1. Principles of classification of substances and mixtures on basis of their toxicological properties – Health hazards Semira Hajrlahović Mehić, LL.M. Tatjana Humar – Jurič, M.Sc.

2. Content General information on HH Where to get data?
Evaluation & reviewing the information
Decision on classification

3. General information NEW - CLP: 1. Acute toxicity
2. Skin corrosion/irritation
3. Serious eye damage/eye irritation
4. Respiratory or skin sensitisation
5. Germ cell mutagenicity
6. Carcinogenicity
7. Reproductive toxicity
8. STOT – single exposure
9. STOT – repeated exposure
10. Aspiration hazard
OLD -DSD:
1. Very toxic
2. Toxic
3. Harmful
4. Corrosive
5. Irritant
6. Sensitisation
7. Carcinogenic
8. Mutagenic
9. Toxic to reproduction

4. General information NEW CLP/GHS classification criteria:
Human Health- new Hazard Classes with categories
Specific Target Organ
Serious Eye Damage/Eye Irritation
Aspiration

5. General information NEW CLP lassification criteria:
Human Health- new Hazard Classes with categories
Specific Target Organ
Single exposure
Repeted Exposure
Serious Eye Damage/Eye Irritation
Aspiration

6. Why do we need GHS? Substance - oral toxicity LD50 = 257 mg/kg
GHS Danger (Skull & Cross Bones)
Transport liquid: slightly toxic; solid: not classified
EU Harmful (St Andrew’s Cross)
US Toxic
CAN Toxic
Australia Harmful
India Non-toxic
Japan Toxic
Malaysia Harmful
Thailand Harmful
New Zealand Hazardous
China Not Dangerous
Korea Toxic

7. General information NEW - CLP: 1. Acute toxicity
2. Skin corrosion/irritation
3. Serious eye damage/eye irritation
4. Respiratory or skin sensitisation
5. Germ cell mutagenicity
6. Carcinogenicity
7. Reproductive toxicity
8. STOT – single exposure
9. STOT – repeated exposure
10.Aspiration hazard
OLD -DSD:
1. Very toxic
2. Toxic
3. Harmful
4. Corrosive
5. Irritant
6. Sensitisation
7. Carcinogenic
8. Mutagenic
9. Toxic to reproduction

8. Health hazards under CLP
Hazard class
Hazard category
Acute oral toxicity
Acute dermal toxicity
Acute inhalation toxicity 1 2 3 4 1 2 3 4 1 2 3 4
Skin corrosion/irritation
Corrosive
Irritation 1A 1B 1C 2
Severe eye damage/eye irritation 1 2
Sensitisation: respiratory 1A 1B
Sensitisation: skin 1A 1B
Germ cell mutagenicity 1A 1B 2
Carcinogenicity 1A 1B 2
Reproductive toxicity 1A 1B 2
Lactation
STOT – single exposure
STOT – repeated exposure 1 2 3 1 2
Aspiration hazard 1

9. Human Health hazards- examples
Cat.
Criteria
STOT SE 1
Substances that have produced significant toxicity in humans following single exposure – evidence from humans or epidemiological studies or observations from relevant animal tests at low exposure Guidance value range rat oral = C ≤ 300 2
Observations from relevant animal tests at moderate exposure Guidance value range rat oral = 2000 ≥ C > 300 3
Transient target organ effects – includes narcotic effects and respiratory tract irritation. Alter human function for a short duration after exposure

10. General Information Animal welfare is a big goal of GHS/CLP
All tests carried out according to scientifically valid and internationally recognised testing methods are accepted
New tests should be avoided where ever possible – all available data have to be considered:
Human data
Ex-vivo methods
In-vitro methods
In-silico methods (grouping, read-across, (Q)SARs)
Peer reviewed publications

11. General Information
In an „overall weight of evidence“ approach all gathered data has to be evaluated – and it has to be veryfied wether there is enough information to decide: classification – yes/no
If there is not enough information – new tests have to be carried out. Testing methods recommended in Reg.(EC) No. 440/2008
In case a validated in vitro test or other alternative method exists – no animal test (Dir. 86/609/EEC)

12. CLP : DSD • Skin corrosion • Very toxic Corrosive • Harmful
Acute toxicity
(Cat 4)
• Skin irritation
• Eye irritation
• Skin sensitisa.
• STOT, SE
(Cat. 3)
Respiratory sensitisation
• Germ cell mutagenicity
•carcinogrnicity rreproductiv toxicity
• STOT, single &
repeated exposure
• Aspiration hazard
Acute toxicity
(Cat 1-3)
• Skin corrosion
• Serious eye damage
• Very toxic
• Toxic
• CMR
Corrosive
• Harmful
• Irritant

13. General information NEW - CLP: 1. Acute toxicity
2. Skin corrosion/irritation
3. Serious eye damage/eye irritation
4. Respiratory or skin sensitisation
5. Germ cell mutagenicity
6. Carcinogenicity
7. Reproductive toxicity
8. STOT – single exposure
9. STOT – repeated exposure
10. Aspiration hazard
OLD -DSD:
1. Very toxic
2. Toxic
3. Harmful
4. Corrosive
5. Irritant
6. Sensitisation
7. Carcinogenic
8. Mutagenic
9. Toxic to reproduction

14. Acute toxicity Adverse effects occurring following
oral or dermal administration of a single dose or multiple doses within 24h
or an inhalation exposure of 4h
Numeric criteria for 4 toxicity categories
LD50/LC50: mean lethal dose
Def.: Statistically derived value/range; it is assumed that 50% of the animals die at that dose

15. Skin corrosion / irritation
Skin Corrosion – Category 1:
CLP: Irreversible skin damage: visible necrosis into dermis after exposure up to 4h:
typically ulcers, bleeding, bloody scabs
+ by the end of observation at 14 days by discolouration (blanching of skin), complete areas of alopecia & scars
in at least 1 of 3 animals
DSD: full thickness destruction of skin tissue, exposure up to 4 hours, in at least 1 of 3 animals

16. Skin corrosion / irritation
Skin irritation – category 2:
CLP: reversible skin damage after exposure up to 4h
Criteria for skin irritation:
In at least 2 of 3 animals a mean value of ≥ 2,3 - < 4,0 for
erythema/eschar or oedema from gradings after 24h, 48h, 72h after patch removal or,
If reactions are delayed from grades on 3 consecutive days after the onset of skin reactions (according to OECD 404);
Inflammation in 2 of 3 animals, that persists until end of observationperiod particularly taking into account alopecia (limited area),hyperkeratosis, hyperplasia and scaling; or
exemption: very definite positive effects in a single animal – even ifcriteria above not fulfilled

17. Skin corrosion / irritation
Skin irritation – category 2: comparison to DSD:
DSD: substances causing significant inflammation of the skin which persists for at least 24 hours (exposure up to 4 hours, in at least 2 of 3 animals)
Mean value of scores for either erythema/eschar formation or oedema formation in 2 out of 3 animals ≥ 2 typ. after 24h, 48h, 72h
=> DSD stricter than CLP (score for classification ≥ 2,3)

18. Skin corrosion / irritation
Before tests are carried out several factors
determining the corrosion/irritation potential need to be considered:
Existing human experience?
Animal data?
In vitro alternatives?
Information from structurally related compounds?
Substance with extreme pH values (≤ 2 or ≥ 11,5)
Is the substance a peroxide?

19. Serious eye damage / irritation
Serious eye damage – category 1:
CLP: production of tissue damage in the eye, or serious physical decay of vision which is not fully reversible within 21 days of application
DSD: R41-Risk of serious damage to eyes:
severe ocular lesions which occur within 72 hours after exposure and which persist for at least 24 h.
=> DSD similar to CLP

20. Serious eye damage / irritation
Eye irritation – category 2:
DSD: R36 - Irritating to eyes
=> CLP stricter than DSD
In addition to skin effects:
Skin corrosion has to be evaluated prior to consideration of eye effects -> Skin corrosive substances are considered as leading to serious eye damage Category 1

21. Respiratory or skin sensitisation
Respiratory sensitiser: substance that will lead to a hypersensitivity of the airways following inhalation of thesubstance
Skin sensitiser: substance that will lead to an allergic response following skin contact
=> Same definitions in CLP and DS

22. Germ cell mutagenicity
Classification criteria of old and new system are comaparable:
Category 1 => Category 1A
Category 2 => Category 1B
Category 3 => Category 2

23. Carcinogenicity
Criteria for classification - new and old system are almost identical:
Cat. 1 => Cat. 1A: Human studies that establish a causal relationship between human exposure and development of cancer – epidemiological studies in which Chance, bias & confounding could be ruled out (sufficient evidence)
Cat. 2 => Cat. 1B: Results from animal studies => causal relationship between exposure & increased incidence of malignant neoplasms or an appropriate combination of benign and malignant neoplasms (sufficient evidence)
Cat. 3 => Cat. 2: evidence from human &/or animal studies which is not sufficiently convincing to place the substance in category 1A or 1B (limited evidence)

24. Reproductive toxicity
Criteria for classification - new and old system are almost identical :
Cat. 1 => Cat. 1A: Known human reproductive toxicant(known)
Cat. 2 => Cat. 1B: Data from animal studies (presumed)
Cat. 3 => Cat. 2: Some evidence from humans or experimental animals – evidence is not sufficiently convincing to place in Cat.1A or 1B (suspected)
R64 => H362: human and animal data

25. Specific target organ toxicity (STOT), single exposure(SE)
Specific non-lethal target organ toxicity after single exposure to a substance
All significant health effects not covered by any other hazard class (eg: acute toxicity, CMR,…)
reversible & irreversible
immediate & delayed
significant chenges in single organs or biological system or
generalised changes of a less severe nature involving several organs

26. Specific target organ toxicity (STOT), single exposure(SE)
Determine of primary target organ of toxicity and to classify for that purpose – eg: hepatotoxicants, neurotoxicants
Secondary effects:should not be included
Categories 1,2,3
Descrimination between STOT, single exposure & Acute toxicity: main criterion = lethality
Avoid classifcation in both hazard classes!

27. Specific target organ toxicity (STOT), repeated exposure(RE)
Specific tearget organ toxicity after repeated exposure to a substance (including lethal effects)
All significant health effects not covered by any other hazard class (eg: acute toxicity, CMR,…)
reversible & irreversible
immediate & delayed
significant chenges in single organs or biological system or
generalised changes of a less severe nature involving several organs
Categoriea 1,2,3

28. Aspiration hazard
Aspiration is the entry of a liquid or solid substance/mixture directly (through the oral or nasal cavity)or indirectly (from vomiting) into the trachea and lower respiratory systems
Aspiration toxicity includes severe acute effects such as:
chemical pneumonia,
pulmonary injury or
death following aspiration

29. General information
Chemicals placed on the Serbian market shall be classified by using of:
Harmonised classifications (in both systems)
Self-classification by application of the criteria (in both systems, but some NEW issues in CLP/GHS system)
Use of translation tables (NEW issue)
Use of classification and labelling inventory (NEW issue)

30. General information Self-classification
= the supplier’s decision on a particular classification
For substances: must be done for those hazards where no harmonised classification exists.
For mixtures: has always to be done. Any available harmonised classifications of the substances contained in the mixture must be taken into account.
The classification criteria are in Part 2-5 of Annex I to CLP/GHS Rulebook!

31. General information
Four basic steps to self-classify a substance or mixture:
1. Collection of available information
Test data, non-test data, human data, other
2. Examination of data
Expert judgement- assessment of the available data by a qualified, experienced and
knowledgeable person as to its relevance, adequacy and reliability
3. Evaluate & review the information
Apply criteria
Weight of evidence
4. Decision on classification
If substance/mixture meets criteria assign classification
Hazard class and category

32. Collection of available information (1)
First check what kind of information or data are already available "in-house“:
Open literature or databases (intrenet, online databasaes) often use secondary data
sources, but original source should be cited and checked (sufficient documentation,
quality!!).= Expert judgement- assessment is needed
Check the List of Classified Substances first before starting to gather information!

33. Collection of available information (2)
Data from tests
All tests carried out according to scientifically valid and internationally recognised
testing methods (GLP!) are accepted
Animal welfare is a big goal of CLP/GHS
New tests should be avoided where ever possible – all available data have to be
considered:
- Human data (!)
- Ex-vivo methods
- In-vitro methods
- In-silico methods (grouping, read-across, (Q)SARs) …

34. Collection of available information (3)
Data from tests
Testing of substances for the purpose of classification
Supplier may decide to conduct new testing.But provide that he has exhausted all other means of generating information
Testing on animals: wherever possible and alternative methods (including in vitro testing, the use of (Q)SARs, read-across …)
Tests on human, human and non-human primates: prohibited for the purposes of classification. But existing data from: accident records, epidemiological and clinical studies, can be used.

35. Collection of available information (4)
Data from tests
Testing of mixture for the purpose of classification
Only when the supplier has exhausted all other means of generating information, new tests may be performed BUT, NOT for CMR effects
Classification for HH based on available information (including test data) on the
mixtures themselves and on information on the substances
USE:
all available information on the ingredients of the mixture to derive a classification!

36. Collection of available information (5)
Apart of the tests data are useful sources of information:
Data from SDS
Data from the LIST OF CLASSIFIED SUBSTANCES
Data from C&L INVENTORY LIST
Other sources

37. Collection of available information (6)
Data from SDS
SDS is the most useful sorce of information
SDS:
safety information on classified chemicals , in EU including information from the relevant CSR down the supply chain
Shall enable users to take the necessary measures relating to protection of human health and safety at the workplace, and protection of the environment.

38. SDS: Timeline of changing
Data from SDS
SDS: Timeline of changing
1 Dec Dec Jun Jun 2017
Placed on the market :
before 1 Dec 2010
during 1 Dec Jun 2015
from 1 Jun 2015
from 1 Jun 2017
SUB
ZMES
MIX
SUB
SNOV
MIX
ZMES
SUB
SNOV
MIX
ZMES
… old format of SDS shall be accepted (unless the chemicals
shall be relabelled and repackaged)
… SDS complying with Annex I to Regulation (EU) 453/2010 shall be used
… SDS complying with Annex II to Regulation (EU) 453/2010 shall be used
… SDS for substances
… SDS for mixtures
SUB
MIX

39. Collection of available information (7)
Data from the LIST OF CLASSIFIED SUBSTANCES
the use of a harmonised classification from the List of Classified Substances is mandatory
Data from C&L INVENTORY LIST
The Inventory list will an EU database on C&L information of notified and registered substances. It will also contain the list of harmonised classifications It will be established and maintained by European Chemicals Agency (ECHA).
the use of Inventory list will NOT be mandatory

40. Collection of available information Evaluation & reviewing the information:
The classification criteria are in Part 2-5 of Annex I to CLP/GHS Rulebook!
Other sources:
For OLD system
On the website of Serbian Chemical Agency:
- Upostvo za klasufikacijo, pakovanje, obeležavanje i reklamiranje hemikalija (2010)
For NEW system
- GHS (CLP/GHS system ) in practice
On the website:
- Guidances on CLP (= EU GHS)
- Guidance on application of the CLP (= EU GHS) criteria
- EU FAQ regarding CLP in EU and useful links
Decision on classification

41. Hazard identification
Conclusion
Classification is the starting point for hazard communication:
Data collection
Informing:
Label Public
awareness
SDS
Hazard identification

42. Thank you!
Thank you! 25