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Index Set of rules before REACH Regulation REACH REGULATION REGISTRATION EVALUATION AUTHORISATION RESTRICTION Classification and Labelling Shared-Information-Down Stream Users
Regulation EC 1272/2008 for classification,
labelling and packaging of substance and mixture:
Classification
Labelling and
Packaging of substances and mixtures
•Harmonized system of criteria and application principles, came in force on 20th of
January 2009
•Replace/will replace
− Directive 67/548/CEE (hazard substances)
− Directive 1999/45/CE (hazard mixtures)
•During the transition period 2010 – 2015 will be used both systems of classification
What is CLP Regulation?
• It applies to the production and use of chemical substances and mixtures, regardless of quantity produced per year. • it is not about the rules of transportation, but ensures the compliance with them
Title 1. Art.1 Application field
Exeptions − radioactive substances and mixtures, substances and mixtures which are subject to customs supervision, non-isolated intermediates, substances and mixtures for scientific research and development, which are not placed on the market and wastes. − medicinal products, veterinary medicinal products, food and feeding stuffs, cosmetic products.
• Substance: a chemical element and its compounds
in the natural state or obtained by any manufacturing
process, including any additive necessary to preserve its
stability and any impurity deriving from the process used,
but excluding any solvent which may be separated
without affecting the stability of the substance or
changing its composition
• Mixture: mixture or solution composed of two or
more substances
HAZARD RISK
HAZARD Intrinsic property of a dangerous substance or physical state that can cause damage to humans and/or the environment RISK probability that a particular event will occur in a given period or in specified circumstances
Risk = EFFECTS X EXPOSURE
The hazard classes are divided into categories that specify the severity and are defined
in Parts 2 to 5 of Annex I
Title 1. Art.3
«Hazardous substances and mixtures and
specification of hazard classes»
Hazard type physical health environmental
Hazard classes 16 classes
of physical
hazard
9 classes
of health
hazard
2 classes
of environmental
hazard
2.1 Explosives (Unstable explosives, Divisions 1.1, 1.2, 1.3, 1.4, 1.5, e 1.6 )
2.2 Flammable gases (Categories 1 and 2)
2.3 Flammable aerosol (Categories 1 and 2)
2.4 Oxidising gases (Category 1)
2.5 Gases under pressure (compressed gases, liquefied gases, dissolved
gases or refrigerated liquefied gases)
2.6 Flammable liquids (Categories 1, 2 and 3)
2.7 Flammable solids (Categories 1 and 2)
2.8 Self-reactive substances and mixtures (Types A, B, C, D, E, F, and G)
2.9 Pyrophoric liquids (Category 1)
2.10 Pyrophoric solids (Category 1)
2.11 Self-heating substances and mixtures (Categories 1 and 2)
2.12 Substances and mixtures which in contact with water emit flammable
gases (Categories 1, 2 and 3)
2.13 Oxidising liquids (Categories 1, 2 and 3)
2.14 Oxidising solids (Categories 1, 2 and 3)
2.15 Organic peroxides (Types A, B, C, D, E, F and G)
2.16 Corrosive to metals (Category 1)
Classes/categories of PHYSICAL HAZARD
Acute toxicity, (Categories 1, 2, 3 and 4)
Skin corrosion/irritation, (Categories 1A, 1B, 1C and 2)
Serious eye damage/eye irritation, (Categories 1 and 2)
Respiratory or skin sensitisation (Category 1)
Classes/categories of HEALTH HAZARDS
Germ cell mutagenicity, (Category 1A, 1B and 2)
Carcinogenicity, (Category 1A, 1B and 2)
Reproductive toxicity (Category 1A, 1B and 2) plus 1 hazard
category for lactation effects
Specific target organ toxicity (STOT) — single exposure
(Categories 1, 2 and Category 3 that only includes narcotic effects
and respiratory tract irritation)
Specific target organ toxicity (STOT) — repeated exposure
(Categories 1 and 2) Aspiration hazard (Category 1)
Hazardous to the aquatic environment
− acute aquatic hazard Category 1
− long-term aquatic hazard
Categories 1, 2, 3, and 4
Classes/categories of ENVIRONMENTAL HAZARD
Hazardous to the ozone layer
Different system of classification
Substance X: acute oral toxicity LD50=257 mg/Kg
CAN: Toxic
USA:Toxic
Corea: Toxic
China: NON HAZARD
Japan: Toxic
India: Non Toxic
New Zeland: Hazard
Malaysia: Harmful
AUS: Harmful
GHS Hazard Toxic Category 3
Comparison between the classification systems most
relevant:
ONU Recommendations on the Transport
European Directives on substances and mixtures
U.S. and Canadian regulations on the workplace, consumer
products, biocides and plant protection
Elimination of differences with the definition of a system
to be used as a common denominator for other systems
or countries:
Global Harmonization System of Classification and Labelling of
Chemicals (GHS) published in 2003 and developed in the
United States since 1992
Principles of classification Harmonization Process
Principle “building block approach”:
allows you to exclude certain classes or hazard categories "less serious “
and preserve other not present in GHS.
The CLP takes all GHS hazard classes, but
excludes some categories not present in the
current EU regulations:
• Flammable liquids, Category 4
• Acute toxicity, category 5
• Corrosion / irritation category 3
• Aspiration Hazard Category 2
• Acute aquatic toxicity category 2 and 3
Transposition from GHS to CLP
Purpose and scope
The purpose of this Regulation is to ensure a high level of protection of
human health and the environment
• Harmonising the criteria for classification of substances and mixtures, and the rules on
labelling and packaging for hazardous substances and mixtures
• providing an obligation for:
i) manufacturers, importers and downstream users to classify substances and mixtures
placed on the market;
(ii) suppliers to label and package substances and mixture placed on the market;
(iii) manufacturers, producers of articles and importers to classify those substances not
placed on the market that are subject to registration or notification under REACH
• providing an obligation for manufacturers and importers of substances to notify the Agency
of such classifications and label elements
• establishing a list of substances with their harmonised classifications and labelling
elements
• establishing a classification and labelling inventory of substances
Title 1: General issues
The "body" of the Regulation on the general rules and principles is made
up of seven titles and seven technical annexes.
CLP Regulation stucture
Title I General issues
Title II Hazard identification, evaluation and classification
Title III
Hazard communication in the form of label
Title IV Packaging
Title V
Harmonisation of classification and labelling of substances and the classification and labelling inventory
Title VI
Competent authorities and enforcement
Title VII Common and final provision
Annex I Classification and labelling requirement for hazardous substances and mixture
Annex II Special rules for labelling and packaging of certain substances and mixture
Annex III
List of Hazard Statements and supplement hazard information and supplemental label elements
Annex IV List of Precautionary Statements
Annex V
Hazard pictograms
Annex VI
Harmonised classification and labelling for certain hazardous substances
Annex VII Translation table from classification under Directive 67/548/EEC to classification under this Regulation
CLP Regulation stucture Technical annex
• 1° ATP Regulation 790/2009/EC in force since 5th of September 2009
Applied since 1st December 2010
• 2° ATP: Regulation 286/2011/EC in force since19th of April 2011
Applied since 1st of December 2012 to substances
since 1st of June 2015 to mixtures.
• 3° ATP: Regulation 618/2012/EC in force since10th of July 2012 (updates the list of substances with
harmonised classification and labelling)
Applied since 1st of December 2013
• 4° ATP: Regulation 487/2013/EC in force since 8th of May 2013 (brings CLP into line with
the 4th revised edition of GHS)
Applied since 1st of December 2014 to substances
since 1st of June 2015 to mixtures.
• 5° ATP: Regulation 944/2013/EC in force since 2nd of October 2013 (brings CLP into line with
the 5th revised edition of GHS)
Adaptation to Technical and scientific Progresses (ATPs)
Definition based on Reach:
•article: an object which during production is given a special shape, surface or design
which determines its function to a greater degree than does its chemical composition;
•manifacturer: any natural or legal person established within the Community who
manufactures a substance within the Community;
•importer: any natural or legal person established within the Community who is
responsible for import;
•down stream user: any natural or legal person established within the Community, other
than the manufacturer or the importer, who uses a substance, either on its own or in a
mixture, in the course of his industrial or professional activities. A distributor or a
consumer is not a downstream user. A re-importer exempted pursuant to Article 2(7)(c) of
Regulation (EC) No 1907/2006 shall be regarded as a downstream user;
•distributor: any natural or legal person established within the Community, including a
retailer, who only stores and places on the market a substance, on its own or in a mixture, for third parties;
Title 1. Art.2 Definition
or
•on Self-classification applying the criteria
established by the CLP Regulation if not present in Annex VI or
properties other than those harmonized in Annex VI
Classification Substances are classified
•on the base of Harmonised Classification
reported in Annex VI of CLP Regulation,
Mixture are always classified
• on Self-classification applying the criteria
established by the CLP Regulation
• Classify, package and label according to CLP for placing on the
market
• Classify to register or notify under REACH
• Notify the C & L to ECHA for the Inventory
• Update the C & L in the case of new scientific and technical
informations
• Submit a proposal for the updating of harmonized C & L the
Competent Authorities of the Member States (MSCA), in the
event of new information,
• Keep all the details used for C & L available for at least 10 years
Art.4: What are the obligations for companies?
• epidemiological data
• cases and experience on humans
• any other scientific information adequate,
reliable and scientifically valid
Title II: Article 5 Identification and examination of available information
on substances
a) Test results for the physical-chemical properties
(if missing, new tests has to be done)
b) Results of assays for toxicological and ecotoxicological if available
(except for CMR properties and biodegradability),
or
- By analogy (bridging principles) with a mixture of similar
composition for which you have data, or
- Based on the properties of the components (that must be known) by
calculation
Title II: Article 6 Identification and examination of available information
on mixtures
•further experiments on animals, if necessary, according to Directive
86/609/EEC, shall be undertaken only if there are no alternatives that
provide adequate reliability and quality of data.
•are prohibited tests on non-human primates
•no tests on humans. The data obtained from other sources, such as
clinical trials, however, can be used for the purposes of this Regulation.
Title II Art. 7: Animal and human testing
Regulation on methods EC 440/2008 of 30th of May 2008 published on Official Journal L 142 of 31st of May 2008 and modified from Regulation 761/2009
• Where new tests for physical hazards are carried out for
the purposes of this Regulation, they shall be carried out, at
the latest from 1 January 2014, in compliance with a
relevant recognised quality system or by laboratories
complying with a relevant recognised standard.
• The new ecotoxicological or toxicological tests shall be in
conformity with Article 13, paragraph 4 of Regulation (EC)
No. 1907/2006 which provides for the implementation under the Good Laboratory Practice (GLP)
Title II Art 8(5): Generating new information for substances and mixtures
Application CLP: timeline
Harmonized classification : Methanol
Physico-chemical properties:
Flammability, explosivity, oxidising
(as obtained from laboratory tests)
Toxic effects on humans and animals
acute toxicity, irritation, corrosivity, sensitization, repeated dose toxicity,
mutagenicity, carcinogenicity, reproductive toxicity
(inferred from epidemiological studies or test on laboratory animals)
Toxic effects on environment
(deduced from physico-chemical properties and essays on
environmental indicators)
Hazard classification
on the base of
▼ Tests according to the methods of Regulation 440/2008
or in accordance with the Manual of Tests and Criteria used for
the transport sector:
www.unece.org/trans/ danger/publi/manual_e. html
▼ If data are available from tests different from that in the
previous point, a prior judgment of an expert is necessary
stating that quality and suitability for the type of hazard in
question is assured
▼ In some cases, the experience can prove properties
different from those shown by tests, which must be considered
for classifying (example: ammonium nitrate is explosive, but
test for explosivity is negative; volatile substances mixed with
halogenated hydrocarbons, but test
negative) Flammable liquids can be classified for calculation (Annex 1 2.6.4.2 e 2.6.4.3)
Classification for physical hazards
Tests according to the methods of Regulation 440/2008 or in accordance
with the OECD guidelines
How to evaluate the toxicity of a substance?
Qualitative evaluation:
the toxic action depends on the interaction of the molecular structure of the
substance with the biological mechanisms of receptor
Quantitative evaluation:
the toxic action occurs ONLY after a certain dose (in the environment or
in some organs) in proportion to the dose called “Dose-Response
Relationship”: measure of how many individuals within a relatively large
group show to suffer toxic effects at a given dose (eg. concentration per unit weight) of the substance.
Classification for hazards to human health
Toxicity_single exposure
LD50/LC50 = Median lethal dose- single dose, or
concentration that causes the death of 50% of
treated animals
Toxicity_repeated dose exposure
NOEL = NO EFFECT LEVEL , concentration or
dose at which an individual may be exposed
during the whole life without adverse effects on health
Toxicological parameters
• Ethyl alcohol 10.000
• Sodium chloride 4.000
• Ferrous sulphate1.500
• Morphine sulfate 900
• DDT 100
• Strychnine sulphate 2
• Nicotine 1
• Tetrodotoxin 0,1
• Dioxin 0,001 • Botulinum toxin 0,00001
LD50 Acute (mg/kg/body weight) for some substances
Chemicals absorbed can act both as a systemic
toxic for the whole body, or they can attack specific
organs:
Corrosion/Irritation
Sensitisation
Aspiration hazard
Specific target organ toxicity single and repeated
exposure
Cancerogenicity
Mutagenicity
Toxic for reproduction
Other effects
Health Effects: Acute oral toxicity classification criteria
When the inhalation toxicity is due to the corrosiveness you add the EU
H701: "corrosive to the respiratory tract" and you can add the pictogram of the
corrosion
Very toxic LD50 < 25 mg/Kg
Toxic 25 < LD50 < 200mg/Kg
Harmful 200 < LD50 < 2000mg/Kg
Category 1 LD50/ATE<5
mg/Kg
Category 2 5 < LD50/ATE >50
mg/Kg
Category 3 50 < LD50/ATE >300
mg/Kg
Category 4 300 < LD50/ATE >2000
mg/Kg
200-300
EU
CLP
If the total concentration of the
components of unknown acute toxicity
is 10%
If the total concentration of
the components of
unknown acute toxicity is
> 10%,
Acute toxicity: Classification of mixtures from component (additivity formula)
The components devoid of information are not considered significant if
<1% even for the purposes of application of the second formula
ATE: Acute Toxicity Estimate
Sperimental value of LD50 or LC50
or
The converted value (estimate) of the acute
toxicity (Table 3.1.2 in Annex) for a test result as a range or a set of classification
Acute toxicity
ATE: Acute Toxicity Estimate
Exposure routes Toxicity range or category
ATE
Oral (mg/Kg/body
weight)
0 < Category 1 ≤ 5 5 < Category 2 ≤ 50
50 < Category 3 ≤ 300 300 < Category 4 ≤ 2000
2000 < Category 5 ≤ 5000
0,5 5
100 500
2500
Table 3.1.2 ATE conversion of the classification categories or ranges of
experimentally obtained acute toxicity
ATE (Acute Toxicity Estimate)
Example of classification of a mixture for acute toxicity
Classifed components Conc (%) Data
Component 1 8 Oral rat LD50: 200 mg/Kg
Component 2 20 Oral rat Cat. 4 (ATE=500)
Component 3 40 Oral rat LD50: 1050 mg/Kg
Result: ATE mixture = 847.5 mg/kg.
Based on data on the components the mixture is classified as a category 4
for the acute oral toxicity.
Health effects_criteria for classification Corrosion / irritation
«Causes severe skin burns and eye damage» Category 1 H314
«Causes severe burns» R35
«Causes burns» R34
«Irritating to skin» R38
Category 1 A
Category 1B
Category 1C
«Causes skin irritation. » H315
EU 67/548
CLP
Esposure (corrosion)
Observation period
Change the scores from >2 to
2.3÷ 4 on 2/3 of the treated animals
Corrosive Corrosive Irritant
Category 2
Skin corrosion/irritation
• Use existing data on humans or animals
• Avoid as much as possible in vivo testing for skin
corrosion / irritation
• Use, if possible, in vitro alternatives
• Consider the extreme value of pH (≤ 2 and ≥ 11.5) for
corrosion (to take into account the buffering capacity)
Does the alkali/acid reserve indicate that mixture may be corrosive?
Skin corrosive cat. 1A
Test in vitro available Skin corrosive cat. 1A
Test in vitro for corrosion Skin corrosive cat. 1A/1B/1C. If not possible cat. 1
Test in vitro for irritation Irritant
Non irritant
yes
no
no
positive
positive
yes
negative
negative
Mixture: effects on skin; extreme value of pH pH ≤ 2 o ≥ 11.5
Example for skin irritation
Skin Irritant Cat 2 because the average erythema is > 2.3 in 2 of three
animals as the average of 24, 48 and 72 hours
May cause sensitisation by inhalation
R42
May cause sensitisation by skin contact
R43
May cause allergy or asthma symptoms or breathing difficulties if inhaled
H334 Category 1
May cause an allergic skin reaction
H317 Category 1
EU 67/548
CLP
Effects
Sensitization by skin contact in a substantial number of persons or
positive results in appropriate tests on animals
Harmful Irritant
There is a good correspondence with Xi R42 and Xn R43
Health effects_criteria for classification respiratory or skin sensitisation
Specific hypersensitivity of the respiratory tract of man and/or positive data from animal studies
Data from human experience (*)
epidemiological studies
reported cases
The respiratory sensitisation can be induced either by
inhalation and for dermal contact
There are no validated animal tests for respiratory
sensitisation
measurements of Immunoglobulin E (IgE) and other
specific immunological parameters in mice; and specific
pulmonary responses in guinea pigs may indicate a potential sensitiser
Respiratory sensitisation
(*) When considering the human evidence, to decide on the
classification must also be taken into account: the size of the exposed population and the extent of exposure.
Updating of the criteria for skin and respiratory
sensitisation: two sub-categories 1A and 1B to
distinguish between strong and weak sensitiser when
the data permit ( level of positive responses frequency
in animal studies or human cases)
Information for protecting already sensitised
individuals who may exhibit an allergic response at low doses.
Regolation 286/2011 (2°ATP) 10th of March 2011
Test Criteria for 1A Criteria for 1B
LLNA (local lymph node assay)
EC3 ≤ 2 % EC3> 2 %
GPMT (the guinea pig maximisation test )
≥ 30 % respond to ≤ 0,1 % of the intradermal induction dose or ≥ 60 % respond to 0,1 % < conc. ≤ 1 % of the intradermal induction dose
From ≥ 30 % to < 60 % respond to 0,1% < dose ≤ 1 % of the intradermal induction dose or From ≥ 30 % respond to > 1 % of the intradermal induction dose
Test of Buehler ≥15 % respond to ≤ 0,2 % of the topic induction dose or ≥ 60 % respond to 0,2 %< dose ≤ 20 % of the topic induction dose
From ≥ 15 % to < 60 % respond to 0,2 % < dose ≤ 20 % of the topic induction dose or ≥ 15 % respond to > 20 % of the topic induction dose
Results of animal tests to distinguish between the two subcategories
Skin sensitisation CLP Criteria 67/548 Criteria
Beuhler test: 4/20 (80% subst. A) ie 20% positive 0/10 (control tests)
>15% positive ≥15% positive Dose >20%
≥15% positive
GPMT: 15/20 (1% subst. A) ie 75% positive 0/10 (control tests)
>60% positive 1A: ≥60% positive to 0,1%<conc >1%
≥30% positive
Example skin sensitisation
75% positive in GPMT justify the classification as cat.1A
Components classified as:
Limit concentrations for the classification of a mixture as:
Skin sensitiser Respiratory sensitiser
Solids/liquids Gas
Skin sensitiser 1 and 1B
≥0,1% (note 1) ≥ 1%
Respiratory Sensitiser 1 and 1B
≥0,1% (note 1) ≥ 1%
≥0,1% (note 1) ≥ 0,2%
Skin sensitiser 1A
≥0,01% (note 1) ≥ 0,11%
Respiratory sensitiser 1A
≥0,01% (note 1) ≥ 0,1%
Note 1: notation on the label and SDS required
Criteria 1272/2008 in black/ new criteria added with II ATP in violet
Mixture: Respiratory or Skin Sensitisation
Health effects_criteria for classification for Cancerogenicity/Mutagenicity/ Toxicity for
Reproduction (CMR)
Category 1 R45 (R49)/ R46/R60-61
Category 2 R45 (R49)/ R46/R60-61
Category 3 R40/R68/R62-63
Category 1 H350/H340/H360
Category 1A Category 1B
Category 2
H351/H341/H361
CLP
Substances recognized as known C/M/R for
humans
Substances to be considered C/M/R for
humans
Concern due to the possible effects C/M/R
EU 67/548
Component classified as:
Category 1 A M/C
Category 1 B M/C
Category 2 M/C
Category 1 A ≥ 0,1%
Category 1 B ≥ 0,1%
Category 2 ≥ 0,1% [Note 1]
Note:
The concentration limits in the table apply to solids and liquids (w/w
units) and to gas (v/v units)
Note 1:
If a Category 2 carcinogen is present in the mixture as an ingredient at
a concentration ≥ 0,1% a SDS shall be available for the mixture upon
request.
The transposition of the old into the new classification is
practically a direct
Mixture: Mutagenics and Cancerogenics (non additive)
Component classified as:
Category 1 A Category 1 B
Category 2
Category 1 A ≥ 0,3%
Category 1 B ≥ 0,3%
Category 2 ≥ 3,0% [Note 1]
Additional category for effects on or via lactation
≥ 0,3% [Note 1]
Note:
The concentration limits in the table apply to solids and liquids (w/w units) and to gas
(v/v units)
Note 1:
If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects
on or via lactation is present in the mixture as an ingredient at a concentration at or
above 0,1 %, a SDS shall be available for the mixture upon request.
Mixture: Reproductive toxicity (non additive)
(0.5% according to 67/548)
(5% according to 67/548)
For mixtures do not change the limits for C and M but change to R
Repro cat 1, cat 2 Conc. >0,5%
Repro cat 3 Conc > 5%
Cat 1 A,B Conc>0,3%
Cat 2 Conc> 3%
Mixture CMR: Differences between 67/548 and CLP
“Danger of very serious irreversible effects”
R39
“Possible risk of irreversible effects”
R68
“Irritating to respiratory system”
R37
“Causes damage to organs”
H370 Category 1
“May cause damage to organs ”
H371 Category 2
“May cause respiratory irritation” H335
“May cause drowsiness or dizziness” H336
Category 3
CLP
Strong evidence of very serious injuries, non-lethal,
reversible or irreversible
Strong evidence of damage, non-lethal, reversible or
irreversible
Organ-specific effects
often transient
EU 67/548
Effects
Very Toxic/Toxic
Harmful Irritant
Health effects_criteria for classification for Specific target organ toxicity (STOT) —
single exposure (SE)
Human data from epidemiological studies or reported
cases
Data from observations during acute toxicity studies on
animals (clinical findings, effects on target organs and tissues)
Difficult to infer from older studies that detected only the
lethality
If the lethality is a consequence of a certain effect, this does
not imply classification as STOT-SE
Are not available in vitro tests
Health effects_criteria for classification for Specific target organ toxicity (STOT) —
single exposure (SE)
Specific target organ toxicity (STOT) Single Exposure (SE)
Route of exposure
Cat. 1 Cat. 2 Cat. 3
Oral (rat) mg/Kg body weight
C ≤ 300 300 < C ≤ 2000 Transient target organ effects. This category only includes narcotic effects and respiratory tract irritation. The effects are reversible and values guide does not apply
Dermal (rat or rabbit) mg/Kg body weight
C ≤ 1000
1000 < C ≤ 2000
Inhalation (rat) Gas ppmV/4h
C ≤ 2500
2500 < C ≤ 5000
Inhalation (rat) vapour mg/l/4h
C ≤ 10
10 < C ≤ 20
Inhalation (rat) dust/mist/fume mg/l/4h
C ≤ 1,0 1,0 < C ≤ 5,0
• The hazard must contain the main organs affected by the toxic
effects (not more than three). When the organs are so many you use
the generic phrase "organ damage". The organs are not deducible
from the old classifications
• The route of exposure can be specified only if you can prove that
there is no danger for the remaining routes.
• Category 3 is assigned regardless of cat1 and 2
• If lethality is a consequence of an effect, this does not imply
classification as STOT-SE. Acute Toxicity and STOT classes are
independent, but should not be considered twice for the same effect
• If the serious effects are present at lower values, at least an order of
magnitude, in respect of the lowest guideline value (300 mg / kg, oral) apply specific limits (SCLS)
STOT SE
“Danger of serious damage to health by prolonged exposure”
R48
“Danger of serious damage to health by prolonged exposure”
R48
“Causes damage to organs through prolonged or repeated exposure”
H372 Category 1
“May cause damage to organs through prolonged or repeated exposure”
H373 Category 2
EU 67/548
CLP
Effects Adverse effects in humans based on animal data
Harmful
Severe toxicity or deemed capable of causing severe toxicity to humans
Toxic
Health effects_criteria for classification for Specific target organ toxicity (STOT) —
repeated exposure (RE)
Specific target organ toxicity (STOT)
Repeated Exposure (RE)
Route of exposure
Cat. 1 Warning: HAZARD
Cat. 2 Warning: ATTENTION
Oral (rat) mg/Kg body weight
C ≤ 10 10 < C ≤ 100
Dermal (rat or rabbit) mg/Kg body weight
C ≤ 20
20 < C ≤ 200
Inhalation (rat) Gas ppmV/4h
C ≤ 50
50 < C ≤ 250
Inhalation (rat) vapour mg/l/4h
C ≤ 0,2
0,2 < C ≤ 1,0
Inhalation (rat) dust/mist/fume mg/l/4h
C ≤ 0,02 0,02 < C ≤ 0,2
C= Guide values for dose/conc. that cause effects
Human data from epidemiological studies or reported
cases
Data from repeated dose toxicity tests on animals (rat and
mouse) for 28 days, 90 days, 2 years
Has to be considered also:
Studies on other species if available
Studies of carcinogenicity, neurotoxicity, reproductive
toxicity if available
Are not available in vitro tests
is necessary to identify the major organs involved in the toxic effects , and not include side effects
Health effects_criteria for classification for Specific target organ toxicity (STOT) —
repeated exposure (RE)
We consider the significant effects and severe toxicity, ie,
morphological and functional disorders of toxicological
relevance
The effects should be relevant to humans
Guideline values are reported in studies with exposure to
90 days
To derive the guideline values at 28 days and two years
applies Haber's rule, namely that the product of dose and
exposure must remain the same.
Then for 28 days to multiply by 3 and for two years divide
to 4 Are fixed specific limits in the same way STOT SE
Health effects_criteria for classification for Specific target organ toxicity (STOT) —
repeated exposure (RE)
Component classified as:
Generic limit for the classification of the mixture:
Cat. 1 Cat. 2
STOT Cat. 1 ≥ 10% 1%≤ C ≤ 10%
STOT Cat. 2 ≥ 10%
If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1.0% a SDS shall be available for the mixture upon request.
Mixture:STOT SE and STOT RE (non additive)
Acute aquatic toxicity
Degradation (biotic or abiotic for organic
substances)
potential bioaccumulation
Chronic aquatic toxicity
Classification for environment– Basic elements
The parameters for estimating the aquatic toxicity (LC50)
and degradation (BOD / COD) are unchanged
Chronic toxicity is still based on the parameters of acute
toxicity in combination with the persistence parameters
The criteria for assessing the bioaccumulation change
The limit of log Kow goes from 3 to 4 and the limit of the
BCF (bioconcentration factor) from 100 to 500
(The values according to 65/548/EC were more restrictive)
Regulation CLP_ classification criteria:
What changes for the effects on the environment?
Substances hazardous to the aquatic environment : Acute toxicity
Category 1
Warning: ATTENTION Risk phrases Very toxic to aquatic life
96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants)
≤ 1 mg/l and/or ≤ 1 mg/l and/or ≤ 1 mg/l
Substances hazardous to the aquatic environment : Chronic toxicity
Category 1
Warning: ATTENTION Hazard statement Very toxic to aquatic life with long lasting effects
96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the
experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)
≤ 1 mg/l and/or ≤ 1 mg/l and/or ≤ 1 mg/l
Category 2
No warning Hazard statement Toxic to aquatic life with long lasting effects
96 h LC50 (fish) 48 h EC50( crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)
1 < conc ≤ 10 mg/l and/or 1 < conc ≤ 10 mg/l and/or 1 < conc ≤ 10 mg/l
Category 3
No pictogram Hazard statement Harmful to aquatic life with long lasting effects
96 h LC50 (fish) 48 h EC50 (crustacea) 72 h o 96 h (algae or other acquatic plants) and the substance is not rapidly degradable and/or the experimentally determined BCF ≥ 500 (or, if absent, the log Kow ≥ 4)
10 < conc ≤ 100 mg/l and/or 10 < conc ≤ 100 mg/l and/or 10 < conc ≤ 100 mg/l
Category 4
No symbol and no warnings. Poorly soluble substances for which no acute toxicity is recorded at levels up to the water solubility, and which are not rapidly degradable and Kow ≥ 4 except if BCF <500 or NOEC> 1 mg / l, or evidence of rapid degradation in the environment
Mixture classification for enviromental hazard
Additive method (only for acute toxicity)
Ci = concentration of the component i (%
by weight)
L(E) C50i = LC50 or EC50 of the component i
n= number of components
L(E)C50m= L(E)C50 the part of the mixture
for which data assay are available
Only to be used for components when there is no harmonised classification,
but it has the data for acute toxicity. In fact, expert judgment is required to
select high quality data and the most appropriate of an entire set of data for
aquatic toxicity
When a substance classified in Category 1
acute or chronic it is necessary to indicate an
appropriate multiplying factor M
Sum of components classified as Mixture classification
Acute 1 (Chronic 1) x M 25% Acute 1 (Chronic 1)
We use the M-factor indicated for substances in
Annex VI. If not specified it must be obtained from
LC 50 value in order to apply the formulas of the summation method
Factor M
Factor M
L(E)C50 M (multiplying factor)
0,1 < L(E)C50 ≤ 1 1
0,01 < L(E)C50 ≤ 0,1 10
0,001 < L(E)C50 ≤ 0,01 100
0,0001 < L(E)C50 ≤ 0,001 1000
0,00001 < L(E)C50 ≤ 0,0001 10000
Continue in factor 10 intervals Continue in factor 10 intervals
Chronic 1 x M ≥25% Chronic 1
(M x 10 x Chronic 1) + Chronic 2 ≥25% Chronic 2
(M x 100 x Chronic 1) + (Mx10xChronic 2)+ Chronic 3 ≥25% Chronic 3
Chronic 1+ Chronic 2+ Chronic 3+ Chronic 4 ≥25% Chronic 4
This method including the calculation for
acute toxicity is used when the classifications
and M are known, but not the LC50 (as you use the ATE in the case of acute toxicity)
Mixture classification for environmental hazard on the base of the sum of components (%) classified for chronic toxicity
M also serves to establish the values of cut-
off values different from those generic.
Cut-off/M = 0,1% / M
Example:
Substance A with M= 100 The component is relevant from 0.001 %
Factor M and Cut Off
Ci = concentration of component i (% by weight)
Cj = concentration of component j (% by weight)
NOECi = NOEC( or other chronic parameters) of the component i
including the rapidly degradable components
NOECj = NOEC(or other chronic parameters) of the component j
including the rapidly degradable components
n= number of components
eqNOECm= NOEC equivalent the part of the mixture for which data
assay are available
Mixture classification for environmental hazard_Additive method for
Chronic toxicity
When a substance is classified in Category 1 acute or chronic it
is necessary to indicate an appropriate multiplication factor M
are used specific limits and M-factors listed in
Annex VI, if present, otherwise those notified to
the Classification Inventory, including those
relating to harmonized classifications without M-
factors listed in Annex VI
But if they are not listed in Annex VI should not
mean that M = 1?
Not for now, because all were not evaluated but
the new substances included and classified for the environment will have M factor.
SCL and Factor M
Acute toxicity for health hazard
Acute and chronic toxicity for environmental
hazard
Skin and eye corrosion/irritation
STOT SE cat 3 (ex R37)
STOT RE cat 3 (ex R67)
Additivity
Skin and eye sensitiser
Mutagenesis
Carcinogenesis
Reproductive toxicity
STOT SE e RE cat. 1 and 2
Risk for aspiration (ex R65)
Skin and eye corrosion/irritation in particular cases
Non-additivity
Classification by physical aspects: the results of tests
Classification for aspects of human health and the
environment :
Test results, if available
Bridging principle, if applicable
Quali quantitative composition
Component classification
If you get a mixture from one or more mixtures the
mentioned data are required for each of the component
mixtures
Only for acute toxicity on human health computing
system can be applied directly if the ATE of the
component mixtures are known, considering them as if they were substances
Summary of the minimum information necessary to classify the mixtures
QUESTION : Skin Corrosion/Irritation
N
animal
Erithema grade after….. Edema grade after…. Erithema
average
Edema
average
1h 24h 48h 72h 7gg 14gg 1h 24h 48h 72h 7gg 14g
g
1 3 3 2 1 0 1 3 2 2 0
2 2 2 1 1 0 1 1 1 0 0
3 2 2 2 1 0 0 1 3 2 2 0
How the substance is classifed?
QUESTION A mixture is composed by:
Substance
%
w/w
Classification
according to CLP
ATE /DL50(oral)
mg/Kg
Substance 1 10 Acute toxicity C.4, H302 500
Substance 2 10 Acute toxicity C.3, oral,
H301
unknown
Substance 3 2 TAcute toxicity 2, H300 50
Substance 4 78 No > 5000
How it is classified and labelled the mixture?
Parathion
Butyl benzyl
phthalate
(BBP)
Nonylphenol
ECO-TOXICOLOGICAL DATA
EC50 Daphnia magna, 48 h = 0,37 µg/L
LC50 Fish, Lepomis macrochirus, 96 h = 18 µg/L
log Kow= 3,15
BCF = 400
Non rapidly degradable
ErC50 Algae (Selenastrum capricornutum), 72 h = 0,2 mg/L
EC50 Daphnia magna, 48 h = 2,2 mg/L
log Kow= 4.7
BCF = 663 – 772
Rapidly degradable
EC50 Crustacea, 48 h = 0,0207 mg/L
LC50 Fish, Lepomis macrochirus, 96 h = 0,128 mg/l
log Kow= 4.5
BCF = 1300
Non rapidly degradable
SUBSTANCE % w/w
Parathion 0,002
Butyl benzyl phthalate (BBP)
1
Nonylphenol 0,02
How the mixture has to be classified according to CLP?