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.
A.0.2.3 The term "scientifically validated"
refers to the process by which the reliabilityand the
relevance of a procedure are established for a particular
purpose. Any test that determines hazardous properties,
which is conducted according to recognized scientific
principles, can be used for purposes of a hazard determination
for health hazards. Test conditions need to be standardized
so that the results are reproducible with a given substance,
and the standardized test yields "valid" data
for defining the hazard class of concern.
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.
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 considered 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
considered 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 those 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;
(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 cut-off
values/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 cut-off values/concentration limits
A.0.4.3.1 When classifying
an untested mixture based on the hazards of its ingredients,
cutoff values/concentration limits for the classified
ingredients of the mixture are used for several hazard
classes. While the adopted cut-off values/concentration
limits adequately identify the hazard for most mixtures,
there may be some that contain hazardous ingredients at
lower concentrations than the specified cut-off values/concentration
limits that still pose an identifiable hazard. There may
also be cases where the cut-off value/concentration limit
is considerably lower than the 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 cut-off value/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 cut-off value/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 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 mixture, when produced by or under the control
of the same chemical 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
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) A + B;
(ii) 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.
A1. 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.
Note: Gas concentrations
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,
(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 substances the test atmosphere will be a
vapor which consists of a combination of liquid and gaseous
phases. For other substances the test atmosphere may consist
of a vapor which is nearly all the gaseous phase. In these
latter 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:
A.1.3.2 Classification
of mixtures for acute toxicity may be carried out for each
route of exposure, but is only required 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 acute 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.1.3.6.2.4.
(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.1.3.6.2.4.
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 Classification
of mixtures based on ingredients of the mixture (additivity
formula)
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, or have an oral or dermal LD50
greater than 2000 but less than or equal to 5000 mg/kg
body weight (or the equivalent dose for inhalation);
(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.1.3.6.2.4.
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:
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%, and the mixture has not been classified based on
testing of the mixture as a whole, 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 to this section, Allocation of Label Elements
and Appendix D
to this section, Safety Data Sheets.)
Where an ingredient with unknown
acute toxicity is used in a mixture at a concentration >=
1%, and the mixture is not classified based on testing of
the mixture as a whole, a statement that X% of the mixture
consists of ingredient(s) of unknown acute toxicity is required
on the label and safety data sheet in such cases; see Appendix
C to this section, Allocation of Label Elements
and Appendix D
to this section, Safety Data Sheets.)
A.1.3.6.2.4 If the total
concentration of the relevant 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
relevant ingredient(s) with unknown acute toxicity is >
10%, the formula presented in A.1.3.6.1 is corrected to
adjust for the percentage of the unknown ingredient(s) as
follows:
A.2
SKIN CORROSION/IRRITATION
A.2.1 Definitions and general considerations
A.2.1.1 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.2.1.2 Skin corrosion/irritation shall be classified
using a tiered approach as detailed in figure A.2.1. Emphasis
shall be placed upon existing human data (See A.0.2.6),
followed by other sources of information. Classification
results directly when the data satisfy the criteria in this
section. In case the criteria cannot be directly applied,
classification of a substance or a mixture is made on the
basis of the total weight of evidence (See A.0.3.1). This
means that all available information bearing on the determination
of skin corrosion/irritation is considered together, including
the results of appropriate scientifically validated in-vitro
tests, relevant animal data, and human data such as epidemiological
and clinical studies and well-documented case reports and
observations.
A.2.2 Classification criteria
for substances using animal test data
A.2.2.1 Corrosion
A.2.2.1.1 A corrosive substance is a chemical 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.2.2.1.2 Three sub-categories of
Category 1 are provided in Table A.2.1, all of which shall
be regulated as Category 1.
A.2.2.2 Irritation
A.2.2.2.1 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.
A.2.2.2.2 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.2.2.2.3. 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 chemical should be considered to be
an irritant.
A.2.3 Classification Criteria
for Substances Using Other Data Elements
A.2.3.1 Existing human
and animal data including information from single or repeated
exposure should be the first line of analysis, as they give
information directly relevant to effects on the skin. If a
substance is highly toxic by the dermal route, a skin corrosion/irritation
study may not be practicable 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. When
observations are made of skin corrosion/irritation in acute
toxicity studies and are observed up through the limit dose,
these data may be used for classification provided that the
dilutions used and species tested are equivalent. In vitro
alternatives that have been scientifically validated shall
be used to make classification decisions. Solid substances
(powders) may become corrosive or irritant when moistened
or in contact with moist skin or mucous membranes. Likewise,
pH extremes like <=2 and >=11.5 may indicate skin effects,
especially when associated with significant buffering capacity.
Generally, such substances are expected to produce significant
effects on the skin. In the absence of any other information,
a substance is considered corrosive (Skin Category 1) if it
has a pH <=2 or a pH >=11.5. However, if consideration
of alkali/acid reserve suggests the substance or mixture may
not be corrosive despite the low or high pH value, then further
evaluation may be necessary. In some cases enough information
may be available from structurally related compounds to make
classification decisions.
A.2.3.2 A tiered approach
to the evaluation of initial information shall be used (Figure
A.2.1) recognizing that all elements may not be relevant in
certain cases.
A.2.3.3 The tiered approach
explains how to organize information on a substance and to
make a weight-of-evidence decision about hazard assessment
and hazard classification.
A.2.3.4 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 not all parameters. 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-bycase determinations are necessary.
A.2.4 Classification criteria
for mixtures
A.2.4.1 Classification
of mixtures when data are available for the complete mixture
A.2.4.1.1 The mixture shall be classified using the
criteria for substances (See A.2.3).
A.2.4.2 Classification of mixtures when data are
not available for the complete mixture: bridging principles
A.2.4.2.1 Where the mixture itself has not been tested
to determine its skin corrosion/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.2.4.3 Classification of mixtures when data are
available for all ingredients or only for some ingredients
of the mixture
A.2.4.3.1 For purposes of classifying the skin corrosion/irritation
hazards of mixtures in the tiered approach:
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 the classifier has reason to suspect that
an ingredient present at a concentration <1% will affect
classification of the mixture for skin corrosion/irritation,
that ingredient shall also be considered relevant.
A.2.4.3.2 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.2.4.3.3 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.2.4.3.4 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.2.4.3.1 and
A.2.4.3.2 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 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 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.2.4.3.5 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 A.2.3 and A.2.4. In these
cases the mixture could be classified according to those
data (See Use of cut-off values/concentration limits, paragraph
A.0.4.3 of this Appendix).
A.2.4.3.6 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 shall
be classified accordingly (See Use of cut-off values /concentration
limits, paragraph A.0.4.3 of this Appendix).
A.3
SERIOUS EYE DAMAGE /EYE IRRITATION
A.3.1 Definitions and general considerations
A.3.1.1 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.3.1.2 Serious eye damage/eye irritation shall be
classified using a tiered approach as detailed in figure
A.3.1. Emphasis shall be placed upon existing human data
(See A.0.2.6), followed by animal data, followed by other
sources of information. Classification results directly
when the data satisfy the criteria in this section. In case
the criteria cannot be directly applied, classification
of a substance or a mixture is made on the basis of the
total weight of evidence (See A.0.3.1). This means that
all available information bearing on the determination of
serious eye damage/eye irritation is considered together,
including the results of appropriate scientifically validated
in vitro tests, relevant animal data, and human data such
as epidemiological and clinical studies and well-documented
case reports and observations.
A.3.2 Classification criteria
for substances using animal 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 and/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.
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.
A.3.2.3 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 Existing human and animal data should be
the first line of analysis, as they give information directly
relevant to effects on the eye. Possible skin corrosion
shall 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 scientifically validated and
accepted shall be used to make classification decisions.
Likewise, pH extremes like <= 2 and >= 11.5, may indicate
serious eye damage, especially when associated with significant
buffering capacity. Generally, such substances are expected
to produce significant effects on the eyes. In the absence
of any other information, a mixture/substance is considered
to cause serious eye damage (Eye Category 1) if it has a
pH <= 2 or >=11.5. However, if consideration of acid/alkaline
reserve suggests the substance may not have the potential
to cause serious eye damage despite the low or high pH value,
then further valuation may be necessary. In some cases enough
information may be available from structurally related compounds
to make classification decisions.
A.3.3.2 A tiered approach to the evaluation of initial
information shall be used where applicable, recognizing
that all elements may not be relevant in certain cases (Figure
A.3.1).
A.3.3.3 The tiered approach explains how to organize
existing information on a substance and to make a weight-of-evidence
decision, where appropriate, about hazard assessment and
hazard classification.
A.3.3.4 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, consideration should be given to the totality
of existing information and making an overall weight of
evidence determination. This is especially true when there
is conflict in information available on some parameters.
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
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, chemical 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. In the absence of any other information, a mixture
is considered to cause serious eye damage (Eye Category
1) if it has a pH <=2 or >= 11.5. However, if consideration
of acid/alkaline 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 evaluation may be
necessary.
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 eye 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 For purposes of classifying the eye corrosion/irritation
hazards of mixtures in the tiered approach:
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 the classifier has reason to suspect that
an ingredient present at a concentration <1% will affect
classification of the mixture for eye corrosion/irritation,
that ingredient shall also be considered relevant.
A.3.4.3.2 In general, the approach to classification
of mixtures as seriously damaging to the eye or eye irritant
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 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 as seriously damaging to the eye or an eye irritant.
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 cut-off values/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 cut-off values/concentration
limits).
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.
A.4.2.1.1.2 Where data
are not sufficient for sub-categorization, respiratory sensitizers
shall be classified in Category 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.
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) The size of the population exposed;
(b) The extent of exposure.
A.4.2.1.2.3 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;
(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 studies(1)
which may be indicative of the potential of a substance
to cause sensitization by inhalation in humans (2)
may include:
(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 preventive
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 bronchia hyperactivity, they should
not be considered as respiratory sensitizers.
(a) Measurements of Immunoglobulin E (IgE) and
other specific immunologicalparameters, for example in
mice
(b) Specific pulmonary responses in guinea pigs.
A.4.2.2 Skin sensitizers
A.4.2.2.1 Hazard categories
A.4.2.2.1.1 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 subcategories 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.4.2.2.1.2 Where data are not sufficient for sub-categorization,
skin sensitizers shall be classified in Category 1.
A.4.2.2.2 Human evidence
A.4.2.2.2.1 Human evidence for sub-category 1A may
include:
(a) Positive responses
at <=500 µg/cm2 (Human Repeat Insult Patch Test
(HRIPT), Human Maximization Test (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.
A.4.2.2.2.2 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.
A.4.2.2.3 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 index of three or more is considered a
positive response in the local lymph node assay. (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).
A.4.2.2.3.2 Animal test
results for sub-category 1A can include data with values
indicated in Table A.4.3 below:
A.4.2.2.3.3 Animal test
results for sub-category 1B can include data with values
indicated in Table A.4.4 below:
A.4.2.2.4 Specific considerations
A.4.2.2.4.1 For classification of a substance, evidence
shall include one or more 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.
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) 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.
A.4.2.2.4.4 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 shall 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.
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.
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.
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. 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
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 (It should be noted that
the classification criteria for health hazards 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 limits or additivity. However,
this approach is not used for Germ Cell Mutagenicity. These
criteria for Germ Cell Mutagenicity consider the cut-off
values/concentration limits 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.)
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.
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.
A.5.3.2 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 accordance with
the following bridging principles as found in paragraph
A.0.5 of this Appendix: Dilution, Batching, and Substantially
similar mixtures.
A.5.4 Examples of scientifically
validated test methods:
A.5.4.1 Examples of in vivo
heritable germ cell mutagenicity tests are:
(a) Rodent dominant
lethal mutation test (OECD 478)
(b) Mouse heritable translocation assay (OECD 485)
(c) Mouse specific locus test
A.5.4.2 Examples of in vivo somatic cell mutagenicity tests
are:
(a) Mammalian bone
marrow chromosome aberration test (OECD 475)
(b) Mouse spot test (OECD 484)
(c) Mammalian erythrocyte micronucleus test (OECD
474)
A.5.4.3 Examples of mutagenicity/genotoxicity
tests in germ cells are:
(a) Mutagenicity tests:
(i) Mammalian spermatogonial
chromosome aberration test (OECD 483)
(ii) Spermatid micronucleus assay
(b) Genotoxicity tests:
(i) Sister chromatid
exchange analysis in spermatogonia
(ii) Unscheduled DNA synthesis test (UDS) in testicular
cells
A.5.4.4 Examples of genotoxicity
tests in somatic cells are:
(a) Liver Unscheduled
DNA Synthesis (UDS) in vivo (OECD 486)
(b) Mammalian bone marrow Sister Chromatid Exchanges
(SCE)
A.5.4.5 Examples of in vitro mutagenicity tests are:
(a) In vitro mammalian
chromosome aberration test (OECD 473)
(b) In vitro mammalian cell gene mutation test
(OECD 476)
(c) Bacterial reverse mutation tests (OECD 471)
A.5.4.6 As new, scientifically validated tests arise,
these may also be used in the total weight of evidence to
be considered.
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(See Non-mandatory Appendix
F Part A for further guidance regarding hazard classification
for carcinogenicity. This appendix is consistent with the
GHS and is provided as guidance excerpted from the International
Agency for Research on Cancer (IARC) Monographs on
the Evaluation of Carcinogenic Risks to Humans (2006)).
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.
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. (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 non-mandatory 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.
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 (It
should be noted that the classification criteria for health
hazards 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
limit or additivity. However, this approach is not used
for Carcinogenicity. These criteria for Carcinogenicity
consider the cut-off values/concentration limits 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).
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.
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 conclusivetaking
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
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.
A.6.4 Classification of carcinogenicity(See
Non-mandatory Appendix F for further guidance regarding
hazard classification for carcinogenicity and how to relate
carcinogenicity classification information from IARC and
NTP to GHS).
A.6.4.1 Chemical manufacturers, importers and employers
evaluating chemicals may treat the following sources as
establishing that a substance is a carcinogen or potential
carcinogen for hazard communication purposes in lieu of
applying the criteria described herein:
A.6.4.1.1 National Toxicology
Program (NTP), Report on Carcinogens (latest
edition);
A.6.4.1.2 International Agency for Research on Cancer
(IARC) Monographs on the Evaluation of Carcinogenic
Risks to Humans (latest editions)
A.6.4.2 Where OSHA has included cancer as a health
hazard to be considered by classifiers for a chemical covered
by 29 CFR part 1910, Subpart Z, Toxic and Hazardous Substances,
chemical manufacturers, importers, and employers shall classify
the chemical as a carcinogen.
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 or via lactation shall be classified
in a separate hazard category in accordance with Figure
A.7.1(b).
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 considered together in 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
maynot 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 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
maternally mediated 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 a useful indicator of maternal toxicity because
of normal fluctuations in body weight during pregnancy.
(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 classification. In all
cases of this nature, expert judgment must be used to assess
the adequacy of the data. Inadequate data shall 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 (It should be noted that
the classification criteria for health hazards 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 limits or additivity. However,
this approach is not used for Reproductive Toxicity. These
criteria for Reproductive Toxicity consider the cut-off
values/concentration limits 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).
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 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.
A.7.3.2 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.
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.
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 available 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 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,
(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.
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 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 scientifically
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.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
tract irritation;
(d) There are currently no scientifically 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,
(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.
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.
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.
A.9
SPECIFIC TARGET ORGAN TOXICITY REPEATED OR PROLONGED EXPOSURE
A.9.1 Definitions and general
considerations
B 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, e.g., 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.
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. 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 life threatening 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,
(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 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 Habers
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:
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:
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
possible 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 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 scientifically 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 these data. Care shall be exercised in evaluating
data on mixtures, that the dose, duration, observation or
analysis, do not render the results inconclusive.
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.
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.
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:
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 self-pressurized 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.
A.10.2 Classification criteria
for substances
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.
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