(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.<IP_ADDRESS>   A number of scientifically validated test methods are available, including methods for developmental toxicity testing (e.g., OECD Test Guideline 414, ICH Guideline S5A, 1993), methods for peri- and post-natal toxicity testing (e.g., ICH S5B, 1995), and methods for one or two-generation toxicity testing (e.g., OECD Test Guidelines 415, 416)
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   However, specification of the actual "limit dose" will depend upon the test method that has been employed to provide the test results.
A.7.3   Classification Criteria for Mixtures9
    9It should be noted that the classification criteria for health hazards usually include a tiered scheme in which test data available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable bridging principles, and lastly, cut-off values/concentration limits or additivity. However, this approach is not used for Reproductive Toxicity. These criteria for Reproductive Toxicity consider the cut-off values/concentration limits as the primary tier and allow the classification to be modified only on a case-by-case evaluation based on available test data for the mixture as a whole.
A.7.3.1   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   The mixture shall be classified for effects on or via lactation when at least one ingredient has been classified for effects on or via lactation and is present at or above the appropriate cut-off value/concentration limit specified in Table A.7.1 for the additional category for effects on or via lactation.
    Table A.7.1 -- Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Reproductive Toxicants or for Effects on or via Lactation That Trigger Classification of the Mixture
Ingredients classified as:
Cut-off values/concentration limits triggering classification of a mixture as:

Category 1 reproductive toxicant
Category 2 reproductive toxicant
Additional category for
effects on or via lactation
Category 1 reproductive toxicant
>=0.1%

Category 2 reproductive toxicant

>=0.1%

Additional category for effects on or via lactation

>=0.1%
A.7.3.2   Classification of Mixtures When Data Are Available for the Complete Mixture
    Available test data for the mixture as a whole may be used for classification on a case-by-case basis. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations and analysis (e.g., statistical analysis, test sensitivity) of reproduction test systems.
A.7.3.3   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its reproductive toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data shall be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, and Substantially similar mixtures.
A.8   SPECIFIC TARGET ORGAN TOXICITY SINGLE EXPOSURE
A.8.1   Definitions and General Considerations
    A.8.1.1   Specific target organ toxicity -- single exposure, (STOT-SE) means specific, non-lethal target organ toxicity arising from a single exposure to a chemical. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed and not specifically addressed in A.1 to A.7 and A.10 of this Appendix are included. Specific target organ toxicity following repeated exposure is classified in accordance with SPECIFIC TARGET ORGAN TOXICITY -- REPEATED EXPOSURE (A.9 of this Appendix) and is therefore not included here.
    A.8.1.2   Classification identifies the chemical as being a specific target organ toxicant and, as such, it presents a potential for adverse health effects in people who are exposed to it.
    A.8.1.3   The adverse health effects produced by a single exposure include consistent and identifiable toxic effects in humans; or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or hematology of the organism, and these changes are relevant for human health. Human data is the primary source of evidence for this hazard class.
    A.8.1.4   Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalized changes of a less severe nature involving several organs.
    A.8.1.5   Specific target organ toxicity can occur by any route that is relevant for humans, i.e., principally oral, dermal or inhalation.
    A.8.1.6   The classification criteria for specific organ systemic toxicity single exposure are organized as criteria for substances Categories 1 and 2 (See A.8.2.1), criteria for substances Category 3 (See A.8.2.2) and criteria for mixtures (See A.8.3). See also Figure A.8.1.
A.8.2   Classification Criteria for Substances
A.8.2.1   Substances of Category 1 and Category 2
    A.<IP_ADDRESS>   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.<IP_ADDRESS>). Substances shall then be classified in Category 1 or 2, depending upon the nature and severity of the effect(s) observed, in accordance with Figure A.8.1.
    Figure A.8.1 -- Hazard Categories for Specific Target Organ Toxicity Following Single Exposure

CATEGORY 1: Substances that have produced significant toxicity in humans, or that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to produce significant toxicity in humans following single exposure
Substances are classified in Category 1 for STOT-SE on the basis of:
(a) reliable and good quality evidence from human cases or epidemiological studies; or
(b) observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (See A.<IP_ADDRESS>) to be used as part of weight-of-evidence evaluation.
CATEGORY 2: Substances that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to be harmful to human health following single exposure
Substances are classified in Category 2 for STOT-SE on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (See A.<IP_ADDRESS>) in order to help in classification.
In exceptional cases, human evidence can also be used to place a substance in Category 2 (See A.<IP_ADDRESS>).
CATEGORY 3: Transient target organ effects
There are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. This category only includes narcotic effects and respiratory tract irritation. Substances are classified specifically for these effects as discussed in A.8.2.2.
Note: The primary target organ/system shall be identified where possible, and where this is not possible, the substance shall be identified as a general toxicant. The data shall be evaluated and, where possible, shall not include secondary effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).
    A.<IP_ADDRESS>   The relevant route(s) of exposure by which the classified substance produces damage shall be identified.
    A.<IP_ADDRESS>   Classification is determined by expert judgment, on the basis of the weight of all evidence available including the guidance presented below.
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   Effects considered to support classification for Category 1 and 2
    A.<IP_ADDRESS>.1   Classification is supported by evidence associating single exposure to the substance with a consistent and identifiable toxic effect.
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.3   Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, and macroscopic and microscopic pathological examination and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and evidence relevance to human health, must be taken into consideration in the classification process. Relevant toxic effects in humans and/or animals include, but are not limited to:
    (a) Morbidity resulting from single exposure;
    (b) Significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (e.g., sight, hearing and sense of smell);
    (c) Any consistent and significant adverse change in clinical biochemistry, hematology, or urinalysis parameters;
    (d) Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed at microscopic examination;
    (e) Multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;
    (f) Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction; and,
    (g) Evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>.3   The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table A.8.1.
    Table A.8.1 -- Guidance Value Ranges for Single-Dose Exposures
Route of exposure
Units
Guidance value ranges for:

Category 1
Category 2
Category 3
Oral (rat)
mg/kg body weight
C <=300
2000 >=C >300
Guidance values do not apply.
Dermal (rat or rabbit)
mg/kg body weight
C <=1,000
2000 >=C >1,000

Inhalation (rat) gas
ppmV/4h
C <=2,500
20,000 >=C >2,500

Inhalation (rat) vapor
mg/1/4h
C <=10
20 >=C >10

Inhalation (rat) dust/mist/fume
mg/l/4h
C <=1.0
5.0 >=C >1.0

    A.<IP_ADDRESS>.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.<IP_ADDRESS>.5   Thus, it is feasible that a specific profile of toxicity occurs at a dose/concentration below the guidance value, e.g., <2000 mg/kg body weight by the oral route, however the nature of the effect may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at above a guidance value, e.g., >=2000 mg/kg body weight by the oral route, and in addition there is supplementary information from other sources, e.g., other single dose studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.
    A.<IP_ADDRESS>   Other considerations
    A.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>.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.<IP_ADDRESS>   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.<IP_ADDRESS>   Criteria for narcotic effects
    The criteria for classifying substances in Category 3 for narcotic effects are:
    (a) Central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness; and,
    (b) Narcotic effects observed in animal studies may include lethargy, lack of coordination righting reflex, narcosis, and ataxia. If these effects are not transient in nature, then they shall be considered for classification as Category 1 or 2.
A.8.3   Classification Criteria for Mixtures
    A.8.3.1   Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures may be classified for specific target organ toxicity following single exposure, repeated exposure, or both.
A.8.3.2   Classification of Mixtures When Data Are Available for the Complete Mixture
    When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture shall be classified by weight of evidence evaluation of this data. Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.
A.8.3.3   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data shall be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category, Substantially similar mixtures, or Aerosols.
A.8.3.4   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, repeated exposure, or both when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate cut-off value/concentration limit specified in Table A.8.2 for Categories 1 and 2, respectively.
    Table A.8.2 -- Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as a Specific Target Organ Toxicant That Would Trigger Classification of the Mixture as Category 1 or 2
Ingredient classified as:
Cut-off values/concentration limits triggering classification of a mixture as:

Category 1
Category 2
Category 1   Target organ toxicant
>=1.0%

Category 2   Target organ toxicant

>=1.0%
    A.<IP_ADDRESS>   These cut-off values and consequent classifications shall be applied equally and appropriately to both single- and repeated-dose target organ toxicants.
    A.<IP_ADDRESS>   Mixtures shall be classified for either or both single and repeated dose toxicity independently.
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   Care shall be exercised when extrapolating the toxicity of a mixture that contains Category 3 ingredient(s). A cut-off value/concentration limit of 20%, considered as an additive of all Category 3 ingredients for each hazard endpoint, is appropriate; however, this cut-off value/concentration limit may be higher or lower depending on the Category 3 ingredient(s) involved and the fact that some effects such as respiratory tract irritation may not occur below a certain concentration while other effects such as narcotic effects may occur below this 20% value. Expert judgment shall be exercised. Respiratory tract irritation and narcotic effects are to be evaluated separately in accordance with the criteria given in A.8.2.2. When conducting classifications for these hazards, the contribution of each ingredient should be considered additive, unless there is evidence that the effects are not additive.
A.9   SPECIFIC TARGET ORGAN TOXICITY REPEATED OR PROLONGED EXPOSURE
A.9.1   Definitions and general considerations
    A.9.1.1   Specific target organ toxicity -- repeated exposure (STOT-RE) means specific target organ toxicity arising from repeated exposure to a substance or mixture. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed and not specifically addressed in A.1 to A.7 and A.10 of this Appendix are included. Specific target organ toxicity following a single-event exposure is classified in accordance with SPECIFIC TARGET ORGAN TOXICITY -- SINGLE EXPOSURE (A.8 of this Appendix) and is therefore not included here.
    A.9.1.2   Classification identifies the substance or mixture as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.
    A.9.1.3   These adverse health effects produced by repeated exposure include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or hematology of the organism and these changes are relevant for human health. Human data will be the primary source of evidence for this hazard class.
    A.9.1.4   Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalized changes of a less severe nature involving several organs.
    A.9.1.5   Specific target organ toxicity can occur by any route that is relevant for humans, e.g., principally oral, dermal or inhalation.
A.9.2   Classification Criteria for Substances
    A.9.2.1   Substances shall be classified as STOT-RE by expert judgment on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), (See A.9.2.9). Substances shall be placed in one of two categories, depending upon the nature and severity of the effect(s) observed, in accordance with Figure A.9.1.
    Figure A.9.1 -- Hazard Categories for Specific Target Organ Toxicity Following Repeated Exposure

CATEGORY 1: Substances that have produced significant toxicity in humans, or that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to produce significant toxicity in humans following repeated or prolonged exposure
Substances are classified in Category 1 for specific target organ toxicity (repeated exposure) on the basis of:
(a) reliable and good quality evidence from human cases or epidemiological studies; or,
(b) observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (See A.9.2.9) to be used as part of weight-of-evidence evaluation.
CATEGORY 2: Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated or prolonged exposure
Substances are classified in Category 2 for specific target organ toxicity (repeated exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (See A.9.2.9) in order to help in classification.
In exceptional cases human evidence can also be used to place a substance in Category 2 (See A.9.2.6).
Note: The primary target organ/system shall be identified where possible, or the substance shall be identified as a general toxicant. The data shall be carefully evaluated and, where possible, shall not include secondary effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).
    A.9.2.2   The relevant route of exposure by which the classified substance produces damage shall be identified.
    A.9.2.3   Classification is determined by expert judgment, on the basis of the weight of all evidence available including the guidance presented below.
    A.9.2.4   Weight of evidence of all data, including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.
    A.9.2.5   The information required to evaluate specific target organ toxicity comes either from repeated exposure in humans, e.g., exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include hematological, clinico-chemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species may also be used. Other long-term exposure studies, e.g., for carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.
    A.9.2.6   In exceptional cases, based on expert judgment, it may be appropriate to place certain substances with human evidence of specific target organ toxicity in Category 2: (a) when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or (b) based on the nature and severity of effects. Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.
A.9.2.7   Effects Considered To Support Classification
    A.<IP_ADDRESS>   Classification is supported by reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect.
    A.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   Thus for Category 1 classification, significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals and seen to occur at or below the (suggested) guidance values (C) as indicated in Table A.9.1 would justify classification:
    Table A.9.1 -- Guidance Values To Assist in Category 1 Classification
    [Applicable to a 90-day study]
Route of exposure
Units
Guidance values
(dose/concentration)
Oral (rat)
mg/kg body weight/day
C <=10.
Dermal (rat or rabbit)
mg/kg body weight/day
C <=20.
Inhalation (rat) gas
ppmV/6h/day
C <=50.
Inhalation (rat) vapor
mg/liter/6h/day
C <=0.2.
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
C <=0.02.
    A.<IP_ADDRESS>   For Category 2 classification, significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals and seen to occur within the (suggested) guidance value ranges as indicated in Table A.9.2 would justify classification:
    Table A.9.2 -- Guidance Values To Assist in Category 2 Classification
    [Applicable to a 90-day study]
Route of exposure
Units
Guidance values
(dose/concentration)
Oral (rat)
mg/kg body weight/day
10 <C <=100.
Dermal (rat or rabbit)
mg/kg body weight/day
20 <C <=200.
Inhalation (rat) gas
ppmV/6h/day
50 <C <=250.
Inhalation (rat) vapor
mg/liter/6h/day
0.2 <C <=1.0.
Inhalation (rat) dust/mist/fume
mg/liter/6h/day
0.02 <C <=0.2.
    A.<IP_ADDRESS>   The guidance values and ranges mentioned in A.<IP_ADDRESS> and A.<IP_ADDRESS> 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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   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.<IP_ADDRESS>   A substance that has not been tested for specific target organ toxicity may in certain instances, where appropriate, be classified on the basis of data from a scientifically validated structure activity relationship and expert judgment-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.
A.9.3   Classification Criteria for Mixtures
    A.9.3.1   Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures may be classified for specific target organ toxicity following single exposure, repeated exposure, or both.
A.9.3.2   Classification of Mixtures When Data Are Available for the Complete Mixture
    When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture shall be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.
A.9.3.3   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data shall be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution; Batching; Concentration of mixtures; Interpolation within one toxicity category; Substantially similar mixtures; and Aerosols.
A.9.3.4   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, repeated exposure, or both when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant and is present at or above the appropriate cut-off value/concentration limit specified in Table A.9.3 for Category 1 and 2 respectively.
    Table A.9.3 -- Cut-Off Value/Concentration Limits of Ingredients of a Mixture Classified as a Specific Target Organ Toxicant That Would Trigger Classification of the Mixture as Category 1 or 2
Ingredient classified as:
Cut-off values/concentration
limits triggering classification of a
mixture as:

Category 1
Category 2
Category 1   Target organ toxicant
>=1.0%

Category 2   Target organ toxicant

>=1.0%
    A.<IP_ADDRESS>   These cut-off values and consequent classifications shall be applied equally and appropriately to both single- and repeated-dose target organ toxicants.
    A.<IP_ADDRESS>   Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.
    A.<IP_ADDRESS>   Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause specific target organ toxicity at <1% concentration when other ingredients in the mixture are known to potentiate its toxic effect.
A.10   ASPIRATION HAZARD
A.10.1   Definitions and General and Specific Considerations
    A.10.1.1   Aspiration means the entry of a liquid or solid chemical directly through the oral or nasal cavity, or indirectly from vomiting, into the trachea and lower respiratory system.
    A.10.1.2   Aspiration toxicity includes severe acute effects such as chemical pneumonia, varying degrees of pulmonary injury or death following aspiration.
    A.10.1.3   Aspiration is initiated at the moment of inspiration, in the time required to take one breath, as the causative material lodges at the crossroad of the upper respiratory and digestive tracts in the laryngopharyngeal region.
    A.10.1.4   Aspiration of a substance or mixture can occur as it is vomited following ingestion. This may have consequences for labeling, particularly where, due to acute toxicity, a recommendation may be considered to induce vomiting after ingestion. However, if the substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce vomiting may need to be modified.
A.10.1.5   Specific Considerations
    A.<IP_ADDRESS>   The classification criteria refer to kinematic viscosity. The following provides the conversion between dynamic and kinematic viscosity:

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    A.<IP_ADDRESS>   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.<IP_ADDRESS>   Classification of aerosol/mist products.
    Aerosol and mist products are usually dispensed in containers such as self-pressurized containers, trigger and pump sprayers. Classification for these products shall be considered if their use may form a pool of product in the mouth, which then may be aspirated. If the mist or aerosol from a pressurized container is fine, a pool may not be formed. On the other hand, if a pressurized container dispenses product in a stream, a pool may be formed that may then be aspirated. Usually, the mist produced by trigger and pump sprayers is coarse and therefore, a pool may be formed that then may be aspirated. When the pump mechanism may be removed and contents are available to be swallowed then the classification of the products should be considered.
A.10.2   Classification Criteria for Substances
    Table A.10.1 -- Criteria for Aspiration Toxicity
Category
Criteria
Category 1: Chemicals known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard
A substance shall be classified in Category 1:
(a) If reliable and good quality human evidence indicates that it causes aspiration toxicity (See note); or
(b) If it is a hydrocarbon and has a kinematic viscosity <=20.5 mm[2]/s, measured at 40 °C.
    Note: Examples of substances included in Category 1 are certain hydrocarbons, turpentine and pine oil.
A.10.3   Classification Criteria for Mixtures
A.10.3.1   Classification When Data Are Available for the Complete Mixture
    A mixture shall be classified in Category 1 based on reliable and good quality human evidence.
A.10.3.2   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its aspiration toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazard of the mixture, these data shall be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution; Batching; Concentration of mixtures; Interpolation within one toxicity category; and Substantially similar mixtures. For application of the dilution bridging principle, the concentration of aspiration toxicants shall not be less than 10%.
A.10.3.3   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   A mixture which contains >=10% of an ingredient or ingredients classified in Category 1, and has a kinematic viscosity <=20.5 mm2/s, measured at 40 °C, shall be classified in Category 1.
    A.<IP_ADDRESS>   In the case of a mixture which separates into two or more distinct layers, one of which contains >=10% of an ingredient or ingredients classified in Category 1 and has a kinematic viscosity <=20.5 mm2/s, measured at 40 °C, then the entire mixture shall be classified in Category 1.
Appendix B to §1910.1200 -- Physical Criteria (Mandatory)
B.1   EXPLOSIVES
B.1.1   Definitions and General Considerations
    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) above which are manufactured with the view to producing a practical explosive or pyrotechnic effect.
B.1.2   Classification Criteria
    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 contain only extremely insensitive detonating chemicals and which demonstrate a negligible probability of accidental initiation or propagation.
B.1.3   Additional Classification Considerations
    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 the 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) or an oxidizing solid (See B.14) is determined by Test Series 8 tests.
    Note: Classification of solid chemicals shall be based on tests performed on the chemical as presented. If, for example, for the purposes of supply or transport, the same chemical is to be presented in a physical form different from that which was tested and which is considered likely to materially alter its performance in a classification test, classification must be based on testing of the chemical in the new form.
    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.
    Note: Neither a Series 1 type (a) propagation of detonation test nor a Series 2 type (a) test of sensitivity to detonative shock is necessary if the exothermic decomposition energy of organic materials is less than 800 J/g.
    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:
  CXHyOz + [x + (y/4) − (z/2)] O2 --> x. CO2 + (y/2) H2O
using the formula:
  oxygen balance = −1600 [2x + (y/2) −z]/molecular weight;
    or
    (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.
B.2   FLAMMABLE GASES
B.2.1   Definition
    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).
B.2.2   Classification Criteria
    A flammable gas shall be classified in one of the two categories for this class in accordance with Table B.2.1:
    Table B.2.1 -- Criteria for Flammable Gases
Category
Criteria
1
Gases, which at 20 °C (68 °F) and a standard pressure of 101.3 kPa (14.7 psi):

      (a) are ignitable when in a mixture of 13% or less by volume in air; or

      (b) have a flammable range with air of at least 12 percentage points regardless of the lower flammable limit.
2
Gases, other than those of Category 1, which, at 20 °C (68 °F) and a standard pressure of 101.3 kPa (14.7 psi), have a flammable range while mixed in air.
    Note: Aerosols should not be classified as flammable gases. See B.3.
B.2.3   Additional Classification Considerations
    Flammability shall be determined by tests or by calculation in accordance with ISO 10156 (incorporated by reference; See §1910.6). Where insufficient data are available to use this method, equivalent validated methods may be used.
B.3   FLAMMABLE AEROSOLS
B.3.1   Definition
    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.3.2   Classification Criteria
    B.3.2.1   Aerosols shall be considered for classification as flammable if they contain any component which is classified as flammable in accordance with this Appendix, i.e.:
Flammable liquids (See B.6);
Flammable gases (See B.2);
Flammable solids (See B.7).
    Note 1: Flammable components do not include pyrophoric, self-heating or water-reactive chemicals.
    Note 2: Flammable aerosols do not fall additionally within the scope of flammable gases, flammable liquids, or flammable solids.
    B.3.2.2   A flammable aerosol shall be classified in one of the two categories for this class in accordance with Table B.3.1.
    Table B.3.1 -- Criteria for Flammable Aerosols
Category
Criteria
1
Contains >=85% flammable components and the chemical heat of combustion is >=30 kJ/g; or
(a) For spray aerosols, in the ignition distance test, ignition occurs at a distance >=75 cm (29.5 in), or
(b) For foam aerosols, in the aerosol foam flammability test
(i) The flame height is >=20 cm (7.87 in) and the flame duration >=2 s; or
(ii) The flame height is >=4 cm (1.57 in) and the flame duration >=7 s
2
Contains >1% flammable components, or the heat of combustion is >=20 kJ/g; and
(a) for spray aerosols, in the ignition distance test, ignition occurs at a distance >=15 cm (5.9 in), or
in the enclosed space ignition test, the
(i) Time equivalent is <=300 s/m[3]; or
(ii) Deflagration density is <=300 g/m[3]
(b) For foam aerosols, in the aerosol foam flammability test, the flame height is >=4 cm and the flame duration is >=2 s
and it does not meet the criteria for Category 1
    Note: Aerosols not submitted to the flammability classification procedures in this Appendix shall be classified as extremely flammable (Category 1).
B.3.3   Additional Classification Considerations
    B.3.3.1   To classify a flammable 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 aerosol formulation, the chemical heat of combustion is the summation of the weighted heats of combustion for the individual components, as follows:

    View or download PDF
Where:
  ΔHc = chemical heat of combustion (kJ/g);
  wi% = mass fraction of component i in the product;
  ΔHc(i) = specific heat of combustion (kJ/g) of component i in the product;
    The chemical heats of combustion shall be found in literature, calculated or determined by tests (See ASTM D240-02, ISO 13943, Sections 86.1 to 86.3, and NFPA 30B (incorporated by reference; See §1910.6)).
    B.3.3.3   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 the of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6).
B.4   OXIDIZING GASES
B.4.1   Definition
    Oxidizing gas means any gas which may, generally by providing oxygen, cause or contribute to the combustion of other material more than air does.
    Note: "Gases which cause or contribute to the combustion of other material more than air does" means pure gases or gas mixtures with an oxidizing power greater than 23.5% (as determined by a method specified in ISO 10156 or 10156-2 (incorporated by reference, See §1910.6) or an equivalent testing method.)
B.4.2   Classification Criteria
    An oxidizing gas shall be classified in a single category for this class in accordance with Table B.4.1:
    Table B.4.1 -- Criteria for Oxidizing Gases
Category
Criteria
1
Any gas which may, generally by providing oxygen, cause or contribute to the combustion of other material more than air does.
B.4.3   Additional Classification Considerations
    Classification shall be in accordance with tests or calculation methods as described in ISO 10156 (incorporated by reference; See §1910.6) and ISO 10156-2 (incorporated by reference; See §1910.6).
B.5   GASES UNDER PRESSURE
B.5.1   Definition
    Gases under pressure are gases which are contained in a receptacle at a pressure of 200 kPa (29 psi) (gauge) or more, or which are liquefied or liquefied and refrigerated.
    They comprise compressed gases, liquefied gases, dissolved gases and refrigerated liquefied gases.
B.5.2   Classification Criteria
    Gases under pressure shall be classified in one of four groups in accordance with Table B.5.1:
    Table B.5.1 -- Criteria for Gases Under Pressure
Group
Criteria
Compressed gas
A gas which when under pressure is entirely gaseous at −50 °C (−8 °F), including all gases with a critical temperature[1] <=−50 °C (−58 °F).
Liquefied gas
A gas which when under pressure is partially liquid at temperatures above −50 °C (−58 °F). A distinction is made between:

(a) High pressure liquefied gas: A gas with a critical temperature[1] between −50 °C (−58 °F) and + 65 °C (149 °F); and

(b) Low pressure liquefied gas: A gas with a critical temperature[1] above + 65 °C (149 °F).
Refrigerated liquefied gas
A gas which is made partially liquid because of its low temperature.
Dissolved gas
A gas which when under pressure is dissolved in a liquid phase solvent.
    1The critical temperature is the temperature above which a pure gas cannot be liquefied, regardless of the degree of compression.
B.6   FLAMMABLE LIQUIDS
B.6.1   Definition
    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.
B.6.2   Classification Criteria
    A flammable liquid shall be classified in one of four categories in accordance with Table B.6.1:
    Table B.6.1 -- Criteria for Flammable Liquids
Category
Criteria
1
Flash point <23 °C (73.4 °F) and initial boiling point <=35 °C (95 °F).
2
Flash point <23 °C (73.4 °F) and initial boiling point >35 °C (95 °F).
3
Flash point >=23 °C (73.4 °F) and <=60 °C (140 °F).
4
Flash point >60 °C (140 °F) and <=93 °C (199.4 °F).
B.6.3   Additional Classification Considerations
    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 other method specified in GHS Revision 3, 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).
B.7   FLAMMABLE SOLIDS
B.7.1   Definitions
    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   Classification Criteria
    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 the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), Part III, sub-section 33.2.1, 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 the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.7.1:
    Table B.7.1 -- Criteria for Flammable Solids
Category
Criteria
1
Burning rate test:

Chemicals other than metal powders:

(a) Wetted zone does not stop fire; and

(b) Burning time <45 s or burning rate >2.2 mm/s.

Metal powders: Burning time <=5 min.
2
Burning rate test:

Chemicals other than metal powders:

(a) Wetted zone stops the fire for at least 4 min; and

(b) Burning time <45 s or burning rate >2.2 mm/s.

Metal powders: Burning time >5 min and <=10 min.
    Note: Classification of solid chemicals shall be based on tests performed on the chemical as presented. If, for example, for the purposes of supply or transport, the same chemical is to be presented in a physical form different from that which was tested and which is considered likely to materially alter its performance in a classification test, classification must be based on testing of the chemical in the new form.
B.8   SELF-REACTIVE CHEMICALS
B.8.1   Definitions
    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   Classification Criteria
    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   Additional Classification Considerations
    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 the 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 the UN ST/SG/AC.10, Part II, section 28 (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 the 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 <IP_ADDRESS> in Part II of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6)).
B.9   PYROPHORIC LIQUIDS
B.9.1   Definition
    Pyrophoric liquid means a liquid which, even in small quantities, is liable to ignite within five minutes after coming into contact with air.
B.9.2   Classification Criteria
    A pyrophoric liquid shall be classified in a single category for this class using test N.3 in Part III, sub-section <IP_ADDRESS> of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.9.1:
    Table B.9.1 -- Criteria for Pyrophoric Liquids
Category
Criteria
1
The liquid ignites within 5 min when added to an inert carrier and exposed to air, or it ignites or chars a filter paper on contact with air within 5 min.
B.9.3   Additional Classification Considerations
    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)).
B.10   PYROPHORIC SOLIDS
B.10.1   Definition
    Pyrophoric solid means a solid which, even in small quantities, is liable to ignite within five minutes after coming into contact with air.
B.10.2   Classification Criteria
    A pyrophoric solid shall be classified in a single category for this class using test N.2 in Part III, sub-section <IP_ADDRESS> of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.10.1:
    Table B.10.1 -- Criteria for Pyrophoric Solids
Category
Criteria
1
The solid ignites within 5 min of coming into contact with air.
    Note: Classification of solid chemicals shall be based on tests performed on the chemical as presented. If, for example, for the purposes of supply or transport, the same chemical is to be presented in a physical form different from that which was tested and which is considered likely to materially alter its performance in a classification test, classification must be based on testing of the chemical in the new form.
B.10.3   Additional Classification Considerations
    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)).
B.11   SELF-HEATING CHEMICALS
B.11.1   Definition
    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).
    Note: Self-heating of a substance or mixture is a process where the gradual reaction of that substance or mixture with oxygen (in air) generates heat. If the rate of heat production exceeds the rate of heat loss, then the temperature of the substance or mixture will rise which, after an induction time, may lead to self-ignition and combustion.
B.11.2   Classification Criteria
    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 <IP_ADDRESS> of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), the result meets the criteria shown in Table B.11.1.
    Table B.11.1 -- Criteria for Self-Heating Chemicals
Category
Criteria
1
A positive result is obtained in a test using a 25 mm sample cube at 140 °C (284 °F).
2
A negative result is obtained in a test using a 25 mm cube sample at 140 °C (284 °F), a positive result is obtained in a test using a 100 mm sample cube at 140 °C (284 °F), and:

(a) The unit volume of the chemical is more than 3 m[3]; or

(b) A positive result is obtained in a test using a 100 mm cube sample at 120 °C (248 °F) and the unit volume of the chemical is more than 450 liters; or

(c) A positive result is obtained in a test using a 100 mm cube sample at 100 °C (212 °F).
    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   Additional Classification Considerations
    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.
B.12   CHEMICALS WHICH, IN CONTACT WITH WATER, EMIT FLAMMABLE GASES
B.12.1   Definition
    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   Classification Criteria
    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 <IP_ADDRESS> of the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.12.1:
    Table B.12.1 -- Criteria for Chemicals Which, in Contact With Water, Emit Flammable Gases
Category
Criteria
1
Any chemical which reacts vigorously with water at ambient temperatures and demonstrates generally a tendency for the gas produced to ignite spontaneously, or which reacts readily with water at ambient temperatures such that the rate of evolution of flammable gas is equal to or greater than 10 liters per kilogram of chemical over any one minute.
2
Any chemical which reacts readily with water at ambient temperatures such that the maximum rate of evolution of flammable gas is equal to or greater than 20 liters per kilogram of chemical per hour, and which does not meet the criteria for Category 1.
3
Any chemical which reacts slowly with water at ambient temperatures such that the maximum rate of evolution of flammable gas is equal to or greater than 1 liter per kilogram of chemical per hour, and which does not meet the criteria for Categories 1 and 2.
    Note: Classification of solid chemicals shall be based on tests performed on the chemical as presented. If, for example, for the purposes of supply or transport, the same chemical is to be presented in a physical form different from that which was tested and which is considered likely to materially alter its performance in a classification test, classification must be based on testing of the chemical in the new form.
    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.
B.12.3   Additional Classification Considerations
    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.
B.13   OXIDIZING LIQUIDS
B.13.1   Definition
    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.
B.13.2   Classification Criteria
    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 the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.13.1:
    Table B.13.1 -- Criteria for Oxidizing Liquids
Category
Criteria
1
Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, spontaneously ignites; or the mean pressure rise time of a 1:1 mixture, by mass, of chemical and cellulose is less than that of a 1:1 mixture, by mass, of 50% perchloric acid and cellulose;
2
Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, exhibits a mean pressure rise time less than or equal to the mean pressure rise time of a 1:1 mixture, by mass, of 40% aqueous sodium chlorate solution and cellulose; and the criteria for Category 1 are not met;
3
Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, exhibits a mean pressure rise time less than or equal to the mean pressure rise time of a 1:1 mixture, by mass, of 65% aqueous nitric acid and cellulose; and the criteria for Categories 1 and 2 are not met.
B.13.3   Additional Classification Considerations
    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 the 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.
B.14   OXIDIZING SOLIDS
B.14.1   Definition
    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.
B.14.2   Classification Criteria
    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 the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.14.1:
    Table B.14.1 -- Criteria for Oxidizing Solids
Category
Criteria
1
Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time less than the mean burning time of a 3:2 mixture, by mass, of potassium bromate and cellulose.
2
Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time equal to or less than the mean burning time of a 2:3 mixture (by mass) of potassium bromate and cellulose and the criteria for Category 1 are not met.
3
Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time equal to or less than the mean burning time of a 3:7 mixture (by mass) of potassium bromate and cellulose and the criteria for Categories 1 and 2 are not met.
    Note 1: Some oxidizing solids may present explosion hazards under certain conditions (e.g., when stored in large quantities). For example, some types of ammonium nitrate may give rise to an explosion hazard under extreme conditions and the "Resistance to detonation test" (IMO: Code of Safe Practice for Solid Bulk Cargoes, 2005, Annex 3, Test 5) may be used to assess this hazard. When information indicates that an oxidizing solid may present an explosion hazard, it shall be indicated on the Safety Data Sheet.
    Note 2: Classification of solid chemicals shall be based on tests performed on the chemical as presented. If, for example, for the purposes of supply or transport, the same chemical is to be presented in a physical form different from that which was tested and which is considered likely to materially alter its performance in a classification test, classification must be based on testing of the chemical in the new form.
B.14.3   Additional Classification Considerations
    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 precedence over test results.
B.15   ORGANIC PEROXIDES
B.15.1   Definition
    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   Classification Criteria
    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.
    Note: The available oxygen content (%) of an organic peroxide mixture is given by the formula:

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Where:
  ni = number of peroxygen groups per molecule of organic peroxide i;
  ci = concentration (mass %) of organic peroxide i;
  mi = molecular mass of organic peroxide i.
    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   Additional Classification Considerations
    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 the 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 the 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.
B.16   CORROSIVE TO METALS
B.16.1   Definition
    A chemical which is corrosive to metals means a chemical which by chemical action will materially damage, or even destroy, metals.
B.16.2   Classification Criteria
    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 the UN ST/SG/AC.10 (incorporated by reference; See §1910.6), in accordance with Table B.16.1:
    Table B.16.1 -- Criteria for Chemicals Corrosive to Metal
Category
Criteria
1
Corrosion rate on either steel or aluminium surfaces exceeding 6.25 mm per year at a test temperature of 55 °C (131 °F) when tested on both materials.
    Note: Where an initial test on either steel or aluminium indicates the chemical being tested is corrosive, the follow-up test on the other metal is not necessary.
B.16.3   Additional Classification Considerations
    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.
Appendix C to §1910.1200 -- Allocation of Label Elements (Mandatory)
    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   Precedence of Hazard Information
    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   Hazard Statement Text
    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   Pictograms
    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.

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C.2.4   Precautionary Statement Text
    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   In most cases, the precautionary statements are independent (e.g., the phrases for explosive 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). An order of precedence may be imposed by the chemical manufacturer, importer or responsible party in situations where phrases concern "Response." Rapid action may be crucial. For example, if a chemical is carcinogenic and acutely toxic, rapid action may be crucial, and first aid measures for acute toxicity will take precedence over those for long-term effects. In addition, medical attention to delayed health effects may be required in cases of incidental exposure, even if not associated with immediate symptoms of intoxication.
    C.2.4.8   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.3   Supplementary Hazard Information
    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 is required on the label.

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Appendix D to §1910.1200 -- Safety Data Sheets (Mandatory)
    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. 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.
    Table D.1 -- Minimum Information for an SDS
Heading
Subheading
1. Identification
(a) Product identifier used on the label;
(b) Other means of identification;
(c) Recommended use of the chemical and restrictions on use;
(d) Name, address, and telephone number of the chemical manufacturer, importer, or other responsible party;
(e) Emergency phone number.
2. Hazard(s) identification
(a) Classification of the chemical in accordance with paragraph (d) of §1910.1200;
(b) Signal word, hazard statement(s), symbol(s) and precautionary statement(s) in accordance with paragraph (f) of §1910.1200. (Hazard symbols may be provided as graphical reproductions in black and white or the name of the symbol, e.g., flame, skull and crossbones);
(c) Describe any hazards not otherwise classified that have been identified during the classification process;
(d) Where an ingredient with unknown acute toxicity is used in a mixture at a concentration >=1% and the mixture is not classified based on testing of the mixture as a whole, a statement that X% of the mixture consists of ingredient(s) of unknown acute toxicity is required.
3. Composition/information on ingredients
Except as provided for in paragraph (i) of §1910.1200 on trade secrets:

For Substances

(a) Chemical name;

(b) Common name and synonyms;

(c) CAS number and other unique identifiers;

(d) Impurities and stabilizing additives which are themselves classified and which contribute to the classification of the substance.

For Mixtures

In addition to the information required for substances:

(a) The chemical name and concentration (exact percentage) or concentration ranges of all ingredients which are classified as health hazards in accordance with paragraph (d) of §1910.1200 and

(1) Are present above their cut-off/concentration limits; or

(2) Present a health risk below the cut-off/concentration limits.

(b) The concentration (exact percentage) shall be specified unless a trade secret claim is made in accordance with paragraph (i) of §1910.1200, when there is batch-to-batch variability in the production of a mixture, or for a group of substantially similar mixtures (See A.<IP_ADDRESS>) with similar chemical composition. In these cases, concentration ranges may be used.

For All Chemicals Where a Trade Secret is Claimed

Where a trade secret is claimed in accordance with paragraph (i) of §1910.1200, a statement that the specific chemical identity and/or exact percentage (concentration) of composition has been withheld as a trade secret is required.
4. First-aid measures
(a) Description of necessary measures, subdivided according to the different routes of exposure, i.e., inhalation, skin and eye contact, and ingestion;
(b) Most important symptoms/effects, acute and delayed.
(c) Indication of immediate medical attention and special treatment needed, if necessary.
5. Fire-fighting measures
(a) Suitable (and unsuitable) extinguishing media.
(b) Specific hazards arising from the chemical (e.g., nature of any hazardous combustion products).
(c) Special protective equipment and precautions for fire-fighters.
6. Accidental release measures
(a) Personal precautions, protective equipment, and emergency procedures.
(b) Methods and materials for containment and cleaning up.
7. Handling and storage
(a) Precautions for safe handling.
(b) Conditions for safe storage, including any incompatibilities.
8. Exposure controls/personal protection
(a) OSHA permissible exposure limit (PEL), American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV), and any other exposure limit used or recommended by the chemical manufacturer, importer, or employer preparing the safety data sheet, where available.
(b) Appropriate engineering controls.
(c) Individual protection measures, such as personal protective equipment.
9. Physical and chemical properties
(a) Appearance (physical state, color, etc.);

(b) Odor;

(c) Odor threshold;

(d) pH;

(e) Melting point/freezing point;

(f) Initial boiling point and boiling range;

(g) Flash point;

(h) Evaporation rate;

(i) Flammability (solid, gas);

(j) Upper/lower flammability or explosive limits;

(k) Vapor pressure;

(l) Vapor density;

(m) Relative density;

(n) Solubility(ies);

(o) Partition coefficient: n-octanol/water;

(p) Auto-ignition temperature;

(q) Decomposition temperature;

(r) Viscosity.
10. Stability and reactivity
(a) Reactivity;

(b) Chemical stability;

(c) Possibility of hazardous reactions;

(d) Conditions to avoid (e.g., static discharge, shock, or vibration);

(e) Incompatible materials;

(f) Hazardous decomposition products.
11. Toxicological information
Description of the various toxicological (health) effects and the available data used to identify those effects, including:

(a) Information on the likely routes of exposure (inhalation, ingestion, skin and eye contact);

(b) Symptoms related to the physical, chemical and toxicological characteristics;

(c) Delayed and immediate effects and also chronic effects from short- and long-term exposure;

(d) Numerical measures of toxicity (such as acute toxicity estimates).

(e) Whether the hazardous chemical is listed in the National Toxicology Program (NTP) Report on Carcinogens (latest edition) or has been found to be a potential carcinogen in the International Agency for Research on Cancer (IARC) Monographs (latest edition), or by OSHA.
12. Ecological information (Non-mandatory)
(a) Ecotoxicity (aquatic and terrestrial, where available);
(b) Persistence and degradability;
(c) Bioaccumulative potential;
(d) Mobility in soil;
(e) Other adverse effects (such as hazardous to the ozone layer).
13. Disposal considerations (Non-mandatory)
Description of waste residues and information on their safe handling and methods of disposal, including the disposal of any contaminated packaging.
14. Transport information (Non-mandatory)
(a) UN number;

(b) UN proper shipping name;

(c) Transport hazard class(es);

(d) Packing group, if applicable;

(e) Environmental hazards (e.g., Marine pollutant (Yes/No));

(f) Transport in bulk (according to Annex II of MARPOL 73/78 and the IBC Code);

(g) Special precautions which a user needs to be aware of, or needs to comply with, in connection with transport or conveyance either within or outside their premises.
15. Regulatory information (Non-mandatory)
Safety, health and environmental regulations specific for the product in question.
16. Other information, including date of preparation or last revision
The date of preparation of the SDS or the last change to it.
Appendix E to §1910.1200 -- Definition of "Trade Secret" (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.
Appendix F to §1910.1200 -- Guidance for Hazard Classifications Re: Carcinogenicity (Non-Mandatory)
    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.
Part A: Background Guidance1
    1The text of Appendix F, Part A, on the IARC Monographs, is paraphrased from the 2006 Preamble to the "Monographs on the Evaluation of Carcinogenic Risks to Humans"; the Classifier is referred to the full IARC Preamble for the complete text. The text is not part of the agreed GHS text on the harmonized system developed by the OECD Task Force-HCL.
    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.
Guidance on How To Consider Important Factors in Classification of Carcinogenicity (See Reference Section)
    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.
Mode of Action
    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.
Responses in Multiple Animal Experiments
    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.<IP_ADDRESS> 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.
Responses Are in One Sex or Both Sexes
    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.
Confounding Effects of Excessive Toxicity or Localized Effects
    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.
Tumor Type, Reduced Tumor Latency
    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° 1472). Even when a particular tumor type may be discounted, expert judgment must be used in assessing the total tumor profile in any animal experiment.
    2While most international agencies do not consider kidney tumors coincident with α2u-globulin nephropathy to be a predictor of risk in humans, this view is not universally held. (See: Doi et al., 2007).
Part B: International Agency for Research on Cancer (IARC)3
    3Preamble of the International Agency for Research on Cancer (IARC) "Monographs on the Evaluation of Carcinogenic Risks to Humans" (2006).
    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: