Download:
pdf |
pdfAPPENDIX A – HEALTH HAZARD CRITERIA (MANDATORY)
A.0 GENERAL CLASSIFICATION CONSIDERATIONS
A.0.1
Classification
A.0.1.1
The term “hazard classification” is used to indicate that only the intrinsic
hazardous properties of chemicals are considered. Hazard classification incorporates three steps:
(a) identification of relevant data regarding the hazards of a chemical;
(b) subsequent review of those data to ascertain the hazards associated with the
chemical;
(c) determination of whether the chemical will be classified as hazardous and the
degree of hazard.
A.0.1.2
For many hazard classes, the criteria are semi-quantitative or qualitative and
expert judgment is required to interpret the data for classification purposes.
A.0.2
Available data, test methods and test data quality
A.0.2.1
There is no requirement for testing chemicals.
A.0.2.2
The criteria for determining health hazards are test method neutral, i.e., they do
not specify particular test methods, as long as the methods are scientifically validated
procedures.
A.0.2.3
The term “scientifically validated” refers to the process by which the reliability
and the relevance of a procedure are established for a particular purpose.
A.0.2.4
Existing test data are acceptable for classifying chemicals, although expert
judgment also may be needed for classification purposes.
A.0.2.5
The effect of a chemical on biological systems is influenced, by the physicochemical properties of the substance and/or ingredients of the mixture and the way in which
ingredient substances are biologically available. A chemical need not be classified when it can be
shown by conclusive experimental data from scientifically validated test methods that the
chemical is not biologically available.
A.0.2.6
For classification purposes, epidemiological data and experience on the effects of
chemicals on humans (e.g., occupational data, data from accident databases) shall be taken into
account in the evaluation of human health hazards of a chemical.
517
A.0.3
Classification based on weight of evidence
A.0.3.1
For some hazard classes, classification results directly when the data satisfy the
criteria. For others, classification of a chemical shall be determined on the basis of the total
weight of evidence using expert judgment. This means that all available information bearing on
the classification of hazard shall be considered together, including the results of valid in vitro
tests, relevant animal data, and human experience such as epidemiological and clinical studies
and well-documented case reports and observations.
A.0.3.2
The quality and consistency of the data shall be considered. Information on
chemicals related to the material being classified shall be considered as appropriate, as well as
site of action and mechanism or mode of action study results. Both positive and negative results
shall be assembled together in a single weight of evidence determination.
A.0.3.3
Positive effects which are consistent with the criteria for classification, whether
seen in humans or animals, shall normally justify classification. Where evidence is available
from both humans and animals and there is a conflict between the findings, the quality and
reliability of the evidence from both sources shall be evaluated in order to resolve the question of
classification. Reliable, good quality human data shall generally have precedence over other
data. However, even well-designed and conducted epidemiological studies may lack a sufficient
number of subjects to detect relatively rare but still significant effects, or to assess potentially
confounding factors. Therefore, positive results from well-conducted animal studies are not
necessarily negated by the lack of positive human experience but require an assessment of the
robustness, quality and statistical power of both the human and animal data.
A.0.3.4
Route of exposure, mechanistic information, and metabolism studies are pertinent
to determining the relevance of an effect in humans. When such information raises doubt about
relevance in humans, a lower classification may be warranted. When there is scientific evidence
demonstrating that the mechanism or mode of action is not relevant to humans, the chemical
should not be classified.
A.0.3.5
Both positive and negative results are assembled together in the weight of
evidence determination. However, a single positive study performed according to good scientific
principles and with statistically and biologically significant positive results may justify
classification.
A.0.4
Considerations for the classification of mixtures
A.0.4.1
For most hazard classes, the recommended process of classification of mixtures is
based on the following sequence:
(a) Where test data are available for the complete mixture, the classification of
the mixture will always be based on that data;
(b) Where test data are not available for the mixture itself, the bridging principles
designated in each health hazard chapter of this appendix shall be considered
for classification of the mixture;
518
For health hazards,
(c) If test data are not available for the mixture itself, and the available
information is not sufficient to allow application of the above-mentioned
bridging principles, then the method(s) described in each chapter for
estimating the hazards based on the information known will be applied to
classify the mixture (e.g., application of concentration limits).
A.0.4.2
An exception to the above order or precedence is made for Carcinogenicity, Germ
Cell Mutagenicity, and Reproductive Toxicity. For these three hazard classes, mixtures shall be
classified based upon information on the ingredient substances, unless on a case-by-case basis,
justification can be provided for classifying based upon the mixture as a whole. See chapters
A.5, A.6, and A.7 for further information on case-by-case bases.
A.0.4.3
Use of concentration limits
A.0.4.3.1
When classifying an untested mixture based on the hazards of its ingredients,
concentration limits for the classified ingredients of the mixture are used for several hazard
classes. While the adopted concentration limits adequately identify the hazard for most mixtures,
there may be some that contain hazardous ingredients at lower concentrations than the specified
concentration limits that still pose an identifiable hazard. There may also be cases where the
concentration limit is considerably lower than could be expected on the basis of an established
non-hazardous level for an ingredient.
A.0.4.3.2
If the classifier has information that the hazard of an ingredient will be evident
(i.e., it presents a health risk) below the specified concentration limit, the mixture containing that
ingredient shall be classified accordingly.
A.0.4.3.3
In exceptional cases, conclusive data may demonstrate that the hazard of an
ingredient will not be evident (i.e., it does not present a health risk) when present at a level above
the specified concentration limit(s). In these cases the mixture may be classified according to
those data. The data must exclude the possibility that the ingredient will behave in the mixture in
a manner that would increase the hazard over that of the pure substance. Furthermore, the
mixture must not contain ingredients that would affect that determination.
A.0.4.4
Synergistic or antagonistic effects
When performing an assessment in accordance with these requirements, the
evaluator must take into account all available information about the potential occurrence of
synergistic effects among the ingredients of the mixture. Lowering classification of a mixture to
a less hazardous category on the basis of antagonistic effects may be done only if the
determination is supported by sufficient data.
A.0.5
Bridging principles for the classification of mixtures where test data are not
available for the complete mixture
A.0.5.1
Where the mixture itself has not been tested to determine its toxicity, but there are
sufficient data on both the individual ingredients and similar tested mixtures to adequately
519
characterize the hazards of the mixture, these data shall be used in accordance with the following
bridging principles, subject to any specific provisions for mixtures for each hazard class. These
principles ensure that the classification process uses the available data to the greatest extent
possible in characterizing the hazards of the mixture.
A.0.5.1.1
Dilution
For mixtures classified in accordance with A.1 through A.10 of this Appendix, if
a tested mixture is diluted with a diluent that has an equivalent or lower toxicity classification
than the least toxic original ingredient, and which is not expected to affect the toxicity of other
ingredients, then:
(a) the new diluted mixture shall be classified as equivalent to the original tested
mixture; or
(b) for classification of acute toxicity in accordance with A.1 of this Appendix,
paragraph A.1.3.6 (the additivity formula) shall be applied.
A.0.5.1.2
Batching
For mixtures classified in accordance with A.1 through A.10 of this Appendix, the
toxicity of a tested production batch of a mixture can be assumed to be substantially equivalent
to that of another untested production batch of the same commercial product, when produced by
or under the control of the same manufacturer, unless there is reason to believe there is
significant variation such that the toxicity of the untested batch has changed. If the latter occurs,
a new classification is necessary.
A.0.5.1.3
Concentration of mixtures
For mixtures classified in accordance with A.1, A.2, A.3, A.8, A.9, or A.10 of this
Appendix, if a tested mixture is classified in Category 1, and the concentration of the ingredients
of the tested mixture that are in Category 1 is increased, the resulting untested mixture shall be
classified in Category 1.
A.0.5.1.4
Interpolation within one toxicity category
For mixtures classified in accordance with A.1, A.2, A.3, A.8, A.9, or A.10 of this
Appendix, for three mixtures (A, B and C) with identical ingredients, where mixtures A and B
have been tested and are in the same toxicity category, and where untested mixture C has the
same toxicologically active ingredients as mixtures A and B but has concentrations of
toxicologically active ingredients intermediate to the concentrations in mixtures A and B, then
mixture C is assumed to be in the same toxicity category as A and B.
A.0.5.1.5
Substantially similar mixtures
520
For mixtures classified in accordance with A.1 through A.10 of this Appendix,
given the following set of conditions:
(a) Where there are two mixtures:
(i)
(ii)
A + B;
C + B;
(b) the concentration of ingredient B is essentially the same in both mixtures;
(c) the concentration of ingredient A in mixture (i) equals that of ingredient C in
mixture (ii);
(d) and data on toxicity for A and C are available and substantially equivalent;
i.e., they are in the same hazard category and are not expected to affect the
toxicity of B; then
If mixture (i) or (ii) is already classified based on test data, the other mixture can
be assigned the same hazard category.
A.0.5.1.6
Aerosols
For mixtures classified in accordance with A.1, A.2, A.3, A.4, A.8, or A.9 of this
Appendix, an aerosol form of a mixture shall be classified in the same hazard category as the
tested, non-aerosolized form of the mixture, provided the added propellant does not affect the
toxicity of the mixture when spraying.
521
A.1 ACUTE TOXICITY
A.1.1
Definition
Acute toxicity refers to those adverse effects occurring following oral or dermal
administration of a single dose of a substance, or multiple doses given within 24 hours, or an
inhalation exposure of 4 hours.
A.1.2
Classification criteria for substances
A.1.2.1
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 cut-off criteria as shown
in Table A.1.1. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or
LC50 (inhalation) values or as acute toxicity estimates (ATE). See the footnotes following Table
A.1.1 for further explanation on the application of these values.
Table A.1.1: Acute toxicity hazard categories and acute toxicity estimate (ATE) values
defining the respective categories
Exposure route
Category 1
Category 2
Category 3
Category 4
Oral (mg/kg bodyweight)
see:
Notes (a)(b)
≤5
>5 and ≤ 50
>50 and ≤ 300
>300 and ≤ 2000
Dermal (mg/kg bodyweight)
see:
Notes (a)(b)
≤5
>50 and ≤ 200
>200 and ≤ 1000
> 1000 and ≤ 2000
≤ 100
>100 and ≤ 500
>500 and ≤ 2500
>2500 and ≤ 20000
≤ 0.5
>0.5 and ≤ 2.0
>2.0 and ≤ 10.0
>10.0 and ≤ 20.0
≤ 0.05
>0.05 and ≤ 0.5
>0.5 and ≤ 1.0
>1.0 and ≤ 5.0
Inhalation - Gases (ppmV)
see:
Note (a)
Note (b)
Note (c)
Inhalation - Vapors (mg/l)
see:
Note (a)
Note (b)
Note (c)
Note (d)
Inhalation –
Dusts and Mists (mg/l)
see:
Note (a)
Note (b)
Note (c)
Note:
Gases concentration are expressed in parts per million per volume (ppmV).
Notes to Table A.1.1:
(a) The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where
available ;
(b) The acute toxicity estimate (ATE) for the classification of a substance or ingredient in a mixture is derived
using:
(i) the LD50/LC50 where available. Otherwise,
522
(ii) the appropriate conversion value from Table 1.2 that relates to the results of a range test, or
(iii) the appropriate conversion value from Table 1.2 that relates to a classification category;
(c) Inhalation cut-off values in the table are based on 4 hour testing exposures. Conversion of existing
inhalation toxicity data which has been generated according to 1 hour exposure is achieved by dividing by
a factor of 2 for gases and vapors and 4 for dusts and mists;
(d) For some chemicals the test atmosphere may consist of a vapor which is near the gaseous phase. In these
cases, classification is based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV),
Category 3 (2500 ppmV), Category 4 (20000 ppmV).
The terms “dust”, “mist” and “vapor” are defined as follows:
(i) Dust: solid particles of a substance or mixture suspended in a gas (usually air);
(ii) Mist: liquid droplets of a substance or mixture suspended in a gas (usually air);
(iii) Vapor: the gaseous form of a substance or mixture released from its liquid or solid state.
A.1.2.3
The preferred test species for evaluation of acute toxicity by the oral and
inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal
toxicity. Test data already generated for the classification of chemicals under existing systems
should be accepted when reclassifying these chemicals under the harmonized system. When
experimental data for acute toxicity are available in several animal species, scientific judgment
should be used in selecting the most appropriate LD50 value from among scientifically validated
tests.
A.1.3
Classification criteria for mixtures
A.1.3.1
The approach to classification of mixtures for acute toxicity is tiered, and is
dependent upon the amount of information available for the mixture itself and for its ingredients.
The flow chart of Figure A.1.1 indicates the process that must be followed:
523
Figure A.1.1: Tiered approach to classification of mixtures for acute toxicity
Test data on the mixture as a whole
No
Sufficient data available on
similar mixtures to estimate
classification hazards
Yes
Yes
Apply bridging principles in 1.3.5
CLASSIFY
Apply formula in 1.3.6.1
CLASSIFY
Apply formula in 1.3.6.1
CLASSIFY
Apply formula in 1.3.6.1 (unknown
ingredients ≤ 10%) or
Apply formula in 1.3.6.2.3 (unknown
ingredients > 10%)
CLASSIFY
No
Available data for all
ingredients
Yes
No
Other data available to
estimate conversion values for
classification
Yes
No
Convey hazards of the known
ingredients
A.1.3.2
Classification of mixtures for acute toxicity can be carried out for each route of
exposure, but is only needed for one route of exposure as long as this route is followed
(estimated or tested) for all ingredients and there is no relevant evidence to suggest acute toxicity
by multiple routes. When there is relevant evidence of toxicity by multiple routes of exposure,
classification is to be conducted for all appropriate routes of exposure. All available information
shall be considered. The pictogram and signal word used shall reflect the most severe hazard
category; and all relevant hazard statements shall be used.
A.1.3.3
For purposes of classifying the hazards of mixtures in the tiered approach:
(a) The “relevant ingredients” of a mixture are those which are present in
concentrations ≥ 1% (weight/weight for solids, liquids, dusts, mists and
vapors and volume/volume for gases). If there is reason to suspect that an
ingredient present at a concentration < 1% will affect classification of the
mixture for acute toxicity, that ingredient shall also be considered relevant.
Consideration of ingredients present at a concentration < 1% is particularly
important when classifying untested mixtures which contain ingredients that
are classified in Category 1 and Category 2;
(b) Where a classified mixture is used as an ingredient of another mixture, the
actual or derived acute toxicity estimate (ATE) for that mixture is used when
calculating the classification of the new mixture using the formulas in
A.1.3.6.1 and A.1.3.6.2.3.
524
(c). If the converted acute toxicity point estimates for all ingredients of a
mixture are within the same category, then the mixture should be classified
in that category.
(d) When only range data (or acute toxicity hazard category information) are
available for ingredients in a mixture, they may be converted to point
estimates in accordance with Table A.1.2 when calculating the classification
of the new mixture using the formulas in A.1.3.6.1 and A.1.3.6.2.3.
A.1.3.4
Classification of mixtures where acute toxicity test data are available for the
complete mixture
Where the mixture itself has been tested to determine its acute toxicity, it is
classified according to the same criteria as those used for substances, presented in Table A.1.1. If
test data for the mixture are not available, the procedures presented below must be followed.
A.1.3.5
Classification of mixtures where acute toxicity test data are not available for
the complete mixture: bridging principles
A.1.3.5.1
Where the mixture itself has not been tested to determine its acute toxicity, but
there are sufficient data on both the individual ingredients and similar tested mixtures to
adequately characterize the hazards of the mixture, these data will be used in accordance with the
following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching,
Concentration of mixtures, Interpolation within one toxicity category, Substantially similar
mixtures, and Aerosols.
A.1.3.6
formula)
Classification of mixtures based on ingredients of the mixture (additivity
A.1.3.6.1
Data available for all ingredients
The acute toxicity estimate (ATE) of ingredients is considered as follows:
(a) Include ingredients with a known acute toxicity, which fall into any of the
acute toxicity categories;
(b) Ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);
(c) Ignore ingredients if the data available are from a limit dose test (at the upper
threshold for Category 4 for the appropriate route of exposure as provided in
Table A.1.1) and do not show acute toxicity.
Ingredients that fall within the scope of this paragraph are considered to be
ingredients with a known acute toxicity estimate (ATE). See note (b) to Table
A.1.1 and paragraph A.1.3.3 for appropriate application of available data to the
equation below, and paragraph A.1.3.6.2.3.”.
525
The ATE of the mixture is determined by calculation from the ATE values for all
relevant ingredients according to the following formula below for oral, dermal or inhalation
toxicity:
100
Ci
=∑
ATEmix n ATE
i
where:
Ci
=
concentration of ingredient i
n ingredients and i is running from 1 to n
ATEi =
Acute toxicity estimate of ingredient i.
A.1.3.6.2
Data are not available for one or more ingredients of the mixture
A.1.3.6.2.1 Where an ATE is not available for an individual ingredient of the mixture, but
available information provides a derived conversion value, the formula in A.1.3.6.1 may be
applied. This information may include evaluation of:
(a) Extrapolation between oral, dermal and inhalation acute toxicity estimates.
Such an evaluation requires appropriate pharmacodynamic and
pharmacokinetic data;
(b) Evidence from human exposure that indicates toxic effects but does not
provide lethal dose data;
(c) Evidence from any other toxicity tests/assays available on the substance that
indicates toxic acute effects but does not necessarily provide lethal dose data;
or
(d) Data from closely analogous substances using structure/activity relationships.
A.1.3.6.2.2 This approach requires substantial supplemental technical information, and a
highly trained and experienced expert, to reliably estimate acute toxicity. If sufficient
information is not available to reliably estimate acute toxicity, proceed to the provisions of
A.1.3.6.2.3.
A.1.3.6.2.3 In the event that an ingredient with unknown acute toxicity is used in a mixture at
a concentration ≥ 1%, the mixture cannot be attributed a definitive acute toxicity estimate. In
this situation the mixture is classified based on the known ingredients only. (Note: A statement
that × percent of the mixture consists of ingredient(s) of unknown toxicity is required on the
label and safety data sheet in such cases; see Appendix C, Allocation of Label Elements and
Appendix D, Safety Data Sheets.)
A.1.3.6.2.4 If the total concentration of the ingredient(s) with unknown acute toxicity is
≤ 10% then the formula presented in A.1.3.6.1 must be used. If the total concentration of the
ingredient(s) with unknown toxicity is > 10%, the formula presented in A.1.3.6.1 is corrected to
adjust for the total percentage of the unknown ingredient(s) as follows:
526
100 − (∑ C unknown if > 10% )
ATE mix
Ci
=∑
n ATE i
Table A.1.2:
Conversion from experimentally obtained acute toxicity range values
(or acute toxicity hazard categories) to acute toxicity point estimates for use in the formulas
for the classification of mixtures
Exposure routes
Oral
(mg/kg bodyweight )
Dermal
(mg/kg bodyweight)
Gases
(ppmV)
Vapors
(mg/l)
Dust/mist
(mg/l)
Note:
Classification category or experimentally obtained
acute toxicity range estimate
0
< Category 1
≤ 5
5
< Category 2 ≤ 50
50
< Category 3 ≤ 300
300
< Category 4 ≤ 2000
0
< Category 1 ≤ 50
50
< Category 2 ≤ 200
200
< Category 3 ≤ 1000
1000 < Category 4 ≤ 2000
0
< Category 1 ≤ 100
100
< Category 2 ≤ 500
500
< Category 3 ≤ 2500
2500 < Category 4 ≤ 20000
0
< Category 1 ≤ 0.5
0.5
< Category 2 ≤ 2.0
2.0
< Category 3 ≤ 10.0
10.0 < Category 4 ≤ 20.0
0
< Category 1 ≤ 0.05
0.05 < Category 2 ≤ 0.5
0.5
< Category 3 ≤ 1.0
1.0
< Category 4 ≤ 5.0
Gases concentration are expressed in parts per million per volume (ppmV).
527
Converted Acute Toxicity
point estimate
0.5
5
100
500
5
50
300
1100
10
100
700
4500
0.05
0.5
3
11
0.005
0.05
0.5
1.5
A.2 SKIN CORROSION/IRRITATION
A.2.1
Definitions
Skin corrosion is the production of irreversible damage to the skin; namely,
visible necrosis through the epidermis and into the dermis, following the application of a test
substance for up to 4 hours. .Corrosive reactions are typified by ulcers, bleeding, bloody scabs,
and, by the end of observation at 14 days, by discoloration due to blanching of the skin, complete
areas of alopecia, and scars. Histopathology should be considered to evaluate questionable
lesions.
Skin irritation is the production of reversible damage to the skin following the
application of a test substance for up to 4 hours.
A.2.2
Classification criteria for substances using test data
A.2.2.1
Corrosion
A.2.2.2
A single harmonized corrosion category is provided in Table A.2.1, using the
results of animal testing. A corrosive is a substance that produces destruction of skin tissue,
namely, visible necrosis through the epidermis and into the dermis, in at least 1 of 3 tested
animals after exposure up to a 4 hour duration. Corrosive reactions are typified by ulcers,
bleeding, bloody scabs and, by the end of observation at 14 days, by discoloration due to
blanching of the skin, complete areas of alopecia and scars. Histopathology should be
considered to discern questionable lesions.
A.2.2.3
Three sub-categories of Category 1 are provided in Table A.2.1, all of which will
be regulated as Category 1.
Table A.2.1: Skin corrosion category and sub-categories a
Category 1: Corrosive
Corrosive in ≥ 1 of 3 animals
Corrosive sub-categories
Exposure
a
Observation
1A
≤ 3 min
≤1h
1B
> 3 min ≤ 1 h
≤ 14 days
1C
>1h≤4h
≤ 14 days
The use of human data is discussed in Appendix A.0.2.6.
A.2.3
Irritation
A.2.3.1
A single irritant category (Category 2) is presented in the Table A.2.2. The major
criterion for the irritant category is that at least 2 tested animals have a mean score of ≥ 2.3 ≤ 4.0.
528
Table A.2.2
Skin irritation categorya
Criteria
Irritant
(Category 2)
a
(1) Mean value of ≥ 2.3 ≤ 4.0 for erythema/eschar or for oedema in at least 2 of 3 tested
animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are
delayed, from grades on 3 consecutive days after the onset of skin reactions; or
(2) 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
(3) In some cases where there is pronounced variability of response among animals, with
very definite positive effects related to chemical exposure in a single animal but less
than the criteria above.
The use of human data is discussed in Appendix A.0.
A.2.3.2
Animal irritant responses within a test can be quite variable, as they are with
corrosion. A separate irritant criterion accommodates cases when there is a significant irritant
response but less than the mean score criterion for a positive test. For example, a substance might
be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score
throughout the study, including lesions persisting at the end of an observation period of normally
14 days. Other responses could also fulfil this criterion. However, it should be ascertained that
the responses are the result of chemical exposure. Addition of this criterion increases the
sensitivity of the classification system.
A.2.3.3
Reversibility of skin lesions is another consideration in evaluating irritant
responses. When inflammation persists to the end of the observation period in 2 or more test
animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and
scaling, then a material should be considered to be an irritant.
A.2.4
Classification Criteria for Substances Using Other Data Elements
A.2.4.1
Several factors must be considered in determining the corrosion and irritation
potential of substances when no clear data exist for those substances:
•
Solid substances (powders) may become corrosive or irritant when moistened or
in contact with moist skin or mucous membranes.
•
Existing human experience and data including from single or repeated exposure
and animal observations and data shall be the first line of analysis, as they give
information directly relevant to effects on the skin.
•
In some cases enough information may be available from structurally related
compounds to make classification decisions.
•
pH extremes ≤ 2 and ≥ 11.5 may indicate skin effects, especially when buffering
capacity is known, although the correlation is not perfect. Generally, such agents
are expected to produce significant effects on the skin.
529
•
If a chemical is highly toxic by the dermal route, data from dermal testing for skin
irritation/corrosion may not be available since the amount of test substance to be
applied would considerably exceed the toxic dose and, consequently, would result
in the death of the animals.
•
In vitro alternatives that have been validated and accepted may also be used to
help make classification decisions.
All the above information that is available on a substance shall be evaluated.
Although information might be gained from the evaluation of single parameters within a tier (see
A.2.4), there is merit in considering the totality of existing information and making an overall
weight of evidence determination. This is especially true when there is information available on
some but not all parameters. Primary emphasis shall be placed upon existing human experience
and data, followed by animal experience and testing data, followed by other sources of
information, but case-by-case determinations are necessary.
A.2.4.2
A tiered approach to the evaluation of initial information shall be considered,
where applicable (Figure A.2.1), recognizing that all elements may not be relevant in certain
cases.
530
Figure A.2.1: Tiered evaluation of skin corrosion and irritation potential
Step
Parameter
Finding
Conclusion
1a
Existing human or animal
experience
Corrosive
Category 1
Irritant
Category 2
Not corrosive or
irritant
Not classified
Corrosive
Category 1
Irritant
Category 2
pH ≤ 2 or ≥ 11.5
Category 1
Positive response
Category 1
Positive response
Category 2
Not corrosive or no data
1b
Existing human or animal
experience
Not irritant or no data
1c
Existing human or animal
experience
No data
2a
Structure-activity relationships
Not corrosive or no data
2b
Structure-activity relationships
Not irritating or no data
3
pH with buffering (a)
Not pH extreme or no data
4
Valid and accepted in vitro
skin corrosion test
Negative response or no data
5
Valid and accepted in vitro
skin irritation test (b)
Negative response or no data
Not classified
(a) Measurement of pH alone may be adequate, but assessment of acid or alkali reserve is preferable; methods are
needed to assess buffering capacity;
(b) Presently there are no validated and accepted in vitro test methods for skin irritation.
A.2.5
Classification criteria for mixtures
A.2.5.1
Classification of mixtures when data are available for the complete mixture
531
A.2.5.1.1
A.2.4).
The mixture shall be classified using the criteria for substances (see A.2.2 to
A.2.5.2
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.2.5.2.1
Where the mixture itself has not been tested to determine its skin
irritation/corrosion, but there are sufficient data on both the individual ingredients and similar
tested mixtures to adequately characterize the hazards of the mixture, these data will be used in
accordance with the following bridging principles, as found in paragraph A.0.5 of this Appendix:
Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category,
Substantially similar mixtures, and Aerosols.
A.2.5.3
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.2.5.3.1
In order to make use of all available data for purposes of classifying the skin
irritation/corrosion hazards of mixtures, the following assumption has been made and is applied
where appropriate in the tiered approach:
The “relevant ingredients” of a mixture are those which are present in
concentrations ≥ 1% (w/w for solids, liquids, dusts, mists and vapors and v/v for gases), unless
there is a presumption (e.g. in the case of corrosive ingredients) that an ingredient present at a
concentration < 1% can still be relevant for classifying the mixture for skin irritation/corrosion.
A.2.5.3.2
In general, the approach to classification of mixtures as irritant or corrosive to
skin when data are available on the ingredients, but not on the mixture as a whole, is based on
the theory of additivity, such that each corrosive or irritant ingredient contributes to the overall
irritant or corrosive properties of the mixture in proportion to its potency and concentration. A
weighting factor of 10 is used for corrosive ingredients when they are present at a concentration
below the concentration limit for classification with Category 1, but are at a concentration that
will contribute to the classification of the mixture as an irritant. The mixture is classified as
corrosive or irritant when the sum of the concentrations of such ingredients exceeds a cut-off
value/concentration limit.
A.2.5.3.3
Table A.2.3 below provides the cut-off value/concentration limits to be used to
determine if the mixture is considered to be an irritant or a corrosive to the skin.
A.2.5.3.4
Particular care shall be taken when classifying certain types of chemicals such as
acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in
A.2.5.3.1 and A.2.5.3.2 might not work given that many of such substances are corrosive or
irritant at concentrations < 1%. For mixtures containing strong acids or bases the pH should be
used as classification criteria since pH will be a better indicator of corrosion than the
concentration limits of Table A.2.3. A mixture containing corrosive or irritant ingredients that
cannot be classified based on the additivity approach shown in Table A.2.3, due to chemical
characteristics that make this approach unworkable, should be classified as skin Category 1 if it
contains ≥ 1% of a corrosive ingredient and as skin Category 2 when it contains ≥ 3% of an
532
irritant ingredient. Classification of mixtures with ingredients for which the approach in Table
A.2.3 does not apply is summarized in Table A.2.4 below.
A.2.5.3.5
On occasion, reliable data may show that the skin corrosion/irritation of an
ingredient will not be evident when present at a level above the generic concentration cut-off
values mentioned in Tables 3.2.3 and 3.2.4. In these cases the mixture could be classified
according to those data (see Use of concentration limits, paragraph A.0.4.3 of this Appendix).
A.2.5.3.6
If there are data showing that (an) ingredient(s) may be corrosive or irritant at a
concentration of < 1% (corrosive) or < 3% (irritant), the mixture shall be classified accordingly
(see Use of concentration limits, paragraph A.0.4.3 of this Appendix).
Table A.2.3: Concentration of ingredients of a mixture classified as skin Category 1 or 2
that would trigger classification of the mixture as hazardous to skin (Category 1 or 2)
Concentration triggering classification of a mixture as:
Sum of ingredients
classified as:
Skin Category 1
Skin corrosive
Skin irritant
Category 1
Category 2
≥ 5%
≥ 1% but < 5%
Skin Category 2
≥ 10%
(10 × Skin Category 1) +
Skin Category 2
≥ 10%
Table A.2.4: Concentration of ingredients of a mixture for which the additivity approach
does not apply, that would trigger classification of the mixture as hazardous to skin
Concentration:
Mixture classified as:
Skin
Acid with pH ≤ 2
≥ 1%
Category 1
Base with pH ≥ 11.5
≥ 1%
Category 1
Other corrosive (Category 1)
ingredients for which additivity
does not apply
≥ 1%
Category 1
Other irritant (Category 2)
ingredients for which additivity
does not apply, including acids and
bases
≥ 3%
Category 2
Ingredient:
533
A.3 SERIOUS EYE DAMAGE /EYE IRRITATION
A.3.1
Definitions
Serious eye damage is the production of tissue damage in the eye, or serious
physical decay of vision, following application of a test substance to the anterior surface of the
eye, which is not fully reversible within 21 days of application.
Eye irritation is the production of changes in the eye following the application of
test substance to the anterior surface of the eye, which are fully reversible within 21 days of
application.
A.3.2
Classification criteria for substances using test data
A.3.2.1
Irreversible effects on the eye/serious damage to eyes (Category 1)
A single hazard category is provided in Table A.3.1, for substances that have the
potential to seriously damage the eyes. Category 1, irreversible effects on the eye, includes the
criteria listed below. These observations include animals with grade 4 cornea lesions and other
severe reactions (e.g. destruction of cornea) observed at any time during the test, as well as
persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and
interference with the function of the iris or other effects that impair sight. In this context,
persistent lesions are considered those which are not fully reversible within an observation
period of normally 21 days. Category 1 also contains substances fulfilling the criteria of corneal
opacity ≥ 3 or iritis > 1.5 detected in a Draize eye test with rabbits, because severe lesions like
these usually do not reverse within a 21-day observation period.
Table A.3.1: Irreversible eye effects a
An eye irritant Category 1 (irreversible effects on the eye) is a substance that produces:
(a)
at least in one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not
fully reversed within an observation period of normally 21 days; and/or
(b)
at least in 2 of 3 tested animals, a positive response of:
(i) corneal opacity ≥ 3; and/or
(ii) iritis > 1.5;
calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the substance.
a
The use of human data is discussed in paragraph A.0.2.6.
A.3.2.2
Reversible effects on the eye (Category 2)
A single category is provided in Table A.3.2 for substances that have the potential
to induce reversible eye irritation.
534
Table A.3.2: Reversible eye effects
An eye irritant Category 2A (irritating to eyes) is a substance that produces:
(a)
at least in 2 of 3 tested animals a positive response of:
(i) corneal opacity ≥ 1; and/or
(ii) iritis ≥ 1; and/or
(iii) conjunctival redness ≥ 2; and/or
(iv) conjunctival edema (chemosis) ≥ 2
calculated as the mean scores following grading at 24, 48 and 72 hours after installation of the substance, and
which fully reverses within an observation period of normally 21 days.
For those chemicals where there is pronounced variability among animal
responses, this information may be taken into account in determining the classification.
A.3.3
Classification Criteria for Substances Using Other Data Elements
A.3.3.1
A tiered evaluation scheme that combines pre-existing information on serious
ocular tissue damage and on eye irritation (including data relating to historical human or animal
experience) as well as considerations on structure-activity relationships (SAR) or structureproperty relationships (SPR) and the output of validated in vitro tests shall be used for substances
where no clear test data exist for those substances:
A.3.3.2
All existing information on a substance shall be reviewed and several factors
considered in determining the serious eye damage or irritation potential of substances:
•
Accumulated human and animal data shall be the first line of analysis, as it gives
information directly relevant to effects on the eye.
•
In some cases enough information may be available from structurally related
compounds to make hazard decisions.
•
Likewise, pH extremes like ≤ 2 and ≥ 11.5 may produce serious eye damage,
especially when associated with significant buffering capacity. Such agents are
expected to produce significant effects on the eyes.
•
Possible skin corrosion has to be evaluated prior to consideration of serious eye
damage/eye irritation in order to avoid testing for local effects on eyes with skin
corrosive substances.
•
In vitro alternatives that have been validated and accepted may be used to make
classification decisions.
A.3.3.3
All the above information that is available on a substance shall be evaluated.
Although information might be gained from the evaluation of single parameters within a tier,
there is merit in considering the totality of existing information and making an overall weight of
evidence determination. This is especially true when there is information available on some but
535
not all parameters. Generally, primary emphasis shall be placed upon expert judgment,
considering human experience with the substance, followed by the outcome of skin irritation
testing and of well validated alternative methods.
A.3.3.4
A tiered approach to the evaluation of initial information shall be considered
where applicable, recognizing that all elements may not be relevant in certain cases (Figure
A.3.1).
A.3.3.5
The proposed tiered testing approach provides good guidance on how to organize
existing information on a substance and to make a weight-of-evidence decision, where
appropriate, about hazard assessment and hazard classification.
536
Figure A.3.1: Evaluation strategy for serious eye damage and eye irritation
(see also Figure A.2.1)
Step
Parameter
Findings
Conclusions
1a
Data relating to historical
human or animal experience
Serious eye damage
Category 1
Eye irritant
Category 2
Skin corrosive
Category 1
No or No Evaluation
1b
Data relating to historical
human or animal experience
No or No Evaluation
1c
Data relating to historical
human or animal experience
Skin irritant
Category 2
No or No Evaluation
2a
Structure activity
relationships (SAR)
Severe damage to
eyes
Category 1
Eye irritant
Category 2
No or don’t know
2b
Structure activity
relationships (SAR)
No or No Evaluation
2c
Structure activity relationships
(SAR)
Skin corrosive
Category 1
pH ≥ 11.5 or pH ≤ 2
(considering acid or
alkaline reserve)
Category 1
Yes
Category 1
No or No Evaluation
3a
pH/acid or alkaline reserve
3b
2 < pH < 11.5
(no buffering potential)
4
Other information indicating the
material is a skin corrosive
No
(Cont’d on next page)
537
Figure A.3.1 (cont'd): Evaluation strategy for serious eye damage and eye irritation
(see also Figure A.2.1)
Step
Parameter
Findings
Conclusions
5
Is a valid in vitro test available
to assess severe damage to eyes
No
Go to step 6
5a
In vitro test for severe eye
irritation
Severe damage to eyes
Category 1
No
Not Classified
Eye irritant
Category 2
Not a severe eye irritant
6
Is a valid in vitro test for eye
irritation available
Yes
6a
In vitro eye irritation test
No indication of eye irritant
properties
Not Classified
Notes to Figure A.3.1:
Step 1a/b:
Data relating to historical human or animal experience: pre-existing information on eye irritation and
skin corrosion are shown separately because evaluation of skin corrosion has to be considered if there
is no information on local effects on eyes. Analysis of pre-existing experience with the substance may
identify serious eye damage, corrosion and irritation potential for both skin and eye effects:
(i) Step 1a - reliable determination of eye irritancy basing on human or animal experience - depends
on expert judgment: in most cases human experience is based on accidental events and thus, the
local effects detected after an accident have to be compared with classification criteria created for
evaluation of animal test data;
(ii) Step 1b - evaluation of data on skin corrosivity - skin corrosive substances shall be considered as
leading to serious damage to the eyes as well (Category 1).
Step 2a/b/c: SAR (Structure Activity Relationships) for eye irritation and skin corrosion are shown separately but in
reality would probably be done in parallel. Scientifically validated and accepted SAR approaches shall
be used. The SAR analysis may identify serious eye damage, corrosion and irritation potential for both
skin and eye effects:
(i) Step 2a - reliable determination of eye irritancy only by theoretical evaluations - in most cases it
will only be appropriate for substances that are homologous to agents with very well known
properties;
(ii) Step 2c - theoretical evaluation of skin corrosivity - skin corrosive substances shall be considered
as leading to serious damage to the eyes as well (Category 1).
Step 3: pH extremes like ≤ 2 and ≥ 11.5 may indicate strong local effects, especially in combination with
assessment of acid or alkaline reserve, substances exhibiting such physico-chemical properties should be
considered as leading to serious damage to eyes (Category 1).
Step 4: All attainable information shall be used, including human experience.
Step 5: These must be scientifically validated, alternative methods for the assessment of eye irritation/ or serious
damage to eyes (e.g. irreversible corneal opacity)
Step 6: At present this step seems not to be achievable in the near future. If such methods are developed, they must
be scientifically, validated alternative methods for the reliable assessment of (reversible) eye irritation.
538
A.3.4
Classification criteria for mixtures
A.3.4.1
Classification of mixtures when data are available for the complete mixture
A.3.4.1.1
The mixture will be classified using the criteria for substances, and taking into
account the testing and evaluation strategies used to develop data for these hazard classes.
A.3.4.1.2
Unlike other hazard classes, there are alternative tests available for skin
corrosivity of certain types of chemicals that can give an accurate result for classification
purposes, as well as being simple and relatively inexpensive to perform. When considering
testing of the mixture, manufacturers are encouraged to use a tiered weight of evidence strategy
as included in the criteria for classification of substances for skin corrosion and serious eye
damage and eye irritation to help ensure an accurate classification, as well as avoid unnecessary
animal testing. A mixture is considered to cause serious eye damage (Eye Category 1) if it has a
pH ≤ 2 or ≥ 11.5. If consideration of alkali/acid reserve suggests the substance or mixture may
not have the potential to cause serious eye damage despite the low or high pH value, then further
testing needs to be carried out to confirm this, preferably by use of an appropriate validated in
vitro test.
A.3.4.2
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.3.4.2.1
Where the mixture itself has not been tested to determine its skin corrosivity or
potential to cause serious eye damage or irritation, but there are sufficient data on both the
individual ingredients and similar tested mixtures to adequately characterize the hazards of the
mixture, these data will be used in accordance with the following bridging principles, as found in
paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation
within one toxicity category, Substantially similar mixtures, and Aerosols.
A.3.4.3
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.3.4.3.1
In order to make use of all available data for purposes of classifying the eye
irritation/serious eye damaging properties of the mixtures, the following assumption has been
made and is applied where appropriate in the tiered approach:
The “relevant ingredients” of a mixture are those which are present in
concentrations ≥ 1% (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless
there is a presumption (e.g., in the case of corrosive ingredients) that an ingredient present at a
concentration < 1% can still be relevant for classifying the mixture for eye irritation/serious eye
damage.
A.3.4.3.2
In general, the approach to classification of mixtures as eye irritant or seriously
damaging to the eye when data are available on the ingredients, but not on the mixture as a
whole, is based on the theory of additivity, such that each corrosive or irritant ingredient
contributes to the overall irritant or corrosive properties of the mixture in proportion to its
potency and concentration. A weighting factor of 10 is used for corrosive ingredients when they
are present at a concentration below the concentration limit for classification with Category 1,
539
but are at a concentration that will contribute to the classification of the mixture as an irritant.
The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the
concentrations of such ingredients exceeds a threshold cut-off value/concentration limit.
A.3.4.3.3
Table A.3.3 provides the cut-off value/concentration limits to be used to
determine if the mixture should be classified an irritant or a seriously damaging to the eye.
A.3.4.3.4
Particular care must be taken when classifying certain types of chemicals such as
acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in
A.3.4.3.1 and A.3.4.3.2 might not work given that many of such substances are corrosive or
irritant at concentrations < 1 %. For mixtures containing strong acids or bases, the pH should be
used as classification criteria (see A.3.4.1) since pH will be a better indicator of serious eye
damage than the concentration limits of Table A.3.3. A mixture containing corrosive or irritant
ingredients that cannot be classified based on the additivity approach applied in Table A.3.3 due
to chemical characteristics that make this approach unworkable, should be classified as Eye
Category 1 if it contains ≥ 1% of a corrosive ingredient and as Eye Category 2 when it contains ≥
3% of an irritant ingredient. Classification of mixtures with ingredients for which the approach
in Table A.3.3 does not apply is summarized in Table A.3.4.
A.3.4.3.5
On occasion, reliable data may show that the reversible/irreversible eye effects of
an ingredient will not be evident when present at a level above the generic cut-off
values/concentration limits mentioned in Tables A.3.3 and A.3.4. In these cases the mixture
could be classified according to those data (see also A.0.4.3 Use of concentration limits”). On
occasion, when it is expected that the skin corrosion/irritation or the reversible/irreversible eye
effects of an ingredient will not be evident when present at a level above the generic
concentration/cut-off levels mentioned in Tables A.3.3 and A.3.4, testing of the mixture may be
considered. In those cases, the tiered weight of evidence strategy should be applied as referred to
in section A.3.3, Figure A.3.1 and explained in detail in this chapter.
A.3.4.3.6
If there are data showing that (an) ingredient(s) may be corrosive or irritant at a
concentration of < 1% (corrosive) or < 3% (irritant), the mixture should be classified accordingly
(see also paragraph A.0.4.3,Use of concentration limits).
Table A.3.3: Concentration of ingredients of a mixture classified as skin Category 1 and/or
eye Category 1 or 2 that would trigger classification of the mixtures as hazardous to the eye
Concentration triggering classification of a mixture as
Irreversible eye effects
Reversible eye effects
Category 1
Category 2
≥ 3%
≥ 1% but < 3%
Sum of ingredients classified as
Eye or skin Category 1
Eye Category 2
≥ 10%
(10 × eye Category 1) + eye Category 2
≥ 10%
≥ 3%
Skin Category 1 + eye Category 1
10 × (skin Category 1 + eye Category 1) + eye
Category 2
≥ 1% but < 3%
≥ 10%
540
Table A.3.4: Concentration of ingredients of a mixture for which the additivity approach
does not apply, that would trigger classification of the mixture as hazardous to the eye
Ingredient
Concentration
Mixture classified as:
Eye
Acid with pH ≤ 2
≥ 1%
Category 1
Base with pH ≥ 11.5
≥ 1%
Category 1
Other corrosive (Category 1) ingredients for which additivity does
not apply
≥ 1%
Category 1
Other irritant (Category 2) ingredients for which additivity does
not apply, including acids and bases
≥ 3%
Category 2
541
A.4 RESPIRATORY OR SKIN SENSITIZATION
A.4.1
Definitions and general considerations
A.4.1.1
Respiratory sensitizer means a chemical that will lead to hypersensitivity of the airways
following inhalation of the chemical.
Skin sensitizer means a chemical that will lead to an allergic response following skin
contact.
A.4.1.2
For the purpose of this chapter, sensitization includes two phases: the first phase
is induction of specialized immunological memory in an individual by exposure to an allergen.
The second phase is elicitation, i.e., production of a cell-mediated or antibody-mediated allergic
response by exposure of a sensitized individual to an allergen.
A.4.1.3
For respiratory sensitization, the pattern of induction followed by elicitation
phases is shared in common with skin sensitization. For skin sensitization, an induction phase is
required in which the immune system learns to react; clinical symptoms can then arise when
subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a
consequence, predictive tests usually follow this pattern in which there is an induction phase, the
response to which is measured by a standardized elicitation phase, typically involving a patch
test. The local lymph node assay is the exception, directly measuring the induction response.
Evidence of skin sensitization in humans normally is assessed by a diagnostic patch test.
A.4.1.4
Usually, for both skin and respiratory sensitization, lower levels are necessary for
elicitation than are required for induction.
A.4.1.5
The hazard class “respiratory or skin sensitization” is differentiated into:
(a)
Respiratory sensitization; and
(b)
Skin sensitization
A.4.2
Classification criteria for substances
A.4.2.1
Respiratory sensitizers
A.4.2.1.1
Hazard categories
A.4.2.1.1.1 Effects seen in either humans or animals will normally justify classification in a
weight of evidence approach for respiratory sensitizers. Substances may be allocated to one of
the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the
criteria given in Table A.4.1 and on the basis of reliable and good quality evidence from human
cases or epidemiological studies and/or observations from appropriate studies in experimental
animals.
542
Table A.4.1: Hazard category and sub-categories for respiratory sensitizers
CATEGORY 1:
Respiratory sensitizer
A substance is classified as a respiratory sensitizer
(a) if there is evidence in humans that the substance can lead to specific
respiratory hypersensitivity and/or
1
(b) if there are positive results from an appropriate animal test.
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.1 Severity of reaction may also be considered.
Sub-category 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.1 Severity of reaction may also be considered.
A.4.2.1.2
Human evidence
A.4.2.1.2.1
Evidence that a substance can lead to specific respiratory hypersensitivity will normally
be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other
hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition
will have the clinical character of an allergic reaction. However, immunological mechanisms do not have
to be demonstrated.
A.4.2.1.2.2
When considering the human evidence, it is necessary that in addition to the evidence
from the cases, the following be taken into account:
A.4.2.1.2.3
(a)
the size of the population exposed;
(b)
the extent of exposure.
The evidence referred to above could be:
(a)
clinical history and data from appropriate lung function tests related to exposure to
the substance, confirmed by other supportive evidence which may include:
(i)
in vivo immunological test (e.g., skin prick test);
(ii)
in vitro immunological test (e.g., serological analysis);
(iii) studies that may indicate other specific hypersensitivity reactions where
immunological mechanisms of action have not been proven, e.g., repeated
low-level irritation, pharmacologically mediated effects;
1
At this writing, recognized and validated animal models for the testing of respiratory hypersensitivity are not
available. Under certain circumstances, data from animal studies may provide valuable information in a weight of
evidence assessment.
543
(iv) a chemical structure related to substances known to cause respiratory
hypersensitivity;
(b)
data from positive bronchial challenge tests with the substance conducted
according to accepted guidelines for the determination of a specific hypersensitivity
reaction.
A.4.2.1.2.4
Clinical history should include both medical and occupational history to determine a
relationship between exposure to a specific substance and development of respiratory hypersensitivity.
Relevant information includes aggravating factors both in the home and workplace, the onset and
progress of the disease, family history and medical history of the patient in question. The medical history
should also include a note of other allergic or airway disorders from childhood and smoking history.
A.4.2.1.2.5
The results of positive bronchial challenge tests are considered to provide sufficient
evidence for classification on their own. It is, however, recognized that in practice many of the
examinations listed above will already have been carried out.
A.4.2.1.3
Animal studies
A.4.2.1.3.1
Data from appropriate animal studies1 which may be indicative of the potential of a
2
substance to cause sensitization by inhalation in humans may include:
(a)
measurements of Immunoglobulin E (IgE) and other specific immunological
parameters, for example in mice;
(b)
specific pulmonary responses in guinea pigs.
A.4.2.2
Skin sensitizers
A.4.2.2.1
Hazard categories
Effects seen in either humans or animals will normally justify classification in a weight
of evidence approach for skin sensitizers. Substances may be allocated to one of the two sub-categories
1A or 1B using a weight of evidence approach in accordance with the criteria given in Table A.4.2 and on
the basis of reliable and good quality evidence from human cases or epidemiological studies and/or
observations from appropriate studies in experimental animals according to the guidance values provided
in A.4.2.2.2.1 and A.4.2.2.3.2 for sub-category 1A and in A.4.2.2.2.2 and A.4.2.2.3.3 for sub-category
1B.
A.4.2.2.1.1
1
At this writing, recognized and validated animal models for the testing of respiratory hypersensitivity are not
available. Under certain circumstances, data from animal studies may provide valuable information in a weight of
evidence assessment.
2
The mechanisms by which substances induce symptoms of asthma are not yet fully known. For preventative
measures, these substances are considered respiratory sensitizers. However, if on the basis of the evidence, it can
be demonstrated that these substances induce symptoms of asthma by irritation only in people with bronchial
hyperreactivity, they should not be considered as respiratory sensitizers.
544
Table A.4.2: Hazard category and sub-categories for skin sensitizers
CATEGORY 1:
Skin sensitizer
A substance is classified as a skin sensitizer
(a) if there is evidence in humans that the substance can lead to sensitization by
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
sensitization in humans. Severity of reaction may also be considered.
Sub-category 1B:
Substances showing a low to moderate frequency of occurrence in humans and/or
a low to moderate potency in animals can be presumed to have the potential to
produce sensitization in humans. Severity of reaction may also be considered.
A.4.2.2.2
Human evidence
A.4.2.2.2.1
Human evidence for sub-category 1A may include:
A.4.2.2.2.2
A.4.2.2.3
(a)
positive responses at ≤ 500 µg/cm2 (HRIPT, HMT – induction threshold);
(b)
diagnostic patch test data where there is a relatively high and substantial incidence
of reactions in a defined population in relation to relatively low exposure;
(c)
other epidemiological evidence where there is a relatively high and substantial
incidence of allergic contact dermatitis in relation to relatively low exposure.
Human evidence for sub-category 1B may include:
(a)
positive responses at > 500 µg/cm2 (HRIPT, HMT – induction threshold);
(b)
diagnostic patch test data where there is a relatively low but substantial incidence
of reactions in a defined population in relation to relatively high exposure;
(c)
other epidemiological evidence where there is a relatively low but substantial
incidence of allergic contact dermatitis in relation to relatively high exposure.
Animal studies
A.4.2.2.3.1
For Category 1, when an adjuvant type test method for skin sensitization is used, a
response of at least 30% of the animals is considered as positive. For a non-adjuvant Guinea pig test
method a response of at least 15% of the animals is considered positive. For Category 1, a stimulation
3
index of three or more is considered a positive response in the local lymph node assay.
3
Test methods for skin sensitization are described in OECD Guideline 406 (the Guinea Pig Maximization test and
the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided
that they are scientifically validated. The Mouse Ear Swelling Test (MEST), appears to be a reliable screening
test to detect moderate to strong sensitizers, and can be used, in accordance with professional judgment, as a first
stage in the assessment of skin sensitization potential.
545
A.4.2.2.3.2
A.4.3
Animal test results for sub-category 1A can include data with values indicated in Table
Table A.4.3: Animal test results for sub-category 1A
Assay
Criteria
Local lymph node assay
EC3 value ≤ 2%
Guinea pig maximization test
≥ 30% responding at ≤ 0.1% intradermal induction dose or
≥ 60% responding at > 0.1% to ≤ 1% intradermal induction dose
Buehler assay
≥15% responding at ≤ 0.2% topical induction dose or
≥ 60% responding at > 0.2% to ≤ 20% topical induction dose
A.4.2.2.3.3
A.4.4 below:
Animal test results for sub-category 1B can include data with values indicated in Table
Table A.4.4: Animal test results for sub-category 1B
Assay
Criteria
Local lymph node assay
EC3 value > 2%
Guinea pig maximization
test
≥ 30% to < 60% responding at > 0.1% to ≤ 1% intradermal induction dose
or
≥ 30% responding at > 1% intradermal induction dose
Buehler assay
≥ 15% to < 60% responding at > 0.2% to ≤ 20% topical induction dose or
≥ 15% responding at > 20% topical induction dose
A.4.2.2.4
Specific considerations
A.4.2.2.4.1
For classification of a substance, evidence should include any or all of the following
using a weight of evidence approach:
(a)
Positive data from patch testing, normally obtained in more than one dermatology
clinic;
(b)
Epidemiological studies showing allergic contact dermatitis caused by the
substance. Situations in which a high proportion of those exposed exhibit
characteristic symptoms are to be looked at with special concern, even if the
number of cases is small;
(c)
Positive data from appropriate animal studies;
(d)
Positive data from experimental studies in man (see paragraph A.0.2.6 of this
Appendix);
(e)
Well documented episodes of allergic contact dermatitis, normally obtained in
more than one dermatology clinic;
(f)
Severity of reaction may also be considered.
546
A.4.2.2.4.2
Evidence from animal studies is usually much more reliable than evidence from human
exposure. However, in cases where evidence is available from both sources, and there is conflict between
the results, the quality and reliability of the evidence from both sources must be assessed in order to
resolve the question of classification on a case-by-case basis. Normally, human data are not generated in
controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk
assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin
sensitization are usually derived from case-control or other, less defined studies. Evaluation of human
data must, therefore, be carried out with caution as the frequency of cases reflect, in addition to the
inherent properties of the substances, factors such as the exposure situation, bioavailability, individual
predisposition and preventive measures taken. Negative human data should not normally be used to
negate positive results from animal studies. For both animal and human data, consideration should be
given to the impact of vehicle.
A.4.2.2.4.3
If none of the above-mentioned conditions are met, the substance need not be classified as
a skin sensitizer. However, a combination of two or more indicators of skin sensitization, as listed below,
may alter the decision. This shall be considered on a case-by-case basis.
A.4.2.2.4.4
(a)
Isolated episodes of allergic contact dermatitis;
(b)
Epidemiological studies of limited power, e.g., where chance, bias or confounders
have not been ruled out fully with reasonable confidence;
(c)
Data from animal tests, performed according to existing guidelines, which do not
meet the criteria for a positive result described in A.4.2.2.3, but which are
sufficiently close to the limit to be considered significant;
(d)
Positive data from non-standard methods;
(e)
Positive results from close structural analogues.
Immunological contact urticaria
A.4.2.2.4.4.1 Substances meeting the criteria for classification as respiratory sensitizers may, in
addition, cause immunological contact urticaria. Consideration shall be given to classifying these
substances as skin sensitizers.
A.4.2.2.4.4.2 Substances which cause immunological contact urticaria without meeting the criteria for
respiratory sensitizers shall be considered for classification as skin sensitizers.
A.4.2.2.4.4.3 There is no recognized animal model available to identify substances which cause
immunological contact urticaria. Therefore, classification will normally be based on human evidence,
similar to that for skin sensitization.
A.4.3
Classification criteria for mixtures
A.4.3.1
Classification of mixtures when data are available for the complete mixture
When reliable and good quality evidence, as described in the criteria for substances, from
human experience or appropriate studies in experimental animals, is available for the mixture, then the
mixture can be classified by weight of evidence evaluation of these data. Care must be exercised in
evaluating data on mixtures that the dose used does not render the results inconclusive.
547
A.4.3.2
Classification of mixtures when data are not available for the complete mixture:
bridging principles
A.4.3.2.1
Where the mixture itself has not been tested to determine its sensitizing properties, but
there are sufficient data on both the individual ingredients and similar tested mixtures to adequately
characterize the hazards of the mixture, these data will be used in accordance with the following agreed
bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of
mixtures, Interpolation, Substantially similar mixtures, and Aerosols.
A.4.3.3
Classification of mixtures when data are available for all ingredients or only for
some ingredients of the mixture
The mixture shall be classified as a respiratory or skin sensitizer when at least one
ingredient has been classified as a respiratory or skin sensitizer and is present at or above the appropriate
cut-off value/concentration limit for the specific endpoint as shown in Table A.4.5.
Table A.4.5: Cut-off values/concentration limits of ingredients of a mixture classified as either
respiratory sensitizers or skin sensitizers that would trigger classification of the mixture
Ingredient classified as:
Cut-off values/concentration limits
triggering classification of a mixture as:
Respiratory sensitizer
Category 1
Solid/Liquid
Gas
Respiratory sensitizer
Category 1
≥ 0.1%
≥ 0.1%
Respiratory sensitizer
Sub-category 1A
≥ 0.1%
≥ 0.1%
Respiratory sensitizer
Sub-category 1B
≥ 1.0%
≥ 0.2%
Skin sensitizer
Category 1
All physical states
Skin sensitizer
Category 1
≥ 0.1%
Skin sensitizer
Sub-category 1A
≥ 0.1%
Skin sensitizer
Sub-category 1B
≥ 1.0%
548
A.5 GERM CELL MUTAGENICITY
A.5.1
Definitions and general considerations
A.5.1.1
A mutation is defined as a permanent change in the amount or structure of the
genetic material in a cell. The term mutation applies both to heritable genetic changes that may
be manifested at the phenotypic level and to the underlying DNA modifications when known
(including, for example, specific base pair changes and chromosomal translocations). The term
mutagenic and mutagen will be used for agents giving rise to an increased occurrence of
mutations in populations of cells and/or organisms.
A.5.1.2
The more general terms genotoxic and genotoxicity apply to agents or processes
which alter the structure, information content, or segregation of DNA, including those which
cause DNA damage by interfering with normal replication processes, or which in a nonphysiological manner (temporarily) alter its replication. Genotoxicity test results are usually
taken as indicators for mutagenic effects.
A.5.1.3
This hazard class is primarily concerned with chemicals that may cause mutations
in the germ cells of humans that can be transmitted to the progeny.
However,
mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also
considered in classifying substances and mixtures within this hazard class.
A.5.2
Classification criteria for substances
A.5.2.1
The classification system provides for two different categories of germ cell
mutagens to accommodate the weight of evidence available. The two-category system is
described in the Figure A.5.1.
549
Figure A.5.1: Hazard categories for germ cell mutagens
CATEGORY 1:
Substances known to induce heritable mutations or to be regarded as if they induce
heritable mutations in the germ cells of humans
Category 1A:
Substances known to induce heritable mutations in germ cells of humans
Positive evidence from human epidemiological studies.
Category 1B:
Substances which should be regarded as if they induce heritable mutations in the germ
cells of humans
(a) Positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or
(b) Positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination
with some evidence that the substance has potential to cause mutations to germ cells. This
supporting evidence may, for example, be derived from mutagenicity/genotoxic 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 germ cells; or
(c) 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
aneuploidy in sperm cells of exposed people.
CATEGORY 2:
Substances which cause concern for humans owing to the possibility that they may induce
heritable mutations in the germ cells of humans
Positive evidence obtained from experiments in mammals and/or in some cases from in vitro
experiments, obtained from:
(a) Somatic cell mutagenicity tests in vivo, in mammals; or
(b) Other in vivo somatic cell genotoxicity tests which are supported by positive results from in
vitro mutagenicity assays.
Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which
also show chemical structure activity relationship to known germ cell mutagens, should
be considered for classification as Category 2 mutagens.
A.5.2.2
Specific considerations for classification of substances as germ cell mutagens:
A.5.2.2.1
To arrive at a classification, test results are considered from experiments
determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals.
Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered.
A.5.2.2.2
The system is hazard based, classifying chemicals on the basis of their intrinsic
ability to induce mutations in germ cells. The scheme is, therefore, not meant for the
(quantitative) risk assessment of chemical substances.
A.5.2.2.3
Classification for heritable effects in human germ cells is made on the basis of
scientifically validated tests.1 Evaluation of the test results shall be done using expert judgment
and all the available evidence shall be weighed for classification.
A.5.2.2.4
The classification of substances shall be based on the total weight of evidence
available, using expert judgment. In those instances where a single well-conducted test is used
for classification, it shall provide clear and unambiguously positive results. The relevance of the
550
route of exposure used in the study of the substance compared to the route of human exposure
should also be taken into account.
A.5.3
Classification criteria for mixtures 4
A.5.3.1
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.5.3.1.1
Classification of mixtures shall be based on the available test data for the
individual ingredients of the mixture using cut-off values/concentration limits for the ingredients
classified as germ cell mutagens.
A.5.3.1.2
The mixture will be classified as a mutagen when at least one ingredient has been
classified as a Category 1A, Category 1B or Category 2 mutagen and is present at or above the
appropriate cut-off value/concentration limit as shown in Table A.5.1 below for Category 1 and 2
respectively.
Table A.5.1: Cut-off values/concentration limits of ingredients of a mixture classified as
germ cell mutagens that would trigger classification of the mixture
Cut-off/concentration limits triggering classification of a mixture as:
Ingredient classified as:
Category 1 mutagen
Category 2 mutagen
Category 1A/B mutagen
≥ 0.1 %
-
-
≥ 1.0%
Category 2 mutagen
Note:
A.5.3.2
The cut-off values/concentration limits in the table above apply to solids and liquids (w/w units) as well as
gases (v/v units).
Classification of mixtures when data are available for the mixture itself
The classification may be modified on a case-by-case basis based on the available
test data for the mixture as a whole. In such cases, the test results for the mixture as a whole
must be shown to be conclusive taking into account dose and other factors such as duration,
observations and analysis (e.g. statistical analysis, test sensitivity) of germ cell mutagenicity test
systems.
A.5.3.3
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.5.3.3.1
Where the mixture itself has not been tested to determine its germ cell
mutagenicity hazard, but there are sufficient data on both the individual ingredients and similar
tested mixtures to adequately characterize the hazards of the mixture, these data will be used in
4
It should be noted that the classification criteria for the GHS usually include a tiered scheme in which test data
available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable
bridging principles, and lastly, cut-off values/concentration or additivity. However, this approach is not used for
Germ Cell Mutagenicity. These criteria for Germ Cell Mutagenicity consider the cut-off levels as the primary tier
and allow the classification to be modified only on a case-by-case evaluation based on available test data for the
mixture as a whole.
551
accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix:
Dilution, Batching, and Substantially similar mixtures.
Examples of in vivo heritable germ cell mutagenicity tests are:
•
•
•
Rodent dominant lethal mutation test (OECD 478)
Mouse heritable translocation assay (OECD 485)
Mouse specific locus test
Examples of in vivo somatic cell mutagenicity tests are:
•
•
•
Mammalian bone marrow chromosome aberration test (OECD 475)
Mouse spot test (OECD 484)
Mammalian erythrocyte micronucleus test (OECD 474)
Examples of mutagenicity/genotoxicity tests in germ cells are:
(a) Mutagenicity tests:
a. Mammalian spermatogonial chromosome aberration test (OECD 483)
b. Spermatid micronucleus assay
(b) Genotoxicity tests:
a. Sister chromatid exchange analysis in spermatogonia
b. Unscheduled DNA synthesis test (UDS) in testicular cells
Examples of genotoxicity tests in somatic cells are:
•
•
Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)
Mammalian bone marrow Sister Chromatid Exchanges (SCE)
Examples of in vitro mutagenicity tests are:
•
•
•
In vitro mammalian chromosome aberration test (OECD 473)
In vitro mammalian cell gene mutation test (OECD 476)
Bacterial reverse mutation tests (OECD 471)
As new, scientifically validated, tests arise, these may also be used in the total weight of
evidence to be considered.
552
A.6 CARCINOGENICITY
A.6.1
Definitions
Carcinogen means a substance or a mixture of substances which induce cancer or
increase its incidence. Substances and mixtures which have induced benign and malignant
tumors in well-performed experimental studies on animals are considered also to be presumed or
suspected human carcinogens unless there is strong evidence that the mechanism of tumor
formation is not relevant for humans.
Classification of a substance or mixture as posing a carcinogenic hazard is based
on its inherent properties and does not provide information on the level of the human cancer risk
which the use of the substance or mixture may represent.
A.6.2
Classification criteria for substances 5
A.6.2.1
For the purpose of classification for carcinogenicity, substances are allocated to
one of two categories based on strength of evidence and additional weight of evidence
considerations. In certain instances, route-specific classification may be warranted.
5
See Non-mandatory Appendix F for further guidance regarding hazard classification for carcinogenicity. This
appendix is consistent with the GHS and is provided as guidance excerpted from monographs of the International
Agency for Research on Cancer (IARC) Monographs programme on the evaluation of the strength and evidence
of carcinogenic risks to humans.
553
Figure A.6.1: Hazard categories for carcinogens
CATEGORY 1:
Known or presumed human carcinogens
The classification of a substance as a Category 1 carcinogen is done on the basis of
epidemiological and/or animal data. This classification is further distinguished on the basis of
whether the evidence for classification is largely from human data (Category 1A) or from
animal data (Category 1B):
Category 1A:
Known to have carcinogenic potential for humans. Classification in this category is largely
based on human evidence.
Category 1B:
Presumed to have carcinogenic potential for humans. Classification in this category is
largely based on animal evidence.
The classification of a substance in Category 1A and 1B is based on strength of evidence
together with weight of evidence considerations (see paragraph A.6.2.5). Such evidence may be
derived from:
- human studies that establish a causal 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 judgment 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.
CATEGORY 2:
Suspected human carcinogens
The classification of a substance in Category 2 is done on the basis of evidence obtained from
human and/or animal studies, but which is not sufficiently convincing to place the substance in
Category 1A or B. This classification is based on strength of evidence together with weight of
evidence considerations (see paragraph A.6.2.5). Such evidence may be from either limited
evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in
animal studies. Positive results in any carcinogenicity study performed according to good
scientific principles with statistically significant results qualifies for referencing the chemical as,
at the least a Category 2 carcinogen.
A.6.2.2
Classification as a carcinogen is made on the basis of evidence from reliable and
acceptable methods, and is intended to be used for substances which have an intrinsic property to
produce such toxic effects. The evaluations are to be based on all existing data, peer-reviewed
published studies and additional data accepted by regulatory agencies.
A.6.2.3
Carcinogen classification is a one-step, criterion-based process that involves two
interrelated determinations: evaluations of strength of evidence and consideration of all other
relevant information to place substances with human cancer potential into hazard categories.
A.6.2.4
Strength of evidence involves the enumeration of tumors in human and animal
studies and determination of their level of statistical significance. Sufficient human evidence
demonstrates causality between human exposure and the development of cancer, whereas
sufficient evidence in animals shows a causal relationship between the agent and an increased
incidence of tumors. Limited evidence in humans is demonstrated by a positive association
between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in
animals is provided when data suggest a carcinogenic effect, but are less than sufficient.
554
(Guidance on consideration of important factors in the classification of carcinogenicity and a
more detailed description of the terms “limited” and “sufficient” have been developed by the
International Agency for Research on Cancer (IARC) and are provided in Appendix F.)
A.6.2.5
Weight of evidence: Beyond the determination of the strength of evidence for
carcinogenicity, a number of other factors should be considered that influence the overall
likelihood that an agent may pose a carcinogenic hazard in humans. The full list of factors that
influence this determination is very lengthy, but some of the important ones are considered here.
A.6.2.5.1
These factors can be viewed as either increasing or decreasing the level of concern
for human carcinogenicity. The relative emphasis accorded to each factor depends upon the
amount and coherence of evidence bearing on each. Generally there is a requirement for more
complete information to decrease than to increase the level of concern. Additional considerations
should be used in evaluating the tumor findings and the other factors in a case-by-case manner.
A.6.2.5.2
Some important factors which may be taken into consideration, when assessing
the overall level of concern are:
(a) Tumor type and background incidence;
(b) Multisite responses;
(c) Progression of lesions to malignancy;
(d) Reduced tumor latency;
Additional factors which may increase or decrease the level of concern include:
(e) Whether responses are in single or both sexes;
(f) Whether responses are in a single species or several species;
(g) Structural similarity or not to a substance(s) for which there is good evidence
of carcinogenicity;
(h) Routes of exposure;
(i) Comparison of absorption, distribution, metabolism and excretion between
test animals and humans;
(j) The possibility of a confounding effect of excessive toxicity at test doses;
and,
(k) Mode of action and its relevance for humans, such as mutagenicity,
cytotoxicity with growth stimulation, mitogenesis, immunosuppression.
Mutagenicity: It is recognized that genetic events are central in the overall process
of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a
substance has a potential for carcinogenic effects.
555
A.6.2.5.3
A substance that has not been tested for carcinogenicity may in certain instances
be classified in Category 1A, Category 1B, or Category 2 based on tumor data from a structural
analogue together with substantial support from consideration of other important factors such as
formation of common significant metabolites, e.g., for benzidine congener dyes.
A.6.2.5.4
The classification should also take into consideration whether or not the substance
is absorbed by a given route(s); or whether there are only local tumors at the site of
administration for the tested route(s), and adequate testing by other major route(s) show lack of
carcinogenicity.
A.6.2.5.5
It is important that whatever is known of the physico-chemical, toxicokinetic and
toxicodynamic properties of the substances, as well as any available relevant information on
chemical analogues, i.e., structure activity relationship, is taken into consideration when
undertaking classification.
A.6.3
Classification criteria for mixtures 6
A.6.3.1
The mixture shall be classified as a carcinogen when at least one ingredient has
been classified as a Category 1 or Category 2 carcinogen and is present at or above the
appropriate cut-off value/concentration limit as shown in Table A.6.1.
Table A.6.1: Cut-off values/concentration limits of ingredients of a mixture classified as
carcinogen that would trigger classification of the mixture
Ingredient classified as:
Category 1 carcinogen
Category 1 carcinogen
Category 2 carcinogen
≥ 0.1 %
≥ 0.1% (note 1)
Category 2 carcinogen
Note 1: If a Category 2 carcinogen ingredient is present in the mixture at a concentration between 0.1% and 1%,
information is required on the SDS for a product, however, a label warning is optional If a Category 2
carcinogen ingredient is present in the mixture at a concentration of ≥ 1%, both an SDS and a label is
required and the information must be included on each.
A.6.3.2
Classification of mixtures when data are available for the complete mixture
A mixture may be classified based on the available test data for the mixture as a
whole. In such cases, the test results for the mixture as a whole must be shown to be conclusive
taking into account dose and other factors such as duration, observations and analysis (e.g.,
statistical analysis, test sensitivity) of carcinogenicity test systems.
A.6.3.3
Classification of mixtures when data are not available for the complete
mixture: bridging principles
6
It should be noted that the classification criteria for the GHS usually include a tiered scheme in which test data
available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable
bridging principles, and lastly, cut-off values/concentration or additivity. However, this approach is not used for
Carcinogenicity. These criteria for Carcinogenicity consider the cut-off levels as the primary tier and allow the
classification to be modified only on a case-by-case evaluation based on available test data for the mixture as a
whole.
556
Where the mixture itself has not been tested to determine its carcinogenic hazard,
but there are sufficient data on both the individual ingredients and similar tested mixtures to
adequately characterize the hazards of the mixture, these data will be used in accordance with the
following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution; Batching;
and Substantially similar mixtures.
557
A.7 REPRODUCTIVE TOXICITY
A.7.1
Definitions and general considerations
A.7.1.1
Reproductive toxicity includes adverse effects on sexual function and fertility in
adult males and females, as well as adverse effects on development of the offspring. Some
reproductive toxic effects cannot be clearly assigned to either impairment of sexual function and
fertility or to developmental toxicity. Nonetheless, chemicals with these effects shall be
classified as reproductive toxicants.
For classification purposes, the known induction of genetically based inheritable
effects in the offspring is addressed in Germ cell mutagenicity (see A.5).
A.7.1.2
Adverse effects on sexual function and fertility means any effect of chemicals that
interferes with reproductive ability or sexual capacity. This includes, but is not limited to,
alterations to the female and male reproductive system, adverse effects on onset of puberty,
gamete production and transport, reproductive cycle normality, sexual behaviour, fertility,
parturition, pregnancy outcomes, premature reproductive senescence, or modifications in other
functions that are dependent on the integrity of the reproductive systems.
A.7.1.3
Adverse effects on development of the offspring means any effect of chemicals
which interferes with normal development of the conceptus either before or after birth, which is
induced during pregnancy or results from parental exposure. These effects can be manifested at
any point in the life span of the organism. The major manifestations of developmental toxicity
include death of the developing organism, structural abnormality, altered growth and functional
deficiency.
A.7.1.4
Adverse effects on or via lactation are also included in reproductive toxicity, but
for classification purposes, such effects are treated separately (see A.7.2.1).
A.7.2
Classification criteria for substances
A.7.2.1
For the purpose of classification for reproductive toxicity, substances shall be
classified in one of two categories in accordance with Figure A.7.1(a). Effects on sexual function
and fertility, and on development, shall be considered. In addition, effects on lactation shall be
classified in a separate hazard category in accordance with Figure A.7.1(b).
558
Figure A.7.1 (a): Hazard categories for reproductive toxicants
CATEGORY 1:
Known or presumed human reproductive toxicant
Substance shall be classified in Category 1 for reproductive toxicity when they are known to
have produced an adverse effect on sexual function and fertility or on development 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 from human data (Category 1A) or
from animal data (Category 1B).
Category 1A:
Known human reproductive toxicant
The classification of a substance in this category is largely based on evidence from humans.
Category 1B:
Presumed human reproductive toxicant
The classification of a substance in this category is largely based on evidence from
experimental animals. Data from animal studies shall provide sufficient evidence of an
adverse effect on sexual function and fertility or on development in the absence of other toxic
effects, or if occurring 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.
CATEGORY 2:
Suspected human reproductive toxicant
Substances shall be classified in Category 2 for reproductive toxicity when there is some
evidence from humans or experimental animals, possibly supplemented with other
information, of an adverse effect on sexual function and fertility, or on development, in the
absence of other toxic effects, or if occurring together with other toxic effects the adverse
effect on reproduction is considered not to be a secondary non-specific consequence of the
other toxic effects, and where the evidence is not sufficiently convincing to place the
substance in Category 1. For instance, deficiencies in the study may make the quality of
evidence less convincing, and in view of this, Category 2 would be the more appropriate
classification.
Figure A.7.1 (b): Hazard category for effects on or via lactation
EFFECTS ON OR VIA LACTATION
Effects on or via lactation shall be classified in a separate single category. Chemicals that are absorbed by women
and have been shown to interfere with lactation or that may be present (including metabolites) in breast milk in
amounts sufficient to cause concern for the health of a breastfed child, shall be classified to indicate this property
hazardous to breastfed babies. This classification shall be assigned on the basis of:
(a) absorption, metabolism, distribution and excretion studies that indicate the likelihood the substance would
be present in potentially toxic levels in breast milk; 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 effect on the quality of the milk; and/or
(c) human evidence indicating a hazard to babies during the lactation period.
559
A.7.2.2
Basis of classification
A.7.2.2.1
Classification is made on the basis of the criteria, outlined above, an assessment of
the total weight of evidence, and the use of expert judgment. Classification as a reproductive
toxicant is intended to be used for substances which have an intrinsic, specific property to
produce an adverse effect on reproduction and substances should not be so classified if such an
effect is produced solely as a non-specific secondary consequence of other toxic effects.
A.7.2.2.2
In the evaluation of toxic effects on the developing offspring, it is important to
consider the possible influence of maternal toxicity.
A.7.2.2.3
For human evidence to provide the primary basis for a Category 1A classification
there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used
for classification shall be from well conducted epidemiological studies, if available, which
include the use of appropriate controls, balanced assessment, and due consideration of bias or
confounding factors. Less rigorous data from studies in humans may be sufficient for a Category
1A classification if supplemented with adequate data from studies in experimental animals, but
classification in Category 1B may also be considered.
A.7.2.3
Weight of evidence
A.7.2.3.1
Classification as a reproductive toxicant is made on the basis of an assessment of
the total weight of evidence using expert judgment. This means that all available information that
bears on the determination of reproductive toxicity is considered together. Included is
information such as epidemiological studies and case reports in humans and specific
reproduction studies along with sub-chronic, chronic and special study results in animals that
provide relevant information regarding toxicity to reproductive and related endocrine organs.
Evaluation of substances chemically related to the material under study may also be included,
particularly when information on the material is scarce. The weight given to the available
evidence will be influenced by factors such as the quality of the studies, consistency of results,
nature and severity of effects, level of statistical significance for intergroup differences, number
of endpoints affected, relevance of route of administration to humans and freedom from bias.
Both positive and negative results are assembled together into a weight of evidence
determination. However, a single, positive study performed according to good scientific
principles and with statistically or biologically significant positive results may justify
classification (see also A.7.2.2.3).
A.7.2.3.2
Toxicokinetic studies in animals and humans, site of action and mechanism or
mode of action study results may provide relevant information, which could reduce or increase
concerns about the hazard to human health. If it is conclusively demonstrated that the clearly
identified mechanism or mode of action has no relevance for humans or when the toxicokinetic
differences are so marked that it is certain that the hazardous property will not be expressed in
humans then a chemical which produces an adverse effect on reproduction in experimental
animals should not be classified.
A.7.2.3.3
In some reproductive toxicity studies in experimental animals the only effects
recorded may be considered of low or minimal toxicological significance and classification may
560
not necessarily be the outcome. These effects include, for example, small changes in semen
parameters or in the incidence of spontaneous defects in the fetus, small changes in the
proportions of common fetal variants such as are observed in skeletal examinations, or in fetal
weights, or small differences in postnatal developmental assessments.
A.7.2.3.4
Data from animal studies shall provide sufficient evidence of specific
reproductive toxicity in the absence of other systemic toxic effects. However, if developmental
toxicity occurs together with other toxic effects in the dam (mother), the potential influence of
the generalized adverse effects should be assessed to the extent possible. The preferred approach
is to consider adverse effects in the embryo/fetus first, and then evaluate maternal toxicity, along
with any other factors which are likely to have influenced these effects, as part of the weight of
evidence. In general, developmental effects that are observed at maternally toxic doses should
not be automatically discounted. Discounting developmental effects that are observed at
maternally toxic doses can only be done on a case-by-case basis when a causal relationship is
established or refuted.
A.7.2.3.5
If appropriate information is available it is important to try to determine whether
developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific
secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the
presence of maternal toxicity should not be used to negate findings of embryo/fetal effects,
unless it can be clearly demonstrated that the effects are secondary non-specific effects. This is
especially the case when the effects in the offspring are significant, e.g., irreversible effects such
as structural malformations. In some situations it is reasonable to assume that reproductive
toxicity is due to a secondary consequence of maternal toxicity and discount the effects, for
example if the chemical is so toxic that dams fail to thrive and there is severe inanition; they are
incapable of nursing pups; or they are prostrate or dying.
A.7.2.4
Maternal toxicity
A.7.2.4.1
Development of the offspring throughout gestation and during the early postnatal
stages can be influenced by toxic effects in the mother either through non-specific mechanisms
related to stress and the disruption of maternal homeostasis, or by specific maternally-mediated
mechanisms. So, in the interpretation of the developmental outcome to decide classification for
developmental effects it is important to consider the possible influence of maternal toxicity. This
is a complex issue because of uncertainties surrounding the relationship between maternal
toxicity and developmental outcome. Expert judgment and a weight of evidence approach, using
all available studies, shall be used to determine the degree of influence to be attributed to
maternal toxicity when interpreting the criteria for classification for developmental effects. The
adverse effects in the embryo/fetus shall be first considered, and then maternal toxicity, along
with any other factors which are likely to have influenced these effects, as weight of evidence, to
help reach a conclusion about classification.
A.7.2.4.2
Based on pragmatic observation, it is believed that maternal toxicity may,
depending on severity, influence development via non-specific secondary mechanisms,
producing effects such as depressed fetal weight, retarded ossification, and possibly resorptions
and certain malformations in some strains of certain species. However, the limited numbers of
studies which have investigated the relationship between developmental effects and general
561
maternal toxicity have failed to demonstrate a consistent, reproducible relationship across
species. Developmental effects which occur even in the presence of maternal toxicity are
considered to be evidence of developmental toxicity, unless it can be unequivocally
demonstrated on a case by case basis that the developmental effects are secondary to maternal
toxicity. Moreover, classification shall be considered where there is a significant toxic effect in
the offspring, e.g., irreversible effects such as structural malformations, embryo/fetal lethality, or
significant post-natal functional deficiencies.
A.7.2.4.3
Classification shall not automatically be discounted for chemicals that produce
developmental toxicity only in association with maternal toxicity, even if a specific maternallymediated mechanism has been demonstrated. In such a case, classification in Category 2 may be
considered more appropriate than Category 1. However, when a chemical is so toxic that
maternal death or severe inanition results, or the dams (mothers) are prostrate and incapable of
nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a
secondary consequence of maternal toxicity and discount the developmental effects.
Classification is not necessarily the outcome in the case of minor developmental changes, e.g., a
small reduction in fetal/pup body weight or retardation of ossification when seen in association
with maternal toxicity.
A.7.2.4.4
Some of the endpoints used to assess maternal toxicity are provided below. Data
on these endpoints, if available, shall be evaluated in light of their statistical or biological
significance and dose-response relationship.
(a) Maternal mortality: An increased incidence of mortality among the treated
dams over the controls shall be considered evidence of maternal toxicity if
the increase occurs in a dose-related manner and can be attributed to the
systemic toxicity of the test material. Maternal mortality greater than 10% is
considered excessive and the data for that dose level shall not normally be
considered to need further evaluation.
(b) Mating index (Number of animals with seminal plugs or sperm/Number of
mated × 100)
(c) Fertility index (Number of animals with implants/Number of matings × 100)
(d) Gestation length (If allowed to deliver)
(e) Body weight and body weight change: Consideration of the maternal body
weight change and/or adjusted (corrected) maternal body weight shall be
included in the evaluation of maternal toxicity whenever such data are
available. The calculation of an adjusted (corrected) mean maternal body
weight change, which is the difference between the initial and terminal body
weight minus the gravid uterine weight (or alternatively, the sum of the
weights of the fetuses), may indicate whether the effect is maternal or
intrauterine. In rabbits, the body weight gain may not be useful indicators of
maternal toxicity because of normal fluctuations in body weight during
pregnancy.
562
(f) Food and water consumption (if relevant): The observation of a significant
decrease in the average food or water consumption in treated dams (mothers)
compared to the control group may be useful in evaluating maternal toxicity,
particularly when the test material is administered in the diet or drinking
water. Changes in food or water consumption must be evaluated in
conjunction with maternal body weights when determining if the effects
noted are reflective of maternal toxicity or more simply, unpalatability of the
test material in feed or water.
(g) Clinical evaluations (including clinical signs, markers, and hematology and
clinical chemistry studies): The observation of increased incidence of
significant clinical signs of toxicity in treated dams (mothers) relative to the
control group is useful in evaluating maternal toxicity. If this is to be used as
the basis for the assessment of maternal toxicity, the types, incidence, degree
and duration of clinical signs shall be reported in the study. Clinical signs of
maternal intoxication include, but are not limited to: coma, prostration,
hyperactivity, loss of righting reflex, ataxia, or labored breathing.
(h) Post-mortem data: Increased incidence and/or severity of post-mortem
findings may be indicative of maternal toxicity. This can include gross or
microscopic pathological findings or organ weight data, including absolute
organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio.
When supported by findings of adverse histopathological effects in the
affected organ(s), the observation of a significant change in the average
weight of suspected target organ(s) of treated dams (mothers), compared to
those in the control group, may be considered evidence of maternal toxicity.
A.7.2.5
Animal and experimental data
A.7.2.5.1
A number of scientifically validated test methods are available, including methods
for developmental toxicity testing (e.g., OECD Test Guideline 414, ICH Guideline S5A, 1993),
methods for peri- and post-natal toxicity testing (e.g., ICH S5B, 1995), and methods for one or
two-generation toxicity testing (e.g., OECD Test Guidelines 415, 416)
A.7.2.5.2
Results obtained from screening tests (e.g., OECD Guidelines 421 - Reproduction/
Developmental Toxicity Screening Test, and 422 - Combined Repeated Dose Toxicity Study
with Reproduction/Development Toxicity Screening Test) can also be used to justify
classification, although the quality of this evidence is less reliable than that obtained through full
studies.
A.7.2.5.3
Adverse effects or changes, seen in short- or long-term repeated dose toxicity
studies, which are judged likely to impair reproductive function and which occur in the absence
of significant generalized toxicity, may be used as a basis for classification, e.g.,
histopathological changes in the gonads.
A.7.2.5.4
Evidence from in vitro assays, or non-mammalian tests, and from analogous
substances using structure-activity relationship (SAR), can contribute to the procedure for
563
classification. In all cases of this nature, expert judgment must be used to assess the adequacy of
the data. Inadequate data should not be used as a primary support for classification.
A.7.2.5.5
It is preferable that animal studies are conducted using appropriate routes of
administration which relate to the potential route of human exposure. However, in practice,
reproductive toxicity studies are commonly conducted using the oral route, and such studies will
normally be suitable for evaluating the hazardous properties of the substance with respect to
reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified
mechanism or mode of action has no relevance for humans or when the toxicokinetic differences
are so marked that it is certain that the hazardous property will not be expressed in humans then a
substance which produces an adverse effect on reproduction in experimental animals should not
be classified.
A.7.2.5.6
Studies involving routes of administration such as intravenous or intraperitoneal
injection, which may result in exposure of the reproductive organs to unrealistically high levels
of the test substance, or elicit local damage to the reproductive organs, e.g., by irritation, must be
interpreted with extreme caution and on their own are not normally the basis for classification.
A.7.2.5.7
There is general agreement about the concept of a limit dose, above which the
production of an adverse effect may be considered to be outside the criteria which lead to
classification. Some test guidelines specify a limit dose, other test guidelines qualify the limit
dose with a statement that higher doses may be necessary if anticipated human exposure is
sufficiently high that an adequate margin of exposure would not be achieved. Also, due to
species differences in toxicokinetics, establishing a specific limit dose may not be adequate for
situations where humans are more sensitive than the animal model.
A.7.2.5.8
In principle, adverse effects on reproduction seen only at very high dose levels in
animal studies (for example doses that induce prostration, severe inappetence, excessive
mortality) do not normally lead to classification, unless other information is available, for
example, toxicokinetics information indicating that humans may be more susceptible than
animals, to suggest that classification is appropriate.
A.7.2.5.9
However, specification of the actual “limit dose” will depend upon the test
method that has been employed to provide the test results.
A.7.3
Classification criteria for mixtures 7
A.7.3.1
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.7.3.1.1
The mixture shall be classified as a reproductive toxicant when at least one
ingredient has been classified as a Category 1 or Category 2 reproductive toxicant and is present
7
It should be noted that the classification criteria for the GHS usually include a tiered scheme in which test data
available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable
bridging principles, and lastly, cut-off values/concentration or additivity. However, this approach is not used for
Reproductive Toxicity. These criteria for Reproductive Toxicity consider the cut-off levels as the primary tier and
allow the classification to be modified only on a case-by-case evaluation based on available test data for the
mixture as a whole.
564
at or above the appropriate cut-off value/concentration limit specified in Table A.7.1 for
Category 1 and 2, respectively.
A.7.3.1.2
The mixture shall be classified for effects on or via lactation when at least one
ingredient has been classified for effects on or via lactation and is present at or above the
appropriate cut-off value/concentration limit specified in Table A.7.1 for the additional category
for effects on or via lactation.
Table A.7.1: Cut-off values/concentration limits of ingredients of a mixture classified as
reproductive toxicants or for effects on or via lactation that trigger classification of the
mixture
Ingredients classified as:
Category 1
reproductive toxicant
Cut-off values/concentration limits triggering classification of a mixture as:
Additional category
for effects on or via
Category 1
Category 2
reproductive toxicant reproductive toxicant
lactation
≥ 0.1%
Category 2
reproductive toxicant
≥ 0.1 %
Additional category for effects
on or via lactation
A.7.3.2
≥ 0.1 %
Classification of mixtures when data are available for the complete mixture
Available test data for the mixture as a whole may be used for classification on a
case-by-case basis. In such cases, the test results for the mixture as a whole must be shown to be
conclusive taking into account dose and other factors such as duration, observations and analysis
(e.g., statistical analysis, test sensitivity) of reproduction test systems.
A.7.3.3
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.7.3.3.1
Where the mixture itself has not been tested to determine its reproductive toxicity,
but there are sufficient data on both the individual ingredients and similar tested mixtures to
adequately characterize the hazards of the mixture, these data shall be used in accordance with
the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution,
Batching, and Substantially similar mixtures.
565
A.8 SPECIFIC TARGET ORGAN TOXICITY
SINGLE EXPOSURE
A.8.1
Definitions and general considerations
A.8.1.1
Specific target organ toxicity - single exposure, (STOT-SE) means specific, nonlethal target organ toxicity arising from a single exposure to a chemical. All significant health
effects that can impair function, both reversible and irreversible, immediate and/or delayed and
not specifically addressed in A.1 to A.7 and A.10 of this Appendix are included. Specific target
organ toxicity following repeated exposure is classified in accordance with SPECIFIC TARGET
ORGAN TOXICITY – REPEATED EXPOSURE (A.9 of this Appendix) and is therefore not
included here.
A.8.1.2
Classification identifies the chemical as being a specific target organ toxicant and,
as such, it presents a potential for adverse health effects in people who are exposed to it.
A.8.1.3
The adverse health effects produced by a single exposure include consistent and
identifiable toxic effects in humans; or, in experimental animals, toxicologically significant
changes which have affected the function or morphology of a tissue/organ, or have produced
serious changes to the biochemistry or hematology of the organism, and these changes are
relevant for human health. Human data is the primary source of evidence for this hazard class.
A.8.1.4
Assessment shall take into consideration not only significant changes in a single
organ or biological system but also generalized changes of a less severe nature involving several
organs.
A.8.1.5
Specific target organ toxicity can occur by any route that is relevant for humans,
i.e., principally oral, dermal or inhalation.
A.8.1.6
The classification criteria for specific organ systemic toxicity single exposure are
organized as criteria for substances Categories 1 and 2 (see A.8.2.1), criteria for substances
Category 3 (see A.8.2.2) and criteria for mixtures (see A.8.3). See also Figure A.8.1.
A.8.2
Classification criteria for substances
A.8.2.1
Substances of Category 1 and Category 2
A.8.2.1.1
Substances shall be classified for immediate or delayed effects separately, by the
use of expert judgment on the basis of the weight of all evidence available, including the use of
recommended guidance values (see A.8.2.1.9). Substances shall then be classified in Category 1
or 2, depending upon the nature and severity of the effect(s) observed, in accordance with Figure
A.8.1.
566
Figure A.8.1: Hazard categories for specific target organ toxicity following single exposure
CATEGORY 1:
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 STOT-SE on the basis of:
(a) reliable and good quality evidence from human cases or epidemiological studies; or
(b) 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 below (see
A.8.2.1.9) to be used as part of weight-of-evidence evaluation.
CATEGORY 2:
Substances that, on the basis of evidence from studies in experimental animals, can be
presumed to have the potential to be harmful to human health following single exposure
Substances are classified in Category 2 for STOT-SE 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 below (see A.8.2.1.9) in order to help in classification.
In exceptional cases, human evidence can also be used to place a substance in Category 2 (see
A.8.2.1.6).
CATEGORY 3:
Transient target organ effects
There 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 adversely 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. This category only
includes narcotic effects and respiratory tract irritation. Substances are classified specifically
for these effects as discussed in A.8.2.2.
Note:
The primary target organ organ/system shall be identified where possible, and where this is not possible,
the substance shall be identified as a general toxicant. The data shall be evaluated and, where possible,
shall not include secondary effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or
gastro-intestinal systems).
A.8.2.1.2
The relevant route(s) of exposure by which the classified substance produces
damage shall be identified.
A.8.2.1.3
Classification is determined by expert judgment, on the basis of the weight of all
evidence available including the guidance presented below.
A.8.2.1.4
Weight of evidence of all data, including human incidents, epidemiology, and
studies conducted in experimental animals is used to substantiate specific target organ toxic
effects that merit classification.
A.8.2.1.5
The information required to evaluate specific target organ toxicity comes either
from single exposure in humans, e.g., exposure at home, in the workplace or environmentally, or
from studies conducted in experimental animals. The standard animal studies in rats or mice that
provide this information are acute toxicity studies which can include clinical observations and
detailed macroscopic and microscopic examination to enable the toxic effects on target
567
tissues/organs to be identified. Results of acute toxicity studies conducted in other species may
also provide relevant information.
A.8.2.1.6
In exceptional cases, based on expert judgment, it may be appropriate to place
certain substances with human evidence of target organ toxicity in Category 2: (a) when the
weight of human evidence is not sufficiently convincing to warrant Category 1 classification,
and/or (b) based on the nature and severity of effects. Dose/concentration levels in humans shall
not be considered in the classification and any available evidence from animal studies shall be
consistent with the Category 2 classification. In other words, if there are also animal data
available on the substance that warrant Category 1 classification, the chemical shall be classified
as Category 1.
A.8.2.1.7
Effects considered to support classification for Category 1 and 2
A.8.2.1.7.1 Classification is supported by evidence associating single exposure to the
substance with a consistent and identifiable toxic effect.
A.8.2.1.7.2 Evidence from human experience/incidents is usually restricted to reports of
adverse health consequences, often with uncertainty about exposure conditions, and may not
provide the scientific detail that can be obtained from well-conducted studies in experimental
animals.
A.8.2.1.7.3 Evidence from appropriate studies in experimental animals can furnish much
more detail, in the form of clinical observations, and macroscopic and microscopic pathological
examination and this can often reveal hazards that may not be life-threatening but could indicate
functional impairment. Consequently all available evidence, and evidence relevance to human
health, must be taken into consideration in the classification process. Relevant toxic effects in
humans and/or animals include, but are not limited to:
(a) Morbidity resulting from single exposure;
(b) Significant functional changes, more than transient in nature, in the
respiratory system, central or peripheral nervous systems, other organs or
other organ systems, including signs of central nervous system depression
and effects on special senses (e.g., sight, hearing and sense of smell);
(c) Any consistent and significant adverse change in clinical biochemistry,
hematology, or urinalysis parameters;
(d) Significant organ damage that may be noted at necropsy and/or subsequently
seen or confirmed at microscopic examination;
(e) Multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital
organs with regenerative capacity;
(f) Morphological changes that are potentially reversible but provide clear
evidence of marked organ dysfunction; and,
568
(g) Evidence of appreciable cell death (including cell degeneration and reduced
cell number) in vital organs incapable of regeneration.
A.8.2.1.8
Effects considered not to support classification for Category 1 and 2
Effects may be seen in humans and/or animals that do not justify classification.
Such effects include, but are not limited to:
(a) Clinical observations or small changes in bodyweight gain, food consumption
or water intake that may have some toxicological importance but that do not,
by themselves, indicate “significant” toxicity;
(b) Small changes in clinical biochemistry, hematology or urinalysis parameters
and/or transient effects, when such changes or effects are of doubtful or of
minimal toxicological importance;
(c) Changes in organ weights with no evidence of organ dysfunction;
(d) Adaptive responses that are not considered toxicologically relevant; and,
(e) Substance-induced species-specific mechanisms of toxicity, i.e.,
demonstrated with reasonable certainty to be not relevant for human health,
shall not justify classification.
A.8.2.1.9
Guidance values to assist with classification based on the results obtained from
studies conducted in experimental animals for Category 1 and 2
A.8.2.1.9.1 In order to help reach a decision about whether a substance shall be classified or
not, and to what degree it shall be classified (Category 1 vs. Category 2), dose/concentration
“guidance values” are provided for consideration of the dose/concentration which has been
shown to produce significant health effects. The principal argument for proposing such guidance
values is that all chemicals are potentially toxic and there has to be a reasonable
dose/concentration above which a degree of toxic effect is acknowledged.
A.8.2.1.9.2 Thus, in animal studies, when significant toxic effects are observed that indicate
classification, consideration of the dose/concentration at which these effects were seen, in
relation to the suggested guidance values, provides useful information to help assess the need to
classify (since the toxic effects are a consequence of the hazardous property(ies) and also the
dose/concentration).
A.8.2.1.9.3 The guidance value (C) ranges for single-dose exposure which has produced a
significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in
Table A.8.1.
569
Table A.8.1: Guidance value ranges for single-dose exposures
Guidance value ranges for:
Route of exposure
Units
Category 1
Category 2
Oral (rat)
mg/kg body weight
C ≤ 300
2000 ≥ C > 300
Dermal (rat or rabbit)
mg/kg body weight
C ≤ 1000
2000 ≥ C > 1000
Inhalation (rat) gas
ppmV/4h
C ≤ 2500
20,000 ≥ C > 2500
Inhalation (rat) vapor
mg/1/4h
C ≤ 10
20 ≥ C > 10
Inhalation (rat) dust/mist/fume
mg/l/4h
C ≤ 1.0
5.0 ≥ C > 1.0
Category 3
Guidance
values do not
apply
A.8.2.1.9.4 The guidance values and ranges mentioned in Table A.8.1 are intended only for
guidance purposes, i.e., to be used as part of the weight of evidence approach, and to assist with
decisions about classification. They are not intended as strict demarcation values. Guidance
values are not provided for Category 3 since this classification is primarily based on human data;
animal data may be included in the weight of evidence evaluation.
A.8.2.1.9.5 Thus, it is feasible that a specific profile of toxicity occurs at a dose/concentration
below the guidance value, e.g., < 2000 mg/kg body weight by the oral route, however the nature
of the effect may result in the decision not to classify. Conversely, a specific profile of toxicity
may be seen in animal studies occurring at above a guidance value, e.g., ≥ 2000 mg/kg body
weight by the oral route, and in addition there is supplementary information from other sources,
e.g., other single dose studies, or human case experience, which supports a conclusion that, in
view of the weight of evidence, classification is the prudent action to take.
A.8.2.1.10
Other considerations
A.8.2.1.10.1 When a substance is characterized only by use of animal data (typical of new
substances, but also true for many existing substances), the classification process includes
reference to dose/concentration guidance values as one of the elements that contribute to the
weight of evidence approach.
A.8.2.1.10.2 When well-substantiated human data are available showing a specific target organ
toxic effect that can be reliably attributed to single exposure to a substance, the substance shall
be classified. Positive human data, regardless of probable dose, predominates over animal data.
Thus, if a substance is unclassified because specific target organ toxicity observed was
considered not relevant or significant to humans, if subsequent human incident data become
available showing a specific target organ toxic effect, the substance shall be classified.
A.8.2.1.10.3 A substance that has not been tested for specific target organ toxicity shall, where
appropriate, be classified on the basis of data from a validated structure activity relationship and
expert judgment-based extrapolation from a structural analogue that has previously been
classified together with substantial support from consideration of other important factors such as
formation of common significant metabolites.
570
A.8.2.2
Substances of Category 3
A.8.2.2.1
Criteria for respiratory tract irritation
The criteria for classifying substances as Category 3 for respiratory tract irritation
are:
(a) Respiratory irritant effects (characterized by localized redness, edema,
pruritis and/or pain) that impair function with symptoms such as cough, pain,
choking, and breathing difficulties are included. It is recognized that this
evaluation is based primarily on human data;
(b) Subjective human observations supported by objective measurements of clear
respiratory tract irritation (RTI) (e.g., electrophysiological responses,
biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);
(c) The symptoms observed in humans shall also be typical of those that would
be produced in the exposed population rather than being an isolated
idiosyncratic reaction or response triggered only in individuals with
hypersensitive airways. Ambiguous reports simply of “irritation” should be
excluded as this term is commonly used to describe a wide range of
sensations including those such as smell, unpleasant taste, a tickling
sensation, and dryness, which are outside the scope of classification for
respiratory track irritation;
(d) There are currently no validated animal tests that deal specifically with RTI;
however, useful information may be obtained from the single and repeated
inhalation toxicity tests. For example, animal studies may provide useful
information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and
histopathology (e.g., hyperemia, edema, minimal inflammation, thickened
mucous layer) which are reversible and may be reflective of the characteristic
clinical symptoms described above. Such animal studies can be used as part
of weight of evidence evaluation; and,
(e) This special classification will occur only when more severe organ effects
including the respiratory system are not observed as those effects would
require a higher classification.
A.8.2.2.2
Criteria for narcotic effects
The criteria for classifying substances in Category 3 for narcotic effects are:
(a) Central nervous system depression including narcotic effects in humans such
as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of
coordination, and vertigo are included. These effects can also be manifested
as severe headache or nausea, and can lead to reduced judgment, dizziness,
irritability, fatigue, impaired memory function, deficits in perception and
coordination, reaction time, or sleepiness; and,
571
(b) Narcotic effects observed in animal studies may include lethargy, lack of
coordination righting reflex, narcosis, and ataxia. If these effects are not
transient in nature, then they shall be considered for classification as
Category 1 or 2.
A.8.3
Classification criteria for mixtures
A.8.3.1
Mixtures are classified using the same criteria as for substances, or alternatively as
described below. As with substances, mixtures may be classified for specific target organ
toxicity following single exposure, repeated exposure, or both.
A.8.3.2
Classification of mixtures when data are available for the complete mixture
When reliable and good quality evidence from human experience or appropriate
studies in experimental animals, as described in the criteria for substances, is available for the
mixture, then the mixture shall be classified by weight of evidence evaluation of this data. Care
shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis,
do not render the results inconclusive.
A.8.3.3
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.8.3.3.1
Where the mixture itself has not been tested to determine its specific target organ
toxicity, but there are sufficient data on both the individual ingredients and similar tested
mixtures to adequately characterize the hazards of the mixture, these data shall be used in
accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix:
Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category,
Substantially similar mixtures, or Aerosols.
A.8.3.4
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.8.3.4.1
Where there is no reliable evidence or test data for the specific mixture itself, and
the bridging principles cannot be used to enable classification, then classification of the mixture
is based on the classification of the ingredient substances. In this case, the mixture shall be
classified as a specific target organ toxicant (specific organ specified), following single exposure,
repeated exposure, or both when at least one ingredient has been classified as a Category 1 or
Category 2 specific target organ toxicant and is present at or above the appropriate cut-off
value/concentration limit specified in Table A.8.2 for Categories 1 and 2, respectively, in
accordance with the principles of A.0.2.1 in this Appendix.
572
Table A.8.2: Cut-off values/concentration limits of ingredients of a mixture classified as a
specific target organ toxicant that would trigger classification of the mixture as Category 1
or 2
Cut-off values/concentration limits triggering classification of a
mixture as:
Ingredient classified as:
Category 1
Target organ toxicant
Category 1
Category 2
≥ 1.0 %
Category 2
Target organ toxicant
≥ 1.0 %
A.8.3.4.2
These cut-off values and consequent classifications shall be applied equally and
appropriately to both single- and repeated-dose target organ toxicants.
A.8.3.4.3
Mixtures shall be classified for either or both single and repeated dose toxicity
independently.
A.8.3.4.4
Care shall be exercised when toxicants affecting more than one organ system are
combined that the potentiation or synergistic interactions are considered, because certain
substances can cause target organ toxicity at < 1% concentration when other ingredients in the
mixture are known to potentiate its toxic effect. See A.0.2.1.
A.8.3.4.5
Care shall be exercised when extrapolating the toxicity of a mixture that contains
Category 3 ingredient(s). A cut-off value/concentration limit of 20%, considered as an additive
of all Category 3 ingredients for each hazard endpoint, is appropriate; however, this cut-off
value/concentration limit may be higher or lower depending on the Category 3 ingredient(s)
involved and the fact that some effects such as respiratory tract irritation may not occur below a
certain concentration, while other effects such as narcotic effects may occur below this 20%
value. Expert judgment shall be exercised. Respiratory tract irritation and narcotic effects are to
be evaluated separately in accordance with the criteria given in A.8.2.2. When conducting
classifications for these hazards, the contribution of each ingredient should be considered
additive, unless there is evidence that the effects are not additive.
573
A.9 SPECIFIC TARGET ORGAN TOXICITY
REPEATED OR PROLONGED EXPOSURE
A.9.1
Definitions and general considerations
A.9.1.1
Specific target organ toxicity - repeated exposure (STOT-RE) means specific
target organ toxicity arising from repeated exposure to a substance or mixture. All significant
health effects that can impair function, both reversible and irreversible, immediate and/or
delayed and not specifically addressed in A.1 to A.7 and A.10 of this Appendix are included.
Specific target organ toxicity following a single-event exposure is classified in accordance with
SPECIFIC TARGET ORGAN TOXICITY – SINGLE EXPOSURE (A.8 of this Appendix) and
is therefore not included here.
A.9.1.2
Classification identifies the substance or mixture as being a specific target organ
toxicant and, as such, it may present a potential for adverse health effects in people who are
exposed to it.
A.9.1.3
These adverse health effects produced by repeated exposure include consistent
and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant
changes which have affected the function or morphology of a tissue/organ, or have produced
serious changes to the biochemistry or hematology of the organism and these changes are
relevant for human health. Human data will be the primary source of evidence for this hazard
class.
A.9.1.4
Assessment shall take into consideration not only significant changes in a single
organ or biological system but also generalized changes of a less severe nature involving several
organs.
A.9.1.5
Specific target organ toxicity can occur by any route that is relevant for humans,
i.e., principally oral, dermal or inhalation.
A.9.2
Classification criteria for substances
A.9.2.1
Substances shall be classified as STOT - RE by expert judgment on the basis of
the weight of all evidence available, including the use of recommended guidance values which
take into account the duration of exposure and the dose/concentration which produced the
effect(s), (see A.9.2.9). Substances shall be placed in one of two categories, depending upon the
nature and severity of the effect(s) observed, in accordance with Figure A.9.1.
574
Figure A.9.1: Hazard categories for specific target organ toxicity following repeated
exposure
CATEGORY 1:
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 or prolonged exposure
Substances are classified in Category 1 for specific target organ toxicity (repeated exposure) on
the basis of:
(a) reliable and good quality evidence from human cases or epidemiological studies; or,
(b) 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 below (see
A.9.2.9) to be used as part of weight-of- evidence evaluation.
CATEGORY 2:
Substances that, on the basis of evidence from studies in experimental animals can be
presumed to have the potential to be harmful to human health following repeated or
prolonged 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 below (see A.9.2.9) in order
to help in classification.
In exceptional cases human evidence can also be used to place a substance in Category 2 (see
A.9.2.6).
Note:
The primary target organ/system shall be identified where possible, or the substance shall be identified as a
general toxicant. The data shall be carefully evaluated and, where possible, shall not include secondary
effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).
A.9.2.2
The relevant route of exposure by which the classified substance produces damage
shall be identified.
A.9.2.3
Classification is determined by expert judgment, on the basis of the weight of all
evidence available including the guidance presented below.
A.9.2.4
Weight of evidence of all data, including human incidents, epidemiology, and
studies conducted in experimental animals, is used to substantiate specific target organ toxic
effects that merit classification.
A.9.2.5
The information required to evaluate specific target organ toxicity comes either
from repeated exposure in humans, e.g., exposure at home, in the workplace or environmentally,
or from studies conducted in experimental animals. The standard animal studies in rats or mice
that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include
hematological, clinico-chemical and detailed macroscopic and microscopic examination to
enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies
performed in other species may also be used. Other long-term exposure studies, e.g., for
carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific
target organ toxicity that could be used in the assessment of classification.
575
A.9.2.6
In exceptional cases, based on expert judgment, it may be appropriate to place
certain substances with human evidence of specific target organ toxicity in Category 2: (a) when
the weight of human evidence is not sufficiently convincing to warrant Category 1 classification,
and/or (b) based on the nature and severity of effects. Dose/concentration levels in humans shall
not be considered in the classification and any available evidence from animal studies shall be
consistent with the Category 2 classification. In other words, if there are also animal data
available on the substance that warrant Category 1 classification, the substance shall be classified
as Category 1.
A.9.2.7
Effects considered to support classification
A.9.2.7.1
Classification is supported by reliable evidence associating repeated exposure to
the substance with a consistent and identifiable toxic effect.
A.9.2.7.2
Evidence from human experience/incidents is usually restricted to reports of
adverse health consequences, often with uncertainty about exposure conditions, and may not
provide the scientific detail that can be obtained from well-conducted studies in experimental
animals.
A.9.2.7.3
Evidence from appropriate studies in experimental animals can furnish much
more detail, in the form of clinical observations, hematology, clinical chemistry, macroscopic
and microscopic pathological examination and this can often reveal hazards that may not be lifethreatening but could indicate functional impairment. Consequently all available evidence, and
relevance to human health, must be taken into consideration in the classification process.
Relevant toxic effects in humans and/or animals include, but are not limited to:
(a) Morbidity or death resulting from repeated or long-term exposure. Morbidity
or death may result from repeated exposure, even to relatively low
doses/concentrations, due to bioaccumulation of the substance or its
metabolites, or due to the overwhelming of the de-toxification process by
repeated exposure;
(b) Significant functional changes in the central or peripheral nervous systems or
other organ systems, including signs of central nervous system depression
and effects on special senses (e.g., sight, hearing and sense of smell);
(c) Any consistent and significant adverse change in clinical biochemistry,
hematology, or urinalysis parameters;
(d) Significant organ damage that may be noted at necropsy and/or subsequently
seen or confirmed at microscopic examination;
(e) Multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital
organs with regenerative capacity;
(f) Morphological changes that are potentially reversible but provide clear
evidence of marked organ dysfunction (e.g., severe fatty change in the liver);
and,
576
(g) Evidence of appreciable cell death (including cell degeneration and reduced
cell number) in vital organs incapable of regeneration.
A.9.2.8
Effects considered not to support classification
Effects may be seen in humans and/or animals that do not justify classification.
Such effects include, but are not limited to:
(a) Clinical observations or small changes in bodyweight gain, food consumption
or water intake that may have some toxicological importance but that do not,
by themselves, indicate “significant” toxicity;
(b) Small changes in clinical biochemistry, hematology or urinalysis parameters
and /or transient effects, when such changes or effects are of doubtful or of
minimal toxicological importance;
(c) Changes in organ weights with no evidence of organ dysfunction;
(d) Adaptive responses that are not considered toxicologically relevant;
(e) Substance-induced species-specific mechanisms of toxicity, i.e.,
demonstrated with reasonable certainty to be not relevant for human health,
shall not justify classification.
A.9.2.9
Guidance values to assist with classification based on the results obtained from
studies conducted in experimental animals
A.9.2.9.1
In studies conducted in experimental animals, reliance on observation of effects
alone, without reference to the duration of experimental exposure and dose/concentration, omits
a fundamental concept of toxicology, i.e., all substances are potentially toxic, and what
determines the toxicity is a function of the dose/concentration and the duration of exposure. In
most studies conducted in experimental animals the test guidelines use an upper limit dose value.
A.9.2.9.2
In order to help reach a decision about whether a substance shall be classified or
not, and to what degree it shall be classified (Category 1 vs. Category 2), dose/concentration
“guidance values” are provided in Table A.9.1 for consideration of the dose/concentration which
has been shown to produce significant health effects. The principal argument for proposing such
guidance values is that all chemicals are potentially toxic and there has to be a reasonable
dose/concentration above which a degree of toxic effect is acknowledged. Also, repeated-dose
studies conducted in experimental animals are designed to produce toxicity at the highest dose
used in order to optimize the test objective and so most studies will reveal some toxic effect at
least at this highest dose. What is therefore to be decided is not only what effects have been
produced, but also at what dose/concentration they were produced and how relevant is that for
humans.
A.9.2.9.3
Thus, in animal studies, when significant toxic effects are observed that indicate
classification, consideration of the duration of experimental exposure and the dose/concentration
at which these effects were seen, in relation to the suggested guidance values, provides useful
577
information to help assess the need to classify (since the toxic effects are a consequence of the
hazardous property(ies) and also the duration of exposure and the dose/concentration).
A.9.2.9.4
The decision to classify at all can be influenced by reference to the
dose/concentration guidance values at or below which a significant toxic effect has been
observed.
A.9.2.9.5
The guidance values refer to effects seen in a standard 90-day toxicity study
conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for
toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to
Haber’s rule for inhalation, which states essentially that the effective dose is directly proportional
to the exposure concentration and the duration of exposure. The assessment should be done on a
case-by-case basis; for example, for a 28-day study the guidance values below would be
increased by a factor of three.
A.9.2.9.6
Thus for Category 1 classification, significant toxic effects observed in a 90-day
repeated-dose study conducted in experimental animals and seen to occur at or below the
(suggested) guidance values (C) as indicated in Table A.9.1 would justify classification:
Table A.9.1: Guidance values to assist in Category 1 classification
(applicable to a 90-day study)
Units
Guidance values
(dose/concentration)
Oral (rat)
mg/kg body weight/day
C ≤ 10
Dermal (rat or rabbit)
mg/kg body weight/day
C ≤ 20
ppmV/6h/day
C ≤ 50
Inhalation (rat) vapor
mg/liter/6h/day
C ≤ 0.2
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
C ≤ 0.02
Route of exposure
Inhalation (rat) gas
A.9.2.9.7
For Category 2 classification, significant toxic effects observed in a 90-day
repeated-dose study conducted in experimental animals and seen to occur within the (suggested)
guidance value ranges as indicated in Table A.9.2 would justify classification:
Table A.9.2: Guidance values to assist in Category 2 classification
(applicable to a 90-day study)
Units
Guidance value range
(dose/concentration)
Oral (rat)
mg/kg body weight/day
10 < C ≤ 100
Dermal (rat or rabbit)
mg/kg body weight/day
20 < C ≤ 200
ppmV/6h/day
50 < C ≤ 250
Inhalation (rat) vapor
mg/liter/6h/day
0.2 < C ≤ 1.0
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
0.02 < C ≤ 0.2
Route of exposure
Inhalation (rat) gas
578
A.9.2.9.8
The guidance values and ranges mentioned in A.2.9.9.6 and A.2.9.9.7 are intended
only for guidance purposes, i.e., to be used as part of the weight of evidence approach, and to
assist with decisions about classification. They are not intended as strict demarcation values.
A.9.2.9.9
Thus, it is feasible that a specific profile of toxicity occurs in repeat-dose animal
studies at a dose/concentration below the guidance value, e.g., < 100 mg/kg body weight/day by
the oral route, however the nature of the effect, e.g., nephrotoxicity seen only in male rats of a
particular strain known to be susceptible to this effect, may result in the decision not to classify.
Conversely, a specific profile of toxicity may be seen in animal studies occurring at above a
guidance value, e.g., ≥ 100 mg/kg body weight/day by the oral route, and in addition there is
supplementary information from other sources, e.g., other long-term administration studies, or
human case experience, which supports a conclusion that, in view of the weight of evidence,
classification is prudent.
A.9.2.10
Other considerations
A.9.2.10.1
When a substance is characterized only by use of animal data (typical of new
substances, but also true for many existing substances), the classification process includes
reference to dose/concentration guidance values as one of the elements that contribute to the
weight of evidence approach.
A.9.2.10.2
When well-substantiated human data are available showing a specific target organ
toxic effect that can be reliably attributed to repeated or prolonged exposure to a substance, the
substance shall be classified. Positive human data, regardless of probable dose, predominates
over animal data. Thus, if a substance is unclassified because no specific target organ toxicity
was seen at or below the dose/concentration guidance value for animal testing, if subsequent
human incident data become available showing a specific target organ toxic effect, the substance
shall be classified.
A.9.2.10.3
A substance that has not been tested for specific target organ toxicity may in
certain instances, where appropriate, be classified on the basis of data from a validated structure
activity relationship and expert judgment-based extrapolation from a structural analogue that has
previously been classified together with substantial support from consideration of other
important factors such as formation of common significant metabolites.
A.9.3
Classification criteria for mixtures
A.9.3.1
Mixtures are classified using the same criteria as for substances, or alternatively as
described below. As with substances, mixtures may be classified for specific target organ
toxicity following single exposure, repeated exposure, or both.
A.9.3.2
Classification of mixtures when data are available for the complete mixture
When reliable and good quality evidence from human experience or appropriate
studies in experimental animals, as described in the criteria for substances, is available for the
mixture, then the mixture shall be classified by weight of evidence evaluation of this data. Care
shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis,
do not render the results inconclusive.
579
A.9.3.3
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.9.3.3.1
Where the mixture itself has not been tested to determine its specific target organ
toxicity, but there are sufficient data on both the individual ingredients and similar tested
mixtures to adequately characterize the hazards of the mixture, these data shall be used in
accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix:
Dilution; Batching; Concentration of mixtures; Interpolation within one toxicity category;
Substantially similar mixtures; and Aerosols.
A.9.3.4
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.9.3.4.1
Where there is no reliable evidence or test data for the specific mixture itself, and
the bridging principles cannot be used to enable classification, then classification of the mixture
is based on the classification of the ingredient substances. In this case, the mixture shall be
classified as a specific target organ toxicant (specific organ specified), following single exposure,
repeated exposure, or both when at least one ingredient has been classified as a Category 1 or
Category 2 specific target organ toxicant and is present at or above the appropriate cut-off
value/concentration limit specified in Table A.9.3 for Category 1 and 2 respectively in
accordance with A.0.2.1.
Table A.9.3: Cut-off value/concentration limits of ingredients of a mixture classified as a
specific target organ toxicant that would trigger classification of the mixture as Category 1
or 2
Ingredient classified as:
Category 1
Target organ toxicant
Cut-off values/concentration limits triggering classification of a mixture as:
Category 1
Category 2
≥ 1.0 %
Category 2
Target organ toxicant
≥ 1.0 %
A.9.3.4.2
These cut-off values and consequent classifications shall be applied equally and
appropriately to both single- and repeated-dose target organ toxicants.
A.9.3.4.3
Mixtures shall be classified for either or both single- and repeated-dose toxicity
independently.
A.9.3.4.4
Care shall be exercised when toxicants affecting more than one organ system are
combined that the potentiation or synergistic interactions are considered, because certain
substances can cause specific target organ toxicity at < 1% concentration when other ingredients
in the mixture are known to potentiate its toxic effect. See A.0.2.1.
580
A.10 ASPIRATION HAZARD
A.10.1
Definitions and general and specific considerations
A.10.1.1
Aspiration means the entry of a liquid or solid chemical directly through the oral
or nasal cavity, or indirectly from vomiting, into the trachea and lower respiratory system.
A.10.1.2
Aspiration toxicity includes severe acute effects such as chemical pneumonia,
varying degrees of pulmonary injury or death following aspiration.
A.10.1.3
Aspiration is initiated at the moment of inspiration, in the time required to take
one breath, as the causative material lodges at the crossroad of the upper respiratory and
digestive tracts in the laryngopharyngeal region.
A.10.1.4
Aspiration of a substance or mixture can occur as it is vomited following
ingestion. This may have consequences for labeling, particularly where, due to acute toxicity, a
recommendation may be considered to induce vomiting after ingestion. However, if the
substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce
vomiting may need to be modified.
A.10.1.5
Specific considerations
A.10.1.5.1
The classification criteria refer to kinematic viscosity. The following provides the
conversion between dynamic and kinematic viscosity:
Dynamic viscosity (mPa·s)
= Kinematic viscosity (mm 2 /s)
3
Density (g/cm )
A.10.1.5.2 Although the definition of aspiration in A.10.1.1 includes the entry of solids into
the respiratory system, classification according to (b) in table A.10.1 for Category 1 is intended
to apply to liquid substances and mixtures only.
A.10.1.5.3
Classification of aerosol/mist products
Aerosol and mist products are usually dispensed in containers such as selfpressurized containers, trigger and pump sprayers. Classification for these products shall be
considered if their use may form a pool of product in the mouth, which then may be aspirated. If
the mist or aerosol from a pressurized container is fine, a pool may not be formed. On the other
hand, if a pressurized container dispenses product in a stream, a pool may be formed that may
then be aspirated. Usually, the mist produced by trigger and pump sprayers is coarse and
therefore, a pool may be formed that then may be aspirated. When the pump mechanism may be
removed and contents are available to be swallowed then the classification of the products should
be considered.
581
A.10.2
Classification criteria for substances
Table A.10.1: Criteria for aspiration toxicity
Category
Category 1: Chemicals known
to cause human aspiration
toxicity hazards or to be
regarded as if they cause human
aspiration toxicity hazard
Criteria
A substance shall be classified in Category 1:
(a) If reliable and good quality human evidence indicates that it causes
aspiration toxicity (See note 1); or
(b) If it is a hydrocarbon and has a kinematic viscosity ≤ 20.5 mm2/s,
measured at 40° C.
Note 1: Examples of substances included in Category 1 are certain hydrocarbons, turpentine and pine oil.
A.10.3
Classification criteria for mixtures
A.10.3.1
Classification when data are available for the complete mixture
A mixture shall be classified in Category 1 based on reliable and good quality
human evidence.
A.10.3.2
Classification of mixtures when data are not available for the complete
mixture: bridging principles
A.10.3.2.1
Where the mixture itself has not been tested to determine its aspiration toxicity,
but there are sufficient data on both the individual ingredients and similar tested mixtures to
adequately characterize the hazard of the mixture, these data shall be used in accordance with the
following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution; Batching;
Concentration of mixtures; Interpolation within one toxicity category; and Substantially similar
mixtures. For application of the dilution bridging principle, the concentration of aspiration
toxicants shall not be less than 10%.
A.10.3.3
Classification of mixtures when data are available for all ingredients or only
for some ingredients of the mixture
A.10.3.3.1
A mixture which contains ≥ 10% of an ingredient or ingredients classified in
Category 1, and has a kinematic viscosity ≤ 20.5 mm2/s, measured at 40 °C, shall be classified in
Category 1.
A.10.3.3.2
In the case of a mixture which separates into two or more distinct layers, one of
which contains ≥ 10 % of an ingredient or ingredients classified in Category 1 and has a
kinematic viscosity ≤ 20.5 mm2/s, measured at 40 °C, then the entire mixture shall be classified
in Category 1.
582
583
| File Type | application/pdf |
| Author | Adia's Computer |
| File Modified | 2009-09-03 |
| File Created | 2009-09-03 |