Transcript Principles of classification of substances and mixtures on basis of

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.
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Content
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General information on HH
Where to get data?
Evaluation & reviewing the information
Decision on classification
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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
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General information
NEW CLP/GHS classification criteria:

Human Health- new Hazard Classes with categories
 Specific Target Organ
 Serious Eye Damage/Eye Irritation
 Aspiration
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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
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Why do we need GHS?
Substance - oral toxicity LD50 = 257 mg/kg
GHS
Transport
EU
US
CAN
Australia
India
Japan
Malaysia
Thailand
New Zealand
China
Korea
Danger (Skull & Cross Bones)
liquid: slightly toxic; solid: not classified
Harmful (St Andrew’s Cross)
Toxic
Toxic
Harmful
Non-toxic
Toxic
Harmful
Harmful
Hazardous
Not Dangerous
Toxic
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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
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Health hazards under CLP
Hazard class
Acute oral toxicity
Acute dermal toxicity
Acute inhalation toxicity
Skin corrosion/irritation
Severe eye damage/eye irritation
Sensitisation: respiratory
Sensitisation: skin
Hazard category
1
1
1
2
3
2
3
2
3
Corrosive
1A 1B 1C
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4
4
Irritation
2
1
2
1A
1A
1B
1B
Germ cell mutagenicity
Carcinogenicity
1A
1B
2
1A
1B
2
Reproductive toxicity
1A
1B
2
STOT – single exposure
STOT – repeated exposure
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1
2
2
3
Aspiration hazard
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Lactation
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Human Health hazardsexamples
Hazard
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
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Transient target organ effects – includes narcotic effects and
respiratory tract irritation. Alter human function for a short
duration after exposure
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General Information
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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:
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Human data
Ex-vivo methods
In-vitro methods
In-silico methods (grouping, read-across, (Q)SARs)
Peer reviewed publications
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General Information
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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)
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CLP : DSD
Acute
toxicity
(Cat 1-3)
Acute toxicity
(Cat 4)
• Skin irritation
• Eye irritation
• Skin sensitisa.
• STOT, SE
(Cat. 3)
• Very toxic
• Toxic
• CMR
Respiratory
sensitisation
• Germ cell
mutagenicity
•carcinogrnicity
rreproductiv toxicity
• STOT, single &
repeated exposure
• Aspiration hazard
• Harmful
• Skin corrosion
• Serious eye damage
Corrosive
• Irritant
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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
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Acute toxicity
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Adverse effects occurring following
 oral
or dermal administration of a single dose or
multiple doses within 24h
 or an inhalation exposure of 4h
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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
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Skin corrosion / irritation
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Skin Corrosion – Category 1:
CLP: Irreversible skin damage: visible
necrosis into dermis after exposure up to 4h:
 typically
 + by the
ulcers, bleeding, bloody scabs
end of observation at 14 days by
discolouration (blanching of skin), complete areas of
alopecia & scars
 in at least 1 of 3 animals
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DSD: full thickness destruction of skin tissue,
exposure up to 4 hours, in at least 1 of 3 animals
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Skin corrosion / irritation
Skin irritation – category 2:
 CLP: reversible skin damage after exposure up to 4h
 Criteria for skin irritation:
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In at least 2 of 3 animals a mean value of ≥ 2,3 - < 4,0 for
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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);
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Inflammation in 2 of 3 animals, that persists until end of
observationperiod particularly taking into account alopecia (limited
area),hyperkeratosis, hyperplasia and scaling; or
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exemption: very definite positive effects in a single animal – even
ifcriteria above not fulfilled
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Skin corrosion / irritation
Skin irritation – category 2: comparison to DSD:
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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)
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Skin corrosion / irritation
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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?
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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
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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
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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
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Germ cell mutagenicity
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Classification criteria of old and new
system are comaparable:
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Category 1 => Category 1A
 Category 2 => Category 1B
 Category 3 => Category 2
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Carcinogenicity
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Criteria for classification - new and old system are
almost identical:
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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)
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Reproductive toxicity
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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)
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R64 => H362: human and animal data
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Specific target organ toxicity
(STOT), single exposure(SE)
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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,…)
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
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reversible & irreversible
immediate & delayed
significant chenges in single organs or biological system or
generalised changes of a less severe nature involving several
organs
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Specific target organ toxicity
(STOT), single exposure(SE)
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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!
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Specific target organ toxicity
(STOT), repeated exposure(RE)
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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,…)


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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
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Aspiration hazard
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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
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General information
Chemicals placed on the Serbian market shall be classified by using of:
1.
Harmonised classifications (in both systems)
2.
Self-classification by application of the criteria (in both systems, but some
NEW issues in CLP/GHS system)
3.
Use of translation tables (NEW issue)
4.
Use of classification and labelling inventory (NEW issue)
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General information
Self-classification
= the supplier’s decision on a particular classification
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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!
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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
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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!
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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) …
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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.
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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!
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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
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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.
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Data from SDS
SDS: Timeline of changing
1 Dec 2010
Placed on the market :
before 1 Dec 2010
1 Dec 2012
1 Jun 2015
1 Jun 2017
SUB
MIX
ZMES
Placed on the market :
during 1 Dec 2010 1 Jun
2015
SNOV
SUB
ZMES
MIX
Placed on the market :
from 1 Jun 2015
SNOV
SUB
Placed on the market :
from 1 Jun 2017
… old format of SDS shall be accepted (unless the chemicals
shall be relabelled and repackaged)
ZMES
MIX
SUB
… SDS for substances
MIX
… SDS for mixtures
… 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
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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
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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
On the website of Serbian Chemical Agency:
- 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
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Conclusion
Classification is the starting point for hazard communication:
Data
collection
Informing:
Hazard
identification
Label
Public
awareness
SDS
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Thank you!
Thank you!
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