A.0.1.1 The term “hazard classification” is used to indicate that only the intrinsic hazardous properties of chemicals are considered. Hazard classification incorporates three steps:

(a) Identification of relevant data regarding the hazards of a chemical;

(b) Subsequent review of those data to ascertain the hazards associated with the chemical;

(c) Determination of whether the chemical will be classified as hazardous and the degree of hazard.

A.0.1.2 For many hazard classes, the criteria are semi-quantitative or qualitative and expert judgment is required to interpret the data for classification purposes.

A.0.1.3 Where impurities, additives or individual constituents of a substance or mixture have been identified and are themselves classified, they should be taken into account during classification if they exceed the cut-off value/concentration limit for a given hazard class.

A.0.2.1 There is no requirement for testing chemicals.

A.0.2.2 The criteria for determining health hazards are test method neutral, i.e., they do not specify particular test methods, as long as the methods are scientifically validated.

A.0.2.3 The term “scientifically validated” refers to the process by which the reliability and the relevance of a procedure are established for a particular purpose. Any test that determines hazardous properties, which is conducted according to recognized scientific principles, can be used for purposes of a hazard determination for health hazards. Test conditions need to be standardized so that the results are reproducible with a given substance, and the standardized test yields “valid” data for defining the hazard class of concern.

A.0.2.4 Existing test data are acceptable for classifying chemicals, although expert judgment also may be needed for classification purposes.

A.0.2.5 The effect of a chemical on biological systems is influenced, by the physico-chemical properties of the substance and/or ingredients of the mixture and the way in which ingredient substances are biologically available. A chemical need not be classified when it can be shown by conclusive experimental data from scientifically validated test methods that the chemical is not biologically available.

A.0.2.6 For classification purposes, epidemiological data and experience on the effects of chemicals on humans (e.g., occupational data, data from accident databases) shall be taken into account in the evaluation of human health hazards of a chemical.

A.0.3.1 For some hazard classes, classification results directly when the data satisfy the criteria. For others, classification of a chemical shall be determined on the basis of the total weight of evidence using expert judgment. This means that all available information bearing on the classification of hazard shall be considered together, including the results of valid in vitro tests, relevant animal data, and human experience such as epidemiological and clinical studies and well-documented case reports and observations.

A.0.3.2 The quality and consistency of the data shall be considered. Information on chemicals related to the material being classified shall be considered as appropriate, as well as site of action and mechanism or mode of action study results. Both positive and negative results shall be considered together in a single weight-of-evidence determination.

A.0.3.3 Positive effects which are consistent with the criteria for classification, whether seen in humans or animals, shall normally justify classification. Where evidence is available from both humans and animals and there is a conflict between the findings, the quality and reliability of the evidence from both sources shall be evaluated in order to resolve the question of classification. Reliable, good quality human data shall generally have precedence over other data. However, even well-designed and conducted epidemiological studies may lack a sufficient number of subjects to detect relatively rare but still significant effects, or to assess potentially confounding factors. Therefore, positive results from well-conducted animal studies are not necessarily negated by the lack of positive human experience but require an assessment of the robustness, quality and statistical power of both the human and animal data.

A.0.3.4 Route of exposure, mechanistic information, and metabolism studies are pertinent to determining the relevance of an effect in humans. When such information raises doubt about relevance in humans, a lower classification may be warranted. When there is scientific evidence demonstrating that the mechanism or mode of action is not relevant to humans, the chemical should not be classified.

A.0.3.5 Both positive and negative results are considered together in the weight of evidence determination. However, a single positive study performed according to good scientific principles and with statistically and biologically significant positive results may justify classification.

A.0.4.1 Except as provided in A.0.4.2, the process of classification of mixtures is based on the following sequence:

(a) Where test data are available for the complete mixture, the classification of the mixture will always be based on those data;

(b) Where test data are not available for the mixture itself, the bridging principles designated in each health hazard chapter of this appendix shall be considered for classification of the mixture;

(c) If test data are not available for the mixture itself, and the available information is not sufficient to allow application of the above-mentioned bridging principles, then the method(s) described in each chapter for estimating the hazards based on the information known will be applied to classify the mixture (e.g., application of cut-off values/concentration limits).

A.0.4.2 An exception to the above order or precedence is made for Carcinogenicity, Germ Cell Mutagenicity, and Reproductive Toxicity. For these three hazard classes, mixtures shall be classified based upon information on the ingredient substances, unless on a case-by-case basis, justification can be provided for classifying based upon the mixture as a whole. See A.5, A.6, and A.7 of this section 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.0.5.1 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.4, A.8, A.9, or A.10 of this Appendix, if a tested mixture is classified in Category 1, and the concentration of the ingredients of the tested mixture that are in Category 1 is increased, the resulting untested mixture shall be classified in Category 1.

A.0.5.1.4 Interpolation within one hazard category

For mixtures classified in accordance with A.1, A.2, A.3, A.4, A.8, A.9, or A.10 of this Appendix, for three mixtures (A, B and C) with identical ingredients, where mixtures A and B have been tested and are in the same hazard category, and where untested mixture C has the same toxicologically active ingredients as mixtures A and B but has concentrations of toxicologically active ingredients intermediate to the concentrations in mixtures A and B, then mixture C is assumed to be in the same hazard category as A and B.

A.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.

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

A.1.2.1 Substances can be allocated to one of four hazard categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric cut-off criteria as shown in Table A.1.1. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE). While some in vivo methods determine LD50/LC50 values directly, other newer in vivo methods (e.g., using fewer animals) consider other indicators of acute toxicity, such as significant clinical signs of toxicity, which are used by reference to assign the hazard category. See the footnotes following Table A.1.1 for further explanation on the application of these values.

A.1.2.3 The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. Test data already generated for the classification of chemicals under existing systems should be accepted when reclassifying these chemicals under the harmonized system. When experimental data for acute toxicity are available in several animal species, scientific judgment should be used in selecting the most appropriate LD50 value from among scientifically validated tests. In cases where data from human experience (i.e., occupational data, data from accident databases, epidemiology studies, clinical reports) is also available, it should be considered in a weight of evidence approach consistent with the principles described in A.0.3.

A.1.2.4 In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity was corrosivity of the substance or mixture, the classifier must consider if the chemical is corrosive to the respiratory tract. Corrosion of the respiratory tract is defined as destruction of the respiratory tract tissue after a single, limited period of exposure analogous to skin corrosion; this includes destruction of the mucosa. The corrosivity evaluation could be based on expert judgment using such evidence as: human and animal experience, existing (in vitro) data, Ph values, information from similar substances or any other pertinent data.

A.1.2.4.1 If the classifier determines the chemical is corrosive to the respiratory tract and data are available that indicate that the effect leads to lethality, then in addition to the appropriate acute toxicity pictogram and hazard statement, the chemical must be labelled with the hazard statement “corrosive to the respiratory tract” and the corrosive pictogram.

A.1.2.4.2 If the classifier determines the chemical is corrosive to the respiratory tract and the effect does not lead to lethality, then the chemical must be addressed in the Specific Target Organ Toxicity hazard classes (see A.8). If data is insufficient for classification under STOT, but the classifier determines, based on skin or eye data, that the chemical may be corrosive to the respiratory tract, then the hazard must be addressed using data for classification in the skin corrosion/irritation hazard class (see A.2) or Serious Eye Damage/Eye irritation hazard class (see A.3).

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

A.1.3.2 Classification of mixtures for acute toxicity may be carried out for each route of exposure, but is only required for one route of exposure as long as this route is followed (estimated or tested) for all ingredients and there is no relevant evidence to suggest acute toxicity by multiple routes. When there is relevant evidence of acute toxicity by multiple routes of exposure, classification is to be conducted for all appropriate routes of exposure. All available information shall be considered. The pictogram and signal word used shall reflect the most severe hazard category; and all relevant hazard statements shall be used.

A.1.3.3 For purposes of classifying the hazards of mixtures in the tiered approach:

(a) The “relevant ingredients” of a mixture are those which are present in concentrations ≥1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases). If there is reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for acute toxicity, that ingredient shall also be considered relevant. Consideration of ingredients present at a concentration <1% is particularly important when classifying untested mixtures which contain ingredients that are classified in Category 1 and Category 2;

(b) Where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture is used when calculating the classification of the new mixture using the formulas in A.1.3.6.1 and A.1.3.6.2.4.

(c) If the converted acute toxicity point estimates for all ingredients of a mixture are within the same category, then the mixture should be classified in that category.

(d) When only range data (or acute toxicity hazard category information) are available for ingredients in a mixture, they may be converted to point estimates in accordance with Table A.1.2 when calculating the classification of the new mixture using the formulas in A.1.3.6.1 and A.1.3.6.2.4.

A.1.3.4 Classification of mixtures where acute toxicity test data are available for the complete mixture

Where the mixture itself has been tested to determine its acute toxicity, it is classified according to the same criteria as those used for substances, presented in Table A.1.1. If test data for the mixture are not available, the procedures presented below must be followed.

A.1.3.5 Classification of mixtures where acute toxicity test data are not available for the complete mixture: bridging principles

Where the mixture itself has not been tested to determine its acute toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one hazard category, Substantially similar mixtures, and Aerosols.

A.1.3.6 Classification of mixtures based on ingredients of the mixture (additivity formula)

A.1.3.6.1 Data available for all ingredients.

The acute toxicity estimate (ATE) of ingredients is considered as follows:

(a) Include ingredients with a known acute toxicity, which fall into any of the acute hazard categories, or have an oral or dermal LD50 greater than 2000 but less than or equal to 5000 mg/kg body weight (or the equivalent dose for inhalation);

(b) Ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

(c) Ignore ingredients if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table A.1.1) and do not show acute toxicity.

Ingredients that fall within the scope of this paragraph are considered to be ingredients with a known acute toxicity estimate (ATE). See note (b) to Table A.1.1 and paragraph A.1.3.3 for appropriate application of available data to the equation below, and paragraph A.1.3.6.2.4.

The ATE of the mixture is determined by calculation from the ATE values for all relevant ingredients according to the following formula below for oral, dermal or inhalation toxicity:

A.1.3.6.2 Data are not available for one or more ingredients of the mixture.

A.1.3.6.2.1 Where an ATE is not available for an individual ingredient of the mixture, but available information provides a derived conversion value, the formula in A.1.3.6.1 may be applied. This information may include evaluation of:

(a) Extrapolation between oral, dermal and inhalation acute toxicity estimates. Such an evaluation requires appropriate pharmacodynamic and pharmacokinetic data;

(b) Evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

(c) Evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

(d) Data from closely analogous substances using structure/activity relationships.

A.1.3.6.2.2 This approach requires substantial supplemental technical information, and a highly trained and experienced expert, to reliably estimate acute toxicity. If sufficient information is not available to reliably estimate acute toxicity, proceed to the provisions of A.1.3.6.2.4.

A.1.3.6.2.3 In the event that an ingredient with unknown acute toxicity is used in a mixture at a concentration ≥1%, and the mixture has not been classified based on testing of the mixture as a whole, the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture is classified based on the known ingredients only.

A.1.3.6.2.4 If the total concentration of the relevant ingredient(s) with unknown acute toxicity is ≤10% then the formula presented in A.1.3.6.1 must be used. If the total concentration of the relevant ingredient(s) with unknown acute toxicity is >10%, the formula presented in A.1.3.6.1 is corrected to adjust for the percentage of the unknown ingredient(s) as follows:

A.2.1.1 Skin corrosion refers to the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after initial exposure to a substance or mixture.

Skin irritation refers to the production of reversible damage to the skin occurring after initial exposure to a substance or mixture.

A.2.1.2 To classify, all available and relevant information on skin corrosion/irritation is collected and its quality in terms of adequacy and reliability is assessed. Wherever possible classification should be based on data generated using internationally validated and accepted methods, such as OECD Test Guidelines (TG) or equivalent methods. Sections A.2.2.1 to A.2.2.6 provide classification criteria for the different types of information that may be available.

A.2.1.3 A tiered approach (see A.2.2.7) organizes the available information into levels/tiers and provides for decision-making in a structured and sequential manner. Classification results directly when the information consistently satisfies the criteria. However, where the available information gives inconsistent and/or conflicting results within a tier, classification of a substance or a mixture is made on the basis of the weight of evidence within that tier. In some cases when information from different tiers gives inconsistent and/or conflicting results (see A.2.2.7.3) or where data individually are insufficient to conclude on the classification, an overall weight of evidence approach is used (see A.0.3).

Substances shall be allocated to one of the following categories within this hazard class:

(a) Category 1 (skin corrosion)

This category may be further divided into up to three sub-categories (1A, 1B, and 1C), which can be used by those authorities requiring more than one designation for corrosivity.

Corrosive substances should be classified in Category 1 where sub-categorization is not required by a competent authority or where data are not sufficient for sub-categorization.

When data are sufficient, substances may be classified in one of the three sub-categories 1A, 1B, or 1C.

(b) Category 2 (skin irritation)

A.2.2.1 Classification Based on Standard Human Data

Existing reliable and good quality human data on skin corrosion/irritation should be given high weight for classification. Existing human data could be derived from single or repeated exposure(s), for example in occupational, consumer, transport or emergency response scenarios and epidemiological and clinical studies in well-documented case reports and observations (see A.0.2.6 and A.0.3). Although human data from accident or poison center databases can provide evidence for classification, absence of incidents is not itself evidence for no classification, as exposures are generally unknown or uncertain.

A.2.2.2 Classification Based on Standard Animal Test Data

OECD TG 404 is the currently available internationally validated and accepted animal test for classification as skin corrosive or irritant (See Table A.2.1 and A.2.2) and is the standard animal test. The current version of OECD TG 404 uses a maximum of 3 animals. Results from animal studies conducted under previous versions of OECD TG 404 that used more than 3 animals are also considered standard animal tests.

A.2.2.2.1 Skin Corrosion

A.2.2.2.1.1 A substance is corrosive to the skin when it produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after initial exposure up to a 4-hour duration.

A.2.2.2.1.2 Three sub-categories of Category 1 are provided in Table A.2.1, all of which shall be regulated as Category 1.

A.2.2.2.2 Skin Irritation

A.2.2.2.2.1 A substance is irritant to skin when it produces reversible damage to the skin following its application for up to 4 hours.

A.2.2.2.2.2 A single irritant category (Category 2) is presented in the Table A.2.2. A substance is irritant to skin, when after the first application, it produces reversible damage to the skin following its application for up to 4 hours. An irritation category (Category 2) is provided that:

(a) recognizes that some test substances may lead to effects which persist throughout the length of the test; and

(b) acknowledges that animal responses in a test may be variable.

A.2.2.2.2.3 Reversibility of skin lesions is another consideration in evaluating irritant responses. When inflammation persists to the end of the observation period in two or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a chemical should be considered to be an irritant.

A.2.2.2.2.4 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 should be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score according to test method used throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses should also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure. Addition of this criterion increases the sensitivity of the classification system.

A.2.2.3 Classification Based on In Vitro/Ex Vivo Data

A.2.2.3.1 The currently available individual in vitro/ex vivo test methods address either skin irritation or skin corrosion, but do not address both endpoints in one single test. Therefore, classification based solely on in vitro/ex vivo test results may require data from more than one method.

A.2.2.3.2 Wherever possible classification should be based on data generated using internationally validated and accepted in vitro/ex vivo test methods, and the classification criteria provided in these test methods needs to be applied. In vitro/ex vivo data can only be used for classification when the tested substance is within the applicability domain of the test methods used. Additional limitations described in the published literature should also be taken into consideration.

A.2.2.3.3 Skin corrosion

A.2.2.3.3.1 Where tests have been undertaken in accordance with OECD Test Guidelines (TGs) 430, 431, or 435, a substance is classified for skin corrosion in category 1 (and, where possible and required into sub-categories 1A, 1B, or 1C) based on the criteria in Table A.2.6.

A.2.2.3.3.2 Some in vitro/ex vivo methods do not allow differentiation between sub-categories 1B and 1C. Where existing in vitro/ex vivo data cannot distinguish between the sub-categories, additional information has to be taken into account to differentiate between these two sub-categories. Where no or insufficient additional information is available, category 1 is applied.

A.2.2.3.3.3 A substance identified as not corrosive should be considered for classification as skin irritant.

A.2.2.3.4 Skin irritation

A.2.2.3.4.1 Where a conclusion of corrosivity can be excluded and where tests have been undertaken in accordance with OECD Test Guideline 439, a substance is classified for skin irritation in category 2 based on the criteria in Table A.2.7.

A.2.2.3.4.2 A negative result in an internationally accepted and validated in vitro/ex vivo test for skin irritation, e.g., OECD TG 439, can be used to conclude as not classified for skin irritation.

A.2.2.4 Classification Based on Other, Existing Skin Data in Animals

Other existing skin data in animals may be used for classification, but there may be limitations regarding the conclusions that can be drawn if a substance is highly toxic via the dermal route, an in vivo skin corrosion/irritation study may not have been conducted 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 of skin corrosion/irritation in acute toxicity studies are made, these data may be used for classification, provided that the dilutions used and species tested are relevant. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes. This is generally indicated in the standardized test methods.

A.2.2.5 Classification Based on Chemical Properties

Skin effects may be indicated by pH extremes such as ≤2 and ≥11.5 especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered corrosive (Skin Category 1) if it has a pH ≤2 or a pH ≥11.5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH, this needs to be confirmed by other data, preferably from an appropriate validated in vitro/ex vivo test. Buffering capacity and pH can be determined by test methods including OECD TG 122.

A.2.2.6 Classification Based on Non-Test Methods

A.2.2.6.1 Classification, including non-classification, can be based on non-test methods, with due consideration of reliability and applicability, on a case-by-case basis. Such methods include computer models predicting qualitative structure-activity relationships (structural alerts, SAR); quantitative structure-activity relationships (QSARs); computer expert systems; and read-across using analogue and category approaches.

A.2.2.6.2 Read-across using analogue or category approaches requires sufficiently reliable test data on similar substance(s) and justification of the similarity of the tested substance(s) with the substance(s) to be classified. Where adequate justification of the read-across approach is provided, it has in general higher weight than (Q)SARs.

A.2.2.6.3 Classification based on (Q)SARs requires sufficient data and validation of the model. The validity of the computer models and the prediction should be assessed using internationally recognized principles for the validation of (Q)SARs. With respect to reliability, lack of alerts in a SAR or expert system is not sufficient evidence for no classification.

A.2.2.7 Classification in a Tiered Approach

A.2.2.7.1 A tiered approach to the evaluation of initial information should be considered, where applicable (Figure A.2.1), recognizing that not all elements may be relevant. However, all available and relevant information of sufficient quality needs to be examined for consistency with respect to the resulting classification.

A.2.2.7.2 In the tiered approach (Figure A.2.1), existing human and animal data form the highest tier, followed by in vitro/ex vivo data, other existing skin data in animals, and then other sources of information. Where information from data within the same tier is inconsistent and/or conflicting, the conclusion from that tier is determined by a weight of evidence approach.

A.2.2.7.3 Where information from several tiers is inconsistent and/or conflicting with respect to the resulting classification, information of sufficient quality from a higher tier is generally given a higher weight than information from a lower tier. However, when information from a lower tier would result in a stricter classification than information from a higher tier and there is concern for misclassification, then classification is determined by an overall weight of evidence approach. The same would apply in the case where there is human data indicating irritation but positive results from an in vitro/ex vivo test for corrosion.

(a) Before applying the approach, the explanatory text in A.2.2.7 should be consulted. Only adequate and reliable data of sufficient quality should be included in applying the tiered approach.

(b) Information may be inconclusive for various reasons, e.g.:

A.2.3.1 Classification of Mixtures When Data Are Available for the Complete Mixture

A.2.3.1.1 In general, the mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class (as illustrated in Figure A.2.1) and A.2.3.1.2 and A.2.3.1.3. If classification is not possible using the tiered approach, then the approach described in A.2.3.2, or, if that is not applicable A.2.2.3.3 should be followed.

A.2.3.1.2 In vitro/ex vivo data generated from validated test methods may not have been validated using mixtures; although these methods are considered broadly applicable to mixtures, they can only be used for classification of mixtures when all ingredients of the mixture fall within the applicability domain of the test methods used. Specific limitations regarding applicability domains are described in the respective test methods, and should be taken into consideration as well as any further information on the limitations from the published literature. Where there is reason to assume or evidence indicating that the applicability domain of a particular test method is limited, data interpretation should be exercised with caution, or the results should be considered not applicable.

A.2.3.1.3 In the absence of any other information, a mixture is considered corrosive (Skin Category 1) if it has a pH ≤2 or a pH ≥11.5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably from an appropriate validated in vitro/ex vivo test.

A.2.3.2 Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles

A.2.3.2.1 Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles, as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one hazard category, Substantially similar mixtures, and Aerosols.

A.2.3.3 Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture

A.2.3.3.1 In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The “relevant ingredients” of a mixture are those which are present in concentrations ≥1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases.). If the classifier has reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for skin corrosion/irritation, that ingredient shall also be considered relevant.

A.2.3.3.2 In general, the approach to classification of mixtures as corrosive or irritant to the skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each corrosive or irritant ingredient contributes to the overall corrosive or irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for corrosive ingredients when they are present at a concentration below the concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as an irritant. The mixture is classified as corrosive or irritant when the sum of the concentrations of such ingredients exceeds a cut-off value/concentration limit.

A.2.3.3.3 Table A.2.3 below provides the cut-off value/concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

A.2.3.3.4 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.2.3.3.1 and A.2.3.3.2 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 in Table A.2.3. A mixture containing corrosive or irritant ingredients that cannot be classified based on the additivity approach shown in Table A.2.3, due to chemical characteristics that make this approach unworkable, should be classified as skin corrosion Category 1 if it contains ≥1% of a corrosive ingredient and as skin irritation Category 2 when it contains ≥3% of an irritant ingredient. Classification of mixtures with ingredients for which the approach in Table A.2.3 does not apply is summarized in Table A.2.4 below.

A.2.3.3.5 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 cut-off values/concentration limits mentioned in Tables A.2.3 and A.2.4. In these cases the mixture could be classified according to those data (See Use of cut-off values/concentration limits, paragraph A.0.4.3 of this Appendix).

A.2.3.3.6 If there are data showing that (an) ingredient(s) may be corrosive or irritant to skin at a concentration of <1% (corrosive) or <3% (irritant), the mixture shall be classified accordingly (See Use of cut-off values/concentration limits, paragraph A.0.4.3 of this Appendix).

A.3.1.1 Serious eye damage refers to the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation refers to the production of changes in the eye, which are fully reversible, occurring after exposure of the eye to a substance or mixture.

A.3.1.2 Serious eye damage/eye irritation shall be classified using a tiered approach as detailed in Figure A.3.1. Emphasis shall be placed upon existing human data (See A.0.2.6), followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria in this section. In case the criteria cannot be directly applied, classification of a substance or a mixture is made on the basis of the total weight of evidence (See A.0.3.1). This means that all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate scientifically validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations.

Substances are allocated to one of the categories within this hazard class, Category 1 (serious eye damage) or Category 2 (eye irritation), as follows:

(a) Category 1 (serious eye damage/irreversible effects on the eye): substances that have the potential to seriously damage the eyes (see Table A.3.1).

(b) Category 2 (eye irritation/reversible effects on the eye): substances that have the potential to induce reversible eye irritation (see Table A.3.2).

A.3.2.1 Classification Based on Standard Animal Test Data

A.3.2.1.1 Serious eye damage (Category 1)/Irreversible effects on the eye

A single hazard category is provided in Table A.3.1, for substances that have the potential to seriously damage the eyes. Category 1, irreversible effects on the eye, includes the criteria listed below. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g., destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Category 1 also contains substances fulfilling the criteria of corneal opacity ≥ 3 and/or iritis > 1.5 observed in at least 2 of 3 tested animals detected in a Draize eye test with rabbits, because severe lesions like these usually do not reverse within a 21-day observation period.

A.3.2.1.2 Eye irritation (category 2)/reversible effects on the eye

A single Category 2 is provided in Table A.3.2 for substances that have the potential to induce reversible eye irritation.

When data are available, substances may be classified into Category 2A and Category 2B:

(a) For substances inducing eye irritant effects reversing within an observation time of normally 21 days, Category 2A applies.

(b) For substances inducing eye irritant effects reversing within an observation time of 7 days, Category 2B applies.

When a substance is classified as Category 2, without further categorization, the classification criteria are the same as those for 2A.

A.3.2.1.3 For those substances where there is pronounced variability among animal responses this information must be taken into account in determining the classification.

A.3.2.2.1 A tiered approach to the evaluation of initial information shall be used where applicable, recognizing that all elements may not be relevant in certain cases (Figure A.3.1).

A.3.2.2.2 Existing human and animal data should be the first line of analysis, as they give information directly relevant to effects on the eye. Possible skin corrosion shall be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances.

A.3.2.2.3 In vitro alternatives that have been validated and accepted should be used to make classification decisions.

A.3.2.2.4 Likewise, pH extremes like ≤2 and ≥11.5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤2 or ≥11.5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

A.3.2.2.5 In some cases sufficient information may be available from structurally related substances to make classification decisions.

A.3.2.2.6 The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification (ideally without conducting new animal tests). Animal testing with corrosive substances should be avoided wherever possible. Although information might be gained from the evaluation of single parameters within a tier, consideration should be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

A.3.2.2.7 The tiered approach explains how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. 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.

a Existing human or animal data could be derived from single or repeated exposure(s), for example in occupational, consumer, transport, or emergency response scenarios; or from purposely-generated data from animal studies conducted according to validated and internationally accepted test methods. Although human data from accident or poison center databases can provide evidence for classification, absence of incidents is not itself evidence for no classification as exposures are generally unknown or uncertain;

b Classify in the appropriate category as applicable;

c Existing animal data should be carefully reviewed to determine if sufficient serious eye damage/eye irritation evidence is available through other, similar information. It is recognized that not all skin irritants are eye irritants. Expert judgment should be exercised prior to making such a determination;

d Evidence from studies using validated protocols with isolated human/animal tissues or other non-tissue-based, validated protocols should be assessed. Examples of internationally accepted, validated test methods for identifying eye corrosives and severe irritants (i.e., Serious Eye Damage) include OECD Test Guidelines 437 (Bovine Corneal Opacity and Permeability (BCOP)), 438 (Isolated Chicken Eye (ICE) and 460 (Fluorescein leakage (FL)). Presently there are no validated and internationally accepted in vitro test methods for identifying eye irritation. A positive test result from a validated in vitro test on skin corrosion would lead to the conclusion to classify as causing serious eye damage;

e Measurement of pH alone may be adequate, but assessment of acid/alkaline reserve (buffering capacity) would be preferable. Presently, there is no validated and internationally accepted method for assessing this parameter;

f All information that is available on a substance must 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 may lead to classification for eye irritation. Negative results from applicable validated in vitro tests are considered in the total weight of evidence evaluation.

A.3.3.1 Classification of Mixtures When Data Are Available for the Complete Mixture

A.3.3.1.1 The mixture will be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class (as illustrated in Figure A.3.1).

A.3.3.1.2 When considering testing of the mixture, chemical manufacturers shall use a tiered approach as included in the criteria for classification of substances for skin corrosion and serious eye damage and eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤2 or ≥11.5. However, if consideration of acid/alkaline reserve suggests the mixture may not have the potential to cause serious eye damage despite the low or high pH value, then further evaluation may be necessary.

A.3.3.2 Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles

A.3.3.2.1 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 hazard category, Substantially similar mixtures, and Aerosols.

A.3.3.3 Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture

A.3.3.3.1 For purposes of classifying the serious eye damage/eye irritation hazards of mixtures in the tiered approach:

The “relevant ingredients” of a mixture are those which are present in concentrations ≥1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases.) If the classifier has reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for serious eye damage/eye irritation, that ingredient shall also be considered relevant.

A.3.3.3.2 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 skin corrosive or serious eye damage/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as serious eye damaging/eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a threshold cut-off value/concentration limit.

A.3.3.3.3 Table A.3.3 provides the cut-off value/concentration limits to be used to determine if the mixture must be classified as seriously damaging to the eye or an eye irritant.

A.3.3.3.4 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.3.3.3.1 and A.3.3.3.2 might not work given that many of such substances are seriously damaging to the eye/eye irritating at concentrations <1%. For mixtures containing strong acids or bases, the pH should be used as classification criteria (See A.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the concentration limits of Table A.3.3. A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach applied in Table A.3.3 due to chemical characteristics that make this approach unworkable, should be classified as serious eye damage (Category 1) if it contains ≥1% of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥3% of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table A.3.3 does not apply is summarized in Table A.3.4.

A.3.3.3.5 On occasion, reliable data may show that the irreversible/reversible eye effects of an ingredient will not be evident when present at a level above the generic cut-off values/concentration limits mentioned in Tables A.3.3 and A.3.4. In these cases the mixture could be classified according to those data (See also A.0.4.3 Use of cut-off values/concentration limits”). On occasion, when it is expected that the skin corrosion/irritation or the reversible/irreversible eye effects of an ingredient will not be evident when present at a level above the generic concentration/cut-off levels mentioned in Tables A.3.3 and A.3.4, testing of the mixture may be considered. In those cases, the tiered weight of evidence approach should be applied as referred to in section A.3.2, Figure A.3.1 and explained in detail in this chapter.

A.3.3.3.6 If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of ≤1% (corrosive to the skin or seriously damaging to the eye) or ≤3% (eye irritant), the mixture shall be classified accordingly (See also paragraph A.0.4.3, Use of cut-off values/concentration limits).

A.4.1.1 Respiratory sensitization refers to hypersensitivity of the airways occurring after inhalation of a substance or mixture.

Skin sensitization refers to an allergic response occurring after skin contact with a substance or mixture.

A.4.1.2 For the purpose of this chapter, sensitization includes two phases: the first phase is induction of specialized immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e., production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitized individual to an allergen.

A.4.1.3 For respiratory sensitization, the pattern of induction followed by elicitation phases is shared in common with skin sensitization. For skin sensitization, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardized elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitization in humans normally is assessed by a diagnostic patch test.

A.4.1.4 Usually, for both skin and respiratory sensitization, lower levels are necessary for elicitation than are required for induction.

A.4.1.5 The hazard class “respiratory or skin sensitization” is differentiated into:

(a) Respiratory sensitization; and

(b) Skin sensitization

A.4.2.1 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.

A.4.2.1.2 Human Evidence

A.4.2.1.2.1 Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

A.4.2.1.2.2 When considering the human evidence, it is necessary that in addition to the evidence from the cases, the following be taken into account:

(a) The size of the population exposed;

(b) The extent of exposure.

A.4.2.1.3 The evidence referred to above could be:

(a) Clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) In vivo immunological test (e.g., skin prick test);

(ii) In vitro immunological test (e.g., serological analysis);

(iii) Studies that may indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g., repeated low-level irritation, pharmacologically mediated effects;

(iv) A chemical structure related to substances known to cause respiratory hypersensitivity;

(b) Data from positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

A.4.2.1.2.4 Clinical history should include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history should also include a note of other allergic or airway disorders from childhood and smoking history.

A.4.2.1.2.5 The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is, however, recognized that in practice many of the examinations listed above will already have been carried out.

A.4.2.1.3 Animal studies

A.4.2.1.2.3 Data from appropriate animal studies 2 which may be indicative of the potential of a substance to cause sensitization by inhalation in humans 3 may include:

(a) Measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice

(b) Specific pulmonary responses in guinea pigs.

A.4.2.2.1 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.

A.4.2.2.2 Human Evidence

A.4.2.2.2.1 Human evidence for sub-category 1A may include:

(a) Positive responses at ≤500 µg/cm2 (Human Repeat Insult Patch Test (HRIPT), Human Maximization Test (HMT)—induction threshold);

(b) Diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) Other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

A.4.2.2.2.2 Human evidence for sub-category 1B may include:

(a) Positive responses at >500 µg/cm2 (HRIPT, HMT—induction threshold);

(b) Diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) Other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

A.4.2.2.3 Animal Studies

A.4.2.2.3.1 For Category 1, when an adjuvant type test method for skin sensitization is used, a response of at least 30% of the animals is considered as positive. For a non-adjuvant Guinea pig test method, a response of at least 15% of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. 4

A.4.2.2.3.2 Animal test results for sub-category 1A can include data with values indicated in the following Table A.4.3:

A.4.2.2.3.3 Animal test results for sub-category 1B can include data with values indicated in Table A.4.4 below:

A.4.2.2.4.1 For classification of a substance, evidence shall include one or more of the following using a weight of evidence approach:

(a) Positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) Epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) Positive data from appropriate animal studies;

(d) Positive data from experimental studies in humans (See paragraph A.0.2.6 of this Appendix);

(e) Well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) Severity of reaction.

A.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.4.3.1 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 within one hazard category/subcategory, Substantially similar mixtures, and Aerosols.

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

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

A.5.1.1 Germ cell mutagenicity refers to heritable gene mutations, including heritable structure and numerical chromosome aberrations in germ cells occurring after exposure to a substance or mixture.

A.5.1.2 A mutation is defined as a permanent change in the amount or structure of the genetic material in a cell. The term mutation applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including, for example, specific base pair changes and chromosomal translocations). The term mutagenic and mutagen will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.

A.5.1.3 The more general terms genotoxic and genotoxicity apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replication processes, or which in a non-physiological manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators for mutagenic effects.

A.5.1.4 This hazard class is primarily concerned with chemicals that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and mixtures within this hazard class.

A.5.2.1 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

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show 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.5.3.1 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.

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.5.4.1 Examples of in vivo heritable germ cell mutagenicity tests are:

(a) Rodent dominant lethal mutation test (OECD 478)

(b) Mouse heritable translocation assay (OECD 485)

(c) Mouse specific locus test

A.5.4.2 Examples of in vivo somatic cell mutagenicity tests are:

(a) Mammalian bone marrow chromosome aberration test (OECD 475)

(b) Mammalian erythrocyte micronucleus test (OECD 474)

A.5.4.3 Examples of mutagenicity/genotoxicity tests in germ cells are:

(a) Mutagenicity tests:

(i) Mammalian spermatogonial chromosome aberration test (OECD 483)

(ii) Spermatid micronucleus assay

(b) Genotoxicity tests:

(i) Sister chromatid exchange analysis in spermatogonia

(ii) Unscheduled DNA synthesis test (UDS) in testicular cells

A.5.4.4 Examples of genotoxicity tests in somatic cells are:

(a) Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)

(b) Mammalian bone marrow Sister Chromatid Exchanges (SCE)

A.5.4.5 Examples of in vitro mutagenicity tests are:

(a) In vitro mammalian chromosome aberration test (OECD 473)

(b) In vitro mammalian cell gene mutation test (OECD 476)

(c) Bacterial reverse mutation tests (OECD 471)

A.5.4.6 As new, scientifically validated tests arise, these may also be used in the total weight of evidence to be considered.

Carcinogenicity refers to the induction of cancer or an increase in the incidence of cancer occurring after exposure to a substance or mixture. Substances and mixtures which have induced benign and malignant tumors in well-performed experimental studies on animals are considered also to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumor formation is not relevant for humans.

Classification of a substance or mixture as posing a carcinogenic hazard is based on its inherent properties and does not provide information on the level of the human cancer risk which the use of the substance or mixture may represent.

A.6.2.1 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

A.6.2.2 Classification as a carcinogen is made on the basis of evidence from reliable and acceptable methods, and is intended to be used for substances which have an intrinsic property to produce such toxic effects. The evaluations are to be based on all existing data, peer-reviewed published studies and additional data accepted by regulatory agencies.

A.6.2.3 Carcinogen classification is a one-step, criterion-based process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.

A.6.2.4 Strength of evidence involves the enumeration of tumors in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the agent and an increased incidence of tumors. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. (Guidance on consideration of important factors in the classification of carcinogenicity and a more detailed description of the terms “limited” and “sufficient” have been developed by the International Agency for Research on Cancer (IARC) and are provided in non-mandatory appendix F of this section.)

A.6.2.5 Weight of evidence: Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors should be considered that influence the overall likelihood that an agent may pose a carcinogenic hazard in humans. The full list of factors that influence this determination is very lengthy, but some of the important ones are considered here.

A.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.6.3.1 The mixture shall be classified as a carcinogen when at least one ingredient has been classified as a Category 1 or Category 2 carcinogen and is present at or above the appropriate cut-off value/concentration limit as shown in Table A.6.1.

A.6.3.2 Classification of mixtures when data are available for the complete mixture

A mixture may be classified based on the available test data for the mixture as a whole. In such cases, the test results for the mixture as a whole must be shown to be 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.6.4.1 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, chemical manufacturers, importers, and employers shall classify the chemical as a carcinogen.

A.7.1.1 Reproductive toxicity refers to adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring, occurring after exposure to a substance or mixture. Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function and fertility or to developmental toxicity. Nonetheless, substances and mixtures with these effects shall be classified as reproductive toxicants. For classification purposes, the known induction of genetically based inheritable effects in the offspring is addressed in Germ cell mutagenicity (See A.5).

A.7.1.2 Adverse effects on sexual function and fertility means any effect of chemicals that interferes with reproductive ability or sexual capacity. This includes, but is not limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behavior, 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.7.2.1 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

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

A.7.2.2 Basis of Classification

A.7.2.2.1 Classification is made on the basis of the criteria, outlined above, an assessment of the total weight of evidence, and the use of expert judgment. Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances should not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.

A.7.2.2.2 In the evaluation of toxic effects on the developing offspring, it is important to consider the possible influence of maternal toxicity.

A.7.2.2.3 For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall be from well conducted epidemiological studies, if available, which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans may be sufficient for a Category 1A classification if supplemented with adequate data from studies in experimental animals, but classification in Category 1B may also be considered.

A.7.2.3 Weight of Evidence

A.7.2.3.1 Classification as a reproductive toxicant is made on the basis of an assessment of the total weight of evidence using expert judgment. This means that all available information that bears on the determination of reproductive toxicity is considered together. Included is information such as epidemiological studies and case reports in humans and specific reproduction studies along with sub-chronic, chronic and special study results in animals that provide relevant information regarding toxicity to reproductive and related endocrine organs. Evaluation of substances chemically related to the material under study may also be included, particularly when information on the material is scarce. The weight given to the available evidence will be influenced by factors such as the quality of the studies, consistency of results, nature and severity of effects, level of statistical significance for intergroup differences, number of endpoints affected, relevance of route of administration to humans and freedom from bias. Both positive and negative results are considered together in a weight of evidence determination. However, a single, positive study performed according to good scientific principles and with statistically or biologically significant positive results may justify classification (See also A.7.2.2.3).

A.7.2.3.2 Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information, which could reduce or increase concerns about the hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a chemical which produces an adverse effect on reproduction in experimental animals should not be classified.

A.7.2.3.3 In some reproductive toxicity studies in experimental animals the only effects recorded may be considered of low or minimal toxicological significance and classification 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 × 100)

(c) Fertility index (Number of animals with implants/Number of matings × 100)

(d) Gestation length (If allowed to deliver)

(e) Body weight and body weight change: Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight shall be included in the evaluation of maternal toxicity whenever such data are available. The calculation of an adjusted (corrected) mean maternal body weight change, which is the difference between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the weights of the fetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the body weight gain may not be a useful indicator of maternal toxicity because of normal fluctuations in body weight during pregnancy.

(f) Food and water consumption (if relevant): The observation of a significant decrease in the average food or water consumption in treated dams (mothers) compared to the control group may be useful in evaluating maternal toxicity, particularly when the test material is administered in the diet or drinking water. Changes in food or water consumption must be evaluated in conjunction with maternal body weights when determining if the effects noted are reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.

(g) Clinical evaluations (including clinical signs, markers, and hematology and clinical chemistry studies): The observation of increased incidence of significant clinical signs of toxicity in treated dams (mothers) relative to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be reported in the study. Clinical signs of maternal intoxication include, but are not limited to: coma, prostration, hyperactivity, loss of righting reflex, ataxia, or labored breathing.

(h) Post-mortem data: Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity. This can include gross or microscopic pathological findings or organ weight data, including absolute organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by findings of adverse histopathological effects in the affected organ(s), the observation of a significant change in the average weight of suspected target organ(s) of treated dams (mothers), compared to those in the control group, may be considered evidence of maternal toxicity.

A.7.2.5 Animal and Experimental Data

A.7.2.5.1 A number of scientifically validated test methods are available, including methods for developmental toxicity testing (e.g., OECD Test Guideline 414, ICH Guideline S5A, 1993), methods for peri- and post-natal toxicity testing (e.g., ICH S5B, 1995), and methods for one or two-generation toxicity testing (e.g., OECD Test Guidelines 415, 416, 443).

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

A.7.3.1.1 The mixture shall be classified as a reproductive toxicant when at least one ingredient has been classified as a Category 1 or Category 2 reproductive toxicant and is present at or above the appropriate cut-off value/concentration limit specified in Table A.7.1 for Category 1 and 2, respectively.

A.7.3.1.2 The mixture shall be classified for effects on or via lactation when at least one ingredient has been classified for effects on or via lactation and is present at or above the appropriate cut-off value/concentration limit specified in Table A.7.1 for the additional category for effects on or via lactation.

A.7.3.2 Classification of Mixtures When Data Are Available for the Complete Mixture

Available test data for the mixture as a whole may be used for classification on a case-by-case basis. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations and analysis (e.g., statistical analysis, test sensitivity) of reproduction test systems.

A.7.3.3 Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles

A.7.3.1.1 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.8.1.1 Specific target organ toxicity—single exposure, (STOT-SE) refers to specific, non-lethal toxic effects on target organs occurring after a single 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 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 target organ 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.8.2.1.1 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.

Note: For these categories the specific target organ/system that has been primarily affected by the classified substance may be identified, or the substance may be identified as a general toxicant. Attempts should be made to determine the primary target organ/system of toxicity and classify for that purpose, e.g., hepatotoxicants, neurotoxicants. One should carefully evaluate the data and, where possible, not include secondary effects, e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems.

A.8.2.1.2 The relevant route(s) of exposure by which the classified substance produces damage shall be identified.

A.8.2.1.3 Classification is determined by expert judgment, on the basis of the weight of all evidence available including the guidance presented below.

A.8.2.1.4 Weight of evidence of all 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.8.2.1.7.1 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 relevance to human health, must be taken into consideration in the classification process. Relevant toxic effects in humans and/or animals include, but are not limited to:

(a) Morbidity resulting from single exposure;

(b) Significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (e.g., sight, hearing and sense of smell);

(c) Any consistent and significant adverse change in clinical biochemistry, hematology, or urinalysis parameters;

(d) Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e) Multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f) Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction; and,

(g) Evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

A.8.2.1.8 Effects Considered Not To Support Classification for Category 1 and 2

Effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:

(a) Clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate “significant” toxicity;

(b) Small changes in clinical biochemistry, hematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or of minimal toxicological importance;

(c) Changes in organ weights with no evidence of organ dysfunction;

(d) Adaptive responses that are not considered toxicologically relevant; and,

(e) Substance-induced species-specific mechanisms of toxicity, i.e., demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

A.8.2.1.9 Guidance Values To Assist With Classification Based on the Results Obtained From Studies Conducted in Experimental Animals for Category 1 and 2

A.8.2.1.9.1 In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 vs. Category 2), dose/concentration “guidance values” are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all chemicals are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged.

A.8.2.1.9.2 Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the dose/concentration).

A.8.2.1.9.3 The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table A.8.1.

A.8.2.1.9.4 The guidance values and ranges mentioned in Table A.8.1 are intended only for guidance purposes, i.e., to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values. Guidance values are not provided for Category 3 since this classification is primarily based on human data; animal data may be included in the weight of evidence evaluation.

A.8.2.1.9.5 Thus, it is feasible that a specific profile of toxicity occurs at a dose/concentration below the guidance value, e.g., <2,000 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., ≥2,000 mg/kg body weight by the oral route, and in addition there is supplementary information from other sources, e.g., other single dose studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.

A.8.2.1.10 Other Considerations

A.8.2.1.10.1 When a substance is characterized only by use of animal data the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

A.8.2.1.10.2 When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to single exposure to a substance, the substance shall be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because specific target organ toxicity observed was considered not relevant or significant to humans, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

A.8.2.1.10.3 A substance that has not been tested for specific target organ toxicity shall, where appropriate, be classified on the basis of data from a scientifically validated structure activity relationship and expert judgment-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

A.8.2.2 Substances of Category 3

A.8.2.2.1 Criteria for respiratory tract irritation

The criteria for classifying substances as Category 3 for respiratory tract irritation are:

(a) Respiratory irritant effects (characterized by localized redness, edema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. It is recognized that this evaluation is based primarily on human data;

(b) Subjective human observations supported by objective measurements of clear respiratory tract irritation (RTI) (e.g., electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);

(c) The symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of “irritation” should be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory tract irritation;

(d) There are currently no scientifically validated animal tests that deal specifically with RTI; however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc.) and histopathology (e.g., hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation; and,

(e) This special classification will occur only when more severe organ effects including the respiratory system are not observed as those effects would require a higher classification.

A.8.2.2.2 Criteria for Narcotic Effects

The criteria for classifying substances in Category 3 for narcotic effects are:

(a) Central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness; and,

(b) Narcotic effects observed in animal studies may include lethargy, lack of coordination righting reflex, narcosis, and ataxia. If these effects are not transient in nature, then they shall be considered for classification as Category 1 or 2.

A.8.3.1 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 hazard category, Substantially similar mixtures, or Aerosols.

A.8.3.4 Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture

A.8.3.4.1 Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, repeated exposure, or both when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate cut-off value/concentration limit specified in Table A.8.2 for Categories 1 and 2, respectively.

A.8.3.4.2 These cut-off values and consequent classifications shall be applied equally and appropriately to both single- and repeated-dose target organ toxicants.

A.8.3.4.3 Mixtures shall be classified for either or both single and repeated dose toxicity independently.

A.8.3.4.4 Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at <1% concentration when other ingredients in the mixture are known to potentiate its toxic effect.

A.8.3.4.5 Care shall be exercised when extrapolating the toxicity of a mixture that contains Category 3 ingredient(s). A cut-off value/concentration limit of 20%, considered as an additive of all Category 3 ingredients for each hazard endpoint, is appropriate; however, this cut-off value/concentration limit may be higher or lower depending on the Category 3 ingredient(s) involved and the fact that some effects such as respiratory tract irritation may not occur below a certain concentration while other effects such as narcotic effects may occur below this 20% value. Expert judgment shall be exercised. Respiratory tract irritation and narcotic effects are to be evaluated separately in accordance with the criteria given in A.8.2.2. When conducting classifications for these hazards, the contribution of each ingredient should be considered additive, unless there is evidence that the effects are not additive.

A.8.3.4.6 In cases where the additivity approach is used for Category 3 ingredients, the “relevant ingredients” of a mixture are those which are present in concentrations ≥1% (w/w for solids, liquids, dusts, mists, and vapours and v/v for gases), unless there is a reason to suspect that an ingredient present at a concentration <1% is still relevant when classifying the mixture for respiratory tract irritation or narcotic effects.

A.9.1.1 Specific target organ toxicity—repeated exposure (STOT-RE) refers to specific toxic effects on target organs occurring after 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.9.2.1 Substances shall be classified as STOT—RE by expert judgment on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), (See A.9.2.9). Substances shall be placed in one of two categories, depending upon the nature and severity of the effect(s) observed, in accordance with Figure A.9.1.

A.9.2.2 The relevant route of exposure by which the classified substance produces damage shall be identified.

A.9.2.3 Classification is determined by expert judgment, on the basis of the weight of all evidence available including the guidance presented below.

A.9.2.4 Weight of evidence of all data, including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.

A.9.2.5 The information required to evaluate specific target organ toxicity comes either from repeated exposure in humans, e.g., exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include hematological, clinico-chemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species may also be used. Other long-term exposure studies, e.g., for carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.

A.9.2.6 In exceptional cases, based on expert judgment, it may be appropriate to place certain substances with human evidence of specific target organ toxicity in Category 2: (a) when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or (b) based on the nature and severity of effects. Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.

A.9.2.7 Effects Considered To Support Classification

A.9.2.7.1 Classification is supported by reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect.

A.9.2.7.2 Evidence from human experience/incidents is usually restricted to reports of adverse health consequences, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

A.9.2.7.3 Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, hematology, clinical chemistry, macroscopic and microscopic pathological examination and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently, all available evidence, and relevance to human health, must be taken into consideration in the classification process. Relevant toxic effects in humans and/or animals include, but are not limited to:

(a) Morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, or due to the overwhelming of the de-toxification process by repeated exposure;

(b) Significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g., sight, hearing and sense of smell);

(c) Any consistent and significant adverse change in clinical biochemistry, hematology, or urinalysis parameters;

(d) Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e) Multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f) Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction (e.g., severe fatty change in the liver); and,

(g) Evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

A.9.2.8 Effects Considered Not To Support Classification

Effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:

(a) Clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate “significant” toxicity;

(b) Small changes in clinical biochemistry, hematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or of minimal toxicological importance;

(c) Changes in organ weights with no evidence of organ dysfunction;

(d) Adaptive responses that are not considered toxicologically relevant;

(e) Substance-induced species-specific mechanisms of toxicity, i.e., demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

A.9.2.9 Guidance Values To Assist With Classification Based on the Results Obtained From Studies Conducted in Experimental Animals

A.9.2.9.1 In studies conducted in experimental animals, reliance on observation of effects alone, without reference to the duration of experimental exposure and dose/concentration, omits a fundamental concept of toxicology, i.e., all substances are potentially toxic, and what determines the toxicity is a function of the dose/concentration and the duration of exposure. In most studies conducted in experimental animals the test guidelines use an upper limit dose value.

A.9.2.9.2 In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 vs. Category 2), dose/concentration “guidance values” are provided in Table A.9.1 for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all chemicals are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged. Also, repeated-dose studies conducted in experimental animals are designed to produce toxicity at the highest dose used in order to optimize the test objective and so most studies will reveal some toxic effect at least at this highest dose. What is therefore to be decided is not only what effects have been produced, but also at what dose/concentration they were produced and how relevant is that for humans.

A.9.2.9.3 Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the duration of experimental exposure and the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the duration of exposure and the dose/concentration).

A.9.2.9.4 The decision to classify at all can be influenced by reference to the dose/concentration guidance values at or below which a significant toxic effect has been observed.

A.9.2.9.5 The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to 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:

A.9.2.9.7 For Category 2 classification, significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals and seen to occur within the (suggested) guidance value ranges as indicated in Table A.9.2 would justify classification:

A.9.2.9.8 The guidance values and ranges mentioned in A.2.9.9.6 and A.2.9.9.7 are intended only for guidance purposes, i.e., to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values.

A.9.2.9.9 Thus, it is possible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, e.g., <100 mg/kg body weight/day by the oral route, however the nature of the effect, e.g., nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect, may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at above a guidance value, e.g., ≥100 mg/kg body weight/day by the oral route, and in addition there is supplementary information from other sources, e.g., other long-term administration studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is prudent.

A.9.2.10 Other Considerations

A.9.2.10.1 When a substance is characterized only by use of animal data the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

A.9.2.10.2 When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to repeated or prolonged exposure to a substance, the substance shall be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

A.9.2.10.3 A substance that has not been tested for specific target organ toxicity may in certain instances, where appropriate, be classified on the basis of data from a scientifically validated structure activity relationship and expert judgment-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

A.9.3.1 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.9.3.3.1 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 hazard category; Substantially similar mixtures; and Aerosols.

A.9.3.4 Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture

A.9.3.4.1 Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, repeated exposure, or both when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate cut-off value/concentration limit specified in Table A.9.3 for Category 1 and 2 respectively.

A.9.3.4.2 These cut-off values and consequent classifications shall be applied equally and appropriately to both single- and repeated-dose target organ toxicants.

A.9.3.4.3 Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.

A.9.3.4.4 Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause specific target organ toxicity at <1% concentration when other ingredients in the mixture are known to potentiate its toxic effect.

A.10.1.1 Aspiration hazard refers to severe acute effects such as chemical pneumonia, pulmonary injury or death occurring after aspiration of a substance or mixture.

A.10.1.2 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.10.1.3 Aspiration is initiated at the moment of inspiration, in the time required to take one breath, as the causative material lodges at the crossroad of the upper respiratory and digestive tracts in the laryngopharyngeal region.

A.10.1.4 Aspiration of a substance or mixture can occur as it is vomited following ingestion. This may have consequences for labeling, particularly where, due to acute toxicity, a recommendation may be considered to induce vomiting after ingestion. However, if the substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce vomiting may need to be modified.

A.10.1.5 Specific Considerations

A.10.1.5.1 The classification criteria refer to kinematic viscosity. The following provides the conversion between dynamic and kinematic viscosity:

A.10.1.5.2 Although the definition of aspiration in A.10.1.1 includes the entry of solids into the respiratory system, classification according to (b) in table A.10.1 for Category 1 is intended to apply to liquid substances and mixtures only.

A.10.1.5.3 Classification of aerosol/mist products

Aerosol and mist products are usually dispensed in containers such as self- pressurized containers, trigger and pump sprayers. Classification for these products shall be considered if their use may form a pool of product in the mouth, which then may be aspirated. If the mist or aerosol from a pressurized container is fine, a pool may not be formed. On the other hand, if a pressurized container dispenses product in a stream, a pool may be formed that may then be aspirated. Usually, the mist produced by trigger and pump sprayers is coarse and therefore, a pool may be formed that then may be aspirated. When the pump mechanism may be removed and contents are available to be swallowed then the classification of the products should be considered.

A.10.3.1 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.10.3.2.1 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 hazard 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 The “relevant ingredients” of a mixture are those which are present in concentrations ≥1%.

A.10.3.3.2 Category 1

A.10.3.3.2.1 A mixture is classified as Category 1 when the sum of the concentrations of Category 1 ingredients is ≥10%, and the mixture has a kinematic viscosity of ≤20.5 mm 2/s, measured at 40 °C.

A.10.3.3.2.2 In the case of a mixture which separates into two or more distinct layers, the entire mixture is classified as Category 1 if in any distinct layer the sum of the concentrations of Category 1 ingredients is ≥10%, and it has a kinematic viscosity of ≤20.5 mm 2/s, measured at 40 °C.

B.1.1.1 An explosive chemical is a solid or liquid chemical which is in itself capable by chemical reaction of producing gas at such a temperature and pressure and at such a speed as to cause damage to the surroundings. Pyrotechnic chemicals are included even when they do not evolve gases.

A pyrotechnic chemical is a chemical designed to produce an effect by heat, light, sound, gas or smoke or a combination of these as the result of non-detonative self-sustaining exothermic chemical reactions.

An explosive item is an item containing one or more explosive chemicals.

A pyrotechnic item is an item containing one or more pyrotechnic chemicals.

An unstable explosive is an explosive which is thermally unstable and/or too sensitive for normal handling, transport, or use.

An intentional explosive is a chemical or item which is manufactured with a view to produce a practical explosive or pyrotechnic effect.

B.1.1.2 The class of explosives comprises:

(a) Explosive chemicals;

(b) Explosive items, except devices containing explosive chemicals in such quantity or of such a character that their inadvertent or accidental ignition or initiation shall not cause any effect external to the device either by projection, fire, smoke, heat or loud noise; and

(c) Chemicals and items not included under (a) and (b) of this section which are manufactured with the view to producing a practical explosive or pyrotechnic effect.

Chemicals and items of this class shall be classified as unstable explosives or shall be assigned to one of the following six divisions depending on the type of hazard they present:

(a) Division 1.1—Chemicals and items which have a mass explosion hazard (a mass explosion is one which affects almost the entire quantity present virtually instantaneously);

(b) Division 1.2—Chemicals and items which have a projection hazard but not a mass explosion hazard;

(c) Division 1.3—Chemicals and items which have a fire hazard and either a minor blast hazard or a minor projection hazard or both, but not a mass explosion hazard:

(i) Combustion of which gives rise to considerable radiant heat; or

(ii) Which burn one after another, producing minor blast or projection effects or both;

(d) Division 1.4—Chemicals and items which present no significant hazard: chemicals and items which present only a small hazard in the event of ignition or initiation. The effects are largely confined to the package and no projection of fragments of appreciable size or range is to be expected. An external fire shall not cause virtually instantaneous explosion of almost the entire contents of the package;

(e) Division 1.5—Very insensitive chemicals which have a mass explosion hazard: chemicals which have a mass explosion hazard but are so insensitive that there is very little probability of initiation or of transition from burning to detonation under normal conditions;

(f) Division 1.6—Extremely insensitive items which do not have a mass explosion hazard: items which predominantly contain extremely insensitive detonating chemicals and which demonstrate a negligible probability of accidental initiation or propagation.

B.1.3.1 Explosives shall be classified as unstable explosives or shall be assigned to one of the six divisions identified in B.1.2 in accordance with the three step procedure in Part I of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6). The first step is to ascertain whether the substance or mixture has explosive effects (Test Series 1). The second step is the acceptance procedure (Test Series 2 to 4) and the third step is the assignment to a hazard division (Test Series 5 to 7). The assessment whether a candidate for “ammonium nitrate emulsion or suspension or gel, intermediate for blasting explosives (ANE)” is insensitive enough for inclusion as an oxidizing liquid (see B.13 of this appendix) or an oxidizing solid (see B.14 of this appendix) is determined by Test Series 8 tests of UN ST/SG/AC.10/.

B.1.3.2 Explosive properties are associated with the presence of certain chemical groups in a molecule which can react to produce very rapid increases in temperature or pressure. The screening procedure in B.1.3.1 is aimed at identifying the presence of such reactive groups and the potential for rapid energy release. If the screening procedure identifies the chemical as a potential explosive, the acceptance procedure (see section 10.3 of the UN ST/SG/AC.10 (incorporated by reference; see § 1910.6)) is necessary for classification.

B.1.3.3 If a mixture contains any known explosives, the acceptance procedure is necessary for classification.

B.1.3.4 A chemical is not classified as explosive if:

(a) There are no chemical groups associated with explosive properties present in the molecule. Examples of groups which may indicate explosive properties are given in Table A6.1 in Appendix 6 of the UN ST/SG/AC.10 (incorporated by reference; See § 1910.6); or

(b) The substance contains chemical groups associated with explosive properties which include oxygen and the calculated oxygen balance is less than −200.

The oxygen balance is calculated for the chemical reaction:

(c) The organic substance or a homogenous mixture of organic substances contains chemical groups associated with explosive properties but the exothermic decomposition energy is less than 500 J/g and the onset of exothermic decomposition is below 500 °C (932 °F). The exothermic decomposition energy may be determined using a suitable calorimetric technique; or

(d) For mixtures of inorganic oxidizing substances with organic material(s), the concentration of the inorganic oxidizing substance is:

(i) less than 15%, by mass, if the oxidizing substance is assigned to Category 1 or 2;

(ii) less than 30%, by mass, if the oxidizing substance is assigned to Category 3.

Flammable gas means a gas having a flammable range with air at 20 °C (68 °F) and a standard pressure of 101.3 kPa (14.7 psi).

A pyrophoric gas means a flammable gas that is liable to ignite spontaneously in air at a temperature of 54 °C (130 °F) or below.

A chemically unstable gas means a flammable gas that is able to react explosively even in the absence of air or oxygen.

B.2.2.1 A flammable gas shall be classified in Category 1A, 1B, or 2 in accordance with Table B.2.1:

B.2.3.1 Flammability shall be determined by tests or by calculation in accordance with ISO 10156:1996 or ISO 10156:2017 (incorporated by reference; see § 1910.6) and, if using fundamental burning velocity for Category 1B, use Annex C: Method of test for burning velocity measurement of flammable gases of ISO 817:2014(E) (incorporated by reference; see § 1910.6). Where insufficient data are available to use this method, equivalent validated methods may be used.

B.2.3.2 Pyrophoricity shall be determined at 130 °F (54 °C) in accordance with either IEC 60079-20-1 or DIN 51794:2003 (incorporated by reference; see § 1910.6).

B.2.3.3 The classification procedure for pyrophoric gases need not be applied when experience in production or handling shows that the substance does not ignite spontaneously on coming into contact with air at a temperature of 130 °F (54 °C) or below. Flammable gas mixtures, which have not been tested for pyrophoricity and which contain more than one percent pyrophoric components shall be classified as a pyrophoric gas. Expert judgement on the properties and physical hazards of pyrophoric gases and their mixtures should be used in assessing the need for classification of flammable gas mixtures containing one percent or less pyrophoric components. In this case, testing need only be considered if expert judgement indicates a need for additional data to support the classification process.

B.2.3.4 Chemical instability shall be determined in accordance with the method described in Part III of the UN ST/SG/AC.10/11/Rev.6 (incorporated by reference; see § 1910.6). If the calculations performed in accordance with ISO 10156:1996 or ISO 10156:2017 (incorporated by reference; see § 1910.6) show that a gas mixture is not flammable, no additional testing is required for determining chemical instability for classification purposes.

Aerosol means any non-refillable receptacle containing a gas compressed, liquefied or dissolved under pressure, and fitted with a release device allowing the contents to be ejected as particles in suspension in a gas, or as a foam, paste, powder, liquid or gas.

B.3.1.2.1 Aerosols are classified in one of three categories, depending on their flammable properties and their heat of combustion. Aerosols shall be considered for classification in Categories 1 or 2 if they contain more than 1% components (by mass) which are classified as flammable in accordance with this Appendix B, i.e.:

Flammable gases (see B.2);

Flammable liquids (see B.6)

Flammable solids (see B.7)

or if their heat of combustion is at least 20 kJ/g.

B.3.1.2.2 An aerosol shall be classified in one of the three categories for this class in accordance with Table B.3.1.

B.3.2.1 Definition

Chemicals under pressure are liquids or solids (e.g., pastes or powders), pressurized with a gas at a pressure of 200 kPa (gauge) or more at 20 °C in pressure receptacles other than aerosol dispensers and which are not classified as gases under pressure.

B.3.2.2 Classification Criteria

B.3.2.2.1 Chemicals under pressure are classified in one of three categories of this hazard class, in accordance with Table B.3.2, depending on their content of flammable components and their heat of combustion

B.3.2.2.2 Flammable components are components which are classified as flammable in accordance with the GHS criteria, i.e.:

B.3.3.1 To classify an aerosol, data on its flammable components, on its chemical heat of combustion and, if applicable, the results of the aerosol foam flammability test (for foam aerosols) and of the ignition distance test and enclosed space test (for spray aerosols) are necessary.

B.3.3.2 The chemical heat of combustion (ΔHc), in kilojoules per gram (kJ/g), is the product of the theoretical heat of combustion (ΔHcomb), and a combustion efficiency, usually less than 1.0 (a typical combustion efficiency is 0.95 or 95%).

For a composite formulation, the chemical heat of combustion is the summation of the weighted heats of combustion for the individual components, as follows:

B.3.3.3 The chemical heats of combustion shall be found in literature, calculated or determined by tests: (see ASTM D240; Sections 86.1 to 86.3 of ISO 13943; and NFPA 30B (incorporated by reference; see § 1910.6)).

B.3.3.4 The Ignition Distance Test, Enclosed Space Ignition Test and Aerosol Foam Flammability Test shall be performed in accordance with sub-sections 31.4, 31.5 and 31.6 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6).

Oxidizing gas means any gas which may, generally by providing oxygen, cause or contribute to the combustion of other material more than air does.

An oxidizing gas shall be classified in a single category for this class in accordance with Table B.4.1:

Classification shall be in accordance with tests or calculation methods as described in ISO 10156:1996, ISO 10156:2017 or 10156-2:2005 (incorporated by reference; see § 1910.6).

Gases under pressure are gases which are contained in a receptacle at a pressure of 200 kPa (29 psi) (gauge) or more at 20 °C (68 °F), or which are liquefied or liquefied and refrigerated.

They comprise compressed gases, liquefied gases, dissolved gases and refrigerated liquefied gases.

Gases under pressure shall be classified in one of four groups in accordance with Table B.5.1:

Flammable liquid means a liquid having a flash point of not more than 93 °C (199.4 °F).

Flash point means the minimum temperature at which a liquid gives off vapor in sufficient concentration to form an ignitable mixture with air near the surface of the liquid, as determined by a method identified in Section B.6.3 of this appendix.

A flammable liquid shall be classified in one of four categories in accordance with Table B.6.1 of this appendix:

The flash point shall be determined in accordance with ASTM D56-05, ASTM D3278, ASTM D3828, ASTM D93-08 (incorporated by reference, see § 1910.6), or any method specified in 29 CFR 1910.106(a)(14). It may also be determined by any other method specified in GHS Revision 7, Chapter 2.6.

The initial boiling point shall be determined in accordance with ASTM D86-07a or ASTM D1078 (incorporated by reference; see § 1910.6). 9

Flammable solid means a solid which is a readily combustible solid, or which may cause or contribute to fire through friction.

Readily combustible solids are powdered, granular, or pasty chemicals which are dangerous if they can be easily ignited by brief contact with an ignition source, such as a burning match, and if the flame spreads rapidly.

B.7.2.1 Powdered, granular or pasty chemicals shall be classified as flammable solids when the time of burning of one or more of the test runs, performed in accordance with the test method described in Part III, sub-section 33.2.1 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6), is less than 45 s or the rate of burning is more than 2.2 mm/s (0.0866 in/s).

B.7.2.2 Powders of metals or metal alloys shall be classified as flammable solids when they can be ignited and the reaction spreads over the whole length of the sample in 10 min or less.

B.7.2.3 Solids which may cause fire through friction shall be classified in this class by analogy with existing entries (e.g., matches) until definitive criteria are established.

B.7.2.4 A flammable solid shall be classified in one of the two categories for this class using Method N.1 as described in Part III, sub-section 33.2.1 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6), in accordance with Table B.7.1:

Self-reactive chemicals are thermally unstable liquid or solid chemicals liable to undergo a strongly exothermic decomposition even without participation of oxygen (air). This definition excludes chemicals classified under this section as explosives, organic peroxides, oxidizing liquids or oxidizing solids.

A self-reactive chemical is regarded as possessing explosive properties when in laboratory testing the formulation is liable to detonate, to deflagrate rapidly or to show a violent effect when heated under confinement.

B.8.2.1 A self-reactive chemical shall be considered for classification in this class unless:

(a) It is classified as an explosive according to B.1 of this appendix;

(b) It is classified as an oxidizing liquid or an oxidizing solid according to B.13 or B.14 of this appendix, except that a mixture of oxidizing substances which contains 5% or more of combustible organic substances shall be classified as a self-reactive chemical according to the procedure defined in B.8.2.2;

(c) It is classified as an organic peroxide according to B.15 of this appendix;

(d) Its heat of decomposition is less than 300 J/g; or

(e) Its self-accelerating decomposition temperature (SADT) is greater than 75 °C (167 °F) for a 50 kg (110 lb) package.

B.8.2.2 Mixtures of oxidizing substances, meeting the criteria for classification as oxidizing liquids or oxidizing solids, which contain 5% or more of combustible organic substances and which do not meet the criteria mentioned in B.8.2.1(a), (c), (d) or (e), shall be subjected to the self-reactive chemicals classification procedure in B.8.2.3. Such a mixture showing the properties of a self-reactive chemical type B to F shall be classified as a self-reactive chemical.

B.8.2.3 Self-reactive chemicals shall be classified in one of the seven categories of “types A to G” for this class, according to the following principles:

(a) Any self-reactive chemical which can detonate or deflagrate rapidly, as packaged, will be defined as self-reactive chemical TYPE A;

(b) Any self-reactive chemical possessing explosive properties and which, as packaged, neither detonates nor deflagrates rapidly, but is liable to undergo a thermal explosion in that package will be defined as self-reactive chemical TYPE B;

(c) Any self-reactive chemical possessing explosive properties when the chemical as packaged cannot detonate or deflagrate rapidly or undergo a thermal explosion will be defined as self-reactive chemical TYPE C;

(d) Any self-reactive chemical which in laboratory testing meets the criteria in (d)(i), (ii), or (iii) will be defined as self-reactive chemical TYPE D:

(i) Detonates partially, does not deflagrate rapidly and shows no violent effect when heated under confinement; or

(ii) Does not detonate at all, deflagrates slowly and shows no violent effect when heated under confinement; or

(iii) Does not detonate or deflagrate at all and shows a medium effect when heated under confinement;

(e) Any self-reactive chemical which, in laboratory testing, neither detonates nor deflagrates at all and shows low or no effect when heated under confinement will be defined as self-reactive chemical TYPE E;

(f) Any self-reactive chemical which, in laboratory testing, neither detonates in the cavitated state nor deflagrates at all and shows only a low or no effect when heated under confinement as well as low or no explosive power will be defined as self-reactive chemical TYPE F;

(g) Any self-reactive chemical which, in laboratory testing, neither detonates in the cavitated state nor deflagrates at all and shows no effect when heated under confinement nor any explosive power, provided that it is thermally stable (self- accelerating decomposition temperature is 60 °C (140 °F) to 75 °C (167 °F) for a 50 kg (110 lb) package), and, for liquid mixtures, a diluent having a boiling point greater than or equal to 150 °C (302 °F) is used for desensitization will be defined as self-reactive chemical TYPE G. If the mixture is not thermally stable or a diluent having a boiling point less than 150 °C (302 °F) is used for desensitization, the mixture shall be defined as self-reactive chemical TYPE F.

B.8.3.1 For purposes of classification, the properties of self-reactive chemicals shall be determined in accordance with test series A to H as described in Part II of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6).

B.8.3.2 Self-accelerating decomposition temperature (SADT) shall be determined in accordance with Part II, section 28 of UN ST/SG/AC.10, (incorporated by reference; see § 1910.6).

B.8.3.3 The classification procedures for self-reactive substances and mixtures need not be applied if:

(a) There are no chemical groups present in the molecule associated with explosive or self-reactive properties; examples of such groups are given in Tables A6.1 and A6.2 in the Appendix 6 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6); or

(b) For a single organic substance or a homogeneous mixture of organic substances, the estimated SADT is greater than 75 °C (167 °F) or the exothermic decomposition energy is less than 300 J/g. The onset temperature and decomposition energy may be estimated using a suitable calorimetric technique (See 20.3.3.3 in Part II of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6)).

Pyrophoric liquid means a liquid which, even in small quantities, is liable to ignite within five minutes after coming into contact with air.

A pyrophoric liquid shall be classified in a single category for this class using test N.3 in Part III, sub-section 33.3.1.5 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6), in accordance with Table B.9.1 of this appendix:

The classification procedure for pyrophoric liquids need not be applied when experience in production or handling shows that the chemical does not ignite spontaneously on coming into contact with air at normal temperatures (i.e., the substance is known to be stable at room temperature for prolonged periods of time (days)).

Pyrophoric solid means a solid which, even in small quantities, is liable to ignite within five minutes after coming into contact with air.

A pyrophoric solid shall be classified in a single category for this class using test N.2 in Part III, sub-section 33.3.1.4 of UN ST/SG/AC.10 (incorporated by reference; see § 1910.6), in accordance with Table B.10.1 of this appendix:

The classification procedure for pyrophoric solids need not be applied when experience in production or handling shows that the chemical does not ignite spontaneously on coming into contact with air at normal temperatures (i.e., the chemical is known to be stable at room temperature for prolonged periods of time (days)).

A self-heating chemical is a solid or liquid chemical, other than a pyrophoric liquid or solid, which, by reaction with air and without energy supply, is liable to self-heat; this chemical differs from a pyrophoric liquid or solid in that it will ignite only when in large amounts (kilograms) and after long periods of time (hours or days).

B.11.2.1 A self-heating chemical shall be classified in one of the two categories for this class if, in tests performed in accordance with test method N.4 in Part III, sub-section 33.3.1.6 of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6), the result meets the criteria shown in Table B.11.1.

B.11.2.2 Chemicals with a temperature of spontaneous combustion higher than 50 ° C (122 ° F) for a volume of 27 m3 shall not be classified as self-heating chemicals.

B.11.2.3 Chemicals with a spontaneous ignition temperature higher than 50° C (122° F) for a volume of 450 liters shall not be classified in Category 1 of this class.

B.11.3.1 The classification procedure for self-heating chemicals need not be applied if the results of a screening test can be adequately correlated with the classification test and an appropriate safety margin is applied.

B.11.3.2 Examples of screening tests are:

(a) The Grewer Oven test (VDI guideline 2263, part 1, 1990, Test methods for the Determination of the Safety Characteristics of Dusts) with an onset temperature 80°K above the reference temperature for a volume of 1 l;

(b) The Bulk Powder Screening Test (Gibson, N. Harper, D. J. Rogers, R. Evaluation of the fire and explosion risks in drying powders, Plant Operations Progress, 4 (3), 181-189, 1985) with an onset temperature 60°K above the reference temperature for a volume of 1 l.

Chemicals which, in contact with water, emit flammable gases are solid or liquid chemicals which, by interaction with water, are liable to become spontaneously flammable or to give off flammable gases in dangerous quantities.

B.12.2.1 A chemical which, in contact with water, emits flammable gases shall be classified in one of the three categories for this class, using test N.5 in Part III, sub-section 33.4.1.4 of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6), in accordance with Table B.12.1 of this appendix:

B.12.2.2 A chemical is classified as a chemical which, in contact with water, emits flammable gases if spontaneous ignition takes place in any step of the test procedure.

The classification procedure for this class need not be applied if:

(a) The chemical structure of the chemical does not contain metals or metalloids;

(b) Experience in production or handling shows that the chemical does not react with water, (e.g., the chemical is manufactured with water or washed with water); or

(c) The chemical is known to be soluble in water to form a stable mixture.

Oxidizing liquid means a liquid which, while in itself not necessarily combustible, may, generally by yielding oxygen, cause, or contribute to, the combustion of other material.

An oxidizing liquid shall be classified in one of the three categories for this class using test O.2 in Part III, sub-section 34.4.2 of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6), in accordance with Table B.13.1:

B.13.3.1 For organic chemicals, the classification procedure for this class shall not be applied if:

(a) The chemical does not contain oxygen, fluorine or chlorine; or

(b) The chemical contains oxygen, fluorine or chlorine and these elements are chemically bonded only to carbon or hydrogen.

B.13.3.2 For inorganic chemicals, the classification procedure for this class shall not be applied if the chemical does not contain oxygen or halogen atoms.

B.13.3.3 In the event of divergence between test results and known experience in the handling and use of chemicals which shows them to be oxidizing, judgments based on known experience shall take precedence over test results.

B.13.3.4 In cases where chemicals generate a pressure rise (too high or too low), caused by chemical reactions not characterizing the oxidizing properties of the chemical, the test described in Part III, sub-section 34.4.2 of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6) shall be repeated with an inert substance (e.g., diatomite (kieselguhr)) in place of the cellulose in order to clarify the nature of the reaction.

Oxidizing solid means a solid which, while in itself is not necessarily combustible, may, generally by yielding oxygen, cause, or contribute to, the combustion of other material.

An oxidizing solid shall be classified in one of the three categories for this class using test O.1 in Part III, sub-section 34.4.1, of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6) or test O.3 in Part III, sub-section 34.4.3 of UN ST/SG/AC.10/11 (incorporated by reference, see § 1910.6), in accordance with Table B.14.1:

B.14.3.1 For organic chemicals, the classification procedure for this class shall not be applied if:

(a) The chemical does not contain oxygen, fluorine or chlorine; or

(b) The chemical contains oxygen, fluorine or chlorine and these elements are chemically bonded only to carbon or hydrogen.

B.14.3.2 For inorganic chemicals, the classification procedure for this class shall not be applied if the chemical does not contain oxygen or halogen atoms.

B.14.3.3 In the event of divergence between test results and known experience in the handling and use of chemicals which shows them to be oxidizing, judgements based on known experience shall take procedure over test results.

B.15.1.1 Organic peroxide means a liquid or solid organic chemical which contains the bivalent -0-0- structure and as such is considered a derivative of hydrogen peroxide, where one or both of the hydrogen atoms have been replaced by organic radicals. The term organic peroxide includes organic peroxide mixtures containing at least one organic peroxide. Organic peroxides are thermally unstable chemicals, which may undergo exothermic self-accelerating decomposition. In addition, they may have one or more of the following properties:

(a) Be liable to explosive decomposition;

(b) Burn rapidly;

(c) Be sensitive to impact or friction;

(d) React dangerously with other substances.

B.15.1.2 An organic peroxide is regarded as possessing explosive properties when in laboratory testing the formulation is liable to detonate, to deflagrate rapidly or to show a violent effect when heated under confinement.

B.15.2.1 Any organic peroxide shall be considered for classification in this class, unless it contains:

(a) Not more than 1.0% available oxygen from the organic peroxides when containing not more than 1.0% hydrogen peroxide; or

(b) Not more than 0.5% available oxygen from the organic peroxides when containing more than 1.0% but not more than 7.0% hydrogen peroxide.

B.15.2.2 Organic peroxides shall be classified in one of the seven categories of “Types A to G” for this class, according to the following principles:

(a) Any organic peroxide which, as packaged, can detonate or deflagrate rapidly shall be defined as organic peroxide TYPE A;

(b) Any organic peroxide possessing explosive properties and which, as packaged, neither detonates nor deflagrates rapidly, but is liable to undergo a thermal explosion in that package shall be defined as organic peroxide TYPE B;

(c) Any organic peroxide possessing explosive properties when the chemical as packaged cannot detonate or deflagrate rapidly or undergo a thermal explosion shall be defined as organic peroxide TYPE C;

(d) Any organic peroxide which in laboratory testing meets the criteria in (d)(i), (ii), or (iii) shall be defined as organic peroxide TYPE D:

(i) Detonates partially, does not deflagrate rapidly and shows no violent effect when heated under confinement; or

(ii) Does not detonate at all, deflagrates slowly and shows no violent effect when heated under confinement; or

(iii) Does not detonate or deflagrate at all and shows a medium effect when heated under confinement;

(e) Any organic peroxide which, in laboratory testing, neither detonates nor deflagrates at all and shows low or no effect when heated under confinement shall be defined as organic peroxide TYPE E;

(f) Any organic peroxide which, in laboratory testing, neither detonates in the cavitated state nor deflagrates at all and shows only a low or no effect when heated under confinement as well as low or no explosive power shall be defined as organic peroxide TYPE F;

(g) Any organic peroxide which, in laboratory testing, neither detonates in the cavitated state nor deflagrates at all and shows no effect when heated under confinement nor any explosive power, provided that it is thermally stable (self-accelerating decomposition temperature is 60 ° C (140 ° F) or higher for a 50 kg (110 lb) package), and, for liquid mixtures, a diluent having a boiling point of not less than 150 ;° C (302 ° F) is used for desensitization, shall be defined as organic peroxide TYPE G. If the organic peroxide is not thermally stable or a diluent having a boiling point less than 150 ° C (302° F) is used for desensitization, it shall be defined as organic peroxide TYPE F.

B.15.3.1 For purposes of classification, the properties of organic peroxides shall be determined in accordance with test series A to H as described in Part II of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6).

B.15.3.2 Self-accelerating decomposition temperature (SADT) shall be determined in accordance with UN ST/SG/AC.10 (incorporated by reference, see § 1910.6), Part II, section 28.

B.15.3.3 Mixtures of organic peroxides may be classified as the same type of organic peroxide as that of the most dangerous ingredient. However, as two stable ingredients can form a thermally less stable mixture, the SADT of the mixture shall be determined.

A chemical which is corrosive to metals means a chemical which by chemical action will materially damage, or even destroy, metals.

A chemical which is corrosive to metals shall be classified in a single category for this class, using the test in Part III, sub-section 37.4 of UN ST/SG/AC.10 (incorporated by reference, see § 1910.6), in accordance with Table B.16.1:

The specimen to be used for the test shall be made of the following materials:

(a) For the purposes of testing steel, steel types S235JR+CR (1.0037 resp. St 37- 2), S275J2G3+CR (1.0144 resp. St 44-3), ISO 3574, Unified Numbering System (UNS) G 10200, or SAE 1020;

(b) For the purposes of testing aluminium: non-clad types 7075-T6 or AZ5GU-T6.

Desensitized explosives are solid or liquid explosive chemicals which are phlegmatized 10 to suppress their explosive properties in such a manner that they do not mass explode and do not burn too rapidly and therefore may be exempted from the hazard class “Explosives” (Chapter B.1; see also Note 2 of paragraph B.1.3). 11

B.17.1.1 The class of desensitized explosives comprises:

(a) Solid desensitized explosives: explosive substances or mixtures which are wetted with water or alcohols or are diluted with other substances, to form a homogeneous solid mixture to suppress their explosive properties.

(b) Liquid desensitized explosives: explosive substances or mixtures which are dissolved or suspended in water or other liquid substances, to form a homogeneous liquid mixture to suppress their explosive properties.

B.17.2.1 Any explosive which is desensitized shall be considered in this class, unless:

(a) It is intended to produce a practical, explosive or pyrotechnic effect; or

It has a mass explosion hazard according to test series 6 (a) or 6 (b) or its corrected burning rate according to the burning rate test described in part V, subsection 51.4 of UN ST/SG/AC.10/11/Rev.6 (incorporated by reference, see § 1910.6) is greater than 1200 kg/min; or

(b) Its exothermic decomposition energy is less than 300 J/g.

B.17.2.2 Desensitized explosives shall be classified in one of the four categories of this class depending on the corrected burning rate (Ac) using the test “burning rate test (external fire)” described in Part V, sub-section 51.4 of UN ST/SG/AC.10/11/Rev.6 (incorporated by reference, see § 1910.6), according to Table B.17.1:

B.17.3.1 The classification procedure for desensitized explosives does not apply if:

(a) The substances or mixtures contain no explosives according to the criteria in Chapter B.1; or

(b) The exothermic decomposition energy is less than 300 J/g.

B.17.3.2 The exothermic decomposition energy shall be determined using the explosive already desensitized (i.e., the homogenous solid or liquids mixture formed by the explosive and the substance(s) used to suppress its explosive properties). The exothermic decomposition energy may be estimated using a suitable calorimetric technique (see Section 20, sub-section 20.3.3.3 in Part II of UN ST/SG/AC.10/11/Rev. 6 (incorporated by reference, see § 1910.6).

C.1 The label for each hazardous chemical shall include the product identifier used on the safety data sheet.

C.1.1 The labels on shipped containers shall also include the name, address, and telephone number of the chemical manufacturer, importer, or responsible party.

C.2 The label for each hazardous chemical that is classified shall include the signal word, hazard statement(s), pictogram(s), and precautionary statement(s) specified in C.4 for each hazard class and associated hazard category, except as provided for in C.2.1 through C.2.4.

C.2.1.1 If the signal word “Danger” is included, the signal word “Warning” shall not appear;

C.2.1.2 If the skull and crossbones pictogram is included, the exclamation mark pictogram shall not appear where it is used for acute toxicity;

C.2.1.3 If the corrosive pictogram is included, the exclamation mark pictogram shall not appear where it is used for skin or eye irritation;

C.2.1.4 If the health hazard pictogram is included for respiratory sensitization, the exclamation mark pictogram shall not appear where it is used for skin sensitization or for skin or eye irritation.

C.2.2.1 The text of all applicable hazard statements shall appear on the label, except as otherwise specified. The information in italics shall be included as part of the hazard statement as provided. For example: “causes damage to organs (state all organs affected) through prolonged or repeated exposure (state route of exposure if no other routes of exposure cause the hazard)”. Hazard statements may be combined where appropriate to reduce the information on the label and improve readability, as long as all of the hazards are conveyed as required.

C.2.2.2 If the chemical manufacturer, importer, or responsible party can demonstrate that all or part of the hazard statement is inappropriate to a specific substance or mixture, the corresponding statement may be omitted from the label.

C.2.3.1 Pictograms shall be in the shape of a square set at a point and shall include a black hazard symbol on a white background with a red frame sufficiently wide to be clearly visible. A square red frame set at a point without a hazard symbol is not a pictogram and is not permitted on the label.

C.2.3.2 One of eight standard hazard symbols shall be used in each pictogram. The eight hazard symbols are depicted in Figure C.1. A pictogram using the exclamation mark symbol is presented in Figure C.2, for the purpose of illustration.

C.2.3.3 The exclamation mark pictogram is permitted (but not required) for HNOCs as long as the words “Hazard Not Otherwise Classified” or the letters “HNOC” appear below the pictogram.

C.2.3.4 Pictograms may only appear once on a label. If multiple hazards require the use of the same pictogram, it may not appear a second time on the label.

C.2.4.1 There are four types of precautionary statements presented, “prevention,” “response,” “storage,” and “disposal.” The core part of the precautionary statement is presented in bold print. This is the text, except as otherwise specified, that shall appear on the label. Where additional information is required, it is indicated in plain text.

C.2.4.2 When a backslash or diagonal mark (/) appears in the precautionary statement text, it indicates that a choice has to be made between the separated phrases. In such cases, the chemical manufacturer, importer, or responsible party can choose the most appropriate phrase(s). For example, “Wear protective gloves/protective clothing/eye protection/face protection” could read “wear eye protection”.

C.2.4.3 When three full stops (. . .) appear in the precautionary statement text, they indicate that all applicable conditions are not listed. For example, in “Use explosion-proof electrical/ventilating/lighting/. . ./equipment”, the use of “. . .” indicates that other equipment may need to be specified. In such cases, the chemical manufacturer, importer, or responsible party can choose the other conditions to be specified.

C.2.4.4 When text in italics is used in a precautionary statement, this indicates specific conditions applying to the use or allocation of the precautionary statement. For example, “Use explosion-proof electrical/ventilating/lighting/. . ./equipment” is only required for flammable solids “if dust clouds can occur”. Text in italics is intended to be an explanatory, conditional note and is not intended to appear on the label.

C.2.4.5 Where square brackets ([ ]) appear around text in a precautionary statement, this indicates that the text in square brackets is not appropriate in every case and should be used only in certain circumstances. In these cases, conditions for use explaining when the text should be used are provided. For example, one precautionary statement states: “[In case of inadequate ventilation] wear respiratory protection.” This statement is given with the condition for use “- text in square brackets may be used if additional information is provided with the chemical at the point of use that explains what type of ventilation would be adequate for safe use”. This means that, if additional information is provided with the chemical explaining what type of ventilation would be adequate for safe use, the text in square brackets should be used and the statement would read: “In case of inadequate ventilation wear respiratory protection.” However, if the chemical is supplied without such ventilation information, the text in square brackets should not be used, and the precautionary statement should read: “Wear respiratory protection.”

C.2.4.6 Precautionary statements may be combined or consolidated to save label space and improve readability. For example, “Keep away from heat, sparks and open flame,” “Store in a well-ventilated place” and “Keep cool” can be combined to read “Keep away from heat, sparks and open flame and store in a cool, well-ventilated place.”

C.2.4.7 Precautionary statements may incorporate minor textual variations from the text prescribed in this Appendix if these variations assist in communicating safety information (e.g., spelling variations, synonyms or other equivalent terms) and the safety advice is not diluted or compromised. Any variations must be used consistently on the label and the safety data sheet.

C.2.4.8 In most cases, the precautionary statements are independent (e.g., the phrases for explosives hazards do not modify those related to certain health hazards, and products that are classified for both hazard classes shall bear appropriate precautionary statements for both). Where a chemical is classified for a number of hazards, and the precautionary statements are similar, the most stringent shall be included on the label (this will be applicable mainly to preventive measures).

C.2.4.9 If the chemical manufacturer, importer, or responsible party can demonstrate that a precautionary statement is inappropriate to a specific substance or mixture, the precautionary statement may be omitted from the label.

C.2.4.10 Where a substance or mixture is classified for a number of health hazards, this may trigger multiple precautionary statements relating to medical response, e.g., calling a poison center/doctor/. . . and getting medical advice/attention.

In general, the following principles should be applied:

(a) Where the classification of a substance or mixture triggers several different precautionary statements, a system of prioritization should be applied. If the same medical response statement is triggered multiple times, the label need only include one precautionary statement reflecting the response at the highest level with the greatest urgency, which should always be combined with at least one route of exposure or symptom “IF” statement.

(b) Routes of exposure, including “IF exposed or concerned,” may be combined when triggered with a medical response statement. If the response statement is triggered with three or more routes of exposure, “IF exposed or concerned” may be used. However, relevant “IF” statements describing symptoms must be included in full. If a route of exposure is triggered multiple times, it need only be included once.

(c) This does not apply to “Get medical advice/attention if you feel unwell” or “Get immediate medical advice/attention” when they are combined with an “If” statement and must appear without prioritization.

C.3.1 To ensure that non-standardized information does not lead to unnecessarily wide variation or undermine the required information, supplementary information on the label is limited to when it provides further detail and does not contradict or cast doubt on the validity of the standardized hazard information.

C.3.2 Where the chemical manufacturer, importer, or distributor chooses to add supplementary information on the label, the placement of supplemental information shall not impede identification of information required by this section.

C.3.3 Where an ingredient with unknown acute toxicity is used in a mixture at a concentration ≥1%, and the mixture is not classified based on testing of the mixture as a whole, a statement that X% of the mixture consists of ingredient(s) of unknown acute toxicity (oral/dermal/inhalation) is required on the label and safety data sheet.

A safety data sheet (SDS) shall include the information specified in Table D.1 under the section number and heading indicated for sections 1-11 and 16. While each section of the SDS must contain all of the specified information, preparers of safety data sheets are not required to present the information in any particular order within each section. If no relevant information is found for any given subheading within a section, the SDS shall clearly indicate that no applicable information is available. Sections 12-15 may be included in the SDS, but are not mandatory.

The following is a reprint of the Restatement of Torts section 757, comment b (1939):

b. Definition of trade secret. A trade secret may consist of any formula, pattern, device or compilation of information which is used in one's business, and which gives him an opportunity to obtain an advantage over competitors who do not know or use it. It may be a formula for a chemical compound, a process of manufacturing, treating or preserving materials, a pattern for a machine or other device, or a list of customers. It differs from other secret information in a business (see s759 of the Restatement of Torts which is not included in this Appendix) in that it is not simply information as to single or ephemeral events in the conduct of the business, as, for example, the amount or other terms of a secret bid for a contract or the salary of certain employees, or the security investments made or contemplated, or the date fixed for the announcement of a new policy or for bringing out a new model or the like. A trade secret is a process or device for continuous use in the operations of the business. Generally it relates to the production of goods, as, for example, a machine or formula for the production of an article. It may, however, relate to the sale of goods or to other operations in the business, such as a code for determining discounts, rebates or other concessions in a price list or catalogue, or a list of specialized customers, or a method of bookkeeping or other office management.

Secrecy. The subject matter of a trade secret must be secret. Matters of public knowledge or of general knowledge in an industry cannot be appropriated by one as his secret. Matters which are completely disclosed by the goods which one markets cannot be his secret. Substantially, a trade secret is known only in the particular business in which it is used. It is not requisite that only the proprietor of the business know it. He may, without losing his protection, communicate it to employees involved in its use. He may likewise communicate it to others pledged to secrecy. Others may also know of it independently, as, for example, when they have discovered the process or formula by independent invention and are keeping it secret. Nevertheless, a substantial element of secrecy must exist, so that, except by the use of improper means, there would be difficulty in acquiring the information. An exact definition of a trade secret is not possible. Some factors to be considered in determining whether given information is one's trade secret are: (1) The extent to which the information is known outside of his business; (2) the extent to which it is known by employees and others involved in his business; (3) the extent of measures taken by him to guard the secrecy of the information; (4) the value of the information to him and his competitors; (5) the amount of effort or money expended by him in developing the information; (6) the ease or difficulty with which the information could be properly acquired or duplicated by others.

Novelty and prior art. A trade secret may be a device or process which is patentable; but it need not be that. It may be a device or process which is clearly anticipated in the prior art or one which is merely a mechanical improvement that a good mechanic can make. Novelty and invention are not requisite for a trade secret as they are for patentability. These requirements are essential to patentability because a patent protects against unlicensed use of the patented device or process even by one who discovers it properly through independent research. The patent monopoly is a reward to the inventor. But such is not the case with a trade secret. Its protection is not based on a policy of rewarding or otherwise encouraging the development of secret processes or devices. The protection is merely against breach of faith and reprehensible means of learning another's secret. For this limited protection it is not appropriate to require also the kind of novelty and invention which is a requisite of patentability. The nature of the secret is, however, an important factor in determining the kind of relief that is appropriate against one who is subject to liability under the rule stated in this Section. Thus, if the secret consists of a device or process which is a novel invention, one who acquires the secret wrongfully is ordinarily enjoined from further use of it and is required to account for the profits derived from his past use. If, on the other hand, the secret consists of mechanical improvements that a good mechanic can make without resort to the secret, the wrongdoer's liability may be limited to damages, and an injunction against future use of the improvements made with the aid of the secret may be inappropriate.

The mandatory criteria for classification of a chemical for carcinogenicity under HCS (§ 1910.1200) are found in Appendix A.6 to this section. This non-mandatory Appendix provides additional guidance on hazard classification for carcinogenicity. Part A of Appendix F includes background guidance provided by GHS based on the Preamble of the International Agency for Research on Cancer (IARC) “Monographs on the Evaluation of Carcinogenic Risks to Humans” (2006). Part B provides IARC classification information. Part C provides background guidance from the National Toxicology Program (NTP) “Report on Carcinogens” (RoC), and Part D is a table that compares GHS carcinogen hazard categories to carcinogen classifications under IARC and NTP, allowing classifiers to be able to use information from IARC and NTP RoC carcinogen classifications to complete their classifications under the GHS, and thus the HCS.

As noted in Footnote 6 of Appendix A.6. to this section, the GHS includes as guidance for classifiers information taken from the Preamble of the International Agency for Research on Cancer (IARC) “Monographs on the Evaluation of Carcinogenic Risks to Humans” (2006), providing guidance on the evaluation of the strength and evidence of carcinogenic risks to humans. This guidance also discusses some additional considerations in classification and an approach to analysis, rather than hard-and-fast rules. Part A is consistent with Appendix A.6, and should help in evaluating information to determine carcinogenicity.

Carcinogenicity in humans:

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

(a) Sufficient evidence of carcinogenicity: A causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.

(b) Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.

In some instances, the above categories may be used to classify the degree of evidence related to carcinogenicity in specific organs or tissues.

Carcinogenicity in experimental animals:

The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

(a) Sufficient evidence of carcinogenicity: A causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in two or more species of animals or two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumors in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence.

Exceptionally, a single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumor or age at onset, or when there are strong findings of tumors at multiple sites.

(b) Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. the evidence of carcinogenicity is restricted to a single experiment; there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.

The weight of evidence analysis called for in GHS and the HCS (§ 1910.1200) is an integrative approach that considers important factors in determining carcinogenic potential along with the strength of evidence analysis. The IPCS “Conceptual Framework for Evaluating a Mode of Action for Chemical Carcinogenesis” (2001), International Life Sciences Institute (ILSI) “Framework for Human Relevance Analysis of Information on Carcinogenic Modes of Action” (Meek, et al., 2003; Cohen et al., 2003, 2004), and Preamble to the IARC Monographs (2006; Section B.6. (Scientific Review and Evaluation; Evaluation and Rationale)) provide a basis for systematic assessments that may be performed in a consistent fashion. The IPCS also convened a panel in 2004 to further develop and clarify the human relevance framework. However, the above documents are not intended to dictate answers, nor provide lists of criteria to be checked off.

Various documents on carcinogen assessment all note that mode of action in and of itself, or consideration of comparative metabolism, should be evaluated on a case-by-case basis and are part of an analytic evaluative approach. One must look closely at any mode of action in animal experiments, taking into consideration comparative toxicokinetics/toxicodynamics between the animal test species and humans to determine the relevance of the results to humans. This may lead to the possibility of discounting very specific effects of certain types of substances. Life stage-dependent effects on cellular differentiation may also lead to qualitative differences between animals and humans. Only if a mode of action of tumor development is conclusively determined not to be operative in humans may the carcinogenic evidence for that tumor be discounted. However, a weight of evidence evaluation for a substance calls for any other tumorigenic activity to be evaluated, as well.

Positive responses in several species add to the weight of evidence that a substance is a carcinogen. Taking into account all of the factors listed in A.6.2.5.2 and more, such chemicals with positive outcomes in two or more species would be provisionally considered to be classified in GHS Category 1B until human relevance of animal results are assessed in their entirety. It should be noted, however, that positive results for one species in at least two independent studies, or a single positive study showing unusually strong evidence of malignancy may also lead to Category 1B.

Any case of gender-specific tumors should be evaluated in light of the total tumorigenic response to the substance observed at other sites (multi-site responses or incidence above background) in determining the carcinogenic potential of the substance.

If tumors are seen only in one sex of an animal species, the mode of action should be carefully evaluated to see if the response is consistent with the postulated mode of action. Effects seen only in one sex in a test species may be less convincing than effects seen in both sexes, unless there is a clear patho-physiological difference consistent with the mode of action to explain the single sex response.

Tumors occurring only at excessive doses associated with severe toxicity generally have doubtful potential for carcinogenicity in humans. In addition, tumors occurring only at sites of contact and/or only at excessive doses need to be carefully evaluated for human relevance for carcinogenic hazard. For example, forestomach tumors, following administration by gavage of an irritating or corrosive, non-mutagenic chemical, may be of questionable relevance. However, such determinations must be evaluated carefully in justifying the carcinogenic potential for humans; any occurrence of other tumors at distant sites must also be considered.

Unusual tumor types or tumors occurring with reduced latency may add to the weight of evidence for the carcinogenic potential of a substance, even if the tumors are not statistically significant.

Toxicokinetic behavior is normally assumed to be similar in animals and humans, at least from a qualitative perspective. On the other hand, certain tumor types in animals may be associated with toxicokinetics or toxicodynamics that are unique to the animal species tested and may not be predictive of carcinogenicity in humans. Very few such examples have been agreed internationally. However, one example is the lack of human relevance of kidney tumors in male rats associated with compounds causing α2u-globulin nephropathy (IARC, Scientific Publication N° 147 2 ). Even when a particular tumor type may be discounted, expert judgment must be used in assessing the total tumor profile in any animal experiment.

IARC Carcinogen Classification Categories:

Group 1: The agent is carcinogenic to humans

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity.

Group 2:

This category includes agents for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents are assigned to either Group 2A (probably carcinogenic to humans) or Group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and mechanistic and other relevant data. The terms probably carcinogenic and possibly carcinogenic have no quantitative significance and are used simply as descriptors of different levels of evidence of human carcinogenicity, with probably carcinogenic signifying a higher level of evidence than possibly carcinogenic.

Group 2A: The agent is probably carcinogenic to human.

This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans. An agent may be assigned to this category if it clearly belongs, based on mechanistic considerations, to a class of agents for which one or more members have been classified in Group 1 or Group 2A.

Group 2B: The agent is possibly carcinogenic to humans.

This category is used for agents for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent for which there is inadequate evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals together with supporting evidence from mechanistic and other relevant data may be placed in this group. An agent may be classified in this category solely on the basis of strong evidence from mechanistic and other relevant data.

The criteria for listing an agent, substance, mixture, or exposure circumstance in the Report on Carcinogens (RoC) are as follows:

Known To Be A Human Carcinogen: There is sufficient evidence of carcinogenicity from studies in humans 5 that indicates a causal relationship between exposure to the agent, substance, or mixture, and human cancer.

Reasonably Anticipated To Be A Human Carcinogen: There is limited evidence of carcinogenicity from studies in humans that indicates that a causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding factors, could not adequately be excluded,

Conclusions regarding carcinogenicity in humans or experimental animals are based on scientific judgment, with consideration given to all relevant information. Relevant information includes, but is not limited to, dose response, route of exposure, chemical structure, metabolism, pharmacokinetics, sensitive sub-populations, genetic effects, or other data relating to mechanism of action or factors that may be unique to a given substance. For example, there may be substances for which there is evidence of carcinogenicity in laboratory animals, but there are compelling data indicating that the agent acts through mechanisms that do not operate in humans and would therefore not reasonably be anticipated to cause cancer in humans.

The following table may be used to perform hazard classifications for carcinogenicity under the HCS (§ 1910.1200). It relates the approximated GHS hazard categories for carcinogenicity to the classifications provided by IARC and NTP, as described in Parts B and C of this Appendix.

Note 1:

1. Limited evidence of carcinogenicity from studies in humans (corresponding to IARC 2A/GHS 1B);

2. Sufficient evidence of carcinogenicity from studies in experimental animals (again, essentially corresponding to IARC 2A/GHS 1B);

3. Less than sufficient evidence of carcinogenicity in humans or laboratory animals; however:

a. The agent, substance, or mixture belongs to a well-defined, structurally-related class of substances whose members are listed in a previous RoC as either “Known” or “Reasonably Anticipated” to be a human carcinogen, or

b. There is convincing relevant information that the agent acts through mechanisms indicating it would likely cause cancer in humans.