015

30 Main steps to a successful registration 1. Know your portfolio 2. Find your coregistrants and agree on data sharing 3. Prepare and submit your IUCLID dossier 4. Keep your registration up-to-date 30 Copyright Gradient 2015

31 Substance identification and characterization Why it s so important? 31 Copyright Gradient 2015

32 Substance Identification and Characterization Allow Joint Registration-Proves that your substance fits the Substance Identification Profile (SIP) developed by the Substance Information Exchange Forum (SIEF) Robust Hazard Identification It is the area most likely to be found to be inadequate during ECHA compliance checks 66% of dossiers reviewed in 2012 had short comings in substance identity Can lead to significant delays 32 Copyright Gradient 2015

33 Substance Identification Name (in IUPAC nomenclature, CAS RN, EINECS) Well-Defined Substances: Mono-constituents : Identify the constituent present at 80 % Multi-constituents: Identify all constituents present at 10% UVCB (Unknown or Variable composition, Complex reaction products or Biological materials) Identify all constituents 10% Identify by source, process, known composition, etc Molecular Information Molecular and structural formulas (SMILES notation) Molecular weight or range (difficult for polymers) Composition (must equal 100%) Purity Additives 33 Copyright Gradient 2015

34 Characterization Testing: Analytical Confirmation of Substance Identity Standard Tests for Organic Substances Standard Tests for Inorganic Substances Required Ultraviolet and Visible Absorption Spectroscopy (UV/Vis) Infrared Spectroscopy (IR) Nuclear Magnetic Resonance Spectroscopy (NMR) Required X-Ray Diffraction (XRD) X-Ray Fluorescence (XRF) Atomic Absorption Spectroscopy (AAS) When appropriate Gas Chromatography (GC) High-Performance Liquid Chromatography (HPLC) UVCBs and other difficult to characterize substances may require other tests Optical Activity 34 Copyright Gradient 2015

35 Data Requirements What are the data requirements for REACH 2018 registration substances? 35 Copyright Gradient 2015

36 Data Requirement (1-10 Tonnes/Year) Type Vertebrate (N=2) Non-vertebrate (N=6) Physical- Chemical (N=13) Data Acute toxicity oral (rat); In vivo skin sensitization (guinea pig) In vitro skin irritation/corrosion (Ex: OECD 439 Reconstructed Human Epidermis Test Method); In vitro eye irritation (Ex: OECD 437 Bovine Corneal Opacity and Permeability); In vitro gene mutation in bacteria (Ex: Ames Assay); Short-term toxicity on invertebrates (Ex: OECD 202 Daphnia Magna); Growth inhibition study aquatic plants (Ex: OECD 201 Algal); Ready biodegradability Melting/freezing point; Relative density; Water solubility; Partition coefficient; Flash-point; Flammability; Explosive properties; Self-ignition temperature; Oxidizing properties; Vapor pressure; Surface tension; Boiling point; Granulometry 36 Copyright Gradient 2015

37 Data Requirement ( Tonnes/Year) Type Data All data requirements from 1-10 tonnes/year (Max N=21), plus the following Vertebrate Short-term repeated dose toxicity (28-day); (N=8) Screening for reproductive/developmental toxicity (54-day); Acute toxicity inhalation + dermal; In vivo skin + eye irritation; Testing proposal for in vivo genotoxicity; Non-vertebrate (N=6) Chemical Safety Report (CSR) Short-term toxicity on fish or proposal for long-term toxicity on fish; etc In vitro mutagenicity study in mammalian cells or In vitro micronucleus study; In vitro gene mutation in mammalian cells; Hydrolysis; etc Calculate risk (Risk=Hazard x Exposure) Must know own exposure scenario (ECHA guidance available) CSR can be few pages long Must submit to ECHA a downstream user report Take Home: Registrants must use existing information and non-test methods to meet information requirements (Max N=35 tests + CSR). Testing on vertebrate animals should only be used as a last resort. 37 Copyright Gradient 2015

38 Hazard Assessment Required, but why should one care about getting this right? 38 Copyright Gradient 2015

39 Importance of Getting Hazards "Right" Correctly characterize risk in the chemical safety report (CSR), required for tonnes/year substances Hazard x Exposure = Risk Accurately convey hazards to workers and the public Ensure adequate worker protections Confidential Business Information (CBI) In many countries, specific hazards trigger mandatory safety datasheet (SDS) disclosure. This could lead to lose of proprietary information 39 Copyright Gradient 2015

40 Hazard Assessment What can I do to get it right? 40 Copyright Gradient 2015

41 Environment Human Health Physical Safety Acute Aquatic Toxicity Acute Toxicity Explosive Chronic Aquatic Toxicity Skin Damage Pyrotechnic Bioaccumulation Eye Damage Flammable Gas Biodegradation (persistent/inherent) Reproductive Toxicity Oxidizing Gas Ozone Hazard Mutagenicity Gases Under Pressure 41 Copyright Gradient 2015 Carcinogenicity Sensitizer Acute Target Organ Toxicity Chronic Target Organ Toxicity Aspiration Hazard Globally Harmonized System of Classification and Labeling of Chemicals (GHS) Version 6 Flammable Liquid Flammable Solid Self-Reactive Substance Pyrophoric (Liquids and Solids) Self-Heating Substance Emit Flammable Gases in Contact with Water Oxidizing Liquid Oxidizing Solid Organic Peroxide Corrosive to Metals Desensitized Explosives (new) Pyrophoric Gases (new)

42 Hazard Determination Considerations 1. Conflicting Data 2. No data 3. Read-across 4. Structural alert/predictive toxicology software 5. Data-waiving 42 Copyright Gradient 2015

43 What to do With Conflicting Data? Chemical X (UVCB and with Impurities) Endpoint Company Own Data Publically Available Data on Chemical X Acute Aquatic Not Classified Aquatic Cat. 1 Acute (H400) Mutagenicity No Data Positive in vitro Ames test What would you do in this scenario? 43 Copyright Gradient 2015

44 What to do With Conflicting Data? Chemical X (UVCB with Impurities) Endpoint Acute Aquatic Mutagenicity Company Own Data Not Classified No Data Publically Available Data on Chemical X Aquatic Cat. 1 Acute (H400) Positive in vitro Ames test Hazard Determination Not Classified 1. Chemical X is a UVCB? 1. Get impurity data and study details for publically available study 2. Commission an in vitro Ames test Take Home: Not straight forward. Have a weight of evidence rationale for your hazard determination. Document! 44 Copyright Gradient 2015

45 What to do With No Data? Read-Across: Identification and evaluation of a similar chemical that informs the toxicity of the chemical of concern by chemists and toxicologist (not by software) Ex: 1-octanol as a read-across for 1-hexanol Advantage better informed hazard evaluation & SDS, ensure chemicals are used more safely, minimizes analytical costs and dependence on animal testing, and helps industry to comply with regulations Disadvantage required high-qualified chemists and toxicologist 45 Copyright Gradient 2015

46 What to do With No Data? (Read-Across) Chemical Y (ph=2) Chemical Y Read-across Toxicological Data Hazard Determination No Company Test Data No data Daphnia Magna 48 hr EC 50 = 0.66 mg/l (OECD 202); Corrosive to skin in rabbits with necrosis (OECD 404) Aquatic Acute 1 (H400); Skin Corrosive 1B (H314) What would you do in this scenario? 46 Copyright Gradient 2015

47 What to do With No Data? (Read-Across) Chemical Y (ph=2) Chemical Y Read-across Toxicological Data Hazard Determination No Company Test Data Aquatic? Skin Corrosive 1B (H314) Daphnia Magna 48 hr EC 50 = 0.66 mg/l (OECD 202); Corrosive to skin in rabbits (OECD 404) Aquatic Acute 1 (H400); Skin Corrosive 1B (H314) Take Home: No data is not an appropriate response. Registrants must use existing information and non-test methods to meet information requirements. Read-across can be employed as way to meet information requirement and minimize animal testing. 47 Copyright Gradient 2015

48 What to do With No Data? Structural Alert/Predictive Toxicology Software Identification of potential hazards for chemical of concern Ex: ToxTree, OECD QSAR Toolbox, DEREK, ECOSAR Advantage Cost (ToxTree, OECD QSAR Toolbox, ECOSAR); Quick turn around Disadvantage Cost (DEREK); Poor underlying dataset for polymers, UVCBs, niche chemicals; Require in-depth chemistry and toxicology knowledge; Not user friendly 48 Copyright Gradient 2015

49 What to do With No Data? Structural Alert/Predictive Toxicology Software Quote from ECHA Chapter R.4 Evaluation of Available Data "To be used as a replacement for experimental data, it is necessary, but not sufficient, for a (Q)SAR model to be valid. The (Q)SAR model should also be shown to be applicable to the substance of interest, to determine whether the model estimate is reliable for the intended purpose." Take Home: Usage of predicted hazards to toxicity profile is dependent on your company's risk tolerance. Keep in mind of all the implications of hazard assessment: Chemical Safety Report (Hazard x Exposure = Risk) and Confidential Business Information (CBI). 49 Copyright Gradient 2015

50 What to do With No Data? Data-waiving Testing for a specific endpoint may be omitted if testing is Technically not possible, or Not scientifically necessary, or Can prove exposure scenario does not apply to substance (only for endpoints in Annexes IX-X and sections 8.6 (repeated dose toxicity) and 8.7 (reproductive toxicity) in Annex VIII 50 Copyright Gradient 2015

51 Data-Waiving Examples Tonnes/Year Type Vertebrate Nonvertebrate Physical- Chemical Common reasons for waiving requirements in parenthesis Short-term repeated dose toxicity-28d (existing or planned 90d study, non-applicable exposure routes); In vivo skin sensitization (corrosive or <2 ph >11); Testing proposal for in vivo genotoxicity (no positive results from any of the in vitro or in vivo studies); Acute toxicity dermal (corrosive); etc In vitro skin irritation/corrosion (corrosive, no irritation observed up to dermal LD50 of 2,000 mg/kg bw); Short-term toxicity on invertebrates (highly insoluble); In vitro gene mutation in bacteria (Substance is antimicrobial); Degradation (inorganic); etc Partition coefficient (inorganic); Water solubility (hydrolytically unstable at ph 4, 7, and 9); Vapor pressure (MP > 300⁰C); Boiling point (gas or decomposes before boiling); etc Take Home: Need supporting evidence for your waiving basis. Cannot just be a statement. 51 Copyright Gradient 2015

52 Technical Conclusions for a Successful REACH 2018 Registration Substance characterization/identification 66% of dossiers reviewed in 2012 had short comings in substance identity. Registrants must clearly identify all constituents of their substances and provide rigorous analytical support (including raw data, instrument calibration, calculations) for their conclusions or face potential delays. Data-requirements Data requirement increase with higher tonnage. Registrants must use existing information and non-test methods to meet information requirements. Testing on vertebrate animals should only be used as a last resort. Assessing hazards and risks Getting the hazards "right" is important for worker safety, legal implications, and Confidential Business Information (CBI). Getting the hazards "right" depends on understanding nuances of GHS, underlying data source, multiple approach for data-gaps, etc. 52 Copyright Gradient 2015

53 Thank you! Questions?

54 Thank you! Jiaru Zhang Gradient 20 University Road Cambridge, MA Ari S. Lewis Gradient 20 University Road Cambridge, MA Sandra Meijer The REACH Centre Lancaster University Lancaster, Lancashire LA1 4YQ Rosalinda Gioia The REACH Centre Lancaster University Lancaster, Lancashire LA1 4YQ 54 Copyright Gradient 2015