1. REACH: same substance identity (RIP 3.10) Dr. Erwin Annys Sr. Advisor Product & Innovation Policy WERCS 2007 EU User group Napoli 31/05/07

2. 2 WERCS EU User group 2007 – Erwin Annys What is the same substance: two steps What is my substances ? Identification: name, CAS number, EC number, … Description: Impurities Production process, purification process, … Analytical data : Spectra Chromatograms Is my substance the same as the substance of another registrant ?

3. 3 WERCS EU User group 2007 – Erwin Annys Substance identification is important REACH is based on substances There are changes from EINECS reporting rules For pre-registrations and registrations you need to define your substances Identification of same substances is important for data sharing/consortium/SIEF formation, grouping and for non-phase-in substance registrations Identification of the substance used to generate (existing) data is important

4. 4 WERCS EU User group 2007 – Erwin Annys REACH definition of “substance” A chemical element and its compounds in the natural state or obtained by any manufacturing process Including Any additive necessary to preserve its stability Any impurity deriving from the process used Excluding Any solvent which may be separated without affecting the stability of the substance or changing its composition

5. 5 WERCS EU User group 2007 – Erwin Annys REACH Definition of “Substance” The definition goes beyond the “textbook definition” of a pure compound defined by a single molecule RIP 3.10 explains how to interpret the definition RIP 3.10 explains how to name and describe substances for (pre-) registration

6. 6 WERCS EU User group 2007 – Erwin Annys Identification for pre-registration Full substance identification NOT required To be submitted: Name of the substance (IUPAC or other international chemical name) EC-number (if available & appropriate) CAS name and CAS number (if available) Substance identification to facilitate the formation of SIEFs

7. 7 WERCS EU User group 2007 – Erwin Annys Identification for registration Registration Shall include information on the identification of the substance Shall be adequate to enable each substance to be identified sufficiently If not technically possible or scientifically necessary to give information on a substance parameter a scientific justification is needed

8. 8 WERCS EU User group 2007 – Erwin Annys Identification for registration Identification parameters listed in Annex VI: IUPAC and/or other names, EC-number, CAS name/ number, other identifiers Molecular and structural information (e.g. formulae, MW, SMILES code, optical activity….) Chemical composition (constituents, impurities, additives for stabilization) Supporting analytical data (IR,UV, NMR, MS, HPLC, GC etc., as appropriate)

9. 9 WERCS EU User group 2007 – Erwin Annys Constituents Individual chemical species (molecules) in a substance are called constituents A substance consists of “constituents” A preparation consists of “components” or “ingredients” Constituent ≠ component or ingredient

10. 10 WERCS EU User group 2007 – Erwin Annys Types of substance Well defined substances: Mono-constituent substances One main constituent ≥80% Multi-constituent substances Two or more main constituents between 10 - 80% In both cases ca.100% of the composition can be defined

11. 11 WERCS EU User group 2007 – Erwin Annys Types of substance Poorly defined or variable substances: Also known as UVCB-substances of Unknown or Variable composition, Complex reaction products or Biological materials Cannot be sufficiently identified by their composition Number of constituents is relatively large Composition largely unknown, very variable or poorly predictable

12. 12 WERCS EU User group 2007 – Erwin Annys Mono-constituent substances One constituent substance Main constituent > 80% (w/w) Impurities < 10% (w/w) ∑ main constituent, impurities and additives = 100% Impurities > 1% and impurities relevant for classification must be mentioned (name, CAS nr,…) Name: name of the main constituent

13. 13 WERCS EU User group 2007 – Erwin Annys Mono-constituent substances Main Constituent%Impurity%Name m-xylene91o-xylene5m-xylene o-xylene87m-xylene10o-xylene Examples

14. 14 WERCS EU User group 2007 – Erwin Annys Mono-constituent substances Deviation from 80% rule is possible with justification, if: The range of concentrations for the main constituent and the impurities overlap the 80% criterion and the main constituent is only occasionally ≤ 80 % The main constituent is < 80% but the substance can be shown to have similar physico-chemical properties and the same hazard profile as other mono-constituent substances with the same identity that fulfill the 80% rule

15. 15 WERCS EU User group 2007 – Erwin Annys Multi-constituent substances Multiple constituent substance Two or more constituents > 10% en < 80% Impurities < 10% ∑ main constituents, impurities and additives = 100% Impurities > 1% and impurities relevant for classification must be mentioned (name, CAS nr,…) Name: mixture of

16. 16 WERCS EU User group 2007 – Erwin Annys Multi-constituent substances Main Constituents %Impurity%Name m-xylene o-xylene 50 45 p-xylene5Mixture of: m-xylene and o-xylene Example

17. 17 WERCS EU User group 2007 – Erwin Annys Well defined but more identifiers needed Some substances need to be defined by more than just their chemical composition Same naming and identification rules as mono- or multi-constituent substances PLUS Other physical or characteristic parameters: e.g. crystallomorphology, (geological) mineral composition Examples: some crystalline inorganic minerals such as aragonite (a specific form of CaCO3) Additional analytical evidence required e.g. X-ray diffraction, elemental analysis

18. 18 WERCS EU User group 2007 – Erwin Annys UVCB substances Any substance which is not a “well defined substance” RIP 3.10 gives generic guidance on main parameters to identify UVCB’s (additional to Annex VI part 2) If the substance can be fully identified it is wise to treat it as a well-defined substance, not a UVCB A UVCB of the same composition but derived from a different source and/or process is a different substance, and will likely require a separate registration Specific detailed guidance for: Substances with variations in C-chain length Substances obtained from oil and oil-like sources

19. 19 WERCS EU User group 2007 – Erwin Annys General guidance for UVCBs Main constituents and impurities not really distinguished Chemical composition and identity of constituents should be given as far as is known Can describe in a more general way than for well- defined substances (e.g. linear fatty acids C8-C16) Composition can be described in terms of indexes, fingerprints, reference standards etc. All known constituents present at >10% should be specified by name, CAS number, typical concentration and ranges All constituents relevant for classification must be identified Unknown constituents identified by general chemical description, where possible

20. 20 WERCS EU User group 2007 – Erwin Annys General guidance for UVCB’s Naming should be in the order of source and then process Biological sources are identified by the name of the species Non-biological sources are identified by the starting materials Processes are identified by: Type of chemical reaction (e.g. alkylation, chlorination) Refinement step (e.g. extraction, fractionation, concentration)

21. 21 WERCS EU User group 2007 – Erwin Annys Types of UVCB substances Biological substances Process is synthesis Includes chemical or biochemical derivatives of plant extracts Process is refinement Includes extracts and concentrates of plant extracts Chemical and mineral substances Process is synthesis Poorly defined chemical reaction products Process is refinement Includes petroleum substances, purified minerals

22. 22 WERCS EU User group 2007 – Erwin Annys UVCB Example Chemical derivative of a plant extract: Fatty acids, coco, compounds with diethanolamine UVCB because Complex mixture of amides formed from various fatty acids present in the coconut oil Ratio of fatty acids can vary in the source EC 263-153-4CAS 61790-63-4Condensation products of coco fatty acids and diethanolamine

23. 23 WERCS EU User group 2007 – Erwin Annys UVCB Example A refined product of a plant-derived substance: Turpentine oil EC: 232-350-7CAS: 8006-64-2 Any of the volatile predominately terpenic fractions or distillates resulting from the solvent extraction of; gum collection from, or pulping of softwoods. Composed primarily of the C10H16 terpene hydrocarbons: alpha-pinene, beta-pinene, limonene, 3-carene, camphene. May contain other acyclic, monocyclic or bicyclic terpenenes, oxygenated terpenes and anethole. Exact composition varies with refining methods and the age, location and species of the softwood source

24. 24 WERCS EU User group 2007 – Erwin Annys UVCB Example A chemical derivative of a chemical Reaction product of a di-carboxylic acid and amino-alcohol UVCB because Complicated mixture of amides and esters EC 294-006-2CAS: 91672-02-5Reaction products of nonanedioicacid and 2-amino- 2-methyl-1-propanol

25. 25 WERCS EU User group 2007 – Erwin Annys Checking if substances are the same Needs expert judgement Equivalent substances should contain the same main constituents: Apply ≥ 80% (mono-const.) and 10 – 80 % (multi-const.) rules No differentation between “pure”, “technical”, “analytical” grades

26. 26 WERCS EU User group 2007 – Erwin Annys Checking if substances are the same If substances are “similar enough” then data sharing is possible However, if impurity profile differs markedly then data sharing (or even presence in same SIEF) may not be appropriate Data sharing may also be possible with similar (but not “the same”) substances by grouping, category approach, read-across (see RIPs 3.3 and 3.4)

27. 27 WERCS EU User group 2007 – Erwin Annys Same/different substances: examples Hydrates and water-free substances considered the same Chiral centres are mixture of racemates (in absence of proof of the contrary) Acids or bases and their salts are different Salts of different cations (Na, K, Ca, etc.) are different Branched vs linear, saturated vs unsaturated are different

28. 28 WERCS EU User group 2007 – Erwin Annys Remaining issues RIP 3.10 has not addressed all cases “Reaction products” issue: Mixed reaction products must be registered as substance (multi-constituent or UVCB) Cannot register individual constituents UVCB’s: Different sources may mean different substances, even if composition is very similar RIP 3.10 appears to demand “complete” similarity to be the “same substance

29. 29 WERCS EU User group 2007 – Erwin Annys