1. Classification of substances and mixtures on the basis of health hazard Semira 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:
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)

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: 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 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
The minimum lethal dose reported of 300 mg/kg is used as equivalent ATE; according to Table the resulting classification is Category 3

9. Methanol: STOT (SE)
Annex I , Classification criteria for Categories 1 and 2
See Table : 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

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/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!

12. 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!

13. 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

14. 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

15. 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)

16. 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

17. 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 %

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

19. 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 in Annex I,
relating to a value from a range test or to
a classification category 19

20. Acute toxicity LD50 or LC50-value or
Converted value (point estimate) for acute toxicity from Table 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 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

23. 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 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

24. 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

25. 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%

26. 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

27. 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

28. 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

29. 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

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

31. Thank you!
Thank you! 25