(1) The purpose of this section is to ensure that the hazards of
all chemicals produced or imported are classified, and that information
concerning the classified hazards is transmitted to employers and
employees. The requirements of this section are intended to be
consistent with the provisions of the United Nations Globally
Harmonized System of Classification and Labeling of Chemicals (GHS),
Revision 7. The transmittal of information is to be accomplished by
means of comprehensive hazard communication programs, which are to
include container labeling and other forms of warning, safety data
sheets and employee training.
* * * * *
    (b) * * *
    (6) * * *
    (x) Nuisance particulates where the chemical manufacturer or
importer can establish that they do not pose any physical hazard,
health hazard, or other hazards covered under this section;
* * * * *
    (c) * * *
    Bulk shipment means any hazardous chemical transported where the
mode of transportation (vehicle) comprises the immediate container
(i.e., contained in tanker truck, rail car, or intermodal container).
* * * * *
    Combustible dust means finely divided solid particles of a
substance or mixture that are liable to catch fire or explode on
ignition when dispersed in air or other oxidizing media.
* * * * *
    Exposure or exposed means that an employee is subjected in the
course of employment to a hazardous chemical, and includes potential
(e.g., accidental or possible) exposure. ``Subjected'' in terms of
health hazards includes any route of entry (e.g., inhalation,
ingestion, skin contact or absorption).
* * * * *
    Gas means a substance which--at 122 [deg]F (50 [deg]C) has a vapor
pressure greater than 43.51 PSI (300 kPa) (absolute); or

is completely gaseous at 68 [deg]F (20 [deg]C) at a standard pressure
of 14.69 PSI (101.3 kPa).
* * * * *
    Hazardous chemical means any chemical which is classified as a
physical hazard or a health hazard, a simple asphyxiant, combustible
dust, or hazard not otherwise classified.
* * * * *
    Immediate outer package means the first package enclosing the
container of hazardous chemical.
* * * * *
    Liquid means a substance or mixture which at 122 [deg]F (50 [deg]C)
has a vapor pressure of not more than 43.51 PSI (300 kPa (3 bar)),
which is not completely gaseous at 68 [deg]F (20 [deg]C) and at a
standard pressure of 101.3 kPa, and which has a melting point or
initial melting point of 68 [deg]F (20 [deg]C) or less at a standard
pressure of 14.69 PSI (101.3 kPa). A viscous substance or mixture for
which a specific melting point cannot be determined shall be subjected
to ASTM D 4359-90 (2019) (Standard Test Method for Determining Whether
a Material Is a Liquid or a Solid) (incorporated by reference; see
Sec.  1910.6); or to the test for determining fluidity (penetrometer
test) prescribed in the European Agreement Concerning the International
Carriage of Dangerous Goods by Road (ADR), section 2.3.4 of Annex A
(2019) (incorporated by reference; see Sec.  1910.6).
* * * * *
    Physical hazard means a chemical that is classified as posing one
of the following hazardous effects: Explosive; flammable (gases,
liquids, or solids); aerosols; oxidizer (liquid, solid or gas); self-
reactive; pyrophoric (liquid or solid); self-heating; organic peroxide;
corrosive to metal; gas under pressure; in contact with water emits
flammable gas; or desensitized explosive. The criteria for determining
whether a chemical is classified as a physical hazard are detailed in
appendix B to this section.
    Physician or other licensed health care professional (PLHCP) means
an individual whose legally permitted scope of practice (i.e., license,
registration, or certification) allows the individual to independently
provide or be delegated the responsibility to provide some or all of
the health care services referenced in paragraph (i) of this section.
* * * * *
    Released for shipment means a chemical that has been packaged and
labeled in the manner in which it will be distributed or sold.
* * * * *
    Solid means a substance or mixture which does not meet the
definitions of liquid or gas.
* * * * *
    (d) * * *
    (1) Chemical manufacturers and importers shall evaluate chemicals
produced in their workplaces or imported by them to classify the
chemicals in accordance with this section. For each chemical, the
chemical manufacturer or importer shall determine the hazard classes,
and where appropriate, the category of each class that apply to the
chemical being classified under normal conditions of use and
foreseeable emergencies. The hazard classification shall include any
hazards associated with a change in the chemical's physical form or
resulting from a reaction with other chemicals under normal conditions
of use. Employers are not required to classify chemicals unless they
choose not to rely on the classification performed by the chemical
manufacturer or importer for the chemical to satisfy this paragraph
(d)(1).
* * * * *
    (e) * * *
    (4) The employer shall make the written hazard communication
program available, upon request, to employees, their designated
representatives, the Assistant Secretary and the Director, in
accordance with the requirements of Sec.  1910.1020(e).
* * * * *
    (f) * * *
    (1) Labels on shipped containers. The chemical manufacturer,
importer, or distributor shall ensure that each container of hazardous
chemicals leaving the workplace is labeled, tagged or marked. Hazards
not otherwise classified and hazards resulting from a reaction with
other chemicals under normal conditions of use do not have to be
addressed on the container. Where the chemical manufacturer, importer,
or distributor is required to label, tag or mark the following shall be
provided:
    (i) Product identifier;
    (ii) Signal word;
    (iii) Hazard statement(s);
    (iv) Pictogram(s);
    (v) Precautionary statement(s);
    (vi) Name, address, and telephone number of the chemical
manufacturer, importer, or other responsible party; and
    (vii) Date chemical is released for shipment.
* * * * *
    (5) Transportation. (i) Chemical manufacturers, importers, or
distributors shall ensure that each container of hazardous chemicals
leaving the workplace is labeled, tagged, or marked in accordance with
this section in a manner which does not conflict with the requirements
of the Hazardous Materials Transportation Act (49 U.S.C. 1801 et seq.)
and regulations issued under that Act by the Department of
Transportation.
    (ii) The label for bulk shipments of hazardous chemicals may be on
the immediate container or may be transmitted with the shipping papers,
bills of lading, or other technological or electronic means so that it
is immediately available to workers in printed form on the receiving
end of shipment.
    (iii) Where a pictogram required by the Department of
Transportation under title 49 of the Code of Federal Regulations
appears on the label for a shipped container, the pictogram specified
in appendix C.4 of this section for the same hazard is not required on
the label.
* * * * *
    (11) Release for shipment. Chemical manufacturers, importers,
distributors, or employers who become newly aware of any significant
information regarding the hazards of a chemical shall revise the labels
for the chemical within six months of becoming aware of the new
information, and shall ensure that labels on containers of hazardous
chemicals shipped after that time contain the new information.
Chemicals that have been released for shipment and are awaiting future
distribution need not be relabeled; however, the chemical manufacturer
or importer must provide the updated label for each individual
container with each shipment. If the chemical is not currently produced
or imported, the chemical manufacturer, importer, distributor, or
employer shall add the information to the label before the chemical is
shipped or introduced into the workplace again.
    (12) Small container labelling. (i) This paragraph (f)(12) applies
where the chemical manufacturer, importer, or distributor can
demonstrate that it is not feasible to use pull-out labels, fold-back
labels, or tags containing the full label information required by
paragraph (f)(1) of this section.
    (ii) For a container less than or equal to 100 ml capacity, the
chemical manufacturer, importer, or distributor must include, at a
minimum, the following information on the label of the container:
    (A) Product identifier;
    (B) Pictogram(s);
    (C) Signal word;
    (D) Chemical manufacturer's name and phone number; and
    (E) A statement that the full label information for the hazardous
chemical

is provided on the immediate outer package.
    (iii) For a container less than or equal to 3 ml capacity, where
the chemical manufacturer, importer, or distributor can demonstrate
that any label interferes with the normal use of the container, no
label is required, but the container must bear, at a minimum, the
product identifier.
    (iv) For all small containers covered by paragraph (f)(12)(ii) or
(iii) of this section, the immediate outer package must include:
    (A) The full label information required by paragraph (f)(1) of this
section for each hazardous chemical in the immediate outer package. The
label must not be removed or defaced, as required by paragraph (f)(9)
of this section.
    (B) A statement that the small container(s) inside must be stored
in the immediate outer package bearing the complete label when not in
use.
    (g) * * *
    (2) The chemical manufacturer or importer shall ensure that the
safety data sheet is in English (although the employer may maintain
copies in other languages as well), and includes at least the following
section numbers and headings, and associated information under each
heading, in the order listed (See appendix D to this section for the
specific content of each section of the safety data sheet):
* * * * *
    (10) Safety data sheets may be kept in any form, including as
operating procedures, and may be stored in such a way to cover groups
of hazardous chemicals in a work area where it may be more appropriate
to address the hazards of a process rather than individual hazardous
chemicals. However, the employer shall ensure that in all cases the
required information is provided for each hazardous chemical, and is
readily accessible during each work shift to employees when they are in
their work area(s).
* * * * *
    (i) * * *
    (1) The chemical manufacturer, importer, or employer may withhold
the specific chemical identity, including the chemical name, other
specific identification of a hazardous chemical, or the exact
percentage (concentration) or concentration range of the substance in a
mixture, from section 3 of the safety data sheet, provided that:
    (i) The claim that the information withheld is a trade secret can
be supported;
    (ii) Information contained in the safety data sheet concerning the
properties and effects of the hazardous chemical is disclosed;
    (iii) The safety data sheet indicates that the specific chemical
identity and/or concentration or concentration range of composition is
being withheld as a trade secret;
    (iv) If the concentration or concentration range is being claimed
as a trade secret then the safety data sheet provides the ingredient's
concentration as one of the prescribed ranges in paragraphs
(i)(1)(iv)(A) through (M) of this section.
    (A) From 0.1% to 1%;
    (B) From 0.5% to 1.5%;
    (C) From 1% to 5%;
    (D) From 3% to 7%;
    (E) From 5% to 10%;
    (F) From 7% to 13%;
    (G) From 10% to 30%;
    (H) From 15% to 40%;
    (I) From 30% to 60%;
    (J) From 45% to 70%;
    (K) From 60% to 80%;
    (L) From 65% to 85%; and
    (M) From 80% to 100%.
    (v) The prescribed concentration range used must be the narrowest
range possible. If the exact concentration range falls between 0.1% and
30% and does not fit entirely into one of the prescribed concentration,
a single range created by the combination of two applicable consecutive
ranges (e.g., between (i)(1)(iv)(A) and (G)) may be disclosed instead,
provided that the combined concentration range does not include any
range that falls entirely outside the exact concentration range in
which the ingredient is present.
    (vi) The specific chemical identity and exact concentration or
concentration range is made available to health professionals,
employees, and designated representatives in accordance with the
applicable provisions of this paragraph (i).
    (2) Where a treating PLHCP determines that a medical emergency
exists and the specific chemical identity and/or specific concentration
or concentration range of a hazardous chemical is necessary for
emergency or first-aid treatment, the chemical manufacturer, importer,
or employer shall immediately disclose the specific chemical identity
or percentage composition of a trade secret chemical to that treating
PLHCP, regardless of the existence of a written statement of need or a
confidentiality agreement. The chemical manufacturer, importer, or
employer may require a written statement of need and confidentiality
agreement, in accordance with the provisions of paragraphs (i)(3) and
(4) of this section, as soon as circumstances permit.
    (3) In non-emergency situations, a chemical manufacturer, importer,
or employer shall, upon request, disclose a specific chemical identity
or exact concentration or concentration range, otherwise permitted to
be withheld under paragraph (i)(1) of this section, to a health
professional (e.g., PLHCP, industrial hygienist, toxicologist, or
epidemiologist) providing medical or other occupational health services
to exposed employee(s), and to employees or designated representatives,
if:
* * * * *
    (j) Dates. (1) This section is effective [DATE 60 DAYS AFTER DATE
OF PUBLICATION OF FINAL RULE IN THE FEDERAL REGISTER].
    (2) Chemical manufacturers, importers, and distributors evaluating
substances shall be in compliance with all modified provisions of this
section no later than [DATE ONE YEAR AFTER EFFECTIVE DATE OF FINAL
RULE].
    (3) Chemical manufacturers, importers, and distributors evaluating
mixtures shall be in compliance with all modified provisions of this
section no later than 24 months after [DATE TWO YEARS AFTER EFFECTIVE
DATE OF FINAL RULE].
* * * * *

Appendix A to Sec.  1910.1200--Health Hazard Criteria (Mandatory)

A.0 General Classification Considerations

A.0.1 Classification

    A.0.1.1 The term ``hazard classification'' is used to indicate
that only the intrinsic hazardous properties of chemicals are
considered. Hazard classification incorporates three steps:
    (a) Identification of relevant data regarding the hazards of a
chemical;
    (b) Subsequent review of those data to ascertain the hazards
associated with the chemical;
    (c) Determination of whether the chemical will be classified as
hazardous and the degree of hazard.
    A.0.1.2 For many hazard classes, the criteria are semi-
quantitative or qualitative and expert judgment is required to
interpret the data for classification purposes.
    A.0.1.3 Where impurities, additives or individual constituents
of a substance or mixture have been identified and are themselves
classified, they should be taken into account during classification
if they exceed the cut-off value/concentration limit for a given
hazard class.

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 reliability and 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 physico-chemical 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 Except as provided in A.0.4.2, the 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.<IP_ADDRESS> When classifying an untested mixture based on the
hazards of its ingredients, cut-off 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> Concentration of mixtures
    For mixtures classified in accordance with A.1, A.2, A.3, A.4,
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.<IP_ADDRESS> Interpolation within one hazard category
    For mixtures classified in accordance with A.1, A.2, A.3, A.4,
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 hazard 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 hazard category as A and B.
    A.<IP_ADDRESS> 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.<IP_ADDRESS> 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.

A.1 Acute Toxicity

A.1.1 Definition

    Acute toxicity refers to serious adverse health effects (i.e.,
lethality) occurring after a single or short-term oral, dermal, or
inhalation exposure to a substance or mixture.

A.1.2 Classification Criteria for Substances

    A.1.2.1 Substances can be allocated to one of four hazard
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). While some in vivo methods determine
LD50/LC50 values directly, other newer in vivo
methods (e.g., using fewer animals) consider other indicators of
acute toxicity, such as significant clinical signs of toxicity,
which are used by reference to assign the hazard category. See the
footnotes following Table A.1.1 for further explanation on the
application of these values.

[GRAPHIC] [TIFF OMITTED] TP16FE21.077

    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. In
cases where data from human experience (i.e., occupational data,
data from accident databases, epidemiology studies, clinical
reports) is also available, it should be considered in a weight of
evidence approach consistent with the principles described in A.0.3.
    A.1.2.4 In addition to classification for inhalation toxicity,
if data are available that indicates that the mechanism of toxicity
was corrosivity of the substance or mixture, the classifier must
consider if the chemical is corrosive to the respiratory tract.
Corrosion of the respiratory tract is defined as destruction of the
respiratory tract tissue after a single, limited period of exposure
analogous to skin corrosion; this includes destruction of the
mucosa. The corrosivity evaluation could be based on expert judgment
using such evidence as: Human and animal experience, existing (in
vitro) data, pH values, information from similar substances or any
other pertinent data.
    A.<IP_ADDRESS> If the classifier determines the chemical is corrosive
to the respiratory tract and data are available that indicate that
the effect leads to lethality, then the chemical must be labelled
with the hazard statement ``corrosive to the respiratory tract.''
    A.<IP_ADDRESS> If the classifier determines the chemical is corrosive
to the respiratory tract and the effect does not lead to lethality,
then the chemical must be addressed in the Specific Target Organ
Toxicity hazard classes (see A.8 and A.9).

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:
[GRAPHIC] [TIFF OMITTED] TP16FE21.080

    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.<IP_ADDRESS> and A.<IP_ADDRESS>.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.<IP_ADDRESS> and A.<IP_ADDRESS>.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.<IP_ADDRESS> 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 hazard category, Substantially
similar mixtures, and Aerosols.

A.1.3.6 Classification of Mixtures Based on Ingredients of the
Mixture (Additivity Formula)

    A.<IP_ADDRESS> 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 hazard categories, or have an oral or
dermal LD50 greater than 2,000 but less than or equal to
5,000 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.<IP_ADDRESS>.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:
[GRAPHIC] [TIFF OMITTED] TP16FE21.081

where:

Ci = concentration of ingredient i
n ingredients and i is running from 1 to n
ATEi = acute toxicity estimate of ingredient i.

    A.<IP_ADDRESS> Data are not available for one or more ingredients of
the mixture
    A.<IP_ADDRESS>.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.<IP_ADDRESS> 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.<IP_ADDRESS>.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.<IP_ADDRESS>.4.
    A.<IP_ADDRESS>.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 x percent of the
mixture consists of ingredient(s) of unknown acute (oral/dermal/
inhalation) 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.<IP_ADDRESS>.4 If the total concentration of the relevant
ingredient(s) with unknown acute toxicity is <=10% then the formula
presented in A.<IP_ADDRESS> must be used. If the total concentration of
the relevant ingredient(s) with unknown acute toxicity is >10%, the
formula presented in A.<IP_ADDRESS> is corrected to adjust for the
percentage of the unknown ingredient(s) as follows:
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A.2 Skin Corrosion/Irritation

A.2.1 Definitions and General Considerations

    A.2.1.1 Skin corrosion refers to the production of irreversible
damage to the skin; namely, visible necrosis through the epidermis
and into the dermis occurring after exposure to a substance or
mixture.
    Skin irritation refers to the production of reversible damage to
the skin occurring after exposure to a substance or mixture.
    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 existing
animal data, followed by in vitro data and then 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

    Substances shall be allocated to one of the following categories
within this hazard class:
    (a) Category 1 (skin corrosion)
    This category may be further divided into up to three sub-
categories (1A, 1B and 1C)
    (b) Category 2 (skin irritation)

A.2.2.1 Classification Based on Standard Animal Test Data

A.<IP_ADDRESS> Skin Corrosion

    A.<IP_ADDRESS> A substance is corrosive to the skin when it produces
destruction of skin tissue, namely, visible necrosis through the
epidermis and into the dermis, in at least one tested animal after
exposure up to a 4-hour duration.
    A.<IP_ADDRESS> Three sub-categories of Category 1 are provided in
Table A.2.1, all of which shall be regulated as Category 1.

       Table A.2.1--Skin Corrosion Category and Sub-Categories \a\
------------------------------------------------------------------------
                                                     Criteria
------------------------------------------------------------------------
Category 1..............................  Destruction of skin tissue,
                                           namely, visible necrosis
                                           through the epidermis and
                                           into the dermis, in at least
                                           one tested animal after
                                           exposure <=4 h.
Sub-category 1A.........................  Corrosive responses in at
                                           least one animal following
                                           exposure <=3 min during an
                                           observation period <=1 h.
Sub-category 1B.........................  Corrosive responses in at
                                           least one animal following
                                           exposure >3 min and <=1 h and
                                           observations <=14 days.
Sub-category 1C.........................  Corrosive responses in at
                                           least one animal after
                                           exposures >1 h and <=4 h and
                                           observations <=14 days.
------------------------------------------------------------------------
\a\ The use of human data is discussed in A.2.3.

A.2.2.2 Skin Irritation

    A.<IP_ADDRESS> A single irritant category (Category 2) is presented
in the Table A.2.2. A substance is irritant to skin when it produces
reversible damage to the skin following its application for up to 4
hours.
    The major criterion for the irritant category is that at least 2
tested animals have a mean score of >=2.3 <=4.0.
    A.<IP_ADDRESS> An irritation category (Category 2) is provided that:
    (a) Recognizes that some test substances may lead to effects
which persist throughout the length of the test; and
    (b) acknowledges that animal responses in a test may be
variable.
    A.<IP_ADDRESS> Reversibility of skin lesions is another consideration
in evaluating irritant responses. When inflammation persists to the
end of the observation period in two 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.<IP_ADDRESS> 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 fulfill 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.

                Table A.2.2--Skin Irritation Category a b
------------------------------------------------------------------------
                                                     Criteria
------------------------------------------------------------------------
Irritant (Category 2)...................  (1) Mean score of >=2.3 <=4.0
                                           for erythema/eschar or for
                                           edema in at least 2 of 3
                                           tested animals from gradings
                                           at 24, 48 and 72 hours after
                                           patch removal or, if
                                           reactions are delayed, from
                                           grades on 3 consecutive days
                                           after the onset of skin
                                           reactions; or
                                          (2) Inflammation that persists
                                           to the end of the observation
                                           period normally 14 days in at
                                           least 2 animals, particularly
                                           taking into account alopecia
                                           (limited area),
                                           hyperkeratosis, hyperplasia,
                                           and scaling; or
                                          (3) In some cases where there
                                           is pronounced variability of
                                           response among animals, with
                                           very definite positive
                                           effects related to chemical
                                           exposure in a single animal
                                           but less than the criteria
                                           above.
------------------------------------------------------------------------
\a\ Grading criteria are understood as described in OECD Test Guideline
  404.

A.2.3 Classification in a Tiered Approach

    A.2.3.1 A tiered approach to the evaluation of initial
information shall be used (Figure A.2.1) recognizing that not all
elements may be relevant.
    A.2.3.2 Existing human and animal data including information
from single or repeated exposure should be the first line of
evaluation, as they give information directly relevant to effects on
the skin.
    A.2.3.3 Acute dermal toxicity data may be used for
classification. 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. Solid substances
(powders) may become corrosive or irritant when moistened or in
contact with moist skin or mucous membranes.
    A.2.3.4 In vitro alternatives that have been scientifically
validated shall be used to make classification decisions.
    A.2.3.5 Likewise, pH extremes like <=2 and >=11.5 may indicate
skin effects, especially when associated with significant acid/
alkaline reserve (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 acid/alkaline reserve suggests the
substance or mixture may not be corrosive despite the low or high pH
value, this needs to be confirmed by other data, preferably data
from an appropriate validated in vitro test.
    A.2.3.6 In some cases sufficient information may be available
from structurally related substances to make classification
decisions.
    A.2.3.7 The tiered approach explains how to organize existing
information on a substance and to make a weight of evidence decision
about hazard assessment and hazard classification (ideally without
conducting new animal tests). 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.
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BILLING CODE 4510-26-C

A.2.4 Classification Criteria for Mixtures

A.2.4.1 Classification of Mixtures When Data Are Available for the
Complete Mixture

    A.<IP_ADDRESS> The mixture shall be classified using the criteria for
substances, taking into account the tiered approach to evaluate data
for this hazard class (as illustrated in Figure A.2.1).
    A.<IP_ADDRESS> When considering testing of the mixture, classifiers
must use a tiered approach as included in the criteria for
classification of substances for skin corrosion and irritation to
help ensure an accurate classification, as well as to avoid
unnecessary animal testing. In the absence of any other information,
a mixture is considered corrosive (Skin Category 1) if it has a pH
<=2 or a pH >=11.5. However, if consideration of acid/alkaline
reserve suggests the mixture may not be corrosive despite the low or
high pH value, then further evaluation may be necessary.

A.2.4.2 Classification of Mixtures When Data Are Not Available for the
Complete Mixture: Bridging Principles

    A.<IP_ADDRESS> Where the mixture itself has not been tested to
determine its skin corrosion/irritation potential, 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 hazard 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.<IP_ADDRESS> In order to make use of all available data for
purposes of classifying the skin corrosion/irritation hazards of
mixtures, the following assumption has been made and is applied
where appropriate in the tiered approach:
    The ``relevant ingredients'' of a mixture are those which are
present in concentrations >=1% (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.<IP_ADDRESS> In general, the approach to classification of mixtures
as corrosive or irritant to the 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 corrosive or irritant
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.<IP_ADDRESS> Table A.2.3 below provides the cut-off value/
concentration limits to be used to determine if the mixture is
considered to be corrosive or irritant to the skin.
    A.<IP_ADDRESS> 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.<IP_ADDRESS> and A.<IP_ADDRESS> 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 in 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 corrosion Category 1 if it contains
>=1% of a corrosive ingredient and as skin irritation 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.<IP_ADDRESS> 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 cut-off values/concentration
limits 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.<IP_ADDRESS> If there are data showing that (an) ingredient(s) may
be corrosive or irritant to skin 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).

  Table A.2.3--Concentration of Ingredients of a Mixture Classified as Skin Category 1 or 2 That Would Trigger
                               Classification of the Mixture as Hazardous to Skin
                                                [Category 1 or 2]
----------------------------------------------------------------------------------------------------------------
                                                            Concentration triggering classification of a mixture
                                                                                as:
                                                          ------------------------------------------------------
            Sum of ingredients classified as:               Skin corrosive              Skin irritant
                                                          ------------------------------------------------------
                                                              Category 1                  Category 2
----------------------------------------------------------------------------------------------------------------
Skin Category 1..........................................              >=5%  >=1% but <5%
Skin Category 2..........................................  ................  >=10%
(10 x Skin Category 1) + Skin Category 2.................  ................  >=10%
----------------------------------------------------------------------------------------------------------------
Note: Where data are available and the sub-categories of skin Category 1 (corrosive) are used, the sum of all
  ingredients of a mixture classified as sub-category 1A, 1B or 1C respectively, must each be >=5% in order to
  classify the mixture as either skin sub-category 1A, 1B or 1C. Where the sum of 1A ingredients is <5% but the
  sum of 1A + 1B ingredients is >=5%, the mixturemust be classified as sub-category 1B. Similarly, where the sum
  of 1A + 1B ingredients is <5% but the sum of 1A + 1B + 1C ingredients is >=5% the mixture must be classified
  as sub-category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without
  sub-categorization, the mixture must be classified as Category 1 without sub-categorization if the sum of all
  ingredients corrosive to skin is >=5%.

     Table A.2.4--Concentration of Ingredients of a Mixture When the
Additivity Approach Does Not Apply, That Would Trigger Classification of
                    the Mixture as Hazardous to Skin
------------------------------------------------------------------------
                                                      Mixture classified
           Ingredient:              Concentration:         as: Skin
------------------------------------------------------------------------
Acid with pH <=2.................              >=1%  Category 1.
Base with pH >=11.5..............              >=1%  Category 1.
Other corrosive (Category 1)                   >=1%  Category 1.
 ingredient.
Other irritant (Category 2)                    >=3%  Category 2.
 ingredient, including acids and
 bases.
------------------------------------------------------------------------

A.3 Serious Eye Damage/Eye Irritation

A.3.1 Definitions and General Considerations

    A.3.1.1 Serious eye damage refers to the production of tissue
damage in the eye, or serious physical decay of vision, which is not
fully reversible, occurring after exposure of the eye to a substance
or mixture.
    Eye irritation refers to the production of changes in the eye,
which are fully reversible, occurring after exposure of the eye to a
substance or mixture.
    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
existing animal data, followed by in vitro data and then 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

    Substances are allocated to one of the categories within this
hazard class, Category 1 (serious eye damage) or Category 2 (eye
irritation), as follows:
    (a) Category 1 (serious eye damage/irreversible effects on the
eye): Substances that have the potential to seriously damage the
eyes (see Table A.3.1).
    (b) Category 2 (eye irritation/reversible effects on the eye):
Substances that have the potential to induce reversible eye
irritation (see Table A.3.2).
    A.3.2.1 Classification based on standard animal test data.
    A.<IP_ADDRESS> Serious eye damage (Category 1)/Irreversible effects
on the eye.
    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 observed in at least 2 of 3 tested animals detected in a
Draize eye test with rabbits, because severe lesions like these
usually do not reverse within a 21-day observation period.

Table A.3.1--Serious Eye Damage/Irreversible Effects on the Eye Category
                                    a
------------------------------------------------------------------------
                                                     Criteria
------------------------------------------------------------------------
Category 1: Serious eye damage/           A substance that produces:
 Irreversible effects on the eye.         (a) In at least one animal
                                           effects on the cornea, iris
                                           or conjunctiva that are not
                                           expected to reverse or have
                                           not fully reversed within an
                                           observation period of
                                           normally 21 days; and/or
                                          (b) in at least 2 of 3 tested
                                           animals, a positive response
                                           of:
                                             (i) Corneal opacity >=3;
                                              and/or
                                             (ii) iritis >1.5;
                                          calculated as the mean scores
                                           following grading at 24, 48
                                           and 72 hours after
                                           instillation of the test
                                           material.
------------------------------------------------------------------------
\a\ Grading criteria are understood as described in OECD Test Guideline
  405.

    A.3.2.2 Eye irritation (Category 2)/Reversible effects on the
eye.
    A.<IP_ADDRESS> A single Category 2 is provided in Table A.3.2 for
substances that have the potential to induce reversible eye
irritation.
    When data are available, substances may be classified into
Category 2A and Category 2B:
    (a) For substances inducing eye irritant effects reversing
within an observation time of normally 21 days, Category 2A applies.
    (b) For substances inducing eye irritant effects reversing
within an observation time of 7 days, Category 2B applies.
    When a substance is classified as Category 2, without further
categorization, the classification criteria are the same as those
for 2A.
    A.3.2.3 For those substances where there is pronounced
variability among animal responses, this information may be taken
into account in determining the classification.

         Table A.3.2--Reversible Effects on the Eye Categories a
------------------------------------------------------------------------
                                                Criteria
------------------------------------------------------------------------
                                Substances that have the potential to
                                 induce reversible eye irritation.
Category 2/2A.................  Substances that produce in at least 2 of
                                 3 tested animals a positive response
                                 of:
                                   (a) corneal opacity >=1; and/or
                                   (b) iritis >=1; and/or
                                   (c) conjunctival redness >=2; and/or
                                   (d) conjunctival edema (chemosis) >=2
                                calculated as the mean scores following
                                 grading at 24, 48 and 72 hours after
                                 instillation of the test material, and
                                 which fully reverses within an
                                 observation period of normally 21 days.
Category 2B...................  Within Category 2A an eye irritant is
                                 considered mildly irritating to eyes
                                 (Category 2B) when the effects listed
                                 above are fully reversible within 7
                                 days of observation.
------------------------------------------------------------------------
\a\ Grading criteria are understood as described in OECD Test Guideline
  405.

A.3.3 Classification in a Tiered Approach

    A.3.3.1 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.3.3.2 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 any testing for serious eye damage/eye irritation
in order to avoid testing for local effects on eyes with skin
corrosive substances.
    A.3.3.3 In vitro alternatives that have been scientifically
validated and accepted shall be used to make classification
decisions.
    A.3.3.4 Likewise, pH extremes like <=2 and >=11.5, may indicate
serious eye damage, especially when associated with significant
acid/alkaline reserve (buffering capacity). Generally, such
substances are expected to produce significant effects on the eyes.
In the absence of any other information, a substance is considered
to cause serious eye damage (Category 1) if it has a pH <=2 or
>=11.5.

However, if consideration of acid/alkaline reserve suggests the
substance may not cause serious eye damage despite the low or high
pH value, this needs needs to be confirmed by other data, preferably
by data from an appropriate validated in vitro test.
    A.3.3.5 In some cases sufficient information may be available
from structurally related substances to make classification
decisions.
    A.3.3.6 The tiered approach explains how to organize existing
information and to make a weight-of-evidence decision about hazard
assessment and hazard classification (ideally without conducting new
animal tests). Animal testing with corrosive substances should be
avoided wherever possible. 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.
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A.3.4 Classification Criteria for Mixtures

A.3.4.1 Classification of Mixtures When Data Are Available for the
Complete Mixture

    A.<IP_ADDRESS> The mixture will be classified using the criteria for
substances, and taking into account the tiered approach to evaluate
data for this hazard class (as illustrated in Figure A.3.1).
    A.<IP_ADDRESS> When considering testing of the mixture, chemical
manufacturers shall use a tiered approach 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 to avoid unnecessary animal testing. In
the absence of any other information, a mixture is considered to
cause serious eye damage (Category 1) if it has a pH <=2 or >=11.5.
However, if consideration of acid/alkaline reserve suggests the
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.<IP_ADDRESS> 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 hazard 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.<IP_ADDRESS> For purposes of classifying the serious eye damage/eye
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
serious eye damage/eye irritation, that ingredient shall also be
considered relevant.
    A.<IP_ADDRESS> 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 skin corrosive or
serious eye damage/eye irritant ingredient contributes to the
overall serious eye damage/eye irritation properties of the mixture
in proportion to its potency and concentration. A weighting factor
of 10 is used for skin corrosive and serious eye damaging
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 serious eye damaging/eye 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.<IP_ADDRESS> Table A.3.3 provides the cut-off value/concentration
limits to be used to determine if the mixture must be classified as
seriously damaging to the eye or an eye irritant.
    A.<IP_ADDRESS> 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.<IP_ADDRESS> and A.<IP_ADDRESS> might not work given that many of such
substances are seriously damaging to the eye/eye irritating 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 (subject to
consideration of acid/alkali reserve) than the concentration limits
of Table A.3.3. A mixture containing skin corrosive or serious eye
damaging/eye irritating 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 serious eye damage (Category 1) if it contains >=1% of
a skin corrosive or serious eye damaging ingredient and as Eye
Irritation (Category 2) when it contains >=3% of an eye 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.<IP_ADDRESS> On occasion, reliable data may show that the
irreversible/reversible 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 approach should be applied as referred to in section A.3.3,
Figure A.3.1 and explained in detail in this chapter.
    A.<IP_ADDRESS> If there are data showing that (an) ingredient(s) may
be corrosive to the skin or seriously damaging to the eye/eye
irritating at a concentration of <1% (corrosive to the skin or
seriously damaging to the eye) or <3% (eye irritant), the mixture
shall be classified accordingly (See also paragraph A.0.4.3, Use of
cut-off values/concentration limits).

  Table A.3.3--Concentration of Ingredients of a Mixture Classified as
      Skin Category 1 and/or Eye Category 1 or 2 That Would Trigger
         Classification of the Mixtures as Hazardous to the Eye
------------------------------------------------------------------------
                                 Concentration triggering classification
                                             of a mixture as
 Sum of ingredients classified -----------------------------------------
              as                  Serious eye damage     Eye irritation
                               -----------------------------------------
                                      Category 1         Category 2/2A
------------------------------------------------------------------------
Skin corrosion (Category 1) +                   >=3%   >=1% but <3%.
 Serious eye damage (Category
 1) \a\.
Eye irritation (Category 2)...  .....................  \b\ >=10%.
10 x (Skin corrosion (Category  .....................  >=10%.
 1) + Serious eye damage
 (Category 1)) \a\ + Eye
 irritation (Category 2).
------------------------------------------------------------------------
Notes:
\a\ If an ingredient is classified as both skin Category 1 and eye
  Category 1 its concentration is considered only once in the
  calculation.
\b\ A mixture may be classified as Eye Irritation Category 2B in cases
  when all relevant ingredients are classified as Eye Irritation
  Category 2B.

  Table A.3.4--Concentration of Ingredients of a Mixture for Which the
Additivity Approach Does Not Apply, That Would Trigger Classification of
                   the Mixture as Hazardous to the Eye
------------------------------------------------------------------------
                                  Concentration   Mixture classified as:
           Ingredient                  (%)
------------------------------------------------------------------------
Acid with pH <=2...............              >=1  Serious eye damage
                                                   (Category 1).
Base with pH >=11.5............              >=1  Serious eye damage
                                                   (Category 1).
Other skin corrosive or serious              >=1  Serious eye damage
 eye damage (Category 1)                           (Category 1).
 ingredients.
Other eye irritant (Category 2)              >=3  Eye irritation
 ingredients.                                      (Category 2).
------------------------------------------------------------------------

A.4 Respiratory or Skin Sensitization

A.4.1 Definitions and General Considerations

    A.4.1.1 Respiratory sensitization refers to hypersensitivity of
the airways occurring after inhalation of a substance or mixture.
    Skin sensitization refers to an allergic response occurring
after skin contact with a substance or mixture.
    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.<IP_ADDRESS> Hazard categories
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.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.

     Table A.4.1--Hazard Category and Sub-Categories for Respiratory
                               Sensitizers
------------------------------------------------------------------------
          Category 1:                    Respiratory sensitizer
------------------------------------------------------------------------
                                A substance is classified as a
                                 respiratory sensitizer:
                                (a) If there is evidence in humans that
                                 the substance can lead to specific
                                 respiratory hypersensitivity and/or
                                (b) if there are positive results from
                                 an appropriate animal test.\1\
Sub-category 1A:..............  Substances showing a high frequency of
                                 occurrence in humans; or a probability
                                 of occurrence of a high sensitization
                                 rate in humans based on animal or other
                                 tests.1 Severity of reaction may also
                                 be considered.
Sub-category 1B:..............  Substances showing a low to moderate
                                 frequency of occurrence in humans; or a
                                 probability of occurrence of a low to
                                 moderate sensitization rate in humans
                                 based on animal or other tests.\1\
                                 Severity of reaction may also be
                                 considered.
------------------------------------------------------------------------

    A.<IP_ADDRESS> Human evidence
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS> Animal studies
    A.<IP_ADDRESS>.1 Data from appropriate animal studies \2\ which may
be indicative of the potential of a substance to cause sensitization
by inhalation in humans \3\ may include:
---------------------------------------------------------------------------

    \2\ 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.
    \3\ 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 bronchial
hyperactivity, they should not be considered as respiratory
sensitizers.
---------------------------------------------------------------------------

    (a) Measurements of Immunoglobulin E (IgE) and other specific
immunological parameters, for example in mice.
    (b) Specific pulmonary responses in guinea pigs.

A.4.2.2 Skin Sensitizers

    A.<IP_ADDRESS> Hazard categories
    A.<IP_ADDRESS>.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 sub-
categories 1A or 1B using a weight of evidence approach in
accordance with the criteria given in Table A.4.2 and on the basis
of reliable and good quality evidence from human cases or
epidemiological studies and/or observations from appropriate studies
in experimental animals according to the guidance values provided in
A.<IP_ADDRESS>.1 and A.<IP_ADDRESS>.2 for sub-category 1A and in A.<IP_ADDRESS>.2
and A.<IP_ADDRESS>.3 for sub-category 1B.
    A.<IP_ADDRESS>.2 Where data are not sufficient for sub-
categorization, skin sensitizers shall be classified in Category 1.

  Table A.4.2--Hazard Category and Sub-Categories for Skin Sensitizers
------------------------------------------------------------------------
          Category 1:                        Skin sensitizer
------------------------------------------------------------------------
                                A substance is classified as a skin
                                 sensitizer:
                                (a) If there is evidence in humans that
                                 the substance can lead to sensitization
                                 by skin contact in a substantial number
                                 of persons, or
                                (b) if there are positive results from
                                 an appropriate animal test.
Sub-category 1A:..............  Substances showing a high frequency of
                                 occurrence in humans and/or a high
                                 potency in animals can be presumed to
                                 have the potential to produce
                                 significant sensitization in humans.
                                 Severity of reaction may also be
                                 considered.
Sub-category 1B:..............  Substances showing a low to moderate
                                 frequency of occurrence in humans and/
                                 or a low to moderate potency in animals
                                 can be presumed to have the potential
                                 to produce sensitization in humans.
                                 Severity of reaction may also be
                                 considered.
------------------------------------------------------------------------

    A.<IP_ADDRESS> Human evidence
    A.<IP_ADDRESS>.1 Human evidence for sub-category 1A may include:
    (a) Positive responses at <=500 [micro]g/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.<IP_ADDRESS>.2 Human evidence for sub-category 1B may include:
    (a) Positive responses at >500 [micro]g/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.<IP_ADDRESS> Animal studies
    A.<IP_ADDRESS>.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.\4\
---------------------------------------------------------------------------

    \4\ 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.<IP_ADDRESS>.2 Animal test results for sub-category 1A can include
data with values indicated in Table A.4.3 below:

          Table A.4.3--Animal Test Results for Sub-Category 1A
------------------------------------------------------------------------
             Assay                              Criteria
------------------------------------------------------------------------
Local lymph node assay........  EC3 value <=2%.
Guinea pig maximization test..  >=30% responding at <=0.1% intradermal
                                 induction dose or >=60% responding at
                                 >0.1% to <=1% intradermal induction
                                 dose.

Buehler assay.................  >=15% responding at <=0.2% topical
                                 induction dose or >=60% responding at
                                 >0.2% to <=20% topical induction dose.
------------------------------------------------------------------------
Note: EC3 refers to the estimated concentration of test chemical
  required to induce a stimulation index of 3 in the local lymph node
  assay.

    A.<IP_ADDRESS>.3 Animal test results for sub-category 1B can include
data with values indicated in the following Table A.4.4:

          Table A.4.4--Animal Test Results for Sub-Category 1B
------------------------------------------------------------------------
             Assay                              Criteria
------------------------------------------------------------------------
Local lymph node assay........  EC3 value >2%.
Guinea pig maximization test..  >=30% to <60% responding at >0.1% to
                                 <=1% intradermal induction dose or
                                 >=30% responding at >1% intradermal
                                 induction dose.
Buehler assay.................  >=15% to <60% responding at >0.2% to
                                 <=20% topical induction dose or >=15%
                                 responding at >20% topical induction
                                 dose.
------------------------------------------------------------------------
Note: EC3 refers to the estimated concentration of test chemical
  required to induce a stimulation index of 3 in the local lymph node
  assay.

    A.<IP_ADDRESS> Specific considerations
    A.<IP_ADDRESS>.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 humans (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.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>, 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.<IP_ADDRESS>.4 Immunological contact urticaria
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.4.2 Substances which cause immunological contact
urticaria without meeting the criteria for respiratory sensitizers
shall be considered for classification as skin sensitizers.
    A.<IP_ADDRESS>.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.<IP_ADDRESS> 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 within one hazard category/
subcategory, Substantially similar mixtures, and Aerosols.

A.4.3.3 Classification of Mixtures When Data Are Available for All
Ingredients or Only for Some Ingredients of the Mixture

    The mixture shall be classified as a respiratory or skin
sensitizer when at least one ingredient has been classified as a
respiratory or skin sensitizer and is present at or above the
appropriate cut-off value/concentration limit for the specific
endpoint as shown in Table A.4.5.

  Table A.4.5--Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Either Respiratory
                Sensitizers or Skin Sensitizers That Would Trigger Classification of the Mixture
----------------------------------------------------------------------------------------------------------------
                                                               Cut-off values/concentration limits triggering
                                                                      classification of a mixture as:
                                                          ------------------------------------------------------
                                                               Respiratory sensitizer         Skin sensitizer
                Ingredient classified as:                            Category 1                  Category 1
                                                          ------------------------------------------------------
                                                            Solid/Liquid                    All physical states
                                                                 (%)             Gas                (%)
----------------------------------------------------------------------------------------------------------------
Respiratory Sensitizer: Category 1.......................           >=0.1           >=0.1  .....................
Respiratory Sensitizer: Sub-category 1A..................           >=0.1           >=0.1  .....................
Respiratory Sensitizer: Sub-category 1B..................           >=1.0           >=0.2  .....................
Skin Sensitizer: Category 1..............................  ..............  ..............                  >=0.1
Skin Sensitizer: Sub-category 1A.........................  ..............  ..............                  >=0.1
Skin Sensitizer: Sub-category 1B.........................  ..............  ..............                  >=1.0
----------------------------------------------------------------------------------------------------------------

A.5 Germ Cell Mutagenicity

A.5.1 Definitions and General Considerations

    A.5.1.1 Germ cell mutagenicity refers to heritable gene
mutations, including heritable structural and numerical chromosome
aberrations in germ cells occurring after exposure to a substance or
mixture.
    A.5.1.2 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.5.1.3 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 non-physiological manner (temporarily) alter its replication.
Genotoxicity test results are usually taken as indicators for
mutagenic effects.
    A.5.1.4 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.

         Figure A.5.1--Hazard Categories for Germ Cell Mutagens
------------------------------------------------------------------------

-------------------------------------------------------------------------
CATEGORY 1: Substances known to induce heritable mutations or to be
 regarded as if they induce heritable mutations in the germ cells of
 humans.
    Category 1A: Substances known to induce heritable mutations in germ
     cells of humans. Positive evidence from human epidemiological
     studies.
    Category 1B: Substances which should be regarded as if they induce
     heritable mutations in the germ cells of humans:
        (a) Positive result(s) from in vivo heritable germ cell
         mutagenicity tests in mammals; or
        (b) Positive result(s) from in vivo somatic cell mutagenicity
         tests in mammals, in combination with some evidence that the
         substance has potential to cause mutations to germ cells. This
         supporting evidence may, for example, be derived from
         mutagenicity/genotoxicity tests in germ cells in vivo, or by
         demonstrating the ability of the substance or its metabolite(s)
         to interact with the genetic material of germ cells; or
        (c) Positive results from tests showing mutagenic effects in the
         germ cells of humans, without demonstration of transmission to
         progeny; for example, an increase in the frequency of
         aneuploidy in sperm cells of exposed people.
CATEGORY 2: Substances which cause concern for humans owing to the
 possibility that they may induce heritable mutations in the germ cells
 of humans.
Positive evidence obtained from experiments in mammals and/or in some
 cases from in vitro experiments, obtained from:
    (a) Somatic cell mutagenicity tests in vivo, in mammals; or
    (b) Other in vivo somatic cell genotoxicity tests which are
     supported by positive results from in vitro mutagenicity assays.
------------------------------------------------------------------------
Note: Substances which are positive in in vitro mammalian mutagenicity
  assays, and which also show chemical structure activity relationship
  to known germ cell mutagens, should be considered for classification
  as Category 2 mutagens.

    A.5.2.2 Specific considerations for classification of substances
as germ cell mutagens:
    A.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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 5
---------------------------------------------------------------------------

    \5\ 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.<IP_ADDRESS> Classification of mixtures shall be based on the
available test data for the

individual ingredients of the mixture using cut-off values/
concentration limits for the ingredients classified as germ cell
mutagens.
    A.<IP_ADDRESS> The mixture will be classified as a mutagen when at
least one ingredient has been classified as a Category 1A, Category
1B or Category 2 mutagen and is present at or above the appropriate
cut-off value/concentration limit as shown in Table A.5.1 below for
Category 1 and 2 respectively.

  Table A.5.1--Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Germ Cell Mutagens
                                That Would Trigger Classification of the Mixture
----------------------------------------------------------------------------------------------------------------
                                                                       Cut-off/concentration limits triggering
                                                                           classification of a mixture as:
                     Ingredient classified as:                     ---------------------------------------------
                                                                      Category 1 mutagen     Category 2 mutagen
----------------------------------------------------------------------------------------------------------------
Category 1A/B mutagen.............................................                >=0.1%   .....................
Category 2 mutagen................................................  .....................                >=1.0%
----------------------------------------------------------------------------------------------------------------
Note: The cut-off values/concentration limits in the table above apply to solids and liquids (w/w units) as well
  as gases (v/v units).

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.<IP_ADDRESS> 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) 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

    Carcinogenicity refers to the induction of cancer or an increase
in the incidence of cancer occurring after exposure to a substance
or mixture. 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 6
---------------------------------------------------------------------------

    \6\ See Non-mandatory appendix F of this section, 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.

             Figure A.6.1--Hazard Categories for Carcinogens
------------------------------------------------------------------------

-------------------------------------------------------------------------
CATEGORY 1: Known or presumed human carcinogens. The classification of a
 substance as a Category 1 carcinogen is done on the basis of
 epidemiological and/or animal data. This classification is further
 distinguished on the basis of whether the evidence for classification
 is largely from human data (Category 1A) or from animal data (Category
 1B):
    Category 1A: Known to have carcinogenic potential for humans.
     Classification in this category is largely based on human evidence.
    Category 1B: Presumed to have carcinogenic potential for humans.
     Classification in this category is largely based on animal
     evidence. The classification of a substance in Category 1A and 1B
     is based on strength of evidence together with weight of evidence
     considerations (See paragraph A.6.2.5). Such evidence may be
     derived from:
        --human studies that establish a causal relationship between
         human exposure to a substance and the development of cancer
         (known human carcinogen); or
        --animal experiments for which there is sufficient evidence to
         demonstrate animal carcinogenicity (presumed human carcinogen).
    In addition, on a case by case basis, scientific judgment may
     warrant a decision of presumed human carcinogenicity derived from
     studies showing limited evidence of carcinogenicity in humans
     together with limited evidence of carcinogenicity in experimental
     animals.

CATEGORY 2: Suspected human carcinogens. The classification of a
 substance in Category 2 is done on the basis of evidence obtained from
 human and/or animal studies, but which is not sufficiently convincing
 to place the substance in Category 1A or B. This classification is
 based on strength of evidence together with weight of evidence
 considerations (See paragraph A.6.2.5). Such evidence may be from
 either limited evidence of carcinogenicity in human studies or from
 limited evidence of carcinogenicity in animal studies.
Other considerations: Where the weight of evidence for the
 carcinogenicity of a substance does not meet the above criteria, any
 positive study conducted in accordance with established scientific
 principles, and which reports statistically significant findings
 regarding the carcinogenic potential of the substance, must be noted on
 the safety data sheet.
------------------------------------------------------------------------

    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 of this section.)
    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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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.<IP_ADDRESS> 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 7
---------------------------------------------------------------------------

    \7\ 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.

  Table A.6.1--Cut-Off Values/Concentration Limits of Ingredients of a
  Mixture Classified as Carcinogen That Would Trigger Classification of
                               the Mixture
------------------------------------------------------------------------
                                        Category 1         Category 2
     Ingredient classified as:          carcinogen         carcinogen
------------------------------------------------------------------------
Category 1 carcinogen.............            >=0.1%   .................
Category 2 carcinogen.............  .................   >=0.1% (note 1)
------------------------------------------------------------------------
Note: If a Category 2 carcinogen ingredient is present in the mixture at
  a concentration between 0.1% and 1%, information is required on the
  SDS for a product. However, a label warning is optional. If a Category
  2 carcinogen ingredient is present in the mixture at a concentration
  of =1%, both an SDS and a label is required and the
  information must be included on each.

A.6.3.2 Classification of Mixtures When Data Are Available for the
Complete Mixture

    A mixture may be classified based on the available test data for
the mixture as a whole. In such cases, the test results for the
mixture as a whole must be shown to be conclusive taking into
account dose and other factors such as duration, observations and
analysis (e.g., statistical analysis, test sensitivity) of
carcinogenicity test systems.

A.6.3.3 Classification of Mixtures When Data Are Not Available for the
Complete Mixture: Bridging Principles

    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 8
---------------------------------------------------------------------------

    \8\ See Non-mandatory appendix F of this section 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.<IP_ADDRESS> National Toxicology Program (NTP), ``Report on
Carcinogens'' (latest edition);
    A.<IP_ADDRESS> 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 this section
subpart, 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 refers to adverse effects on
sexual function and fertility in adult males and females, as well as
developmental toxicity in the offspring, occurring after exposure to
a substance or mixture. Some reproductive toxic effects cannot be
clearly assigned to either impairment of sexual function and
fertility or to developmental toxicity. Nonetheless, substances and
mixtures 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).

      Figure A.7.1(a)--Hazard Categories for Reproductive Toxicants
------------------------------------------------------------------------

-------------------------------------------------------------------------
CATEGORY 1: Known or presumed human reproductive toxicant. Substance
 shall be classified in Category 1 for reproductive toxicity when they
 are known to have produced an adverse effect on sexual function and
 fertility or on development in humans or when there is evidence from
 animal studies, possibly supplemented with other information, to
 provide a strong presumption that the substance has the capacity to
 interfere with reproduction in humans. The classification of a
 substance is further distinguished on the basis of whether the evidence
 for classification is primarily from human data (Category 1A) or from
 animal data (Category 1B).
    Category 1A: Known human reproductive toxicant. The classification
     of a substance in this category is largely based on evidence from
     humans.
    Category 1B: Presumed human reproductive toxicant. The
     classification of a substance in this category is largely based on
     evidence from experimental animals. Data from animal studies shall
     provide sufficient evidence of an adverse effect on sexual function
     and fertility or on development in the absence of other toxic
     effects, or if occurring together with other toxic effects the
     adverse effect on reproduction is considered not to be a secondary
     non-specific consequence of other toxic effects. However, when
     there is mechanistic information that raises doubt about the
     relevance of the effect for humans, classification in Category 2
     may be more appropriate.
CATEGORY 2: Suspected human reproductive toxicant. Substances shall be
 classified in Category 2 for reproductive toxicity when there is some
 evidence from humans or experimental animals, possibly supplemented
 with other information, of an adverse effect on sexual function and
 fertility, or on development, in the absence of other toxic effects, or
 if occurring together with other toxic effects the adverse effect on
 reproduction is considered not to be a secondary non-specific
 consequence of the other toxic effects, and where the evidence is not
 sufficiently convincing to place the substance in Category 1. For
 instance, deficiencies in the study may make the quality of evidence
 less convincing, and in view of this, Category 2 would be the more
 appropriate classification.
------------------------------------------------------------------------

    Figure A.7.1(b)--Hazard Category for Effects on or Via Lactation
------------------------------------------------------------------------

-------------------------------------------------------------------------
                       Effects on or Via Lactation

Effects on or via lactation shall be classified in a separate single
 category. Chemicals that are absorbed by women and have been shown to
 interfere with lactation or that may be present (including metabolites)
 in breast milk in amounts sufficient to cause concern for the health of
 a breastfed child, shall be classified to indicate this property.
 Classification for effects via lactation shall be assigned on the basis
 of:
    (a) Absorption, metabolism, distribution and excretion studies that
     indicate the likelihood the substance would be present in
     potentially toxic levels in breast milk; and/or
    (b) results of one or two generation studies in animals which
     provide clear evidence of adverse effect in the offspring due to
     transfer in the milk or adverse effect on the quality of the milk;
     and/or
    (c) human evidence indicating a hazard to babies during the
     lactation period.
------------------------------------------------------------------------

A.7.2.2 Basis of Classification

    A.<IP_ADDRESS> 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.<IP_ADDRESS> In the evaluation of toxic effects on the developing
offspring, it is important to consider the possible influence of
maternal toxicity.
    A.<IP_ADDRESS> 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