standard, except pursuant to a Federally-approved state plan.
    (b) * * *
    (1) This section requires chemical manufacturers or importers to
classify the hazards of chemicals which they produce or import, and all
employers to provide information to their employees about the hazardous
chemicals to which they are exposed, by means of a hazard communication
program, labels and other forms of warning, safety data sheets, and
information and training. In addition, this section requires
distributors to transmit the required information to employers.
(Employers who do not produce or import chemicals need only focus on
those parts of this rule that deal with establishing a workplace
program and communicating information to their workers.)
* * * * *
    (3) * * *
    (iv) Laboratory employers that ship hazardous chemicals are
considered to be either a chemical manufacturer or a distributor under
this rule, and thus must ensure that any containers of hazardous
chemicals leaving the laboratory are labeled in accordance with
paragraph (f) of this section, and that a safety data sheet is provided
to distributors and other employers in accordance with paragraphs
(g)(6) and (g)(7) of this section.
* * * * *
    (5) * * *
    (iv) Any distilled spirits (beverage alcohols), wine, or malt
beverage intended for nonindustrial use, as such terms are defined in
the Federal Alcohol Administration Act (27 U.S.C. 201 et seq.) and
regulations issued under that Act, when subject to the labeling
requirements of that Act and labeling regulations issued under that Act
by the Bureau of Alcohol, Tobacco, Firearms and Explosives;
* * * * *
    (6) * * *
    (ii) Any hazardous substance as such term is defined by the
Comprehensive Environmental Response, Compensation and Liability Act
(CERCLA) (42 U.S.C. 9601 et seq.) when the hazardous substance is the
focus of remedial or removal action being conducted under CERCLA in
accordance with Environmental Protection Agency regulations.
* * * * *
    (c) * * *
    Chemical means any substance, or mixture of substances.
* * * * *
    Chemical name means the scientific designation of a chemical in
accordance with the nomenclature system developed by the International
Union of Pure and Applied Chemistry (IUPAC) or the Chemical Abstracts
Service (CAS) rules of nomenclature, or a name that will clearly
identify the chemical for the purpose of conducting a hazard
classification.
    Classification means to identify the relevant data regarding the
hazards of a chemical; review those data to ascertain the hazards
associated with the chemical; and decide whether the chemical will be
classified as hazardous according to the definition of hazardous
chemical in this section. In addition, classification for health and
physical hazards includes the determination of the degree of hazard,
where appropriate, by comparing the data with the criteria for health
and physical hazards.
* * * * *
    Hazard category means the division of criteria within each hazard
class, e.g., oral acute toxicity and flammable liquids include four
hazard categories. These categories compare hazard severity within a
hazard class and should not be taken as a comparison of hazard
categories more generally.
    Hazard class means the nature of the physical or health hazards,
e.g., flammable solid, carcinogen, oral acute toxicity.
    Hazard not otherwise classified (HNOC) means an adverse physical or
health effect identified through evaluation of scientific evidence
during the classification process that does not meet the specified
criteria for the physical and health hazard classes addressed in this
section. This does not extend coverage to adverse physical and health
effects for which there is a hazard class addressed in this section,
but the effect either falls below the cut-off value/concentration limit
of the hazard class or is under a GHS hazard category that has not been
adopted by OSHA (e.g., acute toxicity Category 5).
    Hazard statement means a statement assigned to a hazard class and
category that describes the nature of the hazard(s) of a chemical,
including, where appropriate, the degree of hazard.
    Hazardous chemical means any chemical which is classified as a
physical hazard or a health hazard, a

simple asphyxiant, combustible dust, pyrophoric gas, or hazard not
otherwise classified.
    Health hazard means a chemical which is classified as posing one of
the following hazardous effects: acute toxicity (any route of
exposure); skin corrosion or irritation; serious eye damage or eye
irritation; respiratory or skin sensitization; germ cell mutagenicity;
carcinogenicity; reproductive toxicity; specific target organ toxicity
(single or repeated exposure); or aspiration hazard. The criteria for
determining whether a chemical is classified as a health hazard are
detailed in Appendix A to Sec.  1910.1200--Health Hazard Criteria.
* * * * *
    Label means an appropriate group of written, printed or graphic
information elements concerning a hazardous chemical that is affixed
to, printed on, or attached to the immediate container of a hazardous
chemical, or to the outside packaging.
    Label elements means the specified pictogram, hazard statement,
signal word and precautionary statement for each hazard class and
category.
    Mixture means a combination or a solution composed of two or more
substances in which they do not react.
    Physical hazard means a chemical that is classified as posing one
of the following hazardous effects: explosive; flammable (gases,
aerosols, liquids, or solids); oxidizer (liquid, solid or gas); self-
reactive; pyrophoric (liquid or solid); self-heating; organic peroxide;
corrosive to metal; gas under pressure; or in contact with water emits
flammable gas. See Appendix B to Sec.  1910.1200--Physical Hazard
Criteria.
    Pictogram means a composition that may include a symbol plus other
graphic elements, such as a border, background pattern, or color, that
is intended to convey specific information about the hazards of a
chemical. Eight pictograms are designated under this standard for
application to a hazard category.
    Precautionary statement means a phrase that describes recommended
measures that should be taken to minimize or prevent adverse effects
resulting from exposure to a hazardous chemical, or improper storage or
handling.
    Product identifier means the name or number used for a hazardous
chemical on a label or in the SDS. It provides a unique means by which
the user can identify the chemical. The product identifier used shall
permit cross-references to be made among the list of hazardous
chemicals required in the written hazard communication program, the
label and the SDS.
* * * * *
    Pyrophoric gas means a chemical in a gaseous state that will ignite
spontaneously in air at a temperature of 130 degrees F (54.4 degrees C)
or below.
* * * * *
    Safety data sheet (SDS) means written or printed material
concerning a hazardous chemical that is prepared in accordance with
paragraph (g) of this section.
    Signal word means a word used to indicate the relative level of
severity of hazard and alert the reader to a potential hazard on the
label. The signal words used in this section are ``danger'' and
``warning.'' ``Danger'' is used for the more severe hazards, while
``warning'' is used for the less severe.
    Simple asphyxiant means a substance or mixture that displaces
oxygen in the ambient atmosphere, and can thus cause oxygen deprivation
in those who are exposed, leading to unconsciousness and death.
* * * * *
    Substance means chemical elements and their compounds in the
natural state or obtained by any production process, including any
additive necessary to preserve the stability of the product and any
impurities deriving from the process used, but excluding any solvent
which may be separated without affecting the stability of the substance
or changing its composition.
    Trade secret means any confidential formula, pattern, process,
device, information or compilation of information that is used in an
employer's business, and that gives the employer an opportunity to
obtain an advantage over competitors who do not know or use it.
Appendix E to Sec.  1910.1200--Definition of Trade Secret, sets out the
criteria to be used in evaluating trade secrets.
* * * * *
    (d) Hazard classification. (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. 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 requirement.
    (2) Chemical manufacturers, importers or employers classifying
chemicals shall identify and consider the full range of available
scientific literature and other evidence concerning the potential
hazards. There is no requirement to test the chemical to determine how
to classify its hazards. Appendix A to Sec.  1910.1200 shall be
consulted for classification of health hazards, and Appendix B to Sec.
1910.1200 shall be consulted for the classification of physical
hazards.
    (3) Mixtures. (i) Chemical manufacturers, importers, or employers
evaluating chemicals shall follow the procedures described in
Appendices A and B to Sec.  1910.1200 to classify the hazards of the
chemicals, including determinations regarding when mixtures of the
classified chemicals are covered by this section.
    (ii) When classifying mixtures they produce or import, chemical
manufacturers and importers of mixtures may rely on the information
provided on the current safety data sheets of the individual
ingredients, except where the chemical manufacturer or importer knows,
or in the exercise of reasonable diligence should know, that the safety
data sheet misstates or omits information required by this section.
* * * * *
    (e) * * *
    (1) * * *
    (i) A list of the hazardous chemicals known to be present using a
product identifier that is referenced on the appropriate safety data
sheet (the list may be compiled for the workplace as a whole or for
individual work areas); and,
* * * * *
    (f) Labels and other forms of warning--(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 do not
have to be addressed on the container. Where the chemical manufacturer
or importer is required to label, tag or mark the following information
shall be provided:
    (i) Product identifier;
    (ii) Signal word;
    (iii) Hazard statement(s);
    (iv) Pictogram(s);
    (v) Precautionary statement(s); and,
    (vi) Name, address, and telephone number of the chemical
manufacturer, importer, or other responsible party.
    (2) The chemical manufacturer, importer, or distributor shall
ensure that the information provided under paragraphs (f)(1)(i) through
(v) of this section is in accordance with Appendix

C to Sec.  1910.1200, for each hazard class and associated hazard
category for the hazardous chemical, prominently displayed, and in
English (other languages may also be included if appropriate).
    (3) The chemical manufacturer, importer, or distributor shall
ensure that the information provided under paragraphs (f)(1)(ii)
through (iv) of this section is located together on the label, tag, or
mark.
    (4) Solid materials. (i) For solid metal (such as a steel beam or a
metal casting), solid wood, or plastic items that are not exempted as
articles due to their downstream use, or shipments of whole grain, the
required label may be transmitted to the customer at the time of the
initial shipment, and need not be included with subsequent shipments to
the same employer unless the information on the label changes;
    (ii) The label may be transmitted with the initial shipment itself,
or with the safety data sheet that is to be provided prior to or at the
time of the first shipment; and,
    (iii) This exception to requiring labels on every container of
hazardous chemicals is only for the solid material itself, and does not
apply to hazardous chemicals used in conjunction with, or known to be
present with, the material and to which employees handling the items in
transit may be exposed (for example, cutting fluids or pesticides in
grains).
    (5) 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.
    (6) Workplace labeling. Except as provided in paragraphs (f)(7) and
(f)(8) of this section, the employer shall ensure that each container
of hazardous chemicals in the workplace is labeled, tagged or marked
with either:
    (i) The information specified under paragraphs (f)(1)(i) through
(v) of this section for labels on shipped containers; or,
    (ii) Product identifier and words, pictures, symbols, or
combination thereof, which provide at least general information
regarding the hazards of the chemicals, and which, in conjunction with
the other information immediately available to employees under the
hazard communication program, will provide employees with the specific
information regarding the physical and health hazards of the hazardous
chemical.
    (7) The employer may use signs, placards, process sheets, batch
tickets, operating procedures, or other such written materials in lieu
of affixing labels to individual stationary process containers, as long
as the alternative method identifies the containers to which it is
applicable and conveys the information required by paragraph (f)(6) of
this section to be on a label. The employer shall ensure the written
materials are readily accessible to the employees in their work area
throughout each work shift.
    (8) The employer is not required to label portable containers into
which hazardous chemicals are transferred from labeled containers, and
which are intended only for the immediate use of the employee who
performs the transfer. For purposes of this section, drugs which are
dispensed by a pharmacy to a health care provider for direct
administration to a patient are exempted from labeling.
    (9) The employer shall not remove or deface existing labels on
incoming containers of hazardous chemicals, unless the container is
immediately marked with the required information.
    (10) The employer shall ensure that workplace labels or other forms
of warning are legible, in English, and prominently displayed on the
container, or readily available in the work area throughout each work
shift. Employers having employees who speak other languages may add the
information in their language to the material presented, as long as the
information is presented in English as well.
    (11) 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. 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.
    (g) Safety data sheets. (1) Chemical manufacturers and importers
shall obtain or develop a safety data sheet for each hazardous chemical
they produce or import. Employers shall have a safety data sheet in the
workplace for each hazardous chemical which they use.
    (2) The chemical manufacturer or importer preparing the safety data
sheet shall ensure that it 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 Sec.
1910.1200--Safety Data Sheets, for the specific content of each section
of the safety data sheet):
    (i) Section 1, Identification;
    (ii) Section 2, Hazard(s) identification;
    (iii) Section 3, Composition/information on ingredients;
    (iv) Section 4, First-aid measures;
    (v) Section 5, Fire-fighting measures;
    (vi) Section 6, Accidental release measures;
    (vii) Section 7, Handling and storage;
    (viii) Section 8, Exposure controls/personal protection;
    (ix) Section 9, Physical and chemical properties;
    (x) Section 10, Stability and reactivity;
    (xi) Section 11, Toxicological information;
    (xii) Section 12, Ecological information;
    (xiii) Section 13, Disposal considerations;
    (xiv) Section 14, Transport information;
    (xv) Section 15, Regulatory information; and
    (xvi) Section 16, Other information, including date of preparation
or last revision.
    Note 1 to paragraph (g)(2): To be consistent with the GHS, an SDS
must also include the headings in paragraphs (g)(2)(xii) through
(g)(2)(xv) in order.
    Note 2 to paragraph (g)(2): OSHA will not be enforcing information
requirements in sections 12 through 15, as these areas are not under
its jurisdiction.
    (3) If no relevant information is found for any sub-heading within
a section on the safety data sheet, the chemical manufacturer, importer
or employer preparing the safety data sheet shall mark it to indicate
that no applicable information was found.
* * * * *
    (5) The chemical manufacturer, importer or employer preparing the
safety data sheet shall ensure that the information provided accurately
reflects the scientific evidence used in making the hazard
classification. If the chemical manufacturer, importer or employer
preparing the safety data sheet becomes newly aware of any significant
information regarding the hazards of a chemical, or ways to protect
against the hazards, this new information shall be added to the safety
data sheet within three months. If the chemical is not

currently being produced or imported, the chemical manufacturer or
importer shall add the information to the safety data sheet before the
chemical is introduced into the workplace again.
* * * * *
    (8) The employer shall maintain in the workplace copies of the
required safety data sheets for each hazardous chemical, and shall
ensure that they are readily accessible during each work shift to
employees when they are in their work area(s). (Electronic access and
other alternatives to maintaining paper copies of the safety data
sheets are permitted as long as no barriers to immediate employee
access in each workplace are created by such options.)
* * * * *
    (11) Safety data sheets shall also be made readily available, upon
request, to designated representatives, the Assistant Secretary, and
the Director, in accordance with the requirements of Sec.
1910.1020(e).
    (h) * * *
    (1) Employers shall provide employees with effective information
and training on hazardous chemicals in their work area at the time of
their initial assignment, and whenever a new chemical hazard the
employees have not previously been trained about is introduced into
their work area. Information and training may be designed to cover
categories of hazards (e.g., flammability, carcinogenicity) or specific
chemicals. Chemical-specific information must always be available
through labels and safety data sheets.
* * * * *
    (3) * * *
    (ii) The physical, health, simple asphyxiation, combustible dust,
and pyrophoric gas hazards, as well as hazards not otherwise
classified, of the chemicals in the work area;
* * * * *
    (iv) The details of the hazard communication program developed by
the employer, including an explanation of the labels received on
shipped containers and the workplace labeling system used by their
employer; the safety data sheet, including the order of information and
how employees can obtain and use the appropriate hazard information.
    (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) of the substance in a mixture, from the
safety data sheet, provided that:
* * * * *
    (iii) The safety data sheet indicates that the specific chemical
identity and/or percentage of composition is being withheld as a trade
secret; and,
    (iv) The specific chemical identity and percentage is made
available to health professionals, employees, and designated
representatives in accordance with the applicable provisions of this
paragraph (i).
    (2) Where a treating physician or nurse determines that a medical
emergency exists and the specific chemical identity and/or specific
percentage of composition 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
physician or nurse, 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 percentage composition, otherwise permitted to be withheld under
paragraph (i)(1) of this section, to a health professional (i.e.
physician, industrial hygienist, toxicologist, epidemiologist, or
occupational health nurse) providing medical or other occupational
health services to exposed employee(s), and to employees or designated
representatives, if:
* * * * *
    (iii) The request explains in detail why the disclosure of the
specific chemical identity or percentage composition is essential and
that, in lieu thereof, the disclosure of the following information to
the health professional, employee, or designated representative, would
not satisfy the purposes described in paragraph (i)(3)(ii) of this
section:
* * * * *
    (7) If the chemical manufacturer, importer, or employer denies a
written request for disclosure of a specific chemical identity or
percentage composition, the denial must:
* * * * *
    (iii) Include evidence to support the claim that the specific
chemical identity or percent of composition is a trade secret;
* * * * *
    (v) Explain in detail how alternative information may satisfy the
specific medical or occupational health need without revealing the
trade secret.
* * * * *
    (9) * * *
    (i) The chemical manufacturer, importer, or employer has supported
the claim that the specific chemical identity or percentage composition
is a trade secret;
* * * * *
    (10) * * *
    (i) If OSHA determines that the specific chemical identity or
percentage composition requested under paragraph (i)(3) of this section
is not a ``bona fide'' trade secret, or that it is a trade secret, but
the requesting health professional, employee, or designated
representative has a legitimate medical or occupational health need for
the information, has executed a written confidentiality agreement, and
has shown adequate means to protect the confidentiality of the
information, the chemical manufacturer, importer, or employer will be
subject to citation by OSHA.
    (ii) If a chemical manufacturer, importer, or employer demonstrates
to OSHA that the execution of a confidentiality agreement would not
provide sufficient protection against the potential harm from the
unauthorized disclosure of a trade secret, the Assistant Secretary may
issue such orders or impose such additional limitations or conditions
upon the disclosure of the requested chemical information as may be
appropriate to assure that the occupational health services are
provided without an undue risk of harm to the chemical manufacturer,
importer, or employer.
    (11) If a citation for a failure to release trade secret
information is contested by the chemical manufacturer, importer, or
employer, the matter will be adjudicated before the Occupational Safety
and Health Review Commission in accordance with the Act's enforcement
scheme and the applicable Commission rules of procedure. In accordance
with the Commission rules, when a chemical manufacturer, importer, or
employer continues to withhold the information during the contest, the
Administrative Law Judge may review the citation and supporting
documentation ``in camera'' or issue appropriate orders to protect the
confidentiality of such matters.
* * * * *
    (j) Effective dates. (1) Employers shall train employees regarding
the new label elements and safety data sheets format by December 1,
2013.
    (2) Chemical manufacturers, importers, distributors, and employers

shall be in compliance with all modified provisions of this section no
later than June 1, 2015, except:
    (i) After December 1, 2015, the distributor shall not ship
containers labeled by the chemical manufacturer or importer unless the
label has been modified to comply with paragraph (f)(1) of this
section.
    (ii) All employers shall, as necessary, update any alternative
workplace labeling used under paragraph (f)(6) of this section, update
the hazard communication program required by paragraph (h)(1), and
provide any additional employee training in accordance with paragraph
(h)(3) for newly identified physical or health hazards no later than
June 1, 2016.
    (3) Chemical manufacturers, importers, distributors, and employers
may comply with either Sec.  1910.1200 revised as of October 1, 2011,
or the current version of this standard, or both during the transition
period.

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.0.2 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 For most hazard classes, the recommended process of
classification of mixtures is based on the following sequence:
    (a) Where test data are available for the complete mixture, the
classification of the mixture will always be based on those data;
    (b) Where test data are not available for the mixture itself,
the bridging principles designated in each health hazard chapter of
this appendix shall be considered for classification of the mixture;
    (c) If test data are not available for the mixture itself, and
the available information is not sufficient to allow application of
the above-mentioned bridging principles, then the method(s)
described in each chapter for estimating the hazards based on the
information known will be applied to classify the mixture (e.g.,
application of cut-off values/concentration limits).
    A.0.4.2 An exception to the above order or precedence is made
for Carcinogenicity, Germ Cell Mutagenicity, and Reproductive
Toxicity. For these three hazard classes, mixtures shall be
classified based upon information on the ingredient substances,
unless on a case-by-case basis, justification can be provided for
classifying based upon the mixture as a whole. See chapters A.5,
A.6, and A.7 for further information on case-by-case bases.
    A.0.4.3 Use of cut-off values/concentration limits.
    A.<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.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 toxicity category.
    For mixtures classified in accordance with A.1, A.2, A.3, A.8,
A.9, or A.10 of this Appendix, for three mixtures (A, B and C) with
identical ingredients, where mixtures A and B have been tested and
are in the same toxicity category, and where untested mixture C has
the same toxicologically active ingredients as mixtures A and B but
has concentrations of toxicologically active ingredients
intermediate to the concentrations in mixtures A and B, then mixture
C is assumed to be in the same toxicity category as A and B.
    A.<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 those adverse effects occurring
following oral or dermal administration of a single dose of a
substance, or multiple doses given within 24 hours, or an inhalation
exposure of 4 hours.

A.1.2 Classification Criteria for Substances

    A.1.2.1 Substances can be allocated to one of four toxicity
categories based on acute toxicity by the oral, dermal or inhalation
route according to the numeric cut-off criteria as shown in Table
A.1.1. Acute toxicity values are expressed as (approximate) LD50
(oral, dermal) or LC50 (inhalation) values or as acute toxicity
estimates (ATE). See the footnotes following Table A.1.1 for further
explanation on the application of these values.

 Table A.1.1--Acute Toxicity Hazard Categories and Acute Toxicity Estimate (ATE) Values Defining the Respective
                                                   Categories
----------------------------------------------------------------------------------------------------------------
          Exposure route             Category 1         Category 2           Category 3           Category 4
----------------------------------------------------------------------------------------------------------------
Oral (mg/kg bodyweight)
    see: Note (a), Note (b)......             <=5  >5 and <=50........  >50 and <=300......  >300 and <=2000.
Dermal (mg/kg bodyweight)
    see: Note (a), Note (b)......             <=5  >50 and <=200......  >200 and <=1000....  >1000 and <=2000.
Inhalation--Gases (ppmV)
    see: Note (a), Note (b), Note           <=100  >100 and <=500.....  >500 and <=2500....  >2500 and <=20000.
     (c).
Inhalation--Vapors (mg/l)
    see: Note (a), Note (b), Note           <=0.5  >0.5 and <=2.0.....  >2.0 and <=10.0....  >10.0 and <=20.0.
     (c), Note (d).
Inhalation--Dusts and Mists (mg/
 l)
    see: Note (a), Note (b), Note          <=0.05  >0.05 and <=0.5....  >0.5 and <=1.0.....  >1.0 and <=5.0.
     (c).
----------------------------------------------------------------------------------------------------------------
Note: Gas concentrations are expressed in parts per million per volume (ppmV).
Notes to Table A.1.1:
(a) The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50
  Stewardwhere available;
(b) The acute toxicity estimate (ATE) for the classification of a substance or ingredient in a mixture is
  derived using:
(i) the LD50/LC50 where available. Otherwise,
(ii) the appropriate conversion value from Table 1.2 that relates to the results of a range test, or
(iii) the appropriate conversion value from Table 1.2 that relates to a classification category;
(c) Inhalation cut-off values in the table are based on 4 hour testing exposures. Conversion of existing
  inhalation toxicity data which has been generated according to 1 hour exposure is achieved by dividing by a
  factor of 2 for gases and vapors and 4 for dusts and mists;
(d) For some substances the test atmosphere will be a vapor which consists of a combination of liquid and
  gaseous phases. For other substances the test atmosphere may consist of a vapor which is nearly all the
  gaseous phase. In these latter cases, classification is based on ppmV as follows: Category 1 (100 ppmV),
  Category 2 (500 ppmV), Category 3 (2500 ppmV), Category 4 (20000 ppmV).
The terms ``dust'', ``mist'' and ``vapor'' are defined as follows:
(i) Dust: solid particles of a substance or mixture suspended in a gas (usually air);
(ii) Mist: liquid droplets of a substance or mixture suspended in a gas (usually air);
(iii) Vapor: the gaseous form of a substance or mixture released from its liquid or solid state.

    A.1.2.3 The preferred test species for evaluation of acute
toxicity by the oral and inhalation routes is the rat, while the rat
or rabbit are preferred for evaluation of acute dermal toxicity.
Test data already generated for the classification of chemicals
under existing systems should be accepted when reclassifying these
chemicals under the harmonized system. When experimental data for
acute toxicity are available in several animal species, scientific
judgment should be used in selecting the most appropriate
LD50 value from among scientifically validated tests.

A.1.3 Classification Criteria for Mixtures

    A.1.3.1 The approach to classification of mixtures for acute
toxicity is tiered, and is dependent upon the amount of information
available for the mixture itself and for its ingredients. The flow
chart of Figure A.1.1 indicates the process that must be followed:
[GRAPHIC] [TIFF OMITTED] TR26MR12.060

    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 toxicity 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 categories, or have an oral or dermal
LD50 greater than 2000 but less than or equal to 5000 mg/
kg body weight (or the equivalent dose for inhalation);

    (b) Ignore ingredients that are presumed not acutely toxic
(e.g., water, sugar);
    (c) Ignore ingredients if the data available are from a limit
dose test (at the upper threshold for Category 4 for the appropriate
route of exposure as provided in Table A.1.1) and do not show acute
toxicity.
    Ingredients that fall within the scope of this paragraph are
considered to be ingredients with a known acute toxicity estimate
(ATE). See note (b) to Table A.1.1 and paragraph A.1.3.3 for
appropriate application of available data to the equation below, and
paragraph A.<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] TR26MR12.061

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>.3.
    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 toxicity is required on
the label and safety data sheet in such cases; see Appendix C to
this section, Allocation of Label Elements and Appendix D to this
section, Safety Data Sheets.)
    Where an ingredient with unknown acute toxicity is used in a
mixture at a concentration >=1%, and the mixture is not classified
based on testing of the mixture as a whole, a statement that X% of
the mixture consists of ingredient(s) of unknown acute toxicity is
required on the label and safety data sheet in such cases; see
Appendix C to this section, Allocation of Label Elements and
Appendix D to this section, Safety Data Sheets.)
    A.<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:
[GRAPHIC] [TIFF OMITTED] TR26MR12.062

   Table A.1.2--Conversion From Experimentally Obtained Acute Toxicity
  Range Values (or Acute Toxicity Hazard Categories) to Acute Toxicity
    Point Estimates for Use in the Formulas for the Classification of
                                Mixtures
------------------------------------------------------------------------
                                 Classification category
                                    or experimentally        Converted
        Exposure routes               obtained acute      acute toxicity
                                 toxicity range estimate  point estimate
------------------------------------------------------------------------
Oral (mg/kg bodyweight ).......  0 =1 of 3 animals
        Category 1: corrosive               Corrosive sub-     -------------------------------------------------
                                              categories                Exposure               Observation
----------------------------------------------------------------------------------------------------------------
                                       1A.....................  <=3 min................  <=1 h.
                                       1B.....................  >3 min <=1 h...........  <=14 days.
                                       1C.....................  >1 h <=4 h.............  <=14 days.
----------------------------------------------------------------------------------------------------------------

A.2.2.2 Irritation

    A.<IP_ADDRESS> A single irritant category (Category 2) is presented
in the Table A.2.2. The major criterion for the irritant category is
that at least 2 tested animals have a mean score of >=2.3 <=4.0.

                  Table A.2.2--Skin Irritation Category
------------------------------------------------------------------------
                                                Criteria
------------------------------------------------------------------------
Irritant (Category 2)........  (1) Mean value 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.<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 fulfil this
criterion. However, it should be ascertained that the responses are
the result of chemical exposure. Addition of this criterion
increases the sensitivity of the classification system.
    A.<IP_ADDRESS> Reversibility of skin lesions is another consideration
in evaluating irritant responses. When inflammation persists to the
end of the observation period in 2 or more test animals, taking into
consideration alopecia (limited area), hyperkeratosis, hyperplasia
and scaling, then a chemical should be considered to be an irritant.

A.2.3 Classification Criteria for Substances Using Other Data Elements

    A.2.3.1 Existing human and animal data including information
from single or repeated exposure should be the first line of
analysis, as they give information directly relevant to effects on
the skin. If a substance is highly toxic by the dermal route, a skin
corrosion/irritation study may not be practicable since the amount
of test substance to be applied would considerably exceed the toxic
dose and, consequently, would result in the death of the animals.
When observations are made of skin corrosion/irritation in acute
toxicity studies and are observed up through the limit dose, these
data may be used for classification provided that the dilutions used
and species tested are equivalent. In vitro alternatives that have
been scientifically validated shall be used to make classification
decisions. Solid substances (powders) may become corrosive or
irritant when moistened or in contact with moist skin or mucous
membranes. Likewise, pH extremes like <=2 and >=11.5 may indicate
skin effects, especially when associated with significant buffering
capacity. Generally, such substances are expected to produce
significant effects on the skin. In the absence of any other
information, a substance is considered corrosive (Skin Category 1)
if it has a pH <=2 or a pH >=11.5. However, if consideration of
alkali/acid reserve suggests the substance or mixture may not be
corrosive despite the low or high pH value, then further evaluation
may be necessary. In some cases enough information may be available
from structurally related compounds to make classification
decisions.
    A.2.3.2 A tiered approach to the evaluation of initial
information shall be used (Figure A.2.1) recognizing that all
elements may not be relevant in certain cases.
    A.2.3.3 The tiered approach explains how to organize information
on a substance and to make a weight-of-evidence decision about
hazard assessment and hazard classification.
    A.2.3.4 All the above information that is available on a
substance shall be evaluated. Although information might be gained
from the evaluation of single parameters within a

tier, there is merit in considering the totality of existing
information and making an overall weight of evidence determination.
This is especially true when there is information available on some
but not all parameters. Emphasis shall be placed upon existing human
experience and data, followed by animal experience and testing data,
followed by other sources of information, but case-by-case
determinations are necessary.
BILLING CODE 4510-26-P

[GRAPHIC] [TIFF OMITTED] TR26MR12.063

[GRAPHIC] [TIFF OMITTED] TR26MR12.064

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 (See A.2.3).

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, but there are sufficient
data on both the individual ingredients and similar tested mixtures
to adequately characterize the hazards of the mixture, these data
will be used in accordance with the following bridging principles,
as found in paragraph A.0.5 of this Appendix: Dilution, Batching,
Concentration of mixtures, Interpolation within one toxicity
category, Substantially similar mixtures, and Aerosols.

A.2.4.3 Classification of Mixtures When Data Are Available for All
Ingredients or Only for Some Ingredients of the Mixture

    A.<IP_ADDRESS> For purposes of classifying the skin corrosion/
irritation hazards of mixtures in the tiered approach:
    The ``relevant ingredients'' of a mixture are those which are
present in concentrations >1% (weight/weight for solids, liquids,
dusts, mists and vapors and volume/volume for gases.) If the
classifier has reason to suspect that an ingredient present at a
concentration <1% will affect classification of the mixture for skin
corrosion/irritation, that ingredient shall also be considered
relevant.
    A.<IP_ADDRESS> In general, the approach to classification of mixtures
as irritant or corrosive to skin when data are available on the
ingredients, but not on the mixture as a whole, is based on the
theory of additivity, such that each corrosive or irritant
ingredient contributes to the overall irritant or corrosive
properties of the mixture in proportion to its potency and
concentration. A weighting factor of 10 is used for corrosive
ingredients when they are present at a concentration below the
concentration limit for classification with Category 1, but are at a
concentration that will contribute to the classification of the
mixture as an irritant. The mixture is classified as corrosive or
irritant when the sum of the concentrations of such ingredients
exceeds a cut-off value/concentration limit.
    A.<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 an irritant or a corrosive 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 of Table A.2.3. A mixture
containing corrosive or irritant ingredients that cannot be
classified based on the additivity approach shown in Table A.2.3,
due to chemical characteristics that make this approach unworkable,
should be classified as Skin Category 1 if it contains >=1% of a
corrosive ingredient and as Skin Category 2 when it contains >=3% of
an irritant ingredient. Classification of mixtures with ingredients
for which the approach in Table A.2.3 does not apply is summarized
in Table A.2.4 below.
    A.<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 concentration cut-off values
mentioned in Tables A.2.3 and A.2.4. In these cases the mixture
could be classified according to those data (See Use of cut-off
values/concentration limits, paragraph A.0.4.3 of this Appendix).
    A.<IP_ADDRESS> If there are data showing that (an) ingredient(s) may
be corrosive or irritant at a concentration of <1% (corrosive) or
<3% (irritant), the mixture shall be classified accordingly (See Use
of cut-off values/concentration limits, paragraph A.0.4.3 of this
Appendix).

  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  ..................  >=10%.
 Category 2.
------------------------------------------------------------------------

  Table A.2.4--Concentration of Ingredients of a Mixture for Which the
Additivity Approach Does Not Apply, That Would Trigger Classification of
                    the Mixture as Hazardous to Skin
------------------------------------------------------------------------
                                                    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.
 ingredients for which
 additivity does not apply.
Other irritant (Category 2)                  >=3%  Category 2.
 ingredients for which
 additivity does not apply,
 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 is the production of tissue damage in
the eye, or serious physical decay of vision, following application
of a test substance to the anterior surface of the eye, which is not
fully reversible within 21 days of application.
    Eye irritation is the production of changes in the eye following
the application of test substance to the anterior surface of the
eye, which are fully reversible within 21 days of application.
    A.3.1.2 Serious eye damage/eye irritation shall be classified
using a tiered approach as detailed in Figure A.3.1. Emphasis shall
be placed upon existing human data (See A.0.2.6), followed by animal
data, followed by other sources of information. Classification
results directly when the data satisfy the criteria in this section.
In case the criteria cannot be directly applied, classification of a
substance or a mixture is made on the basis of the total weight of
evidence (See A.0.3.1). This means that all available information
bearing on the determination of serious eye damage/eye irritation is
considered together, including the results of appropriate
scientifically validated in vitro tests, relevant animal data, and
human data such as epidemiological and clinical studies and well-
documented case reports and observations.

A.3.2 Classification Criteria for Substances Using Animal Test Data

    A.3.2.1 Irreversible effects on the eye/serious damage to eyes
(Category 1).
    A single hazard category is provided in Table A.3.1, for
substances that have the potential to seriously damage the eyes.
Category 1, irreversible effects on the eye, includes the criteria
listed below. These observations include animals with grade 4 cornea
lesions and other severe reactions (e.g. destruction of cornea)
observed at any time during the test, as well as persistent corneal
opacity, discoloration of the cornea by a dye substance, adhesion,
pannus, and interference with the function of the iris or other
effects that impair sight. In this context, persistent lesions are
considered those which are not fully reversible within an
observation period of normally 21 days. Category 1 also contains
substances fulfilling the criteria of corneal opacity >=3 and/or
iritis >1.5 detected in a Draize eye test with rabbits, because
severe lesions like these usually do not reverse within a 21-day
observation period.

                  Table A.3.1--Irreversible Eye Effects
------------------------------------------------------------------------

-------------------------------------------------------------------------
A substance is classified as Serious Eye Damage Category 1 (irreversible
 effects on the eye) when it produces:
    (a) at least in one tested animal, effects on the cornea, iris or
     conjunctiva that are not expected to reverse or have not fully
     reversed within an observation period of normally 21 days; and/or
    (b) at least in 2 of 3 tested animals, a positive response of:
        (i) corneal opacity >=3; and/or
        (ii) iritis >1.5;
        calculated as the mean scores following grading at 24, 48 and 72
         hours after instillation of the substance.
------------------------------------------------------------------------

    A.3.2.2 Reversible effects on the eye (Category 2).
    A single category is provided in Table A.3.2 for substances that
have the potential to induce reversible eye irritation.

                   Table A.3.2--Reversible Eye Effects
------------------------------------------------------------------------

-------------------------------------------------------------------------
A substance is classified as Eye irritant Category 2A (irritating to
 eyes) when it produces in at least in 2 of 3 tested animals a positive
 response of:
    (i) corneal opacity >=1; and/or
    (ii) iritis >=1; and/or
    (iii) conjunctival redness >=2; and/or
    (iv) conjunctival edema (chemosis) >=2

    calculated as the mean scores following grading at 24, 48 and 72
     hours after instillation of the substance, and which fully reverses
     within an observation period of normally 21 days.
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.3.2.3 For those chemicals where there is pronounced
variability among animal responses, this information may be taken
into account in determining the classification.

A.3.3 Classification Criteria for Substances Using Other Data Elements

    A.3.3.1 Existing human and animal data should be the first line
of analysis, as they give information directly relevant to effects
on the eye. Possible skin corrosion shall be evaluated prior to
consideration of serious eye damage/eye irritation in order to avoid
testing for local effects on eyes with skin corrosive substances. In
vitro alternatives that have been scientifically validated and
accepted shall be used to make classification decisions. Likewise,
pH extremes like <=2 and >=11.5, may indicate serious eye damage,
especially when associated with significant buffering capacity.
Generally, such substances are expected to produce significant
effects on the eyes. In the absence of any other information, a
mixture/substance is considered to cause serious eye damage (Eye
Category 1) if it has a pH <=2 or >=11.5. However, if consideration
of acid/alkaline reserve suggests the substance may not have the
potential to cause serious eye damage despite the low or high pH
value, then further evaluation may be necessary. In some cases
enough information may be available from structurally related
compounds to make classification decisions.
    A.3.3.2 A tiered approach to the evaluation of initial
information shall be used where applicable, recognizing that all
elements may not be relevant in certain cases (Figure A.3.1).
    A.3.3.3 The tiered approach explains how to organize existing
information on a substance and to make a weight-of-evidence
decision, where appropriate, about hazard assessment and hazard
classification.
    A.3.3.4 All the above information that is available on a
substance shall be evaluated. Although information might be gained
from the evaluation of single parameters within a tier,
consideration should be given to the totality of existing
information and making an overall weight-of-evidence determination.
This is especially true when there is conflict in information
available on some parameters.
BILLING CODE 4510-26-P

[GRAPHIC] [TIFF OMITTED] TR26MR12.065

[GRAPHIC] [TIFF OMITTED] TR26MR12.066

BILLING CODE 4510-26-C

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.
    A.<IP_ADDRESS> Unlike other hazard classes, there are alternative
tests available for skin corrosivity of certain types of chemicals
that can give an accurate result for classification purposes, as
well as being simple and relatively inexpensive to perform. When
considering testing of the mixture, chemical manufacturers are
encouraged to use a tiered weight of evidence strategy as included
in the criteria for classification of substances for skin corrosion
and serious eye damage and eye irritation to help ensure an accurate
classification, as well as avoid unnecessary animal testing. In the
absence of any other information, a mixture is considered to cause
serious eye damage (Eye Category 1) if it has a pH <=2 or >=11.5.
However, if consideration of acid/alkaline reserve suggests the
substance or mixture may not have the potential to cause serious eye
damage despite the low or high pH value, then further evaluation may
be necessary.

A.3.4.2 Classification of Mixtures When Data Are Not Available for the
Complete Mixture: Bridging Principles

    A.<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 toxicity category,
Substantially similar mixtures, and Aerosols.

A.3.4.3 Classification of Mixtures When Data Are Available for All
Ingredients or Only for Some Ingredients of the Mixture

    A.<IP_ADDRESS> For purposes of classifying the eye corrosion/
irritation hazards of mixtures in the tiered approach:
    The ``relevant ingredients'' of a mixture are those which are
present in concentrations >1% (weight/weight for solids, liquids,
dusts, mists and vapors and volume/volume for gases). If the
classifier has reason to suspect that an ingredient present at a
concentration <1% will affect classification of the mixture for eye
corrosion/irritation, that ingredient shall also be considered
relevant.
    A.<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 corrosive or
irritant ingredient contributes to the overall irritant or corrosive
properties of the mixture in proportion to its potency and
concentration. A weighting factor of 10 is used for corrosive
ingredients when they are present at a concentration below the
concentration limit for classification with Category 1, but are at a
concentration that will contribute to the classification of the
mixture as an irritant. The mixture is classified as seriously
damaging to the eye or eye irritant when the sum of the
concentrations of such ingredients exceeds a threshold cut-off
value/concentration limit.
    A.<IP_ADDRESS> Table A.3.3 provides the cut-off value/concentration
limits to be used to determine if the mixture should be classified
as seriously damaging to the eye or an eye irritant.
    A.<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 corrosive or irritant at concentrations <1%. For
mixtures containing strong acids or bases, the pH should be used as
classification criteria (See A.3.4.1) since pH will be a better
indicator of serious eye damage than the concentration limits of
Table A.3.3. A mixture containing corrosive or irritant ingredients
that cannot be classified based on the additivity approach applied
in Table A.3.3 due to chemical characteristics that make this
approach unworkable, should be classified as Eye Category 1 if it
contains >=1% of a corrosive ingredient and as Eye Category 2 when
it contains >=3% of an irritant ingredient. Classification of
mixtures with ingredients for which the approach in Table A.3.3 does
not apply is summarized in Table A.3.4.
    A.<IP_ADDRESS> On occasion, reliable data may show that the
reversible/irreversible eye effects of an ingredient will not be
evident when present at a level above the generic cut-off values/
concentration limits mentioned in Tables A.3.3 and A.3.4. In these
cases the mixture could be classified according to those data (See
also A.0.4.3 Use of cut-off values/concentration limits''). On
occasion, when it is expected that the skin corrosion/irritation or
the reversible/irreversible eye effects of an ingredient will not be
evident when present at a level above the generic concentration/cut-
off levels mentioned in Tables A.3.3 and A.3.4, testing of the
mixture may be considered. In those cases, the tiered weight of
evidence strategy should be applied as referred to in section A.3.3,
Figure A.3.1 and explained in detail in this chapter.
    A.<IP_ADDRESS> If there are data showing that (an) ingredient(s) may
be corrosive or irritant at a concentration of <1% (corrosive) or
<3% (irritant), the mixture should be classified accordingly (See
also paragraph A.0.4.3, Use of cut-off values/concentration limits).

 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:       Irreversible eye effects             Reversible eye effects
                                        ------------------------------------------------------------------------
                                                  Category 1                          Category 2
----------------------------------------------------------------------------------------------------------------
Eye or Skin Category 1.................                         >=3%  >=1% but <3%.

Eye Category 2.........................  ...........................  >=10%.
(10 x Eye Category 1) + Eye Category 2.  ...........................  >=10%.
Skin Category 1 + Eye Category 1.......                         >=3%  >=1% but <3%.
10 x (Skin Category 1 + Eye Category 1)  ...........................  >=10%.
 + Eye Category 2.
----------------------------------------------------------------------------------------------------------------
Note: A mixture may be classified as Eye Category 2B in cases when all relevant ingredients are classified as
  Eye 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
------------------------------------------------------------------------
                                                    Mixture  classified
          Ingredient              Concentration           as: Eye
------------------------------------------------------------------------
Acid with pH <=2..............               >=1%  Category 1.
Base with pH >=11.5...........               >=1%  Category 1.
Other corrosive (Category 1)                 >=1%  Category 1.
 ingredients for which
 additivity does not apply.
Other irritant (Category 2)                  >=3%  Category 2.
 ingredients for which
 additivity does not apply,
 including acids and bases.
------------------------------------------------------------------------

A.4 RESPIRATORY OR SKIN SENSITIZATION

A.4.1 Definitions and General Considerations

    A.4.1.1 Respiratory sensitizer means a chemical that will lead
to hypersensitivity of the airways following inhalation of the
chemical.
    Skin sensitizer means a chemical that will lead to an allergic
response following skin contact.
    A.4.1.2 For the purpose of this chapter, sensitization includes
two phases: the first phase is induction of specialized
immunological memory in an individual by exposure to an allergen.
The second phase is elicitation, i.e., production of a cell-mediated
or antibody-mediated allergic response by exposure of a sensitized
individual to an allergen.
    A.4.1.3 For respiratory sensitization, the pattern of induction
followed by elicitation phases is shared in common with skin
sensitization. For skin sensitization, an induction phase is
required in which the immune system learns to react; clinical
symptoms can then arise when subsequent exposure is sufficient to
elicit a visible skin reaction (elicitation phase). As a
consequence, predictive tests usually follow this pattern in which
there is an induction phase, the response to which is measured by a
standardized elicitation phase, typically involving a patch test.
The local lymph node assay is the exception, directly measuring the
induction response. Evidence of skin sensitization in humans
normally is assessed by a diagnostic patch test.
    A.4.1.4 Usually, for both skin and respiratory sensitization,
lower levels are necessary for elicitation than are required for
induction.
    A.4.1.5 The hazard class ``respiratory or skin sensitization''
is differentiated into:
    (a) Respiratory sensitization; and
    (b) Skin sensitization.

A.4.2 Classification Criteria for Substances

A.4.2.1 Respiratory Sensitizers

    A.<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.

     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.
------------------------------------------------------------------------

---------------------------------------------------------------------------

    \1\ At this writing, recognized and validated animal models for
the testing of respiratory hypersensitivity are not available. Under
certain circumstances, data from animal studies may provide valuable
information in a weight of evidence assessment.
---------------------------------------------------------------------------

    A.<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 [mu]g/cm\2\ (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 [mu]g/cm\2\ (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 Table A.4.4 below:

          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 man (See
paragraph A.0.2.6 of this Appendix);
    (e) Well documented episodes of allergic contact dermatitis,
normally obtained in more than one dermatology clinic;
    (f) Severity of reaction.
    A.<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, 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:
                                      --------------------------------------------------------------------------
      Ingredient classified as:                Respiratory Sensitizer Category 1             Skin Sensitizer
                                      --------------------------------------------------        Category 1
                                                                                ------------------------
                                             Solid/liquid                 Gas              All physical states
----------------------------------------------------------------------------------------------------------------
Respiratory Sensitizer, Category 1...                   >=0.1%                   >=0.1%  .......................
Respiratory Sensitizer, Sub-category                    >=0.1%                   >=0.1%  .......................
 1A..................................
Respiratory Sensitizer, Sub-category                    >=1.0%                   >=0.2%  .......................
 1B..................................
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 A mutation is defined as a permanent change in the
amount or structure of the genetic material in a cell. The term
mutation applies both to heritable genetic changes that may be
manifested at the phenotypic level and to the underlying DNA
modifications when known (including, for example, specific base pair
changes and chromosomal translocations). The term mutagenic and
mutagen will be used for agents giving rise to an increased
occurrence of mutations in populations of cells and/or organisms.
    A.5.1.2 The more general terms genotoxic and genotoxicity apply
to agents or processes which alter the structure, information
content, or segregation of DNA, including those which cause DNA
damage by interfering with normal replication processes, or which in
a non-physiological manner (temporarily) alter its replication.
Genotoxicity test results are usually taken as indicators for
mutagenic effects.
    A.5.1.3 This hazard class is primarily concerned with chemicals
that may cause mutations in the germ cells of humans that can be
transmitted to the progeny. However, mutagenicity/genotoxicity tests
in vitro and in mammalian somatic cells in vivo are also considered
in classifying substances and mixtures within this hazard class.

A.5.2 Classification Criteria for Substances

    A.5.2.1 The classification system provides for two different
categories of germ cell mutagens to accommodate the weight of
evidence available. The two-category system is described in the
Figure A.5.1.

         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) Mouse spot test (OECD 484)
    (c) Mammalian erythrocyte micronucleus test (OECD 474)
A.5.4.3 Examples of mutagenicity/genotoxicity tests in germ cells
are:
    (a) Mutagenicity tests:
    (i) Mammalian spermatogonial chromosome aberration test (OECD
483)
    (ii) Spermatid micronucleus assay
    (b) Genotoxicity tests:
    (i) Sister chromatid exchange analysis in spermatogonia
    (ii) Unscheduled DNA synthesis test (UDS) in testicular cells
A.5.4.4 Examples of genotoxicity tests in somatic cells are:
    (a) Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)
    (b) Mammalian bone marrow Sister Chromatid Exchanges (SCE)
A.5.4.5 Examples of in vitro mutagenicity tests are:
    (a) In vitro mammalian chromosome aberration test (OECD 473)
    (b) In vitro mammalian cell gene mutation test (OECD 476)
    (c) Bacterial reverse mutation tests (OECD 471)
A.5.4.6 As new, scientifically validated tests arise, these may also
be used in the total weight of evidence to be considered.

A.6 CARCINOGENICITY

A.6.1 Definitions

    Carcinogen means a substance or a mixture of substances which
induce cancer or increase its incidence. Substances and mixtures
which have induced benign and malignant tumors in well-performed
experimental studies on animals are considered also to be presumed
or suspected human carcinogens unless there is strong evidence that
the mechanism of tumor formation is not relevant for humans.
    Classification of a substance or mixture as posing a
carcinogenic hazard is based on its inherent properties and does not
provide information on the level of the human cancer risk which the
use of the substance or mixture may represent.

A.6.2 Classification Criteria for Substances 6
---------------------------------------------------------------------------

    \6\ See Non-mandatory Appendix F Part A for further guidance
regarding hazard classification for carcinogenicity. This appendix
is consistent with the GHS adn 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).
    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
           Ingredient classified as:                carcinogen                 Category 2  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 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 29 CFR part
1910, Subpart Z, Toxic and Hazardous Substances, chemical
manufacturers, importers, and employers shall classify the chemical
as a carcinogen.

A.7 REPRODUCTIVE TOXICITY

A.7.1 Definitions and General Considerations

    A.7.1.1 Reproductive toxicity includes adverse effects on sexual
function and fertility in adult males and females, as well as
adverse effects on development of the offspring. Some reproductive
toxic effects cannot be clearly assigned to either impairment of
sexual function and fertility or to developmental toxicity.
Nonetheless, chemicals with these effects shall be classified as
reproductive toxicants.
    For classification purposes, the known induction of genetically
based inheritable effects in the offspring is addressed in Germ cell
mutagenicity (See A.5).
    A.7.1.2 Adverse effects on sexual function and fertility means
any effect of chemicals that interferes with reproductive ability or
sexual capacity. This includes, but is not limited to, alterations
to the female and male reproductive system, adverse effects on onset
of puberty, gamete production and transport, reproductive cycle
normality, sexual behaviour, fertility, parturition, pregnancy
outcomes, premature reproductive senescence, or modifications in
other functions that are dependent on the integrity of the
reproductive systems.
    A.7.1.3 Adverse effects on development of the offspring means
any effect of chemicals which interferes with normal development of
the conceptus either before or after birth, which is induced during
pregnancy or results from parental exposure. These effects can be
manifested at any point in the life span of the organism. The major
manifestations of developmental toxicity include death of the
developing organism, structural abnormality, altered growth and
functional deficiency.