(ii) Product identifier and words, pictures, symbols, or combination thereof, which provide at least general information regarding the hazards of the chemicals, and which, in conjunction with the other information immediately available to employees under the hazard communication program, will provide employees with the specific information regarding the physical and health hazards of the hazardous chemical.
    (7) The employer may use signs, placards, process sheets, batch tickets, operating procedures, or other such written materials in lieu of affixing labels to individual stationary process containers, as long as the alternative method identifies the containers to which it is applicable and conveys the information required by paragraph (f)(6) of this section to be on a label. The employer shall ensure the written materials are readily accessible to the employees in their work area throughout each work shift.
    (8) The employer is not required to label portable containers into which hazardous chemicals are transferred from labeled containers, and which are intended only for the immediate use of the employee who performs the transfer. For purposes of this section, drugs which are dispensed by a pharmacy to a health care provider for direct administration to a patient are exempted from labeling.
    (9) The employer shall not remove or deface existing labels on incoming containers of hazardous chemicals, unless the container is immediately marked with the required information.
    (10) The employer shall ensure that workplace labels or other forms of warning are legible, in English, and prominently displayed on the container, or readily available in the work area throughout each work shift. Employers having employees who speak other languages may add the information in their language to the material presented, as long as the information is presented in English as well.
    (11) Chemical manufacturers, importers, distributors, or employers who become newly aware of any significant information regarding the hazards of a chemical shall revise the labels for the chemical within six months of becoming aware of the new information, and shall ensure that labels on containers of hazardous chemicals shipped after that time contain the new information. If the chemical is not currently produced or imported, the chemical manufacturer, importer, distributor, or employer shall add the information to the label before the chemical is shipped or introduced into the workplace again.
    (g) Safety data sheets. (1) Chemical manufacturers and importers shall obtain or develop a safety data sheet for each hazardous chemical they produce or import. Employers shall have a safety data sheet in the workplace for each hazardous chemical which they use.
    (2) The chemical manufacturer or importer preparing the safety data sheet shall ensure that it is in English (although the employer may maintain copies in other languages as well), and includes at least the following section numbers and headings, and associated information under each heading, in the order listed (See Appendix D to §1910.1200 -- Safety Data Sheets, for the specific content of each section of the safety data sheet):
    (i) Section 1, Identification;
    (ii) Section 2, Hazard(s) identification;
    (iii) Section 3, Composition/information on ingredients;
    (iv) Section 4, First-aid measures;
    (v) Section 5, Fire-fighting measures;
    (vi) Section 6, Accidental release measures;
    (vii) Section 7, Handling and storage;
    (viii) Section 8, Exposure controls/personal protection;
    (ix) Section 9, Physical and chemical properties;
    (x) Section 10, Stability and reactivity;
    (xi) Section 11, Toxicological information;
    (xii) Section 12, Ecological information;
    (xiii) Section 13, Disposal considerations;
    (xiv) Section 14, Transport information;
    (xv) Section 15, Regulatory information; and
    (xvi) Section 16, Other information, including date of preparation or last revision.
    Note 1 to paragraph (g)(2): To be consistent with the GHS, an SDS must also include the headings in paragraphs (g)(2)(xii) through (g)(2)(xv) in order.
    Note 2 to paragraph (g)(2): OSHA will not be enforcing information requirements in sections 12 through 15, as these areas are not under its jurisdiction.
    (3) If no relevant information is found for any sub-heading within a section on the safety data sheet, the chemical manufacturer, importer or employer preparing the safety data sheet shall mark it to indicate that no applicable information was found.
    (4) Where complex mixtures have similar hazards and contents (i.e., the chemical ingredients are essentially the same, but the specific composition varies from mixture to mixture), the chemical manufacturer, importer or employer may prepare one safety data sheet to apply to all of these similar mixtures.
    (5) The chemical manufacturer, importer or employer preparing the safety data sheet shall ensure that the information provided accurately reflects the scientific evidence used in making the hazard classification. If the chemical manufacturer, importer or employer preparing the safety data sheet becomes newly aware of any significant information regarding the hazards of a chemical, or ways to protect against the hazards, this new information shall be added to the safety data sheet within three months. If the chemical is not currently being produced or imported, the chemical manufacturer or importer shall add the information to the safety data sheet before the chemical is introduced into the workplace again.
    (6)(i) Chemical manufacturers or importers shall ensure that distributors and employers are provided an appropriate safety data sheet with their initial shipment, and with the first shipment after a safety data sheet is updated;
    (ii) The chemical manufacturer or importer shall either provide safety data sheets with the shipped containers or send them to the distributor or employer prior to or at the time of the shipment;
    (iii) If the safety data sheet is not provided with a shipment that has been labeled as a hazardous chemical, the distributor or employer shall obtain one from the chemical manufacturer or importer as soon as possible; and,
    (iv) The chemical manufacturer or importer shall also provide distributors or employers with a safety data sheet upon request.
    (7)(i) Distributors shall ensure that material data sheets, and updated information, are provided to other distributors and employers with their initial shipment and with the first shipment after a safety data sheet is updated;
    (ii) The distributor shall either provide safety data sheets with the shipped containers, or send them to the other distributor or employer prior to or at the time of the shipment;
    (iii) Retail distributors selling hazardous chemicals to employers having a commercial account shall provide a safety data sheet to such employers upon request, and shall post a sign or otherwise inform them that a material safety data sheet is available;
    (iv) Wholesale distributors selling hazardous chemicals to employers over-the-counter may also provide safety data sheets upon the request of the employer at the time of the over-the-counter purchase, and shall post a sign or otherwise inform such employers that a material safety data sheet is available;
    (v) If an employer without a commercial account purchases a hazardous chemical from a retail distributor not required to have safety data sheets on file (i.e., the retail distributor does not have commercial accounts and does not use the materials), the retail distributor shall provide the employer, upon request, with the name, address, and telephone number of the chemical manufacturer, importer, or distributor from which a safety data sheet can be obtained;
    (vi) Wholesale distributors shall also provide safety data sheets to employers or other distributors upon request; and,
    (vii) Chemical manufacturers, importers, and distributors need not provide safety data sheets to retail distributors that have informed them that the retail distributor does not sell the product to commercial accounts or open the sealed container to use it in their own workplaces.
    (8) The employer shall maintain in the workplace copies of the required safety data sheets for each hazardous chemical, and shall ensure that they are readily accessible during each work shift to employees when they are in their work area(s). (Electronic access and other alternatives to maintaining paper copies of the safety data sheets are permitted as long as no barriers to immediate employee access in each workplace are created by such options.)
    (9) Where employees must travel between workplaces during a workshift, i.e., their work is carried out at more than one geographical location, the safety data sheets may be kept at the primary workplace facility. In this situation, the employer shall ensure that employees can immediately obtain the required information in an emergency.
    (10) Safety data sheets may be kept in any form, including operating procedures, and may be designed to cover groups of hazardous chemicals in a work area where it may be more appropriate to address the hazards of a process rather than individual hazardous chemicals. However, the employer shall ensure that in all cases the required information is provided for each hazardous chemical, and is readily accessible during each work shift to employees when they are in their work area(s).
    (11) Safety data sheets shall also be made readily available, upon request, to designated representatives, the Assistant Secretary, and the Director, in accordance with the requirements of §1910.1020(e).
    (h) Employee information and training. (1) Employers shall provide employees with effective information and training on hazardous chemicals in their work area at the time of their initial assignment, and whenever a new chemical hazard the employees have not previously been trained about is introduced into their work area. Information and training may be designed to cover categories of hazards (e.g., flammability, carcinogenicity) or specific chemicals. Chemical-specific information must always be available through labels and safety data sheets.
    (2) Information. Employees shall be informed of:
    (i) The requirements of this section;
    (ii) Any operations in their work area where hazardous chemicals are present; and,
    (iii) The location and availability of the written hazard communication program, including the required list(s) of hazardous chemicals, and safety data sheets required by this section.
    (3) Training. Employee training shall include at least:
    (i) Methods and observations that may be used to detect the presence or release of a hazardous chemical in the work area (such as monitoring conducted by the employer, continuous monitoring devices, visual appearance or odor of hazardous chemicals when being released, etc.);
    (ii) The physical, health, simple asphyxiation, combustible dust, and pyrophoric gas hazards, as well as hazards not otherwise classified, of the chemicals in the work area;
    (iii) The measures employees can take to protect themselves from these hazards, including specific procedures the employer has implemented to protect employees from exposure to hazardous chemicals, such as appropriate work practices, emergency procedures, and personal protective equipment to be used; and,
    (iv) The details of the hazard communication program developed by the employer, including an explanation of the labels received on shipped containers and the workplace labeling system used by their employer; the safety data sheet, including the order of information and how employees can obtain and use the appropriate hazard information.
    (i) Trade secrets. (1) The chemical manufacturer, importer, or employer may withhold the specific chemical identity, including the chemical name, other specific identification of a hazardous chemical, or the exact percentage (concentration) of the substance in a mixture, from the safety data sheet, provided that:
    (i) The claim that the information withheld is a trade secret can be supported;
    (ii) Information contained in the safety data sheet concerning the properties and effects of the hazardous chemical is disclosed;
    (iii) The safety data sheet indicates that the specific chemical identity and/or percentage of composition is being withheld as a trade secret; and,
    (iv) The specific chemical identity and percentage is made available to health professionals, employees, and designated representatives in accordance with the applicable provisions of this paragraph (i).
    (2) Where a treating physician or nurse determines that a medical emergency exists and the specific chemical identity and/or specific percentage of composition of a hazardous chemical is necessary for emergency or first-aid treatment, the chemical manufacturer, importer, or employer shall immediately disclose the specific chemical identity or percentage composition of a trade secret chemical to that treating physician or nurse, regardless of the existence of a written statement of need or a confidentiality agreement. The chemical manufacturer, importer, or employer may require a written statement of need and confidentiality agreement, in accordance with the provisions of paragraphs (i)(3) and (4) of this section, as soon as circumstances permit.
    (3) In non-emergency situations, a chemical manufacturer, importer, or employer shall, upon request, disclose a specific chemical identity or percentage composition, otherwise permitted to be withheld under paragraph (i)(1) of this section, to a health professional (i.e., physician, industrial hygienist, toxicologist, epidemiologist, or occupational health nurse) providing medical or other occupational health services to exposed employee(s), and to employees or designated representatives, if:
    (i) The request is in writing;
    (ii) The request describes with reasonable detail one or more of the following occupational health needs for the information:
    (A) To assess the hazards of the chemicals to which employees will be exposed;
    (B) To conduct or assess sampling of the workplace atmosphere to determine employee exposure levels;
    (C) To conduct pre-assignment or periodic medical surveillance of exposed employees;
    (D) To provide medical treatment to exposed employees;
    (E) To select or assess appropriate personal protective equipment for exposed employees;
    (F) To design or assess engineering controls or other protective measures for exposed employees; and,
    (G) To conduct studies to determine the health effects of exposure.
    (iii) The request explains in detail why the disclosure of the specific chemical identity or percentage composition is essential and that, in lieu thereof, the disclosure of the following information to the health professional, employee, or designated representative, would not satisfy the purposes described in paragraph (i)(3)(ii) of this section:
    (A) The properties and effects of the chemical;
    (B) Measures for controlling workers' exposure to the chemical;
    (C) Methods of monitoring and analyzing worker exposure to the chemical; and,
    (D) Methods of diagnosing and treating harmful exposures to the chemical;
    (iv) The request includes a description of the procedures to be used to maintain the confidentiality of the disclosed information; and,
    (v) The health professional, and the employer or contractor of the services of the health professional (i.e., downstream employer, labor organization, or individual employee), employee, or designated representative, agree in a written confidentiality agreement that the health professional, employee, or designated representative, will not use the trade secret information for any purpose other than the health need(s) asserted and agree not to release the information under any circumstances other than to OSHA, as provided in paragraph (i)(6) of this section, except as authorized by the terms of the agreement or by the chemical manufacturer, importer, or employer.
    (4) The confidentiality agreement authorized by paragraph (i)(3)(iv) of this section:
    (i) May restrict the use of the information to the health purposes indicated in the written statement of need;
    (ii) May provide for appropriate legal remedies in the event of a breach of the agreement, including stipulation of a reasonable pre-estimate of likely damages; and,
    (iii) May not include requirements for the posting of a penalty bond.
    (5) Nothing in this standard is meant to preclude the parties from pursuing non-contractual remedies to the extent permitted by law.
    (6) If the health professional, employee, or designated representative receiving the trade secret information decides that there is a need to disclose it to OSHA, the chemical manufacturer, importer, or employer who provided the information shall be informed by the health professional, employee, or designated representative prior to, or at the same time as, such disclosure.
    (7) If the chemical manufacturer, importer, or employer denies a written request for disclosure of a specific chemical identity or percentage composition, the denial must:
    (i) Be provided to the health professional, employee, or designated representative, within thirty days of the request;
    (ii) Be in writing;
    (iii) Include evidence to support the claim that the specific chemical identity or percent of composition is a trade secret;
    (iv) State the specific reasons why the request is being denied; and,
    (v) Explain in detail how alternative information may satisfy the specific medical or occupational health need without revealing the trade secret.
    (8) The health professional, employee, or designated representative whose request for information is denied under paragraph (i)(3) of this section may refer the request and the written denial of the request to OSHA for consideration.
    (9) When a health professional, employee, or designated representative refers the denial to OSHA under paragraph (i)(8) of this section, OSHA shall consider the evidence to determine if:
    (i) The chemical manufacturer, importer, or employer has supported the claim that the specific chemical identity or percentage composition is a trade secret;
    (ii) The health professional, employee, or designated representative has supported the claim that there is a medical or occupational health need for the information; and,
    (iii) The health professional, employee or designated representative has demonstrated adequate means to protect the confidentiality.
    (10)(i) If OSHA determines that the specific chemical identity or percentage composition requested under paragraph (i)(3) of this section is not a "bona fide" trade secret, or that it is a trade secret, but the requesting health professional, employee, or designated representative has a legitimate medical or occupational health need for the information, has executed a written confidentiality agreement, and has shown adequate means to protect the confidentiality of the information, the chemical manufacturer, importer, or employer will be subject to citation by OSHA.
    (ii) If a chemical manufacturer, importer, or employer demonstrates to OSHA that the execution of a confidentiality agreement would not provide sufficient protection against the potential harm from the unauthorized disclosure of a trade secret, the Assistant Secretary may issue such orders or impose such additional limitations or conditions upon the disclosure of the requested chemical information as may be appropriate to assure that the occupational health services are provided without an undue risk of harm to the chemical manufacturer, importer, or employer.
    (11) If a citation for a failure to release trade secret information is contested by the chemical manufacturer, importer, or employer, the matter will be adjudicated before the Occupational Safety and Health Review Commission in accordance with the Act's enforcement scheme and the applicable Commission rules of procedure. In accordance with the Commission rules, when a chemical manufacturer, importer, or employer continues to withhold the information during the contest, the Administrative Law Judge may review the citation and supporting documentation "in camera" or issue appropriate orders to protect the confidentiality of such matters.
    (12) Notwithstanding the existence of a trade secret claim, a chemical manufacturer, importer, or employer shall, upon request, disclose to the Assistant Secretary any information which this section requires the chemical manufacturer, importer, or employer to make available. Where there is a trade secret claim, such claim shall be made no later than at the time the information is provided to the Assistant Secretary so that suitable determinations of trade secret status can be made and the necessary protections can be implemented.
    (13) Nothing in this paragraph shall be construed as requiring the disclosure under any circumstances of process information which is a trade secret.
    (j) Effective dates. (1) Employers shall train employees regarding the new label elements and safety data sheets format by December 1, 2013.
    (2) Chemical manufacturers, importers, distributors, and employers shall be in compliance with all modified provisions of this section no later than June 1, 2015, except:
    (i) After December 1, 2015, the distributor shall not ship containers labeled by the chemical manufacturer or importer unless the label has been modified to comply with paragraph (f)(1) of this section.
    (ii) All employers shall, as necessary, update any alternative workplace labeling used under paragraph (f)(6) of this section, update the hazard communication program required by paragraph (h)(1), and provide any additional employee training in accordance with paragraph (h)(3) for newly identified physical or health hazards no later than June 1, 2016.
    (3) Chemical manufacturers, importers, distributors, and employers may comply with either §1910.1200 revised as of October 1, 2011, or the current version of this standard, or both during the transition period.
Appendix A to §1910.1200 -- Health Hazard Criteria (Mandatory)
A.0   GENERAL CLASSIFICATION CONSIDERATIONS
A.0.1   Classification
    A.0.1.1   The term "hazard classification" is used to indicate that only the intrinsic hazardous properties of chemicals are considered. Hazard classification incorporates three steps:
    (a) Identification of relevant data regarding the hazards of a chemical;
    (b) Subsequent review of those data to ascertain the hazards associated with the chemical;
    (c) Determination of whether the chemical will be classified as hazardous and the degree of hazard.
    A.0.1.2   For many hazard classes, the criteria are semi-quantitative or qualitative and expert judgment is required to interpret the data for classification purposes.
A.0.2   Available Data, Test Methods and Test Data Quality
    A.0.2.1   There is no requirement for testing chemicals.
    A.0.2.2   The criteria for determining health hazards are test method neutral, i.e., they do not specify particular test methods, as long as the methods are scientifically validated.
    A.0.2.3   The term "scientifically validated" refers to the process by which the reliability and the relevance of a procedure are established for a particular purpose. Any test that determines hazardous properties, which is conducted according to recognized scientific principles, can be used for purposes of a hazard determination for health hazards. Test conditions need to be standardized so that the results are reproducible with a given substance, and the standardized test yields "valid" data for defining the hazard class of concern.
    A.0.2.4   Existing test data are acceptable for classifying chemicals, although expert judgment also may be needed for classification purposes.
    A.0.2.5   The effect of a chemical on biological systems is influenced, by the physico-chemical properties of the substance and/or ingredients of the mixture and the way in which ingredient substances are biologically available. A chemical need not be classified when it can be shown by conclusive experimental data from scientifically validated test methods that the chemical is not biologically available.
    A.0.2.6   For classification purposes, epidemiological data and experience on the effects of chemicals on humans (e.g., occupational data, data from accident databases) shall be taken into account in the evaluation of human health hazards of a chemical.
A.0.3   Classification Based on Weight of Evidence
    A.0.3.1   For some hazard classes, classification results directly when the data satisfy the criteria. For others, classification of a chemical shall be determined on the basis of the total weight of evidence using expert judgment. This means that all available information bearing on the classification of hazard shall be considered together, including the results of valid in vitro tests, relevant animal data, and human experience such as epidemiological and clinical studies and well-documented case reports and observations.
    A.0.3.2   The quality and consistency of the data shall be considered. Information on chemicals related to the material being classified shall be considered as appropriate, as well as site of action and mechanism or mode of action study results. Both positive and negative results shall be considered together in a single weight-of-evidence determination.
    A.0.3.3   Positive effects which are consistent with the criteria for classification, whether seen in humans or animals, shall normally justify classification. Where evidence is available from both humans and animals and there is a conflict between the findings, the quality and reliability of the evidence from both sources shall be evaluated in order to resolve the question of classification. Reliable, good quality human data shall generally have precedence over other data. However, even well-designed and conducted epidemiological studies may lack a sufficient number of subjects to detect relatively rare but still significant effects, or to assess potentially confounding factors. Therefore, positive results from well-conducted animal studies are not necessarily negated by the lack of positive human experience but require an assessment of the robustness, quality and statistical power of both the human and animal data.
    A.0.3.4   Route of exposure, mechanistic information, and metabolism studies are pertinent to determining the relevance of an effect in humans. When such information raises doubt about relevance in humans, a lower classification may be warranted. When there is scientific evidence demonstrating that the mechanism or mode of action is not relevant to humans, the chemical should not be classified.
    A.0.3.5   Both positive and negative results are considered together in the weight of evidence determination. However, a single positive study performed according to good scientific principles and with statistically and biologically significant positive results may justify classification.
A.0.4   Considerations for the Classification of Mixtures
    A.0.4.1   For most hazard classes, the recommended process of classification of mixtures is based on the following sequence:
    (a) Where test data are available for the complete mixture, the classification of the mixture will always be based on those data;
    (b) Where test data are not available for the mixture itself, the bridging principles designated in each health hazard chapter of this appendix shall be considered for classification of the mixture;
    (c) If test data are not available for the mixture itself, and the available information is not sufficient to allow application of the above-mentioned bridging principles, then the method(s) described in each chapter for estimating the hazards based on the information known will be applied to classify the mixture (e.g., application of cut-off values/concentration limits).
    A.0.4.2   An exception to the above order or precedence is made for Carcinogenicity, Germ Cell Mutagenicity, and Reproductive Toxicity. For these three hazard classes, mixtures shall be classified based upon information on the ingredient substances, unless on a case-by-case basis, justification can be provided for classifying based upon the mixture as a whole. See chapters A.5, A.6, and A.7 for further information on case-by-case bases.
    A.0.4.3   Use of cut-off values/concentration limits.
    A.<IP_ADDRESS>   When classifying an untested mixture based on the hazards of its ingredients, cut-off values/concentration limits for the classified ingredients of the mixture are used for several hazard classes. While the adopted cut-off values/concentration limits adequately identify the hazard for most mixtures, there may be some that contain hazardous ingredients at lower concentrations than the specified cut-off values/concentration limits that still pose an identifiable hazard. There may also be cases where the cut-off value/concentration limit is considerably lower than the established non-hazardous level for an ingredient.
    A.<IP_ADDRESS>   If the classifier has information that the hazard of an ingredient will be evident (i.e., it presents a health risk) below the specified cut-off value/concentration limit, the mixture containing that ingredient shall be classified accordingly.
    A.<IP_ADDRESS>   In exceptional cases, conclusive data may demonstrate that the hazard of an ingredient will not be evident (i.e., it does not present a health risk) when present at a level above the specified cut-off value/concentration limit(s). In these cases the mixture may be classified according to those data. The data must exclude the possibility that the ingredient will behave in the mixture in a manner that would increase the hazard over that of the pure substance. Furthermore, the mixture must not contain ingredients that would affect that determination.
    A.0.4.4   Synergistic or antagonistic effects.
    When performing an assessment in accordance with these requirements, the evaluator must take into account all available information about the potential occurrence of synergistic effects among the ingredients of the mixture. Lowering classification of a mixture to a less hazardous category on the basis of antagonistic effects may be done only if the determination is supported by sufficient data.
A.0.5   Bridging Principles for the Classification of Mixtures Where Test Data Are Not Available for the Complete Mixture
    A.0.5.1   Where the mixture itself has not been tested to determine its toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data shall be used in accordance with the following bridging principles, subject to any specific provisions for mixtures for each hazard class. These principles ensure that the classification process uses the available data to the greatest extent possible in characterizing the hazards of the mixture.
    A.<IP_ADDRESS>   Dilution.
    For mixtures classified in accordance with A.1 through A.10 of this Appendix, if a tested mixture is diluted with a diluent that has an equivalent or lower toxicity classification than the least toxic original ingredient, and which is not expected to affect the toxicity of other ingredients, then:
    (a) The new diluted mixture shall be classified as equivalent to the original tested mixture; or
    (b) For classification of acute toxicity in accordance with A.1 of this Appendix, paragraph A.1.3.6 (the additivity formula) shall be applied.
    A.<IP_ADDRESS>   Batching.
    For mixtures classified in accordance with A.1 through A.10 of this Appendix, the toxicity of a tested production batch of a mixture can be assumed to be substantially equivalent to that of another untested production batch of the same mixture, when produced by or under the control of the same chemical manufacturer, unless there is reason to believe there is significant variation such that the toxicity of the untested batch has changed. If the latter occurs, a new classification is necessary.
    A.<IP_ADDRESS>   Concentration of mixtures.
    For mixtures classified in accordance with A.1, A.2, A.3, A.8, A.9, or A.10 of this Appendix, if a tested mixture is classified in Category 1, and the concentration of the ingredients of the tested mixture that are in Category 1 is increased, the resulting untested mixture shall be classified in Category 1.
    A.<IP_ADDRESS>   Interpolation within one toxicity category.
    For mixtures classified in accordance with A.1, A.2, A.3, A.8, A.9, or A.10 of this Appendix, for three mixtures (A, B and C) with identical ingredients, where mixtures A and B have been tested and are in the same toxicity category, and where untested mixture C has the same toxicologically active ingredients as mixtures A and B but has concentrations of toxicologically active ingredients intermediate to the concentrations in mixtures A and B, then mixture C is assumed to be in the same toxicity category as A and B.
    A.<IP_ADDRESS>   Substantially similar mixtures.
    For mixtures classified in accordance with A.1 through A.10 of this Appendix, given the following set of conditions:
    (a) Where there are two mixtures:
    (i) A + B;
    (ii) C + B;
    (b) The concentration of ingredient B is essentially the same in both mixtures;
    (c) The concentration of ingredient A in mixture (i) equals that of ingredient C in mixture (ii);
    (d) And data on toxicity for A and C are available and substantially equivalent; i.e., they are in the same hazard category and are not expected to affect the toxicity of B; then
    If mixture (i) or (ii) is already classified based on test data, the other mixture can be assigned the same hazard category.
    A.<IP_ADDRESS>   Aerosols.
    For mixtures classified in accordance with A.1, A.2, A.3, A.4, A.8, or A.9 of this Appendix, an aerosol form of a mixture shall be classified in the same hazard category as the tested, non-aerosolized form of the mixture, provided the added propellant does not affect the toxicity of the mixture when spraying.
A.1   ACUTE TOXICITY
A.1.1   Definition
    Acute toxicity refers to those adverse effects occurring following oral or dermal administration of a single dose of a substance, or multiple doses given within 24 hours, or an inhalation exposure of 4 hours.
A.1.2   Classification Criteria for Substances
    A.1.2.1   Substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric cut-off criteria as shown in Table A.1.1. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE). See the footnotes following Table A.1.1 for further explanation on the application of these values.
    Table A.1.1 -- Acute Toxicity Hazard Categories and Acute Toxicity Estimate (ATE) Values Defining the Respective Categories
Exposure route
Category 1
Category 2
Category 3
Category 4
Oral (mg/kg bodyweight)

see: Note (a)
<=5
>5 and <=50
>50 and <=300
>300 and <=2000.
Note (b)

Dermal (mg/kg bodyweight)

see: Note (a)
<=50
>50 and <=200
>200 and <=1000
>1000 and <=2000.
Note (b)

Inhalation -- Gases (ppmV)

see: Note (a)
<=100
>100 and <=500
>500 and <=2500
>2500 and <=20000.
Note (b)

Note (c)

Inhalation -- Vapors (mg/l)

see: Note (a)
<=0.5
>0.5 and <=2.0
>2.0 and <=10.0
>10.0 and <=20.0.
Note (b)

Note (c)

Note (d)

Inhalation -- Dusts and Mists (mg/l)

see: Note (a)
<=0.05
>0.05 and <=0.5
>0.5 and <=1.0
>1.0 and <=5.0.
Note (b)

Note (c)

    Note: Gas concentrations are expressed in parts per million per volume (ppmV).
    Notes to Table A.1.1:
    (a) The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where available;
    (b) The acute toxicity estimate (ATE) for the classification of a substance or ingredient in a mixture is derived using:
    (i) the LD50/LC50 where available. Otherwise,
    (ii) the appropriate conversion value from Table 1.2 that relates to the results of a range test, or
    (iii) the appropriate conversion value from Table 1.2 that relates to a classification category;
    (c) Inhalation cut-off values in the table are based on 4 hour testing exposures. Conversion of existing inhalation toxicity data which has been generated according to 1 hour exposure is achieved by dividing by a factor of 2 for gases and vapors and 4 for dusts and mists;
    (d) For some substances the test atmosphere will be a vapor which consists of a combination of liquid and gaseous phases. For other substances the test atmosphere may consist of a vapor which is nearly all the gaseous phase. In these latter cases, classification is based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2500 ppmV), Category 4 (20000 ppmV).
    The terms "dust", "mist" and "vapor" are defined as follows:
    (i) Dust: solid particles of a substance or mixture suspended in a gas (usually air);
    (ii) Mist: liquid droplets of a substance or mixture suspended in a gas (usually air);
    (iii) Vapor: the gaseous form of a substance or mixture released from its liquid or solid state.
    A.1.2.3   The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. Test data already generated for the classification of chemicals under existing systems should be accepted when reclassifying these chemicals under the harmonized system. When experimental data for acute toxicity are available in several animal species, scientific judgment should be used in selecting the most appropriate LD50 value from among scientifically validated tests.
A.1.3   Classification Criteria for Mixtures
    A.1.3.1   The approach to classification of mixtures for acute toxicity is tiered, and is dependent upon the amount of information available for the mixture itself and for its ingredients. The flow chart of Figure A.1.1 indicates the process that must be followed:

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    A.1.3.2   Classification of mixtures for acute toxicity may be carried out for each route of exposure, but is only required for one route of exposure as long as this route is followed (estimated or tested) for all ingredients and there is no relevant evidence to suggest acute toxicity by multiple routes. When there is relevant evidence of acute toxicity by multiple routes of exposure, classification is to be conducted for all appropriate routes of exposure. All available information shall be considered. The pictogram and signal word used shall reflect the most severe hazard category; and all relevant hazard statements shall be used.
    A.1.3.3   For purposes of classifying the hazards of mixtures in the tiered approach:
    (a) The "relevant ingredients" of a mixture are those which are present in concentrations >=1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases). If there is reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for acute toxicity, that ingredient shall also be considered relevant. Consideration of ingredients present at a concentration <1% is particularly important when classifying untested mixtures which contain ingredients that are classified in Category 1 and Category 2;
    (b) Where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture is used when calculating the classification of the new mixture using the formulas in A.<IP_ADDRESS> and A.<IP_ADDRESS>.4.
    (c) If the converted acute toxicity point estimates for all ingredients of a mixture are within the same category, then the mixture should be classified in that category.
    (d) When only range data (or acute toxicity hazard category information) are available for ingredients in a mixture, they may be converted to point estimates in accordance with Table A.1.2 when calculating the classification of the new mixture using the formulas in A.<IP_ADDRESS> and A.<IP_ADDRESS>.4.
A.1.3.4   Classification of Mixtures Where Acute Toxicity Test Data Are Available for the Complete Mixture
    Where the mixture itself has been tested to determine its acute toxicity, it is classified according to the same criteria as those used for substances, presented in Table A.1.1. If test data for the mixture are not available, the procedures presented below must be followed.
A.1.3.5   Classification of Mixtures Where Acute Toxicity Test Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its acute toxicity, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category, Substantially similar mixtures, and Aerosols.
A.1.3.6   Classification of Mixtures Based on Ingredients of the Mixture (Additivity Formula)
    A.<IP_ADDRESS>   Data available for all ingredients.
    The acute toxicity estimate (ATE) of ingredients is considered as follows:
    (a) Include ingredients with a known acute toxicity, which fall into any of the acute toxicity categories, or have an oral or dermal LD50 greater than 2000 but less than or equal to 5000 mg/kg body weight (or the equivalent dose for inhalation);
    (b) Ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);
    (c) Ignore ingredients if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table A.1.1) and do not show acute toxicity.
    Ingredients that fall within the scope of this paragraph are considered to be ingredients with a known acute toxicity estimate (ATE). See note (b) to Table A.1.1 and paragraph A.1.3.3 for appropriate application of available data to the equation below, and paragraph A.<IP_ADDRESS>.4.
    The ATE of the mixture is determined by calculation from the ATE values for all relevant ingredients according to the following formula below for oral, dermal or inhalation toxicity:

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Where:
  Ci = concentration of ingredient i
  n ingredients and i is running from 1 to n
  ATEi = acute toxicity estimate of ingredient i.
    A.<IP_ADDRESS>   Data are not available for one or more ingredients of the mixture.
    A.<IP_ADDRESS>.1   Where an ATE is not available for an individual ingredient of the mixture, but available information provides a derived conversion value, the formula in A.<IP_ADDRESS> may be applied. This information may include evaluation of:
    (a) Extrapolation between oral, dermal and inhalation acute toxicity estimates. Such an evaluation requires appropriate pharmacodynamic and pharmacokinetic data;
    (b) Evidence from human exposure that indicates toxic effects but does not provide lethal dose data;
    (c) Evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or
    (d) Data from closely analogous substances using structure/activity relationships.
    A.<IP_ADDRESS>.2   This approach requires substantial supplemental technical information, and a highly trained and experienced expert, to reliably estimate acute toxicity. If sufficient information is not available to reliably estimate acute toxicity, proceed to the provisions of A.<IP_ADDRESS>.3.
    A.<IP_ADDRESS>.3   In the event that an ingredient with unknown acute toxicity is used in a mixture at a concentration >=1%, and the mixture has not been classified based on testing of the mixture as a whole, the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture is classified based on the known ingredients only. (Note: A statement that x percent of the mixture consists of ingredient(s) of unknown toxicity is required on the label and safety data sheet in such cases; see Appendix C to this section, Allocation of Label Elements and Appendix D to this section, Safety Data Sheets.)
    Where an ingredient with unknown acute toxicity is used in a mixture at a concentration >=1%, and the mixture is not classified based on testing of the mixture as a whole, a statement that X% of the mixture consists of ingredient(s) of unknown acute toxicity is required on the label and safety data sheet in such cases; see Appendix C to this section, Allocation of Label Elements and Appendix D to this section, Safety Data Sheets.)
    A.<IP_ADDRESS>.4   If the total concentration of the relevant ingredient(s) with unknown acute toxicity is <=10% then the formula presented in A.<IP_ADDRESS> must be used. If the total concentration of the relevant ingredient(s) with unknown acute toxicity is >10%, the formula presented in A.<IP_ADDRESS> is corrected to adjust for the percentage of the unknown ingredient(s) as follows:

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    Table A.1.2 -- Conversion From Experimentally Obtained Acute Toxicity Range Values (or Acute Toxicity Hazard Categories) to Acute Toxicity Point Estimates for Use in the Formulas for the Classification of Mixtures
Exposure routes
Classification category or experimentally obtained acute
toxicity range estimate
Converted acute toxicity point estimate
Oral (mg/kg bodyweight )
0 <Category 1 <=5
0.5

5 <Category 2 <=50
5

50 <Category 3 <=300
100

300 <Category 4 <=2000
500
Dermal (mg/kg bodyweight)
0 <Category 1 <=50
5

50 <Category 2 <=200
50

200 <Category 3 <=1000
300

1000 <Category 4 <=2000
1100
Gases (ppmV)
0 <Category 1 <=100
10

100 <Category 2 <=500
100

500 <Category 3 <=2500
700

2500 <Category 4 <=20000
4500
Vapors (mg/l)
0 <Category 1 <=0.5
0.05

0.5 <Category 2 <=2.0
0.5

2.0 <Category 3 <=10.0
3

10.0 <Category 4 <=20.0
11
Dust/mist (mg/l)
0 <Category 1 <=0.05
0.005

0.05 <Category 2 <=0.5
0.05

0.5 <Category 3 <=1.0
0.5

1.0 <Category 4 <=5.0
1.5
    Note: Gas concentrations are expressed in parts per million per volume (ppmV).
A.2   SKIN CORROSION/IRRITATION
A.2.1   Definitions and General Considerations
    A.2.1.1   Skin corrosion is the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis, following the application of a test substance for up to 4 hours. Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of observation at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia, and scars. Histopathology should be considered to evaluate questionable lesions.
    Skin irritation is the production of reversible damage to the skin following the application of a test substance for up to 4 hours.
    A.2.1.2   Skin corrosion/irritation shall be classified using a tiered approach as detailed in figure A.2.1. Emphasis shall be placed upon existing human data (See A.0.2.6), followed by other sources of information. Classification results directly when the data satisfy the criteria in this section. In case the criteria cannot be directly applied, classification of a substance or a mixture is made on the basis of the total weight of evidence (See A.0.3.1). This means that all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate scientifically validated in-vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations.
A.2.2   Classification Criteria for Substances Using Animal Test Data
A.2.2.1   Corrosion
    A.<IP_ADDRESS>   A corrosive substance is a chemical that produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least 1 of 3 tested animals after exposure up to a 4-hour duration. Corrosive reactions are typified by ulcers, bleeding, bloody scabs and, by the end of observation at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia and scars. Histopathology should be considered to discern questionable lesions.
    A.<IP_ADDRESS>   Three sub-categories of Category 1 are provided in Table A.2.1, all of which shall be regulated as Category 1.
    Table A.2.1 -- Skin Corrosion Category and Sub-Categories
Category 1: corrosive
Corrosive sub-categories
Corrosive in >=1 of 3 animals

Exposure
Observation

1A
<=3 min
<=1 h.

1B
>3 min <=1 h
<=14 days.

1C
>1 h <=4 h
<=14 days.
A.2.2.2   Irritation
    A.<IP_ADDRESS>   A single irritant category (Category 2) is presented in the Table A.2.2. The major criterion for the irritant category is that at least 2 tested animals have a mean score of >=2.3 <=4.0.
    Table A.2.2 -- Skin Irritation Category

Criteria
Irritant (Category 2)
(1) Mean value of >=2.3 <=4.0 for erythema/eschar or for edema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling; or

(3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above.
    A.<IP_ADDRESS>   Animal irritant responses within a test can be quite variable, as they are with corrosion. A separate irritant criterion accommodates cases when there is a significant irritant response but less than the mean score criterion for a positive test. For example, a substance might be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses could also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure. Addition of this criterion increases the sensitivity of the classification system.
    A.<IP_ADDRESS>   Reversibility of skin lesions is another consideration in evaluating irritant responses. When inflammation persists to the end of the observation period in 2 or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a chemical should be considered to be an irritant.
A.2.3   Classification Criteria for Substances Using Other Data Elements
    A.2.3.1   Existing human and animal data including information from single or repeated exposure should be the first line of analysis, as they give information directly relevant to effects on the skin. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study may not be practicable since the amount of test substance to be applied would considerably exceed the toxic dose and, consequently, would result in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification provided that the dilutions used and species tested are equivalent. In vitro alternatives that have been scientifically validated shall be used to make classification decisions. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes. Likewise, pH extremes like <=2 and >=11.5 may indicate skin effects, especially when associated with significant buffering capacity. Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered corrosive (Skin Category 1) if it has a pH <=2 or a pH >=11.5. However, if consideration of alkali/acid reserve suggests the substance or mixture may not be corrosive despite the low or high pH value, then further evaluation may be necessary. In some cases enough information may be available from structurally related compounds to make classification decisions.
    A.2.3.2   A tiered approach to the evaluation of initial information shall be used (Figure A.2.1) recognizing that all elements may not be relevant in certain cases.
    A.2.3.3   The tiered approach explains how to organize information on a substance and to make a weight-of-evidence decision about hazard assessment and hazard classification.
    A.2.3.4   All the above information that is available on a substance shall be evaluated. Although information might be gained from the evaluation of single parameters within a tier, there is merit in considering the totality of existing information and making an overall weight of evidence determination. This is especially true when there is information available on some but not all parameters. Emphasis shall be placed upon existing human experience and data, followed by animal experience and testing data, followed by other sources of information, but case-by-case determinations are necessary.

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A.2.4   Classification Criteria for Mixtures
A.2.4.1   Classification of Mixtures When Data Are Available for the Complete Mixture
    A.<IP_ADDRESS>   The mixture shall be classified using the criteria for substances (See A.2.3).
A.2.4.2   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its skin corrosion/irritation, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles, as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category, Substantially similar mixtures, and Aerosols.
A.2.4.3   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   For purposes of classifying the skin corrosion/irritation hazards of mixtures in the tiered approach:
    The "relevant ingredients" of a mixture are those which are present in concentrations >=1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases.) If the classifier has reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for skin corrosion/irritation, that ingredient shall also be considered relevant.
    A.<IP_ADDRESS>   In general, the approach to classification of mixtures as irritant or corrosive to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each corrosive or irritant ingredient contributes to the overall irritant or corrosive properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for corrosive ingredients when they are present at a concentration below the concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as an irritant. The mixture is classified as corrosive or irritant when the sum of the concentrations of such ingredients exceeds a cut-off value/concentration limit.
    A.<IP_ADDRESS>   Table A.2.3 below provides the cut-off value/concentration limits to be used to determine if the mixture is considered to be an irritant or a corrosive to the skin.
    A.<IP_ADDRESS>   Particular care shall be taken when classifying certain types of chemicals such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in A.<IP_ADDRESS> and A.<IP_ADDRESS> might not work given that many of such substances are corrosive or irritant at concentrations <1%. For mixtures containing strong acids or bases the pH should be used as classification criteria since pH will be a better indicator of corrosion than the concentration limits of Table A.2.3. A mixture containing corrosive or irritant ingredients that cannot be classified based on the additivity approach shown in Table A.2.3, due to chemical characteristics that make this approach unworkable, should be classified as Skin Category 1 if it contains >=1% of a corrosive ingredient and as Skin Category 2 when it contains >=3% of an irritant ingredient. Classification of mixtures with ingredients for which the approach in Table A.2.3 does not apply is summarized in Table A.2.4 below.
    A.<IP_ADDRESS>   On occasion, reliable data may show that the skin corrosion/irritation of an ingredient will not be evident when present at a level above the generic concentration cut-off values mentioned in Tables A.2.3 and A.2.4. In these cases the mixture could be classified according to those data (See Use of cut-off values/concentration limits, paragraph A.0.4.3 of this Appendix).
    A.<IP_ADDRESS>   If there are data showing that (an) ingredient(s) may be corrosive or irritant at a concentration of <1% (corrosive) or <3% (irritant), the mixture shall be classified accordingly (See Use of cut-off values/concentration limits, paragraph A.0.4.3 of this Appendix).
    Table A.2.3 -- Concentration of Ingredients of a Mixture Classified as Skin Category 1 or 2 That Would Trigger Classification of the Mixture as Hazardous to Skin
    [Category 1 or 2]
Sum of ingredients classified as:
Concentration triggering classification of a mixture as:

Skin corrosive
Skin irritant

Category 1
Category 2
Skin Category 1
>=5%
>=1% but <5%.
Skin Category 2

>=10%.
(10 x Skin Category 1) + Skin Category 2

>=10%.
    Table A.2.4 -- Concentration of Ingredients of a Mixture for Which the Additivity Approach Does Not Apply, That Would Trigger Classification of the Mixture as Hazardous to Skin
Ingredient:
Concentration:
Mixture
classified as:
Skin
Acid with pH <=2
>=1%
Category 1.
Base with pH >=11.5
>=1%
Category 1.
Other corrosive (Category 1) ingredients for which additivity does not apply
>=1%
Category 1.
Other irritant (Category 2) ingredients for which additivity does not apply, including acids and bases
>=3%
Category 2.
A.3   SERIOUS EYE DAMAGE/EYE IRRITATION
A.3.1   Definitions and General Considerations
    A.3.1.1   Serious eye damage is the production of tissue damage in the eye, or serious physical decay of vision, following application of a test substance to the anterior surface of the eye, which is not fully reversible within 21 days of application.
    Eye irritation is the production of changes in the eye following the application of test substance to the anterior surface of the eye, which are fully reversible within 21 days of application.
    A.3.1.2   Serious eye damage/eye irritation shall be classified using a tiered approach as detailed in Figure A.3.1. Emphasis shall be placed upon existing human data (See A.0.2.6), followed by animal data, followed by other sources of information. Classification results directly when the data satisfy the criteria in this section. In case the criteria cannot be directly applied, classification of a substance or a mixture is made on the basis of the total weight of evidence (See A.0.3.1). This means that all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate scientifically validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations.
A.3.2   Classification Criteria for Substances Using Animal Test Data
    A.3.2.1   Irreversible effects on the eye/serious damage to eyes (Category 1).
    A single hazard category is provided in Table A.3.1, for substances that have the potential to seriously damage the eyes. Category 1, irreversible effects on the eye, includes the criteria listed below. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g. destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Category 1 also contains substances fulfilling the criteria of corneal opacity >=3 and/or iritis >1.5 detected in a Draize eye test with rabbits, because severe lesions like these usually do not reverse within a 21-day observation period.
    Table A.3.1 -- Irreversible Eye Effects
A substance is classified as Serious Eye Damage Category 1 (irreversible effects on the eye) when it produces:
(a) at least in one tested animal, effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or
(b) at least in 2 of 3 tested animals, a positive response of:
(i) corneal opacity >=3; and/or
(ii) iritis >1.5;
calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the substance.
    A.3.2.2   Reversible effects on the eye (Category 2).
    A single category is provided in Table A.3.2 for substances that have the potential to induce reversible eye irritation.
    Table A.3.2 -- Reversible Eye Effects
A substance is classified as Eye irritant Category 2A (irritating to eyes) when it produces in at least in 2 of 3 tested animals a positive response of:
(i) corneal opacity >=1; and/or
(ii) iritis >=1; and/or
(iii) conjunctival redness >=2; and/or
(iv) conjunctival edema (chemosis) >=2
calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the substance, and which fully reverses within an observation period of normally 21 days.
An eye irritant is considered mildly irritating to eyes (Category 2B) when the effects listed above are fully reversible within 7 days of observation.
    A.3.2.3   For those chemicals where there is pronounced variability among animal responses, this information may be taken into account in determining the classification.
A.3.3   Classification Criteria for Substances Using Other Data Elements
    A.3.3.1   Existing human and animal data should be the first line of analysis, as they give information directly relevant to effects on the eye. Possible skin corrosion shall be evaluated prior to consideration of serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. In vitro alternatives that have been scientifically validated and accepted shall be used to make classification decisions. Likewise, pH extremes like <=2 and >=11.5, may indicate serious eye damage, especially when associated with significant buffering capacity. Generally, such substances are expected to produce significant effects on the eyes. In the absence of any other information, a mixture/substance is considered to cause serious eye damage (Eye Category 1) if it has a pH <=2 or >=11.5. However, if consideration of acid/alkaline reserve suggests the substance may not have the potential to cause serious eye damage despite the low or high pH value, then further evaluation may be necessary. In some cases enough information may be available from structurally related compounds to make classification decisions.
    A.3.3.2   A tiered approach to the evaluation of initial information shall be used where applicable, recognizing that all elements may not be relevant in certain cases (Figure A.3.1).
    A.3.3.3   The tiered approach explains how to organize existing information on a substance and to make a weight-of-evidence decision, where appropriate, about hazard assessment and hazard classification.
    A.3.3.4   All the above information that is available on a substance shall be evaluated. Although information might be gained from the evaluation of single parameters within a tier, consideration should be given to the totality of existing information and making an overall weight-of-evidence determination. This is especially true when there is conflict in information available on some parameters.

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A.3.4   Classification Criteria for Mixtures
A.3.4.1   Classification of Mixtures When Data Are Available for the Complete Mixture
    A.<IP_ADDRESS>   The mixture will be classified using the criteria for substances.
    A.<IP_ADDRESS>   Unlike other hazard classes, there are alternative tests available for skin corrosivity of certain types of chemicals that can give an accurate result for classification purposes, as well as being simple and relatively inexpensive to perform. When considering testing of the mixture, chemical manufacturers are encouraged to use a tiered weight of evidence strategy as included in the criteria for classification of substances for skin corrosion and serious eye damage and eye irritation to help ensure an accurate classification, as well as avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Eye Category 1) if it has a pH <=2 or >=11.5. However, if consideration of acid/alkaline reserve suggests the substance or mixture may not have the potential to cause serious eye damage despite the low or high pH value, then further evaluation may be necessary.
A.3.4.2   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage or eye irritation, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles, as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation within one toxicity category, Substantially similar mixtures, and Aerosols.
A.3.4.3   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   For purposes of classifying the eye corrosion/irritation hazards of mixtures in the tiered approach:
    The "relevant ingredients" of a mixture are those which are present in concentrations >=1% (weight/weight for solids, liquids, dusts, mists and vapors and volume/volume for gases.) If the classifier has reason to suspect that an ingredient present at a concentration <1% will affect classification of the mixture for eye corrosion/irritation, that ingredient shall also be considered relevant.
    A.<IP_ADDRESS>   In general, the approach to classification of mixtures as seriously damaging to the eye or eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each corrosive or irritant ingredient contributes to the overall irritant or corrosive properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for corrosive ingredients when they are present at a concentration below the concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as an irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a threshold cut-off value/concentration limit.
    A.<IP_ADDRESS>   Table A.3.3 provides the cut-off value/concentration limits to be used to determine if the mixture should be classified as seriously damaging to the eye or an eye irritant.
    A.<IP_ADDRESS>   Particular care must be taken when classifying certain types of chemicals such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in A.<IP_ADDRESS> and A.<IP_ADDRESS> might not work given that many of such substances are corrosive or irritant at concentrations <1%. For mixtures containing strong acids or bases, the pH should be used as classification criteria (See A.3.4.1) since pH will be a better indicator of serious eye damage than the concentration limits of Table A.3.3. A mixture containing corrosive or irritant ingredients that cannot be classified based on the additivity approach applied in Table A.3.3 due to chemical characteristics that make this approach unworkable, should be classified as Eye Category 1 if it contains >=1% of a corrosive ingredient and as Eye Category 2 when it contains >=3% of an irritant ingredient. Classification of mixtures with ingredients for which the approach in Table A.3.3 does not apply is summarized in Table A.3.4.
    A.<IP_ADDRESS>   On occasion, reliable data may show that the reversible/irreversible eye effects of an ingredient will not be evident when present at a level above the generic cut-off values/concentration limits mentioned in Tables A.3.3 and A.3.4. In these cases the mixture could be classified according to those data (See also A.0.4.3 Use of cut-off values/concentration limits"). On occasion, when it is expected that the skin corrosion/irritation or the reversible/irreversible eye effects of an ingredient will not be evident when present at a level above the generic concentration/cut-off levels mentioned in Tables A.3.3 and A.3.4, testing of the mixture may be considered. In those cases, the tiered weight of evidence strategy should be applied as referred to in section A.3.3, Figure A.3.1 and explained in detail in this chapter.
    A.<IP_ADDRESS>   If there are data showing that (an) ingredient(s) may be corrosive or irritant at a concentration of <1% (corrosive) or <3% (irritant), the mixture should be classified accordingly (See also paragraph A.0.4.3, Use of cut-off values/concentration limits).
    Table A.3.3 -- Concentration of Ingredients of a Mixture Classified as Skin Category 1 and/or Eye Category 1 or 2 That Would Trigger Classification of the Mixtures as Hazardous to the Eye
Sum of ingredients classified as:
Concentration triggering classification of a mixture as:

Irreversible eye effects
Reversible eye effects

Category 1
Category 2
Eye or Skin Category 1
>=3%
>=1% but <3%.
Eye Category 2

>=10%.
(10 x Eye Category 1) + Eye Category 2

>=10%.
Skin Category 1 + Eye Category 1
>=3%
>=1% but <3%.
10 x (Skin Category 1 + Eye Category 1) + Eye Category 2

>=10%.
    Note: A mixture may be classified as Eye Category 2B in cases when all relevant ingredients are classified as Eye Category 2B.
    Table A.3.4 -- Concentration of Ingredients of a Mixture for Which the Additivity Approach Does Not Apply, That Would Trigger Classification of the Mixture as Hazardous to the Eye
Ingredient
Concentration
Mixture
classified as:
Eye
Acid with pH <=2
>=1%
Category 1.
Base with pH >=11.5
>=1%
Category 1.
Other corrosive (Category 1) ingredients for which additivity does not apply
>=1%
Category 1.
Other irritant (Category 2) ingredients for which additivity does not apply, including acids and bases
>=3%
Category 2.
A.4   RESPIRATORY OR SKIN SENSITIZATION
A.4.1   Definitions and General Considerations
    A.4.1.1   Respiratory sensitizer means a chemical that will lead to hypersensitivity of the airways following inhalation of the chemical.
    Skin sensitizer means a chemical that will lead to an allergic response following skin contact.
    A.4.1.2   For the purpose of this chapter, sensitization includes two phases: the first phase is induction of specialized immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e., production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitized individual to an allergen.
    A.4.1.3   For respiratory sensitization, the pattern of induction followed by elicitation phases is shared in common with skin sensitization. For skin sensitization, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardized elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitization in humans normally is assessed by a diagnostic patch test.
    A.4.1.4   Usually, for both skin and respiratory sensitization, lower levels are necessary for elicitation than are required for induction.
    A.4.1.5   The hazard class "respiratory or skin sensitization" is differentiated into:
    (a) Respiratory sensitization; and
    (b) Skin sensitization.
A.4.2   Classification Criteria for Substances
A.4.2.1   Respiratory Sensitizers
    A.<IP_ADDRESS>   Hazard Categories.
    A.<IP_ADDRESS>.1   Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitizers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table A.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.
    A.<IP_ADDRESS>.2   Where data are not sufficient for sub-categorization, respiratory sensitizers shall be classified in Category 1.
    Table A.4.1 -- Hazard Category and Sub-Categories for Respiratory Sensitizers
Category 1
Respiratory sensitizer

A substance is classified as a respiratory sensitizer.

(a) if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity and/or

(b) if there are positive results from an appropriate animal test.[1]
Sub-category 1A
Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitization rate in humans based on animal or other tests.[1] Severity of reaction may also be considered.
Sub-category 1B
Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitization rate in humans based on animal or other tests.[1] Severity of reaction may also be considered.
    1At this writing, recognized and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.
    A.<IP_ADDRESS>   Human evidence.
    A.<IP_ADDRESS>.1   Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.
    A.<IP_ADDRESS>.2   When considering the human evidence, it is necessary that in addition to the evidence from the cases, the following be taken into account:
    (a) The size of the population exposed;
    (b) The extent of exposure.
    A.<IP_ADDRESS>.3   The evidence referred to above could be:
    (a) Clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:
    (i) In vivo immunological test (e.g., skin prick test);
    (ii) In vitro immunological test (e.g., serological analysis);
    (iii) Studies that may indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g., repeated low-level irritation, pharmacologically mediated effects;
    (iv) A chemical structure related to substances known to cause respiratory hypersensitivity;
    (b) Data from positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.
    A.<IP_ADDRESS>.4   Clinical history should include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history should also include a note of other allergic or airway disorders from childhood and smoking history.
    A.<IP_ADDRESS>.5   The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is, however, recognized that in practice many of the examinations listed above will already have been carried out.
    A.<IP_ADDRESS>   Animal studies.
    A.<IP_ADDRESS>.1   Data from appropriate animal studies2 which may be indicative of the potential of a substance to cause sensitization by inhalation in humans3 may include:
    2At this writing, recognized and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.
    3The mechanisms by which substances induce symptoms of asthma are not yet fully known. For preventive measures, these substances are considered respiratory sensitizers. However, if on the basis of the evidence, it can be demonstrated that these substances induce symptoms of asthma by irritation only in people with bronchial hyperactivity, they should not be considered as respiratory sensitizers.
    (a) Measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice
    (b) Specific pulmonary responses in guinea pigs.
A.4.2.2   Skin Sensitizers
    A.<IP_ADDRESS>   Hazard categories.
    A.<IP_ADDRESS>.1   Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitizers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table A.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in A.<IP_ADDRESS>.1 and A.<IP_ADDRESS>.2 for sub-category 1A and in A.<IP_ADDRESS>.2 and A.<IP_ADDRESS>.3 for sub-category 1B.
    A.<IP_ADDRESS>.2   Where data are not sufficient for sub-categorization, skin sensitizers shall be classified in Category 1.
    Table A.4.2 -- Hazard Category and Sub-Categories for Skin Sensitizers
Category 1
Skin sensitizer

A substance is classified as a skin sensitizer.

(a) if there is evidence in humans that the substance can lead to sensitization by skin contact in a substantial number of persons, or

(b) if there are positive results from an appropriate animal test.
Sub-category 1A
Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitization in humans. Severity of reaction may also be considered.
Sub-category 1B
Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitization in humans. Severity of reaction may also be considered.
    A.<IP_ADDRESS>   Human evidence.
    A.<IP_ADDRESS>.1   Human evidence for sub-category 1A may include:
    (a) Positive responses at <=500 ug/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.<IP_ADDRESS>.2   Human evidence for sub-category 1B may include:
    (a) Positive responses at >500 ug/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.<IP_ADDRESS>   Animal studies
    A.<IP_ADDRESS>.1   For Category 1, when an adjuvant type test method for skin sensitization is used, a response of at least 30% of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15% of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay.4
    4Test methods for skin sensitization are described in OECD Guideline 406 (the Guinea Pig Maximization test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are scientifically validated. The Mouse Ear Swelling Test (MEST), appears to be a reliable screening test to detect moderate to strong sensitizers, and can be used, in accordance with professional judgment, as a first stage in the assessment of skin sensitization potential.
    A.<IP_ADDRESS>.2   Animal test results for sub-category 1A can include data with values indicated in Table A.4.3 below:
    Table A.4.3 -- Animal Test Results for Sub-Category 1A
Assay
Criteria
Local lymph node assay
EC3 value <=2%.
Guinea pig maximization test
>=30% responding at <=0.1% intradermal induction dose or

>=60% responding at >0.1% to <=1% intradermal induction dose.
Buehler assay
>=15% responding at <=0.2% topical induction dose or

>=60% responding at >0.2% to <=20% topical induction dose.
    Note: EC3 refers to the estimated concentration of test chemical required to induce a stimulation index of 3 in the local lymph node assay.
    A.<IP_ADDRESS>.3   Animal test results for sub-category 1B can include data with values indicated in Table A.4.4 below:
    Table A.4.4 -- Animal Test Results for Sub-Category 1B
Assay
Criteria
Local lymph node assay
EC3 value >2%.
Guinea pig maximization test
>=30% to <60% responding at >0.1% to <=1% intradermal induction dose or

>=30% responding at >1% intradermal induction dose.
Buehler assay
>=15% to <60% responding at >0.2% to <=20% topical induction dose or

>=15% responding at >20% topical induction dose.
    Note: EC3 refers to the estimated concentration of test chemical required to induce a stimulation index of 3 in the local lymph node assay.
    A.<IP_ADDRESS>   Specific considerations.
    A.<IP_ADDRESS>.1   For classification of a substance, evidence shall include one or more of the following using a weight of evidence approach:
    (a) Positive data from patch testing, normally obtained in more than one dermatology clinic;
    (b) Epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;
    (c) Positive data from appropriate animal studies;
    (d) Positive data from experimental studies in man (See paragraph A.0.2.6 of this Appendix);
    (e) Well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;
    (f) Severity of reaction.
    A.<IP_ADDRESS>.2   Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitization are usually derived from case-control or other, less defined studies. Evaluation of human data must, therefore, be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.
    A.<IP_ADDRESS>.3   If none of the above-mentioned conditions are met, the substance need not be classified as a skin sensitizer. However, a combination of two or more indicators of skin sensitization, as listed below, may alter the decision. This shall be considered on a case-by-case basis.
    (a) Isolated episodes of allergic contact dermatitis;
    (b) Epidemiological studies of limited power, e.g., where chance, bias or confounders have not been ruled out fully with reasonable confidence;
    (c) Data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in A.<IP_ADDRESS>, but which are sufficiently close to the limit to be considered significant;
    (d) Positive data from non-standard methods;
    (e) Positive results from close structural analogues.
    A.<IP_ADDRESS>.4   Immunological contact urticaria.
    A.<IP_ADDRESS>.4.1   Substances meeting the criteria for classification as respiratory sensitizers may, in addition, cause immunological contact urticaria. Consideration shall be given to classifying these substances as skin sensitizers.
    A.<IP_ADDRESS>.4.2   Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitizers shall be considered for classification as skin sensitizers.
    A.<IP_ADDRESS>.4.3   There is no recognized animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence, similar to that for skin sensitization.
A.4.3   Classification Criteria for Mixtures
A.4.3.1   Classification of Mixtures When Data Are Available for the Complete Mixture
    When reliable and good quality evidence, as described in the criteria for substances, from human experience or appropriate studies in experimental animals, is available for the mixture, then the mixture shall be classified by weight of evidence evaluation of these data. Care must be exercised in evaluating data on mixtures that the dose used does not render the results inconclusive.
A.4.3.2   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its sensitizing properties, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following agreed bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, Concentration of mixtures, Interpolation, Substantially similar mixtures, and Aerosols.
A.4.3.3   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    The mixture shall be classified as a respiratory or skin sensitizer when at least one ingredient has been classified as a respiratory or skin sensitizer and is present at or above the appropriate cut-off value/concentration limit for the specific endpoint as shown in Table A.4.5.
    Table A.4.5 -- Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Either Respiratory Sensitizers or Skin Sensitizers That Would Trigger Classification of the Mixture
Ingredient classified as:
Cut-off values/concentration limits triggering classification of a mixture as:

Respiratory Sensitizer
Category 1
Skin Sensitizer
Category 1

Solid/liquid
Gas
All physical states
Respiratory Sensitizer, Category 1
>=0.1%
>=0.1%

Respiratory Sensitizer, Sub-category 1A
>=0.1%
>=0.1%

Respiratory Sensitizer, Sub-category 1B
>=1.0%
>=0.2%

Skin Sensitizer, Category 1

>=0.1%
Skin Sensitizer, Sub-category 1A

>=0.1%
Skin Sensitizer, Sub-category 1B

>=1.0%
A.5   GERM CELL MUTAGENICITY
A.5.1   Definitions and General Considerations
    A.5.1.1   A mutation is defined as a permanent change in the amount or structure of the genetic material in a cell. The term mutation applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including, for example, specific base pair changes and chromosomal translocations). The term mutagenic and mutagen will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.
    A.5.1.2   The more general terms genotoxic and genotoxicity apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replication processes, or which in a non-physiological manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators for mutagenic effects.
    A.5.1.3   This hazard class is primarily concerned with chemicals that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and mixtures within this hazard class.
A.5.2   Classification Criteria for Substances
    A.5.2.1   The classification system provides for two different categories of germ cell mutagens to accommodate the weight of evidence available. The two-category system is described in the Figure A.5.1.
    Figure A.5.1 -- Hazard Categories for Germ Cell Mutagens

CATEGORY 1: Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.
Category 1A: Substances known to induce heritable mutations in germ cells of humans.
Positive evidence from human epidemiological studies.
Category 1B: Substances which should be regarded as if they induce heritable mutations in the germ cells of humans.
(a) Positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or
(b) Positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. This supporting evidence may, for example, be derived from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or
(c) Positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.
CATEGORY 2: Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans.
Positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:
(a) Somatic cell mutagenicity tests in vivo, in mammals; or
(b) Other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.
Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, should be considered for classification as Category 2 mutagens.
    A.5.2.2   Specific considerations for classification of substances as germ cell mutagens:
    A.<IP_ADDRESS>   To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered.
    A.<IP_ADDRESS>   The system is hazard based, classifying chemicals on the basis of their intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant for the (quantitative) risk assessment of chemical substances.
    A.<IP_ADDRESS>   Classification for heritable effects in human germ cells is made on the basis of scientifically validated tests. Evaluation of the test results shall be done using expert judgment and all the available evidence shall be weighed for classification.
    A.<IP_ADDRESS>   The classification of substances shall be based on the total weight of evidence available, using expert judgment. In those instances where a single well-conducted test is used for classification, it shall provide clear and unambiguously positive results. The relevance of the route of exposure used in the study of the substance compared to the route of human exposure should also be taken into account.
A.5.3   Classification Criteria for Mixtures5
    5It should be noted that the classification criteria for health hazards usually include a tiered scheme in which test data available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable bridging principles, and lastly, cut-off values/concentration limits or additivity. However, this approach is not used for Germ Cell Mutagenicity. These criteria for Germ Cell Mutagenicity consider the cut-off values/concentration limits as the primary tier and allow the classification to be modified only on a case-by-case evaluation based on available test data for the mixture as a whole.
A.5.3.1   Classification of Mixtures When Data Are Available for All Ingredients or Only for Some Ingredients of the Mixture
    A.<IP_ADDRESS>   Classification of mixtures shall be based on the available test data for the individual ingredients of the mixture using cut-off values/concentration limits for the ingredients classified as germ cell mutagens.
    A.<IP_ADDRESS>   The mixture will be classified as a mutagen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 mutagen and is present at or above the appropriate cut-off value/concentration limit as shown in Table A.5.1 below for Category 1 and 2 respectively.
    Table A.5.1 -- Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Germ Cell Mutagens That Would Trigger Classification of the Mixture
Ingredient classified as:
Cut-off/concentration limits triggering classification of a mixture as:

Category 1 mutagen
Category 2 mutagen
Category 1A/B mutagen
>=0.1%

Category 2 mutagen

>=1.0%
    Note: The cut-off values/concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).
A.5.3.2   Classification of Mixtures When Data Are Available for the Mixture Itself
    The classification may be modified on a case-by-case basis based on the available test data for the mixture as a whole. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations and analysis (e.g. statistical analysis, test sensitivity) of germ cell mutagenicity test systems.
A.5.3.3   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    A.<IP_ADDRESS>   Where the mixture itself has not been tested to determine its germ cell mutagenicity hazard, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, and Substantially similar mixtures.
A.5.4   Examples of Scientifically Validated Test Methods
  A.5.4.1   Examples of in vivo heritable germ cell mutagenicity tests are:
    (a) Rodent dominant lethal mutation test (OECD 478)
    (b) Mouse heritable translocation assay (OECD 485)
    (c) Mouse specific locus test
  A.5.4.2   Examples of in vivo somatic cell mutagenicity tests are:
    (a) Mammalian bone marrow chromosome aberration test (OECD 475)
    (b) Mouse spot test (OECD 484)
    (c) Mammalian erythrocyte micronucleus test (OECD 474)
  A.5.4.3   Examples of mutagenicity/genotoxicity tests in germ cells are:
    (a) Mutagenicity tests:
    (i) Mammalian spermatogonial chromosome aberration test (OECD 483)
    (ii) Spermatid micronucleus assay
    (b) Genotoxicity tests:
    (i) Sister chromatid exchange analysis in spermatogonia
    (ii) Unscheduled DNA synthesis test (UDS) in testicular cells
  A.5.4.4   Examples of genotoxicity tests in somatic cells are:
    (a) Liver Unscheduled DNA Synthesis (UDS) in vivo (OECD 486)
    (b) Mammalian bone marrow Sister Chromatid Exchanges (SCE)
  A.5.4.5   Examples of in vitro mutagenicity tests are:
    (a) In vitro mammalian chromosome aberration test (OECD 473)
    (b) In vitro mammalian cell gene mutation test (OECD 476)
    (c) Bacterial reverse mutation tests (OECD 471)
  A.5.4.6   As new, scientifically validated tests arise, these may also be used in the total weight of evidence to be considered.
A.6   CARCINOGENICITY
A.6.1   Definitions
    Carcinogen means a substance or a mixture of substances which induce cancer or increase its incidence. Substances and mixtures which have induced benign and malignant tumors in well-performed experimental studies on animals are considered also to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumor formation is not relevant for humans.
    Classification of a substance or mixture as posing a carcinogenic hazard is based on its inherent properties and does not provide information on the level of the human cancer risk which the use of the substance or mixture may represent.
A.6.2   Classification Criteria for Substances6
    6See Non-mandatory Appendix F Part A for further guidance regarding hazard classification for carcinogenicity. This appendix is consistent with the GHS adn is provided as guidance excerpted from the International Agency for Research on Cancer (IARC) "Monographs on the Evaluation of Carcinogenic Risks to Humans" (2006).
    A.6.2.1 For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional weight of evidence considerations. In certain instances, route-specific classification may be warranted.
    Figure A.6.1 -- Hazard Categories for Carcinogens

CATEGORY 1: Known or presumed human carcinogens.
The classification of a substance as a Category 1 carcinogen is done on the basis of epidemiological and/or animal data. This classification is further distinguished on the basis of whether the evidence for classification is largely from human data (Category 1A) or from animal data (Category 1B):
Category 1A: Known to have carcinogenic potential for humans. Classification in this category is largely based on human evidence.
Category 1B: Presumed to have carcinogenic potential for humans. Classification in this category is largely based on animal evidence.
The classification of a substance in Category 1A and 1B is based on strength of evidence together with weight of evidence considerations (See paragraph A.6.2.5). Such evidence may be derived from:
 -- human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or
 -- animal experiments for which there is sufficient evidence to demonstrate animal carcinogenicity (presumed human carcinogen).
In addition, on a case by case basis, scientific judgment may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.
CATEGORY 2: Suspected human carcinogens.
The classification of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or B. This classification is based on strength of evidence together with weight of evidence considerations (See paragraph A.6.2.5). Such evidence may be from either limited evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.
Other considerations: Where the weight of evidence for the carcinogenicity of a substance does not meet the above criteria, any positive study conducted in accordance with established scientific principles, and which reports statistically significant findings regarding the carcinogenic potential of the substance, must be noted on the safety data sheet.
    A.6.2.2   Classification as a carcinogen is made on the basis of evidence from reliable and acceptable methods, and is intended to be used for substances which have an intrinsic property to produce such toxic effects. The evaluations are to be based on all existing data, peer-reviewed published studies and additional data accepted by regulatory agencies.
    A.6.2.3   Carcinogen classification is a one-step, criterion-based process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.
    A.6.2.4   Strength of evidence involves the enumeration of tumors in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the agent and an increased incidence of tumors. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. (Guidance on consideration of important factors in the classification of carcinogenicity and a more detailed description of the terms "limited" and "sufficient" have been developed by the International Agency for Research on Cancer (IARC) and are provided in non-mandatory Appendix F).
    A.6.2.5   Weight of evidence: Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors should be considered that influence the overall likelihood that an agent may pose a carcinogenic hazard in humans. The full list of factors that influence this determination is very lengthy, but some of the important ones are considered here.
    A.<IP_ADDRESS>   These factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumor findings and the other factors in a case-by-case manner.
    A.<IP_ADDRESS>   Some important factors which may be taken into consideration, when assessing the overall level of concern are:
    (a) Tumor type and background incidence;
    (b) Multisite responses;
    (c) Progression of lesions to malignancy;
    (d) Reduced tumor latency;
    Additional factors which may increase or decrease the level of concern include:
    (e) Whether responses are in single or both sexes;
    (f) Whether responses are in a single species or several species;
    (g) Structural similarity or not to a substance(s) for which there is good evidence of carcinogenicity;
    (h) Routes of exposure;
    (i) Comparison of absorption, distribution, metabolism and excretion between test animals and humans;
    (j) The possibility of a confounding effect of excessive toxicity at test doses; and,
    (k) Mode of action and its relevance for humans, such as mutagenicity, cytotoxicity with growth stimulation, mitogenesis, immunosuppression.
    Mutagenicity: It is recognized that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.
    A.<IP_ADDRESS>   A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B, or Category 2 based on tumor data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g., for benzidine congener dyes.
    A.<IP_ADDRESS>   The classification should also take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumors at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.
    A.<IP_ADDRESS>   It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e., structure activity relationship, is taken into consideration when undertaking classification.
A.6.3   Classification Criteria for Mixtures7
    7It should be noted that the classification criteria for health hazards usually include a tiered scheme in which test data available on the complete mixture are considered as the first tier in the evaluation, followed by the applicable bridging principles, and lastly, cut-off values/concentration limit or additivity. However, this approach is not used for Carcinogenicity. These criteria for Carcinogenicity consider the cut-off values/concentration limits as the primary tier and allow the classification to be modified only on a case-by-case evaluation based on available test data for the mixture as a whole.
    A.6.3.1   The mixture shall be classified as a carcinogen when at least one ingredient has been classified as a Category 1 or Category 2 carcinogen and is present at or above the appropriate cut-off value/concentration limit as shown in Table A.6.1.
    Table A.6.1 -- Cut-Off Values/Concentration Limits of Ingredients of a Mixture Classified as Carcinogen That Would Trigger Classification of the Mixture
Ingredient classified as:
Category 1
carcinogen
Category 2
carcinogen
Category 1 carcinogen
>=0.1%

Category 2 carcinogen

>=0.1% (note 1).
    Note: If a Category 2 carcinogen ingredient is present in the mixture at a concentration between 0.1% and 1%, information is required on the SDS for a product. However, a label warning is optional. If a Category 2 carcinogen ingredient is present in the mixture at a concentration of >=1%, both an SDS and a label is required and the information must be included on each.
A.6.3.2   Classification of Mixtures When Data Are Available for the Complete Mixture
    A mixture may be classified based on the available test data for the mixture as a whole. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations and analysis (e.g., statistical analysis, test sensitivity) of carcinogenicity test systems.
A.6.3.3   Classification of Mixtures When Data Are Not Available for the Complete Mixture: Bridging Principles
    Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are sufficient data on both the individual ingredients and similar tested mixtures to adequately characterize the hazards of the mixture, these data will be used in accordance with the following bridging principles as found in paragraph A.0.5 of this Appendix: Dilution; Batching; and Substantially similar mixtures.
A.6.4   Classification of Carcinogenicity8
    8See Non-mandatory Appendix F for further guidance regarding hazard classification for carcinogenicity and how to relate carcinogenicity classification information from IARC and NTP to GHS.
    A.6.4.1   Chemical manufacturers, importers and employers evaluating chemicals may treat the following sources as establishing that a substance is a carcinogen or potential carcinogen for hazard communication purposes in lieu of applying the criteria described herein:
    A.<IP_ADDRESS>   National Toxicology Program (NTP), "Report on Carcinogens" (latest edition);
    A.<IP_ADDRESS>   International Agency for Research on Cancer (IARC) "Monographs on the Evaluation of Carcinogenic Risks to Humans" (latest editions)
    A.6.4.2   Where OSHA has included cancer as a health hazard to be considered by classifiers for a chemical covered by 29 CFR part 1910, Subpart Z, Toxic and Hazardous Substances, chemical manufacturers, importers, and employers shall classify the chemical as a carcinogen.
A.7   REPRODUCTIVE TOXICITY
A.7.1   Definitions and General Considerations
    A.7.1.1   Reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as adverse effects on development of the offspring. Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function and fertility or to developmental toxicity. Nonetheless, chemicals with these effects shall be classified as reproductive toxicants.
    For classification purposes, the known induction of genetically based inheritable effects in the offspring is addressed in Germ cell mutagenicity (See A.5).
    A.7.1.2   Adverse effects on sexual function and fertility means any effect of chemicals that interferes with reproductive ability or sexual capacity. This includes, but is not limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour, fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in other functions that are dependent on the integrity of the reproductive systems.
    A.7.1.3   Adverse effects on development of the offspring means any effect of chemicals which interferes with normal development of the conceptus either before or after birth, which is induced during pregnancy or results from parental exposure. These effects can be manifested at any point in the life span of the organism. The major manifestations of developmental toxicity include death of the developing organism, structural abnormality, altered growth and functional deficiency.
    A.7.1.4   Adverse effects on or via lactation are also included in reproductive toxicity, but for classification purposes, such effects are treated separately (See A.7.2.1).
A.7.2   Classification Criteria for Substances
    A.7.2.1   For the purpose of classification for reproductive toxicity, substances shall be classified in one of two categories in accordance with Figure A.7.1(a). Effects on sexual function and fertility, and on development, shall be considered. In addition, effects on or via lactation shall be classified in a separate hazard category in accordance with Figure A.7.1(b).
    Figure A.7.1(a) -- Hazard Categories for Reproductive Toxicants
CATEGORY 1: Known or presumed human reproductive toxicant.
Substance shall be classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).
Category 1A: Known human reproductive toxicant.
The classification of a substance in this category is largely based on evidence from humans.
Category 1B: Presumed human reproductive toxicant.
The classification of a substance in this category is largely based on evidence from experimental animals. Data from animal studies shall provide sufficient evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.
CATEGORY 2: Suspected human reproductive toxicant.
Substances shall be classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects, and where the evidence is not sufficiently convincing to place the substance in Category 1. For instance, deficiencies in the study may make the quality of evidence less convincing, and in view of this, Category 2 would be the more appropriate classification.
    Figure A.7.1(b) -- Hazard Category for Effects on or Via Lactation
EFFECTS ON OR VIA LACTATION
Effects on or via lactation shall be classified in a separate single category. Chemicals that are absorbed by women and have been shown to interfere with lactation or that may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified to indicate this property hazardous to breastfed babies. This classification shall be assigned on the basis of:
(a) absorption, metabolism, distribution and excretion studies that indicate the likelihood the substance would be present in potentially toxic levels in breast milk; and/or
(b) results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or
(c) human evidence indicating a hazard to babies during the lactation period.
A.7.2.2   Basis of Classification
    A.<IP_ADDRESS>   Classification is made on the basis of the criteria, outlined above, an assessment of the total weight of evidence, and the use of expert judgment. Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances should not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.
    A.<IP_ADDRESS>   In the evaluation of toxic effects on the developing offspring, it is important to consider the possible influence of maternal toxicity.
    A.<IP_ADDRESS>   For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall be from well conducted epidemiological studies, if available, which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans may be sufficient for a Category 1A classification if supplemented with adequate data from studies in experimental animals, but classification in Category 1B may also be considered.
A.7.2.3   Weight of Evidence
    A.<IP_ADDRESS>   Classification as a reproductive toxicant is made on the basis of an assessment of the total weight of evidence using expert judgment. This means that all available information that bears on the determination of reproductive toxicity is considered together. Included is information such as epidemiological studies and case reports in humans and specific reproduction studies along with sub-chronic, chronic and special study results in animals that provide relevant information regarding toxicity to reproductive and related endocrine organs. Evaluation of substances chemically related to the material under study may also be included, particularly when information on the material is scarce. The weight given to the available evidence will be influenced by factors such as the quality of the studies, consistency of results, nature and severity of effects, level of statistical significance for intergroup differences, number of endpoints affected, relevance of route of administration to humans and freedom from bias. Both positive and negative results are considered together in a weight of evidence determination. However, a single, positive study performed according to good scientific principles and with statistically or biologically significant positive results may justify classification (See also A.<IP_ADDRESS>).
    A.<IP_ADDRESS>   Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information, which could reduce or increase concerns about the hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a chemical which produces an adverse effect on reproduction in experimental animals should not be classified.
    A.<IP_ADDRESS>   In some reproductive toxicity studies in experimental animals the only effects recorded may be considered of low or minimal toxicological significance and classification may not necessarily be the outcome. These effects include, for example, small changes in semen parameters or in the incidence of spontaneous defects in the fetus, small changes in the proportions of common fetal variants such as are observed in skeletal examinations, or in fetal weights, or small differences in postnatal developmental assessments.
    A.<IP_ADDRESS>   Data from animal studies shall provide sufficient evidence of specific reproductive toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs together with other toxic effects in the dam (mother), the potential influence of the generalized adverse effects should be assessed to the extent possible. The preferred approach is to consider adverse effects in the embryo/fetus first, and then evaluate maternal toxicity, along with any other factors which are likely to have influenced these effects, as part of the weight of evidence. In general, developmental effects that are observed at maternally toxic doses should not be automatically discounted. Discounting developmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis when a causal relationship is established or refuted.
    A.<IP_ADDRESS>   If appropriate information is available it is important to try to determine whether developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of maternal toxicity should not be used to negate findings of embryo/fetal effects, unless it can be clearly demonstrated that the effects are secondary non-specific effects. This is especially the case when the effects in the offspring are significant, e.g., irreversible effects such as structural malformations. In some situations it is reasonable to assume that reproductive toxicity is due to a secondary consequence of maternal toxicity and discount the effects, for example if the chemical is so toxic that dams fail to thrive and there is severe inanition; they are incapable of nursing pups; or they are prostrate or dying.
A.7.2.4   Maternal Toxicity
    A.<IP_ADDRESS>   Development of the offspring throughout gestation and during the early postnatal stages can be influenced by toxic effects in the mother either through non-specific mechanisms related to stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. So, in the interpretation of the developmental outcome to decide classification for developmental effects it is important to consider the possible influence of maternal toxicity. This is a complex issue because of uncertainties surrounding the relationship between maternal toxicity and developmental outcome. Expert judgment and a weight of evidence approach, using all available studies, shall be used to determine the degree of influence to be attributed to maternal toxicity when interpreting the criteria for classification for developmental effects. The adverse effects in the embryo/fetus shall be first considered, and then maternal toxicity, along with any other factors which are likely to have influenced these effects, as weight of evidence, to help reach a conclusion about classification.
    A.<IP_ADDRESS>   Based on pragmatic observation, it is believed that maternal toxicity may, depending on severity, influence development via non-specific secondary mechanisms, producing effects such as depressed fetal weight, retarded ossification, and possibly resorptions and certain malformations in some strains of certain species. However, the limited numbers of studies which have investigated the relationship between developmental effects and general maternal toxicity have failed to demonstrate a consistent, reproducible relationship across species. Developmental effects which occur even in the presence of maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case by case basis that the developmental effects are secondary to maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the offspring, e.g., irreversible effects such as structural malformations, embryo/fetal lethality, or significant post-natal functional deficiencies.
    A.<IP_ADDRESS>   Classification shall not automatically be discounted for chemicals that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a chemical is so toxic that maternal death or severe inanition results, or the dams (mothers) are prostrate and incapable of nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification is not necessarily the outcome in the case of minor developmental changes, e.g., a small reduction in fetal/pup body weight or retardation of ossification when seen in association with maternal toxicity.
    A.<IP_ADDRESS>   Some of the endpoints used to assess maternal toxicity are provided below. Data on these endpoints, if available, shall be evaluated in light of their statistical or biological significance and dose-response relationship.
    (a) Maternal mortality: An increased incidence of mortality among the treated dams over the controls shall be considered evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the systemic toxicity of the test material. Maternal mortality greater than 10% is considered excessive and the data for that dose level shall not normally be considered to need further evaluation.
    (b) Mating index (Number of animals with seminal plugs or sperm/Number of mated x 100)
    (c) Fertility index (Number of animals with implants/Number of matings x 100)
    (d) Gestation length (If allowed to deliver)
    (e) Body weight and body weight change: Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight shall be included in the evaluation of maternal toxicity whenever such data are available. The calculation of an adjusted (corrected) mean maternal body weight change, which is the difference between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the weights of the fetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the body weight gain may not be a useful indicator of maternal toxicity because of normal fluctuations in body weight during pregnancy.
    (f) Food and water consumption (if relevant): The observation of a significant decrease in the average food or water consumption in treated dams (mothers) compared to the control group may be useful in evaluating maternal toxicity, particularly when the test material is administered in the diet or drinking water. Changes in food or water consumption must be evaluated in conjunction with maternal body weights when determining if the effects noted are reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.