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

Content Introduction Classification of substance Classification of mixture

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

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

Example: Classification of Substance- Health hazards Methanol Animal data: LD50 rat > 5,000 (mg/kg) No specific target organ toxicity (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)

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

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

Methanol: Acute toxicity Human experience Annex I: 3.1.2.1. Substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric criteria shown in Table 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 following Table 3.1.1 See able 3.1.1. The minimum lethal dose reported of 300 mg/kg is used as equivalent ATE; according to Table 3.1.1 the resulting classification is Category 3

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 specific target organ toxicity effect which is not covered by Acute toxicity

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 ?

Classification of mixtures CLP/GHS self-classification Depending on the information available and on the hazard 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!

Classification of mixtures Bridging principles: when data are not available for 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!

Example 1 A B C B 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 A B C B

Example 1 Substantially similar mixtures: A B C B 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 A B C B

Classification of mixtures Classification based on the concentration of individual ingredients: When available data for all components Calculations using formulas (acute toxicity) based on additivity Concentration limits (tables; other hazard classes than acute toxicity)

Classification of mixture Cut-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 ! 16

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) 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 %

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 the additivity aproch Skin corrosion/irritation Serious eye damage/eye irritation

Classification of mixture Calculations using formulas (acute toxicity) based on additivity 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 i å = n mix ATE C 100 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 19

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

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

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 Sum of ingredients classified as: Concentration triggering classification of a mixture as: Skin Corrosive Skin Irritant Category 1 Category 2 Skin Corrosive Categories 1A, 1B, 1C  5 %  1 % but < 5 % Skin irritant Category 2  10 % (10* x Skin Corrosive Category 1A, 1B, 1C) + * Weighing factor of 10 if Category 1 component ≥ 1% but ≤ 5% in a mixture 22

Example generic concentration limits for reproduction toxicity/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 Ingredient classified as: Concentration triggering classification of a mixture as: Repro cat. 1A Repro cat. 1B Repro cat.2 Effects on or via lactation  0,3 % Repro cat. 2  3,0 % 23

Oral (mg/kg bw) 0 < category 1 ≤ 5 5 < category 2 ≤ 50 Conversion values Where an ATE is not available for an ingredient of a mixture, but available information can provide a value derived from the conversion table, this conversion value may be used for calculation. Conversion from experiementally obtained acute toxicity range values (or acute toxicity hazard categories) to acute toxicity point estimates for classification of the respective routes of exposure Table 3.1.2 Exposure route Classification category or experimentally obtained acute toxicity range estimate Converted acute toxicity point estimate Oral (mg/kg bw) 0 < category 1 ≤ 5 5 < category 2 ≤ 50 50 < category 3 ≤ 300 300 < category 4 ≤ 2000 0,5 5 100 500 24

Example 2 How is classified mixture A? Concentration LD50 oral Classification Substance 1 1% 225 mg/kg Substance 2 3% 100 mg/kg Substance 3 10% Acute tox. category 3, oral Water 76%

Conversion from hazard category to point estimate: Table 3.1.2 Exposure route Classification category or experimentally obtained acute toxicity range estimate Converted acute toxicity point estimate Oral (mg/kg bw) 0 < category 1 ≤ 5 5 < category 2 ≤ 50 50 < category 3 ≤ 300 300 < category 4 ≤ 2000 0,5 5 100 500 26

Classification of a mixture Concentration LD50 oral Classification Substance 1 1% 225 mg/kg Substance 2 3% 100 mg/kg Substance 3 10% Acute tox, cat 3 Water 76% ATE: 100 Ci 100 =∑ ATEi ATEmixture n 1 3 10 100 = + + ATEmixture = 743 mg/kg bw ATEmixture 225 100 100 27

Conversion from hazard category to point estimate: ATEmixture = 743 mg/kg bw Table 3.1.2 Exposure route Classification category or experimentally obtained acute toxicity range estimate Converted acute toxicity point estimate Oral (mg/kg bw) 0 < category 1 ≤ 5 5 < category 2 ≤ 50 50 < category 3 ≤ 300 300 < category 4 ≤ 2000 0,5 5 100 500 28

Classification of a mixture Concentration LD50 oral Classification Substance 1 1% 225 mg/kg Substance 2 3% 100 mg/kg Substance 3 10% Acute tox, cat 3 Water 76% ATE: 100 Ci 100 =∑ ATEi ATEmixture n 1 3 10 100 = + + ATEmixture = 743 mg/kg bw ATEmixture 225 100 100 Classification: Acute tox. cat 4, oral 29

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 H302 Harmful if swallowed

Thank you! Thank you! 25