Health Hazard Criteria (Mandatory)

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

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

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

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

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

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

(a) the new diluted mixture shall be classified as equivalent to the original tested mixture; or

(b) for classification of acute toxicity in accordance with A.1 of this Appendix, paragraph A.1.3.6 (the additivity formula) shall be applied.

(a) Where there are two mixtures: (i) A + B;
(ii) C + B;

(b) the concentration of ingredient B is essentially the same in both mixtures;

(c) the concentration of ingredient A in mixture (i) equals that of ingredient C in mixture (ii);

(d) and data on toxicity for A and C are available and substantially equivalent; i.e., they are in the same hazard category and are not expected to affect the toxicity of B; then

(a) The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD₅₀/LC₅₀ where available;

(b) The acute toxicity estimate (ATE) for the classification of a substance or ingredient in a mixture is derived using:

(i) the LD₅₀/LC₅₀ where available. Otherwise,

(ii) the appropriate conversion value from Table 1.2 that relates to the results of a range test, or

(iii) the appropriate conversion value from Table 1.2 that relates to a classification category;

(c) Inhalation cut-off values in the table are based on 4 hour testing exposures. Conversion of existing inhalation toxicity data which has been generated according to 1 hour exposure is achieved by dividing by a factor of 2 for gases and vapors and 4 for dusts and mists;

(d) For some substances the test atmosphere will be a vapor which consists of a combination of liquid and gaseous phases. For other substances the test atmosphere may consist of a vapor which is nearly all the gaseous phase. In these latter cases, classification is based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2500 ppmV), Category 4 (20000 ppmV).

The terms "dust", "mist" and "vapor" are defined as follows:

(i) Dust: solid particles of a substance or mixture suspended in a gas (usually air);

(ii) Mist: liquid droplets of a substance or mixture suspended in a gas (usually air);

(iii) Vapor: the gaseous form of a substance or mixture released from its liquid or solid state.

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

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

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

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

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

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

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

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

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

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

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

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

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

1. Evidence of existing human or animal data may be derived from single or repeated exposure(s) in occupational, consumer, transportation, or emergency response scenarios; from ethically-conducted human clinical studies; or from purposely-generated data from animal studies conducted according to scientifically validated test methods (at present, there is no internationally accepted test method for human skin irritation testing).
   
2. Classify in the appropriate harmonized category, as shown in Tables A.2.1 and A.2.2.
   
3. Pre-existing animal data (e.g. from an acute dermal toxicity test or a sensitisation test) should be carefully reviewed to determine if sufficient skin corrosion/irritation evidence is available through other, similar information. For example, classification/categorization may be done on the basis of whether a chemical has or has not produced any skin irritation in an acute dermal toxicity test in animals at the limit dose, or produces very toxic effects in an acute dermal toxicity test in animals. In the latter case, the chemical would be classified as being very hazardous by the dermal route for acute toxicity, and it would be moot whether the chemical is also irritating or corrosive on the skin. It should be kept in mind in evaluating acute dermal toxicity information that the reporting of dermal lesions may be incomplete, testing and observations may be made on a species other than the rabbit, and species may differ in sensitivity in their responses.
   
4. Evidence from studies using scientifically validated protocols with isolated human/animal tissues or other, non-tissue-based, though scientifically validated, protocols should be assessed. Examples of scientifically validated test methods for skin corrosion include OECD TG 430 (Transcutaneous Electrical Resistance Test (TER)), 431 (Human Skin Model Test), and 435 (Membrane Barrier Test Method). OECD TG 439 (Reconstructed Human Epidermis Test Method) is a scientifically validated in vitro test method for skin irritation.
   
5. Measurement of pH alone may be adequate, but assessment of acid or alkali reserve (buffering capacity) would be preferable. Presently, there is no scientifically validated and internationally accepted method for assessing this parameter.
   
6. All information that is available on a chemical should be considered and an overall determination made on the total weight of evidence. This is especially true when there is conflict in information available on some parameters. Professional judgment should be exercised in making such a determination.
   

(a) Respiratory sensitization; and

(b) Skin sensitization

(a) the size of the population exposed;

(b) the extent of exposure.

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

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

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

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

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

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

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

(b) specific pulmonary responses in guinea pigs.

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

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

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

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

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

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

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

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

(c) Positive data from appropriate animal studies;

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

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

(f) Severity of reaction.

(a) Isolated episodes of allergic contact dermatitis;

(b) Epidemiological studies of limited power, e.g., where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) Data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in A.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) Positive data from non-standard methods;

(e) Positive results from close structural analogues.

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

(b) Mouse heritable translocation assay (OECD 485)

(c) Mouse specific locus test

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

(b) Mouse spot test (OECD 484)

(c) Mammalian erythrocyte micronucleus test (OECD 474)

(a) Mutagenicity tests:

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

(ii) Spermatid micronucleus assay

(b) Genotoxicity tests:

(i) Sister chromatid exchange analysis in spermatogonia

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

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

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

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

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

(c) Bacterial reverse mutation tests (OECD 471)

(a) Tumor type and background incidence;

(b) Multisite responses;

(c) Progression of lesions to malignancy;

(d) Reduced tumor latency;

Additional factors which may increase or decrease the level of concern include:

(e) Whether responses are in single or both sexes;

(f) Whether responses are in a single species or several species;

(g) Structural similarity or not to a substance(s) for which there is good evidence of carcinogenicity;

(h) Routes of exposure;

(i) Comparison of absorption, distribution, metabolism and excretion between test animals and humans;

(j) The possibility of a confounding effect of excessive toxicity at test doses; and,

(k) Mode of action and its relevance for humans, such as mutagenicity, cytotoxicity with growth stimulation, mitogenesis, immunosuppression.

(a) Maternal mortality: An increased incidence of mortality among the treated dams over the controls shall be considered evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the systemic toxicity of the test material. Maternal mortality greater than 10% is considered excessive and the data for that dose level shall not normally be considered to need further evaluation.

(b) Mating index (Number of animals with seminal plugs or sperm/Number of mated x 100)

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

(d) Gestation length (If allowed to deliver)

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

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

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

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

(a) Morbidity resulting from single exposure;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[77 FR 17790, March 26, 2012; 78 FR 9313, Feb. 8, 2013]