Download CLP criteria for hazard classification of substances and mixtures

CLP criteria for hazard classification
of substances and mixtures
TA Project: Chemical Safety in Croatia
W k h 16-17
Workshop
16 17 JJune 2011
Lennart Dock
Swedish Chemicals Agency
Physical Hazards CLP
Hazard Class
Explosives
Flammable Gases
Fl
Flammable
bl A
Aerosols
l
Oxidising Gases
Gases under pressure
Hazard Category
Unstable
1
1
1
Div1.1 Div 1.2 Div 1.3 Div 1.4 Div 1.5 Div 1.6
2
2
Compressed gas
Liquefied gases
Refrigerated liquefied gases
Dissolved gases
1
2
3
Flammable
Fl
bl Li
Liquids
id
1
2
Flammable Solids
Type A Type B Type C Type D Type E Type F Type G
Self Reactive Chemicals
1
Pyrophoric Liquids
1
P
Pyrophoric
h i S
Solids
lid
1
2
Self Heating Chemicals
1
2
3
Water Reactive - emits Flammable Gases
1
2
3
Oxidising Liquids
1
2
3
O idi i S
Oxidising
Solids
lid
Type A Type B Type C Type D Type E Type F Type G
Organic Peroxides
1
Corrosive to Metals
Criteria for Physical Hazard Classification
•UN Recommendations on the Transport of
Dangerous Goods
Goods, Manual of Tests and Criteria
CLP Annex I, Part 2
TDG Class
GHS Hazard class
1
E l i
Explosives
2
Flammable gases, Oxidising gases, Flammable aerosoles, Gases under
p
pressure
3
Flammable liquids
4.1
Self-reactive substances and mixtures, Flammable solids
4.2
Pyrophoric liquids, Pyrophoric solids, Self-heating substances and mixtures
4.3
g
Substances and mixtures which in contact with water emit flammable gases
5.1
Oxidizing liquids, Oxidizing solids
52
5.2
Organic peroxides
8
Corrosive to metals
Also, GHS categories/types/divisions correlates to TDG packing groups
Health Hazards CLP
Hazard Class
Acute Toxicity
Oral
Dermal
Inhalation
Hazard Category
Serious Eye Damage/Irritation
1
2
3
1
2
3
1
2
3
Corrosive
1A 1B 1C
1
p
y or skin sensitizer
Respiratory
1A
1B
Germ Cell Mutagenicity
1A
1B
2
Carcinogenicity
1A
1B
2
Reproductive Toxicity
1A
1B
2
1
1
1
2
2
3
Skin Corrosion/Irritation
STOT - Single Exposure
STOT - Repeated Exposure
Aspiration hazard
4
4
4
Irritant
2
2
Lactation
Criteria for Health Hazard Classification
•Acute toxicity
Corrosivity/Irritation (skin and eye)
•Corrosivity/Irritation
•Sensitisation (respiratory/dermal)
•CMR
•Specific Target Organ Toxicity and Aspiration
CLP Annex I, Part 3
Acute toxicity: substances
Category
g y1
Category
g y2
Category
g y3
Category
g y4
Oral
((mg/kg
g g bw))
ATE ≤ 5
5 < ATE ≤ 50
50 < ATE ≤ 300
300 < ATE ≤ 2000
Dermal
(mg/kg/bw)
ATE ≤ 50
50 < ATE ≤ 200
200 < ATE ≤ 1000
1000 < ATE ≤ 2000
Gases
(ppmV)
ATE ≤ 100
100< ATE ≤ 500
500 < ATE ≤ 2500
2500 < ATE ≤ 20000
Vapours
(mg/l)
ATE ≤ 0,5
0,5 < ATE ≤ 2.0
2,0 < ATE ≤ 10,0
10,0 < ATE ≤ 20,0
Dust/mists
(mg/l)
ATE ≤ 0,05
0,05 < ATE ≤ 0,5
0,5 < ATE ≤ 1,0
1,0 < ATE ≤ 5,0
Inh
halation
Exposure
p
Route
ATE = acute toxicity estimate
Classification of a mixture based on the acute
toxicity of the ingredients
1) Data available for all ingredients
100
ATEmixture
Ci
i
n
ATEi
=∑
n
Ci
ATEi
= concentration of ingredient ”i” (% w/w or % v/v)
= the individual ingredient from 1 to n
= the number of ingredients
= Acute Toxicity Estimate of ingredient ”i”
Classification of a mixture for acute toxicity
Concentration
ATE
Substance 1
1%
225 mg/kg
Substance 2
3%
100 mg/kg
Substance 3
10%
50 – 300 mg/kg
Water
76%
Classification
acute tox,
tox cat 3
Conversion from range value/category to point estimate
Exposure Route
Category or
experimental estimate
Converted point
estimate
0,5
5
100
500
Dermal (mg/kg/bw)
0 < category 1 ≤ 50
50 < category 2 ≤ 200
200 < category 3 ≤ 1000
1000 < category 4 ≤ 2000
5
50
300
1100
Gases
G
(ppmV)
0 < category
t
1 ≤ 100
100 < category 2 ≤ 500
500 < category 3 ≤ 2500
2500 < category 4 ≤ 20000
10
100
700
4500
Vapours
(mg/l)
0 < category 1 ≤ 0,5
0,5 < category 2 ≤ 2,0
2,0 < category 3 ≤ 10,0
10,0
, < category
g y 4 ≤ 20,0
,
0,05
0,5
3
11
Dust/mists (mg/l)
0 < category 1 ≤ 0,05
0,05 < category 2 ≤ 0,5
0,5 < category 3 ≤ 1,0
1 0 < category 4 ≤ 5
1,0
5,0
0
0,005
0,05
0,5
15
1,5
In
nhalation
n
Orall
O
(mg/kg bw)
0 < category 1 ≤ 5
5 < category 2 ≤ 50
50 < category 3 ≤ 300
300 < category 4 ≤ 2000
Classification of a mixture for acute toxicity
Concentration
ATE
Substance 1
1%
225 mg/kg
Substance 2
3%
100 mg/kg
Substance 3
10%
50 – 300
mg/kg
Water
76%
100
ATEmixture
100
ATEmixture
1
=
225
Ci
=∑ ATE
n
3
+
100
Classification
acute tox,
tox cat 3
P i t estimate:
Point
ti t 100
i
10
+
100
ATEmixture = 743
classification: acute tox, cat 4
Skin corrosive or irritant: substances
Corrosive* in ≥ 1 of 3 animals
category 1:
Corrosive
Subcategory
Exposure
Observation
1A
≤ 3 minutes
≤ 1 hour
1B
> 3 min to ≤ 1 hour
≤ 14 days
1C
> 1 hour to ≤ 4 hours
≤ 14 days
**visible
i ibl necrosis
i th
through
h th
the
epidermis and into the dermis
Skin corrosive or irritant: substances
Criteria
category 2:
Irritant
a)) M
Mean value
l off ≥2,3
≥2 3 - ≤ 4
4.0*
0* ffor erythema/eschar
th
/
h or for
f oedema
d
i att least
in
l
t
2 of 3 tested animals from gradings at 24, 48 or 72 hours after patch
removal or, if reactions are delayed, from grades in 3 consecutive days
after the onset of skin reactions;; or
b) Inflammation that persists to the end of the observation period normally
14 days in at least 2 animals, particularly taking into account alopecia
(limited area), hyperkeratosis, hyperplasia and scaling; or
c) In some cases where
here there is pronounced
prono nced variability
ariabilit of response among
animals, with very definite positive effects related to chemical exposure
in a single animal but less than the criteria above.
* Directive 67/548/EEC: mean value ≥ 2 (2 animals or more)
Skin corrosive or irritant: mixtures
Sum of ingredients
classified
l
ifi d as:
Skin Corrosive Categories
1A, 1B or 1C
Concentration triggering classification
of a mixture as:
Skin Corrosive
Category 1*
Skin Irritant
Category 2
≥ 5%
≥ 1% but < 5%
Skin Irritant Category 2
≥ 10%
(10 x Skin Corrosive Cat.
Cat 1A
1A,
1B or 1C) + Skin Irritant
Category 2
≥ 10%
*The sum of alla ingredients of a mixture classified as Skin Corrosive Category 1A, 1B or 1C
respectively, shall each be ≥ 5% respectively in order to classify the mixture as either Skin
Corrosive Category 1A, 1B or 1C.
If the sum of the Skin Corrosive Category 1A ingredients is < 5% but the sum of Category 1A+1B
ingredients is ≥ 5%, the mixture shall be classified as Skin Corrosive Category 1B.
If the sum of the Skin Corrosive Category 1A+1B ingredients is < 5% but the sum of of Category
1A+1B+1C ingredients is ≥ 5% the mixture shall be classified as Skin Corrosive Category 1C.
Skin corrosive or irritant: mixtures
Ingredient
Concentration
Mixture classified as:
Skin
Acid with pH ≤ 2
≥ 1%
Category 1
Base with pH ≥ 11,5%
≥ 1%
Category 1
Other corrosive (Cat. 1A, 1B or
1C) ingredients for which
additivity does not apply
≥ 1%
Category 1
Other irritant (Cat. 2) ingredients
for which additivity does not
apply, icluding acids and bases.
≥ 3%
Category 2
Serious eye damage/eye irritation:
substances
b t
Criteria
If when
If,
h applied
li d tto th
the eye off an animal,
i l a substance
b t
produces:
d
•
Category 1:
Irreversible
•
effects on
the eye
At least in one animal effects on the cornea, iris or conjunctiva that are not
expected
p
to reverse or have not fully
y reversed within an observation
period of normally 21 days; and/or
At least in 2 of 3 tested animals, a positve response of:
• Corneal opacity ≥ 3 and/or
• iritis > 1
1,5
5
Calculated as the mean score following grading at 24, 48 and 72 hours after
instillation of the test material
Serious eye damage/eye irritation:
substances
b t
Criteria
If,, when applied
pp
to the eye
y of an animal,, a substance produces:
p
•
Category 2:
Irritating to
eyes
At least in 2 of 3 tested animals, a positive response of:
•
•
•
•
Corneal opacity ≥ 1* and/or
iritis > 1 and/or
conjunctival redness ≥ 2** and/or
conjunctival
j
oedema ((chemosis)) ≥ 2
Calculated as the mean score following grading at 24, 48 and 72 hours after
instillation of the test material, and which fully reverses within an
observation period of 21 days
days.
Directive 67/548/EEC: mean scores * ≥ 2 and ** ≥ 2,5
Effects on the eye:
y mixtures
Sum of ingredients classified as:
Eye Effects Category 1 or
Ski Corrosive
Skin
C
i Category
C t
1A 1B or 1C
1A,
Concentration triggering
classification of a mixture
as:
Irreversible Eye
Eff t
Effects
Category 1
Reversible Eye
Eff t
Effects
Category 2
≥ 3%
≥ 1% but < 3%
Eye Effects, Category 2
≥ 10%
(10 x Eye Effects Cat. 1) + Eye Effects Cat. 2
≥ 10%
Skin Corrosive Cat. 1A, 1B or 1C + Eye
Effects Cat. 1
10 x (Skin
(S
C
Corrosive
C 1A, 1B, 1C
Cat.
C + Eye
Effects Cat. 1) + Eye Effects Cat. 2
≥ 3%
≥ 1% but < 3%
≥ 10%
Effects on the eye:
y mixtures
Ingredient
Concentration
Mixture classified as:
Eye
Acid with pH ≤ 2
≥ 1%
Category 1
Base with pH ≥ 11,5%
≥ 1%
Category 1
Other corrosive (Cat. 1)
ingredients for which additivity
does not apply
≥ 1%
Category 1
Other irritant (Cat. 2) ingredients
for which additivity does not apply,
including acids and bases
≥ 3%
Category 2
Respiratory sensitisation: substances
Criteria
A substance is classified as a respiratory sensitizer:
Category 1
a) If there is evidence in humans that the substance can lead
to specific respiratory hypersensitivity, and/or
b) If there are positive results from an appropriate animal test*
S b t
Sub-category
1A
Substances showing a high frequency of occurrence in humans;
or a probability of occurrence of a high sensitization rate in
humans based on animal or other tests.
Severity of reaction may also be considered
Subcategory 1B
Substances showing a low to moderate frequency of occurrence
in humans; or a probability of occurrence of a low to
moderate sensitization rate in humans based on animal or
other tests.
Severity of reaction may also be considered
*presently there are no recognized and validated animal models available
20
Respiratory
p
y sensitisation: mixtures
Ingredient classified as:
Concentration triggering classification of
a mixture as:
Respiratory Sensitiser
Category
g y1
Solid/Liquid
Gas
≥ 0,1%*
≥ 0,1%*
≥ 1,0%**
≥ 0,2%**
Respiratory sensitiser
Sub-category 1A
≥ 0,1%
≥ 0,1%
Respiratory sensitiser
Sub-category 1B
≥ 1,0%
≥ 0,2%
Respiratory sensitiser
Categor 1
Category
*This concentration limit is generally used for the application of the special labelling requirements to protect already
sensitised
iti d iindividuals.
di id l A SDS is
i required
i d ffor th
the mixture
i t
containing
t i i an ingredient
i
di t above
b
thi
this concentration.
t ti
**This concentration limit is used to trigger classification of a mixture as a respiratory sensitiser.
21
Skin sensitisation: substances
Criteria
A substance
b t
is
i classified
l
ifi d as a skin
ki sensitiser:
iti
Category 1
a) If there is evidence in humans that the substance can lead
sensitisation byy skin contact in a substantial number of
persons, or
b) If there are positive results from an appropriate animal test
Sub-category 1A
Substances showing a high frequency of occurrence in humans
and/or a high potency in animals can be presumed to have
the potential to produce significant sensitisation in humans.
Severity of reaction may also be considered
Subcategory 1B
Substances showing a low to moderate frequency of occurrence
in humans and/or a low to moderate potency in animals can
be p
presumed to have the p
potential to p
produce sensitisation
in humans.
Severity of reaction may also be considered
22
Skin sensitisation: mixtures
Ingredient classified as:
Concentration triggering
gg
g
classification of a mixture
as:
Skin sensitiser
Category 1
Skin sensitiser
Category 1
≥ 0,1%*
≥ 1,0%**
1 0%**
Skin sensitiser
Sub-category 1A
≥ 0,1%
Skin sensitiser
Sub-category 1B
≥ 1,0%
*This concentration limit is generally used for the application of the special labelling requirements to protect already
sensitised
iti d iindividuals.
di id l A SDS is
i required
i d ffor th
the mixture
i t
containing
t i i an ingredient
i
di t above
b
thi
this concentration.
t ti
**This concentration limit is used to trigger classification of a mixture as a skin sensitiser.
23
Concentration limits for elicitation of components of a mixture*
Concentration limits for elicitation
Component classified as:
Respiratory sensitiser
Category 1
Solid/liquid
Gas
Respiratory sensitiser,
sensitiser Category 1
≥0
0,1%
1%
≥0
0,1%
1%
Respiratory sensitiser, Sub-category 1A
≥ 0,01%
≥ 0,01%
Respiratory sensitiser, Sub-category 1B
≥ 0,1%
≥ 0,1%
Skin sensitiser
Category 1
All physical states
Ski sensitiser,
Skin
iti
C t
Category
1
≥0
0,1%
1%
Skin sensitiser, Sub-category 1A
≥ 0,01%
Skin sensitiser, Sub-category 1B
≥ 0,1%
*These concentration limit for elicitation is used for the application the special labelling requirements to
protect already sensitised individuals. A SDS is required for the mixture containing a component above this
concentration.
For sensitising substances with specific concentration limit lower than 0,1%, the concentration limit for
elicitation should be set at one tenth of the specific concentration limit.
24
Germ cell mutagenicity: substances
Category
Category 1
Category 1A
Category 1B
Criteria
Substances known to induce heritable mutations or to be regarded as if they induce
heritable mutations in the germ cells of humans.
The classification in Category 1A is based om positive evidence from human
epidemiological studies.
Substances to be regarded as if they induce heritable mutations in the germ cells of
humans.
Classification in Category 1B is based on:
•
Positive result(s) from in vivo heritable germ cell mutagenicity tests in
mammals; or
•
Positive result(s) from in vivo somatic cell mutagenicity test in mammals, in
combination with some evidence that the substance has potential to cause
mutations to germ cells. It is possible to derive this supporting evidence from
mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the
ability of the substance or its metabolite(s) to interact with the genetic material
of g
germ cells;; or
•
Positive results from tests showing mutagenic effects in the germ cells of
humans, without demonstration of transmission to progeny; for example, an
increase in the frequency of aneploidy in sperm cells of exposed people.
Germ cell mutagenicity: substances
Category
Criteria
Substances which cause concern for humans owing to the possibility that they may
induce heritable mutations in the germ cells of humans
Category 2
The classification in Category 2 is based on:
•
Positive evidence obtained from experiments in mammals and/or in some
cases from in vitro experiments, obtained from:
•
Somatic cell mutagenicity tests in vivo, in mammals; or
•
Other in vivo somatic cell genotoxicity tests which are supported by
positive results from in vitro mutagenicity assays.
Substances which are positive in in vitro mammalian mutagenicity assays, and
which also show chemical structure activity relationship to known germ cell
mutagens, shall also be considered for classfication as category 2 mutagens.
Germ cell mutagenicity:
g
y mixtures
Ingredient
classified as:
Concentration limits triggering classification of a
mixture as:
Category
C
t
1A
mutagen
Category
C
t
1B
mutagen
Category
C
t
2
mutagen
≥ 0,1%
-
-
Category 1B
mutagen
-
≥ 0,1%
-
Category 2 mutagen
-
-
≥ 1,0%
Category 1A mutagen
Carcinogenicity: substances
Category
Category 1
Criteria
Known or p
presumed human carcinogens
g
A substance is classified in Category 1 for carcinogenicity on the basis of
epidemiological and/or animal data. A substance may be further distinguished
as:
Category 1A
Known to have carcinogenic potential for humans, classification is largely based on
human evidence, or
Category 1B
Presumed to have carcinogenic potential for humans, classification is largely based
on animal evidence
The classification in Category 1A and 1B is based on strength of evidence together with additional
considerations*. Such evidence may be derived from:
considerations
•
Human studies that establish a casual relationship between human exposure to a substance and the
development of cancer (known human carcinogen); or
•
Animal experiments for which there is sufficient** evidence to demonstrate animal carcinogenicity
(presumed human carcinogen)
In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human
carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together
with limited evidence of carcinogenicity in experimental animals
animals.
*CLP Annex I, section 3.6.2.2
**CLP Annex I, section 3.6.2.2.4
Carcinogenicity: substances
Category
Category 2
Criteria
Suspected human carcinogen
The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or
animal
i l studies,
t di
b t which
but
hi h is
i nott sufficiently
ffi i tl convincing
i i to
t place
l
th substance
the
b t
i Category
in
C t
1A or 1B
1B,
based on strength of evidence together with additional considerations*. Such evidence may be derived
either from limited** evidence of carcinogenicity in human studies or from limited evidence of
carcinogenicity in animal studies.
*CLP Annex I, section 3.6.2.2
**CLP Annex I, section 3.6.2.2.4
Carcinogenicity:
g
y mixtures
Ingredient
classified
as:
Concentration limits triggering classification of a
mixture as:
Category 1A
carcinogen
Category 1B
carcinogen
Category 2
carcinogen
Category 1A
carcinogen
≥ 0,1%
-
-
Category 1B
carcinogen
-
≥ 0,1%
-
Category
C
t
2
carcinogen
-
-
≥ 1,0%*
*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
Reproductive toxicity: substances
Category
Category 1
Criteria
Known or p
presumed human reproductive
p
toxicant
Substances are classified in Category 1 for reprodutive toxicity when they are
known to have produced an adverse effect on sexual function and fertility, or on
development,
p
in humans, or when there is evidence from animal studies,
possibly supplemented with other information, to provide a strong presumption
that the substance has the capacity to interfere with reproduction in humans.
The classification of a substance is further distinguished on the basis of
whether the evidence for classification is primarily
y from human data or from
animal data.
Category 1A
Known human reproductive toxicant, largely based on evidence from humans
Category 1B
Presumed human reproductive toxicant, largely based on data from animal studies.
Such data shall provide clear evidence of an adverse effect on sexual function
and fertility or on development in the absence of other toxic effects, or if
occuring together with other toxic effects the adverse effect on reproduction is
considered not to be a secondary non-specific consequence of other toxic
effects. However, when there is mechanistic information that raises doubt about
the relevance of the effect for humans, classification in Category 2 may be
more appropriate.
Reproductive toxicity: substances
Category
Category 2
Criteria
Suspected human reproductive toxicant
Substances are classified in Category 2 for reproductive toxicity when there is some evidence
from human or experimental animals, possibly supplemented with other information, of an
adverse effect on sexual function and fertility, or on development, and where the evidence
is not sufficiently convincing to place the substance in Category 1. If deficiencies in the
study make the quality of evidence less convincing,
convincing Category 2 could be the more
appropriate classification.
Such effects shall have been observed in the absence of other toxic effects, or if occuring
together with other toxic effects the adverse effect on reproduction is considered not to be
a secondary non-specific consequence of other toxic effects.
Lactation effects: substances
Effects on or via lactation
Effects on or via lactation are allocated to a separate single category. It is recognised that for
many substances there is no information on the potential to cause adverse effetcs on the
offspring via lactation. However, substances which are absorbed by women and have
been shown o interfere with lactation
lactation, or which may be present (including metablites) in
breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall
be classified and labelled to indicate this property hazardous to to breastfed babies. This
classifiaction can be assigned on:
a) Human evidence indicating a hazard to babies during the lactation period; and/or
b) Results of one or two generation studies in animals which provide clear evidence of
adverse effect in the offspring due to transfer in the milk or adverse effects on the quality
of the milk; and/or
c) Absorption, metabolism, distribution and excretion studies that indicate the likelihood that
the substance is present in potentially toxic levels in breast milk.
Reproductive
p
toxicity:
y mixtures
Ingredient
classified as:
Concentration limits triggering classification of a
mixture as:
Category 1A
reproductive
toxicant
Category 1B
reproductive
toxicant
Category 2
reproductive
toxicant
Effects on or
via lactation
Category 1A
reproductive toxicant
≥ 0,3%*
-
-
-
Category 1B
reproductive toxicant
-
≥0
0,3%
3%*
-
-
Category 2
reproductive toxicant
-
-
≥ 3,0%*
-
Effects on or via
lactation
-
-
-
≥ 0,3%*
*If a Cat. 1 or Cat. 2 reproductive toxicant or a substance classified for effects on or via
lactation is present in the mixture as an ingredient at a concentration >0,1%, a SDS
shall be available for the mixture upon request.
Dir 1999/45/EC: ≥ 0.5% [Cat 1 and 2] and ≥ 5% [Cat 3]
Specific target organ toxicity (STOT) – single
exposure: substances
b t
Category
Category 1
Criteria
Substances that have produced significant toxicity in humans or that, on the basis of
evidence from studies in experimental animals, can be presumed to have the
potential to produce significant toxicity in humans following single exposure.
Substances are classified in Category 1 for specific target organ toxicity (single exposure)
on the basis of:
a)
b)
C t
Category
2
Reliable and good quality evidence from human cases or epidemiological studies; or
Observations from appropriate studies in experimental animals in which significant
and/or severe toxic effects, of relevance to human health, were produced at generally
low exposure concentrations. Guidance dose/concentration values are provided in
CLP Annex I, section 3.8.2.1.9, to be used as part of weight-of-evidence evaluation.
Substances
S
bstances that
that, on the basis of e
evidence
idence from st
studies
dies in e
experimental
perimental animals can be
presumed to have the potential to be harmful to human health following single
exposure.
Substances are classified in Category 2 for specific target organ toxicity (single exposure)
on the basis of observations from appropriate studies in experimental animals in
which significant toxic effects, of relevance to human health, were produced at
generally moderate exposure concentrations. Guidance dose/concentration values
are provided in CLP Annex I, section 3.8.2.1.9, in order to help in classification.
In exceptional cases,
cases human evidence can also be used to place a substance in Category
2 (see CLP Annex I, section 3.8.2.1.6.)
Specific target organ toxicity (STOT) – single
exposure: substances
b t
Category
Category 3
Criteria
Transient target organ effects
This category only includes narcotic effects and respiratory tract irritation. These are
target organ effects for which a substance does not meet the criteria to be
classified in Categories 1 or 2 indicated above. These are effects which
adversly alter human function for a short duration after exposure and from
which humans may recover in a reasonable period without leaving significant
alteration of structure or function.
function Substances are classified specifically for
these effects as laid down in CLP Annex I, section 3.8.2.2
STOT SE: Guidance value ranges
Guidance value ranges for:*
Route
R
t off
exposure
U it
Units
Oral (rat)
mg/kg bw
C ≤ 300
300 < C ≤ 2000
Dermal
(rat or rabbit)
mg/kg bw
C ≤ 1000
1000 < C ≤ 2000
Inhalation
(rat) gas
ppmV/4h
C ≤ 2500
2500 < C ≤ 20000
mg/l/4h
g
C ≤ 10
10 < C ≤ 20
C ≤ 1,0
1,0 < C ≤ 5,0
Inhalation
( t) vapour
(rat)
Inhalation (rat)
dust/mist/fume
mg/l/4h
C t
Category
1
C t
Category
2
C t
Category
3
Guidance
values do not
apply (based
on human data)
*The guidance values are intended for guidance purposes to be used as part of the weight-of-evidence
approach and to assist in decision about classification. They are not intended as strict demarcation
values.
STOT SE: mixtures
Ingredient
classified
l
ifi d as:
Generic concentration limits
triggering
gg
g classification of the
mixture as:
Category 1
Category 2
Category 1 STOT
≥ 10%
1 0 ≤ C < 10%
1,0
Category 2 STOT
-
≥ 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
Supporting classification
Not supporting classification
•
•
•
•
•
Substance-related deaths
Major functional changes in the
central
ce
ta o
or pe
peripheral
p e a nervous
e ous
systems (sight, hearing, sense of
smell) or other organ systems (for
example the lung)
Severe disturbances (eg
haematological disturbances
suggesting that they are due to
decreased bone marrow
production of blood cells)
Severe organ damage, especially
heart, nervous system, stem cell
populations
•
•
•
•
Only change in body weight gain,
food consumption or water intake
Small changes (clin chem) which
are of doubtful or minimal
toxicological importance
Changes in organ weights with
no evidence of organ dysfuntion
Adaptive responses (enzyme
i d ti
induction,
liliver h
hypotrophy,
t h
macrophage migration in the lung)
Species-specific mechanism
STOT – repeated exposure: substances
Category
Category 1
Criteria
Substances that have produced significant toxicity in humans or that, on the basis of
evidence from studies in experimental animals, can be presumed to have the
potential to produce significant toxicity in humans following repeated exposure.
Substances are classified in Category 1 for specific target organ toxicity (repeated
exposure) on the basis of:
a)
b)
C t
Category
2
Reliable and good quality evidence from human cases or epidemiological studies; or
Observations from appropriate studies in experimental animals in which significant
and/or severe toxic effects, of relevance to human health, were produced at generally
low exposure concentrations. Guidance dose/concentration values are provided in
CLP Annex I, section 3.9.2.9, to be used as part of weight-of-evidence evaluation.
Substances
S
bstances that
that, on the basis of e
evidence
idence from st
studies
dies in e
experimental
perimental animals can be
presumed to have the potential to be harmful to human health following repeated
exposure.
Substances are classified in Category 2 for specific target organ toxicity (repeated
exposure) on the basis of observations from appropriate studies in experimental
animals in which significant toxic effects, of relevance to human health, were
produced at generally moderate exposure concentrations. Guidance
dose/concentration values are provided in CLP Annex I, section 3.9.2.9, in order to
help in classification
classification.
In exceptional cases, human evidence can also be used to place a substance in Category
2 (see CLP Annex I, section 3.9.2.6.)
STOT RE: Guidance value ranges
g
Guidance value ranges for:*
Route of
exposure
Units
Oral (rat)
mg/kg bw/day
C ≤ 10
10 < C ≤ 100
Dermall
D
(rat or rabbit)
mg/kg bw/day
C ≤ 20
20 < C ≤ 200
Inhalation
(rat) gas
ppmV/6h/day
C ≤ 50
50 < C ≤ 250
mg/l/6h/day
C ≤ 0,2
0,2 < C ≤ 1,0
C ≤ 0,02
0,02 < C ≤ 0,2
Inhalation
((rat)) vapour
p
Inhalation (rat)
dust/mist/fume
mg/l/6h/day
Category
g y1
Category
g y2
*The guidance values are intended for guidance purposes to be used as part of the weight-of-evidence
approach and to assist in decision about classification. They are not intended as strict demarcation
values.
STOT RE: mixtures
Ingredient
classified as:
Generic concentration limits
triggering
gg
g classification of the
mixture as:
Category 1
Category 2
Category 1 STOT
≥ 10%
1 0 ≤ C < 10%
1,0
Category 2 STOT
-
≥ 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
Aspiration hazard
Aspiration:
Entry of a liquid or solid chemical product directly through the oral or nasal
cavity, or from vomiting, into the trachea and lower respiratory system.
H
Hazard:
d
May result in chemical pneumonia, varying
degrees of pulmonary injury or death following
aspiration.
i ti
Data used for classification:




Human experience (e.g. workplace)
Structure-Activity Relationship (e.g. most hydrocarbons)
Phys/chem data (dynamic or kinematic viscosity)
Animal studies (limited value)
Aspiration toxicity
Category
Category 1
Criteria
Substances known to cause human aspiration toxicity hazards or to be regarded
as if they cause human aspiration toxicity hazard.
A substance is classified in Category 1:
a)
b)
Based on reliable and good quality human evidence, or
If it is a hydrocarbon and has a kinematic viscosity of ≤20,5 mm2/s, measured
at 40°C
A mixture which contains a total of ≥10% of a substance or substances classified in
Category 1, and has a kinematic viscosity of ≤20,5 mm2/s measured at vid 40°C, shall
be classified in Category 1.
In the case of a mixture which separates into two or more distinct layers, one of which
contains ≥10% of a substance classified in Category 1 and has a kinematic viscosity of
≤20,5 mm2/s measured at 40°C, then the entire mixture is classified in category 1.
Directive 67/548/EEC: < 7 x 10-6 m2/s (40 °C)
44
Transition from DSD to CLP will lead to
reclassification
l
ifi ti off some mixtures
i t
Mixture
DPD
CLP
1-5% of R34
substances
Not classified
(GCL 5%)
Skin irritant Cat. 2
(GCL 1%)
10-20% of R38
substances
Not classified
(GCL 20%)
Skin irritant Cat. 2
(GCL 10%)
1-3% of R41 or R34
substances
Not classified
(GCL 5%)
Eye irritant Cat.2
(GCL 1%)
3-5% of R41 or R34
substances
Not classified
(GCL 10%)
Serious eye damage Cat.1
(GCL 3%)
10-20% of R36
substances
Not classified
(GCL 20%)
Eye
y irritant Cat.2
(GCL 10%)
3-5% of R62 or R63
substances
Not classified
(GCL 5%)
Reproductive toxicant Cat.2
(GCL 3%)
0,3-0,5% of R60 or
R61 substances
Not classified
(GCL 0,5%)
Reproductive Toxicant Cat.1A/1B
(GCL 0,3%)
Environmental Hazards CLP
Hazard Class
Hazard Category
Hazardous to the aquatic environment
Acute hazard
Chronic (Long-term) hazard
1
1
Hazardous to the ozone layer
1
2
3
Note: GHS Categories Acute 2 and Acute 3 are not normally
used when considering packaged goods, (but for transport of
bulk quantities). Therefore, not part of the EU - Supply and Use
system.
+
4
Criteria for Environmental Hazard
Classification
•Hazardous to the aquatic environment
•Acute (short-term) hazard
•Long-term hazard
CLP Annex I, Part 4
•Hazardous
H
d
tto th
the ozone llayer
CLP Annex I, Part 5
Environmental hazards
• Acute (short-term) aquatic hazard
– The hazard of a chemical caused by its acute toxicity to an
organism during short-term
short term aquatic exposure to that chemical
chemical.
• Long-term
g
aquatic
q
hazard
– The hazard of a chemical caused by its chronic toxicity following
long-term exposure in the aquatic environment.
Note!
Acute & Long-term hazards ≠ Acute & chronic toxicity
Criteria for Acute ((short-term)) aquatic
q
hazard
Based on
ACUTE (or SHORT-TERM)
AQUATIC TOXICITY
Acute toxicity to
Fish
and/or
a
d/o
Crustacea
and/or
Aquatic plant
Lowest value ≤1 mg/l
CATEGORY:
ACUTE 1
Multiplying (M) factors
•
The classifier shall set an M-factor if a substance is classified as Acute1
•
Components classified as Acute 1 may have LC50 or EC50 values well
below 1 mg/l which influence the toxicity of a mixture and should be given
increased weight.
Acute toxicity
M factor
L(E)C50 value
0.1 < L(E)C50 ≤ 1
1
0.01 < L(E)C50  0.1
10
0 001 < L(E)C50  0.01
0.001
0 01
100
0.0001 < L(E)C50  0.001
1000
0.00001 < L(E)C50  0.0001
10000
(continue in factor 10 intervals)
M-factors
are used in the calculation
method for
f classification
f
off a
mixture
Long-term aquatic hazard
LACK OF RAPID
DEGRADABILITY
Biotic/Abiotic
BIOACCUMULATION
Actual or Potential
AQUATIC TOXICITY
Ch i (l
Chronic
(long-term)
t
) toxicity
t i it

The intrinsic property (of a chemical) to cause harm as a result of long
term exposure (in relation to the life-cycle of the organism)

Generally expressed in terms of:
- NOEC
((No Observed Effect Concentration),
),
- ECx
(x% effect concentration), Normally EC10
Sublethal endpoints e.g. Survival, growth and/or
reproduction
Note: Chronic toxicity data are often expensive to generate and
therefore usually less available than acute data.
Criteria for Long-term hazard
(categories Chronic 1-3)
1 3)
Adequate
q
chronic toxicity
y data
available
Non-rapidly
degradable (NRD)
substance
Category:
g y Chronic 1
NOEC or ECx  0,1
Category:
C
t
Ch
Chronic
i 2
0,1 < NOEC or ECx  1
Rapidly degradable
( ) substances
(RD)
Category:
g y Chronic 1
NOEC or ECx  0,01
Category: Chronic 2
0.01 < NOEC or ECx  0,1
Category: Chronic 3
0,1 < NOEC or ECx  1
When adequate chronic toxicity data is lacking,
differentiation is based on acute toxicity data
Acute toxicity
y to fish,,
crustacea or algae
≤1 mg/l
Long
g term aquatic
q
hazard category
LACK OF RAPID
DEGRADATION
CHRONIC 1
AND/OR
> 1 to ≤10 mg/l
> 10 to ≤100 mg/l
CHRONIC 2
BIOACCUMULATION
BCF ≥500
OR IF ABSENT,
OR,
ABSENT
LOG Kow ≥4
CHRONIC 3
M-factors
•
Components classified as Chronic 1 may have L(E)C50 values well below 1
mg/l and/or NOEC/ECx well below 0,1 mg/l which influence the toxicity of a
mixture and should be given increased weight.
Acute toxicity
M factor
Chronic toxicity
M factor
0.1 < L(E)C50 ≤ 1
1
0.01 < NOEC ≤ 0.1
NRDa
components
1
0.01 < L(E)C50  0.1
10
0.001 < NOEC ≤ 0.01
10
1
0.001 < L(E)C50  0.01
100
0.0001 < NOEC ≤ 0.001
100
10
( ) 50  0.001
0.0001 < L(E)C
1000
0.00001 < NOEC ≤ 0.0001
1000
100
0.00001 < L(E)C50  0.0001
10000
0.000001 < NOEC ≤ 0.00001
10000
1000
L(E)C50 value
NOEC value
RDb
components
-
(continue in factor 10 intervals)
(continue in factor 10 intervals)
a
Non-rapidly degradable
b
Rapidly degradable
Chronic category 4
• ‘Safety
Safety Net
Net’ Classification when standard criteria are not
met, but there is a concern
• Criteria not strictly defined, but one example: poorly
soluble substances that are:
NOT RAPIDLY
DEGRADABLE
+ BIOACCUMULATIVE
Classification of a mixture – summation method
Step 1: Mixture classified as Category Chronic 1 if
∑(Chronic Category 1 x M) ≥ 25%
Ingr. A
Ingr. B
Ingr. C
1%
10%
10%
100
75
Chronic 3
50
Chronic 2
25
Chronic 1, M1
Chronic 1,, M10
10% x 1 = 10%
1% x 10 = 10%
Chronic 1, M100
10% + 10% = 20%
20%, which
hi h iis < 25%
25%.
Hence, mixture is not classified as Chronic 1.
Classification of a mixture – summation method
Step 2: Mixture classified as Category Chronic 2 if
∑(Chronic Category 1 x M x 10) + ∑(Chronic Category 2) ≥ 25%
Ingr. A
Ingr. B
Ingr. C
1%
10%
10%
CHRONIC
CATEGORY 2
300
Chronic 3
Chronic 2
10%
Chronic 1, M1
200
10% x 1 x 10 = 100%
100
Chronic 1,, M10
1% x 10 x 10 = 100%
Chronic 1, M100
100% + 100% + 10% = 210%, which is ≥ 25%.
Hence, mixture is classified as Chronic 2.
Environmental Hazard
Hazardous to the ozone layer
Substances
•
if the available evidence concerning its properties and its predicted or
observed environmental fate and behaviour indicate that it may
present a danger to the structure and/or the functioning of the
stratospheric
p
ozone layer.
y
Mixtures
•
Concentration
Co
ce a o limit 0,
0,1%
%