Content

1. Classification of substances and mixtures on the basis of health hazardSemira Hajrlahović Mehić, LL.M.Tatjana Humar – Jurič, M.Sc.

2. Content • Introduction • Classification of substance • Classification of mixture

3. General information Chemicals placed on the Serbian market shall be classified by using of: • Harmonised classifications • Self-classification by application of the criteria • Use of translation tables • Use of classification and labelling inventory

4. General information • The classification criteria are in Part 2-5 of Annex I to CLP/GHS Rulebook! • For OLD system • - Upostvo za klasufikacijo, pakovanje, obeležavanje i reklamiranje hemikalija (2010) • For NEW system • - GHS (CLP/GHS system ) in practice • EU Guidances on CLP • - EU Guidance on application of the CLP (= EU GHS) criteria • - EU FAQ regarding CLP in EU and useful links

5. Example: Classification of Substance- Health hazards • Methanol • Animal data: • LD50rat > 5,000 (mg/kg) • No specific target organtoxicity (impairment of seeing ability) observed in rats, even in high doses • Human experience: • Broad human experience from many case reports about blindness following oral intake. • Methanol is known to cause lethal intoxications in humans (mostly via ingestion) in relatively low doses: ” …minimal lethal dose in the absence of medical treatment is between 300 and 1000 mg/kg” (IPCS)

6. Example: Classification steps • Use of adequate and reliable human data, where animal data are not appropriate • Independent classification for STOT-SE and Acute toxicity due to different effects • Task: • Acute toxicity classification • STOT (SE) classification

7. Methanol : Acute toxicity • Animal data: • The rat is known to be insensitive to the toxicity of methanol and is thus not considered to be a good model for human effects (different effect/mode of action) • Classification not possible

8. Methanol: Acute toxicity • Human experience • Annex I: 3.1.2.1. Substances can be allocated to one of four toxicity categories based on acutetoxicity by the oral, dermal or inhalation route according to the numeric criteria shown inTable 3.1.1. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50(inhalation) values or as acute toxicity estimates (ATE). Explanatory notes are shown followingTable 3.1.1 • See able 3.1.1. • The minimum lethal dosereported of 300 mg/kg is usedas equivalent ATE; accordingto Table 3.1.1 the resultingclassification is Category 3

9. Methanol: STOT (SE) • Annex I , 3.8.2.2 Classification criteria for Categories 1 and 2 • See Table 3.8.1 : Categories for specific target organ toxicity-single exposure • The classification criteria for Category 1 are fulfilled: clear human evidence of a specifictarget organ toxicity effect which is not covered by Acute toxicity

10. Methanol - Conclusion • The standard animal species for single exposure (acute) tests, the rat, is not sensitive, i.e. no appropriate species for this specific target organ effect. • Methanol is classified independently for acute toxicity, since the impairment of vision is not causal for the lethality, i. e. there are different effects. • Methanol - Health hazards classification : • Acute Tox. 3 • STOT SE 1 • Other hazards ?

11. Classification of mixtures CLP/GHSself-classification Depending on the information available and on thehazard under consideration you should classify using following approaches: • Using data on the mixture itself (not for CMR!) • Classification based on the application of bridging principles • Classification based on the concentration of individual ingredients, NOTE: make sure that you choose the most appropriate method for your mixture for each hazard class or category!

12. Classification of mixtures Bridging principles: • when data are notavailablefor all components • = used for classifying untested mixtures, but there are sufficient data on the components and/or similar tested mixtures, these data can be used in accordance with the following bridging principles: • Diluting • Batching • Concentration of highly toxic mixtures • Interpolation within one toxicity category • Substantially similar mixtures • Aerosols All bridging principles do not apply to every health endpoint!

13. Example 1 Starting point: Mixture X Mixture Y= ? Toxic Cat. 3 Tested • Two mixtures with several different ingredients (A, B, C) • Both mixtures have one common ingredient (B) at the same concentration • The concentrations and toxicities (classifications) of the other (A, C) ingredients are the same • Mixture X is classified based on testing

14. Example 1 Substantially similar mixtures: Mixture X Mixture Y= Toxic Cat. 3 Toxic Cat. 3 Tested • The unknown mixture Y is classified in the same way as the tested: Toxic Cat. 3

15. Classification of mixtures Classification based on the concentration of individual ingredients: • When availabledata for all components • Calculations using formulas (acute toxicity) based onadditivity • Concentration limits (tables; other hazard classes thanacute toxicity)

16. Classification of mixtureCut-off values Indicate when the presence of a substance needs to be taken into account for the purpose of classification of a substance or mixture containing that hazardous substance Impurity, additive in a substance or individual constituent in a mixture: Specific concentration limits, SCL (List of classified substances, Inventory) Generic concentration limits, GCL (Annex I) Generic cut-off values (Annex I, Table 1.1) M-Factors (enviromental hazard!) New: SCL shall be set by the suppliers !

17. Hazard class Acute Toxicity: - Category 1 - 3 - Category 4 Skin corrosion/irritation Serious damage to eyes/eye irritation Generic cut-off values to be taken into account 0,1 % 1 % 1 % 1 % Generic cut-off values These values are minimum concentration for substances to be taken into account for classification (even they do NOT trigger classification of the mixture directly) – if is concentration of sub. >generic cut-off value then contribute to the classification Table 1.1 (Annex I)

18. Classification of mixtures Data available for all ingredients: • A hazardous substance needs to be taken into account for the purpose of classification of a mixture if it is present in the mixture above the cutt-off value • Each of these substances contribute to the hazardous properties of the mixture • Use the additivity formula: if the sum of the concentrations is above the limit values -> mixture is classified for that hazard class • Using additivity formula: Acute Toxicity • Using theadditivity aproch Skin corrosion/irritation Serious eye damage/eye irritation

19. Classification of mixture 100 C = å i ATE ATE n mix i ATE: - LD50 or LC50-value, or - Converted value (point estimate) for acute toxicity from Table 3.1.2 in Annex I, relating to a value from a range test or to a classification category Calculations using formulas (acute toxicity) based onadditivity Additivity formula The ATE of the mixture is determined by calculation from the ATE values for the relevant ingredients (for all three routs of exposure) • Ci = concentration of ingredient i • i = the individual ingredient from 1 to n • n = the number of ingredients • ATEi = Acute Toxicity Estimate of ingredient

20. Acute toxicity LD50 or LC50-value or Converted value (point estimate) for acute toxicity from Table 3.1.2 in Annex I, relating to a value from a range test or to a classification category

21. Classification of mixtures Classification based on the concentration of individual ingredients Additive concentration limits • Skin corrosion/irritation • Serious eye damage/eye irritation • STOT SE, Cat. 3 Non- additive concentration limits • Sensitisers (respiratory and skin) • CMR • STOT SE and RE, Cat 1-2 • Aspiration hazard

22. Example of generic concentration limits for skin corrosion/irritation • Additivity approach applies • Generic concentration limits of ingredients classified that trigger classification of the mixture- Table 3.2.3 of Annex I * Weighing factor of 10 if Category 1 component ≥ 1% but ≤ 5% in a mixture

23. Examplegeneric concentration limits for reproductiontoxicity/Effects on or via lactation: • Non-Additivity approach applies • Generic concentration limits of ingredients classified that trigger classification of • the mixture- Table 3.7.2 of Annex I

24. Conversion valuesWhere an ATE is not available for an ingredient of a mixture, but availableinformation canprovide a value derived from the conversion table, thisconversion value may be used for calculation.Conversion from experiementally obtained acute toxicity rangevalues (or acute toxicity hazard categories) to acute toxicity pointestimates for classification of the respective routes of exposure Table 3.1.2

25. Example 2How is classified mixture A?

26. Conversion from hazard category to point estimate: Table 3.1.2

27. Classification of a mixture ATE: 100 Ci 100 =∑ ATEi ATEmixture n 1 3 10 100 = + + ATEmixture = 743mg/kg bw 225 100 100 ATEmixture

28. Conversion from hazard category to point estimate: ATEmixture = 743mg/kg bw Table 3.1.2

29. Classification of a mixture ATE: 100 Ci 100 =∑ ATEi ATEmixture n 1 3 10 100 = + + ATEmixture = 743mg/kg bw 225 100 100 ATEmixture Classification: Acute tox. cat 4, oral

30. Result of example 2: According to table 3.1.1 and Table 3.1.3 (Annex I of CLP/GHS Rulebook) is result: Acute oral tox. 4,H302 Labellling: Warning H302Harmful if swallowed

31. Thank you! Thank you!