Washington Administrative Code › Title 296 - Labor and Industries, Department of › Chapter 296-901 - Globally harmonized system for hazard communication › Section 296-901-14022 - Appendix A - Health hazard criteria

Current through Register Vol. 24-14, July 15, 2024
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) Where test data are available for the complete
				mixture, the classification of the mixture will always be based on
				those data;
(b) Where test data are not available for the mixture
				itself, the bridging principles designated in each health hazard
				chapter of this appendix shall be considered for classification of
				the mixture;
(c) If test data are not available for the mixture
				itself, and the available information is not sufficient to allow
				application of the above-mentioned bridging principles, then the
				method(s) described in each chapter for estimating the hazards based
				on the information known will be applied to classify the mixture
				(e.g., application of cut-off values/concentration limits).
A.0.4.2 An exception to the above order or precedence
				is made for Carcinogenicity, Germ Cell Mutagenicity, and Reproductive
				Toxicity. For these three hazard classes, mixtures shall be
				classified based upon information on the ingredient substances,
				unless on a case-by-case basis, justification can be provided for
				classifying based upon the mixture as a whole. See chapters A.5, A.6,
				and A.7 for further information on case-by-case bases.
A.0.4.3 Use of cut-off values/concentration
				limits
A.0.4.3.1 When classifying an untested mixture based
				on the hazards of its ingredients, 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.0.4.3.2 If the classifier has information that the
				hazard of an ingredient will be evident (i.e., it presents a health
				risk) below the specified cut-off value/concentration limit, the
				mixture containing that ingredient shall be classified
				accordingly.
A.0.4.3.3 In exceptional cases, conclusive data may
				demonstrate that the hazard of an ingredient will not be evident
				(i.e., it does not present a health risk) when present at a level
				above the specified cut-off value/concentration limit(s). In these
				cases the mixture may be classified according to those data. The data
				must exclude the possibility that the ingredient will behave in the
				mixture in a manner that would increase the hazard over that of the
				pure substance. Furthermore, the mixture must not contain ingredients
				that would affect that determination.
A.0.4.4 Synergistic or antagonistic effects
When performing an assessment in accordance with
				these requirements, the evaluator must take into account all
				available information about the potential occurrence of synergistic
				effects among the ingredients of the mixture. Lowering classification
				of a mixture to a less hazardous category on the basis of
				antagonistic effects may be done only if the determination is
				supported by sufficient data.
A.0.5 Bridging principles for the classification of
				mixtures where test data are not available for the complete
				mixture.
A.0.5.1 Where the mixture itself has not been tested
				to determine its toxicity, but there are sufficient data on both the
				individual ingredients and similar tested mixtures to adequately
				characterize the hazards of the mixture, these data shall be used in
				accordance with the following bridging principles, subject to any
				specific provisions for mixtures for each hazard class. These
				principles ensure that the classification process uses the available
				data to the greatest extent possible in characterizing the hazards of
				the mixture.
A.0.5.1.1 Dilution
For mixtures classified in accordance with A.1
				through A.10 of this Appendix, if a tested mixture is diluted with a
				diluent that has an equivalent or lower toxicity classification than
				the least toxic original ingredient, and which is not expected to
				affect the toxicity of other ingredients, then:
(a) the new diluted mixture shall be classified as
				equivalent to the original tested mixture; or
(b) for classification of acute toxicity in
				accordance with A.1 of this Appendix, paragraph A.1.3.6 (the
				additivity formula) shall be applied.
A.0.5.1.2 Batching
For mixtures classified in accordance with A.1
				through A.10 of this Appendix, the toxicity of a tested production
				batch of a mixture can be assumed to be substantially equivalent to
				that of another untested production batch of the same mixture, when
				produced by or under the control of the same chemical manufacturer,
				unless there is reason to believe there is significant variation such
				that the toxicity of the untested batch has changed. If the latter
				occurs, a new classification is necessary.
A.0.5.1.3 Concentration of mixtures
For mixtures classified in accordance with A.1, A.2,
				A.3, A.8, A.9, or A.10 of this Appendix, if a tested mixture is
				classified in Category 1, and the concentration of the ingredients of
				the tested mixture that are in Category 1 is increased, the resulting
				untested mixture shall be classified in Category 1.
A.0.5.1.4 Interpolation within one toxicity
				category
For mixtures classified in accordance with A.1, A.2,
				A.3, A.8, A.9, or A.10 of this Appendix, for three mixtures (A, B and
				C) with identical ingredients, where mixtures A and B have been
				tested and are in the same toxicity category, and where untested
				mixture C has the same toxicologically active ingredients as mixtures
				A and B but has concentrations of toxicologically active ingredients
				intermediate to the concentrations in mixtures A and B, then mixture
				C is assumed to be in the same toxicity category as A and B.
A.0.5.1.5 Substantially similar mixtures
For mixtures classified in accordance with A.1
				through A.10 of this Appendix, given the following set of
				conditions:
(a) Where there are two mixtures:
(i) A + B;
(ii) C + B;
(b) the concentration of ingredient B is essentially
				the same in both mixtures;
(c) the concentration of ingredient A in mixture (i)
				equals that of ingredient C in mixture (ii);
(d) and data on toxicity for A and C are available
				and substantially equivalent; i.e., they are in the same hazard
				category and are not expected to affect the toxicity of B; then
If mixture (i) or (ii) is already classified based on
				test data, the other mixture can be assigned the same hazard
				category.
A.0.5.1.6 Aerosols
For mixtures classified in accordance with A.1, A.2,
				A.3, A.4, A.8, or A.9 of this Appendix, an aerosol form of a mixture
				shall be classified in the same hazard category as the tested,
				non-aerosolized form of the mixture, provided the added propellant
				does not affect the toxicity of the mixture when spraying.
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)
[LESS THAN EQUALS TO]5
>5 and [LESS THAN EQUALS TO]50
>50 and [LESS THAN EQUALS TO]300
>300 and [LESS THAN EQUALS TO]2000
Dermal
(mg/kg bodyweight) see:
Note (a)
Note (b)
[LESS THAN EQUALS TO] 50
>50 and [LESS THAN EQUALS TO]200
>200 and [LESS THAN EQUALS TO]1000
>1000 and [LESS THAN EQUALS TO]2000
Inhalation - Gases
(ppmV) see:
Note (a)
Note (b)
Note (c)
[LESS THAN EQUALS TO]100
>100 and [LESS THAN EQUALS TO]500
>500 and [LESS THAN EQUALS TO]2500
>2500 and [LESS THAN EQUALS TO]20000
Inhalation - Vapors
(mg/l) see:
Note (a)
Note (b)
Note (c)
Note (d)
[LESS THAN EQUALS TO]0.5
>0.5 and [LESS THAN EQUALS TO]2.0
>2.0 and [LESS THAN EQUALS TO]10.0
>10.0 and [LESS THAN EQUALS TO]20.0
Inhalation - Dusts and Mists(mg/l)
						see:
Note (a)
Note (b)
Note (c)
[LESS THAN EQUALS TO]0.05
>0.05 and [LESS THAN EQUALS TO]0.5
>0.5 and [LESS THAN EQUALS TO]1.0
>1.0 and [LESS THAN EQUALS TO]5.0
Note: Gas concentrations are expressed in parts per
				million per volume (ppmV). Notes to Table A.1.1:
(a) The acute toxicity estimate (ATE) for the
				classification of a substance is derived using the LD50/LC50 where
				available;
(b) The acute toxicity estimate (ATE) for the
				classification of a substance or ingredient in a mixture is derived
				using:
(i) the LD50/LC50 where available. Otherwise,
(ii) the appropriate conversion value from Table 1.2
				that relates to the results of a range test, or
(iii) the appropriate conversion value from Table 1.2
				that relates to a classification category;
(c) Inhalation cut-off values in the table are based
				on 4 hour testing exposures. Conversion of existing inhalation
				toxicity data which has been generated according to 1 hour exposure
				is achieved by dividing by a factor of 2 for gases and vapors and 4
				for dusts and mists;
(d) For some substances the test atmosphere will be a
				vapor which consists of a combination of liquid and gaseous phases.
				For other substances the test atmosphere may consist of a vapor which
				is nearly all the gaseous phase. In these latter cases,
				classification is based on ppmV as follows: Category 1 (100 ppmV),
				Category 2 (500 ppmV), Category 3 (2500 ppmV), Category 4 (20000
				ppmV).
The terms "dust", "mist" and "vapor" are defined as
				follows:
(i) Dust: solid particles of a substance or mixture
				suspended in a gas (usually air);
(ii) Mist: liquid droplets of a substance or mixture
				suspended in a gas (usually air);
(iii) Vapor: the gaseous form of a substance or
				mixture released from its liquid or solid state.
A.1.2.3 The preferred test species for evaluation of
				acute toxicity by the oral and inhalation routes is the rat, while
				the rat or rabbit are preferred for evaluation of acute dermal
				toxicity. Test data already generated for the classification of
				chemicals under existing systems should be accepted when
				reclassifying these chemicals under the harmonized system. When
				experimental data for acute toxicity are available in several animal
				species, scientific judgment should be used in selecting the most
				appropriate LD50 value from among scientifically validated
				tests.
A.1.3 Classification criteria for mixtures
A.1.3.1 The approach to classification of mixtures
				for acute toxicity is tiered, and is dependent upon the amount of
				information available for the mixture itself and for its ingredients.
				The flow chart of Figure A.1.1 indicates the process that must be
				followed:
Figure A.1.1: Tiered approach to classification
				of mixtures for acute toxicity
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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 [GREATER THAN EQUALS TO] 1%
				(weight/weight for solids, liquids, dusts, mists and vapors and
				volume/volume for gases). If there is reason to suspect that an
				ingredient present at a concentration < 1% will affect
				classification of the mixture for acute toxicity, that ingredient
				shall also be considered relevant. Consideration of ingredients
				present at a concentration < 1% is particularly important when
				classifying untested mixtures which contain ingredients that are
				classified in Category 1 and Category 2;
(b) Where a classified mixture is used as an
				ingredient of another mixture, the actual or derived acute toxicity
				estimate (ATE) for that mixture is used when calculating the
				classification of the new mixture using the formulas in A.1.3.6.1 and
				A.1.3.6.2.4.
(c) If the converted acute toxicity point estimates
				for all ingredients of a mixture are within the same category, then
				the mixture should be classified in that category.
(d) When only range data (or acute toxicity hazard
				category information) are available for ingredients in a mixture,
				they may be converted to point estimates in accordance with Table
				A.1.2 when calculating the classification of the new mixture using
				the formulas in A.1.3.6.1 and A.1.3.6.2.4.
A.1.3.4 Classification of mixtures where acute
				toxicity test data are available for the complete mixture
Where the mixture itself has been tested to determine
				its acute toxicity, it is classified according to the same criteria
				as those used for substances, presented in Table A.1.1. If test data
				for the mixture are not available, the procedures presented below
				must be followed.
A.1.3.5 Classification of mixtures where acute
				toxicity test data are not available for the complete mixture:
				bridging principles
A.1.3.5.1 Where the mixture itself has not been
				tested to determine its acute toxicity, but there are sufficient data
				on both the individual ingredients and similar tested mixtures to
				adequately characterize the hazards of the mixture, these data will
				be used in accordance with the following bridging principles as found
				in paragraph A.0.5 of this Appendix: Dilution, Batching,
				Concentration of mixtures, Interpolation within one toxicity
				category, Substantially similar mixtures, and Aerosols.
(a) Include ingredients with a known acute toxicity,
				which fall into any of the acute toxicity categories, or have an oral
				or dermal LD50 greater than 2000 but less than or equal to 5000 mg/kg
				body weight (or the equivalent dose for inhalation);
(b) Ignore ingredients that are presumed not acutely
				toxic (e.g., water, sugar);
(c) Ignore ingredients if the data available are from
				a limit dose test (at the upper threshold for Category 4 for the
				appropriate route of exposure as provided in Table A.1.1) and do not
				show acute toxicity.
Ingredients that fall within the scope of this
				paragraph are considered to be ingredients with a known acute
				toxicity estimate (ATE). See note (b) to Table A.1.1 and paragraph
				A.1.3.3 for appropriate application of available data to the equation
				below, and paragraph A.1.3.6.2.4.
The ATE of the mixture is determined by calculation
				from the ATE values for all relevant ingredients according to the
				following formula below for oral, dermal or inhalation
				toxicity:
The ATE of the Mixture 2
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A.1.3.6.2 Data are not available for one or more
				ingredients of the mixture
A.1.3.6.2.1 Where an ATE is not available for an
				individual ingredient of the mixture, but available information
				provides a derived conversion value, the formula in A.1.3.6.1 may be
				applied. This information may include evaluation of:
(a) Extrapolation between oral, dermal and inhalation
				acute toxicity estimates. Such an evaluation requires appropriate
				pharmacodynamic and pharmacokinetic data;
(b) Evidence from human exposure that indicates toxic
				effects but does not provide lethal dose data;
(c) Evidence from any other toxicity tests/assays
				available on the substance that indicates toxic acute effects but
				does not necessarily provide lethal dose data; or
(d) Data from closely analogous substances using
				structure/activity relationships.
A.1.3.6.2.2 This approach requires substantial
				supplemental technical information, and a highly trained and
				experienced expert, to reliably estimate acute toxicity. If
				sufficient information is not available to reliably estimate acute
				toxicity, proceed to the provisions of A.1.3.6.2.3.
A.1.3.6.2.3 In the event that an ingredient with
				unknown acute toxicity is used in a mixture at a concentration
				[GREATER THAN EQUALS TO] 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, Allocation of Label Elements and Appendix
				D, Safety Data Sheets.)
Where an ingredient with unknown acute toxicity is
				used in a mixture at a concentration [GREATER THAN EQUALS TO] 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, Allocation of Label Elements and
				Appendix D, Safety Data Sheets.)
A.1.3.6.2.4 If the total concentration of the
				relevant ingredient(s) with unknown acute toxicity is [LESS THAN
				EQUALS TO] 10% then the formula presented in A.1.3.6.1 must be used.
				If the total concentration of the relevant ingredient(s) with unknown
				acute toxicity is <10%, the formula presented in A.1.3.6.1 is
				corrected to adjust for the percentage of the unknown ingredient(s)
				as follows:
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Table A.1.2: Conversion from experimentally obtained
				acute toxicity range values (or acute toxicity hazard categories) to
				acute toxicity point estimates for use in the formulas for the
				classification of mixtures
Exposure routes
Classification category or experimentally
						obtained acute toxicity range estimate
Converted Acute Toxicity point
						estimate
Oral
(mg/kg bodyweight)
0 <Category 1 [LESS THAN EQUALS TO]
						  5
5 <Category 2 [LESS THAN EQUALS TO] 50
50 <Category 3 [LESS THAN EQUALS TO] 300
300 <Category 4 [LESS THAN EQUALS TO]
						  2000
0.5
5
100
500
Dermal
(mg/kg bodyweight)
0 <Category 1 [LESS THAN EQUALS TO]
						  50
50 <Category 2 [LESS THAN EQUALS TO]
						  200
200 <Category 3 [LESS THAN EQUALS TO]
						  1000
1000 <Category 4 [LESS THAN EQUALS TO]
						  2000
5
50
300
1100
Gases
(ppmV)
0 <Category 1 [LESS THAN EQUALS TO]
						  100
100 <Category 2 [LESS THAN EQUALS TO]
						  500
500 <Category 3 [LESS THAN EQUALS TO]
						  2500
2500 <Category 4 [LESS THAN EQUALS TO]
						  20000
10
100
700
4500
Vapors
(mg/l)
0 <Category 1 [LESS THAN EQUALS TO]
						  0.5
0.5 <Category 2 [LESS THAN EQUALS TO]
						  2.0
2.0 <Category 3 [LESS THAN EQUALS TO]
						  10.0
10.0 <Category 4 [LESS THAN EQUALS TO]
						  20.0
0.05
0.5
3
11
Dust/mist
(mg/l)
0 <Category 1 [LESS THAN EQUALS TO]
						  0.05
0.05 <Category 2 [LESS THAN EQUALS TO]
						  0.5
0.5 <Category 3 [LESS THAN EQUALS TO]
						  1.0
1.0 <Category 4 [LESS THAN EQUALS TO]
						  5.0
0.005
0.05
0.5
1.5
Note: Gas concentrations are expressed in parts per
				million per volume (ppmV).
A.2 SKIN CORROSION/IRRITATION
A.2.1 Definitions and general considerations
A.2.1.1 Skin corrosion is the production of
				irreversible damage to the skin; namely, visible necrosis through the
				epidermis and into the dermis, following the application of a test
				substance for up to 4 hours. Corrosive reactions are typified by
				ulcers, bleeding, bloody scabs, and, by the end of observation at 14
				days, by discoloration due to blanching of the skin, complete areas
				of alopecia, and scars. Histopathology should be considered to
				evaluate questionable lesions.
Skin irritation is the production of reversible
				damage to the skin following the application of a test substance for
				up to 4 hours.
A.2.1.2 Skin corrosion/irritation shall be classified
				using a tiered approach as detailed in figure A.2.1. Emphasis shall
				be placed upon existing human data (See A.0.2.6), followed by other
				sources of information. Classification results directly when the data
				satisfy the criteria in this section. In case the criteria cannot be
				directly applied, classification of a substance or a mixture is made
				on the basis of the total weight of evidence (See A.0.3.1). This
				means that all available information bearing on the determination of
				skin corrosion/irritation is considered together, including the
				results of appropriate scientifically validated in-vitro tests,
				relevant animal data, and human data such as epidemiological and
				clinical studies and well-documented case reports and
				observations.
A.2.2 Classification criteria for substances using
				animal test data
A.2.2.1 Corrosion
A.2.2.1.1 A corrosive substance is a chemical that
				produces destruction of skin tissue, namely, visible necrosis through
				the epidermis and into the dermis, in at least 1 of 3 tested animals
				after exposure up to a 4-hour duration. Corrosive reactions are
				typified by ulcers, bleeding, bloody scabs and, by the end of
				observation at 14 days, by discoloration due to blanching of the
				skin, complete areas of alopecia and scars. Histopathology should be
				considered to discern questionable lesions.
A.2.2.1.2 Three sub-categories of Category 1 are
				provided in Table A.2.1, all of which shall be regulated as Category
				1.
Table A.2.1: Skin corrosion category and
				sub-categories
Category 1: Corrosive
Corrosive sub-categories
Corrosive in [GREATER THAN
						EQUALS TO]1 of 3 animals
Exposure
Observation
1A
[LESS THAN EQUALS TO] 3 min
[LESS THAN EQUALS TO] 1 h
1B
> 3 min [LESS THAN EQUALS TO] 1 h
[LESS THAN EQUALS TO] 14 days
1C
> 1 h [LESS THAN EQUALS TO] 4 h
[LESS THAN EQUALS TO] 14 days
A.2.2.2 Irritation
A.2.2.2.1 A single irritant category (Category 2) is
				presented in the Table A.2.2. The major criterion for the irritant
				category is that at least 2 tested animals have a mean score of
				[GREATER THAN EQUALS TO] 2.3 [GREATER THAN EQUALS TO] 4.0.
Table A.2.2 Skin irritation
				category
Criteria
Irritant (Category 2)
(1) Mean value of [GREATER THAN EQUALS TO] 2.3
						[GREATER THAN EQUALS TO] 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.2.2.2.2 Animal irritant responses within a test can
				be quite variable, as they are with corrosion. A separate irritant
				criterion accommodates cases when there is a significant irritant
				response but less than the mean score criterion for a positive test.
				For example, a substance might be designated as an irritant if at
				least 1 of 3 tested animals shows a very elevated mean score
				throughout the study, including lesions persisting at the end of an
				observation period of normally 14 days. Other responses could also
				fulfill this criterion. However, it should be ascertained that the
				responses are the result of chemical exposure. Addition of this
				criterion increases the sensitivity of the classification
				system.
A.2.2.2.3. Reversibility of skin lesions is another
				consideration in evaluating irritant responses. When inflammation
				persists to the end of the observation period in 2 or more test
				animals, taking into consideration alopecia (limited area),
				hyperkeratosis, hyperplasia and scaling, then a chemical should be
				considered to be an irritant.
A.2.3 Classification Criteria for Substances Using
				Other Data Elements
A.2.3.1 Existing human and animal data including
				information from single or repeated exposure should be the first line
				of analysis, as they give information directly relevant to effects on
				the skin. If a substance is highly toxic by the dermal route, a skin
				corrosion/irritation study may not be practicable since the amount of
				test substance to be applied would considerably exceed the toxic dose
				and, consequently, would result in the death of the animals. When
				observations are made of skin corrosion/irritation in acute toxicity
				studies and are observed up through the limit dose, these data may be
				used for classification provided that the dilutions used and species
				tested are equivalent. In vitro alternatives that have been
				scientifically validated shall be used to make classification
				decisions. Solid substances (powders) may become corrosive or
				irritant when moistened or in contact with moist skin or mucous
				membranes. Likewise, pH extremes like [LESS THAN EQUALS TO] 2 and
				[GREATER THAN EQUALS TO] 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 [LESS THAN EQUALS TO] 2 or
				a pH [GREATER THAN EQUALS TO] 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.
Figure A.2.1: Tiered evaluation of skin
				corrosion and irritation potential
Click Here To
				View Image
Notes to Figure A.2.1:
1.Evidence of existing human or animal data may be
				derived from single or repeated exposure(s) in occupational,
				consumer, transportation, or emergency response scenarios; from
				ethically-conducted human clinical studies; or from
				purposely-generated data from animal studies conducted according to
				scientifically validated test methods (at present, there is no
				internationally accepted test method for human skin irritation
				testing).
2.Classify in the appropriate harmonized category, as
				shown in Tables A.2.1 and A.2.2.
3.Pre-existing animal data (e.g. from an acute dermal
				toxicity test or a sensitisation test) should be carefully reviewed
				to determine if sufficient skin corrosion/irritation evidence is
				available through other, similar information. For example,
				classification/categorization may be done on the basis of whether a
				chemical has or has not produced any skin irritation in an acute
				dermal toxicity test in animals at the limit dose, or produces very
				toxic effects in an acute dermal toxicity test in animals. In the
				latter case, the chemical would be classified as being very hazardous
				by the dermal route for acute toxicity, and it would be moot whether
				the chemical is also irritating or corrosive on the skin. It should
				be kept in mind in evaluating acute dermal toxicity information that
				the reporting of dermal lesions may be incomplete, testing and
				observations may be made on a species other than the rabbit, and
				species may differ in sensitivity in their responses.
4.Evidence from studies using scientifically
				validated protocols with isolated human/animal tissues or other,
				non-tissue-based, though scientifically validated, protocols should
				be assessed. Examples of scientifically validated test methods for
				skin corrosion include OECD TG 430 (Transcutaneous Electrical
				Resistance Test (TER)), 431 (Human Skin Model Test), and 435
				(Membrane Barrier Test Method). OECD TG 439 (Reconstructed Human
				Epidermis Test Method) is a scientifically validated in vitro test
				method for skin irritation.
5.Measurement of pH alone may be adequate, but
				assessment of acid or alkali reserve (buffering capacity) would be
				preferable. Presently, there is no scientifically validated and
				internationally accepted method for assessing this parameter.
6.All information that is available on a chemical
				should be considered and an overall determination made on the total
				weight of evidence. This is especially true when there is conflict in
				information available on some parameters. Professional judgment
				should be exercised in making such a determination.
A.2.4 Classification criteria for mixtures
A.2.4.1 Classification of mixtures when data are
				available for the complete mixture
A.2.4.1.1 The mixture shall be classified using the
				criteria for substances (See A.2.3).
A.2.4.2 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.2.4.2.1 Where the mixture itself has not been
				tested to determine its skin corrosion/irritation, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data will be used in accordance with the following bridging
				principles, as found in paragraph A.0.5 of this Appendix: Dilution,
				Batching, Concentration of mixtures, Interpolation within one
				toxicity category, Substantially similar mixtures, and
				Aerosols.
A.2.4.3 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.2.4.3.1 For purposes of classifying the skin
				corrosion/irritation hazards of mixtures in the tiered
				approach:
The "relevant ingredients" of a mixture are those
				which are present in concentrations [GREATER THAN EQUALS TO] 1%
				(weight/weight for solids, liquids, dusts, mists and vapors and
				volume/volume for gases.) If the classifier has reason to suspect
				that an ingredient present at a concentration < 1% will affect
				classification of the mixture for skin corrosion/irritation, that
				ingredient shall also be considered relevant.
A.2.4.3.2 In general, the approach to classification
				of mixtures as irritant or corrosive to skin when data are available
				on the ingredients, but not on the mixture as a whole, is based on
				the theory of additivity, such that each corrosive or irritant
				ingredient contributes to the overall irritant or corrosive
				properties of the mixture in proportion to its potency and
				concentration. A weighting factor of 10 is used for corrosive
				ingredients when they are present at a concentration below the
				concentration limit for classification with Category 1, but are at a
				concentration that will contribute to the classification of the
				mixture as an irritant. The mixture is classified as corrosive or
				irritant when the sum of the concentrations of such ingredients
				exceeds a cut-off value/concentration limit.
A.2.4.3.3 Table A.2.3 below provides the cut-off
				value/concentration limits to be used to determine if the mixture is
				considered to be an irritant or a corrosive to the skin.
A.2.4.3.4 Particular care shall be taken when
				classifying certain types of chemicals such as acids and bases,
				inorganic salts, aldehydes, phenols, and surfactants. The approach
				explained in A.2.4.3.1 and A.2.4.3.2 might not work given that many
				of such substances are corrosive or irritant at concentrations <
				1%. For mixtures containing strong acids or bases the pH should be
				used as classification criteria since pH will be a better indicator
				of corrosion than the concentration limits of Table A.2.3. A mixture
				containing corrosive or irritant ingredients that cannot be
				classified based on the additivity approach shown in Table A.2.3, due
				to chemical characteristics that make this approach unworkable,
				should be classified as Skin Category 1 if it contains [GREATER THAN
				EQUALS TO] 1% of a corrosive ingredient and as Skin Category 2 when
				it contains [GREATER THAN EQUALS TO] 3% of an irritant ingredient.
				Classification of mixtures with ingredients for which the approach in
				Table A.2.3 does not apply is summarized in Table A.2.4 below.
A.2.4.3.5 On occasion, reliable data may show that
				the skin corrosion/irritation of an ingredient will not be evident
				when present at a level above the generic concentration cut-off
				values mentioned in Tables A.2.3 and A.2.4. In these cases the
				mixture could be classified according to those data (See Use of
				cut-off values/concentration limits, paragraph A.0.4.3 of this
				Appendix).
A.2.4.3.6 If there are data showing that (an)
				ingredient(s) may be corrosive or irritant at a concentration of <
				1% (corrosive) or < 3% (irritant), the mixture shall be classified
				accordingly (See Use of cut-off values/concentration limits,
				paragraph A.0.4.3 of this Appendix).
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)
Sum of ingredients classified
						as:
Concentration triggering
						classification of a mixture as:
Skin corrosive
Skin irritant
Category 1
Category 2
Skin Category 1
[GREATER THAN EQUALS TO] 5%
[GREATER THAN EQUALS TO] 1% but < 5%
Skin Category 2
[GREATER THAN EQUALS TO] 10%
(10 x Skin Category 1) + Skin Category 2
[GREATER THAN EQUALS TO] 10%
Table A.2.4: Concentration of ingredients of a
				mixture for which the additivity approach does not apply, that would
				trigger classification of the mixture as hazardous to
				skin
Ingredient:
Concentration:
Mixture
classified as:
Skin
Acid with pH [LESS THAN EQUALS TO] 2
[GREATER THAN EQUALS TO] 1%
Category 1
Base with pH [GREATER THAN EQUALS TO] 11.5
[GREATER THAN EQUALS TO] 1%
Category 1
Other corrosive (Category 1) ingredients for
						which additivity does not apply
[GREATER THAN EQUALS TO] 1%
Category 1
Other irritant (Category 2) ingredients for
						which additivity does not apply, including acids and bases
[GREATER THAN EQUALS TO] 3%
Category 2
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 [GREATER THAN EQUALS TO] 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.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.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 [LESS THAN EQUALS TO] 2 and
				[GREATER THAN EQUALS TO] 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 [LESS THAN EQUALS TO] 2 or [GREATER THAN
				EQUALS TO] 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.
Figure A.3.1 Evaluation strategy for serious
				eye damage and eye irritation
(See also Figure A.2.1)
Notes to Figure A.3.1:
1 Evidence of existing human or animal data may be
				derived from single or repeated exposure(s) in occupational,
				consumer, transportation, or emergency response scenarios; from
				ethically-conducted human clinical studies; or from
				purposely-generated data from animal studies conducted according to
				scientifically validated test methods. At present, there are no
				internationally accepted test methods for human skin or eye
				irritation testing.
2 Classify in the appropriate harmonized category, as
				shown in Tables A.3.1 and A.3.2. also lead to a conclusion to
				classify as causing Serious Eye
3 Pre-existing animal data should be carefully
				reviewed to determine if sufficient skin or eye corrosion/irritation
				evidence is available through other, similar information.
4 Evidence from studies using scientifically
				validated protocols with isolated human/animal tissues or other,
				non-tissue-based, though scientifically validated, protocols should
				be assessed. Examples of, scientifically validated test methods for
				identifying eye corrosives and severe irritants (i.e., Serious Eye
				Damage) include OECD TG 437 (Bovine Corneal Opacity and Permeability
				(BCOP)) and TG 438 (Isolated Chicken Eye). Positive test results from
				a scientifically validated in vitro test for skin corrosion would
				likely Damage.
5 Measurement of pH alone may be adequate, but
				assessment of acid or alkali reserve (buffering capacity) would be
				preferable.
6 All information that is available on a chemical
				should be considered and an overall determination made on the total
				weight of evidence. This is especially true when there is conflict in
				information available on some parameters. The weight of evidence
				including information on skin irritation could lead to classification
				of eye irritation. It is recognized that not all skin irritants are
				eye irritants as well. Professional judgment should be exercised in
				making such a determination
A.3.4 Classification criteria for mixtures
A.3.4.1 Classification of mixtures when data are
				available for the complete mixture
A.3.4.1.1 The mixture will be classified using the
				criteria for substances
A.3.4.1.2 Unlike other hazard classes, there are
				alternative tests available for skin corrosivity of certain types of
				chemicals that can give an accurate result for classification
				purposes, as well as being simple and relatively inexpensive to
				perform. When considering testing of the mixture chemical
				manufacturers are encouraged to use a tiered weight of evidence
				strategy as included in the criteria for classification of substances
				for skin corrosion and serious eye damage and eye irritation to help
				ensure an accurate classification, as well as avoid unnecessary
				animal testing. In the absence of any other information, a mixture is
				considered to cause serious eye damage (Eye Category 1) if it has a
				pH [LESS THAN EQUALS TO] 2 or [GREATER THAN EQUALS TO] 11.5. However,
				if consideration of acid/alkaline reserve suggests the substance or
				mixture may not have the potential to cause serious eye damage
				despite the low or high pH value, then further evaluation may be
				necessary.
A.3.4.2 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.3.4.2.1 Where the mixture itself has not been
				tested to determine its skin corrosivity or potential to cause
				serious eye damage or eye irritation, but there are sufficient data
				on both the individual ingredients and similar tested mixtures to
				adequately characterize the hazards of the mixture, these data will
				be used in accordance with the following bridging principles, as
				found in paragraph A.0.5 of this Appendix: Dilution, Batching,
				Concentration of mixtures, Interpolation within one toxicity
				category, Substantially similar mixtures, and Aerosols.
A.3.4.3 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.3.4.3.1 For purposes of classifying the eye
				corrosion/irritation hazards of mixtures in the tiered
				approach:
The "relevant ingredients" of a mixture are those
				which are present in concentrations [GREATER THAN EQUALS TO] 1%
				(weight/weight for solids, liquids, dusts, mists and vapors and
				volume/volume for gases) If the classifier has reason to suspect
				that an ingredient present at a concentration < 1% will affect
				classification of the mixture for eye corrosion/irritation, that
				ingredient shall also be considered relevant.
A.3.4.3.2 In general, the approach to classification
				of mixtures as seriously damaging to the eye or eye irritant when
				data are available on the ingredients, but not on the mixture as a
				whole, is based on the theory of additivity, such that each corrosive
				or irritant ingredient contributes to the overall irritant or
				corrosive properties of the mixture in proportion to its potency and
				concentration. A weighting factor of 10 is used for corrosive
				ingredients when they are present at a concentration below the
				concentration limit for classification with Category 1, but are at a
				concentration that will contribute to the classification of the
				mixture as an irritant. The mixture is classified as seriously
				damaging to the eye or eye irritant when the sum of the
				concentrations of such ingredients exceeds a threshold cut-off
				value/concentration limit.
A.3.4.3.3 Table A.3.3 provides the cut-off
				value/concentration limits to be used to determine if the mixture
				should be classified as seriously damaging to the eye or an eye
				irritant.
A.3.4.3.4 Particular care must be taken when
				classifying certain types of chemicals such as acids and bases,
				inorganic salts, aldehydes, phenols, and surfactants. The approach
				explained in A.3.4.3.1 and A.3.4.3.2 might not work given that many
				of such substances are corrosive or irritant at concentrations <
				1%. For mixtures containing strong acids or bases, the pH should be
				used as classification criteria (See A.3.4.1) since pH will be a
				better indicator of serious eye damage than the concentration limits
				of Table A.3.3. A mixture containing corrosive or irritant
				ingredients that cannot be classified based on the additivity
				approach applied in Table A.3.3 due to chemical characteristics that
				make this approach unworkable, should be classified as Eye Category 1
				if it contains [GREATER THAN EQUALS TO] 1% of a corrosive ingredient
				and as Eye Category 2 when it contains [GREATER THAN EQUALS TO] 3% of
				an irritant ingredient. Classification of mixtures with ingredients
				for which the approach in Table A.3.3 does not apply is summarized in
				Table A.3.4.
A.3.4.3.5 On occasion, reliable data may show that
				the reversible/irreversible eye effects of an ingredient will not be
				evident when present at a level above the generic cut-off
				values/concentration limits mentioned in Tables A.3.3 and A.3.4. In
				these cases the mixture could be classified according to those data
				(See also A.0.4.3 Use of cut-off values/concentration limits"). On
				occasion, when it is expected that the skin corrosion/irritation or
				the reversible/irreversible eye effects of an ingredient will not be
				evident when present at a level above the generic
				concentration/cut-off levels mentioned in Tables A.3.3 and A.3.4,
				testing of the mixture may be considered. In those cases, the tiered
				weight of evidence strategy should be applied as referred to in
				section A.3.3, Figure A.3.1 and explained in detail in this
				chapter.
A.3.4.3.6 If there are data showing that (an)
				ingredient(s) may be corrosive or irritant at a concentration of <
				1% (corrosive) or < 3% (irritant), the mixture should be
				classified accordingly (See also paragraph A.0.4.3, Use of cut-off
				values/concentration limits).
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
Sum of ingredients classified
						as:
Concentration triggering
						classification of a mixture as:
Irreversible eye effects
Reversible eye effects
Category 1
Category 2
Eye or Skin Category 1
[GREATER THAN EQUALS TO] 3%
[GREATER THAN EQUALS TO] 1% but < 3%
Eye Category 2
[GREATER THAN EQUALS TO] 10%
(10 x Eye Category 1) + Eye Category 2
[GREATER THAN EQUALS TO] 10%
Skin Category 1 + Eye Category 1
[GREATER THAN EQUALS TO] 3%
[GREATER THAN EQUALS TO] 1% but < 3%
10 x (Skin Category 1 + Eye Category 1) + Eye
						Category 2
[GREATER THAN EQUALS TO] 10%
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
Ingredient
Concentration
Mixture classified as: Eye
Acid with pH [LESS THAN EQUALS TO] 2
[GREATER THAN EQUALS TO] 1%
Category 1
Base with pH [GREATER THAN EQUALS TO] 11.5
[GREATER THAN EQUALS TO] 1%
Category 1
Other corrosive (Category 1) ingredients for
						which additivity does not apply
[GREATER THAN EQUALS TO] 1%
Category 1
Other irritant (Category 2) ingredients for
						which additivity does not apply, including acids and bases
[GREATER THAN EQUALS TO] 3%
Category 2
A.4 RESPIRATORY OR SKIN
				SENSITIZATION
A.4.1 Definitions and general considerations
A.4.1.1 Respiratory sensitizer means a chemical that
				will lead to hypersensitivity of the airways following inhalation of
				the chemical.
Skin sensitizer means a chemical that will lead to an
				allergic response following skin contact.
A.4.1.2 For the purpose of this chapter,
				sensitization includes two phases: the first phase is induction of
				specialized immunological memory in an individual by exposure to an
				allergen. The second phase is elicitation, i.e., production of a
				cell-mediated or antibody-mediated allergic response by exposure of a
				sensitized individual to an allergen.
A.4.1.3 For respiratory sensitization, the pattern of
				induction followed by elicitation phases is shared in common with
				skin sensitization. For skin sensitization, an induction phase is
				required in which the immune system learns to react; clinical
				symptoms can then arise when subsequent exposure is sufficient to
				elicit a visible skin reaction (elicitation phase). As a consequence,
				predictive tests usually follow this pattern in which there is an
				induction phase, the response to which is measured by a standardized
				elicitation phase, typically involving a patch test. The local lymph
				node assay is the exception, directly measuring the induction
				response. Evidence of skin sensitization in humans normally is
				assessed by a diagnostic patch test.
A.4.1.4 Usually, for both skin and respiratory
				sensitization, lower levels are necessary for elicitation than are
				required for induction.
A.4.1.5 The hazard class "respiratory or skin
				sensitization" is differentiated into:
(a) Respiratory sensitization; and
(b) Skin sensitization
A.4.2 Classification criteria for substances
A.4.2.1 Respiratory sensitizers
A.4.2.1.1 Hazard categories
A.4.2.1.1.1 Effects seen in either humans or animals
				will normally justify classification in a weight of evidence approach
				for respiratory sensitizers. Substances may be allocated to one of
				the two sub-categories 1A or 1B using a weight of evidence approach
				in accordance with the criteria given in Table A.4.1 and on the basis
				of reliable and good quality evidence from human cases or
				epidemiological studies and/or observations from appropriate studies
				in experimental animals.
A.4.2.1.1.2 Where data are not sufficient for
				sub-categorization, respiratory sensitizers shall be classified in
				Category 1.
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.
Sub-category 1A:
Substances showing a high frequency of
						occurrence in humans; or a probability of occurrence of a high
						sensitization rate in humans based on animal or other tests.1
						Severity of reaction may also be considered.
Sub-category 1B:
Substances showing a low to moderate frequency
						of occurrence in humans; or a probability of occurrence of a low to
						moderate sensitization rate in humans based on animal or other
						tests.1 Severity of reaction may also be considered.
A.4.2.1.2 Human evidence
A.4.2.1.2.1 Evidence that a substance can lead to
				specific respiratory hypersensitivity will normally be based on human
				experience. In this context, hypersensitivity is normally seen as
				asthma, but other hypersensitivity reactions such as
				rhinitis/conjunctivitis and alveolitis are also considered. The
				condition will have the clinical character of an allergic reaction.
				However, immunological mechanisms do not have to be
				demonstrated.
A.4.2.1.2.2 When considering the human evidence, it
				is necessary that in addition to the evidence from the cases, the
				following be taken into account:
(a) the size of the population exposed;
(b) the extent of exposure.
(a) clinical history and data from appropriate lung
				function tests related to exposure to the substance, confirmed by
				other supportive evidence which may include:
(i) in vivo immunological test (e.g., skin prick
				test);
(ii) in vitro immunological test (e.g., serological
				analysis);
(iii) studies that may indicate other specific
				hypersensitivity reactions where immunological mechanisms of action
				have not been proven, e.g., repeated low-level irritation,
				pharmacologically mediated effects;
(iv) a chemical structure related to substances known
				to cause respiratory hypersensitivity;
(b) data from positive bronchial challenge tests with
				the substance conducted according to accepted guidelines for the
				determination of a specific hypersensitivity reaction.
A.4.2.1.2.4 Clinical history should include both
				medical and occupational history to determine a relationship between
				exposure to a specific substance and development of respiratory
				hypersensitivity. Relevant information includes aggravating factors
				both in the home and workplace, the onset and progress of the
				disease, family history and medical history of the patient in
				question. The medical history should also include a note of other
				allergic or airway disorders from childhood and smoking
				history.
A.4.2.1.2.5 The results of positive bronchial
				challenge tests are considered to provide sufficient evidence for
				classification on their own. It is, however, recognized that in
				practice many of the examinations listed above will already have been
				carried out.
A.4.2.1.3 Animal studies
A.4.2.1.3.1 Data from appropriate animal studies
				which may be indicative of the potential of a substance to cause
				sensitization by inhalation in humans may include:
(a) measurements of Immunoglobulin E (IgE) and other
				specific immunological parameters, for example in mice
(b) specific pulmonary responses in guinea pigs.
				A.4.2.2 Skin sensitizers
A.4.2.2.1 Hazard categories
A.4.2.2.1.1 Effects seen in either humans or animals
				will normally justify classification in a weight of evidence approach
				for skin sensitizers. Substances may be allocated to one of the two
				sub-categories 1A or 1B using a weight of evidence approach in
				accordance with the criteria given in Table A.4.2 and on the basis of
				reliable and good quality evidence from human cases or
				epidemiological studies and/or observations from appropriate studies
				in experimental animals according to the guidance values provided in
				A.4.2.2.2.1 and A.4.2.2.3.2 for sub-category 1A and in A.4.2.2.2.2
				and A.4.2.2.3.3 for sub-category 1B.
A.4.2.2.1.2 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.4.2.2.2 Human evidence
A.4.2.2.2.1 Human evidence for sub-category 1A may
				include:
(a) positive responses at [LESS THAN EQUALS TO] 500
				[MICRO]g/cm2 (Human Repeat Insult Patch Test (HRIPT), Human
				Maximization Test (HMT) - induction threshold);
(b) diagnostic patch test data where there is a
				relatively high and substantial incidence of reactions in a defined
				population in relation to relatively low exposure;
(c) other epidemiological evidence where there is a
				relatively high and substantial incidence of allergic contact
				dermatitis in relation to relatively low exposure.
(a) positive responses at > 500 [MICRO]g/cm2
				(HRIPT, HMT -induction threshold);
(b) diagnostic patch test data where there is a
				relatively low but substantial incidence of reactions in a defined
				population in relation to relatively high exposure;
(c) other epidemiological evidence where there is a
				relatively low but substantial incidence of allergic contact
				dermatitis in relation to relatively high exposure.
A.4.2.2.3 Animal studies
A.4.2.2.3.1 For Category 1, when an adjuvant type
				test method for skin sensitization is used, a response of at least
				30% of the animals is considered as positive. For a non-adjuvant
				Guinea pig test method a response of at least 15% of the animals is
				considered positive. For Category 1, a stimulation index of three or
				more is considered a positive response in the local lymph node
				assay.
A.4.2.2.3.2 Animal test results for sub-category 1A
				can include data with values indicated in Table A.4.3 below:
Table A.4.3: Animal test results for
				sub-category 1A
Assay
Criteria
Local lymph node assay
EC3 value [LESS THAN EQUALS TO] 2%
Guinea pig maximization test
[GREATER THAN EQUALS TO] 30% responding at
						  [LESS THAN EQUALS TO] 0.1% intradermal induction dose or
GREATER THAN EQUALS TO] 60% responding at
						  > 0.1% to [LESS THAN EQUALS TO] 1% intradermal induction
						  dose
Buehler assay
[GREATER THAN EQUALS TO] 15% responding at
						  [LESS THAN EQUALS TO] 0.2% topical induction dose or
[GREATER THAN EQUALS TO] 60% responding at
						  > 0.2% to [LESS THAN EQUALS 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.4.2.2.3.3 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 > 707; 2%
Guinea pig maximization test
[GREATER THAN EQUALS TO] 30% to < 60%
						responding at > 0.1% to [LESS THAN EQUALS TO] 1% intradermal
						induction dose or
[GREATER THAN EQUALS TO] 30% responding at
						  > 1% intradermal induction dose
Buehler assay
[GREATER THAN EQUALS TO] 15% to < 60%
						responding at > 0.2% to [LESS THAN EQUALS TO] 20% topical
						induction dose or
[GREATER THAN EQUALS TO] 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.4.2.2.4 Specific considerations
A.4.2.2.4.1 For classification of a substance,
				evidence shall include one or more of the following using a weight of
				evidence approach:
(a) Positive data from patch testing, normally
				obtained in more than one dermatology clinic;
(b) Epidemiological studies showing allergic contact
				dermatitis caused by the substance. Situations in which a high
				proportion of those exposed exhibit characteristic symptoms are to be
				looked at with special concern, even if the number of cases is
				small;
(c) Positive data from appropriate animal
				studies;
(d) Positive data from experimental studies in man
				(See paragraph A.0.2.6 of this Appendix);
(e) Well documented episodes of allergic contact
				dermatitis, normally obtained in more than one dermatology
				clinic;
(f) Severity of reaction.
A.4.2.2.4.2 Evidence from animal studies is usually
				much more reliable than evidence from human exposure. However, in
				cases where evidence is available from both sources, and there is
				conflict between the results, the quality and reliability of the
				evidence from both sources must be assessed in order to resolve the
				question of classification on a case-by-case basis. Normally, human
				data are not generated in controlled experiments with volunteers for
				the purpose of hazard classification but rather as part of risk
				assessment to confirm lack of effects seen in animal tests.
				Consequently, positive human data on skin sensitization are usually
				derived from case-control or other, less defined studies. Evaluation
				of human data must, therefore, be carried out with caution as the
				frequency of cases reflect, in addition to the inherent properties of
				the substances, factors such as the exposure situation,
				bioavailability, individual predisposition and preventive measures
				taken. Negative human data should not normally be used to negate
				positive results from animal studies. For both animal and human data,
				consideration should be given to the impact of vehicle.
A.4.2.2.4.3 If none of the above-mentioned conditions
				are met, the substance need not be classified as a skin sensitizer.
				However, a combination of two or more indicators of skin
				sensitization, as listed below, may alter the decision. This shall be
				considered on a case-by-case basis.
(a) Isolated episodes of allergic contact
				dermatitis;
(b) Epidemiological studies of limited power, e.g.,
				where chance, bias or confounders have not been ruled out fully with
				reasonable confidence;
(c) Data from animal tests, performed according to
				existing guidelines, which do not meet the criteria for a positive
				result described in A.4.2.2.3, but which are sufficiently close to
				the limit to be considered significant;
(d) Positive data from non-standard methods;
(e) Positive results from close structural
				analogues.
A.4.2.2.4.4 Immunological contact urticaria
A.4.2.2.4.4.1 Substances meeting the criteria for
				classification as respiratory sensitizers may, in addition, cause
				immunological contact urticaria. Consideration shall be given to
				classifying these substances as skin sensitizers.
A.4.2.2.4.4.2 Substances which cause immunological
				contact urticaria without meeting the criteria for respiratory
				sensitizers shall be considered for classification as skin
				sensitizers.
A.4.2.2.4.4.3 There is no recognized animal model
				available to identify substances which cause immunological contact
				urticaria. Therefore, classification will normally be based on human
				evidence, similar to that for skin sensitization.
A.4.3 Classification criteria for mixtures
A.4.3.1 Classification of mixtures when data are
				available for the complete mixture
When reliable and good quality evidence, as described
				in the criteria for substances, from human experience or appropriate
				studies in experimental animals, is available for the mixture, then
				the mixture shall be classified by weight of evidence evaluation of
				these data. Care must be exercised in evaluating data on mixtures
				that the dose used does not render the results inconclusive.
A.4.3.2 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.4.3.2.1 Where the mixture itself has not been
				tested to determine its sensitizing properties, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data will be used in accordance with the following agreed bridging
				principles as found in paragraph A.0.5 of this Appendix: Dilution,
				Batching, Concentration of mixtures, Interpolation, Substantially
				similar mixtures, and Aerosols.
A.4.3.3 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
The mixture shall be classified as a respiratory or
				skin sensitizer when at least one ingredient has been classified as a
				respiratory or skin sensitizer and is present at or above the
				appropriate cut-off value/concentration limit for the specific
				endpoint as shown in Table A.4.5.
Table A.4.5: Cut-off values/concentration
				limits of ingredients of a mixture classified as either respiratory
				sensitizers or skin sensitizers that would trigger classification of
				the mixture
Ingredient classified
						as:
Cut-off values/concentration
						limits triggering classification of a mixture as:
Respiratory Sensitizer
Skin Sensitizer
Category 1
Category 1
Solid/Liquid
Gas
All physical states
Respiratory Sensitizer Category 1
[GREATER THAN EQUALS TO] 0.1%
[GREATER THAN EQUALS TO] 0.1%
Respiratory Sensitizer Sub-category 1A
[GREATER THAN EQUALS TO] 0.1%
[GREATER THAN EQUALS TO] 0.1%
Respiratory Sensitizer Sub-category 1B
[GREATER THAN EQUALS TO] 0.1%
[GREATER THAN EQUALS TO] 0.2%
Skin Sensitizer Category 1
[GREATER THAN EQUALS TO] 0.1%
Skin Sensitizer Sub-category 1A
[GREATER THAN EQUALS TO] 0.1%
Skin Sensitizer Sub-category 1B
[GREATER THAN EQUALS TO] 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,
				mutagenic-ity/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.5.2.2.1 To arrive at a classification, test results
				are considered from experiments determining mutagenic and/or
				genotoxic effects in germ and/or somatic cells of exposed animals.
				Mutagenic and/or genotoxic effects determined in in vitro tests shall
				also be considered.
A.5.2.2.2 The system is hazard based, classifying
				chemicals on the basis of their intrinsic ability to induce mutations
				in germ cells. The scheme is, therefore, not meant for the
				(quantitative) risk assessment of chemical substances.
A.5.2.2.3 Classification for heritable effects in
				human germ cells is made on the basis of scientifically validated
				tests. Evaluation of the test results shall be done using expert
				judgment and all the available evidence shall be weighed for
				classification.
A.5.2.2.4 The classification of substances shall be
				based on the total weight of evidence available, using expert
				judgment. In those instances where a single well-conducted test is
				used for classification, it shall provide clear and unambiguously
				positive results. The relevance of the route of exposure used in the
				study of the substance compared to the route of human exposure should
				also be taken into account.
A.5.3 Classification criteria for mixtures
A.5.3.1 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.5.3.1.1 Classification of mixtures shall be based
				on the available test data for the individual ingredients of the
				mixture using cut-off values/concentration limits for the ingredients
				classified as germ cell mutagens.
A.5.3.1.2 The mixture will be classified as a mutagen
				when at least one ingredient has been classified as a Category 1A,
				Category 1B or Category 2 mutagen and is present at or above the
				appropriate cut-off value/concentration limit as shown in Table A.5.1
				below for Category 1 and 2 respectively.
Table A.5.1: Cut-off values/concentration
				limits of ingredients of a mixture classified as germ cell mutagens
				that would trigger classification of the mixture
Cut-off/concentration limits
						triggering classification of a mixture as:
Ingredient classified as:
Category 1 mutagen
Category 2 mutagen
Category 1 A/B mutagen
[GREATER THAN EQUALS TO] 0.1%
-
Category 2 mutagen
-
[GREATER THAN EQUALS TO] 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.5.3.3.1 Where the mixture itself has not been
				tested to determine its germ cell mutagenicity hazard, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data will be used in accordance with the following bridging
				principles as found in paragraph A.0.5 of this Appendix: Dilution,
				Batching, and Substantially similar mixtures.
A.5.4 Examples of scientifically validated test
				methods:
A.5.4.1 Examples of in vivo heritable germ cell
				mutagenicity tests are:
(a) Rodent dominant lethal mutation test (OECD
				478)
(b) Mouse heritable translocation assay (OECD
				485)
(c) Mouse specific locus test
(a) Mammalian bone marrow chromosome aberration test
				(OECD 475)
(b) Mouse spot test (OECD 484)
(c) Mammalian erythrocyte micronucleus test (OECD
				474)
(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) Liver Unscheduled DNA Synthesis (UDS) in vivo
				(OECD 486)
(b) Mammalian bone marrow Sister Chromatid Exchanges
				(SCE)
(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
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.6.2.5.1 These factors can be viewed as either
				increasing or decreasing the level of concern for human
				carcinogenicity. The relative emphasis accorded to each factor
				depends upon the amount and coherence of evidence bearing on each.
				Generally there is a requirement for more complete information to
				decrease than to increase the level of concern. Additional
				considerations should be used in evaluating the tumor findings and
				the other factors in a case-by-case manner.
A.6.2.5.2 Some important factors which may be taken
				into consideration, when assessing the overall level of concern
				are:
(a) Tumor type and background incidence;
(b) Multisite responses;
(c) Progression of lesions to malignancy;
(d) Reduced tumor latency;
Additional factors which may increase or decrease the
				level of concern include:
(e) Whether responses are in single or both
				sexes;
(f) Whether responses are in a single species or
				several species;
(g) Structural similarity or not to a substance(s)
				for which there is good evidence of carcinogenicity;
(h) Routes of exposure;
(i) Comparison of absorption, distribution,
				metabolism and excretion between test animals and humans;
(j) The possibility of a confounding effect of
				excessive toxicity at test doses; and,
(k) Mode of action and its relevance for humans, such
				as mutagenicity, cytotoxicity with growth stimulation, mitogenesis,
				immunosuppression.
Mutagenicity: It is recognized that genetic events
				are central in the overall process of cancer development. Therefore
				evidence of mutagenic activity in vivo may indicate that a substance
				has a potential for carcinogenic effects.
A.6.2.5.3 A substance that has not been tested for
				carcinogenicity may in certain instances be classified in Category
				1A, Category 1B, or Category 2 based on tumor data from a structural
				analogue together with substantial support from consideration of
				other important factors such as formation of common significant
				metabolites, e.g., for benzidine congener dyes.
A.6.2.5.4 The classification should also take into
				consideration whether or not the substance is absorbed by a given
				route(s); or whether there are only local tumors at the site of
				administration for the tested route(s), and adequate testing by other
				major route(s) show lack of carcinogenicity.
A.6.2.5.5 It is important that whatever is known of
				the physico-chemical, toxicokinetic and toxicodynamic properties of
				the substances, as well as any available relevant information on
				chemical analogues, i.e., structure activity relationship, is taken
				into consideration when undertaking classification.
A.6.3 Classification criteria for mixtures
A.6.3.1 The mixture shall be classified as a
				carcinogen when at least one ingredient has been classified as a
				Category 1 or Category 2 carcinogen and is present at or above the
				appropriate cut-off value/concentration limit as shown in Table
				A.6.1.
Table A.6.1: Cut-off values/concentration
				limits of ingredients of a mixture classified as carcinogen that
				would trigger classification of the mixture
Ingredient classified as:
Category 1 carcinogen
Category 2 carcinogen
Category 1 carcinogen
[GREATER THAN EQUALS TO] 0.1%
Category 2 carcinogen
[GREATER THAN EQUALS TO] 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 [GREATER THAN EQUALS TO] 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
A.6.4.1 Chemical manufacturers, importers and
				employers evaluating chemicals may treat the following sources as
				establishing that a substance is a carcinogen or potential carcinogen
				for hazard communication purposes in lieu of applying the criteria
				described herein:
A.6.4.1.1 National Toxicology Program (NTP), "Report
				on Carcinogens" (latest edition);
A.6.4.1.2 International Agency for Research on Cancer
				(IARC) "Monographs on the Evaluation of Carcinogenic Risks to Humans"
				(latest editions)
A.6.4.2 Where OSHA has included cancer as a health
				hazard to be considered by classifiers for a chemical covered by  29
				CFR part 1910, Subpart Z, Toxic and Hazardous Substances, chemical
				manufacturers, importers, and employers shall classify the chemical
				as a carcinogen.
A.7 REPRODUCTIVE TOXICITY
A.7.1 Definitions and general considerations
A.7.1.1 Reproductive toxicity includes adverse
				effects on sexual function and fertility in adult males and females,
				as well as adverse effects on development of the offspring. Some
				reproductive toxic effects cannot be clearly assigned to either
				impairment of sexual function and fertility or to developmental
				toxicity. Nonetheless, chemicals with these effects shall be
				classified as reproductive toxicants.
For classification purposes, the known induction of
				genetically based inheritable effects in the offspring is addressed
				in Germ cell mutagenicity (See A.5).
A.7.1.2 Adverse effects on sexual function and
				fertility means any effect of chemicals that interferes with
				reproductive ability or sexual capacity. This includes, but is not
				limited to, alterations to the female and male reproductive system,
				adverse effects on onset of puberty, gamete production and transport,
				reproductive cycle normality, sexual behaviour, fertility,
				parturition, pregnancy outcomes, premature reproductive senescence,
				or modifications in other functions that are dependent on the
				integrity of the reproductive systems.
A.7.1.3 Adverse effects on development of the
				offspring means any effect of chemicals which interferes with normal
				development of the conceptus either before or after birth, which is
				induced during pregnancy or results from parental exposure. These
				effects can be manifested at any point in the life span of the
				organism. The major manifestations of developmental toxicity include
				death of the developing organism, structural abnormality, altered
				growth and functional deficiency.
A.7.1.4 Adverse effects on or via lactation are also
				included in reproductive toxicity, but for classification purposes,
				such effects are treated separately (See A.7.2.1).
A.7.2 Classification criteria for substances
A.7.2.1 For the purpose of classification for
				reproductive toxicity, substances shall be classified in one of two
				categories in accordance with Figure A.7.1(a). Effects on sexual
				function and fertility, and on development, shall be considered. In
				addition, effects on or via lactation shall be classified in a
				separate hazard category in accordance with Figure A.7.1(b).
Figure A.7.1
(a)
: Hazard categories for reproductive
				toxicants
CATEGORY 1:
Known or presumed human reproductive
						toxicant
Substance shall be classified in Category 1 for
						reproductive toxicity when they are known to have produced an adverse
						effect on sexual function and fertility or on development in humans
						or when there is evidence from animal studies, possibly supplemented
						with other information, to provide a strong presumption that the
						substance has the capacity to interfere with reproduction in humans.
						The classification of a substance is further distinguished on the
						basis of whether the evidence for classification is primarily from
						human data (Category 1A) or from animal data (Category 1B).
Category 1A:
Known human reproductive toxicant
The classification of a substance in this
						category is largely based on evidence from humans.
Category 1B:
Presumed human reproductive
						toxicant
The classification of a substance in this
						category is largely based on evidence from experimental animals. Data
						from animal studies shall provide sufficient evidence of an adverse
						effect on sexual function and fertility or on development in the
						absence of other toxic effects, or if occurring together with other
						toxic effects the adverse effect on reproduction is considered not to
						be a secondary non-specific consequence of other toxic effects.
						However, when there is mechanistic information that raises doubt
						about the relevance of the effect for humans, classification in
						Category 2 may be more appropriate.
Category 2:
Suspected human reproductive
						toxicant
Substances shall be classified in Category 2 for
						reproductive toxicity when there is some evidence from humans or
						experimental animals, possibly supplemented with other information,
						of an adverse effect on sexual function and fertility, or on
						development, in the absence of other toxic effects, or if occurring
						together with other toxic effects the adverse effect on reproduction
						is considered not to be a secondary non-specific consequence of the
						other toxic effects, and where the evidence is not sufficiently
						convincing to place the substance in Category 1. For instance,
						deficiencies in the study may make the quality of evidence less
						convincing, and in view of this, Category 2 would be the more
						appropriate classification.
Figure A.7.1(b): Hazard category for effects on
				or via lactation
EFFECTS ON OR VIA
						  LACTATION
Effects on or via lactation
shall be classified in a separate single category. Chemicals that are
						  absorbed by women and have been shown to interfere with lactation or
						  that may be present (including metabolites) in breast milk in amounts
						  sufficient to cause concern for the health of a breastfed child,
						  shall be classified to indicate this property hazardous to breastfed
						  babies. This classification shall be assigned on the basis of:
(a) absorption, metabolism, distribution and
						  excretion studies that indicate the likelihood the substance would be
						  present in potentially toxic levels in breast milk; and/or
(b) results of one or two generation studies
						  in animals which provide clear evidence of adverse effect in the
						  offspring due to transfer in the milk or adverse effect on the
						  quality of the milk; and/or
(c) human evidence indicating a hazard to
						  babies during the lactation period.
A.7.2.2 Basis of classification
A.7.2.2.1 Classification is made on the basis of the
				criteria, outlined above, an assessment of the total weight of
				evidence, and the use of expert judgment. Classification as a
				reproductive toxicant is intended to be used for substances which
				have an intrinsic, specific property to produce an adverse effect on
				reproduction and substances should not be so classified if such an
				effect is produced solely as a non-specific secondary consequence of
				other toxic effects.
A.7.2.2.2 In the evaluation of toxic effects on the
				developing offspring, it is important to consider the possible
				influence of maternal toxicity.
A.7.2.2.3 For human evidence to provide the primary
				basis for a Category 1A classification there must be reliable
				evidence of an adverse effect on reproduction in humans. Evidence
				used for classification shall be from well conducted epidemiological
				studies, if available, which include the use of appropriate controls,
				balanced assessment, and due consideration of bias or confounding
				factors. Less rigorous data from studies in humans may be sufficient
				for a Category 1A classification if supplemented with adequate data
				from studies in experimental animals, but classification in Category
				1B may also be considered.
A.7.2.3 Weight of evidence
A.7.2.3.1 Classification as a reproductive toxicant
				is made on the basis of an assessment of the total weight of evidence
				using expert judgment. This means that all available information that
				bears on the determination of reproductive toxicity is considered
				together. Included is information such as epidemiological studies and
				case reports in humans and specific reproduction studies along with
				sub-chronic, chronic and special study results in animals that
				provide relevant information regarding toxicity to reproductive and
				related endocrine organs. Evaluation of substances chemically related
				to the material under study may also be included, particularly when
				information on the material is scarce. The weight given to the
				available evidence will be influenced by factors such as the quality
				of the studies, consistency of results, nature and severity of
				effects, level of statistical significance for inter-group
				differences, number of endpoints affected, relevance of route of
				administration to humans and freedom from bias. Both positive and
				negative results are considered together in a weight of evidence
				determination. However, a single, positive study performed according
				to good scientific principles and with statistically or biologically
				significant positive results may justify classification (See also
				A.7.2.2.3).
A.7.2.3.2 Toxicokinetic studies in animals and
				humans, site of action and mechanism or mode of action study results
				may provide relevant information, which could reduce or increase
				concerns about the hazard to human health. If it is conclusively
				demonstrated that the clearly identified mechanism or mode of action
				has no relevance for humans or when the toxicokinetic differences are
				so marked that it is certain that the hazardous property will not be
				expressed in humans then a chemical which produces an adverse effect
				on reproduction in experimental animals should not be
				classified.
A.7.2.3.3 In some reproductive toxicity studies in
				experimental animals the only effects recorded may be considered of
				low or minimal toxicological significance and classification may not
				necessarily be the outcome. These effects include, for example, small
				changes in semen parameters or in the incidence of spontaneous
				defects in the fetus, small changes in the proportions of common
				fetal variants such as are observed in skeletal examinations, or in
				fetal weights, or small differences in postnatal developmental
				assessments.
A.7.2.3.4 Data from animal studies shall provide
				sufficient evidence of specific reproductive toxicity in the absence
				of other systemic toxic effects. However, if developmental toxicity
				occurs together with other toxic effects in the dam (mother), the
				potential influence of the generalized adverse effects should be
				assessed to the extent possible. The preferred approach is to
				consider adverse effects in the embryo/ fetus first, and then
				evaluate maternal toxicity, along with any other factors which are
				likely to have influenced these effects, as part of the weight of
				evidence. In general, developmental effects that are observed at
				maternally toxic doses should not be automatically discounted.
				Discounting developmental effects that are observed at maternally
				toxic doses can only be done on a case-by-case basis when a causal
				relationship is established or refuted.
A.7.2.3.5 If appropriate information is available it
				is important to try to determine whether developmental toxicity is
				due to a specific maternally mediated mechanism or to a non-specific
				secondary mechanism, like maternal stress and the disruption of
				homeostasis. Generally, the presence of maternal toxicity should not
				be used to negate findings of embryo/fetal effects, unless it can be
				clearly demonstrated that the effects are secondary non-specific
				effects. This is especially the case when the effects in the
				offspring are significant, e.g., irreversible effects such as
				structural malformations. In some situations it is reasonable to
				assume that reproductive toxicity is due to a secondary consequence
				of maternal toxicity and discount the effects, for example if the
				chemical is so toxic that dams fail to thrive and there is severe
				inanition; they are incapable of nursing pups; or they are prostrate
				or dying.
A.7.2.4 Maternal toxicity
A.7.2.4.1 Development of the offspring throughout
				gestation and during the early postnatal stages can be influenced by
				toxic effects in the mother either through non-specific mechanisms
				related to stress and the disruption of maternal homeostasis, or by
				specific maternally-mediated mechanisms. So, in the interpretation of
				the developmental outcome to decide classification for developmental
				effects it is important to consider the possible influence of
				maternal toxicity. This is a complex issue because of uncertainties
				surrounding the relationship between maternal toxicity and
				developmental outcome. Expert judgment and a weight of evidence
				approach, using all available studies, shall be used to determine the
				degree of influence to be attributed to maternal toxicity when
				interpreting the criteria for classification for developmental
				effects. The adverse effects in the embryo/ fetus shall be first
				considered, and then maternal toxicity, along with any other factors
				which are likely to have influenced these effects, as weight of
				evidence, to help reach a conclusion about classification.
A.7.2.4.2 Based on pragmatic observation, it is
				believed that maternal toxicity may, depending on severity, influence
				development via non-specific secondary mechanisms, producing effects
				such as depressed fetal weight, retarded ossification, and possibly
				resorptions and certain malformations in some strains of certain
				species. However, the limited numbers of studies which have
				investigated the relationship between developmental effects and
				general maternal toxicity have failed to demonstrate a consistent,
				reproducible relationship across species. Developmental effects which
				occur even in the presence of maternal toxicity are considered to be
				evidence of developmental toxicity, unless it can be unequivocally
				demonstrated on a case by case basis that the developmental effects
				are secondary to maternal toxicity. Moreover, classification shall be
				considered where there is a significant toxic effect in the
				offspring, e.g., irreversible effects such as structural
				malformations, embryo/fetal lethality, or significant post-natal
				functional deficiencies.
A.7.2.4.3 Classification shall not automatically be
				discounted for chemicals that produce developmental toxicity only in
				association with maternal toxicity, even if a specific
				maternally-mediated mechanism has been demonstrated. In such a case,
				classification in Category 2 may be considered more appropriate than
				Category 1. However, when a chemical is so toxic that maternal death
				or severe inanition results, or the dams (mothers) are prostrate and
				incapable of nursing the pups, it is reasonable to assume that
				developmental toxicity is produced solely as a secondary consequence
				of maternal toxicity and discount the developmental effects.
				Classification is not necessarily the outcome in the case of minor
				developmental changes, e.g., a small reduction in fetal/pup body
				weight or retardation of ossification when seen in association with
				maternal toxicity.
A.7.2.4.4 Some of the endpoints used to assess
				maternal toxicity are provided below. Data on these endpoints, if
				available, shall be evaluated in light of their statistical or
				biological significance and dose-response relationship.
(a) Maternal mortality: An increased incidence of
				mortality among the treated dams over the controls shall be
				considered evidence of maternal toxicity if the increase occurs in a
				dose-related manner and can be attributed to the systemic toxicity of
				the test material. Maternal mortality greater than 10% is considered
				excessive and the data for that dose level shall not normally be
				considered to need further evaluation.
(b) Mating index (Number of animals with seminal
				plugs or sperm/Number of mated x 100)
(c) Fertility index (Number of animals with implants/
				Number of matings x 100)
(d) Gestation length (If allowed to deliver
(e) Body weight and body weight change: Consideration
				of the maternal body weight change and/or adjusted (corrected)
				maternal body weight shall be included in the evaluation of maternal
				toxicity whenever such data are available. The calculation of an
				adjusted (corrected) mean maternal body weight change, which is the
				difference between the initial and terminal body weight minus the
				gravid uterine weight (or alternatively, the sum of the weights of
				the fetuses), may indicate whether the effect is maternal or
				intrauterine. In rabbits, the body weight gain may not be a useful
				indicator of maternal toxicity because of normal fluctuations in body
				weight during pregnancy.
(f) Food and water consumption (if relevant): The
				observation of a significant decrease in the average food or water
				consumption in treated dams (mothers) compared to the control group
				may be useful in evaluating maternal toxicity, particularly when the
				test material is administered in the diet or drinking water. Changes
				in food or water consumption must be evaluated in conjunction with
				maternal body weights when determining if the effects noted are
				reflective of maternal toxicity or more simply, unpalatability of the
				test material in feed or water.
(g) Clinical evaluations (including clinical signs,
				markers, and hematology and clinical chemistry studies): The
				observation of increased incidence of significant clinical signs of
				toxicity in treated dams (mothers) relative to the control group is
				useful in evaluating maternal toxicity. If this is to be used as the
				basis for the assessment of maternal toxicity, the types, incidence,
				degree and duration of clinical signs shall be reported in the study.
				Clinical signs of maternal intoxication include, but are not limited
				to: coma, prostration, hyperactivity, loss of righting reflex,
				ataxia, or labored breathing.
(h) Post-mortem data: Increased incidence and/or
				severity of post-mortem findings may be indicative of maternal
				toxicity. This can include gross or microscopic pathological findings
				or organ weight data, including absolute organ weight, organ to body
				weight ratio, or organ to brain weight ratio. When supported by
				findings of adverse histopathological effects in the affected
				organ(s), the observation of a significant change in the average
				weight of suspected target organ(s) of treated dams (mothers),
				compared to those in the control group, may be considered evidence of
				maternal toxicity.
A.7.2.5 Animal and experimental data
A.7.2.5.1 A number of scientifically validated test
				methods are available, including methods for developmental toxicity
				testing (e.g., OECD Test Guideline 414, ICH Guideline S5A, 1993),
				methods for peri- and post-natal toxicity testing (e.g., ICH S5B,
				1995), and methods for one or two-generation toxicity testing (e.g.,
				OECD Test Guidelines 415, 416)
A.7.2.5.2 Results obtained from screening tests
				(e.g., OECD Guidelines 421 - Reproduction/ Developmental Toxicity
				Screening Test, and 422 - Combined Repeated Dose Toxicity Study with
				Reproduction/Development Toxicity Screening Test) can also be used to
				justify classification, although the quality of this evidence is less
				reliable than that obtained through full studies.
A.7.2.5.3 Adverse effects or changes, seen in short-
				or long-term repeated dose toxicity studies, which are judged likely
				to impair reproductive function and which occur in the absence of
				significant generalized toxicity, may be used as a basis for
				classification, e.g., histopathological changes in the gonads.
A.7.2.5.4 Evidence from in vitro assays, or
				non-mammalian tests, and from analogous substances using
				structure-activity relationship (SAR), can contribute to the
				procedure for classification. In all cases of this nature, expert
				judgment must be used to assess the adequacy of the data. Inadequate
				data shall not be used as a primary support for
				classification.
A.7.2.5.5 It is preferable that animal studies are
				conducted using appropriate routes of administration which relate to
				the potential route of human exposure. However, in practice,
				reproductive toxicity studies are commonly conducted using the oral
				route, and such studies will normally be suitable for evaluating the
				hazardous properties of the substance with respect to reproductive
				toxicity. However, if it can be conclusively demonstrated that the
				clearly identified mechanism or mode of action has no relevance for
				humans or when the toxicokinetic differences are so marked that it is
				certain that the hazardous property will not be expressed in humans
				then a substance which produces an adverse effect on reproduction in
				experimental animals should not be classified.
A.7.2.5.6 Studies involving routes of administration
				such as intravenous or intraperitoneal injection, which may result in
				exposure of the reproductive organs to unrealistically high levels of
				the test substance, or elicit local damage to the reproductive
				organs, e.g., by irritation, must be interpreted with extreme caution
				and on their own are not normally the basis for
				classification.
A.7.2.5.7 There is general agreement about the
				concept of a limit dose, above which the production of an adverse
				effect may be considered to be outside the criteria which lead to
				classification. Some test guidelines specify a limit dose, other test
				guidelines qualify the limit dose with a statement that higher doses
				may be necessary if anticipated human exposure is sufficiently high
				that an adequate margin of exposure would not be achieved. Also, due
				to species differences in toxicokinetics, establishing a specific
				limit dose may not be adequate for situations where humans are more
				sensitive than the animal model.
A.7.2.5.8 In principle, adverse effects on
				reproduction seen only at very high dose levels in animal studies
				(for example doses that induce prostration, severe inappetence,
				excessive mortality) do not normally lead to classification, unless
				other information is available, for example, toxicokinetics
				information indicating that humans may be more susceptible than
				animals, to suggest that classification is appropriate.
A.7.2.5.9 However, specification of the actual "limit
				dose" will depend upon the test method that has been employed to
				provide the test results.
A.7.3 Classification criteria for mixtures
A.7.3.1 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.7.3.1.1 The mixture shall be classified as a
				reproductive toxicant when at least one ingredient has been
				classified as a Category 1 or Category 2 reproductive toxicant and is
				present at or above the appropriate cut-off value/concentration limit
				specified in Table A.7.1 for Category 1 and 2, respectively.
A.7.3.1.2 The mixture shall be classified for effects
				on or via lactation when at least one ingredient has been classified
				for effects on or via lactation and is present at or above the
				appropriate cut-off value/concentration limit specified in Table
				A.7.1 for the additional category for effects on or via
				lactation.
Table A.7.1: Cut-off values/concentration
				limits of ingredients of a mixture classified as reproductive
				toxicants or for
effects on or via lactation that trigger
				classification of the mixture
Ingredient classified
						as:
Cut-off values/concentration
						limits triggering classification of a mixture as:
Category 1
reproductive
toxicant
Category 2
reproductive
toxicant
Additional category
for
						effects on or
via lactation
Category 1 reproductive toxicant
[GREATER THAN EQUALS TO] 0.1%
Category 2 reproductive toxicant
[GREATER THAN EQUALS TO] 0.1%
Additional category for effects on or via
						lactation
[GREATER THAN EQUALS TO] 0.1%
A.7.3.2 Classification of mixtures when data are
				available for the complete mixture
Available test data for the mixture as a whole may be
				used for classification on a case-by-case basis. In such cases, the
				test results for the mixture as a whole must be shown to be
				conclusive taking into account dose and other factors such as
				duration, observations and analysis (e.g., statistical analysis, test
				sensitivity) of reproduction test systems.
A.7.3.3 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.7.3.3.1 Where the mixture itself has not been
				tested to determine its reproductive toxicity, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data shall be used in accordance with the following bridging
				principles as found in paragraph A.0.5 of this Appendix: Dilution,
				Batching, and Substantially similar mixtures.
A.8 SPECIFIC TARGET ORGAN TOXICITY SINGLE
				EXPOSURE
A.8.1 Definitions and general considerations
A.8.1.1 Specific target organ toxicity - single
				exposure, (STOT-SE) means specific, non-lethal target organ toxicity
				arising from a single exposure to a chemical. All significant health
				effects that can impair function, both reversible and irreversible,
				immediate and/or delayed and not specifically addressed in A.1 to A.7
				and A.10 of this Appendix are included. Specific target organ
				toxicity following repeated exposure is classified in accordance with
				SPECIFIC TARGET ORGAN TOXICITY-REPEATED EXPOSURE (A.9 of this
				Appendix) and is therefore not included here.
A.8.1.2 Classification identifies the chemical as
				being a specific target organ toxicant and, as such, it presents a
				potential for adverse health effects in people who are exposed to
				it.
A.8.1.3 The adverse health effects produced by a
				single exposure include consistent and identifiable toxic effects in
				humans; or, in experimental animals, toxicologically significant
				changes which have affected the function or morphology of a
				tissue/organ, or have produced serious changes to the biochemistry or
				hematology of the organism, and these changes are relevant for human
				health. Human data is the primary source of evidence for this hazard
				class.
A.8.1.4 Assessment shall take into consideration not
				only significant changes in a single organ or biological system but
				also generalized changes of a less severe nature involving several
				organs.
A.8.1.5 Specific target organ toxicity can occur by
				any route that is relevant for humans, i.e., principally oral, dermal
				or inhalation.
A.8.1.6 The classification criteria for specific
				organ systemic toxicity single exposure are organized as criteria for
				substances Categories 1 and 2 (See A.8.2.1), criteria for substances
				Category 3 (See A.8.2.2) and criteria for mixtures (See A.8.3). See
				also Figure A.8.1.
A.8.2 Classification criteria for substances
A.8.2.1 Substances of Category 1 and Category
				2
A.8.2.1.1 Substances shall be classified for
				immediate or delayed effects separately, by the use of expert
				judgment on the basis of the weight of all evidence available,
				including the use of recommended guidance values (See A.8.2.1.9).
				Substances shall then be classified in Category 1 or 2, depending
				upon the nature and severity of the effect(s) observed, in accordance
				with Figure A.8.1.
Figure A.8.1: Hazard categories for specific
				target organ toxicity following single exposure
CATEGORY 1:
Substances that have produced significant
						toxicity in humans, or that, on the basis of evidence from studies in
						experimental animals can be presumed to have the potential to produce
						significant toxicity in humans following single exposure
Substances are classified in Category 1 for
						STOT-SE on the basis of:
(a) reliable and good quality evidence from
						human cases or epidemiological studies; or
(b) observations from appropriate studies in
						experimental animals in which significant and/or severe toxic effects
						of relevance to human health were produced at generally low exposure
						concentrations. Guidance dose/concentration values are provided below
						(See A.8.2.1.9) to be used as part of weight-of-evidence evaluation.
CATEGORY 2:
Substances that, on the basis of evidence
						from studies in experimental animals, can be presumed to have the
						potential to be harmful to human health following single
						exposure
Substances are classified in Category 2 for
						STOT-SE on the basis of observations from appropriate studies in
						experimental animals in which significant toxic effects, of relevance
						to human health, were produced at generally moderate exposure
						concentrations. Guidance dose/concentration values are provided below
						(See A.8.2.1.9) in order to help in classification
In exceptional cases, human evidence can also be
						used to place a substance in Category 2 (See A.8.2.1.6).
CATEGORY 3:
Transient target organ effects
There are target organ effects for which a
						substance does not meet the criteria to be classified in Categories 1
						or 2 indicated above. These are effects which adversely alter human
						function for a short duration after exposure and from which humans
						may recover in a reasonable period without leaving significant
						alteration of structure or function. This category only includes
						narcotic effects and respiratory tract irritation. Substances are
						classified specifically for these effects as discussed in A.8.2.2.
Note: The primary target
						organ/system shall be identified where possible, and where this is
						not possible, the substance shall be identified as a general
						toxicant. The data shall be evaluated and, where possible, shall not
						include secondary effects (e.g., a hepatotoxicant can produce
						secondary effects in the nervous or gastrointestinal systems).
A.8.2.1.2 The relevant route(s) of exposure by which
				the classified substance produces damage shall be identified.
A.8.2.1.3 Classification is determined by expert
				judgment, on the basis of the weight of all evidence available
				including the guidance presented below.
A.8.2.1.4 Weight of evidence of all available data,
				including human incidents, epidemiology, and studies conducted in
				experimental animals is used to substantiate specific target organ
				toxic effects that merit classification.
A.8.2.1.5 The information required to evaluate
				specific target organ toxicity comes either from single exposure in
				humans (e.g., exposure at home, in the workplace or environmentally),
				or from studies conducted in experimental animals. The standard
				animal studies in rats or mice that provide this information are
				acute toxicity studies which can include clinical observations and
				detailed macroscopic and microscopic examination to enable the toxic
				effects on target tissues/ organs to be identified. Results of acute
				toxicity studies conducted in other species may also provide relevant
				information.
A.8.2.1.6 In exceptional cases, based on expert
				judgment, it may be appropriate to place certain substances with
				human evidence of target organ toxicity in Category 2: (a) when the
				weight of human evidence is not sufficiently convincing to warrant
				Category 1 classification, and/or (b) based on the nature and
				severity of effects. Dose/concentration levels in humans shall not be
				considered in the classification and any available evidence from
				animal studies shall be consistent with the Category 2
				classification. In other words, if there are also animal data
				available on the substance that warrant Category 1 classification,
				the chemical shall be classified as Category 1.
A.8.2.1.7 Effects considered to support
				classification for Category 1 and 2
A.8.2.1.7.1 Classification is supported by evidence
				associating single exposure to the substance with a consistent and
				identifiable toxic effect.
A.8.2.1.7.2 Evidence from human experience/incidents
				is usually restricted to reports of adverse health consequences,
				often with uncertainty about exposure conditions, and may not provide
				the scientific detail that can be obtained from well-conducted
				studies in experimental animals.
A.8.2.1.7.3 Evidence from appropriate studies in
				experimental animals can furnish much more detail, in the form of
				clinical observations, and macroscopic and microscopic pathological
				examination and this can often reveal hazards that may not be
				life-threatening but could indicate functional impairment.
				Consequently all available evidence, and evidence relevance to human
				health, must be taken into consideration in the classification
				process. Relevant toxic effects in humans and/or animals include, but
				are not limited to:
(a) Morbidity resulting from single exposure;
(b) Significant functional changes, more than
				transient in nature, in the respiratory system, central or peripheral
				nervous systems, other organs or other organ systems, including signs
				of central nervous system depression and effects on special senses
				(e.g., sight, hearing and sense of smell);
(c) Any consistent and significant adverse change in
				clinical biochemistry, hematology, or urinalysis parameters;
(d) Significant organ damage that may be noted at
				necropsy and/or subsequently seen or confirmed at microscopic
				examination;
(e) Multi-focal or diffuse necrosis, fibrosis or
				granuloma formation in vital organs with regenerative
				capacity;
(f) Morphological changes that are potentially
				reversible but provide clear evidence of marked organ dysfunction;
				and,
(g) Evidence of appreciable cell death (including
				cell degeneration and reduced cell number) in vital organs incapable
				of regeneration.
(a) Clinical observations or small changes in
				bodyweight gain, food consumption or water intake that may have some
				toxicological importance but that do not, by themselves, indicate
				"significant" toxicity;
(b) Small changes in clinical biochemistry,
				hematology or urinalysis parameters and/or transient effects, when
				such changes or effects are of doubtful or of minimal toxicological
				importance;
(c) Changes in organ weights with no evidence of
				organ dysfunction;
(d) Adaptive responses that are not considered
				toxicologically relevant; and,
(e) Substance-induced species-specific mechanisms of
				toxicity, i.e., demonstrated with reasonable certainty to be not
				relevant for human health, shall not justify classification.
A.8.2.1.9 Guidance values to assist with
				classification based on the results obtained from studies conducted
				in experimental animals for Category 1 and 2
A.8.2.1.9.1 In order to help reach a decision about
				whether a substance shall be classified or not, and to what degree it
				shall be classified (Category 1 vs. Category 2), dose/concentration
				"guidance values" are provided for consideration of the dose/
				concentration which has been shown to produce significant health
				effects. The principal argument for proposing such guidance values is
				that all chemicals are potentially toxic and there has to be a
				reasonable dose/concentration above which a degree of toxic effect is
				acknowledged.
A.8.2.1.9.2 Thus, in animal studies, when significant
				toxic effects are observed that indicate classification,
				consideration of the dose/concentration at which these effects were
				seen, in relation to the suggested guidance values, provides useful
				information to help assess the need to classify (since the toxic
				effects are a consequence of the hazardous property(ies) and also the
				dose/concentration).
A.8.2.1.9.3 The guidance value (C) ranges for
				single-dose exposure which has produced a significant non-lethal
				toxic effect are those applicable to acute toxicity testing, as
				indicated in Table A.8.1.
Table A.8.1: Guidance value ranges for
				single-dose exposures
Guidance value ranges
						for:
Route of exposure
Units
Category 1
Category 2
Category 3
Oral (rat)
mg/kg body weight
C [LESS THAN EQUALS TO] 300
2000 [GREATER THAN EQUALS TO] C > 300
Guidance values do not apply
Dermal (rat or rabbit)
mg/kg body weight
C [LESS THAN EQUALS TO] 1000
2000 [GREATER THAN EQUALS TO] C > 1000
Inhalation (rat) gas
ppmV/4h
C [LESS THAN EQUALS TO] 2500
20,000 [GREATER THAN EQUALS TO] C > 2500
Inhalation (rat) vapor
mg/l/4h
C [LESS THAN EQUALS TO] 10
20 [GREATER THAN EQUALS TO] C > 10
Inhalation (rat) dust/mist/fume
mg/l/4h
C [LESS THAN EQUALS TO] 1.0
5.0 [GREATER THAN EQUALS TO] C > 1.0
A.8.2.1.9.4 The guidance values and ranges mentioned
				in Table A.8.1 are intended only for guidance purposes, i.e., to be
				used as part of the weight of evidence approach, and to assist with
				decisions about classification. They are not intended as strict
				demarcation values. Guidance values are not provided for Category 3
				since this classification is primarily based on human data; animal
				data may be included in the weight of evidence evaluation.
A.8.2.1.9.5 Thus, it is feasible that a specific
				profile of toxicity occurs at a dose/concentration below the guidance
				value, e.g., < 2000 mg/kg body weight by the oral route, however
				the nature of the effect may result in the decision not to classify.
				Conversely, a specific profile of toxicity may be seen in animal
				studies occurring at above a guidance value, e.g., [GREATER THAN
				EQUALS TO] 2000 mg/kg body weight by the oral route, and in addition
				there is supplementary information from other sources, e.g., other
				single dose studies, or human case experience, which supports a
				conclusion that, in view of the weight of evidence, classification is
				the prudent action to take.
A.8.2.1.10 Other considerations
A.8.2.1.10.1 When a substance is characterized only
				by use of animal data the classification process includes reference
				to dose/concentration guidance values as one of the elements that
				contribute to the weight of evidence approach.
A.8.2.1.10.2 When well-substantiated human data are
				available showing a specific target organ toxic effect that can be
				reliably attributed to single exposure to a substance, the substance
				shall be classified. Positive human data, regardless of probable
				dose, predominates over animal data. Thus, if a substance is
				unclassified because specific target organ toxicity observed was
				considered not relevant or significant to humans, if subsequent human
				incident data become available showing a specific target organ toxic
				effect, the substance shall be classified.
A.8.2.1.10.3 A substance that has not been tested for
				specific target organ toxicity shall, where appropriate, be
				classified on the basis of data from a scientifically validated
				structure activity relationship and expert judgment-based
				extrapolation from a structural analogue that has previously been
				classified together with substantial support from consideration of
				other important factors such as formation of common significant
				metabolites.
A.8.2.2 Substances of Category 3
A.8.2.2.1 Criteria for respiratory tract
				irritation
The criteria for classifying substances as Category 3
				for respiratory tract irritation are:
(a) Respiratory irritant effects (characterized by
				localized redness, edema, pruritis and/or pain) that impair function
				with symptoms such as cough, pain, choking, and breathing
				difficulties are included. It is recognized that this evaluation is
				based primarily on human data;
(b) Subjective human observations supported by
				objective measurements of clear respiratory tract irritation (RTI)
				(e.g., electrophysiological responses, biomarkers of inflammation in
				nasal or bronchoalveolar lavage fluids);
(c) The symptoms observed in humans shall also be
				typical of those that would be produced in the exposed population
				rather than being an isolated idiosyncratic reaction or response
				triggered only in individuals with hypersensitive airways. Ambiguous
				reports simply of "irritation" should be excluded as this term is
				commonly used to describe a wide range of sensations including those
				such as smell, unpleasant taste, a tickling sensation, and dryness,
				which are outside the scope of classification for respiratory tract
				irritation;
(d) There are currently no scientifically validated
				animal tests that deal specifically with RTI; however, useful
				information may be obtained from the single and repeated inhalation
				toxicity tests. For example, animal studies may provide useful
				information in terms of clinical signs of toxicity (dyspnoea,
				rhinitis etc.) and histopathology (e.g., hyperemia, edema, minimal
				inflammation, thickened mucous layer) which are reversible and may be
				reflective of the characteristic clinical symptoms described above.
				Such animal studies can be used as part of weight of evidence
				evaluation; and,
(e) This special classification will occur only when
				more severe organ effects including the respiratory system are not
				observed as those effects would require a higher
				classification.
(a) Central nervous system depression including
				narcotic effects in humans such as drowsiness, narcosis, reduced
				alertness, loss of reflexes, lack of coordination, and vertigo are
				included. These effects can also be manifested as severe headache or
				nausea, and can lead to reduced judgment, dizziness, irritability,
				fatigue, impaired memory function, deficits in perception and
				coordination, reaction time, or sleepiness; and,
(b) Narcotic effects observed in animal studies may
				include lethargy, lack of coordination righting reflex, narcosis, and
				ataxia. If these effects are not transient in nature, then they shall
				be considered for classification as Category 1 or 2.
A.8.3 Classification criteria for mixtures
A.8.3.1 Mixtures are classified using the same
				criteria as for substances, or alternatively as described below. As
				with substances, mixtures may be classified for specific target organ
				toxicity following single exposure, repeated exposure, or
				both.
A.8.3.2 Classification of mixtures when data are
				available for the complete mixture
When reliable and good quality evidence from human
				experience or appropriate studies in experimental animals, as
				described in the criteria for substances, is available for the
				mixture, then the mixture shall be classified by weight of evidence
				evaluation of this data. Care shall be exercised in evaluating data
				on mixtures, that the dose, duration, observation or analysis, do not
				render the results inconclusive.
A.8.3.3 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.8.3.3.1 Where the mixture itself has not been
				tested to determine its specific target organ toxicity, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data shall be used in accordance with the following bridging
				principles as found in paragraph A.0.5 of this Appendix: Dilution,
				Batching, Concentration of mixtures, Interpolation within one
				toxicity category, Substantially similar mixtures, or
				Aerosols.
A.8.3.4 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.8.3.4.1 Where there is no reliable evidence or test
				data for the specific mixture itself, and the bridging principles
				cannot be used to enable classification, then classification of the
				mixture is based on the classification of the ingredient substances.
				In this case, the mixture shall be classified as a specific target
				organ toxicant (specific organ specified), following single exposure,
				repeated exposure, or both when at least one ingredient has been
				classified as a Category 1 or Category 2 specific target organ
				toxicant and is present at or above the appropriate cut-off
				value/concentration limit specified in Table A.8.2 for Categories 1
				and 2, respectively.
Table A.8.2: Cut-off values/concentration
				limits of ingredients of a mixture classified as a specific target
				organ toxicant that would trigger classification of the mixture as
				Category 1 or 2
Cut-off values/concentration
						limits triggering classification of a mixture as:
Ingredient classified as:
Category 1
Category 2
Category 1 Target organ toxicant
[GREATER THAN EQUALS TO] 1.0%
Category 2 Target organ toxicant
[GREATER THAN EQUALS TO] 1.0%
A.8.3.4.2 These cut-off values and consequent
				classifications shall be applied equally and appropriately to both
				single- and repeated-dose target organ toxicants.
A.8.3.4.3 Mixtures shall be classified for either or
				both single and repeated dose toxicity independently.
A.8.3.4.4 Care shall be exercised when toxicants
				affecting more than one organ system are combined that the
				potentiation or synergistic interactions are considered, because
				certain substances can cause target organ toxicity at < 1%
				concentration when other ingredients in the mixture are known to
				potentiate its toxic effect.
A.8.3.4.5 Care shall be exercised when extrapolating
				the toxicity of a mixture that contains Category 3 ingredient(s). A
				cut-off value/concentration limit of 20%, considered as an additive
				of all Category 3 ingredients for each hazard end-point, is
				appropriate; however, this cut-off value/concentration limit may be
				higher or lower depending on the Category 3 ingredient(s) involved
				and the fact that some effects such as respiratory tract irritation
				may not occur below a certain concentration while other effects such
				as narcotic effects may occur below this 20% value. Expert judgment
				shall be exercised. Respiratory tract irritation and narcotic effects
				are to be evaluated separately in accordance with the criteria given
				in A.8.2.2. When conducting classifications for these hazards, the
				contribution of each ingredient should be considered additive, unless
				there is evidence that the effects are not additive.
A.9 SPECIFIC TARGET ORGAN TOXICITY REPEATED OR
				PROLONGED EXPOSURE
A.9.1 Definitions and general considerations
A.9.1.1 Specific target organ toxicity - repeated
				exposure (STOT-RE) means specific target organ toxicity arising from
				repeated exposure to a substance or mixture. All significant health
				effects that can impair function, both reversible and irreversible,
				immediate and/or delayed and not specifically addressed in A.1 to A.7
				and A.10 of this Appendix are included. Specific target organ
				toxicity following a single-event exposure is classified in
				accordance with SPECIFIC TARGET ORGAN TOXICITY - SINGLE EXPOSURE (A.8
				of this Appendix) and is therefore not included here.
A.9.1.2 Classification identifies the substance or
				mixture as being a specific target organ toxicant and, as such, it
				may present a potential for adverse health effects in people who are
				exposed to it.
A.9.1.3 These adverse health effects produced by
				repeated exposure include consistent and identifiable toxic effects
				in humans, or, in experimental animals, toxicologically significant
				changes which have affected the function or morphology of a
				tissue/organ, or have produced serious changes to the biochemistry or
				hematology of the organism and these changes are relevant for human
				health. Human data will be the primary source of evidence for this
				hazard class.
A.9.1.4 Assessment shall take into consideration not
				only significant changes in a single organ or biological system but
				also generalized changes of a less severe nature involving several
				organs.
A.9.1.5 Specific target organ toxicity can occur by
				any route that is relevant for humans, e.g., principally oral, dermal
				or inhalation.
A.9.2 Classification criteria for substances
A.9.2.1 Substances shall be classified as STOT-RE by
				expert judgment on the basis of the weight of all evidence available,
				including the use of recommended guidance values which take into
				account the duration of exposure and the dose/concentration which
				produced the effect(s), (See A.9.2.9). Substances shall be placed in
				one of two categories, depending upon the nature and severity of the
				effect(s) observed, in accordance with Figure A.9.1.
Figure A.9.1: Hazard categories for specific
				target organ toxicity following repeated exposure
CATEGORY 1:
Substances that have produced significant
						toxicity in humans, or that, on the basis of evidence from studies in
						experimental animals can be presumed to have the potential to produce
						significant toxicity in humans following repeated or prolonged
						exposure
Substances are classified in Category 1 for
						specific target organ toxicity (repeated exposure) on the basis of:
(a) reliable and good quality evidence from human
						cases or epidemiological studies; or,
(b) observations from appropriate studies in
						experimental animals in which significant and/or severe toxic
						effects, of relevance to human health, were produced at generally low
						exposure concentrations. Guidance dose/concentration values are
						provided below (See A.9.2.9) to be used as part of weight-of-evidence
						evaluation.
CATEGORY 2:
Substances that, on the basis of evidence
						from studies in experimental animals can be presumed to have the
						potential to be harmful to human health following repeated or
						prolonged exposure
Substances are classified in Category 2 for
						specific target organ toxicity (repeated exposure) on the basis of
						observations from appropriate studies in experimental animals in
						which significant toxic effects, of relevance to human health, were
						produced at generally moderate exposure concentrations. Guidance
						dose/ concentration values are provided below (See A.9.2.9) in order
						to help in classification. In exceptional cases human evidence can
						also be used to place a substance in Category 2 (See A.9.2.6).
Note: The primary target
						organ/system shall be identified where possible, or the substance
						shall be identified as a general toxicant. The data shall be
						carefully evaluated and, where possible, shall not include secondary
						effects (e.g., a hepatotoxicant can produce secondary effects in the
						nervous or gastro-intestinal systems).
A.9.2.2 The relevant route of exposure by which the
				classified substance produces damage shall be identified.
A.9.2.3 Classification is determined by expert
				judgment, on the basis of the weight of all evidence available
				including the guidance presented below.
A.9.2.4 Weight of evidence of all data, including
				human incidents, epidemiology, and studies conducted in experimental
				animals, is used to substantiate specific target organ toxic effects
				that merit classification.
A.9.2.5 The information required to evaluate specific
				target organ toxicity comes either from repeated exposure in humans,
				e.g., exposure at home, in the workplace or environmentally, or from
				studies conducted in experimental animals. The standard animal
				studies in rats or mice that provide this information are 28 day, 90
				day or lifetime studies (up to 2 years) that include hematological,
				clinico-chemical and detailed macroscopic and microscopic examination
				to enable the toxic effects on target tissues/organs to be
				identified. Data from repeat dose studies performed in other species
				may also be used. Other long-term exposure studies, e.g., for
				carcinogenicity, neurotoxicity or reproductive toxicity, may also
				provide evidence of specific target organ toxicity that could be used
				in the assessment of classification.
A.9.2.6 In exceptional cases, based on expert
				judgment, it may be appropriate to place certain substances with
				human evidence of specific target organ toxicity in Category 2: (a)
				when the weight of human evidence is not sufficiently convincing to
				warrant Category 1 classification, and/or (b) based on the nature and
				severity of effects. Dose/concentration levels in humans shall not be
				considered in the classification and any available evidence from
				animal studies shall be consistent with the Category 2
				classification. In other words, if there are also animal data
				available on the substance that warrant Category 1 classification,
				the substance shall be classified as Category 1.
A.9.2.7 Effects considered to support
				classification
A.9.2.7.1 Classification is supported by reliable
				evidence associating repeated exposure to the substance with a
				consistent and identifiable toxic effect.
A.9.2.7.2 Evidence from human experience/incidents is
				usually restricted to reports of adverse health consequences, often
				with uncertainty about exposure conditions, and may not provide the
				scientific detail that can be obtained from well-conducted studies in
				experimental animals.
A.9.2.7.3 Evidence from appropriate studies in
				experimental animals can furnish much more detail, in the form of
				clinical observations, hematology, clinical chemistry, macroscopic
				and microscopic pathological examination and this can often reveal
				hazards that may not be life-threatening but could indicate
				functional impairment. Consequently all available evidence, and
				relevance to human health, must be taken into consideration in the
				classification process. Relevant toxic effects in humans and/or
				animals include, but are not limited to:
(a) Morbidity or death resulting from repeated or
				long-term exposure. Morbidity or death may result from repeated
				exposure, even to relatively low doses/concentrations, due to
				bioaccumulation of the substance or its metabolites, or due to the
				overwhelming of the de-toxification process by repeated
				exposure;
(b) Significant functional changes in the central or
				peripheral nervous systems or other organ systems, including signs of
				central nervous system depression and effects on special senses
				(e.g., sight, hearing and sense of smell);
(c) Any consistent and significant adverse change in
				clinical biochemistry, hematology, or urinalysis parameters;
(d) Significant organ damage that may be noted at
				necropsy and/or subsequently seen or confirmed at microscopic
				examination;
(e) Multi-focal or diffuse necrosis, fibrosis or
				granuloma formation in vital organs with regenerative
				capacity;
(f) Morphological changes that are potentially
				reversible but provide clear evidence of marked organ dysfunction
				(e.g., severe fatty change in the liver); and,
(g) Evidence of appreciable cell death (including
				cell degeneration and reduced cell number) in vital organs incapable
				of regeneration.
(a) Clinical observations or small changes in
				bodyweight gain, food consumption or water intake that may have some
				toxicological importance but that do not, by themselves, indicate
				"significant" toxicity;
(b) Small changes in clinical biochemistry,
				hematology or urinalysis parameters and /or transient effects, when
				such changes or effects are of doubtful or of minimal toxicological
				importance;
(c) Changes in organ weights with no evidence of
				organ dysfunction;
(d) Adaptive responses that are not considered
				toxicologically relevant;
(e) Substance-induced species-specific mechanisms of
				toxicity, i.e., demonstrated with reasonable certainty to be not
				relevant for human health, shall not justify classification.
A.9.2.9 Guidance values to assist with classification
				based on the results obtained from studies conducted in experimental
				animals
A.9.2.9.1 In studies conducted in experimental
				animals, reliance on observation of effects alone, without reference
				to the duration of experimental exposure and dose/concentration,
				omits a fundamental concept of toxicology, i.e., all substances are
				potentially toxic, and what determines the toxicity is a function of
				the dose/concentration and the duration of exposure. In most studies
				conducted in experimental animals the test guidelines use an upper
				limit dose value.
A.9.2.9.2 In order to help reach a decision about
				whether a substance shall be classified or not, and to what degree it
				shall be classified (Category 1 vs. Category 2), dose/concentration
				"guidance values" are provided in Table A.9.1 for consideration of
				the dose/concentration which has been shown to produce significant
				health effects. The principal argument for proposing such guidance
				values is that all chemicals are potentially toxic and there has to
				be a reasonable dose/concentration above which a degree of toxic
				effect is acknowledged. Also, repeated-dose studies conducted in
				experimental animals are designed to produce toxicity at the highest
				dose used in order to optimize the test objective and so most studies
				will reveal some toxic effect at least at this highest dose. What is
				therefore to be decided is not only what effects have been produced,
				but also at what dose/concentration they were produced and how
				relevant is that for humans.
A.9.2.9.3 Thus, in animal studies, when significant
				toxic effects are observed that indicate classification,
				consideration of the duration of experimental exposure and the
				dose/concentration at which these effects were seen, in relation to
				the suggested guidance values, provides useful information to help
				assess the need to classify (since the toxic effects are a
				consequence of the hazardous property(ies) and also the duration of
				exposure and the dose/concentration).
A.9.2.9.4 The decision to classify at all can be
				influenced by reference to the dose/concentration guidance values at
				or below which a significant toxic effect has been observed.
A.9.2.9.5 The guidance values refer to effects seen
				in a standard 90-day toxicity study conducted in rats. They can be
				used as a basis to extrapolate equivalent guidance values for
				toxicity studies of greater or lesser duration, using dose/exposure
				time extrapolation similar to Haber's rule for inhalation, which
				states essentially that the effective dose is directly proportional
				to the exposure concentration and the duration of exposure. The
				assessment should be done on a case-by-case basis; for example, for a
				28-day study the guidance values below would be increased by a factor
				of three.
A.9.2.9.6 Thus for Category 1 classification,
				significant toxic effects observed in a 90-day repeated-dose study
				conducted in experimental animals and seen to occur at or below the
				(suggested) guidance values (C) as indicated in Table A.9.1 would
				justify classification:
Table A.9.1: Guidance values to assist in
				Category 1 classification (applicable to a 90-day
				study)
Route of exposure
Units
Guidance values
						(dose/concentration)
Oral (rat)
mg/kg body weight/day
C [LESS THAN EQUALS TO] 10
Dermal (rat or rabbit)
mg/kg body weight/day
C [LESS THAN EQUALS TO] 20
Inhalation (rat) gas
ppmV/6h/day
C [LESS THAN EQUALS TO] 50
Inhalation (rat) vapor
mg/liter/6h/day
C [LESS THAN EQUALS TO] 0.2
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
C [LESS THAN EQUALS TO] 0.02
A.9.2.9.7 For Category 2 classification, significant
				toxic effects observed in a 90-day repeated-dose study conducted in
				experimental animals and seen to occur within the (suggested)
				guidance value ranges as indicated in Table A.9.2 would justify
				classification:
Table A.9.2: Guidance values to assist in
				Category 2 classification (applicable to a 90-day
				study)
Route of exposure
Units
Guidance values range
						(dose/concentration)
Oral (rat)
mg/kg body weight/day
10 < C [LESS THAN EQUALS TO] 100
Dermal (rat or rabbit)
mg/kg body weight/day
20 < C [LESS THAN EQUALS TO] 200
Inhalation (rat) gas
ppmV/6h/day
50 < C [LESS THAN EQUALS TO] 250
Inhalation (rat) vapor
mg/liter/6h/day
0.2 < C [LESS THAN EQUALS TO] 1.0
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
0.02 < C [LESS THAN EQUALS TO] 0.2
A.9.2.9.8 The guidance values and ranges mentioned in
				A.2.9.9.6 and A.2.9.9.7 are intended only for guidance purposes,
				i.e., to be used as part of the weight of evidence approach, and to
				assist with decisions about classification. They are not intended as
				strict demarcation values.
A.9.2.9.9 Thus, it is possible that a specific
				profile of toxicity occurs in repeat-dose animal studies at a
				dose/concentration below the guidance value, e.g., < 100 mg/kg
				body weight/day by the oral route, however the nature of the effect,
				e.g., nephrotoxicity seen only in male rats of a particular strain
				known to be susceptible to this effect, may result in the decision
				not to classify. Conversely, a specific profile of toxicity may be
				seen in animal studies occurring at above a guidance value, e.g.,
				[GREATER THAN EQUALS TO] 100 mg/kg body weight/day by the oral route,
				and in addition there is supplementary information from other
				sources, e.g., other long-term administration studies, or human case
				experience, which supports a conclusion that, in view of the weight
				of evidence, classification is prudent.
A.9.2.10 Other considerations
A.9.2.10.1 When a substance is characterized only by
				use of animal data the classification process includes reference to
				dose/concentration guidance values as one of the elements that
				contribute to the weight of evidence approach.
A.9.2.10.2 When well-substantiated human data are
				available showing a specific target organ toxic effect that can be
				reliably attributed to repeated or prolonged exposure to a substance,
				the substance shall be classified. Positive human data, regardless of
				probable dose, predominates over animal data. Thus, if a substance is
				unclassified because no specific target organ toxicity was seen at or
				below the dose/concentration guidance value for animal testing, if
				subsequent human incident data become available showing a specific
				target organ toxic effect, the substance shall be classified.
A.9.2.10.3 A substance that has not been tested for
				specific target organ toxicity may in certain instances, where
				appropriate, be classified on the basis of data from a scientifically
				validated structure activity relationship and expert judgment-based
				extrapolation from a structural analogue that has previously been
				classified together with substantial support from consideration of
				other important factors such as formation of common significant
				metabolites.
A.9.3 Classification criteria for mixtures
A.9.3.1 Mixtures are classified using the same
				criteria as for substances, or alternatively as described below. As
				with substances, mixtures may be classified for specific target organ
				toxicity following single exposure, repeated exposure, or
				both.
A.9.3.2 Classification of mixtures when data are
				available for the complete mixture
When reliable and good quality evidence from human
				experience or appropriate studies in experimental animals, as
				described in the criteria for substances, is available for the
				mixture, then the mixture shall be classified by weight of evidence
				evaluation of these data. Care shall be exercised in evaluating data
				on mixtures, that the dose, duration, observation or analysis, do not
				render the results inconclusive.
A.9.3.3 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.9.3.3.1 Where the mixture itself has not been
				tested to determine its specific target organ toxicity, but there are
				sufficient data on both the individual ingredients and similar tested
				mixtures to adequately characterize the hazards of the mixture, these
				data shall be used in accordance with the following bridging
				principles as found in paragraph A.0.5 of this Appendix: Dilution;
				Batching; Concentration of mixtures; Interpolation within one
				toxicity category; Substantially similar mixtures; and
				Aerosols.
A.9.3.4 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.9.3.4.1 Where there is no reliable evidence or test
				data for the specific mixture itself, and the bridging principles
				cannot be used to enable classification, then classification of the
				mixture is based on the classification of the ingredient substances.
				In this case, the mixture shall be classified as a specific target
				organ toxicant (specific organ specified), following single exposure,
				repeated exposure, or both when at least one ingredient has been
				classified as a Category 1 or Category 2 specific target organ
				toxicant and is present at or above the appropriate cut-off
				value/concentration limit specified in Table A.9.3 for Category 1 and
				2 respectively.
Table A.9.3: Cut-off value/concentration limits
				of ingredients of a mixture classified as a specific target organ
				toxicant that would trigger classification of the mixture as Category
				1 or 2
Ingredient classified
						as:
Cut-off
						values/concentration
limits triggering classification of
						a mixture as:
Category 1
Category 2
Category 1 Target organ toxicant
[GREATER THAN EQUALS TO] 1.0%
Category 2 Target organ toxicant
[GREATER THAN EQUALS TO] 1.0%
A.9.3.4.2 These cut-off values and consequent
				classifications shall be applied equally and appropriately to both
				single- and repeated-dose target organ toxicants.
A.9.3.4.3 Mixtures shall be classified for either or
				both single- and repeated-dose toxicity independently.
A.9.3.4.4 Care shall be exercised when toxicants
				affecting more than one organ system are combined that the
				potentiation or synergistic interactions are considered, because
				certain substances can cause specific target organ toxicity at <
				1% concentration when other ingredients in the mixture are known to
				potentiate its toxic effect.
A.10 ASPIRATION HAZARD
A.10.1 Definitions and general and specific
				considerations
A.10.1.1 Aspiration means the entry of a liquid or
				solid chemical directly through the oral or nasal cavity, or
				indirectly from vomiting, into the trachea and lower respiratory
				system.
A.10.1.2 Aspiration toxicity includes severe acute
				effects such as chemical pneumonia, varying degrees of pulmonary
				injury or death following aspiration.
A.10.1.3 Aspiration is initiated at the moment of
				inspiration, in the time required to take one breath, as the
				causative material lodges at the crossroad of the upper respiratory
				and digestive tracts in the laryngopharyngeal region.
A.10.1.4 Aspiration of a substance or mixture can
				occur as it is vomited following ingestion. This may have
				consequences for labeling, particularly where, due to acute toxicity,
				a recommendation may be considered to induce vomiting after
				ingestion. However, if the substance/mixture also presents an
				aspiration toxicity hazard, the recommendation to induce vomiting may
				need to be modified.
A.10.1.5 Specific considerations
A.10.1.5.1 The classification criteria refer to
				kinematic viscosity. The following provides the conversion between
				dynamic and kinematic viscosity:
A.10.1.5 Specific Considerations
A.10.1.5.2 Although the definition of aspiration in
				A.10.1.1 includes the entry of solids into the respiratory system,
				classification according to (b) in table A.10.1 for Category 1 is
				intended to apply to liquid substances and mixtures only.
A.10.1.5.3 Classification of aerosol/mist
				products
Aerosol and mist products are usually dispensed in
				containers such as self-pressurized containers, trigger and pump
				sprayers. Classification for these products shall be considered if
				their use may form a pool of product in the mouth, which then may be
				aspirated. If the mist or aerosol from a pressurized container is
				fine, a pool may not be formed. On the other hand, if a pressurized
				container dispenses product in a stream, a pool may be formed that
				may then be aspirated. Usually, the mist produced by trigger and pump
				sprayers is coarse and therefore, a pool may be formed that then may
				be aspirated. When the pump mechanism may be removed and contents are
				available to be swallowed then the classification of the products
				should be considered.
A.10.2 Classification criteria for substances
Table A.10.1: Criteria for aspiration
				toxicity
Category
Criteria
Category 1: Chemicals known to cause human
						aspiration toxicity hazards or to be regarded as if they cause human
						aspiration toxicity hazard
A substance shall be classified in Category 1:
(a) If reliable and good quality human
						  evidence indicates that it causes aspiration toxicity (See note);
						  or
(b) If it is a hydrocarbon and has a
						  kinematic viscosity [LESS THAN EQUALS TO]20.5
						  mm2/s, measured at 40°C.
Note: Examples of substances included in Category 1
				are certain hydrocarbons, turpentine and pine oil.
A.10.3 Classification criteria for mixtures
A.10.3.1 Classification when data are available for
				the complete mixture
A mixture shall be classified in Category 1 based on
				reliable and good quality human evidence.
A.10.3.2 Classification of mixtures when data are not
				available for the complete mixture: bridging principles
A.10.3.2.1 Where the mixture itself has not been
				tested to determine its aspiration toxicity, but there are sufficient
				data on both the individual ingredients and similar tested mixtures
				to adequately characterize the hazard of the mixture, these data
				shall be used in accordance with the following bridging principles as
				found in paragraph A.0.5 of this Appendix: Dilution; Batching;
				Concentration of mixtures; Interpolation within one toxicity
				category; and Substantially similar mixtures. For application of the
				dilution bridging principle, the concentration of aspiration
				toxicants shall not be less than 10%.
A.10.3.3 Classification of mixtures when data are
				available for all ingredients or only for some ingredients of the
				mixture
A.10.3.3.1 A mixture which contains [GREATER THAN
				EQUALS TO] 10% of an ingredient or ingredients classified in Category
				1, and has a kinematic viscosity [LESS THAN EQUALS TO] 20.5
				mm2/s, measured at 40°C, shall be
				classified in Category 1.
A.10.3.3.2 In the case of a mixture which separates
				into two or more distinct layers, one of which contains [GREATER THAN
				EQUALS TO] 10% of an ingredient or ingredients classified in Category
				1 and has a kinematic viscosity [LESS THAN EQUALS TO] 20.5
				mm2/s, measured at 40°C, then the
				entire mixture shall be classified in Category 1.
Statutory Authority:
				  RCW  49.17.010,
				  49.17.040,
				  49.17.050,
				  49.17.060 and  29 C.F.R.
				  1910  Subpart Z. 13-06-050, § 296-901-14022, filed 3/5/13,
				  effective 4/15/13.