Transforming Our World: Delivering affordable medicines to anyone, anywhere, any day 1 Health hazards of substances Annex 1 – Part 3 of CLP Date: Name:

2 CONTENTS 1.Acute toxicity 2.Corrosion/irritation skin 3.Corrosion/irritation eye 4.Respiratory + skin sensitization 5.Mutagenicity 6.Carcinogenicity 7.Reproductive toxicity 8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

3 CONTENTS 1.Acute toxicity 2.Corrosion/irritation skin 3.Corrosion/irritation eye 4.Respiratory + skin sensitization 5.Mutagenicity 6.Carcinogenicity 7.Reproductive toxicity 8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

4 ACUTE TOXICITY - DEFINITION Acute toxicity = harmful effects after administration of substance/mixture oral, dermal: 1 dose or several doses within 24 hours inhalation: for 4 hours For inhalation, GHS/CLP differentiates between: Dust: solid particles suspended in a gas Mist: liquid droplets suspended in a gas (air) Vapor: the gaseous form of a substance or mixture released from its liquid or solid state Gases

5 ACUTE TOXICITY – CRITERIA CLP: Classification into 4 categories Testing → LD 50 -LC 50 If no tests available → calculated ATE (Acute Toxicity Estimate) for mixtures GHS: 5 categories

6 ACUTE TOXICITY – CRITERIA

7 Minimum classification when converting EC substances with LD50 values to pink zone E.g. substances with R22 become Cat 4 when converted even if LD50 may lie between 200/300 and so fall into Cat 3. ACUTE ORAL TOXICITY – CRITERIA

8 ACUTE ORAL TOXICITY – LABEL ELEMENTS

9 ACUTE ORAL TOXICITY – EXAMPLE Substance X with LD 50 oral, rat = 450 mg/kg b.w. According to CLP: Pictogram: Classification: Acute tox, category 4 Signal word: Warning Hazard indication: H302 Harmful if swallowed

10 Minimum classification when converting EC substances with LD50 values to pink zone  E.g. substances with R21 become Cat 4 when converted even if LD50 may lie between 400/1000 and so fall into Cat 3. ACTUTE DERMAL TOXICITY – CRITERIA

11 ACUTE DERMAL TOXICITY – LABEL ELEMENTS

12 ACUTE DERMAL TOXICITY – EXAMPLE Substance X with LD 50 skin, rat = 450 mg/kg b.w. According to CLP: Pictogram: Classification: Acute tox, category 3 Signal word: Danger Hazard indication: H311 Toxic in contact with skin

13 Differentiation: dust/mist (mg/l) / vapor (mg/l) / gas (ppm) Exposure duration  Standard test 4 hours  If test for 1 hour: extrapolate to 4 hours gases and vapors: LD/LC 50 divide by 2 dusts and mists: LD/LC 50 divide by 4 ACUTE INHALATION TOXICITY

14 Minimum classification when converting EC substances with LC 50 values to pink zone  E.g. substances with R20 become Cat 4 when converted even if LC 50 can also be between 2/10 so fall into Cat 3 ACUTE INHALATION TOXICITY – CRITERIA FOR VAPOURS

15 ACUTE INHALATION TOXICITY – CRITERIA

16 ACUTE INHALATION TOXICITY – LABEL ELEMENTS

17 EUH071 corrosive to the respiratory tract if data indicate that the toxicity arises from corrosive effects then besides classification for toxicity if inhaled, also labeled with EUH071 Annex 2 – EUH071 can also be allocated for corrosive substances for which there are no toxicity data via inhalation Note 1 ACUTE INHALATION TOXICITY – LABEL ELEMENTS

18 ACUTE INHALATION TOXICITY – EXAMPLE Substance X with LC 50 inh rat = 1,500 ppm b.w. According to CLP: Pictogram: Classification: Acute tox, category 3 Signal word: Danger Hazard indication: H331 Toxic if inhaled

19 CONTENTS 1.Acute toxicity  2.Corrosion/irritation skin 3.Corrosion/irritation eye 4.Respiratory + skin sensitization 5.Mutagenicity 6.Carcinogenicity 7.Reproductive toxicity 8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

20 Classification based on acute studies, ≤ 4 h exposure Corrosive for the skin: irreversible damage Signs: necrosis through epidermis into the dermis Typical: ulcers, bleeding, blanching of the skin (after 14 days) Irritating for the skin: reversible damage Signs: inflammation which is reversible (after 14 days) CORROSION/IRRITATION SKIN – DEFINITION

21 CORROSION/IRRITATION SKIN – EXAMPLE After 20 minutes exposure, substance X causes tissue destruction – visible after 2 days According to CLP: Pictogram: Classification: Skin corrosion, category 1B Signal word: Danger Hazard indication: H314 Causes severe skin burns and eye damage

22 Classification based on acute studies Severe eye damage: irreversible damage Eye irritation: reversible damage (similar model as for skin corrosion/irritation) Before carrying out animal tests: if corrosive to skin, then also to the eyes If irritating for the skin, then also for the eyes CORROSION/IRRITATION EYE – DEFINITION

23 CORROSION/IRRITATION EYE – LABEL ELEMENTS

24 CORROSION/IRRITATION EYE – EXAMPLE Substance X applied to front surface of eye (3 rabbits). For corneal opacity: average score from measurements for 24, 48 and 72 hrs after application is 2.9 According to CLP: Pictogram: Classification: Eye irritation, category 2 Signal word: Warning Hazard indication: H319 Causes serious eye irritation

25 Contents 1.Acute toxicity  2.Corrosion/irritation skin  3.Corrosion/irritation eye  4.Respiratory + skin sensitization 5.Mutagenicity 6.Carcinogenicity 7.Reproductive toxicity 8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

26 Differences in sensitization: Respiratory sensitizer Inhalation → hypersensitivity of respiratory tract Skin sensitizer Skin contact → allergic reaction Classification based on: Experience/evidence in humans + results of appropriate animal tests Classification is Yes/No decision: 1 category RESPIRATORY + SKIN SENSITISATION – DEFINITION & CRITERIA

27 RESPIRATORY + SKIN SENSITISATION – LABEL ELEMENTS

28 Substance X causes asthma + alveolitis in humans (= hypersensitivity reaction) and reactions in guinea pigs on skin contact. LABELGHS07 cancelled if GHS08 applies (article 26 d) Signal word: Danger Hazard indication: H334; H317 Pictogram: Classification: Skin sens., category 1 Signal word: Warning Hazard indication: H317 Pictogram: Classification: Resp. sens., category 1 Signal word: Danger Hazard indication: H334 RESPIRATORY + SKIN SENSITISATION – EXAMPLE

29 Contents 1.Acute toxicity  2.Corrosion/irritation skin  3.Corrosion/irritation eye  4.Respiratory + skin sensitization  5.Mutagenicity 6.Carcinogenicity 7.Reproductive toxicity 8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

30 CMR – DEFINITIONS Mutagens –Inheritable mutations to human germ cells Carcinogens –Induces tumor formation or increases its incidence  Reproductive toxicity (Reprotoxic) –Harmful effects on  fertility  development of unborn child (teratogenic)  lactation (harmful to child when breastfeeding)

31 CMR – CRITERIA CMR classifications: all same model Cat. 1 KNOWN harmful effects experience/evidence in humans → Cat. 1A animal testing → Cat. 1B Cat. 2 POSSIBLE harmful effects Muta. 1A, Muta. 1B and Muta. 2 Carc. 1A, Carc. 1B and Carc. 2 Repr. 1A, Repr. 1B and Repr. 2

32 CMR – LABEL ELEMENTS Cat. 1ACat. 1BCat. 2 Pictogram Signal word Danger Mutagenicity May cause genetic defects H340 May cause genetic defects H340 Suspected of causing genetic defects H341 Carcinogenicity May cause cancer H350 May cause cancer H350 Suspected of causing cancer H351 Reproductive toxicity May damage fertility or the unborn child H360 May damage fertility or the unborn child H360 Suspected of damaging the unborn child H361 *Indicate exposure route when proven effect does not occur with other exposure routes

33 CMR – CLP versus DSD DSD: CMR classification into three categories  same criteria in CLP  different numbering of category in CLP DSDCLP Cat. 1 KNOWN effect in humansCat. 1A Cat. 2 KNOWN effect in animal trialsCat. 1B Cat. 3 SUSPECTED effect in humans and/or animals Cat. 2

34 CMR – EFFECTS ON OR VIA LACTATION Additional + separate category of repr. tox. Classification criteria Data from humans and/or animals (limited) Labeling No pictogram No signal word H362: May cause harm to breast-fed children DSD R64: May cause harm to breastfed babies

35 Contents 1.Acute toxicity  2.Corrosion/irritation skin  3.Corrosion/irritation eye  4.Respiratory + skin sensitization  5.Mutagenicity  6.Carcinogenicity  7.Reproductive toxicity  8.Specific target organs - single 9.Specific target organs - repeated 10.Aspiration hazard

36 SPECIFIC TARGET ORGANS (STOT) – DEFINITION STOT = specific, non-lethal effects on target organs -Effect after 1x exposure → single STOT -Effects after ≥ 1 exposure → repeated STOT Examples -Methanol: blindness after 1 exposure → single STOT 1 -Organic phosphochlorides: CNS phosphochloride → repeated STOT 2 phosphochloride → repeated STOT 1

37 Based on: experience/evidence in humans Animal tests (evidential value) Sometimes also structural activity (SAR) Difficult interpretation effect ~ guidance values → Classification by experts SPECIFIC TARGET ORGANS (STOT) – CRITERIA

38 Single STOT: 3 categories Repeated STOT : 2 categories Categorycriteria STOT single 1 STOT repeated 1 significant toxicity in humans or strong evidence from animal trails on LOW exposure STOT single 2 STOT repeated 2 Evidence from animal tests on MODERATE exposure which is significant for humans STOT single 3 Temporary effects on target organs (short duration, reversible) SPECIFIC TARGET ORGANS (STOT) – CRITERIA

39 Cat. 1Cat. 2Cat. 3 Pictogram Signal wordDanger Warning Single STOT Causes damage to organs* H370 May cause damage to organs* H371 May cause respiratory irritation H335 Or May cause drowsiness or dizziness H336 Repeated STOT Causes damage to organs* H372 May cause damage to organs* H373 *Indicate exposure route when proven effect does not occur with other exposure routes Indicate target organs when known and specific SPECIFIC TARGET ORGANS (STOT) – LABEL ELEMENTS

40 DSDCLP R39/26/27/28 R39/23/24/25 H370 STOT single 1 R68/20/21/22H371 STOT single 2 R37H335 STOT single 3 R67H336 STOT single 3 SPECIFIC TARGET ORGANS (STOT) SINGLE – DSD vs CLP

41 DSDCLP R48/23/24/25 H372 STOT repeated 1 R48/20/21/22 H373 STOT repeated 2 R33 H373 STOT repeated 2 SPECIFIC TARGET ORGANS (STOT) REPEATED – DSD vs CLP

42 Reasons: animal tests + moderate dose/concentration above known toxic effect SPECIFIC TARGET ORGANS (STOT) SINGLE – GUIDELINES

43 SPECIFIC TARGET ORGANS (STOT) REPEATED – GUIDELINES

44 Contents 1.Acute toxicity  2.Corrosion/irritation skin  3.Corrosion/irritation eye  4.Respiratory + skin sensitization  5.Mutagenicity  6.Carcinogenicity  7.Reproductive toxicity  8.Specific target organs – single  9.Specific target organs – repeated  10.Aspiration hazard

45 Aspiration hazard After inhalation of liquid or solid through mouth or nose Possible effects: pneumonia, lung damage or death Examples: Hydrocarbons with low boiling point -n-pentane -n-hexane -cyclohexane ASPIRATION HAZARD – DEFINITION

46 Based on: experience/evidence in humans or kinematic viscosity Criterion: Kin. visc ≤ 20.5 mm 2 /s at 40°C Yes/no classification → one category: Asp. Tox. 1 ASPIRATION HAZARD – CRITERIA

47 ASPIRATION HAZARD – LABEL ELEMENTS

48 ASPIRATION HAZARD – DSD vs CLP DSDCLP R65: Harmful: may cause lung damage if swallowed H304: May be fatal if swallowed and enters airways Kinematic viscosity to 7 mm 2 /s Kinematic viscosity to 20.5 mm 2 /s