Hazard Communication. Chemicals Which They Produce Or Im- (A) Purpose

Occupational Safety and Health Admin., Labor § 1910.1200

of a currently effective determination chemicals in the workplace, as well as by the Assistant Secretary of Labor of containers of chemicals being that such program is compatible with shipped to other workplaces; prepara- the requirements of this section. Such tion and distribution of safety data determinations currently are in effect sheets to employees and downstream only in the States of Alabama, Arkan- employers; and development and imple- sas, California, Kansas, Kentucky, mentation of employee training pro- Florida, Mississippi, New Hampshire, grams regarding hazards of chemicals New York, North Carolina, Texas, Ten- and protective measures. Under section nessee, Oregon, Idaho, Arizona, Colo- 18 of the Act, no state or political sub- rado, Louisiana, Nebraska, Wash- division of a state may adopt or en- ington, Maryland, North Dakota, force any requirement relating to the South Carolina, and Georgia. issue addressed by this Federal stand- [39 FR 23502, June 27, 1974, as amended at 43 ard, except pursuant to a Federally-ap- FR 49746, Oct. 24, 1978; 43 FR 51759, Nov. 7, proved state plan. 1978; 49 FR 18295, Apr. 30, 1984; 58 FR 35309, (b) Scope and application. (1) This sec- June 30, 1993. Redesignated at 61 FR 31430, June 20, 1996] tion requires chemical manufacturers or importers to classify the hazards of § 1910.1200 Hazard communication. chemicals which they produce or im- (a) Purpose. (1) The purpose of this port, and all employers to provide in- section is to ensure that the hazards of formation to their employees about the all chemicals produced or imported are hazardous chemicals to which they are classified, and that information con- exposed, by means of a hazard commu- cerning the classified hazards is trans- nication program, labels and other mitted to employers and employees. forms of warning, safety data sheets, The requirements of this section are and information and training. In addi- intended to be consistent with the pro- tion, this section requires distributors visions of the United Nations Globally to transmit the required information Harmonized System of Classification to employers. (Employers who do not and Labelling of Chemicals (GHS), Re- produce or import chemicals need only vision 3. The transmittal of informa- focus on those parts of this rule that tion is to be accomplished by means of deal with establishing a workplace pro- comprehensive hazard communication gram and communicating information programs, which are to include con- to their workers.) tainer labeling and other forms of (2) This section applies to any chem- warning, safety data sheets and em- ical which is known to be present in ployee training. the workplace in such a manner that (2) This occupational safety and employees may be exposed under nor- health standard is intended to address mal conditions of use or in a foresee- comprehensively the issue of able emergency. classifying the potential hazards of (3) This section applies to labora- chemicals, and communicating infor- tories only as follows: mation concerning hazards and appropriate protective measures to employ- (i) Employers shall ensure that labels ees, and to preempt any legislative or on incoming containers of hazardous regulatory enactments of a state, or chemicals are not removed or defaced; political subdivision of a state, per- (ii) Employers shall maintain any taining to this subject. Classifying the safety data sheets that are received potential hazards of chemicals and with incoming shipments of hazardous communicating information con- chemicals, and ensure that they are cerning hazards and appropriate pro- readily accessible during each tective measures to employees, may in- workshift to laboratory employees clude, for example, but is not limited when they are in their work areas; to, provisions for: developing and main- (iii) Employers shall ensure that lab- taining a written hazard communica- oratory employees are provided infor- tion program for the workplace, includ- mation and training in accordance ing lists of hazardous chemicals with paragraph (h) of this section, ex- present; labeling of containers of cept for the location and availability of

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the written hazard communication pro- (ii) Any chemical substance or mix- gram under paragraph (h)(2)(iii) of this ture as such terms are defined in the section; and, Toxic Substances Control Act (15 (iv) Laboratory employers that ship U.S.C. 2601 et seq.), when subject to the hazardous chemicals are considered to labeling requirements of that Act and be either a chemical manufacturer or a labeling regulations issued under that distributor under this rule, and thus Act by the Environmental Protection must ensure that any containers of Agency. hazardous chemicals leaving the lab- (iii) Any food, food additive, color ad- oratory are labeled in accordance with ditive, drug, cosmetic, or medical or paragraph (f) of this section, and that a veterinary device or product, including safety data sheet is provided to dis- materials intended for use as ingredi- tributors and other employers in ac- ents in such products (e.g. flavors and cordance with paragraphs (g)(6) and fragrances), as such terms are defined (g)(7) of this section. in the Federal Food, Drug, and Cos- (4) In work operations where employ- metic Act (21 U.S.C. 301 et seq.) or the ees only handle chemicals in sealed Virus-Serum-Toxin Act of 1913 (21 containers which are not opened under U.S.C. 151 et seq.), and regulations normal conditions of use (such as are issued under those Acts, when they are found in marine cargo handling, subject to the labeling requirements warehousing, or retail sales), this sec- under those Acts by either the Food tion applies to these operations only as and Drug Administration or the De- follows: partment of Agriculture; (i) Employers shall ensure that labels (iv) Any distilled spirits (beverage al- on incoming containers of hazardous cohols), wine, or malt beverage in- chemicals are not removed or defaced; tended for nonindustrial use, as such (ii) Employers shall maintain copies terms are defined in the Federal Alco- of any safety data sheets that are re- hol Administration Act (27 U.S.C. 201 et ceived with incoming shipments of the seq.) and regulations issued under that sealed containers of hazardous chemi- Act, when subject to the labeling re- cals, shall obtain a safety data sheet as quirements of that Act and labeling soon as possible for sealed containers regulations issued under that Act by of hazardous chemicals received with- the Bureau of Alcohol, Tobacco, Fire- out a safety data sheet if an employee arms and Explosives; requests the safety data sheet, and shall ensure that the safety data sheets (v) Any consumer product or haz- are readily accessible during each work ardous substance as those terms are de- shift to employees when they are in fined in the Consumer Product Safety their work area(s); and, Act (15 U.S.C. 2051 et seq.) and Federal (iii) Employers shall ensure that em- Hazardous Substances Act (15 U.S.C. ployees are provided with information 1261 et seq.) respectively, when subject and training in accordance with para- to a consumer product safety standard graph (h) of this section (except for the or labeling requirement of those Acts, location and availability of the written or regulations issued under those Acts hazard communication program under by the Consumer Product Safety Com- paragraph (h)(2)(iii) of this section), to mission; and, the extent necessary to protect them (vi) Agricultural or vegetable seed in the event of a spill or leak of a haz- treated with pesticides and labeled in ardous chemical from a sealed con- accordance with the Federal Seed Act tainer. (7 U.S.C. 1551 et seq.) and the labeling (5) This section does not require la- regulations issued under that Act by beling of the following chemicals: the Department of Agriculture. (i) Any pesticide as such term is de- (6) This section does not apply to: (i) fined in the Federal Insecticide, Fun- Any hazardous waste as such term is gicide, and Rodenticide Act (7 U.S.C. defined by the Solid Waste Disposal 136 et seq.), when subject to the labeling Act, as amended by the Resource Con- requirements of that Act and labeling servation and Recovery Act of 1976, as regulations issued under that Act by amended (42 U.S.C. 6901 et seq.), when the Environmental Protection Agency; subject to regulations issued under

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that Act by the Environmental Protec- or importer of the product, and the use tion Agency; results in a duration and frequency of (ii) Any hazardous substance as such exposure which is not greater than the term is defined by the Comprehensive range of exposures that could reason- Environmental Response, Compensa- ably be experienced by consumers when tion and Liability Act (CERCLA) (42 used for the purpose intended; U.S.C. 9601 et seq.) when the hazardous (x) Nuisance particulates where the substance is the focus of remedial or chemical manufacturer or importer removal action being conducted under can establish that they do not pose any CERCLA in accordance with Environ- physical or health hazard covered mental Protection Agency regulations. under this section; (iii) Tobacco or tobacco products; (xi) Ionizing and nonionizing radi- (iv) Wood or wood products, including ation; and, lumber which will not be processed, (xii) Biological hazards. where the chemical manufacturer or (c) Definitions. Article means a manu- importer can establish that the only factured item other than a fluid or par- hazard they pose to employees is the ticle: (i) which is formed to a specific potential for flammability or combus- shape or design during manufacture; tibility (wood or wood products which (ii) which has end use function(s) de- have been treated with a hazardous pendent in whole or in part upon its chemical covered by this standard, and shape or design during end use; and (iii) wood which may be subsequently sawed which under normal conditions of use or cut, generating dust, are not ex- does not release more than very small empted); quantities, e.g., minute or trace (v) Articles (as that term is defined amounts of a hazardous chemical (as in paragraph (c) of this section); determined under paragraph (d) of this (vi) Food or alcoholic beverages section), and does not pose a physical which are sold, used, or prepared in a hazard or health risk to employees. retail establishment (such as a grocery Assistant Secretary means the Assist- store, restaurant, or drinking place), ant Secretary of Labor for Occupa- and foods intended for personal con- tional Safety and Health, U.S. Depart- sumption by employees while in the ment of Labor, or designee. workplace; Chemical means any substance, or (vii) Any drug, as that term is de- mixture of substances. fined in the Federal Food, Drug, and Chemical manufacturer means an em- Cosmetic Act (21 U.S.C. 301 et seq.), ployer with a workplace where chem- when it is in solid, final form for direct ical(s) are produced for use or distribu- administration to the patient (e.g., tab- tion. lets or pills); drugs which are packaged Chemical name means the scientific by the chemical manufacturer for sale designation of a chemical in accord- to consumers in a retail establishment ance with the nomenclature system de- (e.g., over-the-counter drugs); and veloped by the International Union of drugs intended for personal consump- Pure and Applied Chemistry (IUPAC) tion by employees while in the work- or the Chemical Abstracts Service place (e.g., first aid supplies); (CAS) rules of nomenclature, or a name (viii) Cosmetics which are packaged that will clearly identify the chemical for sale to consumers in a retail estab- for the purpose of conducting a hazard lishment, and cosmetics intended for classification. personal consumption by employees Classification means to identify the while in the workplace; relevant data regarding the hazards of (ix) Any consumer product or haz- a chemical; review those data to ascer- ardous substance, as those terms are tain the hazards associated with the defined in the Consumer Product Safe- chemical; and decide whether the ty Act (15 U.S.C. 2051 et seq.) and Fed- chemical will be classified as hazardous eral Hazardous Substances Act (15 according to the definition of haz- U.S.C. 1261 et seq.) respectively, where ardous chemical in this section. In ad- the employer can show that it is used dition, classification for health and in the workplace for the purpose in- physical hazards includes the deter- tended by the chemical manufacturer mination of the degree of hazard, where

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appropriate, by comparing the data exposure. ‘‘Subjected’’ in terms of with the criteria for health and phys- health hazards includes any route of ical hazards. entry (e.g. inhalation, ingestion, skin Commercial account means an ar- contact or absorption.) rangement whereby a retail distributor Foreseeable emergency means any po- sells hazardous chemicals to an em- tential occurrence such as, but not lim- ployer, generally in large quantities ited to, equipment failure, rupture of over time and/or at costs that are containers, or failure of control equip- below the regular retail price. ment which could result in an uncon- Common name means any designation trolled release of a hazardous chemical or identification such as code name, into the workplace. code number, trade name, brand name Hazard category means the division of or generic name used to identify a criteria within each hazard class, e.g., chemical other than by its chemical oral acute toxicity and flammable liq- name. uids include four hazard categories. Container means any bag, barrel, bot- These categories compare hazard sever- tle, box, can, cylinder, drum, reaction ity within a hazard class and should vessel, storage tank, or the like that not be taken as a comparison of hazard contains a hazardous chemical. For categories more generally. purposes of this section, pipes or piping Hazard class means the nature of the systems, and engines, fuel tanks, or physical or health hazards, e.g., flam- other operating systems in a vehicle, mable solid, carcinogen, oral acute tox- are not considered to be containers. icity. Designated representative means any individual or organization to whom an Hazard not otherwise classified (HNOC) employee gives written authorization means an adverse physical or health ef- to exercise such employee’s rights fect identified through evaluation of under this section. A recognized or cer- scientific evidence during the classi- tified collective bargaining agent shall fication process that does not meet the be treated automatically as a des- specified criteria for the physical and ignated representative without regard health hazard classes addressed in this to written employee authorization. section. This does not extend coverage Director means the Director, National to adverse physical and health effects Institute for Occupational Safety and for which there is a hazard class ad- Health, U.S. Department of Health and dressed in this section, but the effect Human Services, or designee. either falls below the cut-off value/con- Distributor means a business, other centration limit of the hazard class or than a chemical manufacturer or im- is under a GHS hazard category that porter, which supplies hazardous has not been adopted by OSHA (e.g., chemicals to other distributors or to acute toxicity Category 5). employers. Hazard statement means a statement Employee means a worker who may be assigned to a hazard class and category exposed to hazardous chemicals under that describes the nature of the haz- normal operating conditions or in fore- ard(s) of a chemical, including, where seeable emergencies. Workers such as appropriate, the degree of hazard. office workers or bank tellers who en- Hazardous chemical means any chem- counter hazardous chemicals only in ical which is classified as a physical non-routine, isolated instances are not hazard or a health hazard, a simple as- covered. phyxiant, combustible dust, pyrophoric Employer means a person engaged in a gas, or hazard not otherwise classified. business where chemicals are either Health hazard means a chemical used, distributed, or are produced for which is classified as posing one of the use or distribution, including a con- following hazardous effects: acute tox- tractor or subcontractor. icity (any route of exposure); skin cor- Exposure or exposed means that an rosion or irritation; serious eye dam- employee is subjected in the course of age or eye irritation; respiratory or employment to a chemical that is a skin sensitization; germ cell mutage- physical or health hazard, and includes nicity; carcinogenicity; reproductive potential (e.g. accidental or possible) toxicity; specific target organ toxicity

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(single or repeated exposure); or aspira- chemical, or improper storage or han- tion hazard. The criteria for deter- dling. mining whether a chemical is classified Produce means to manufacture, proc- as a health hazard are detailed in Ap- ess, formulate, blend, extract, gen- pendix A to § 1910.1200—Health Hazard erate, emit, or repackage. Criteria. Product identifier means the name or Immediate use means that the haz- number used for a hazardous chemical ardous chemical will be under the con- on a label or in the SDS. It provides a trol of and used only by the person who unique means by which the user can transfers it from a labeled container identify the chemical. The product and only within the work shift in identifier used shall permit cross-ref- which it is transferred. erences to be made among the list of Importer means the first business hazardous chemicals required in the with employees within the Customs written hazard communication pro- Territory of the United States which gram, the label and the SDS. receives hazardous chemicals produced Pyrophoric gas means a chemical in a in other countries for the purpose of gaseous state that will ignite spontane- supplying them to distributors or em- ously in air at a temperature of 130 de- ployers within the United States. grees F (54.4 degrees C) or below. means someone who Label means an appropriate group of Responsible party can provide additional information on written, printed or graphic information the hazardous chemical and appro- elements concerning a hazardous chem- priate emergency procedures, if nec- ical that is affixed to, printed on, or at- essary. tached to the immediate container of a Safety data sheet (SDS) means written hazardous chemical, or to the outside or printed material concerning a haz- packaging. ardous chemical that is prepared in ac- Label elements means the specified cordance with paragraph (g) of this sec- pictogram, hazard statement, signal tion. word and precautionary statement for Signal word means a word used to in- each hazard class and category. dicate the relative level of severity of Mixture means a combination or a so- hazard and alert the reader to a poten- lution composed of two or more sub- tial hazard on the label. The signal stances in which they do not react. words used in this section are ‘‘danger’’ Physical hazard means a chemical and ‘‘warning.’’ ‘‘Danger’’ is used for that is classified as posing one of the the more severe hazards, while ‘‘warn- following hazardous effects: explosive; ing’’ is used for the less severe. flammable (gases, aerosols, liquids, or Simple asphyxiant means a substance solids); oxidizer (liquid, solid or gas); or mixture that displaces oxygen in the self-reactive; pyrophoric (liquid or ambient atmosphere, and can thus solid); self-heating; organic peroxide; cause oxygen deprivation in those who corrosive to metal; gas under pressure; are exposed, leading to unconscious- or in contact with water emits flam- ness and death. mable gas. See Appendix B to Specific chemical identity means the § 1910.1200—Physical Hazard Criteria. chemical name, Chemical Abstracts Pictogram means a composition that Service (CAS) Registry Number, or any may include a symbol plus other graph- other information that reveals the pre- ic elements, such as a border, back- cise chemical designation of the sub- ground pattern, or color, that is in- stance. tended to convey specific information Substance means chemical elements about the hazards of a chemical. Eight and their compounds in the natural pictograms are designated under this state or obtained by any production standard for application to a hazard process, including any additive nec- category. essary to preserve the stability of the Precautionary statement means a product and any impurities deriving phrase that describes recommended from the process used, but excluding measures that should be taken to mini- any solvent which may be separated mize or prevent adverse effects result- without affecting the stability of the ing from exposure to a hazardous substance or changing its composition.

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Trade secret means any confidential (ii) When classifying mixtures they formula, pattern, process, device, infor- produce or import, chemical manufac- mation or compilation of information turers and importers of mixtures may that is used in an employer’s business, rely on the information provided on and that gives the employer an oppor- the current safety data sheets of the tunity to obtain an advantage over individual ingredients, except where competitors who do not know or use it. the chemical manufacturer or importer Appendix E to § 1910.1200—Definition of knows, or in the exercise of reasonable Trade Secret, sets out the criteria to diligence should know, that the safety be used in evaluating trade secrets. data sheet misstates or omits informa- Use means to package, handle, react, tion required by this section. emit, extract, generate as a byproduct, (e) Written hazard communication pro- or transfer. gram. (1) Employers shall develop, im- Work area means a room or defined plement, and maintain at each work- space in a workplace where hazardous place, a written hazard communication chemicals are produced or used, and program which at least describes how where employees are present. the criteria specified in paragraphs (f), Workplace means an establishment, (g), and (h) of this section for labels job site, or project, at one geographical and other forms of warning, safety data location containing one or more work sheets, and employee information and areas. training will be met, and which also in- (d) Hazard classification. (1) Chemical cludes the following: manufacturers and importers shall (i) A list of the hazardous chemicals evaluate chemicals produced in their known to be present using a product workplaces or imported by them to identifier that is referenced on the ap- classify the chemicals in accordance propriate safety data sheet (the list with this section. For each chemical, may be compiled for the workplace as a the chemical manufacturer or importer whole or for individual work areas); shall determine the hazard classes, and, and, where appropriate, the category of each class that apply to the chemical (ii) The methods the employer will being classified. Employers are not re- use to inform employees of the hazards quired to classify chemicals unless of non-routine tasks (for example, the they choose not to rely on the classi- cleaning of reactor vessels), and the fication performed by the chemical hazards associated with chemicals con- manufacturer or importer for the tained in unlabeled pipes in their work chemical to satisfy this requirement. areas. (2) Chemical manufacturers, import- (2) Multi-employer workplaces. Em- ers or employers classifying chemicals ployers who produce, use, or store haz- shall identify and consider the full ardous chemicals at a workplace in range of available scientific literature such a way that the employees of other and other evidence concerning the po- employer(s) may be exposed (for exam- tential hazards. There is no require- ple, employees of a construction con- ment to test the chemical to determine tractor working on-site) shall addition- how to classify its hazards. Appendix A ally ensure that the hazard commu- to § 1910.1200 shall be consulted for clas- nication programs developed and im- sification of health hazards, and Ap- plemented under this paragraph (e) in- pendix B to § 1910.1200 shall be con- clude the following: sulted for the classification of physical (i) The methods the employer will hazards. use to provide the other employer(s) (3) Mixtures. (i) Chemical manufac- on-site access to safety data sheets for turers, importers, or employers evalu- each hazardous chemical the other em- ating chemicals shall follow the proce- ployer(s)’ employees may be exposed to dures described in Appendices A and B while working; to § 1910.1200 to classify the hazards of (ii) The methods the employer will the chemicals, including determina- use to inform the other employer(s) of tions regarding when mixtures of the any precautionary measures that need classified chemicals are covered by this to be taken to protect employees dur- section. ing the workplace’s normal operating

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conditions and in foreseeable emer- tion is located together on the label, gencies; and, tag, or mark. (iii) The methods the employer will (4) Solid materials. (i) For solid metal use to inform the other employer(s) of (such as a steel beam or a metal cast- the labeling system used in the working), solid wood, or plastic items that place. are not exempted as articles due to (3) The employer may rely on an ex- their downstream use, or shipments of isting hazard communication program whole grain, the required label may be to comply with these requirements, transmitted to the customer at the provided that it meets the criteria es- time of the initial shipment, and need tablished in this paragraph (e). not be included with subsequent ship- (4) The employer shall make the ments to the same employer unless the written hazard communication pro- information on the label changes; gram available, upon request, to em- (ii) The label may be transmitted ployees, their designated representatives, the Assistant Secretary and the with the initial shipment itself, or with Director, in accordance with the re- the safety data sheet that is to be pro- quirements of 29 CFR 1910.20 (e). vided prior to or at the time of the first (5) Where employees must travel be- shipment; and, tween workplaces during a workshift, (iii) This exception to requiring la- i.e., their work is carried out at more bels on every container of hazardous than one geographical location, the chemicals is only for the solid material written hazard communication pro- itself, and does not apply to hazardous gram may be kept at the primary chemicals used in conjunction with, or workplace facility. known to be present with, the material (f) Labels and other forms of warning— and to which employees handling the (1) Labels on shipped containers. The items in transit may be exposed (for chemical manufacturer, importer, or example, cutting fluids or pesticides in distributor shall ensure that each con- grains). tainer of hazardous chemicals leaving (5) Chemical manufacturers, import- the workplace is labeled, tagged, or ers, or distributors shall ensure that marked. Hazards not otherwise classi- each container of hazardous chemicals fied do not have to be addressed on the leaving the workplace is labeled, container. Where the chemical manu- tagged, or marked in accordance with facturer or importer is required to this section in a manner which does label, tag or mark the following infor- not conflict with the requirements of mation shall be provided: the Hazardous Materials Transpor- (i) Product identifier; tation Act (49 U.S.C. 1801 et seq.) and (ii) Signal word; regulations issued under that Act by (iii) Hazard statement(s); the Department of Transportation. (iv) Pictogram(s); (6) Workplace labeling. Except as (v) Precautionary statement(s); and, provided in paragraphs (f)(7) and (f)(8) (vi) Name, address, and telephone of this section, the employer shall en- number of the chemical manufacturer, importer, or other responsible party. sure that each container of hazardous (2) The chemical manufacturer, im- chemicals in the workplace is labeled, porter, or distributor shall ensure that tagged or marked with either: the information provided under para- (i) The information specified under graphs (f)(1)(i) through (v) of this sec- paragraphs (f)(1)(i) through (v) of this tion is in accordance with Appendix C section for labels on shipped con- to § 1910.1200, for each hazard class and tainers; or, associated hazard category for the haz- (ii) Product identifier and words, pic- ardous chemical, prominently dis- tures, symbols, or combination thereof, played, and in English (other languages which provide at least general informa- may also be included if appropriate). tion regarding the hazards of the (3) The chemical manufacturer, im- chemicals, and which, in conjunction porter, or distributor shall ensure that with the other information imme- the information provided under para- diately available to employees under graphs (f)(1)(ii) through (iv) of this sec- the hazard communication program,

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will provide employees with the spe- label before the chemical is shipped or cific information regarding the phys- introduced into the workplace again. ical and health hazards of the haz- (g) Safety data sheets. (1) Chemical ardous chemical. manufacturers and importers shall ob- (7) The employer may use signs, plac- tain or develop a safety data sheet for ards, process sheets, batch tickets, op- each hazardous chemical they produce erating procedures, or other such writ- or import. Employers shall have a safe- ten materials in lieu of affixing labels ty data sheet in the workplace for each to individual stationary process con- hazardous chemical which they use. tainers, as long as the alternative (2) The chemical manufacturer or im- method identifies the containers to porter preparing the safety data sheet which it is applicable and conveys the shall ensure that it is in English (al- information required by paragraph though the employer may maintain (f)(6) of this section to be on a label. copies in other languages as well), and The employer shall ensure the written includes at least the following section materials are readily accessible to the numbers and headings, and associated employees in their work area through- information under each heading, in the out each work shift. order listed (See Appendix D to (8) The employer is not required to § 1910.1200—Safety Data Sheets, for the label portable containers into which specific content of each section of the hazardous chemicals are transferred safety data sheet): from labeled containers, and which are (i) Section 1, Identification; intended only for the immediate use of (ii) Section 2, Hazard(s) identifica- the employee who performs the trans- tion; fer. For purposes of this section, drugs (iii) Section 3, Composition/informa- which are dispensed by a pharmacy to tion on ingredients; a health care provider for direct ad- (iv) Section 4, First-aid measures; ministration to a patient are exempted (v) Section 5, Fire-fighting measures; from labeling. (vi) Section 6, Accidental release (9) The employer shall not remove or measures; deface existing labels on incoming containers of hazardous chemicals, unless (vii) Section 7, Handling and storage; the container is immediately marked (viii) Section 8, Exposure controls/ with the required information. personal protection; (10) The employer shall ensure that (ix) Section 9, Physical and chemical workplace labels or other forms of properties; warning are legible, in English, and (x) Section 10, Stability and reac- prominently displayed on the con- tivity; tainer, or readily available in the work (xi) Section 11, Toxicological infor- area throughout each work shift. Em- mation; ployers having employees who speak (xii) Section 12, Ecological informa- other languages may add the information; tion in their language to the material (xiii) Section 13, Disposal consider- presented, as long as the information is ations; presented in English as well. (xiv) Section 14, Transport informa- (11) Chemical manufacturers, import- tion; ers, distributors, or employers who be- (xv) Section 15, Regulatory informa- come newly aware of any significant tion; and information regarding the hazards of a (xvi) Section 16, Other information, chemical shall revise the labels for the including date of preparation or last chemical within six months of becom- revision. ing aware of the new information, and shall ensure that labels on containers NOTE 1 TO PARAGRAPH (g)(2): To be con- of hazardous chemicals shipped after sistent with the GHS, an SDS must also include the headings in paragraphs (g)(2)(xii) that time contain the new information. through (g)(2)(xv) in order. If the chemical is not currently pro- NOTE 2 TO PARAGRAPH (g)(2): OSHA will not duced or imported, the chemical manu- be enforcing information requirements in facturer, importer, distributor, or em- sections 12 through 15, as these areas are not ployer shall add the information to the under its jurisdiction.

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(3) If no relevant information is (7)(i) Distributors shall ensure that found for any sub-heading within a sec- material data sheets, and updated in- tion on the safety data sheet, the formation, are provided to other dis- chemical manufacturer, importer or tributors and employers with their ini- employer preparing the safety data tial shipment and with the first ship- sheet shall mark it to indicate that no ment after a safety data sheet is up- applicable information was found. dated; (4) Where complex mixtures have (ii) The distributor shall either pro- similar hazards and contents (i.e. the vide safety data sheets with the chemical ingredients are essentially shipped containers, or send them to the the same, but the specific composition other distributor or employer prior to varies from mixture to mixture), the or at the time of the shipment; chemical manufacturer, importer or (iii) Retail distributors selling haz- employer may prepare one safety data ardous chemicals to employers having sheet to apply to all of these similar a commercial account shall provide a mixtures. safety data sheet to such employers (5) The chemical manufacturer, im- upon request, and shall post a sign or porter or employer preparing the safe- otherwise inform them that a material ty data sheet shall ensure that the in- safety data sheet is available; formation provided accurately reflects (iv) Wholesale distributors selling the scientific evidence used in making hazardous chemicals to employers the hazard classification. If the chem- over-the-counter may also provide ical manufacturer, importer or em- safety data sheets upon the request of ployer preparing the safety data sheet the employer at the time of the over- becomes newly aware of any significant the-counter purchase, and shall post a information regarding the hazards of a sign or otherwise inform such employ- chemical, or ways to protect against ers that a material safety data sheet is available; the hazards, this new information shall (v) If an employer without a commer- be added to the safety data sheet with- cial account purchases a hazardous in three months. If the chemical is not chemical from a retail distributor not currently being produced or imported, required to have safety data sheets on the chemical manufacturer or importer file (i.e., the retail distributor does not shall add the information to the safety have commercial accounts and does not data sheet before the chemical is intro- use the materials), the retail dis- duced into the workplace again. tributor shall provide the employer, (6)(i) Chemical manufacturers or im- upon request, with the name, address, porters shall ensure that distributors and telephone number of the chemical and employers are provided an appro- manufacturer, importer, or distributor priate safety data sheet with their ini- from which a safety data sheet can be tial shipment, and with the first ship- obtained; ment after a safety data sheet is up- (vi) Wholesale distributors shall also dated; provide safety data sheets to employers (ii) The chemical manufacturer or or other distributors upon request; and, importer shall either provide safety (vii) Chemical manufacturers, im- data sheets with the shipped containers porters, and distributors need not pro- or send them to the distributor or em- vide safety data sheets to retail dis- ployer prior to or at the time of the tributors that have informed them that shipment; the retail distributor does not sell the (iii) If the safety data sheet is not product to commercial accounts or provided with a shipment that has been open the sealed container to use it in labeled as a hazardous chemical, the their own workplaces. distributor or employer shall obtain (8) The employer shall maintain in one from the chemical manufacturer or the workplace copies of the required importer as soon as possible; and, safety data sheets for each hazardous (iv) The chemical manufacturer or chemical, and shall ensure that they importer shall also provide distributors are readily accessible during each work or employers with a safety data sheet shift to employees when they are in upon request. their work area(s). (Electronic access

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and other alternatives to maintaining hazardous chemicals, and safety data paper copies of the safety data sheets sheets required by this section. are permitted as long as no barriers to (3) Training. Employee training shall immediate employee access in each include at least: workplace are created by such options.) (i) Methods and observations that (9) Where employees must travel be- may be used to detect the presence or tween workplaces during a workshift, release of a hazardous chemical in the i.e., their work is carried out at more work area (such as monitoring con- than one geographical location, the ducted by the employer, continuous safety data sheets may be kept at the monitoring devices, visual appearance primary workplace facility. In this sit- or odor of hazardous chemicals when uation, the employer shall ensure that being released, etc.); employees can immediately obtain the (ii) The physical, health, simple as- required information in an emergency. phyxiation, combustible dust, and (10) Safety data sheets may be kept pyrophoric gas hazards, as well as haz- in any form, including operating proce- ards not otherwise classified, of the dures, and may be designed to cover chemicals in the work area; groups of hazardous chemicals in a (iii) The measures employees can work area where it may be more appro- take to protect themselves from these priate to address the hazards of a proc- hazards, including specific procedures ess rather than individual hazardous the employer has implemented to pro- chemicals. However, the employer tect employees from exposure to haz- shall ensure that in all cases the re- ardous chemicals, such as appropriate quired information is provided for each work practices, emergency procedures, hazardous chemical, and is readily ac- and personal protective equipment to cessible during each work shift to em- be used; and, ployees when they are in their work (iv) The details of the hazard communication program developed by the em- area(s). ployer, including an explanation of the (11) Safety data sheets shall also be labels received on shipped containers made readily available, upon request, and the workplace labeling system to designated representatives, the As- used by their employer; the safety data sistant Secretary, and the Director, in sheet, including the order of informa- accordance with the requirements of tion and how employees can obtain and § 1910.1020(e). use the appropriate hazard informa- (h) Employee information and training. tion. (1) Employers shall provide employees (i) Trade secrets. (1) The chemical with effective information and training manufacturer, importer, or employer on hazardous chemicals in their work may withhold the specific chemical area at the time of their initial assign- identity, including the chemical name, ment, and whenever a new chemical other specific identification of a haz- hazard the employees have not pre- ardous chemical, or the exact percent- viously been trained about is intro- age (concentration) of the substance in duced into their work area. Informa- a mixture, from the safety data sheet, tion and training may be designed to provided that: cover categories of hazards (e.g., flam- (i) The claim that the information mability, carcinogenicity) or specific withheld is a trade secret can be sup- chemicals. Chemical-specific informa- ported; tion must always be available through (ii) Information contained in the labels and safety data sheets. safety data sheet concerning the prop- (2) Information. Employees shall be erties and effects of the hazardous informed of: chemical is disclosed; (i) The requirements of this section; (iii) The safety data sheet indicates (ii) Any operations in their work area that the specific chemical identity and/ where hazardous chemicals are present; or percentage of composition is being and, withheld as a trade secret; and, (iii) The location and availability of (iv) The specific chemical identity the written hazard communication pro- and percentage is made available to gram, including the required list(s) of health professionals, employees, and

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designated representatives in accord- (G) To conduct studies to determine ance with the applicable provisions of the health effects of exposure. this paragraph (i). (iii) The request explains in detail (2) Where a treating physician or why the disclosure of the specific nurse determines that a medical emer- chemical identity or percentage com- gency exists and the specific chemical position is essential and that, in lieu identity and/or specific percentage of thereof, the disclosure of the following composition of a hazardous chemical is information to the health professional, necessary for emergency or first-aid employee, or designated representa- treatment, the chemical manufacturer, tive, would not satisfy the purposes de- importer, or employer shall imme- scribed in paragraph (i)(3)(ii) of this diately disclose the specific chemical section: identity or percentage composition of a (A) The properties and effects of the trade secret chemical to that treating chemical; physician or nurse, regardless of the (B) Measures for controlling workers’ existence of a written statement of exposure to the chemical; need or a confidentiality agreement. (C) Methods of monitoring and ana- The chemical manufacturer, importer, lyzing worker exposure to the chem- or employer may require a written ical; and, statement of need and confidentiality (D) Methods of diagnosing and treat- agreement, in accordance with the pro- ing harmful exposures to the chemical; visions of paragraphs (i)(3) and (4) of (iv) The request includes a descrip- this section, as soon as circumstances tion of the procedures to be used to permit. maintain the confidentiality of the dis- (3) In non-emergency situations, a closed information; and, chemical manufacturer, importer, or employer shall, upon request, disclose (v) The health professional, and the a specific chemical identity or percent- employer or contractor of the services age composition, otherwise permitted of the health professional (i.e. down- to be withheld under paragraph (i)(1) of stream employer, labor organization, this section, to a health professional or individual employee), employee, or (i.e. physician, industrial hygienist, designated representative, agree in a toxicologist, epidemiologist, or occupa- written confidentiality agreement that tional health nurse) providing medical the health professional, employee, or or other occupational health services designated representative, will not use to exposed employee(s), and to employ- the trade secret information for any ees or designated representatives, if: purpose other than the health need(s) (i) The request is in writing; asserted and agree not to release the (ii) The request describes with rea- information under any circumstances sonable detail one or more of the fol- other than to OSHA, as provided in lowing occupational health needs for paragraph (i)(6) of this section, except the information: as authorized by the terms of the (A) To assess the hazards of the agreement or by the chemical manu- chemicals to which employees will be facturer, importer, or employer. exposed; (4) The confidentiality agreement au- (B) To conduct or assess sampling of thorized by paragraph (i)(3)(iv) of this the workplace atmosphere to deter- section: mine employee exposure levels; (i) May restrict the use of the infor- (C) To conduct pre-assignment or mation to the health purposes indi- periodic medical surveillance of ex- cated in the written statement of need; posed employees; (ii) May provide for appropriate legal (D) To provide medical treatment to remedies in the event of a breach of the exposed employees; agreement, including stipulation of a (E) To select or assess appropriate reasonable pre-estimate of likely dam- personal protective equipment for ex- ages; and, posed employees; (iii) May not include requirements (F) To design or assess engineering for the posting of a penalty bond. controls or other protective measures (5) Nothing in this standard is meant for exposed employees; and, to preclude the parties from pursuing

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non-contractual remedies to the extent (10)(i) If OSHA determines that the permitted by law. specific chemical identity or percent- (6) If the health professional, em- age composition requested under para- ployee, or designated representative re- graph (i)(3) of this section is not a ceiving the trade secret information ‘‘bona fide’’ trade secret, or that it is a decides that there is a need to disclose trade secret, but the requesting health it to OSHA, the chemical manufac- professional, employee, or designated turer, importer, or employer who pro- representative has a legitimate med- vided the information shall be in- ical or occupational health need for the formed by the health professional, em- information, has executed a written ployee, or designated representative confidentiality agreement, and has prior to, or at the same time as, such shown adequate means to protect the disclosure. confidentiality of the information, the (7) If the chemical manufacturer, im- chemical manufacturer, importer, or porter, or employer denies a written re- employer will be subject to citation by quest for disclosure of a specific chem- OSHA. ical identity or percentage composi- (ii) If a chemical manufacturer, im- tion, the denial must: porter, or employer demonstrates to (i) Be provided to the health profes- OSHA that the execution of a confiden- sional, employee, or designated rep- tiality agreement would not provide resentative, within thirty days of the sufficient protection against the poten- request; tial harm from the unauthorized dis- (ii) Be in writing; closure of a trade secret, the Assistant (iii) Include evidence to support the Secretary may issue such orders or im- claim that the specific chemical iden- pose such additional limitations or tity or percent of composition is a conditions upon the disclosure of the trade secret; requested chemical information as may (iv) State the specific reasons why be appropriate to assure that the occu- the request is being denied; and, pational health services are provided (v) Explain in detail how alternative without an undue risk of harm to the information may satisfy the specific chemical manufacturer, importer, or medical or occupational health need employer. without revealing the trade secret. (11) If a citation for a failure to re- (8) The health professional, em- lease trade secret information is con- ployee, or designated representative tested by the chemical manufacturer, whose request for information is denied importer, or employer, the matter will under paragraph (i)(3) of this section be adjudicated before the Occupational may refer the request and the written Safety and Health Review Commission denial of the request to OSHA for con- in accordance with the Act’s enforce- sideration. ment scheme and the applicable Com- (9) When a health professional, em- mission rules of procedure. In accord- ployee, or designated representative re- ance with the Commission rules, when fers the denial to OSHA under para- a chemical manufacturer, importer, or graph (i)(8) of this section, OSHA shall employer continues to withhold the in- consider the evidence to determine if: formation during the contest, the Ad- (i) The chemical manufacturer, im- ministrative Law Judge may review porter, or employer has supported the the citation and supporting docu- claim that the specific chemical iden- mentation ‘‘in camera’’ or issue appro- tity or percentage composition is a priate orders to protect the confiden- trade secret; tiality of such matters. (ii) The health professional, em- (12) Notwithstanding the existence of ployee, or designated representative a trade secret claim, a chemical manu- has supported the claim that there is a facturer, importer, or employer shall, medical or occupational health need upon request, disclose to the Assistant for the information; and, Secretary any information which this (iii) The health professional, em- section requires the chemical manufac- ployee or designated representative has turer, importer, or employer to make demonstrated adequate means to pro- available. Where there is a trade secret tect the confidentiality. claim, such claim shall be made no

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later than at the time the information A.0.1.2 For many hazard classes, the cri- is provided to the Assistant Secretary teria are semi-quantitative or qualitative so that suitable determinations of and expert judgment is required to interpret trade secret status can be made and the data for classification purposes. the necessary protections can be imple- A.0.2 AVAILABLE DATA, TEST METHODS AND mented. TEST DATA QUALITY (13) Nothing in this paragraph shall be construed as requiring the disclo- A.0.2.1 There is no requirement for testing chemicals. sure under any circumstances of proc- A.0.2.2 The criteria for determining ess information which is a trade secret. health hazards are test method neutral, i.e., (j) Effective dates. (1) Employers shall they do not specify particular test methods, train employees regarding the new as long as the methods are scientifically label elements and safety data sheets validated. format by December 1, 2013. A.0.2.3 The term ‘‘scientifically vali- (2) Chemical manufacturers, import- dated’’ refers to the process by which the re- ers, distributors, and employers shall liability and the relevance of a procedure are be in compliance with all modified pro- established for a particular purpose. Any visions of this section no later than test that determines hazardous properties, June 1, 2015, except: which is conducted according to recognized scientific principles, can be used for purposes (i) After December 1, 2015, the dis- of a hazard determination for health hazards. tributor shall not ship containers la- Test conditions need to be standardized so beled by the chemical manufacturer or that the results are reproducible with a importer unless the label has been given substance, and the standardized test modified to comply with paragraph yields ‘‘valid’’ data for defining the hazard (f)(1) of this section. class of concern. (ii) All employers shall, as necessary, A.0.2.4 Existing test data are acceptable update any alternative workplace la- for classifying chemicals, although expert beling used under paragraph (f)(6) of judgment also may be needed for classification purposes. this section, update the hazard commu- A.0.2.5 The effect of a chemical on bio- nication program required by para- logical systems is influenced, by the physico- graph (h)(1), and provide any additional chemical properties of the substance and/or employee training in accordance with ingredients of the mixture and the way in paragraph (h)(3) for newly identified which ingredient substances are biologically physical or health hazards no later available. A chemical need not be classified than June 1, 2016. when it can be shown by conclusive experi- (3) Chemical manufacturers, import- mental data from scientifically validated ers, distributors, and employers may test methods that the chemical is not biologically available. comply with either § 1910.1200 revised as A.0.2.6 For classification purposes, epide- of October 1, 2011, or the current miological data and experience on the effects version of this standard, or both during of chemicals on humans (e.g., occupational the transition period. data, data from accident databases) shall be taken into account in the evaluation of APPENDIX A TO § 1910.1200—HEALTH HAZARD human health hazards of a chemical. CRITERIA (MANDATORY) A.0.3 CLASSIFICATION BASED ON WEIGHT OF A.0 GENERAL CLASSIFICATION EVIDENCE CONSIDERATIONS A.0.3.1 For some hazard classes, classi- A.0.1 CLASSIFICATION fication results directly when the data sat- A.0.1.1 The term ‘‘hazard classification’’ isfy the criteria. For others, classification of is used to indicate that only the intrinsic a chemical shall be determined on the basis hazardous properties of chemicals are con- of the total weight of evidence using expert sidered. Hazard classification incorporates judgment. This means that all available in- three steps: formation bearing on the classification of (a) Identification of relevant data regard- hazard shall be considered together, including the hazards of a chemical; ing the results of valid in vitro tests, relevant (b) Subsequent review of those data to as- animal data, and human experience such as certain the hazards associated with the epidemiological and clinical studies and chemical; well-documented case reports and observa- (c) Determination of whether the chemical tions. will be classified as hazardous and the degree A.0.3.2 The quality and consistency of the of hazard. data shall be considered. Information on

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chemicals related to the material being clas- mixture (e.g., application of cut-off values/ sified shall be considered as appropriate, as concentration limits). well as site of action and mechanism or A.0.4.2 An exception to the above order or mode of action study results. Both positive precedence is made for Carcinogenicity, and negative results shall be considered to- Germ Cell Mutagenicity, and Reproductive gether in a single weight-of-evidence deter- Toxicity. For these three hazard classes, mination. mixtures shall be classified based upon infor- A.0.3.3 Positive effects which are con- mation on the ingredient substances, unless sistent with the criteria for classification, whether seen in humans or animals, shall on a case-by-case basis, justification can be normally justify classification. Where evi- provided for classifying based upon the mix- dence is available from both humans and ani- ture as a whole. See chapters A.5, A.6, and mals and there is a conflict between the find- A.7 for further information on case-by-case ings, the quality and reliability of the evi- bases. dence from both sources shall be evaluated A.0.4.3 Use of cut-off values/concentration in order to resolve the question of classifica- limits. tion. Reliable, good quality human data A.0.4.3.1 When classifying an untested shall generally have precedence over other mixture based on the hazards of its ingredi- data. However, even well-designed and con- ents, cut-off values/concentration limits for ducted epidemiological studies may lack a the classified ingredients of the mixture are sufficient number of subjects to detect rel- used for several hazard classes. While the atively rare but still significant effects, or to adopted cut-off values/concentration limits assess potentially confounding factors. adequately identify the hazard for most mix- Therefore, positive results from well-con- tures, there may be some that contain haz- ducted animal studies are not necessarily ne- gated by the lack of positive human experi- ardous ingredients at lower concentrations ence but require an assessment of the than the specified cut-off values/concentra- robustness, quality and statistical power of tion limits that still pose an identifiable both the human and animal data. hazard. There may also be cases where the A.0.3.4 Route of exposure, mechanistic in- cut-off value/concentration limit is consider- formation, and metabolism studies are perti- ably lower than the established non-haz- nent to determining the relevance of an ef- ardous level for an ingredient. fect in humans. When such information A.0.4.3.2 If the classifier has information raises doubt about relevance in humans, a that the hazard of an ingredient will be evi- lower classification may be warranted. When dent (i.e., it presents a health risk) below the there is scientific evidence demonstrating specified cut-off value/concentration limit, that the mechanism or mode of action is not the mixture containing that ingredient shall relevant to humans, the chemical should not be classified accordingly. be classified. A.0.3.5 Both positive and negative results A.0.4.3.3 In exceptional cases, conclusive are considered together in the weight of evi- data may demonstrate that the hazard of an dence determination. However, a single posi- ingredient will not be evident (i.e., it does tive study performed according to good sci- not present a health risk) when present at a entific principles and with statistically and level above the specified cut-off value/con- biologically significant positive results may centration limit(s). In these cases the mix- justify classification. ture may be classified according to those data. The data must exclude the possibility A.0.4 CONSIDERATIONS FOR THE that the ingredient will behave in the mix- CLASSIFICATION OF MIXTURES ture in a manner that would increase the A.0.4.1 For most hazard classes, the rec- hazard over that of the pure substance. Fur- ommended process of classification of mix- thermore, the mixture must not contain in- tures is based on the following sequence: gredients that would affect that determina- (a) Where test data are available for the tion. complete mixture, the classification of the A.0.4.4 Synergistic or antagonistic effects. mixture will always be based on those data; When performing an assessment in accord- (b) Where test data are not available for ance with these requirements, the evaluator the mixture itself, the bridging principles must take into account all available infor- designated in each health hazard chapter of this appendix shall be considered for classi- mation about the potential occurrence of fication of the mixture; synergistic effects among the ingredients of (c) If test data are not available for the the mixture. Lowering classification of a mixture itself, and the available information mixture to a less hazardous category on the is not sufficient to allow application of the basis of antagonistic effects may be done above-mentioned bridging principles, then only if the determination is supported by the method(s) described in each chapter for sufficient data. estimating the hazards based on the information known will be applied to classify the

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A.0.5 BRIDGING PRINCIPLES FOR THE CLASSI- B have been tested and are in the same tox- FICATION OF MIXTURES WHERE TEST DATA icity category, and where untested mixture ARE NOT AVAILABLE FOR THE COMPLETE C has the same toxicologically active ingre- MIXTURE dients as mixtures A and B but has concentrations of toxicologically active ingredi- A.0.5.1 Where the mixture itself has not ents intermediate to the concentrations in been tested to determine its toxicity, but mixtures A and B, then mixture C is assumed there are sufficient data on both the indi- to be in the same toxicity category as A and vidual ingredients and similar tested mix- B. tures to adequately characterize the hazards A.0.5.1.5 Substantially similar mixtures. of the mixture, these data shall be used in For mixtures classified in accordance with accordance with the following bridging prin- A.1 through A.10 of this Appendix, given the ciples, subject to any specific provisions for following set of conditions: mixtures for each hazard class. These prin- (a) Where there are two mixtures: ciples ensure that the classification process uses the available data to the greatest ex- (i) A + B; tent possible in characterizing the hazards of (ii) C + B; the mixture. (b) The concentration of ingredient B is es- A.0.5.1.1 Dilution. sentially the same in both mixtures; For mixtures classified in accordance with (c) The concentration of ingredient A in A.1 through A.10 of this Appendix, if a tested mixture (i) equals that of ingredient C in mixture is diluted with a diluent that has an mixture (ii); equivalent or lower toxicity classification (d) And data on toxicity for A and C are than the least toxic original ingredient, and available and substantially equivalent; i.e., which is not expected to affect the toxicity they are in the same hazard category and are of other ingredients, then: not expected to affect the toxicity of B; then (a) The new diluted mixture shall be classi- If mixture (i) or (ii) is already classified fied as equivalent to the original tested mix- based on test data, the other mixture can be ture; or assigned the same hazard category. (b) For classification of acute toxicity in A.0.5.1.6 Aerosols. accordance with A.1 of this Appendix, para- For mixtures classified in accordance with graph A.1.3.6 (the additivity formula) shall A.1, A.2, A.3, A.4, A.8, or A.9 of this Appen- be applied. dix, an aerosol form of a mixture shall be A.0.5.1.2 Batching. classified in the same hazard category as the For mixtures classified in accordance with tested, non-aerosolized form of the mixture, A.1 through A.10 of this Appendix, the tox- provided the added propellant does not affect icity of a tested production batch of a mix- the toxicity of the mixture when spraying. ture can be assumed to be substantially A.1 ACUTE TOXICITY equivalent to that of another untested production batch of the same mixture, when A.1.1 DEFINITION produced by or under the control of the same chemical manufacturer, unless there is reason Acute toxicity refers to those adverse effects to believe there is significant variation such occurring following oral or dermal adminis- that the toxicity of the untested batch has tration of a single dose of a substance, or changed. If the latter occurs, a new classi- multiple doses given within 24 hours, or an fication is necessary. inhalation exposure of 4 hours. A.0.5.1.3 Concentration of mixtures. A.1.2 CLASSIFICATION CRITERIA FOR For mixtures classified in accordance with SUBSTANCES A.1, A.2, A.3, A.8, A.9, or A.10 of this Appen- dix, if a tested mixture is classified in Cat- A.1.2.1 Substances can be allocated to one egory 1, and the concentration of the ingre- of four toxicity categories based on acute dients of the tested mixture that are in Cat- toxicity by the oral, dermal or inhalation egory 1 is increased, the resulting untested route according to the numeric cut-off cri- mixture shall be classified in Category 1. teria as shown in Table A.1.1. Acute toxicity A.0.5.1.4 Interpolation within one toxicity values are expressed as (approximate) LD50 category. (oral, dermal) or LC50 (inhalation) values or For mixtures classified in accordance with as acute toxicity estimates (ATE). See the A.1, A.2, A.3, A.8, A.9, or A.10 of this Appen- footnotes following Table A.1.1 for further dix, for three mixtures (A, B and C) with explanation on the application of these val- identical ingredients, where mixtures A and ues.

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)

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TABLE A.1.1—ACUTE TOXICITY HAZARD CATEGORIES AND ACUTE TOXICITY ESTIMATE (ATE) VALUES DEFINING THE RESPECTIVE CATEGORIES—Continued

Exposure route Category 1 Category 2 Category 3 Category 4

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 eval- value from among scientifically validated uation of acute toxicity by the oral and in- tests. halation routes is the rat, while the rat or rabbit are preferred for evaluation of acute A.1.3 CLASSIFICATION CRITERIA FOR dermal toxicity. Test data already generated MIXTURES for the classification of chemicals under existing systems should be accepted when re- A.1.3.1 The approach to classification of classifying these chemicals under the har- mixtures for acute toxicity is tiered, and is monized system. When experimental data for dependent upon the amount of information acute toxicity are available in several ani- available for the mixture itself and for its in- mal species, scientific judgment should be gredients. The flow chart of Figure A.1.1 in- used in selecting the most appropriate LD50 dicates the process that must be followed:

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A.1.3.2 Classification of mixtures for within the same category, then the mixture acute toxicity may be carried out for each should be classified in that category. route of exposure, but is only required for (d) When only range data (or acute toxicity one route of exposure as long as this route is hazard category information) are available followed (estimated or tested) for all ingredi- for ingredients in a mixture, they may be ents and there is no relevant evidence to sug- converted to point estimates in accordance gest acute toxicity by multiple routes. When with Table A.1.2 when calculating the classi- there is relevant evidence of acute toxicity fication of the new mixture using the for- by multiple routes of exposure, classification mulas in A.1.3.6.1 and A.1.3.6.2.4. is to be conducted for all appropriate routes of exposure. All available information shall A.1.3.4 CLASSIFICATION OF MIXTURES WHERE be considered. The pictogram and signal ACUTE TOXICITY TEST DATA ARE AVAILABLE word used shall reflect the most severe haz- FOR THE COMPLETE MIXTURE ard category; and all relevant hazard state- Where the mixture itself has been tested to ments shall be used. determine its acute toxicity, it is classified A.1.3.3 For purposes of classifying the according to the same criteria as those used hazards of mixtures in the tiered approach: for substances, presented in Table A.1.1. If (a) The ‘‘relevant ingredients’’ of a mixture test data for the mixture are not available, are those which are present in concentra- the procedures presented below must be fol- tions ≥1% (weight/weight for solids, liquids, lowed. dusts, mists and vapors and volume/volume for gases). If there is reason to suspect that A.1.3.5 CLASSIFICATION OF MIXTURES WHERE an ingredient present at a concentration <1% ACUTE TOXICITY TEST DATA ARE NOT will affect classification of the mixture for AVAILABLE FOR THE COMPLETE MIXTURE: acute toxicity, that ingredient shall also be BRIDGING PRINCIPLES considered relevant. Consideration of ingredients present at a concentration <1% is par- A.1.3.5.1 Where the mixture itself has not ticularly important when classifying untest- been tested to determine its acute toxicity, ed mixtures which contain ingredients that but there are sufficient data on both the in- are classified in Category 1 and Category 2; dividual ingredients and similar tested mix- (b) Where a classified mixture is used as an tures to adequately characterize the hazards ingredient of another mixture, the actual or of the mixture, these data will be used in ac- derived acute toxicity estimate (ATE) for cordance with the following bridging prin- that mixture is used when calculating the ciples as found in paragraph A.0.5 of this Ap- classification of the new mixture using the pendix: Dilution, Batching, Concentration of formulas in A.1.3.6.1 and A.1.3.6.2.4. mixtures, Interpolation within one toxicity (c) If the converted acute toxicity point es- category, Substantially similar mixtures, timates for all ingredients of a mixture are and Aerosols.

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A.1.3.6 CLASSIFICATION OF MIXTURES BASED (c) Ignore ingredients if the data available ON INGREDIENTS OF THE MIXTURE are from a limit dose test (at the upper (ADDITIVITY FORMULA) threshold for Category 4 for the appropriate route of exposure as provided in Table A.1.1) A.1.3.6.1 Data available for all ingredi- and do not show acute toxicity. ents. Ingredients that fall within the scope of The acute toxicity estimate (ATE) of in- this paragraph are considered to be ingredi- gredients is considered as follows: ents with a known acute toxicity estimate (a) Include ingredients with a known acute (ATE). See note (b) to Table A.1.1 and para- toxicity, which fall into any of the acute graph A.1.3.3 for appropriate application of toxicity categories, or have an oral or der- available data to the equation below, and

mal LD50 greater than 2000 but less than or paragraph A.1.3.6.2.4. equal to 5000 mg/kg body weight (or the The ATE of the mixture is determined by equivalent dose for inhalation); calculation from the ATE values for all rel- (b) Ignore ingredients that are presumed evant ingredients according to the following not acutely toxic (e.g., water, sugar); formula below for oral, dermal or inhalation toxicity:

Where: A.1.3.6.2.3 In the event that an ingredient Ci = concentration of ingredient i with unknown acute toxicity is used in a n ingredients and i is running from 1 to n mixture at a concentration ≥1%, and the ATEi = acute toxicity estimate of ingredient mixture has not been classified based on i. testing of the mixture as a whole, the mix- A.1.3.6.2 Data are not available for one or ture cannot be attributed a definitive acute more ingredients of the mixture. toxicity estimate. In this situation the mix- A.1.3.6.2.1 Where an ATE is not available ture is classified based on the known ingredi- × for an individual ingredient of the mixture, ents only. (Note: A statement that percent but available information provides a derived of the mixture consists of ingredient(s) of conversion value, the formula in A.1.3.6.1 unknown toxicity is required on the label may be applied. This information may in- and safety data sheet in such cases; see Ap- clude evaluation of: pendix C to this section, Allocation of Label (a) Extrapolation between oral, dermal and Elements and Appendix D to this section, inhalation acute toxicity estimates. Such an Safety Data Sheets.) evaluation requires appropriate Where an ingredient with unknown acute pharmacodynamic and pharmacokinetic toxicity is used in a mixture at a concentra- data; tion ≥1%, and the mixture is not classified (b) Evidence from human exposure that in- based on testing of the mixture as a whole, dicates toxic effects but does not provide le- a statement that X% of the mixture consists thal dose data; of ingredient(s) of unknown acute toxicity is (c) Evidence from any other toxicity tests/ required on the label and safety data sheet in assays available on the substance that indi- such cases; see Appendix C to this section, cates toxic acute effects but does not nec- Allocation of Label Elements and Appendix essarily provide lethal dose data; or D to this section, Safety Data Sheets.) (d) Data from closely analogous substances A.1.3.6.2.4 If the total concentration of the using structure/activity relationships. relevant ingredient(s) with unknown acute A.1.3.6.2.2 This approach requires substan- toxicity is ≤10% then the formula presented tial supplemental technical information, and in A.1.3.6.1 must be used. If the total con- a highly trained and experienced expert, to centration of the relevant ingredient(s) with reliably estimate acute toxicity. If sufficient unknown acute toxicity is >10%, the formula information is not available to reliably esti- presented in A.1.3.6.1 is corrected to adjust mate acute toxicity, proceed to the provi- for the percentage of the unknown ingre- sions of A.1.3.6.2.3. dient(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

Classification category or experimentally obtained Converted Exposure routes acute acute toxicity toxicity range estimate point estimate

Oral (mg/kg bodyweight ) ...... 0

A.2 SKIN CORROSION/IRRITATION information bearing on the determination of skin corrosion/irritation is considered to- A.2.1 DEFINITIONS AND GENERAL gether, including the results of appropriate CONSIDERATIONS scientifically validated in-vitro tests, rel- A.2.1.1 Skin corrosion is the production of evant animal data, and human data such as irreversible damage to the skin; namely, epidemiological and clinical studies and visible necrosis through the epidermis and well-documented case reports and observa- into the dermis, following the application of tions. a test substance for up to 4 hours. Corrosive reactions are typified by ulcers, bleeding, A.2.2 CLASSIFICATION CRITERIA FOR bloody scabs, and, by the end of observation SUBSTANCES USING ANIMAL TEST DATA at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia, and A.2.2.1 CORROSION scars. Histopathology should be considered A.2.2.1.1 A corrosive substance is a chem- to evaluate questionable lesions. ical that produces destruction of skin tissue, Skin irritation is the production of revers- namely, visible necrosis through the epider- ible damage to the skin following the appli- mis and into the dermis, in at least 1 of 3 cation of a test substance for up to 4 hours. A.2.1.2 Skin corrosion/irritation shall be tested animals after exposure up to a 4-hour classified using a tiered approach as detailed duration. Corrosive reactions are typified by in figure A.2.1. Emphasis shall be placed ulcers, bleeding, bloody scabs and, by the end upon existing human data (See A.0.2.6), fol- of observation at 14 days, by discoloration lowed by other sources of information. Clas- due to blanching of the skin, complete areas sification results directly when the data sat- of alopecia and scars. Histopathology should isfy the criteria in this section. In case the be considered to discern questionable le- criteria cannot be directly applied, classi- sions. fication of a substance or a mixture is made A.2.2.1.2 Three sub-categories of Category on the basis of the total weight of evidence 1 are provided in Table A.2.1, all of which (See A.0.3.1). This means that all available shall be regulated as Category 1.

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TABLE A.2.1—SKIN CORROSION CATEGORY AND SUB-CATEGORIES

Corrosive in ≥1 of 3 animals Category 1: corrosive Corrosive sub-categories 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 major criterion for the irritant category is that at least 2 tested animals have a mean A.2.2.2.1 A single irritant category (Cat- ≥ ≤ egory 2) is presented in the Table A.2.2. The 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 defi- nite positive effects related to chemical exposure in a single animal but less than the criteria above.

A.2.2.2.2 Animal irritant responses within the death of the animals. When observations a test can be quite variable, as they are with are made of skin corrosion/irritation in corrosion. A separate irritant criterion ac- acute toxicity studies and are observed up commodates cases when there is a signifi- through the limit dose, these data may be cant irritant response but less than the used for classification provided that the dilu- mean score criterion for a positive test. For tions used and species tested are equivalent. example, a substance might be designated as In vitro alternatives that have been scientif- an irritant if at least 1 of 3 tested animals ically validated shall be used to make classi- shows a very elevated mean score through- fication decisions. Solid substances (pow- out the study, including lesions persisting at ders) may become corrosive or irritant when the end of an observation period of normally moistened or in contact with moist skin or 14 days. Other responses could also fulfil this mucous membranes. Likewise, pH extremes criterion. However, it should be ascertained like ≤2 and ≥11.5 may indicate skin effects, that the responses are the result of chemical especially when associated with significant exposure. Addition of this criterion increases buffering capacity. Generally, such sub- the sensitivity of the classification system. stances are expected to produce significant A.2.2.2.3 Reversibility of skin lesions is effects on the skin. In the absence of any another consideration in evaluating irritant other information, a substance is considered ≤ responses. When inflammation persists to corrosive (Skin Category 1) if it has a pH 2 ≥ the end of the observation period in 2 or or a pH 11.5. However, if consideration of al- more test animals, taking into consideration kali/acid reserve suggests the substance or alopecia (limited area), hyperkeratosis, mixture may not be corrosive despite the low hyperplasia and scaling, then a chemical or high pH value, then further evaluation should be considered to be an irritant. may be necessary. In some cases enough information may be available from struc- A.2.3 CLASSIFICATION CRITERIA FOR turally related compounds to make classi- SUBSTANCES USING OTHER DATA ELEMENTS fication decisions. A.2.3.2 A tiered approach to the evaluation A.2.3.1 Existing human and animal data of initial information shall be used (Figure including information from single or re- A.2.1) recognizing that all elements may not peated exposure should be the first line of be relevant in certain cases. analysis, as they give information directly A.2.3.3 The tiered approach explains how relevant to effects on the skin. If a substance to organize information on a substance and is highly toxic by the dermal route, a skin to make a weight-of-evidence decision about corrosion/irritation study may not be prac- hazard assessment and hazard classification. ticable since the amount of test substance to A.2.3.4 All the above information that is be applied would considerably exceed the available on a substance shall be evaluated. toxic dose and, consequently, would result in Although information might be gained from

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the evaluation of single parameters within a eters. Emphasis shall be placed upon existing tier, there is merit in considering the total- human experience and data, followed by ani- ity of existing information and making an mal experience and testing data, followed by overall weight of evidence determination. other sources of information, but case-by- This is especially true when there is infor- case determinations are necessary. mation available on some but not all param-

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A.2.4 CLASSIFICATION CRITERIA FOR centration <1% will affect classification of MIXTURES the mixture for skin corrosion/irritation, that ingredient shall also be considered rel- A.2.4.1 CLASSIFICATION OF MIXTURES WHEN evant. DATA ARE AVAILABLE FOR THE COMPLETE A.2.4.3.2 In general, the approach to clas- MIXTURE sification of mixtures as irritant or corrosive A.2.4.1.1 The mixture shall be classified to skin when data are available on the ingre- using the criteria for substances (See A.2.3). dients, but not on the mixture as a whole, is based on the theory of additivity, such that A.2.4.2 CLASSIFICATION OF MIXTURES WHEN each corrosive or irritant ingredient contrib- DATA ARE NOT AVAILABLE FOR THE COM- utes to the overall irritant or corrosive prop- PLETE MIXTURE: BRIDGING PRINCIPLES erties of the mixture in proportion to its potency and concentration. A weighting factor A.2.4.2.1 Where the mixture itself has not of 10 is used for corrosive ingredients when been tested to determine its skin corrosion/ they are present at a concentration below irritation, but there are sufficient data on the concentration limit for classification both the individual ingredients and similar with Category 1, but are at a concentration tested mixtures to adequately characterize that will contribute to the classification of the hazards of the mixture, these data will the mixture as an irritant. The mixture is be used in accordance with the following classified as corrosive or irritant when the bridging principles, as found in paragraph sum of the concentrations of such ingredi- A.0.5 of this Appendix: Dilution, Batching, ents exceeds a cut-off value/concentration Concentration of mixtures, Interpolation limit. within one toxicity category, Substantially A.2.4.3.3 Table A.2.3 below provides the similar mixtures, and Aerosols. cut-off value/concentration limits to be used to determine if the mixture is considered to A.2.4.3 CLASSIFICATION OF MIXTURES WHEN be an irritant or a corrosive to the skin. DATA ARE AVAILABLE FOR ALL INGREDIENTS A.2.4.3.4 Particular care shall be taken OR ONLY FOR SOME INGREDIENTS OF THE when classifying certain types of chemicals MIXTURE such as acids and bases, inorganic salts, A.2.4.3.1 For purposes of classifying the aldehydes, phenols, and surfactants. The ap- skin corrosion/irritation hazards of mixtures proach explained in A.2.4.3.1 and A.2.4.3.2 in the tiered approach: might not work given that many of such sub- The ‘‘relevant ingredients’’ of a mixture stances are corrosive or irritant at con- are those which are present in concentra- centrations <1%. For mixtures containing tions ≥1% (weight/weight for solids, liquids, strong acids or bases the pH should be used dusts, mists and vapors and volume/volume as classification criteria since pH will be a for gases.) If the classifier has reason to sus- better indicator of corrosion than the con- pect that an ingredient present at a concentration limits of Table A.2.3. A mixture

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containing corrosive or irritant ingredients ingredient will not be evident when present that cannot be classified based on the at a level above the generic concentration additivity approach shown in Table A.2.3, cut-off values mentioned in Tables A.2.3 and due to chemical characteristics that make A.2.4. In these cases the mixture could be this approach unworkable, should be classi- classified according to those data (See Use of fied as Skin Category 1 if it contains ≥1% of cut-off values/concentration limits, paragraph a corrosive ingredient and as Skin Category A.0.4.3 of this Appendix). 2 when it contains ≥3% of an irritant ingre- A.2.4.3.6 If there are data showing that dient. Classification of mixtures with ingre- (an) ingredient(s) may be corrosive or irri- dients for which the approach in Table A.2.3 tant at a concentration of <1% (corrosive) or does not apply is summarized in Table A.2.4 <3% (irritant), the mixture shall be classified below. accordingly (See Use of cut-off values/con- A.2.4.3.5 On occasion, reliable data may centration limits, paragraph A.0.4.3 of this Ap- show that the skin corrosion/irritation of an pendix).

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]

Concentration triggering classification of a mixture as: Sum of ingredients classified as: Skin corrosive Skin irritant Category 1 Category 2

Skin Category 1 ...... ≥5% ≥1% but <5%. Skin Category 2 ...... ≥10%. (10 × Skin Category 1) + Skin Category 2 ...... ≥10%.

TABLE A.2.4—CONCENTRATION OF INGREDIENTS OF A MIXTURE FOR WHICH THE ADDITIVITY AP- PROACH DOES NOT APPLY, THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE AS HAZ- ARDOUS TO SKIN

Mixture Ingredient: Concentration: 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, includ- ≥3% Category 2. ing acids and bases.

A.3 SERIOUS EYE DAMAGE/EYE criteria in this section. In case the criteria IRRITATION cannot be directly applied, classification of a substance or a mixture is made on the basis A.3.1 DEFINITIONS AND GENERAL of the total weight of evidence (See A.0.3.1). CONSIDERATIONS This means that all available information A.3.1.1 Serious eye damage is the produc- bearing on the determination of serious eye tion of tissue damage in the eye, or serious damage/eye irritation is considered together, physical decay of vision, following applica- including the results of appropriate scientif- tion of a test substance to the anterior sur- ically validated in vitro tests, relevant ani- face of the eye, which is not fully reversible mal data, and human data such as epidemio- within 21 days of application. logical and clinical studies and well-documented case reports and observations. Eye irritation is the production of changes in the eye following the application of test A.3.2 CLASSIFICATION CRITERIA FOR substance to the anterior surface of the eye, SUBSTANCES USING ANIMAL TEST DATA which are fully reversible within 21 days of application. A.3.2.1 Irreversible effects on the eye/seri- A.3.1.2 Serious eye damage/eye irritation ous damage to eyes (Category 1). shall be classified using a tiered approach as A single hazard category is provided in detailed in Figure A.3.1. Emphasis shall be Table A.3.1, for substances that have the po- placed upon existing human data (See tential to seriously damage the eyes. Cat- A.0.2.6), followed by animal data, followed by egory 1, irreversible effects on the eye, in- other sources of information. Classification cludes the criteria listed below. These obser- results directly when the data satisfy the vations include animals with grade 4 cornea

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lesions and other severe reactions (e.g. de- are not fully reversible within an observa- struction of cornea) observed at any time tion period of normally 21 days. Category 1 during the test, as well as persistent corneal also contains substances fulfilling the cri- opacity, discoloration of the cornea by a dye teria of corneal opacity ≥3 and/or iritis >1.5 substance, adhesion, pannus, and inter- detected in a Draize eye test with rabbits, ference with the function of the iris or other because severe lesions like these usually do effects that impair sight. In this context, not reverse within a 21-day observation pe- persistent lesions are considered those which riod.

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 (Cat- A single category is provided in Table A.3.2 egory 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 cially when associated with significant pronounced variability among animal re- buffering capacity. Generally, such sub- sponses, this information may be taken into stances are expected to produce significant account in determining the classification. effects on the eyes. In the absence of any other information, a mixture/substance is A.3.3 CLASSIFICATION CRITERIA FOR considered to cause serious eye damage (Eye SUBSTANCES USING OTHER DATA ELEMENTS Category 1) if it has a pH ≤2 or ≥11.5. How- A.3.3.1 Existing human and animal data ever, if consideration of acid/alkaline reserve should be the first line of analysis, as they suggests the substance may not have the po- give information directly relevant to effects tential to cause serious eye damage despite on the eye. Possible skin corrosion shall be the low or high pH value, then further eval- evaluated prior to consideration of serious uation may be necessary. In some cases eye damage/eye irritation in order to avoid enough information may be available from testing for local effects on eyes with skin structurally related compounds to make corrosive substances. In vitro alternatives classification decisions. that have been scientifically validated and A.3.3.2 A tiered approach to the evalua- accepted shall be used to make classification tion of initial information shall be used decisions. Likewise, pH extremes like ≤2 and ≥11.5, may indicate serious eye damage, espe-

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where applicable, recognizing that all ele- Although information might be gained from ments may not be relevant in certain cases the evaluation of single parameters within a (Figure A.3.1). tier, consideration should be given to the to- A.3.3.3 The tiered approach explains how tality of existing information and making an to organize existing information on a sub- overall weight-of-evidence determination. stance and to make a weight-of-evidence de- This is especially true when there is conflict cision, where appropriate, about hazard as- in information available on some param- sessment and hazard classification. eters. A.3.3.4 All the above information that is available on a substance shall be evaluated.

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A.3.4 CLASSIFICATION CRITERIA FOR to the eye or eye irritant when data are MIXTURES available on the ingredients, but not on the mixture as a whole, is based on the theory of A.3.4.1 CLASSIFICATION OF MIXTURES WHEN additivity, such that each corrosive or irri- DATA ARE AVAILABLE FOR THE COMPLETE tant ingredient contributes to the overall ir- MIXTURE ritant or corrosive properties of the mixture A.3.4.1.1 The mixture will be classified in proportion to its potency and concentra- using the criteria for substances. tion. A weighting factor of 10 is used for cor- A.3.4.1.2 Unlike other hazard classes, rosive ingredients when they are present at a there are alternative tests available for skin concentration below the concentration limit corrosivity of certain types of chemicals for classification with Category 1, but are at that can give an accurate result for classi- a concentration that will contribute to the fication purposes, as well as being simple and classification of the mixture as an irritant. relatively inexpensive to perform. When con- The mixture is classified as seriously dam- sidering testing of the mixture, chemical aging to the eye or eye irritant when the manufacturers are encouraged to use a tiered sum of the concentrations of such ingredi- weight of evidence strategy as included in ents exceeds a threshold cut-off value/con- the criteria for classification of substances centration limit. for skin corrosion and serious eye damage A.3.4.3.3 Table A.3.3 provides the cut-off and eye irritation to help ensure an accurate value/concentration limits to be used to de- classification, as well as avoid unnecessary termine if the mixture should be classified as animal testing. In the absence of any other seriously damaging to the eye or an eye irri- information, a mixture is considered to tant. cause serious eye damage (Eye Category 1) if A.3.4.3.4 Particular care must be taken it has a pH ≤2 or ≥11.5. However, if consider- when classifying certain types of chemicals ation of acid/alkaline reserve suggests the such as acids and bases, inorganic salts, substance or mixture may not have the po- aldehydes, phenols, and surfactants. The ap- tential to cause serious eye damage despite proach explained in A.3.4.3.1 and A.3.4.3.2 the low or high pH value, then further eval- might not work given that many of such sub- uation may be necessary. stances are corrosive or irritant at concentrations <1%. For mixtures containing A.3.4.2 CLASSIFICATION OF MIXTURES WHEN strong acids or bases, the pH should be used DATA ARE NOT AVAILABLE FOR THE COM- as classification criteria (See A.3.4.1) since PLETE MIXTURE: BRIDGING PRINCIPLES pH will be a better indicator of serious eye A.3.4.2.1 Where the mixture itself has not damage than the concentration limits of been tested to determine its skin corrosivity Table A.3.3. A mixture containing corrosive or potential to cause serious eye damage or or irritant ingredients that cannot be classi- eye irritation, but there are sufficient data fied based on the additivity approach applied on both the individual ingredients and simi- in Table A.3.3 due to chemical characteris- lar tested mixtures to adequately charac- tics that make this approach unworkable, terize the hazards of the mixture, these data should be classified as Eye Category 1 if it will be used in accordance with the following contains ≥1% of a corrosive ingredient and as bridging principles, as found in paragraph Eye Category 2 when it contains ≥3% of an A.0.5 of this Appendix: Dilution, Batching, irritant ingredient. Classification of mix- Concentration of mixtures, Interpolation tures with ingredients for which the ap- within one toxicity category, Substantially proach in Table A.3.3 does not apply is sum- similar mixtures, and Aerosols. marized in Table A.3.4. A.3.4.3.5 On occasion, reliable data may A.3.4.3 CLASSIFICATION OF MIXTURES WHEN show that the reversible/irreversible eye ef- DATA ARE AVAILABLE FOR ALL INGREDIENTS fects of an ingredient will not be evident OR ONLY FOR SOME INGREDIENTS OF THE when present at a level above the generic MIXTURE cut-off values/concentration limits men- A.3.4.3.1 For purposes of classifying the tioned in Tables A.3.3 and A.3.4. In these eye corrosion/irritation hazards of mixtures cases the mixture could be classified accord- in the tiered approach: ing to those data (See also A.0.4.3 Use of cut- The ‘‘relevant ingredients’’ of a mixture off values/concentration limits’’). On occasion, are those which are present in concentra- when it is expected that the skin corrosion/ tions ≥1% (weight/weight for solids, liquids, irritation or the reversible/irreversible eye dusts, mists and vapors and volume/volume effects of an ingredient will not be evident for gases.) If the classifier has reason to sus- when present at a level above the generic pect that an ingredient present at a con- concentration/cut-off levels mentioned in centration <1% will affect classification of Tables A.3.3 and A.3.4, testing of the mixture the mixture for eye corrosion/irritation, that may be considered. In those cases, the tiered ingredient shall also be considered relevant. weight of evidence strategy should be ap- A.3.4.3.2 In general, the approach to clas- plied as referred to in section A.3.3, Figure sification of mixtures as seriously damaging A.3.1 and explained in detail in this chapter.

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A.3.4.3.6 If there are data showing that <3% (irritant), the mixture should be classi- (an) ingredient(s) may be corrosive or irri- fied accordingly (See also paragraph A.0.4.3, tant at a concentration of <1% (corrosive) or 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

Concentration triggering classification of a mixture as: Sum of ingredients classified 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 × Eye Category 1) + Eye Category 2 ...... ≥10%. Skin Category 1 + Eye Category 1 ...... ≥3% ≥1% but <3%. 10 × (Skin Category 1 + Eye Category 1) + Eye Category ...... ≥10%. 2. 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 AP- PROACH DOES NOT APPLY, THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE AS HAZ- ARDOUS TO THE EYE

Mixture Ingredient Concentration classified as: Eye

A.4 RESPIRATORY OR SKIN which there is an induction phase, the re- SENSITIZATION sponse to which is measured by a standardized elicitation phase, typically involving a A.4.1 DEFINITIONS AND GENERAL patch test. The local lymph node assay is the CONSIDERATIONS exception, directly measuring the induction A.4.1.1 Respiratory sensitizer means a response. Evidence of skin sensitization in chemical that will lead to hypersensitivity humans normally is assessed by a diagnostic of the airways following inhalation of the patch test. chemical. A.4.1.4 Usually, for both skin and res- Skin sensitizer means a chemical that will piratory sensitization, lower levels are nec- lead to an allergic response following skin essary for elicitation than are required for contact. induction. A.4.1.2 For the purpose of this chapter, A.4.1.5 The hazard class ‘‘respiratory or sensitization includes two phases: the first skin sensitization’’ is differentiated into: phase is induction of specialized (a) Respiratory sensitization; and immunological memory in an individual by (b) Skin sensitization. exposure to an allergen. The second phase is elicitation, i.e., production of a cell-medi- A.4.2 CLASSIFICATION CRITERIA FOR ated or antibody-mediated allergic response SUBSTANCES by exposure of a sensitized individual to an allergen. A.4.2.1 RESPIRATORY SENSITIZERS A.4.1.3 For respiratory sensitization, the pattern of induction followed by elicitation A.4.2.1.1 Hazard Categories. phases is shared in common with skin sen- A.4.2.1.1.1 Effects seen in either humans sitization. For skin sensitization, an induc- or animals will normally justify classification phase is required in which the immune tion in a weight of evidence approach for res- system learns to react; clinical symptoms piratory sensitizers. Substances may be allo- can then arise when subsequent exposure is cated to one of the two sub-categories 1A or sufficient to elicit a visible skin reaction 1B using a weight of evidence approach in ac- (elicitation phase). As a consequence, pre- cordance with the criteria given in Table dictive tests usually follow this pattern in A.4.1 and on the basis of reliable and good

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quality evidence from human cases or epide- A.4.2.1.1.2 Where data are not sufficient miological studies and/or observations from for sub-categorization, respiratory sensi- appropriate studies in experimental animals. tizers 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.

A.4.2.1.2.4 Clinical history should include A.4.2.1.2 Human evidence. both medical and occupational history to de- A.4.2.1.2.1 Evidence that a substance can termine a relationship between exposure to a lead to specific respiratory hypersensitivity specific substance and development of res- will normally be based on human experience. piratory hypersensitivity. Relevant informa- In this context, hypersensitivity is normally tion includes aggravating factors both in the seen as asthma, but other hypersensitivity home and workplace, the onset and progress reactions such as rhinitis/conjunctivitis and of the disease, family history and medical alveolitis are also considered. The condition history of the patient in question. The med- will have the clinical character of an allergic ical history should also include a note of reaction. However, immunological mecha- other allergic or airway disorders from child- nisms do not have to be demonstrated. hood and smoking history. A.4.2.1.2.2 When considering the human A.4.2.1.2.5 The results of positive bron- evidence, it is necessary that in addition to chial challenge tests are considered to pro- the evidence from the cases, the following be vide sufficient evidence for classification on taken into account: their own. It is, however, recognized that in (a) The size of the population exposed; practice many of the examinations listed (b) The extent of exposure. above will already have been carried out. A.4.2.1.2.3 The evidence referred to above A.4.2.1.3 Animal studies. could be: A.4.2.1.3.1 Data from appropriate animal (a) Clinical history and data from appro- studies 2 which may be indicative of the po- priate lung function tests related to expo- tential of a substance to cause sensitization sure to the substance, confirmed by other by inhalation in humans 3 may include: supportive evidence which may include: (a) Measurements of Immunoglobulin E (i) In vivo immunological test (e.g., skin (IgE) and other specific immunological pa- prick test); rameters, for example in mice (ii) In vitro immunological test (e.g., sero- (b) Specific pulmonary responses in guinea logical analysis); pigs. (iii) Studies that may indicate other specific hypersensitivity reactions where A.4.2.2 SKIN SENSITIZERS immunological mechanisms of action have A.4.2.2.1 Hazard categories. not been proven, e.g., repeated low-level irritation, pharmacologically mediated effects; 2 (iv) A chemical structure related to sub- At this writing, recognized and validated stances known to cause respiratory hyper- animal models for the testing of respiratory sensitivity; hypersensitivity are not available. Under cer- (b) Data from positive bronchial challenge tain circumstances, data from animal studies tests with the substance conducted accord- may provide valuable information in a weight of ing to accepted guidelines for the determina- evidence assessment. 3 tion of a specific hypersensitivity reaction. The mechanisms by which substances induce symptoms of asthma are not yet fully known. For preventive measures, these substances are 1 At this writing, recognized and validated considered respiratory sensitizers. However, if animal models for the testing of respiratory on the basis of the evidence, it can be dem- hypersensitivity are not available. Under cer- onstrated that these substances induce symp- tain circumstances, data from animal studies toms of asthma by irritation only in people with may provide valuable information in a weight of bronchial hyperactivity, they should not be con- evidence assessment. sidered as respiratory sensitizers.

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A.4.2.2.1.1 Effects seen in either humans miological studies and/or observations from or animals will normally justify classifica- appropriate studies in experimental animals tion in a weight of evidence approach for according to the guidance values provided in skin sensitizers. Substances may be allo- A.4.2.2.2.1 and A.4.2.2.3.2 for sub-category 1A cated to one of the two sub-categories 1A or and in A.4.2.2.2.2 and A.4.2.2.3.3 for sub-cat- 1B using a weight of evidence approach in ac- egory 1B. cordance with the criteria given in Table A.4.2.2.1.2 Where data are not sufficient A.4.2 and on the basis of reliable and good for sub-categorization, skin sensitizers shall quality evidence from human cases or epide- be classified in Category 1.

TABLE A.4.2—HAZARD CATEGORY AND SUB-CATEGORIES FOR SKIN SENSITIZERS

Category 1 Skin sensitizer

A substance is classified as a skin sensitizer. (a) if there is evidence in humans that the substance can lead to sensitization by skin contact in a substantial number of persons, or (b) if there are positive results from an appropriate animal test. Sub-category 1A ...... Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitization in humans. Severity of reaction may also be considered. Sub-category 1B ...... Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitization in humans. Severity of reaction may also be considered.

A.4.2.2.2 Human evidence. of reactions in a defined population in rela- A.4.2.2.2.1 Human evidence for sub-cat- tion to relatively high exposure; egory 1A may include: (c) Other epidemiological evidence where (a) Positive responses at ≤500 μg/cm2 there is a relatively low but substantial inci- (Human Repeat Insult Patch Test (HRIPT), dence of allergic contact dermatitis in rela- Human Maximization Test (HMT)—induction tion to relatively high exposure. threshold); A.4.2.2.3 Animal studies (b) Diagnostic patch test data where there is a relatively high and substantial incidence A.4.2.2.3.1 For Category 1, when an adju- of reactions in a defined population in rela- vant type test method for skin sensitization tion to relatively low exposure; is used, a response of at least 30% of the ani- (c) Other epidemiological evidence where mals is considered as positive. For a non-ad- there is a relatively high and substantial in- juvant Guinea pig test method a response of cidence of allergic contact dermatitis in re- at least 15% of the animals is considered lation to relatively low exposure. positive. For Category 1, a stimulation index A.4.2.2.2.2 Human evidence for sub-cat- of three or more is considered a positive re- egory 1B may include: sponse in the local lymph node assay.4 (a) Positive responses at >500 μg/cm2 A.4.2.2.3.2 Animal test results for sub-cat- (HRIPT, HMT—induction threshold); egory 1A can include data with values indi- (b) Diagnostic patch test data where there cated in Table A.4.3 below: is a relatively low but substantial incidence

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.

4 Test methods for skin sensitization are de- Mouse Ear Swelling Test (MEST), appears to be scribed in OECD Guideline 406 (the Guinea Pig a reliable screening test to detect moderate to Maximization test and the Buehler guinea pig strong sensitizers, and can be used, in accord- test) and Guideline 429 (Local Lymph Node ance with professional judgment, as a first stage Assay). Other methods may be used provided in the assessment of skin sensitization potential. that they are scientifically validated. The

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

TABLE A.4.4—ANIMAL TEST RESULTS FOR SUB-CATEGORY 1B

Assay Criteria

Local lymph node assay ...... EC3 value >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.4.2.2.4 Specific considerations. A.4.2.2.4.3 If none of the above-mentioned A.4.2.2.4.1 For classification of a sub- conditions are met, the substance need not stance, evidence shall include one or more of be classified as a skin sensitizer. However, a the following using a weight of evidence ap- combination of two or more indicators of proach: skin sensitization, as listed below, may alter (a) Positive data from patch testing, nor- the decision. This shall be considered on a mally obtained in more than one derma- case-by-case basis. tology clinic; (a) Isolated episodes of allergic contact (b) Epidemiological studies showing aller- dermatitis; gic contact dermatitis caused by the sub- (b) Epidemiological studies of limited stance. Situations in which a high propor- power, e.g., where chance, bias or con- tion of those exposed exhibit characteristic founders have not been ruled out fully with symptoms are to be looked at with special reasonable confidence; concern, even if the number of cases is small; (c) Data from animal tests, performed ac- (c) Positive data from appropriate animal cording to existing guidelines, which do not studies; meet the criteria for a positive result described in A.4.2.2.3, but which are sufficiently (d) Positive data from experimental stud- close to the limit to be considered signifi- ies in man (See paragraph A.0.2.6 of this Ap- cant; pendix); (d) Positive data from non-standard meth- (e) Well documented episodes of allergic ods; contact dermatitis, normally obtained in (e) Positive results from close structural more than one dermatology clinic; analogues. (f) Severity of reaction. A.4.2.2.4.4 Immunological contact urti- A.4.2.2.4.2 Evidence from animal studies is caria. usually much more reliable than evidence A.4.2.2.4.4.1 Substances meeting the cri- from human exposure. However, in cases teria for classification as respiratory sensi- where evidence is available from both tizers may, in addition, cause immunological sources, and there is conflict between the re- contact urticaria. Consideration shall be sults, the quality and reliability of the evi- given to classifying these substances as skin dence from both sources must be assessed in sensitizers. order to resolve the question of classifica- A.4.2.2.4.4.2 Substances which cause tion on a case-by-case basis. Normally, immunological contact urticaria without human data are not generated in controlled meeting the criteria for respiratory sensi- experiments with volunteers for the purpose tizers shall be considered for classification of hazard classification but rather as part of as skin sensitizers. risk assessment to confirm lack of effects A.4.2.2.4.4.3 There is no recognized animal seen in animal tests. Consequently, positive model available to identify substances which human data on skin sensitization are usually cause immunological contact urticaria. derived from case-control or other, less de- Therefore, classification will normally be fined studies. Evaluation of human data based on human evidence, similar to that for must, therefore, be carried out with caution skin sensitization. as the frequency of cases reflect, in addition to the inherent properties of the substances, A.4.3 CLASSIFICATION CRITERIA FOR factors such as the exposure situation, bio- MIXTURES availability, individual predisposition and A.4.3.1 CLASSIFICATION OF MIXTURES WHEN preventive measures taken. Negative human DATA ARE AVAILABLE FOR THE COMPLETE data should not normally be used to negate MIXTURE positive results from animal studies. For both animal and human data, consideration When reliable and good quality evidence, should be given to the impact of vehicle. as described in the criteria for substances,

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from human experience or appropriate stud- bridging principles as found in paragraph ies in experimental animals, is available for A.0.5 of this Appendix: Dilution, Batching, the mixture, then the mixture shall be clas- Concentration of mixtures, Interpolation, sified by weight of evidence evaluation of Substantially similar mixtures, and these data. Care must be exercised in evalu- Aerosols. ating data on mixtures that the dose used does not render the results inconclusive. A.4.3.3 CLASSIFICATION OF MIXTURES WHEN DATA ARE AVAILABLE FOR ALL INGREDIENTS A.4.3.2 CLASSIFICATION OF MIXTURES WHEN OR ONLY FOR SOME INGREDIENTS OF THE DATA ARE NOT AVAILABLE FOR THE COM- MIXTURE PLETE MIXTURE: BRIDGING PRINCIPLES A.4.3.2.1 Where the mixture itself has not The mixture shall be classified as a res- been tested to determine its sensitizing prop- piratory or skin sensitizer when at least one erties, but there are sufficient data on both ingredient has been classified as a res- the individual ingredients and similar tested piratory or skin sensitizer and is present at mixtures to adequately characterize the haz- or above the appropriate cut-off value/con- ards of the mixture, these data will be used centration limit for the specific endpoint as in accordance with the following agreed 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 CLASSIFICA- TION OF THE MIXTURE

Cut-off values/concentration limits triggering classification of a mixture as: Respiratory Sensitizer Skin Sensitizer Ingredient classified as: Category 1 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 normal replication processes, or which in a non-physiological manner (temporarily) A.5.1 DEFINITIONS AND GENERAL alter its replication. Genotoxicity test re- CONSIDERATIONS sults are usually taken as indicators for mu- A.5.1.1 A mutation is defined as a perma- tagenic effects. nent change in the amount or structure of A.5.1.3 This hazard class is primarily con- the genetic material in a cell. The term mu- cerned with chemicals that may cause tation applies both to heritable genetic mutations in the germ cells of humans that changes that may be manifested at the can be transmitted to the progeny. However, phenotypic level and to the underlying DNA mutagenicity/genotoxicity tests in vitro and modifications when known (including, for ex- in mammalian somatic cells in vivo are also ample, specific base pair changes and chro- considered in classifying substances and mosomal translocations). The term muta- mixtures within this hazard class. genic and mutagen will be used for agents giv- ing rise to an increased occurrence of A.5.2 CLASSIFICATION CRITERIA FOR mutations in populations of cells and/or or- SUBSTANCES ganisms. A.5.1.2 The more general terms genotoxic A.5.2.1 The classification system provides and genotoxicity apply to agents or processes for two different categories of germ cell which alter the structure, information con- mutagens to accommodate the weight of evi- tent, or segregation of DNA, including those dence available. The two-category system is which cause DNA damage by interfering with 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.

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FIGURE A.5.1—HAZARD CATEGORIES FOR GERM CELL MUTAGENS—Continued 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 classi- ducted test is used for classification, it shall fication of substances as germ cell mutagens: provide clear and unambiguously positive re- A.5.2.2.1 To arrive at a classification, test sults. The relevance of the route of exposure results are considered from experiments de- used in the study of the substance compared termining mutagenic and/or genotoxic ef- to the route of human exposure should also fects in germ and/or somatic cells of exposed be taken into account. animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be con- A.5.3 CLASSIFICATION CRITERIA FOR sidered. MIXTURES 5 A.5.2.2.2 The system is hazard based, classifying chemicals on the basis of their A.5.3.1 CLASSIFICATION OF MIXTURES WHEN intrinsic ability to induce mutations in germ DATA ARE AVAILABLE FOR ALL INGREDIENTS cells. The scheme is, therefore, not meant for OR ONLY FOR SOME INGREDIENTS OF THE the (quantitative) risk assessment of chem- MIXTURE ical substances. A.5.2.2.3 Classification for heritable ef- A.5.3.1.1 Classification of mixtures shall fects in human germ cells is made on the be based on the available test data for the in- basis of scientifically validated tests. Eval- dividual ingredients of the mixture using uation of the test results shall be done using cut-off values/concentration limits for the expert judgment and all the available evi- ingredients classified as germ cell mutagens. dence shall be weighed for classification. A.5.3.1.2 The mixture will be classified as A.5.2.2.4 The classification of substances a mutagen when at least one ingredient has shall be based on the total weight of evi- been classified as a Category 1A, Category 1B dence available, using expert judgment. In or Category 2 mutagen and is present at or those instances where a single well-con-

5 It should be noted that the classification cri- sider the cut-off values/concentration limits as teria for health hazards usually include a tiered the primary tier and allow the classification to scheme in which test data available on the com- be modified only on a case-by-case evaluation plete mixture are considered as the first tier in based on available test data for the mixture as the evaluation, followed by the applicable bridg- a whole. ing 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 con-

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above the appropriate cut-off value/concentration limit as shown in Table A.5.1 below for Category 1 and 2 respectively.

TABLE A.5.1—CUT-OFF VALUES/CONCENTRATION LIMITS OF INGREDIENTS OF A MIXTURE CLASSIFIED AS GERM CELL MUTAGENS THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE

Cut-off/concentration limits triggering classification Ingredient classified as: 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 (b) Genotoxicity tests: DATA ARE AVAILABLE FOR THE MIXTURE (i) Sister chromatid exchange analysis in ITSELF spermatogonia The classification may be modified on a (ii) Unscheduled DNA synthesis test (UDS) case-by-case basis based on the available test in testicular cells data for the mixture as a whole. In such A.5.4.4 Examples of genotoxicity tests in so- cases, the test results for the mixture as a matic cells are: whole must be shown to be conclusive taking (a) Liver Unscheduled DNA Synthesis into account dose and other factors such as (UDS) in vivo (OECD 486) duration, observations and analysis (e.g. sta- (b) Mammalian bone marrow Sister Chro- tistical analysis, test sensitivity) of germ matid Exchanges (SCE) cell mutagenicity test systems. A.5.4.5 Examples of in vitro mutagenicity A.5.3.3 CLASSIFICATION OF MIXTURES WHEN tests are: DATA ARE NOT AVAILABLE FOR THE COM- (a) In vitro mammalian chromosome aber- PLETE MIXTURE: BRIDGING PRINCIPLES ration test (OECD 473) (b) In vitro mammalian cell gene mutation A.5.3.3.1 Where the mixture itself has not test (OECD 476) been tested to determine its germ cell mutagenicity hazard, but there are sufficient data (c) Bacterial reverse mutation tests (OECD on both the individual ingredients and simi- 471) lar tested mixtures to adequately charac- A.5.4.6 As new, scientifically validated tests terize the hazards of the mixture, these data arise, these may also be used in the total will be used in accordance with the following weight of evidence to be considered. bridging principles as found in paragraph A.0.5 of this Appendix: Dilution, Batching, A.6 CARCINOGENICITY and Substantially similar mixtures. A.6.1 DEFINITIONS A.5.4 EXAMPLES OF SCIENTIFICALLY Carcinogen means a substance or a mixture VALIDATED TEST METHODS of substances which induce cancer or in- A.5.4.1 Examples of in vivo heritable germ crease its incidence. Substances and mix- cell mutagenicity tests are: tures which have induced benign and malig- (a) Rodent dominant lethal mutation test nant tumors in well-performed experimental (OECD 478) studies on animals are considered also to be (b) Mouse heritable translocation assay presumed or suspected human carcinogens (OECD 485) unless there is strong evidence that the (c) Mouse specific locus test mechanism of tumor formation is not rel- A.5.4.2 Examples of in vivo somatic cell mu- evant for humans. tagenicity tests are: (a) Mammalian bone marrow chromosome Classification of a substance or mixture as aberration test (OECD 475) posing a carcinogenic hazard is based on its (b) Mouse spot test (OECD 484) inherent properties and does not provide in- (c) Mammalian erythrocyte micronucleus formation on the level of the human cancer test (OECD 474) risk which the use of the substance or mix- A.5.4.3 Examples of mutagenicity/ ture may represent. genotoxicity tests in germ cells are: (a) Mutagenicity tests: (i) Mammalian spermatogonial chromosome aberration test (OECD 483) (ii) Spermatid micronucleus assay

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A.6.2 CLASSIFICATION CRITERIA FOR one of two categories based on strength of SUBSTANCES 6 evidence and additional weight of evidence considerations. In certain instances, route- A.6.2.1 For the purpose of classification for specific classification may be warranted. carcinogenicity, substances are allocated to

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 stances with human cancer potential into made on the basis of evidence from reliable hazard categories. and acceptable methods, and is intended to A.6.2.4 Strength of evidence involves the be used for substances which have an intrin- enumeration of tumors in human and animal sic property to produce such toxic effects. studies and determination of their level of The evaluations are to be based on all exist- statistical significance. Sufficient human ing data, peer-reviewed published studies and evidence demonstrates causality between additional data accepted by regulatory agen- human exposure and the development of can- cies. cer, whereas sufficient evidence in animals A.6.2.3 Carcinogen classification is a one- shows a causal relationship between the step, criterion-based process that involves agent and an increased incidence of tumors. two interrelated determinations: evaluations Limited evidence in humans is demonstrated of strength of evidence and consideration of by a positive association between exposure all other relevant information to place sub- and cancer, but a causal relationship cannot

6 See Non-mandatory Appendix F Part A for cerpted from the International Agency for Re- further guidance regarding hazard classification search on Cancer (IARC) ‘‘Monographs on the for carcinogenicity. This appendix is consistent Evaluation of Carcinogenic Risks to Humans’’ with the GHS adn is provided as guidance ex- (2006).

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be stated. Limited evidence in animals is (i) Comparison of absorption, distribution, provided when data suggest a carcinogenic metabolism and excretion between test ani- effect, but are less than sufficient. (Guidance mals and humans; on consideration of important factors in the (j) The possibility of a confounding effect classification of carcinogenicity and a more of excessive toxicity at test doses; and, detailed description of the terms ‘‘limited’’ (k) Mode of action and its relevance for hu- and ‘‘sufficient’’ have been developed by the mans, such as mutagenicity, cytotoxicity International Agency for Research on Cancer with growth stimulation, mitogenesis, (IARC) and are provided in non-mandatory immunosuppression. Appendix F). Mutagenicity: It is recognized that genetic A.6.2.5 Weight of evidence: Beyond the de- events are central in the overall process of termination of the strength of evidence for cancer development. Therefore evidence of carcinogenicity, a number of other factors mutagenic activity in vivo may indicate that should be considered that influence the over- a substance has a potential for carcinogenic all likelihood that an agent may pose a car- effects. cinogenic hazard in humans. The full list of A.6.2.5.3 A substance that has not been factors that influence this determination is tested for carcinogenicity may in certain in- very lengthy, but some of the important stances be classified in Category 1A, Cat- ones are considered here. egory 1B, or Category 2 based on tumor data A.6.2.5.1 These factors can be viewed as ei- from a structural analogue together with ther increasing or decreasing the level of substantial support from consideration of concern for human carcinogenicity. The rel- other important factors such as formation of ative emphasis accorded to each factor de- common significant metabolites, e.g., for pends upon the amount and coherence of evi- benzidine congener dyes. dence bearing on each. Generally there is a A.6.2.5.4 The classification should also requirement for more complete information take into consideration whether or not the to decrease than to increase the level of con- substance is absorbed by a given route(s); or cern. Additional considerations should be whether there are only local tumors at the used in evaluating the tumor findings and site of administration for the tested route(s), the other factors in a case-by-case manner. and adequate testing by other major route(s) A.6.2.5.2 Some important factors which show lack of carcinogenicity. may be taken into consideration, when as- A.6.2.5.5 It is important that whatever is sessing the overall level of concern are: known of the physico-chemical, toxicokinetic and toxicodynamic properties (a) Tumor type and background incidence; of the substances, as well as any available (b) Multisite responses; relevant information on chemical analogues, (c) Progression of lesions to malignancy; i.e., structure activity relationship, is taken (d) Reduced tumor latency; into consideration when undertaking classi- Additional factors which may increase or fication. decrease the level of concern include: (e) Whether responses are in single or both A.6.3 CLASSIFICATION CRITERIA FOR sexes; MIXTURES 7 (f) Whether responses are in a single spe- A.6.3.1 The mixture shall be classified as a cies or several species; carcinogen when at least one ingredient has (g) Structural similarity or not to a sub- been classified as a Category 1 or Category 2 stance(s) for which there is good evidence of carcinogen and is present at or above the ap- carcinogenicity; propriate cut-off value/concentration limit (h) Routes of exposure; 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

Category 1 Category 2 Ingredient classified as: carcinogen carcinogen

Category 1 carcinogen ...... ≥0.1%

7 It should be noted that the classification cri- proach is not used for Carcinogenicity. These teria for health hazards usually include a tiered criteria for Carcinogenicity consider the cut-off scheme in which test data available on the com- values/concentration limits as the primary tier plete mixture are considered as the first tier in and allow the classification to be modified only the evaluation, followed by the applicable bridg- on a case-by-case evaluation based on available ing principles, and lastly, cut-off values/contest data for the mixture as a whole. centration limit or additivity. However, this ap-

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TABLE A.6.1—CUT-OFF VALUES/CONCENTRATION LIMITS OF INGREDIENTS OF A MIXTURE CLASSIFIED AS CARCINOGEN THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE—Continued

Category 1 Category 2 Ingredient classified as: carcinogen carcinogen

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 A.7 REPRODUCTIVE TOXICITY DATA ARE AVAILABLE FOR THE COMPLETE MIXTURE A.7.1 DEFINITIONS AND GENERAL CONSIDERATIONS A mixture may be classified based on the available test data for the mixture as a A.7.1.1 Reproductive toxicity includes ad- whole. In such cases, the test results for the verse effects on sexual function and fertility in mixture as a whole must be shown to be con- adult males and females, as well as adverse clusive taking into account dose and other effects on development of the offspring. Some factors such as duration, observations and reproductive toxic effects cannot be clearly analysis (e.g., statistical analysis, test sensi- assigned to either impairment of sexual tivity) of carcinogenicity test systems. function and fertility or to developmental toxicity. Nonetheless, chemicals with these A.6.3.3 CLASSIFICATION OF MIXTURES WHEN effects shall be classified as reproductive DATA ARE NOT AVAILABLE FOR THE COM- toxicants. PLETE MIXTURE: BRIDGING PRINCIPLES For classification purposes, the known induction of genetically based inheritable ef- Where the mixture itself has not been test- fects in the offspring is addressed in Germ cell ed to determine its carcinogenic hazard, but mutagenicity (See A.5). there are sufficient data on both the indi- A.7.1.2 Adverse effects on sexual function vidual ingredients and similar tested mix- and fertility means any effect of chemicals tures to adequately characterize the hazards that interferes with reproductive ability or of the mixture, these data will be used in ac- sexual capacity. This includes, but is not cordance with the following bridging prin- limited to, alterations to the female and ciples as found in paragraph A.0.5 of this Ap- male reproductive system, adverse effects on pendix: Dilution; Batching; and Substan- onset of puberty, gamete production and tially similar mixtures. transport, reproductive cycle normality, sex- A.6.4 CLASSIFICATION OF CARCINOGENICITY 8 ual behaviour, fertility, parturition, pregnancy outcomes, premature reproductive se- A.6.4.1 Chemical manufacturers, import- nescence, or modifications in other functions ers and employers evaluating chemicals may that are dependent on the integrity of the re- treat the following sources as establishing productive systems. that a substance is a carcinogen or potential A.7.1.3 Adverse effects on development of the carcinogen for hazard communication pur- offspring means any effect of chemicals poses in lieu of applying the criteria de- which interferes with normal development of scribed herein: the conceptus either before or after birth, A.6.4.1.1 National Toxicology Program which is induced during pregnancy or results (NTP), ‘‘Report on Carcinogens’’ (latest edi- from parental exposure. These effects can be tion); manifested at any point in the life span of A.6.4.1.2 International Agency for Re- the organism. The major manifestations of search on Cancer (IARC) ‘‘Monographs on developmental toxicity include death of the the Evaluation of Carcinogenic Risks to Hu- developing organism, structural abnor- mans’’ (latest editions) mality, altered growth and functional defi- A.6.4.2 Where OSHA has included cancer ciency. as a health hazard to be considered by classi- A.7.1.4 Adverse effects on or via lactation fiers for a chemical covered by 29 CFR part are also included in reproductive toxicity, 1910, Subpart Z, Toxic and Hazardous Sub- but for classification purposes, such effects stances, chemical manufacturers, importers, are treated separately (See A.7.2.1). and employers shall classify the chemical as a carcinogen. A.7.2 CLASSIFICATION CRITERIA FOR SUBSTANCES 8 See Non-mandatory Appendix F for further A.7.2.1 For the purpose of classification guidance regarding hazard classification for for reproductive toxicity, substances shall be carcinogenicity and how to relate carcino- classified in one of two categories in accord- genicity classification information from IARC ance with Figure A.7.1(a). Effects on sexual and NTP to GHS. function and fertility, and on development,

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shall be considered. In addition, effects on or hazard category in accordance with Figure via lactation shall be classified in a separate 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 (Cat- egory 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 in- stance, 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 the use of expert judgment. Classification as a reproductive toxicant is intended to be A.7.2.2.1 Classification is made on the used for substances which have an intrinsic, basis of the criteria, outlined above, an assessment of the total weight of evidence, and

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specific property to produce an adverse ef- property will not be expressed in humans fect on reproduction and substances should then a chemical which produces an adverse not be so classified if such an effect is pro- effect on reproduction in experimental ani- duced solely as a non-specific secondary con- mals should not be classified. sequence of other toxic effects. A.7.2.3.3 In some reproductive toxicity A.7.2.2.2 In the evaluation of toxic effects studies in experimental animals the only ef- on the developing offspring, it is important fects recorded may be considered of low or to consider the possible influence of mater- minimal toxicological significance and clas- nal toxicity. sification may not necessarily be the out- A.7.2.2.3 For human evidence to provide come. These effects include, for example, the primary basis for a Category 1A classi- small changes in semen parameters or in the fication there must be reliable evidence of an incidence of spontaneous defects in the fetus, adverse effect on reproduction in humans. small changes in the proportions of common Evidence used for classification shall be from fetal variants such as are observed in skel- well conducted epidemiological studies, if etal examinations, or in fetal weights, or available, which include the use of appro- small differences in postnatal developmental priate controls, balanced assessment, and assessments. due consideration of bias or confounding fac- A.7.2.3.4 Data from animal studies shall tors. Less rigorous data from studies in hu- provide sufficient evidence of specific repro- mans may be sufficient for a Category 1A ductive toxicity in the absence of other sys- classification if supplemented with adequate temic toxic effects. However, if develop- data from studies in experimental animals, mental toxicity occurs together with other but classification in Category 1B may also be toxic effects in the dam (mother), the poten- considered. tial influence of the generalized adverse effects should be assessed to the extent pos- A.7.2.3 WEIGHT OF EVIDENCE sible. The preferred approach is to consider A.7.2.3.1 Classification as a reproductive adverse effects in the embryo/fetus first, and toxicant is made on the basis of an assess- then evaluate maternal toxicity, along with ment of the total weight of evidence using any other factors which are likely to have expert judgment. This means that all avail- influenced these effects, as part of the able information that bears on the deter- weight of evidence. In general, develop- mination of reproductive toxicity is consid- mental effects that are observed at mater- ered together. Included is information such nally toxic doses should not be automati- as epidemiological studies and case reports cally discounted. Discounting developmental in humans and specific reproduction studies effects that are observed at maternally toxic along with sub-chronic, chronic and special doses can only be done on a case-by-case study results in animals that provide rel- basis when a causal relationship is estab- evant information regarding toxicity to re- lished or refuted. productive and related endocrine organs. A.7.2.3.5 If appropriate information is Evaluation of substances chemically related available it is important to try to determine to the material under study may also be in- whether developmental toxicity is due to a cluded, particularly when information on the specific maternally mediated mechanism or material is scarce. The weight given to the to a non-specific secondary mechanism, like available evidence will be influenced by fac- maternal stress and the disruption of homeo- tors such as the quality of the studies, con- stasis. Generally, the presence of maternal sistency of results, nature and severity of ef- toxicity should not be used to negate find- fects, level of statistical significance for ings of embryo/fetal effects, unless it can be intergroup differences, number of endpoints clearly demonstrated that the effects are affected, relevance of route of administra- secondary non-specific effects. This is espe- tion to humans and freedom from bias. Both cially the case when the effects in the off- positive and negative results are considered spring are significant, e.g., irreversible ef- together in a weight of evidence determina- fects such as structural malformations. In tion. However, a single, positive study per- some situations it is reasonable to assume formed according to good scientific prin- that reproductive toxicity is due to a sec- ciples and with statistically or biologically ondary consequence of maternal toxicity and significant positive results may justify clas- discount the effects, for example if the chem- sification (See also A.7.2.2.3). ical is so toxic that dams fail to thrive and A.7.2.3.2 Toxicokinetic studies in animals there is severe inanition; they are incapable and humans, site of action and mechanism or of nursing pups; or they are prostrate or mode of action study results may provide dying. relevant information, which could reduce or A.7.2.4 MATERNAL TOXICITY increase concerns about the hazard to human health. If it is conclusively demonstrated A.7.2.4.1 Development of the offspring that the clearly identified mechanism or throughout gestation and during the early mode of action has no relevance for humans postnatal stages can be influenced by toxic or when the toxicokinetic differences are so effects in the mother either through non-spe- marked that it is certain that the hazardous cific mechanisms related to stress and the

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disruption of maternal homeostasis, or by A.7.2.4.4 Some of the endpoints used to as- specific maternally-mediated mechanisms. sess maternal toxicity are provided below. So, in the interpretation of the develop- Data on these endpoints, if available, shall mental outcome to decide classification for be evaluated in light of their statistical or developmental effects it is important to con- biological significance and dose-response re- sider the possible influence of maternal tox- lationship. icity. This is a complex issue because of un- (a) Maternal mortality: An increased inci- certainties surrounding the relationship be- dence of mortality among the treated dams tween maternal toxicity and developmental over the controls shall be considered evi- outcome. Expert judgment and a weight of dence of maternal toxicity if the increase oc- evidence approach, using all available stud- curs in a dose-related manner and can be at- ies, shall be used to determine the degree of tributed to the systemic toxicity of the test influence to be attributed to maternal tox- material. Maternal mortality greater than icity when interpreting the criteria for clas- 10% is considered excessive and the data for sification for developmental effects. The ad- that dose level shall not normally be consid- verse effects in the embryo/fetus shall be ered to need further evaluation. first considered, and then maternal toxicity, (b) Mating index (Number of animals with along with any other factors which are like- seminal plugs or sperm/Number of mated × ly to have influenced these effects, as weight 100) of evidence, to help reach a conclusion about (c) Fertility index (Number of animals classification. with implants/Number of matings × 100) A.7.2.4.2 Based on pragmatic observation, (d) Gestation length (If allowed to deliver) it is believed that maternal toxicity may, (e) Body weight and body weight change: depending on severity, influence develop- Consideration of the maternal body weight ment via non-specific secondary mecha- change and/or adjusted (corrected) maternal nisms, producing effects such as depressed body weight shall be included in the evalua- fetal weight, retarded ossification, and pos- tion of maternal toxicity whenever such data sibly resorptions and certain malformations are available. The calculation of an adjusted in some strains of certain species. However, (corrected) mean maternal body weight the limited numbers of studies which have change, which is the difference between the investigated the relationship between devel- initial and terminal body weight minus the opmental effects and general maternal tox- gravid uterine weight (or alternatively, the icity have failed to demonstrate a con- sum of the weights of the fetuses), may indi- sistent, reproducible relationship across spe- cate whether the effect is maternal or intra- cies. Developmental effects which occur even uterine. In rabbits, the body weight gain in the presence of maternal toxicity are con- may not be a useful indicator of maternal sidered to be evidence of developmental tox- toxicity because of normal fluctuations in icity, unless it can be unequivocally dem- body weight during pregnancy. onstrated on a case by case basis that the de- (f) Food and water consumption (if rel- velopmental effects are secondary to mater- evant): The observation of a significant de- nal toxicity. Moreover, classification shall crease in the average food or water consump- be considered where there is a significant tion in treated dams (mothers) compared to toxic effect in the offspring, e.g., irreversible the control group may be useful in evalu- effects such as structural malformations, ating maternal toxicity, particularly when embryo/fetal lethality, or significant post- the test material is administered in the diet natal functional deficiencies. or drinking water. Changes in food or water A.7.2.4.3 Classification shall not auto- consumption must be evaluated in conjunc- matically be discounted for chemicals that tion with maternal body weights when deter- produce developmental toxicity only in asso- mining if the effects noted are reflective of ciation with maternal toxicity, even if a spe- maternal toxicity or more simply, cific maternally-mediated mechanism has unpalatability of the test material in feed or been demonstrated. In such a case, classifica- water. tion in Category 2 may be considered more (g) Clinical evaluations (including clinical appropriate than Category 1. However, when signs, markers, and hematology and clinical a chemical is so toxic that maternal death or chemistry studies): The observation of in- severe inanition results, or the dams (moth- creased incidence of significant clinical signs ers) are prostrate and incapable of nursing of toxicity in treated dams (mothers) rel- the pups, it is reasonable to assume that de- ative to the control group is useful in evalu- velopmental toxicity is produced solely as a ating maternal toxicity. If this is to be used secondary consequence of maternal toxicity as the basis for the assessment of maternal and discount the developmental effects. Clas- toxicity, the types, incidence, degree and du- sification is not necessarily the outcome in ration of clinical signs shall be reported in the case of minor developmental changes, the study. Clinical signs of maternal intoxi- e.g., a small reduction in fetal/pup body cation include, but are not limited to: coma, weight or retardation of ossification when prostration, hyperactivity, loss of righting seen in association with maternal toxicity. reflex, ataxia, or labored breathing.

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(h) Post-mortem data: Increased incidence an adverse effect on reproduction in experi- and/or severity of post-mortem findings may mental animals should not be classified. be indicative of maternal toxicity. This can A.7.2.5.6 Studies involving routes of ad- include gross or microscopic pathological ministration such as intravenous or findings or organ weight data, including ab- intraperitoneal injection, which may result solute organ weight, organ-to-body weight in exposure of the reproductive organs to un- ratio, or organ-to-brain weight ratio. When realistically high levels of the test sub- supported by findings of adverse stance, or elicit local damage to the repro- histopathological effects in the affected ductive organs, e.g., by irritation, must be organ(s), the observation of a significant interpreted with extreme caution and on change in the average weight of suspected their own are not normally the basis for target organ(s) of treated dams (mothers), classification. compared to those in the control group, may A.7.2.5.7 There is general agreement about be considered evidence of maternal toxicity. the concept of a limit dose, above which the production of an adverse effect may be con- A.7.2.5 ANIMAL AND EXPERIMENTAL DATA sidered to be outside the criteria which lead A.7.2.5.1 A number of scientifically vali- to classification. Some test guidelines speci- dated test methods are available, including fy a limit dose, other test guidelines qualify methods for developmental toxicity testing the limit dose with a statement that higher (e.g., OECD Test Guideline 414, ICH Guide- doses may be necessary if anticipated human line S5A, 1993), methods for peri- and post- exposure is sufficiently high that an ade- natal toxicity testing (e.g., ICH S5B, 1995), quate margin of exposure would not be and methods for one or two-generation tox- achieved. Also, due to species differences in icity testing (e.g., OECD Test Guidelines 415, toxicokinetics, establishing a specific limit 416) dose may not be adequate for situations A.7.2.5.2 Results obtained from screening where humans are more sensitive than the tests (e.g., OECD Guidelines 421—Reproduc- animal model. tion/Developmental Toxicity Screening Test, A.7.2.5.8 In principle, adverse effects on and 422—Combined Repeated Dose Toxicity reproduction seen only at very high dose lev- Study with Reproduction/Development Tox- els in animal studies (for example doses that icity Screening Test) can also be used to jus- induce prostration, severe inappetence, ex- tify classification, although the quality of cessive mortality) do not normally lead to this evidence is less reliable than that ob- classification, unless other information is tained through full studies. available, for example, toxicokinetics infor- A.7.2.5.3 Adverse effects or changes, seen mation indicating that humans may be more in short- or long-term repeated dose toxicity susceptible than animals, to suggest that studies, which are judged likely to impair re- classification is appropriate. productive function and which occur in the A.7.2.5.9 However, specification of the ac- absence of significant generalized toxicity, tual ‘‘limit dose’’ will depend upon the test may be used as a basis for classification, e.g., method that has been employed to provide histopathological changes in the gonads. the test results. A.7.2.5.4 Evidence from in vitro assays, or non-mammalian tests, and from analogous A.7.3 CLASSIFICATION CRITERIA FOR substances using structure-activity relation- MIXTURES 9 ship (SAR), can contribute to the procedure for classification. In all cases of this nature, A.7.3.1 CLASSIFICATION OF MIXTURES WHEN expert judgment must be used to assess the DATA ARE AVAILABLE FOR ALL INGREDIENTS adequacy of the data. Inadequate data shall OR ONLY FOR SOME INGREDIENTS OF THE not be used as a primary support for classi- MIXTURE fication. A.7.2.5.5 It is preferable that animal stud- A.7.3.1.1 The mixture shall be classified as ies are conducted using appropriate routes of a reproductive toxicant when at least one in- administration which relate to the potential gredient has been classified as a Category 1 route of human exposure. However, in practice, reproductive toxicity studies are com- 9 It should be noted that the classification cri- monly conducted using the oral route, and teria for health hazards usually include a tiered such studies will normally be suitable for scheme in which test data available on the com- evaluating the hazardous properties of the plete mixture are considered as the first tier in substance with respect to reproductive tox- the evaluation, followed by the applicable bridg- icity. However, if it can be conclusively dem- ing principles, and lastly, cut-off values/con- onstrated that the clearly identified mecha- centration limits or additivity. However, this ap- nism or mode of action has no relevance for proach is not used for Reproductive Toxicity. humans or when the toxicokinetic dif- These criteria for Reproductive Toxicity con- ferences are so marked that it is certain that sider the cut-off values/concentration limits as the hazardous property will not be expressed the primary tier and allow the classification to in humans then a substance which produces be modified only on a case-by-case evaluation

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or Category 2 reproductive toxicant and is one ingredient has been classified for effects present at or above the appropriate cut-off on or via lactation and is present at or above value/concentration limit specified in Table the appropriate cut-off value/concentration A.7.1 for Category 1 and 2, respectively. limit specified in Table A.7.1 for the addi- A.7.3.1.2 The mixture shall be classified tional category for effects on or via lacta- for effects on or via lactation when at least tion.

TABLE A.7.1—CUT-OFF VALUES/CONCENTRATION LIMITS OF INGREDIENTS OF A MIXTURE CLASSIFIED AS REPRODUCTIVE TOXICANTS OR FOR EFFECTS ON OR VIA LACTATION THAT TRIGGER CLASSIFICA- TION OF THE MIXTURE

Cut-off values/concentration limits triggering classification of a mixture as: Ingredients classified as: Category 1 reproductive Category 2 reproductive Additional category for toxicant toxicant effects on or via lactation

Category 1 reproductive toxicant ...... ≥0.1% ...... Category 2 reproductive toxicant ...... ≥0.1% Additional category for effects on or via lactation ...... ≥0.1%

A.7.3.2 CLASSIFICATION OF MIXTURES WHEN peated exposure is classified in accordance DATA ARE AVAILABLE FOR THE COMPLETE with SPECIFIC TARGET ORGAN TOXICITY— MIXTURE REPEATED EXPOSURE (A.9 of this Appen- Available test data for the mixture as a dix) and is therefore not included here. whole may be used for classification on a A.8.1.2 Classification identifies the chem- case-by-case basis. In such cases, the test re- ical as being a specific target organ toxicant sults for the mixture as a whole must be and, as such, it presents a potential for ad- shown to be conclusive taking into account verse health effects in people who are ex- dose and other factors such as duration, ob- posed to it. servations and analysis (e.g., statistical A.8.1.3 The adverse health effects pro- analysis, test sensitivity) of reproduction duced by a single exposure include consistent test systems. and identifiable toxic effects in humans; or, in experimental animals, toxicologically sig- A.7.3.3 CLASSIFICATION OF MIXTURES WHEN nificant changes which have affected the DATA ARE NOT AVAILABLE FOR THE COM- function or morphology of a tissue/organ, or PLETE MIXTURE: BRIDGING PRINCIPLES have produced serious changes to the bio- A.7.3.3.1 Where the mixture itself has not chemistry or hematology of the organism, been tested to determine its reproductive and these changes are relevant for human toxicity, but there are sufficient data on health. Human data is the primary source of both the individual ingredients and similar evidence for this hazard class. tested mixtures to adequately characterize A.8.1.4 Assessment shall take into consid- the hazards of the mixture, these data shall eration not only significant changes in a sin- be used in accordance with the following gle organ or biological system but also gen- bridging principles as found in paragraph eralized changes of a less severe nature in- A.0.5 of this Appendix: Dilution, Batching, volving several organs. and Substantially similar mixtures. A.8.1.5 Specific target organ toxicity can A.8 SPECIFIC TARGET ORGAN TOXICITY occur by any route that is relevant for hu- SINGLE EXPOSURE mans, i.e., principally oral, dermal or inhalation. A.8.1 DEFINITIONS AND GENERAL A.8.1.6 The classification criteria for spe- CONSIDERATIONS cific organ systemic toxicity single exposure A.8.1.1 Specific target organ toxicity—single are organized as criteria for substances Cat- exposure, (STOT–SE) means specific, non-le- egories 1 and 2 (See A.8.2.1), criteria for sub- thal target organ toxicity arising from a sin- stances Category 3 (See A.8.2.2) and criteria gle exposure to a chemical. All significant for mixtures (See A.8.3). See also Figure health effects that can impair function, both A.8.1. reversible and irreversible, immediate and/or delayed and not specifically addressed in A.1 to A.7 and A.10 of this Appendix are included. Specific target organ toxicity following re-

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A.8.2 CLASSIFICATION CRITERIA FOR the use of expert judgment on the basis of SUBSTANCES the weight of all evidence available, including the use of recommended guidance values A.8.2.1 SUBSTANCES OF CATEGORY 1 AND (See A.8.2.1.9). Substances shall then be clas- CATEGORY 2 sified in Category 1 or 2, depending upon the A.8.2.1.1 Substances shall be classified for nature and severity of the effect(s) observed, immediate or delayed effects separately, by in accordance with Figure A.8.1.

FIGURE A.8.1—HAZARD CATEGORIES FOR SPECIFIC TARGET ORGAN TOXICITY FOLLOWING SINGLE EXPOSURE

CATEGORY 1: Substances that have produced significant toxicity in humans, or that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to produce significant toxicity in humans following single exposure Substances are classified in Category 1 for STOT–SE on the basis of: (a) reliable and good quality evidence from human cases or epidemiological studies; or (b) observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (See A.8.2.1.9) to be used as part of weight-of-evidence evaluation. CATEGORY 2: Substances that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to be harmful to human health following single exposure Substances are classified in Category 2 for STOT–SE on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (See A.8.2.1.9) in order to help in classification. In exceptional cases, human evidence can also be used to place a substance in Category 2 (See A.8.2.1.6). CATEGORY 3: Transient target organ effects There are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. This category only includes narcotic effects and respiratory tract irritation. Substances are classified specifically for these effects as discussed in A.8.2.2. Note: The primary target organ/system shall be identified where possible, and where this is not possible, the substance shall be identified as a general toxicant. The data shall be evaluated and, where possible, shall not include secondary effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

A.8.2.1.2 The relevant route(s) of exposure experimental animals. The standard animal by which the classified substance produces studies in rats or mice that provide this in- damage shall be identified. formation are acute toxicity studies which A.8.2.1.3 Classification is determined by can include clinical observations and de- expert judgment, on the basis of the weight tailed macroscopic and microscopic exam- of all evidence available including the guid- ination to enable the toxic effects on target ance presented below. tissues/organs to be identified. Results of A.8.2.1.4 Weight of evidence of all avail- acute toxicity studies conducted in other able data, including human incidents, epide- species may also provide relevant informa- miology, and studies conducted in experi- tion. mental animals is used to substantiate spe- A.8.2.1.6 In exceptional cases, based on ex- cific target organ toxic effects that merit pert judgment, it may be appropriate to classification. A.8.2.1.5 The information required to place certain substances with human evi- evaluate specific target organ toxicity comes dence of target organ toxicity in Category 2: either from single exposure in humans (e.g., (a) when the weight of human evidence is not exposure at home, in the workplace or envi- sufficiently convincing to warrant Category ronmentally), or from studies conducted in

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1 classification, and/or (b) based on the na- number) in vital organs incapable of regen- ture and severity of effects. Dose/concentra- eration. tion levels in humans shall not be considered A.8.2.1.8 Effects considered not to support in the classification and any available evi- classification for Category 1 and 2 dence from animal studies shall be con- Effects may be seen in humans and/or ani- sistent with the Category 2 classification. In mals that do not justify classification. Such other words, if there are also animal data effects include, but are not limited to: available on the substance that warrant Cat- (a) Clinical observations or small changes egory 1 classification, the chemical shall be in bodyweight gain, food consumption or classified as Category 1. water intake that may have some toxi- A.8.2.1.7 Effects considered to support cological importance but that do not, by classification for Category 1 and 2 themselves, indicate ‘‘significant’’ toxicity; A.8.2.1.7.1 Classification is supported by (b) Small changes in clinical biochemistry, evidence associating single exposure to the hematology or urinalysis parameters and/or substance with a consistent and identifiable transient effects, when such changes or ef- toxic effect. fects are of doubtful or of minimal toxi- A.8.2.1.7.2 Evidence from human experi- cological importance; ence/incidents is usually restricted to re- (c) Changes in organ weights with no evi- ports of adverse health consequences, often dence of organ dysfunction; with uncertainty about exposure conditions, and may not provide the scientific detail (d) Adaptive responses that are not consid- that can be obtained from well-conducted ered toxicologically relevant; and, studies in experimental animals. (e) Substance-induced species-specific A.8.2.1.7.3 Evidence from appropriate mechanisms of toxicity, i.e., demonstrated studies in experimental animals can furnish with reasonable certainty to be not relevant much more detail, in the form of clinical ob- for human health, shall not justify classi- servations, and macroscopic and microscopic fication. pathological examination and this can often A.8.2.1.9 Guidance values to assist with reveal hazards that may not be life-threat- classification based on the results obtained ening but could indicate functional impair- from studies conducted in experimental ani- ment. Consequently all available evidence, mals for Category 1 and 2 and evidence relevance to human health, A.8.2.1.9.1 In order to help reach a deci- must be taken into consideration in the clas- sion about whether a substance shall be classification process. Relevant toxic effects in sified or not, and to what degree it shall be humans and/or animals include, but are not classified (Category 1 vs. Category 2), dose/ limited to: concentration ‘‘guidance values’’ are pro- (a) Morbidity resulting from single expo- vided for consideration of the dose/con- sure; centration which has been shown to produce (b) Significant functional changes, more significant health effects. The principal ar- than transient in nature, in the respiratory gument for proposing such guidance values is system, central or peripheral nervous sys- that all chemicals are potentially toxic and tems, other organs or other organ systems, there has to be a reasonable dose/concentra- including signs of central nervous system de- tion above which a degree of toxic effect is pression and effects on special senses (e.g., acknowledged. sight, hearing and sense of smell); A.8.2.1.9.2 Thus, in animal studies, when (c) Any consistent and significant adverse significant toxic effects are observed that in- change in clinical biochemistry, hematology, dicate classification, consideration of the or urinalysis parameters; dose/concentration at which these effects (d) Significant organ damage that may be were seen, in relation to the suggested guid- noted at necropsy and/or subsequently seen ance values, provides useful information to or confirmed at microscopic examination; help assess the need to classify (since the (e) Multi-focal or diffuse necrosis, fibrosis toxic effects are a consequence of the haz- or granuloma formation in vital organs with ardous property(ies) and also the dose/con- regenerative capacity; centration). (f) Morphological changes that are poten- A.8.2.1.9.3 The guidance value (C) ranges tially reversible but provide clear evidence for single-dose exposure which has produced of marked organ dysfunction; and, a significant non-lethal toxic effect are those (g) Evidence of appreciable cell death (in- applicable to acute toxicity testing, as indi- cluding cell degeneration and reduced cell cated in Table A.8.1.

TABLE A.8.1—GUIDANCE VALUE RANGES FOR SINGLE-DOSE EXPOSURES

Guidance value ranges for: Route of exposure Units Category 1 Category 2 Category 3

Oral (rat) ...... mg/kg body weight ...... C ≤300 ...... 2000 ≥C >300 ...... Guidance values do not apply.

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TABLE A.8.1—GUIDANCE VALUE RANGES FOR SINGLE-DOSE EXPOSURES—Continued

Guidance value ranges for: Route of exposure Units Category 1 Category 2 Category 3

Dermal (rat or rabbit) ... mg/kg body weight ...... C ≤1,000 ...... 2000 ≥C >1,000. Inhalation (rat) gas ...... ppmV/4h ...... C ≤2,500 ...... 20,000 ≥C >2,500. Inhalation (rat) vapor ... mg/1/4h ...... C ≤10 ...... 20 ≥C >10. Inhalation (rat) dust/ mg/l/4h ...... C ≤1.0 ...... 5.0 ≥C >1.0. mist/fume.

A.8.2.1.9.4 The guidance values and ranges consideration of other important factors mentioned in Table A.8.1 are intended only such as formation of common significant me- for guidance purposes, i.e., to be used as part tabolites. of the weight of evidence approach, and to assist with decisions about classification. A.8.2.2 SUBSTANCES OF CATEGORY 3 They are not intended as strict demarcation A.8.2.2.1 Criteria for respiratory tract ir- values. Guidance values are not provided for ritation Category 3 since this classification is primarily based on human data; animal data The criteria for classifying substances as may be included in the weight of evidence Category 3 for respiratory tract irritation evaluation. are: A.8.2.1.9.5 Thus, it is feasible that a spe- (a) Respiratory irritant effects (character- cific profile of toxicity occurs at a dose/con- ized by localized redness, edema, pruritis centration below the guidance value, e.g., and/or pain) that impair function with symp- <2000 mg/kg body weight by the oral route, toms such as cough, pain, choking, and however the nature of the effect may result breathing difficulties are included. It is rec- in the decision not to classify. Conversely, a ognized that this evaluation is based pri- specific profile of toxicity may be seen in marily on human data; animal studies occurring at above a guidance (b) Subjective human observations sup- value, e.g., ≥2000 mg/kg body weight by the ported by objective measurements of clear oral route, and in addition there is supple- respiratory tract irritation (RTI) (e.g., mentary information from other sources, electrophysiological responses, biomarkers e.g., other single dose studies, or human case of inflammation in nasal or bronchoalveolar experience, which supports a conclusion lavage fluids); that, in view of the weight of evidence, clas- (c) The symptoms observed in humans sification is the prudent action to take. shall also be typical of those that would be A.8.2.1.10 Other considerations produced in the exposed population rather A.8.2.1.10.1 When a substance is character- than being an isolated idiosyncratic reaction ized only by use of animal data the classi- or response triggered only in individuals fication process includes reference to dose/ with hypersensitive airways. Ambiguous re- concentration guidance values as one of the ports simply of ‘‘irritation’’ should be ex- elements that contribute to the weight of cluded as this term is commonly used to de- evidence approach. scribe a wide range of sensations including A.8.2.1.10.2 When well-substantiated those such as smell, unpleasant taste, a tick- human data are available showing a specific ling sensation, and dryness, which are out- target organ toxic effect that can be reliably side the scope of classification for res- attributed to single exposure to a substance, piratory tract irritation; the substance shall be classified. Positive (d) There are currently no scientifically human data, regardless of probable dose, pre- validated animal tests that deal specifically dominates over animal data. Thus, if a sub- with RTI; however, useful information may stance is unclassified because specific target be obtained from the single and repeated in- organ toxicity observed was considered not halation toxicity tests. For example, animal relevant or significant to humans, if subse- studies may provide useful information in quent human incident data become available terms of clinical signs of toxicity (dyspnoea, showing a specific target organ toxic effect, rhinitis etc) and histopathology (e.g., hyper- the substance shall be classified. emia, edema, minimal inflammation, thick- A.8.2.1.10.3 A substance that has not been ened mucous layer) which are reversible and tested for specific target organ toxicity may be reflective of the characteristic clin- shall, where appropriate, be classified on the ical symptoms described above. Such animal basis of data from a scientifically validated studies can be used as part of weight of evi- structure activity relationship and expert dence evaluation; and, judgment-based extrapolation from a struc- (e) This special classification will occur tural analogue that has previously been clas- only when more severe organ effects includ- sified together with substantial support from ing the respiratory system are not observed

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as those effects would require a higher clas- ating data on mixtures, that the dose, dura- sification. tion, observation or analysis, do not render A.8.2.2.2 Criteria for narcotic effects the results inconclusive. The criteria for classifying substances in Category 3 for narcotic effects are: A.8.3.3 CLASSIFICATION OF MIXTURES WHEN (a) Central nervous system depression in- DATA ARE NOT AVAILABLE FOR THE COM- cluding narcotic effects in humans such as PLETE MIXTURE: BRIDGING PRINCIPLES drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo A.8.3.3.1 Where the mixture itself has not are included. These effects can also be mani- been tested to determine its specific target fested as severe headache or nausea, and can organ toxicity, but there are sufficient data lead to reduced judgment, dizziness, irrita- on both the individual ingredients and simi- bility, fatigue, impaired memory function, lar tested mixtures to adequately charac- deficits in perception and coordination, reac- terize the hazards of the mixture, these data tion time, or sleepiness; and, shall be used in accordance with the fol- (b) Narcotic effects observed in animal lowing bridging principles as found in para- studies may include lethargy, lack of coordi- graph A.0.5 of this Appendix: Dilution, nation righting reflex, narcosis, and ataxia. Batching, Concentration of mixtures, Inter- If these effects are not transient in nature, polation within one toxicity category, Sub- then they shall be considered for classifica- stantially similar mixtures, or Aerosols. tion as Category 1 or 2. A.8.3.4 CLASSIFICATION OF MIXTURES WHEN A.8.3 CLASSIFICATION CRITERIA FOR DATA ARE AVAILABLE FOR ALL INGREDIENTS MIXTURES OR ONLY FOR SOME INGREDIENTS OF THE MIXTURE A.8.3.1 Mixtures are classified using the same criteria as for substances, or alter- A.8.3.4.1 Where there is no reliable evi- natively as described below. As with sub- dence or test data for the specific mixture stances, mixtures may be classified for spe- itself, and the bridging principles cannot be cific target organ toxicity following single used to enable classification, then classifica- exposure, repeated exposure, or both. tion of the mixture is based on the classification of the ingredient substances. In this A.8.3.2 CLASSIFICATION OF MIXTURES WHEN case, the mixture shall be classified as a spe- DATA ARE AVAILABLE FOR THE COMPLETE cific target organ toxicant (specific organ MIXTURE specified), following single exposure, re- When reliable and good quality evidence peated exposure, or both when at least one from human experience or appropriate stud- ingredient has been classified as a Category ies in experimental animals, as described in 1 or Category 2 specific target organ toxicant the criteria for substances, is available for and is present at or above the appropriate the mixture, then the mixture shall be clas- cut-off value/concentration limit specified in sified by weight of evidence evaluation of Table A.8.2 for Categories 1 and 2, respec- this data. Care shall be exercised in evalu- tively.

TABLE A.8.2—CUT-OFF VALUES/CONCENTRATION LIMITS OF INGREDIENTS OF A MIXTURE CLASSIFIED AS A SPECIFIC TARGET ORGAN TOXICANT THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE AS CATEGORY 1 OR 2

Cut-off values/concentration limits triggering classification of Ingredient classified as: a mixture as: Category 1 Category 2

Category 1 Target organ toxicant ...... ≥1.0% Category 2 Target organ toxicant ...... ≥1.0%

A.8.3.4.2 These cut-off values and con- cause certain substances can cause target sequent classifications shall be applied organ toxicity at <1% concentration when equally and appropriately to both single- and other ingredients in the mixture are known repeated-dose target organ toxicants. to potentiate its toxic effect. A.8.3.4.3 Mixtures shall be classified for A.8.3.4.5 Care shall be exercised when ex- either or both single and repeated dose tox- trapolating the toxicity of a mixture that icity independently. contains Category 3 ingredient(s). A cut-off A.8.3.4.4 Care shall be exercised when value/concentration limit of 20%, considered toxicants affecting more than one organ sys- as an additive of all Category 3 ingredients tem are combined that the potentiation or for each hazard endpoint, is appropriate; synergistic interactions are considered, be- however, this cut-off value/concentration

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limit may be higher or lower depending on a potential for adverse health effects in peo- the Category 3 ingredient(s) involved and the ple who are exposed to it. fact that some effects such as respiratory A.9.1.3 These adverse health effects pro- tract irritation may not occur below a cer- duced by repeated exposure include contain concentration while other effects such sistent and identifiable toxic effects in hu- as narcotic effects may occur below this 20% mans, or, in experimental animals, value. Expert judgment shall be exercised. toxicologically significant changes which Respiratory tract irritation and narcotic ef- have affected the function or morphology of fects are to be evaluated separately in ac- a tissue/organ, or have produced serious cordance with the criteria given in A.8.2.2. changes to the biochemistry or hematology When conducting classifications for these of the organism and these changes are rel- hazards, the contribution of each ingredient evant for human health. Human data will be should be considered additive, unless there is the primary source of evidence for this haz- evidence that the effects are not additive. ard class. A.9.1.4 Assessment shall take into consid- A.9 SPECIFIC TARGET ORGAN TOXICITY eration not only significant changes in a sin- REPEATED OR PROLONGED EXPOSURE gle organ or biological system but also generalized changes of a less severe nature in- A.9.1 DEFINITIONS AND GENERAL volving several organs. CONSIDERATIONS A.9.1.5 Specific target organ toxicity can A.9.1.1 Specific target organ toxicity—re- occur by any route that is relevant for hu- peated exposure (STOT–RE) means specific mans, e.g., principally oral, dermal or inha- target organ toxicity arising from repeated lation. exposure to a substance or mixture. All sig- LASSIFICATION CRITERIA FOR nificant health effects that can impair func- A.9.2 C SUBSTANCES tion, both reversible and irreversible, immediate and/or delayed and not specifically ad- A.9.2.1 Substances shall be classified as dressed in A.1 to A.7 and A.10 of this Appen- STOT–RE by expert judgment on the basis of dix are included. Specific target organ tox- the weight of all evidence available, includ- icity following a single-event exposure is ing the use of recommended guidance values classified in accordance with SPECIFIC TAR- which take into account the duration of ex- GET ORGAN TOXICITY—SINGLE EXPOSURE posure and the dose/concentration which pro- (A.8 of this Appendix) and is therefore not induced the effect(s), (See A.9.2.9). Substances cluded here. shall be placed in one of two categories, de- A.9.1.2 Classification identifies the sub- pending upon the nature and severity of the stance or mixture as being a specific target effect(s) observed, in accordance with Figure organ toxicant and, as such, it may present A.9.1.

FIGURE A.9.1—HAZARD CATEGORIES FOR SPECIFIC TARGET ORGAN TOXICITY FOLLOWING REPEATED EXPOSURE

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FIGURE A.9.1—HAZARD CATEGORIES FOR SPECIFIC TARGET ORGAN TOXICITY FOLLOWING REPEATED EXPOSURE—Continued Note: The primary target organ/system shall be identified where possible, or the substance shall be identified as a general toxicant. The data shall be carefully evaluated and, where possible, shall not include secondary effects (e.g., a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

A.9.2.2 The relevant route of exposure by A.9.2.7.2 Evidence from human experience/ which the classified substance produces dam- incidents is usually restricted to reports of age shall be identified. adverse health consequences, often with un- A.9.2.3 Classification is determined by ex- certainty about exposure conditions, and pert judgment, on the basis of the weight of may not provide the scientific detail that all evidence available including the guidance can be obtained from well-conducted studies presented below. in experimental animals. A.9.2.4 Weight of evidence of all data, in- A.9.2.7.3 Evidence from appropriate stud- cluding human incidents, epidemiology, and ies in experimental animals can furnish studies conducted in experimental animals, much more detail, in the form of clinical ob- is used to substantiate specific target organ servations, hematology, clinical chemistry, toxic effects that merit classification. macroscopic and microscopic pathological A.9.2.5 The information required to evalu- examination and this can often reveal haz- ate specific target organ toxicity comes ei- ards that may not be life-threatening but ther from repeated exposure in humans, e.g., could indicate functional impairment. Con- exposure at home, in the workplace or envi- sequently all available evidence, and rel- ronmentally, or from studies conducted in evance to human health, must be taken into experimental animals. The standard animal consideration in the classification process. studies in rats or mice that provide this information are 28 day, 90 day or lifetime stud- Relevant toxic effects in humans and/or ani- ies (up to 2 years) that include mals include, but are not limited to: hematological, clinico-chemical and detailed (a) Morbidity or death resulting from re- macroscopic and microscopic examination to peated or long-term exposure. Morbidity or enable the toxic effects on target tissues/or- death may result from repeated exposure, gans to be identified. Data from repeat dose even to relatively low doses/concentrations, studies performed in other species may also due to bioaccumulation of the substance or be used. Other long-term exposure studies, its metabolites, or due to the overwhelming e.g., for carcinogenicity, neurotoxicity or re- of the de-toxification process by repeated ex- productive toxicity, may also provide evi- posure; dence of specific target organ toxicity that (b) Significant functional changes in the could be used in the assessment of classifica- central or peripheral nervous systems or tion. other organ systems, including signs of cen- A.9.2.6 In exceptional cases, based on ex- tral nervous system depression and effects pert judgment, it may be appropriate to on special senses (e.g., sight, hearing and place certain substances with human evi- sense of smell); dence of specific target organ toxicity in (c) Any consistent and significant adverse Category 2: (a) when the weight of human change in clinical biochemistry, hematology, evidence is not sufficiently convincing to or urinalysis parameters; warrant Category 1 classification, and/or (b) based on the nature and severity of effects. (d) Significant organ damage that may be Dose/concentration levels in humans shall noted at necropsy and/or subsequently seen not be considered in the classification and or confirmed at microscopic examination; any available evidence from animal studies (e) Multi-focal or diffuse necrosis, fibrosis shall be consistent with the Category 2 clas- or granuloma formation in vital organs with sification. In other words, if there are also regenerative capacity; animal data available on the substance that (f) Morphological changes that are poten- warrant Category 1 classification, the sub- tially reversible but provide clear evidence stance shall be classified as Category 1. of marked organ dysfunction (e.g., severe fatty change in the liver); and, A.9.2.7 EFFECTS CONSIDERED TO SUPPORT (g) Evidence of appreciable cell death (in- CLASSIFICATION cluding cell degeneration and reduced cell A.9.2.7.1 Classification is supported by re- number) in vital organs incapable of regen- liable evidence associating repeated exposure eration. to the substance with a consistent and identifiable toxic effect.

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A.9.2.8 EFFECTS CONSIDERED NOT TO that all chemicals are potentially toxic and SUPPORT CLASSIFICATION there has to be a reasonable dose/concentration above which a degree of toxic effect is Effects may be seen in humans and/or ani- acknowledged. Also, repeated-dose studies mals that do not justify classification. Such effects include, but are not limited to: conducted in experimental animals are de- (a) Clinical observations or small changes signed to produce toxicity at the highest in bodyweight gain, food consumption or dose used in order to optimize the test objec- water intake that may have some toxi- tive and so most studies will reveal some cological importance but that do not, by toxic effect at least at this highest dose. themselves, indicate ‘‘significant’’ toxicity; What is therefore to be decided is not only (b) Small changes in clinical biochemistry, what effects have been produced, but also at hematology or urinalysis parameters and/or what dose/concentration they were produced transient effects, when such changes or ef- and how relevant is that for humans. fects are of doubtful or of minimal toxi- A.9.2.9.3 Thus, in animal studies, when cological importance; significant toxic effects are observed that in- (c) Changes in organ weights with no evi- dicate classification, consideration of the du- dence of organ dysfunction; ration of experimental exposure and the (d) Adaptive responses that are not consid- dose/concentration at which these effects ered toxicologically relevant; were seen, in relation to the suggested guid- (e) Substance-induced species-specific ance values, provides useful information to mechanisms of toxicity, i.e., demonstrated help assess the need to classify (since the with reasonable certainty to be not relevant toxic effects are a consequence of the haz- for human health, shall not justify classi- ardous property(ies) and also the duration of fication. exposure and the dose/concentration). A.9.2.9.4 The decision to classify at all can A.9.2.9 GUIDANCE VALUES TO ASSIST WITH be influenced by reference to the dose/con- CLASSIFICATION BASED ON THE RESULTS OB- centration guidance values at or below which TAINED FROM STUDIES CONDUCTED IN EX- a significant toxic effect has been observed. PERIMENTAL ANIMALS A.9.2.9.5 The guidance values refer to ef- A.9.2.9.1 In studies conducted in experi- fects seen in a standard 90-day toxicity study mental animals, reliance on observation of conducted in rats. They can be used as a effects alone, without reference to the dura- basis to extrapolate equivalent guidance val- tion of experimental exposure and dose/con- ues for toxicity studies of greater or lesser centration, omits a fundamental concept of duration, using dose/exposure time extrapo- toxicology, i.e., all substances are poten- lation similar to Haber’s rule for inhalation, tially toxic, and what determines the tox- which states essentially that the effective icity is a function of the dose/concentration dose is directly proportional to the exposure and the duration of exposure. In most studies concentration and the duration of exposure. conducted in experimental animals the test The assessment should be done on a case-by- guidelines use an upper limit dose value. case basis; for example, for a 28-day study A.9.2.9.2 In order to help reach a decision the guidance values below would be in- about whether a substance shall be classified creased by a factor of three. or not, and to what degree it shall be classi- A.9.2.9.6 Thus for Category 1 classifica- fied (Category 1 vs. Category 2), dose/con- tion, significant toxic effects observed in a centration ‘‘guidance values’’ are provided in 90-day repeated-dose study conducted in ex- Table A.9.1 for consideration of the dose/con- perimental animals and seen to occur at or centration which has been shown to produce below the (suggested) guidance values (C) as significant health effects. The principal ar- indicated in Table A.9.1 would justify classi- gument for proposing such guidance values is fication:

TABLE A.9.1—GUIDANCE VALUES TO ASSIST IN CATEGORY 1 CLASSIFICATION [Applicable to a 90-day study]

Guidance values Route of exposure Units (dose/concentration)

Oral (rat) ...... mg/kg body weight/day ...... C ≤10. Dermal (rat or rabbit) ...... mg/kg body weight/day ...... C ≤20. Inhalation (rat) gas ...... ppmV/6h/day ...... C ≤50. Inhalation (rat) vapor ...... mg/liter/6h/day ...... C ≤0.2. Inhalation (rat) dust/mist/fume ...... mg/liter/6h/day ...... C ≤0.02.

A.9.2.9.7 For Category 2 classification, mental animals and seen to occur within the significant toxic effects observed in a 90-day repeated-dose study conducted in experi-

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(suggested) guidance value ranges as indicated in Table A.9.2 would justify classification:

TABLE A.9.2—GUIDANCE VALUES TO ASSIST IN CATEGORY 2 CLASSIFICATION [Applicable to a 90-day study]

Guidance values Route of exposure Units (dose/concentration)

Oral (rat) ...... mg/kg body weight/day ...... 10

A.9.2.9.8 The guidance values and ranges classified on the basis of data from a sci- mentioned in A.2.9.9.6 and A.2.9.9.7 are in- entifically validated structure activity rela- tended only for guidance purposes, i.e., to be tionship and expert judgment-based extrapo- used as part of the weight of evidence ap- lation from a structural analogue that has proach, and to assist with decisions about previously been classified together with sub- classification. They are not intended as stantial support from consideration of other strict demarcation values. important factors such as formation of com- A.9.2.9.9 Thus, it is possible that a specific mon significant metabolites. profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below A.9.3 CLASSIFICATION CRITERIA FOR the guidance value, e.g., <100 mg/kg body MIXTURES weight/day by the oral route, however the nature of the effect, e.g., nephrotoxicity seen A.9.3.1 Mixtures are classified using the only in male rats of a particular strain same criteria as for substances, or alter- known to be susceptible to this effect, may natively as described below. As with sub- result in the decision not to classify. Con- stances, mixtures may be classified for spe- versely, a specific profile of toxicity may be cific target organ toxicity following single seen in animal studies occurring at above a exposure, repeated exposure, or both. guidance value, e.g., ≥100 mg/kg body weight/ day by the oral route, and in addition there A.9.3.2 CLASSIFICATION OF MIXTURES WHEN is supplementary information from other DATA ARE AVAILABLE FOR THE COMPLETE sources, e.g., other long-term administration MIXTURE studies, or human case experience, which supports a conclusion that, in view of the When reliable and good quality evidence weight of evidence, classification is prudent. from human experience or appropriate studies in experimental animals, as described in A.9.2.10 OTHER CONSIDERATIONS the criteria for substances, is available for A.9.2.10.1 When a substance is character- the mixture, then the mixture shall be clas- ized only by use of animal data the classi- sified by weight of evidence evaluation of fication process includes reference to dose/ these data. Care shall be exercised in evalu- concentration guidance values as one of the ating data on mixtures, that the dose, dura- elements that contribute to the weight of tion, observation or analysis, do not render evidence approach. the results inconclusive. A.9.2.10.2 When well-substantiated human data are available showing a specific target A.9.3.3 CLASSIFICATION OF MIXTURES WHEN organ toxic effect that can be reliably attrib- DATA ARE NOT AVAILABLE FOR THE COM- uted to repeated or prolonged exposure to a PLETE MIXTURE: BRIDGING PRINCIPLES substance, the substance shall be classified. A.9.3.3.1 Where the mixture itself has not Positive human data, regardless of probable been tested to determine its specific target dose, predominates over animal data. Thus, if a substance is unclassified because no spe- organ toxicity, but there are sufficient data cific target organ toxicity was seen at or on both the individual ingredients and simi- below the dose/concentration guidance value lar tested mixtures to adequately charac- for animal testing, if subsequent human inci- terize the hazards of the mixture, these data dent data become available showing a spe- shall be used in accordance with the fol- cific target organ toxic effect, the substance lowing bridging principles as found in para- shall be classified. graph A.0.5 of this Appendix: Dilution; A.9.2.10.3 A substance that has not been Batching; Concentration of mixtures; Inter- tested for specific target organ toxicity may polation within one toxicity category; Sub- in certain instances, where appropriate, be stantially similar mixtures; and Aerosols.

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A.9.3.4 CLASSIFICATION OF MIXTURES WHEN tion of the ingredient substances. In this DATA ARE AVAILABLE FOR ALL INGREDIENTS case, the mixture shall be classified as a spe- OR ONLY FOR SOME INGREDIENTS OF THE cific target organ toxicant (specific organ MIXTURE specified), following single exposure, repeated exposure, or both when at least one A.9.3.4.1 Where there is no reliable evi- ingredient has been classified as a Category dence or test data for the specific mixture 1 or Category 2 specific target organ toxicant itself, and the bridging principles cannot be and is present at or above the appropriate used to enable classification, then classifica- cut-off value/concentration limit specified in tion of the mixture is based on the classifica- Table A.9.3 for Category 1 and 2 respectively.

TABLE A.9.3—CUT-OFF VALUE/CONCENTRATION LIMITS OF INGREDIENTS OF A MIXTURE CLASSIFIED AS A SPECIFIC TARGET ORGAN TOXICANT THAT WOULD TRIGGER CLASSIFICATION OF THE MIXTURE AS CATEGORY 1 OR 2

Cut-off values/concentration limits triggering classification of a Ingredient classified as: mixture as: Category 1 Category 2

Category 1 Target organ toxicant ...... ≥1.0% Category 2 Target organ toxicant ...... ≥1.0%

A.9.3.4.2 These cut-off values and con- A.10.1.2 Aspiration toxicity includes se- sequent classifications shall be applied vere acute effects such as chemical pneu- equally and appropriately to both single- and monia, varying degrees of pulmonary injury repeated-dose target organ toxicants. or death following aspiration. A.9.3.4.3 Mixtures shall be classified for A.10.1.3 Aspiration is initiated at the mo- either or both single- and repeated-dose tox- ment of inspiration, in the time required to icity independently. take one breath, as the causative material lodges at the crossroad of the upper res- A.9.3.4.4 Care shall be exercised when piratory and digestive tracts in the toxicants affecting more than one organ sys- laryngopharyngeal region. tem are combined that the potentiation or A.10.1.4 Aspiration of a substance or mix- synergistic interactions are considered, be- ture can occur as it is vomited following in- cause certain substances can cause specific gestion. This may have consequences for la- target organ toxicity at <1% concentration beling, particularly where, due to acute tox- when other ingredients in the mixture are icity, a recommendation may be considered known to potentiate its toxic effect. to induce vomiting after ingestion. However, if the substance/mixture also presents an as- A.10 ASPIRATION HAZARD piration toxicity hazard, the recommendation to induce vomiting may need to be A.10.1 DEFINITIONS AND GENERAL AND modified. SPECIFIC CONSIDERATIONS A.10.1.1 Aspiration means the entry of a A.10.1.5 SPECIFIC CONSIDERATIONS liquid or solid chemical directly through the A.10.1.5.1 The classification criteria refer oral or nasal cavity, or indirectly from vom- to kinematic viscosity. The following pro- iting, into the trachea and lower respiratory vides the conversion between dynamic and system. kinematic viscosity:

A.10.1.5.2 Although the definition of aspi- A.10.1.5.3 Classification of aerosol/mist ration in A.10.1.1 includes the entry of solids products. into the respiratory system, classification Aerosol and mist products are usually dis- according to (b) in table A.10.1 for Category pensed in containers such as self-pressurized 1 is intended to apply to liquid substances and mixtures only.

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containers, trigger and pump sprayers. Clas- the mist produced by trigger and pump sification for these products shall be consid- sprayers is coarse and therefore, a pool may ered if their use may form a pool of product be formed that then may be aspirated. When in the mouth, which then may be aspirated. the pump mechanism may be removed and If the mist or aerosol from a pressurized con- contents are available to be swallowed then tainer is fine, a pool may not be formed. On the classification of the products should be the other hand, if a pressurized container considered. dispenses product in a stream, a pool may be A.10.2 CLASSIFICATION CRITERIA FOR formed that may then be aspirated. Usually, SUBSTANCES

TABLE A.10.1—CRITERIA FOR ASPIRATION TOXICITY

Category Criteria

Category 1: Chemicals known to cause human aspiration tox- A substance shall be classified in Category 1: icity hazards or to be regarded as if they cause human aspi- (a) If reliable and good quality human evidence indicates ration toxicity hazard. that it causes aspiration toxicity (See note); or (b) If it is a hydrocarbon and has a kinematic viscosity ≤20.5 mm2/s, measured at 40 °C. Note: Examples of substances included in Category 1 are certain hydrocarbons, turpentine and pine oil.

A.10.3 CLASSIFICATION CRITERIA FOR APPENDIX B TO § 1910.1200—PHYSICAL CRITERIA MIXTURES (MANDATORY)

A.10.3.1 CLASSIFICATION WHEN DATA ARE B.1 EXPLOSIVES AVAILABLE FOR THE COMPLETE MIXTURE B.1.1 DEFINITIONS AND GENERAL A mixture shall be classified in Category 1 CONSIDERATIONS based on reliable and good quality human evidence. B.1.1.1 An explosive chemical is a solid or liquid chemical which is in itself capable by A.10.3.2 CLASSIFICATION OF MIXTURES WHEN chemical reaction of producing gas at such a DATA ARE NOT AVAILABLE FOR THE COM- temperature and pressure and at such a PLETE MIXTURE: BRIDGING PRINCIPLES speed as to cause damage to the sur- roundings. Pyrotechnic chemicals are in- A.10.3.2.1 Where the mixture itself has not cluded even when they do not evolve gases. been tested to determine its aspiration toxicity, but there are sufficient data on both A pyrotechnic chemical is a chemical de- the individual ingredients and similar tested signed to produce an effect by heat, light, mixtures to adequately characterize the haz- sound, gas or smoke or a combination of ard of the mixture, these data shall be used these as the result of non-detonative self- in accordance with the following bridging sustaining exothermic chemical reactions. principles as found in paragraph A.0.5 of this An explosive item is an item containing one Appendix: Dilution; Batching; Concentration or more explosive chemicals. of mixtures; Interpolation within one tox- A pyrotechnic item is an item containing icity category; and Substantially similar one or more pyrotechnic chemicals. mixtures. For application of the dilution An unstable explosive is an explosive which bridging principle, the concentration of aspi- is thermally unstable and/or too sensitive for ration toxicants shall not be less than 10%. normal handling, transport, or use. An intentional explosive is a chemical or A.10.3.3 CLASSIFICATION OF MIXTURES WHEN item which is manufactured with a view to DATA ARE AVAILABLE FOR ALL INGREDIENTS produce a practical explosive or pyrotechnic OR ONLY FOR SOME INGREDIENTS OF THE effect. MIXTURE B.1.1.2 The class of explosives comprises: A.10.3.3.1 A mixture which contains ≥10% (a) Explosive chemicals; of an ingredient or ingredients classified in (b) Explosive items, except devices con- Category 1, and has a kinematic viscosity taining explosive chemicals in such quantity ≤20.5 mm2/s, measured at 40 °C, shall be clas- or of such a character that their inadvertent sified in Category 1. or accidental ignition or initiation shall not A.10.3.3.2 In the case of a mixture which cause any effect external to the device either separates into two or more distinct layers, by projection, fire, smoke, heat or loud one of which contains ≥10% of an ingredient noise; and or ingredients classified in Category 1 and (c) Chemicals and items not included under has a kinematic viscosity ≤20.5 mm2/s, meas- (a) and (b) above which are manufactured ured at 40 °C, then the entire mixture shall with the view to producing a practical explo- be classified in Category 1. sive or pyrotechnic effect.

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B.1.2 CLASSIFICATION CRITERIA solid (See B.14) is determined by Test Series 8 tests. Chemicals and items of this class shall be classified as unstable explosives or shall be NOTE: Classification of solid chemicals assigned to one of the following six divisions shall be based on tests performed on the depending on the type of hazard they chemical as presented. If, for example, for present: the purposes of supply or transport, the same (a) Division 1.1—Chemicals and items chemical is to be presented in a physical which have a mass explosion hazard (a mass form different from that which was tested explosion is one which affects almost the en- and which is considered likely to materially tire quantity present virtually instanta- alter its performance in a classification test, neously); classification must be based on testing of the (b) Division 1.2—Chemicals and items chemical in the new form. which have a projection hazard but not a B.1.3.2 Explosive properties are associated mass explosion hazard; with the presence of certain chemical groups (c) Division 1.3—Chemicals and items in a molecule which can react to produce which have a fire hazard and either a minor very rapid increases in temperature or pres- blast hazard or a minor projection hazard or sure. The screening procedure in B.1.3.1 is both, but not a mass explosion hazard: aimed at identifying the presence of such re- (i) Combustion of which gives rise to con- active groups and the potential for rapid en- siderable radiant heat; or ergy release. If the screening procedure iden- (ii) Which burn one after another, pro- tifies the chemical as a potential explosive, ducing minor blast or projection effects or the acceptance procedure (See section 10.3 of both; the UN ST/SG/AC.10 (incorporated by ref- (d) Division 1.4—Chemicals and items erence; See § 1910.6)) is necessary for classi- which present no significant hazard: chemi- fication. cals and items which present only a small NOTE: Neither a Series 1 type (a) propaga- hazard in the event of ignition or initiation. tion of detonation test nor a Series 2 type (a) The effects are largely confined to the pack- test of sensitivity to detonative shock is nec- age and no projection of fragments of appre- essary if the exothermic decomposition en- ciable size or range is to be expected. An ex- ergy of organic materials is less than 800 J/ ternal fire shall not cause virtually instanta- g. neous explosion of almost the entire con- B.1.3.3 If a mixture contains any known tents of the package; explosives, the acceptance procedure is nec- (e) Division 1.5—Very insensitive chemi- essary for classification. cals which have a mass explosion hazard: B.1.3.4 A chemical is not classified as ex- chemicals which have a mass explosion haz- plosive if: ard but are so insensitive that there is very (a) There are no chemical groups associ- little probability of initiation or of transi- ated with explosive properties present in the tion from burning to detonation under nor- molecule. Examples of groups which may in- mal conditions; dicate explosive properties are given in (f) Division 1.6—Extremely insensitive Table A6.1 in Appendix 6 of the UN ST/SG/ items which do not have a mass explosion AC.10 (incorporated by reference; See hazard: items which contain only extremely § 1910.6); or insensitive detonating chemicals and which (b) The substance contains chemical demonstrate a negligible probability of acci- groups associated with explosive properties dental initiation or propagation. which include oxygen and the calculated oxygen balance is less than ¥200. B.1.3 ADDITIONAL CLASSIFICATION The oxygen balance is calculated for the CONSIDERATIONS chemical reaction: B.1.3.1 Explosives shall be classified as un- CXHyOz + [x + (y/4) ¥ (z/2)] O2 → x. CO2 + (y/ stable explosives or shall be assigned to one 2) H O of the six divisions identified in B.1.2 in ac- 2 cordance with the three step procedure in using the formula: Part I of the UN ST/SG/AC.10 (incorporated oxygen balance = ¥1600 [2x +(y/2) ¥z]/molec- by reference; See § 1910.6). The first step is to ular weight; ascertain whether the substance or mixture or has explosive effects (Test Series 1). The sec- (c) The organic substance or a homogenous ond step is the acceptance procedure (Test mixture of organic substances contains Series 2 to 4) and the third step is the assign- chemical groups associated with explosive ment to a hazard division (Test Series 5 to 7). properties but the exothermic decomposition The assessment whether a candidate for energy is less than 500 J/g and the onset of ‘‘ammonium nitrate emulsion or suspension exothermic decomposition is below 500 °C or gel, intermediate for blasting explosives (932 °F). The exothermic decomposition en- (ANE)’’ is insensitive enough for inclusion as ergy may be determined using a suitable an oxidizing liquid (See B.13) or an oxidizing calorimetric technique; or

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(d) For mixtures of inorganic oxidizing B.2 FLAMMABLE GASES substances with organic material(s), the concentration of the inorganic oxidizing sub- B.2.1 DEFINITION stance is: Flammable gas means a gas having a flam- (i) Less than 15%, by mass, if the oxidizing mable range with air at 20 °C (68 °F) and a substance is assigned to Category 1 or 2; standard pressure of 101.3 kPa (14.7 psi). (ii) Less than 30%, by mass, if the oxidizing B.2.2 CLASSIFICATION CRITERIA substance is assigned to Category 3. A flammable gas shall be classified in one of the two categories for this class in accordance with Table B.2.1:

TABLE B.2.1—CRITERIA FOR FLAMMABLE GASES

Category Criteria

1 ...... Gases, which at 20 °C (68 °F) and a standard pressure of 101.3 kPa (14.7 psi): (a) are ignitable when in a mixture of 13% or less by volume in air; or (b) have a flammable range with air of at least 12 percentage points regardless of the lower flammable limit. 2 ...... Gases, other than those of Category 1, which, at 20 °C (68 °F) and a standard pressure of 101.3 kPa (14.7 psi), have a flammable range while mixed in air.

NOTE: Aerosols should not be classified as B.3.2 CLASSIFICATION CRITERIA flammable gases. See B.3. B.3.2.1 Aerosols shall be considered for B.2.3 ADDITIONAL CLASSIFICATION classification as flammable if they contain CONSIDERATIONS any component which is classified as flam- Flammability shall be determined by tests mable in accordance with this Appendix, i.e.: or by calculation in accordance with ISO Flammable liquids (See B.6); 10156 (incorporated by reference; See § 1910.6). Flammable gases (See B.2); Where insufficient data are available to use Flammable solids (See B.7). this method, equivalent validated methods NOTE 1: Flammable components do not in- may be used. clude pyrophoric, self-heating or water-reac- B.3 FLAMMABLE AEROSOLS tive chemicals. NOTE 2: Flammable aerosols do not fall ad- B.3.1 DEFINITION ditionally within the scope of flammable Aerosol means any non-refillable receptacle gases, flammable liquids, or flammable sol- containing a gas compressed, liquefied or ids. dissolved under pressure, and fitted with a B.3.2.2 A flammable aerosol shall be clas- release device allowing the contents to be sified in one of the two categories for this ejected as particles in suspension in a gas, or class in accordance with Table B.3.1. as a foam, paste, powder, liquid or gas.

TABLE B.3.1—CRITERIA FOR FLAMMABLE AEROSOLS

Category Criteria

1 ...... Contains ≥ 85% flammable components and the chemical heat of combustion is ≥ 30 kJ/g; or (a) For spray aerosols, in the ignition distance test, ignition occurs at a distance ≥ 75 cm (29.5 in), or (b) For foam aerosols, in the aerosol foam flammability test (i) The flame height is ≥ 20 cm (7.87 in) and the flame duration ≥ 2 s; or (ii) The flame height is ≥ 4 cm (1.57 in) and the flame duration ≥ 7 s 2 ...... Contains > 1% flammable components, or the heat of combustion is ≥ 20 kJ/g; and (a) for spray aerosols, in the ignition distance test, ignition occurs at a distance ≥ 15 cm (5.9 in), or in the enclosed space ignition test, the (i) Time equivalent is ≤ 300 s/m3; or (ii) Deflagration density is ≤ 300 g/m3 (b) For foam aerosols, in the aerosol foam flammability test, the flame height is ≥ 4 cm and the flame duration is ≥ 2 s and it does not meet the criteria for Category 1

NOTE: Aerosols not submitted to the flam- Appendix shall be classified as extremely mability classification procedures in this flammable (Category 1).

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B.3.3 ADDITIONAL CLASSIFICATION B.3.3.2 The chemical heat of combustion CONSIDERATIONS (DHc), in kilojoules per gram (kJ/g), is the product of the theoretical heat of combus- B.3.3.1 To classify a flammable aerosol, tion (DHcomb), and a combustion efficiency, data on its flammable components, on its usually less than 1.0 (a typical combustion chemical heat of combustion and, if applica- efficiency is 0.95 or 95%). ble, the results of the aerosol foam flamma- For a composite aerosol formulation, the bility test (for foam aerosols) and of the igni- chemical heat of combustion is the summa- tion distance test and enclosed space test tion of the weighted heats of combustion for (for spray aerosols) are necessary. the individual components, as follows:

Where: B.4 OXIDIZING GASES Hc = chemical heat of combustion (kJ/g); D B.4.1 DEFINITION wi% = mass fraction of component i in the product; Oxidizing gas means any gas which may, DHc(i) = specific heat of combustion (kJ/g) of generally by providing oxygen, cause or con- component i in the product; tribute to the combustion of other material more than air does. The chemical heats of combustion shall be NOTE: ‘‘Gases which cause or contribute to found in literature, calculated or determined the combustion of other material more than by tests (See ASTM D240–02, ISO 13943, Sec- air does’’ means pure gases or gas mixtures tions 86.1 to 86.3, and NFPA 30B (incor- with an oxidizing power greater than 23.5% porated by reference; See § 1910.6)). (as determined by a method specified in ISO B.3.3.3 The Ignition Distance Test, En- 10156 or 10156–2 (incorporated by reference, closed Space Ignition Test and Aerosol Foam See § 1910.6) or an equivalent testing meth- Flammability Test shall be performed in ac- od.) cordance with sub-sections 31.4, 31.5 and 31.6 of the of the UN ST/SG/AC.10 (incorporated B.4.2 CLASSIFICATION CRITERIA by reference; See § 1910.6). An oxidizing gas shall be classified in a single category for this class in accordance with Table B.4.1:

TABLE B.4.1—CRITERIA FOR OXIDIZING GASES

Category Criteria

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

B.4.3 ADDITIONAL CLASSIFICATION kPa (29 psi) (gauge) or more, or which are CONSIDERATIONS liquefied or liquefied and refrigerated. Classification shall be in accordance with They comprise compressed gases, liquefied tests or calculation methods as described in gases, dissolved gases and refrigerated lique- ISO 10156 (incorporated by reference; See fied gases. § 1910.6) and ISO 10156–2 (incorporated by reference; See § 1910.6). B.5.2 CLASSIFICATION CRITERIA Gases under pressure shall be classified in B.5 GASES UNDER PRESSURE one of four groups in accordance with Table B.5.1 DEFINITION B.5.1: Gases under pressure are gases which are contained in a receptacle at a pressure of 200

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TABLE B.5.1—CRITERIA FOR GASES UNDER PRESSURE

Group Criteria

Compressed gas ...... A gas which when under pressure is entirely gaseous at ¥50 °C (¥8 °F), including all gases with a critical temperature1 ≤¥50 °C (¥58 °F). Liquefied gas ...... A gas which when under pressure is partially liquid at temperatures above ¥50 °C (¥58 °F). A distinction is made between: (a) High pressure liquefied gas: A gas with a critical temperature 1 between ¥50 °C (¥58 °F) and +65 °C (149 °F); and (b) Low pressure liquefied gas: A gas with a critical temperature 1 above +65 °C (149 °F). Refrigerated liquefied gas ..... A gas which is made partially liquid because of its low temperature. Dissolved gas ...... A gas which when under pressure is dissolved in a liquid phase solvent. 1 The critical temperature is the temperature above which a pure gas cannot be liquefied, regardless of the degree of compression.

B.6 FLAMMABLE LIQUIDS mixture with air near the surface of the liquid, as determined by a method identified in B.6.1 DEFINITION Section B.6.3. Flammable liquid means a liquid having a B.6.2 CLASSIFICATION CRITERIA flash point of not more than 93 °C (199.4 °F). Flash point means the minimum tempera- A flammable liquid shall be classified in ture at which a liquid gives off vapor in suffi- one of four categories in accordance with cient concentration to form an ignitable Table B.6.1:

TABLE B.6.1—CRITERIA FOR FLAMMABLE LIQUIDS

Category Criteria

1 ...... Flash point <23 °C (73.4 °F) and initial boiling point ≤35 °C (95 °F). 2 ...... Flash point <23 °C (73.4 °F) and initial boiling point >35 °C (95 °F). 3 ...... Flash point ≥23 °C (73.4 °F) and ≤60 °C (140 °F). 4 ...... Flash point >60 °C (140 °F) and ≤93 °C (199.4 °F).

B.6.3 ADDITIONAL CLASSIFICATION B.7.2 CLASSIFICATION CRITERIA CONSIDERATIONS B.7.2.1 Powdered, granular or pasty The flash point shall be determined in ac- chemicals shall be classified as flammable cordance with ASTM D56–05, ASTM D3278, solids when the time of burning of one or ASTM D3828, ASTM D93–08 (incorporated by more of the test runs, performed in accord- reference; See § 1910.6), or any other method ance with the test method described in the specified in GHS Revision 3, Chapter 2.6. UN ST/SG/AC.10 (incorporated by reference; See § 1910.6), Part III, sub-section 33.2.1, is The initial boiling point shall be deter- less than 45 s or the rate of burning is more mined in accordance with ASTM D86–07a or than 2.2 mm/s (0.0866 in/s). ASTM D1078 (incorporated by reference; See B.7.2.2 Powders of metals or metal alloys § 1910.6). shall be classified as flammable solids when they can be ignited and the reaction spreads B.7 FLAMMABLE SOLIDS over the whole length of the sample in 10 B.7.1 DEFINITIONS min or less. B.7.2.3 Solids which may cause fire Flammable solid means a solid which is a through friction shall be classified in this readily combustible solid, or which may class by analogy with existing entries (e.g., cause or contribute to fire through friction. matches) until definitive criteria are estab- Readily combustible solids are powdered, lished. granular, or pasty chemicals which are dan- B.7.2.4 A flammable solid shall be classi- gerous if they can be easily ignited by brief fied in one of the two categories for this contact with an ignition source, such as a class using Method N.1 as described in Part burning match, and if the flame spreads rap- III, sub-section 33.2.1 of the UN ST/SG/AC.10 idly. (incorporated by reference; See § 1910.6), in accordance with Table B.7.1:

TABLE B.7.1—CRITERIA FOR FLAMMABLE SOLIDS

Category Criteria

1 ...... Burning rate test:

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TABLE B.7.1—CRITERIA FOR FLAMMABLE SOLIDS—Continued

Category Criteria

Chemicals other than metal powders: (a) Wetted zone does not stop fire; and (b) Burning time <45 s or burning rate >2.2 mm/s. Metal powders: Burning time ≤5 min. 2 ...... Burning rate test: Chemicals other than metal powders: (a) Wetted zone stops the fire for at least 4 min; and (b) Burning time <45 s or burning rate >2.2 mm/s. Metal powders: Burning time >5 min and ≤10 min.

NOTE: Classification of solid chemicals mentioned in B.8.2.1 (a), (c), (d) or (e), shall shall be based on tests performed on the be subjected to the self-reactive chemicals chemical as presented. If, for example, for classification procedure in B.8.2.3. Such a the purposes of supply or transport, the same mixture showing the properties of a self-re- chemical is to be presented in a physical active chemical type B to F shall be classi- form different from that which was tested fied as a self-reactive chemical. and which is considered likely to materially B.8.2.3 Self-reactive chemicals shall be alter its performance in a classification test, classified in one of the seven categories of classification must be based on testing of the ‘‘types A to G’’ for this class, according to chemical in the new form. the following principles: (a) Any self-reactive chemical which can B.8 SELF-REACTIVE CHEMICALS detonate or deflagrate rapidly, as packaged, will be defined as self-reactive chemical B.8.1 DEFINITIONS TYPE A; Self-reactive chemicals are thermally unsta- (b) Any self-reactive chemical possessing ble liquid or solid chemicals liable to under- explosive properties and which, as packaged, go a strongly exothermic decomposition neither detonates nor deflagrates rapidly, even without participation of oxygen (air). but is liable to undergo a thermal explosion This definition excludes chemicals classified in that package will be defined as self-reac- under this section as explosives, organic per- tive chemical TYPE B; oxides, oxidizing liquids or oxidizing solids. (c) Any self-reactive chemical possessing A self-reactive chemical is regarded as pos- explosive properties when the chemical as sessing explosive properties when in labora- packaged cannot detonate or deflagrate rap- tory testing the formulation is liable to det- idly or undergo a thermal explosion will be onate, to deflagrate rapidly or to show a vio- defined as self-reactive chemical TYPE C; lent effect when heated under confinement. (d) Any self-reactive chemical which in laboratory testing meets the criteria in B.8.2 CLASSIFICATION CRITERIA (d)(i), (ii), or (iii) will be defined as self-reac- B.8.2.1 A self-reactive chemical shall be tive chemical TYPE D: considered for classification in this class un- (i) Detonates partially, does not deflagrate less: rapidly and shows no violent effect when (a) It is classified as an explosive according heated under confinement; or to B.1 of this appendix; (ii) Does not detonate at all, deflagrates (b) It is classified as an oxidizing liquid or slowly and shows no violent effect when an oxidizing solid according to B.13 or B.14 of heated under confinement; or this appendix, except that a mixture of oxi- (iii) Does not detonate or deflagrate at all dizing substances which contains 5% or more and shows a medium effect when heated of combustible organic substances shall be under confinement; classified as a self-reactive chemical accord- (e) Any self-reactive chemical which, in ing to the procedure defined in B.8.2.2; laboratory testing, neither detonates nor (c) It is classified as an organic peroxide deflagrates at all and shows low or no effect according to B.15 of this appendix; when heated under confinement will be de- (d) Its heat of decomposition is less than fined as self-reactive chemical TYPE E; 300 J/g; or (f) Any self-reactive chemical which, in (e) Its self-accelerating decomposition laboratory testing, neither detonates in the temperature (SADT) is greater than 75 °C cavitated state nor deflagrates at all and (167 °F) for a 50 kg (110 lb) package. shows only a low or no effect when heated B.8.2.2 Mixtures of oxidizing substances, under confinement as well as low or no ex- meeting the criteria for classification as oxi- plosive power will be defined as self-reactive dizing liquids or oxidizing solids, which con- chemical TYPE F; tain 5% or more of combustible organic sub- (g) Any self-reactive chemical which, in stances and which do not meet the criteria laboratory testing, neither detonates in the

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cavitated state nor deflagrates at all and (a) There are no chemical groups present in shows no effect when heated under confine- the molecule associated with explosive or ment nor any explosive power, provided that self-reactive properties; examples of such it is thermally stable (self-accelerating de- groups are given in Tables A6.1 and A6.2 in composition temperature is 60 °C (140 °F) to the Appendix 6 of the UN ST/SG/AC.10 (incor- 75 °C (167 °F) for a 50 kg (110 lb) package), porated by reference; See § 1910.6); or and, for liquid mixtures, a diluent having a (b) For a single organic substance or a ho- boiling point greater than or equal to 150 °C mogeneous mixture of organic substances, (302 °F) is used for desensitization will be de- the estimated SADT is greater than 75 °C fined as self-reactive chemical TYPE G. If (167 °F) or the exothermic decomposition en- the mixture is not thermally stable or a dil- ergy is less than 300 J/g. The onset tempera- ° uent having a boiling point less than 150 C ture and decomposition energy may be esti- ° (302 F) is used for desensitization, the mix- mated using a suitable calorimetric tech- ture shall be defined as self-reactive chem- nique (See 20.3.3.3 in Part II of the UN ST/SG/ ical TYPE F. AC.10 (incorporated by reference; See B.8.3 ADDITIONAL CLASSIFICATION § 1910.6)). CONSIDERATIONS B.9 PYROPHORIC LIQUIDS B.8.3.1 For purposes of classification, the properties of self-reactive chemicals shall be B.9.1 DEFINITION determined in accordance with test series A Pyrophoric liquid means a liquid which, to H as described in Part II of the UN ST/SG/ even in small quantities, is liable to ignite AC.10 (incorporated by reference; See within five minutes after coming into con- § 1910.6). tact with air. B.8.3.2 Self-accelerating decomposition temperature (SADT) shall be determined in B.9.2 CLASSIFICATION CRITERIA accordance with the UN ST/SG/AC.10, Part II, section 28 (incorporated by reference; See A pyrophoric liquid shall be classified in a § 1910.6). single category for this class using test N.3 B.8.3.3 The classification procedures for in Part III, sub-section 33.3.1.5 of the UN ST/ self-reactive substances and mixtures need SG/AC.10 (incorporated by reference; See not be applied if: § 1910.6), in accordance with Table B.9.1:

TABLE B.9.1—CRITERIA FOR PYROPHORIC LIQUIDS

Category Criteria

1 ...... The liquid ignites within 5 min when added to an inert carrier and exposed to air, or it ignites or chars a filter paper on contact with air within 5 min.

B.9.3 ADDITIONAL CLASSIFICATION B.10 PYROPHORIC SOLIDS CONSIDERATIONS B.10.1 DEFINITION The classification procedure for pyrophoric Pyrophoric solid means a solid which, even liquids need not be applied when experience in small quantities, is liable to ignite within in production or handling shows that the five minutes after coming into contact with chemical does not ignite spontaneously on air. coming into contact with air at normal temperatures (i.e., the substance is known to be B.10.2 CLASSIFICATION CRITERIA stable at room temperature for prolonged pe- A pyrophoric solid shall be classified in a riods of time (days)). single category for this class using test N.2 in Part III, sub-section 33.3.1.4 of the UN ST/ SG/AC.10 (incorporated by reference; See § 1910.6), in accordance with Table B.10.1:

TABLE B.10.1—CRITERIA FOR PYROPHORIC SOLIDS

Category Criteria

1 ...... The solid ignites within 5 min of coming into contact with air.

NOTE: Classification of solid chemicals the purposes of supply or transport, the same shall be based on tests performed on the chemical is to be presented in a physical chemical as presented. If, for example, for form different from that which was tested

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and which is considered likely to materially out energy supply, is liable to self-heat; this alter its performance in a classification test, chemical differs from a pyrophoric liquid or classification must be based on testing of the solid in that it will ignite only when in large chemical in the new form. amounts (kilograms) and after long periods of time (hours or days). B.10.3 ADDITIONAL CLASSIFICATION NOTE: Self-heating of a substance or mix- CONSIDERATIONS ture is a process where the gradual reaction The classification procedure for pyrophoric of that substance or mixture with oxygen (in solids need not be applied when experience in air) generates heat. If the rate of heat pro- production or handling shows that the chem- duction exceeds the rate of heat loss, then ical does not ignite spontaneously on coming the temperature of the substance or mixture into contact with air at normal tempera- will rise which, after an induction time, may tures (i.e., the chemical is known to be sta- lead to self-ignition and combustion. ble at room temperature for prolonged peri- B.11.2 CLASSIFICATION CRITERIA ods of time (days)). B.11.2.1 A self-heating chemical shall be B.11 SELF-HEATING CHEMICALS classified in one of the two categories for this class if, in tests performed in accordance B.11.1 DEFINITION with test method N.4 in Part III, sub-section A self-heating chemical is a solid or liquid 33.3.1.6 of the UN ST/SG/AC.10 (incorporated chemical, other than a pyrophoric liquid or by reference; See § 1910.6), the result meets solid, which, by reaction with air and with- the criteria shown in Table B.11.1.

TABLE B.11.1—CRITERIA FOR SELF-HEATING CHEMICALS

Category Criteria

1 ...... A positive result is obtained in a test using a 25 mm sample cube at 140 °C (284 °F). 2 ...... A negative result is obtained in a test using a 25 mm cube sample at 140 °C (284 °F), a positive result is obtained in a test using a 100 mm sample cube at 140 °C (284 °F), and: (a) The unit volume of the chemical is more than 3 m3; or (b) A positive result is obtained in a test using a 100 mm cube sample at 120 °C (248 °F) and the unit volume of the chemical is more than 450 liters; or (c) A positive result is obtained in a test using a 100 mm cube sample at 100 °C (212 °F).

B.11.2.2 Chemicals with a temperature of of the fire and explosion risks in drying pow- spontaneous combustion higher than 50 °C ders, Plant Operations Progress, 4 (3), 181– (122 °F) for a volume of 27 m3 shall not be 189, 1985) with an onset temperature 60°K classified as self-heating chemicals. above the reference temperature for a vol- B.11.2.3 Chemicals with a spontaneous ig- ume of 1 l. nition temperature higher than 50 °C (122 °F) for a volume of 450 liters shall not be classi- B.12 CHEMICALS WHICH, IN CONTACT fied in Category 1 of this class. WITH WATER, EMIT FLAMMABLE GASES

B.11.3 ADDITIONAL CLASSIFICATION B.12.1 DEFINITION CONSIDERATIONS Chemicals which, in contact with water, emit B.11.3.1 The classification procedure for flammable gases are solid or liquid chemicals self-heating chemicals need not be applied if which, by interaction with water, are liable the results of a screening test can be ade- to become spontaneously flammable or to quately correlated with the classification give off flammable gases in dangerous quan- test and an appropriate safety margin is ap- tities. plied. B.11.3.2 Examples of screening tests are: B.12.2 CLASSIFICATION CRITERIA (a) The Grewer Oven test (VDI guideline 2263, part 1, 1990, Test methods for the Deter- B.12.2.1 A chemical which, in contact with mination of the Safety Characteristics of water, emits flammable gases shall be classi- Dusts) with an onset temperature 80°K above fied in one of the three categories for this the reference temperature for a volume of 1 class, using test N.5 in Part III, sub-section l; 33.4.1.4 of the UN ST/SG/AC.10 (incorporated (b) The Bulk Powder Screening Test (Gib- by reference; See § 1910.6), in accordance with son, N. Harper, D. J. Rogers, R. Evaluation Table B.12.1:

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TABLE B.12.1—CRITERIA FOR CHEMICALS WHICH, IN CONTACT WITH WATER, EMIT FLAMMABLE GASES

Category Criteria

1 ...... Any chemical which reacts vigorously with water at ambient temperatures and demonstrates generally a tendency for the gas produced to ignite spontaneously, or which reacts readily with water at ambient temperatures such that the rate of evolution of flammable gas is equal to or greater than 10 liters per kilogram of chemical over any one minute. 2 ...... Any chemical which reacts readily with water at ambient temperatures such that the maximum rate of evolution of flammable gas is equal to or greater than 20 liters per kilogram of chemical per hour, and which does not meet the criteria for Category 1. 3 ...... Any chemical which reacts slowly with water at ambient temperatures such that the maximum rate of evolution of flammable gas is equal to or greater than 1 liter per kilogram of chemical per hour, and which does not meet the criteria for Categories 1 and 2.

NOTE: Classification of solid chemicals (b) Experience in production or handling shall be based on tests performed on the shows that the chemical does not react with chemical as presented. If, for example, for water, (e.g., the chemical is manufactured the purposes of supply or transport, the same with water or washed with water); or chemical is to be presented in a physical (c) The chemical is known to be soluble in form different from that which was tested water to form a stable mixture. and which is considered likely to materially B.13 OXIDIZING LIQUIDS alter its performance in a classification test, classification must be based on testing of the B.13.1 DEFINITION chemical in the new form. Oxidizing liquid means a liquid which, while B.12.2.2 A chemical is classified as a in itself not necessarily combustible, may, chemical which, in contact with water emits generally by yielding oxygen, cause, or con- flammable gases if spontaneous ignition tribute to, the combustion of other material. takes place in any step of the test procedure. B.13.2 CLASSIFICATION CRITERIA B.12.3 ADDITIONAL CLASSIFICATION CONSIDERATIONS An oxidizing liquid shall be classified in one of the three categories for this class The classification procedure for this class using test O.2 in Part III, sub-section 34.4.2 of need not be applied if: the UN ST/SG/AC.10 (incorporated by ref- (a) The chemical structure of the chemical erence; See § 1910.6), in accordance with does not contain metals or metalloids; Table B.13.1:

TABLE B.13.1—CRITERIA FOR OXIDIZING LIQUIDS

Category Criteria

1 ...... Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, spontaneously ignites; or the mean pressure rise time of a 1:1 mixture, by mass, of chemical and cellulose is less than that of a 1:1 mixture, by mass, of 50% perchloric acid and cellulose; 2 ...... Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, exhibits a mean pressure rise time less than or equal to the mean pressure rise time of a 1:1 mixture, by mass, of 40% aqueous sodium chlorate solution and cellulose; and the criteria for Category 1 are not met; 3 ...... Any chemical which, in the 1:1 mixture, by mass, of chemical and cellulose tested, exhibits a mean pressure rise time less than or equal to the mean pressure rise time of a 1:1 mixture, by mass, of 65% aqueous nitric acid and cellulose; and the criteria for Categories 1 and 2 are not met.

B.13.3 ADDITIONAL CLASSIFICATION be applied if the chemical does not contain CONSIDERATIONS oxygen or halogen atoms. B.13.3.3 In the event of divergence be- B.13.3.1 For organic chemicals, the classi- tween test results and known experience in fication procedure for this class shall not be the handling and use of chemicals which applied if: shows them to be oxidizing, judgments based (a) The chemical does not contain oxygen, on known experience shall take precedence fluorine or chlorine; or over test results. (b) The chemical contains oxygen, fluorine B.13.3.4 In cases where chemicals generate or chlorine and these elements are chemi- a pressure rise (too high or too low), caused cally bonded only to carbon or hydrogen. by chemical reactions not characterizing the B.13.3.2 For inorganic chemicals, the clas- oxidizing properties of the chemical, the test sification procedure for this class shall not described in Part III, sub-section 34.4.2 of the

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UN ST/SG/AC.10 (incorporated by reference; generally by yielding oxygen, cause, or con- See § 1910.6) shall be repeated with an inert tribute to, the combustion of other material. substance (e.g., diatomite (kieselguhr)) in place of the cellulose in order to clarify the B.14.2 CLASSIFICATION CRITERIA nature of the reaction. An oxidizing solid shall be classified in one B.14 OXIDIZING SOLIDS of the three categories for this class using test O.1 in Part III, sub-section 34.4.1 of the B.14.1 DEFINITION UN ST/SG/AC.10 (incorporated by reference; Oxidizing solid means a solid which, while See § 1910.6), in accordance with Table B.14.1: in itself is not necessarily combustible, may,

TABLE B.14.1—CRITERIA FOR OXIDIZING SOLIDS

Category Criteria

1 ...... Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time less than the mean burning time of a 3:2 mixture, by mass, of potassium bromate and cellulose. 2 ...... Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time equal to or less than the mean burning time of a 2:3 mixture (by mass) of potassium bromate and cellulose and the criteria for Category 1 are not met. 3 ...... Any chemical which, in the 4:1 or 1:1 sample-to-cellulose ratio (by mass) tested, exhibits a mean burning time equal to or less than the mean burning time of a 3:7 mixture (by mass) of potassium bromate and cellulose and the criteria for Categories 1 and 2 are not met.

NOTE 1: Some oxidizing solids may present shows them to be oxidizing, judgements explosion hazards under certain conditions based on known experience shall take prece- (e.g., when stored in large quantities). For dence over test results. example, some types of ammonium nitrate may give rise to an explosion hazard under B.15 ORGANIC PEROXIDES extreme conditions and the ‘‘Resistance to detonation test’’ (IMO: Code of Safe Practice B.15.1 DEFINITION for Solid Bulk Cargoes, 2005, Annex 3, Test 5) B.15.1.1 Organic peroxide means a liquid or may be used to assess this hazard. When in- solid organic chemical which contains the formation indicates that an oxidizing solid bivalent –0–0– structure and as such is con- may present an explosion hazard, it shall be sidered a derivative of hydrogen peroxide, indicated on the Safety Data Sheet. where one or both of the hydrogen atoms NOTE 2: Classification of solid chemicals have been replaced by organic radicals. The shall be based on tests performed on the term organic peroxide includes organic per- chemical as presented. If, for example, for oxide mixtures containing at least one or- the purposes of supply or transport, the same ganic peroxide. Organic peroxides are ther- chemical is to be presented in a physical mally unstable chemicals, which may under- form different from that which was tested go exothermic self-accelerating decomposi- and which is considered likely to materially tion. In addition, they may have one or more alter its performance in a classification test, of the following properties: classification must be based on testing of the (a) Be liable to explosive decomposition; chemical in the new form. (b) Burn rapidly; B.14.3 ADDITIONAL CLASSIFICATION (c) Be sensitive to impact or friction; CONSIDERATIONS (d) React dangerously with other substances. B.14.3.1 For organic chemicals, the classification procedure for this class shall not be B.15.1.2 An organic peroxide is regarded as applied if: possessing explosive properties when in laboratory testing the formulation is liable to (a) The chemical does not contain oxygen, detonate, to deflagrate rapidly or to show a fluorine or chlorine; or violent effect when heated under confine- (b) The chemical contains oxygen, fluorine ment. or chlorine and these elements are chemically bonded only to carbon or hydrogen. B.15.2 CLASSIFICATION CRITERIA B.14.3.2 For inorganic chemicals, the classification procedure for this class shall not B.15.2.1 Any organic peroxide shall be be applied if the chemical does not contain considered for classification in this class, un- oxygen or halogen atoms. less it contains: B.14.3.3 In the event of divergence be- (a) Not more than 1.0% available oxygen tween test results and known experience in from the organic peroxides when containing the handling and use of chemicals which not more than 1.0% hydrogen peroxide; or

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(b) Not more than 0.5% available oxygen NOTE: The available oxygen content (%) of from the organic peroxides when containing an organic peroxide mixture is given by the more than 1.0% but not more than 7.0% hy- formula: drogen peroxide.

Where: cavitated state nor deflagrates at all and shows no effect when heated under confine- ni = number of peroxygen groups per molecule of organic peroxide i; ment nor any explosive power, provided that ci = concentration (mass %) of organic per- it is thermally stable (self-accelerating de- oxide i; composition temperature is 60 °C (140 °F) or mi = molecular mass of organic peroxide i. higher for a 50 kg (110 lb) package), and, for B.15.2.2 Organic peroxides shall be classi- liquid mixtures, a diluent having a boiling ° ° fied in one of the seven categories of ‘‘Types point of not less than 150 C (302 F) is used A to G’’ for this class, according to the fol- for desensitization, shall be defined as or- lowing principles: ganic peroxide TYPE G. If the organic per- (a) Any organic peroxide which, as pack- oxide is not thermally stable or a diluent aged, can detonate or deflagrate rapidly having a boiling point less than 150 °C (302 shall be defined as organic peroxide TYPE A; °F) is used for desensitization, it shall be de- (b) Any organic peroxide possessing explo- fined as organic peroxide TYPE F. sive properties and which, as packaged, neither detonates nor deflagrates rapidly, but is B.15.3 ADDITIONAL CLASSIFICATION liable to undergo a thermal explosion in that CONSIDERATIONS package shall be defined as organic peroxide B.15.3.1 For purposes of classification, the TYPE B; properties of organic peroxides shall be de- (c) Any organic peroxide possessing explo- termined in accordance with test series A to sive properties when the chemical as pack- H as described in Part II of the UN ST/SG/ aged cannot detonate or deflagrate rapidly AC.10 (incorporated by reference; See or undergo a thermal explosion shall be de- § 1910.6). fined as organic peroxide TYPE C; B.15.3.2 Self-accelerating decomposition (d) Any organic peroxide which in labora- temperature (SADT) shall be determined in tory testing meets the criteria in (d)(i), (ii), accordance with the UN ST/SG/AC.10 (incor- or (iii) shall be defined as organic peroxide porated by reference; See § 1910.6), Part II, TYPE D: section 28. (i) Detonates partially, does not deflagrate B.15.3.3 Mixtures of organic peroxides rapidly and shows no violent effect when may be classified as the same type of organic heated under confinement; or peroxide as that of the most dangerous in- (ii) Does not detonate at all, deflagrates gredient. However, as two stable ingredients slowly and shows no violent effect when can form a thermally less stable mixture, heated under confinement; or the SADT of the mixture shall be deter- (iii) Does not detonate or deflagrate at all mined. and shows a medium effect when heated under confinement; B.16 CORROSIVE TO METALS (e) Any organic peroxide which, in laboratory testing, neither detonates nor B.16.1 DEFINITION deflagrates at all and shows low or no effect when heated under confinement shall be de- A chemical which is corrosive to metals means fined as organic peroxide TYPE E; a chemical which by chemical action will (f) Any organic peroxide which, in labora- materially damage, or even destroy, metals. tory testing, neither detonates in the B.16.2 CLASSIFICATION CRITERIA cavitated state nor deflagrates at all and shows only a low or no effect when heated A chemical which is corrosive to metals under confinement as well as low or no ex- shall be classified in a single category for plosive power shall be defined as organic per- this class, using the test in Part III, sub-sec- oxide TYPE F; tion 37.4 of the UN ST/SG/AC.10 (incor- (g) Any organic peroxide which, in labora- porated by reference; See § 1910.6), in accord- tory testing, neither detonates in the ance with Table B.16.1:

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TABLE B.16.1—CRITERIA FOR CHEMICALS CORROSIVE TO METAL

Category Criteria

1 ...... Corrosion rate on either steel or aluminium surfaces exceeding 6.25 mm per year at a test temperature of 55 °C (131 °F) when tested on both materials.

NOTE: Where an initial test on either steel togram shall not appear where it is used for or aluminium indicates the chemical being acute toxicity; tested is corrosive, the follow-up test on the C.2.1.3 If the corrosive pictogram is in- other metal is not necessary. cluded, the exclamation mark pictogram shall not appear where it is used for skin or B.16.3 ADDITIONAL CLASSIFICATION eye irritation; CONSIDERATIONS C.2.1.4 If the health hazard pictogram is The specimen to be used for the test shall included for respiratory sensitization, the be made of the following materials: exclamation mark pictogram shall not appear where it is used for skin sensitization or (a) For the purposes of testing steel, steel for skin or eye irritation. types S235JR+CR (1.0037 resp.St 37–2), S275J2G3+CR (1.0144 resp.St 44–3), ISO 3574, C.2.2 HAZARD STATEMENT TEXT Unified Numbering System (UNS) G 10200, or SAE 1020; C.2.2.1 The text of all applicable hazard (b) For the purposes of testing aluminium: statements shall appear on the label, except Non-clad types 7075–T6 or AZ5GU–T6. as otherwise specified. The information in italics shall be included as part of the hazard APPENDIX C TO § 1910.1200—ALLOCATION OF statement as provided. For example: ‘‘causes LABEL ELEMENTS (MANDATORY) damage to organs (state all organs affected) through prolonged or repeated exposure C.1 The label for each hazardous chemical (state route of exposure if no other routes of ex- shall include the product identifier used on posure cause the hazard)’’. Hazard statements the safety data sheet. may be combined where appropriate to re- C.1.1 The labels on shipped containers duce the information on the label and im- shall also include the name, address, and prove readability, as long as all of the haz- telephone number of the chemical manufac- ards are conveyed as required. turer, importer, or responsible party. C.2.2.2 If the chemical manufacturer, im- C.2 The label for each hazardous chemical porter, or responsible party can demonstrate that is classified shall include the signal that all or part of the hazard statement is word, hazard statement(s), pictogram(s), and inappropriate to a specific substance or mix- precautionary statement(s) specified in C.4 ture, the corresponding statement may be for each hazard class and associated hazard omitted from the label. category, except as provided for in C.2.1 through C.2.4. C.2.3 PICTOGRAMS C.2.3.1 Pictograms shall be in the shape of C.2.1 PRECEDENCE OF HAZARD INFORMATION a square set at a point and shall include a C.2.1.1 If the signal word ‘‘Danger’’ is in- black hazard symbol on a white background cluded, the signal word ‘‘Warning’’ shall not with a red frame sufficiently wide to be appear; clearly visible. A square red frame set at a C.2.1.2 If the skull and crossbones picto- point without a hazard symbol is not a pictogram is included, the exclamation mark pic- gram and is not permitted on the label.

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C.2.4 PRECAUTIONARY STATEMENT TEXT ets is not appropriate in every case and should be used only in certain cir- C.2.4.1 There are four types of pre- cumstances. In these cases, conditions for cautionary statements presented, ‘‘preven- use explaining when the text should be used tion,’’ ‘‘response,’’ ‘‘storage,’’ and ‘‘dis- are provided. For example, one pre- posal.’’ The core part of the precautionary cautionary statement states: ‘‘[In case of in- statement is presented in bold print. This is adequate ventilation] wear respiratory pro- the text, except as otherwise specified, that tection.’’ This statement is given with the shall appear on the label. Where additional condition for use ‘‘– text in square brackets information is required, it is indicated in may be used if additional information is pro- plain text. vided with the chemical at the point of use C.2.4.2 When a backslash or diagonal that explains what type of ventilation would mark (/) appears in the precautionary state- be adequate for safe use’’. This means that, ment text, it indicates that a choice has to if additional information is provided with be made between the separated phrases. In the chemical explaining what type of ven- such cases, the chemical manufacturer, im- tilation would be adequate for safe use, the porter, or responsible party can choose the text in square brackets should be used and most appropriate phrase(s). For example, the statement would read: ‘‘In case of inad- ‘‘Wear protective gloves/protective clothing/ equate ventilation wear respiratory protec- eye protection/face protection’’ could read tion.’’ However, if the chemical is supplied ‘‘wear eye protection’’. without such ventilation information, the C.2.4.3 When three full stops (* * *) appear text in square brackets should not be used, in the precautionary statement text, they and the precautionary statement should indicate that all applicable conditions are read: ‘‘Wear respiratory protection.’’ not listed. For example, in ‘‘Use explosion- C.2.4.6 Precautionary statements may be proof electrical/ventilating/lighting/* * */ combined or consolidated to save label space equipment’’, the use of ‘‘* * *’’ indicates that and improve readability. For example, ‘‘Keep other equipment may need to be specified. In away from heat, sparks and open flame,’’ such cases, the chemical manufacturer, im- ‘‘Store in a well-ventilated place’’ and ‘‘Keep porter, or responsible party can choose the cool’’ can be combined to read ‘‘Keep away other conditions to be specified. from heat, sparks and open flame and store C.2.4.4 When text in italics is used in a pre- in a cool, well-ventilated place.’’ cautionary statement, this indicates specific C.2.4.7 In most cases, the precautionary conditions applying to the use or allocation statements are independent (e.g., the phrases of the precautionary statement. For exam- for explosive hazards do not modify those re- ple, ‘‘Use explosion-proof electrical/ven- lated to certain health hazards, and products tilating/lighting/* * */equipment’’ is only re- that are classified for both hazard classes quired for flammable solids ‘‘if dust clouds shall bear appropriate precautionary state- can occur’’. Text in italics is intended to be ments for both). Where a chemical is classi- an explanatory, conditional note and is not fied for a number of hazards, and the pre- intended to appear on the label. cautionary statements are similar, the most C.2.4.5 Where square brackets ([ ]) appear stringent shall be included on the label (this around text in a precautionary statement, will be applicable mainly to preventive this indicates that the text in square brack- measures). An order of precedence may be

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imposed by the chemical manufacturer, im- wide variation or undermine the required in- porter or responsible party in situations formation, supplementary information on where phrases concern ‘‘Response.’’ Rapid the label is limited to when it provides fur- action may be crucial. For example, if a ther detail and does not contradict or cast chemical is carcinogenic and acutely toxic, doubt on the validity of the standardized rapid action may be crucial, and first aid hazard information. measures for acute toxicity will take prece- C.3.2 Where the chemical manufacturer, dence over those for long-term effects. In ad- importer, or distributor chooses to add sup- dition, medical attention to delayed health plementary information on the label, the effects may be required in cases of incidental exposure, even if not associated with imme- placement of supplemental information shall diate symptoms of intoxication. not impede identification of information re- C.2.4.8 If the chemical manufacturer, im- quired by this section. porter, or responsible party can demonstrate C.3.3 Where an ingredient with unknown that a precautionary statement is inappro- acute toxicity is used in a mixture at a con- priate to a specific substance or mixture, the centration ≥1%, and the mixture is not clas- precautionary statement may be omitted sified based on testing of the mixture as a from the label. whole, a statement that X% of the mixture consists of ingredient(s) of unknown acute C.3 SUPPLEMENTARY HAZARD INFORMATION toxicity is required on the label. C.3.1 To ensure that non-standardized information does not lead to unnecessarily

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APPENDIX D TO § 1910.1200—SAFETY DATA section number and heading indicated for SHEETS (MANDATORY) sections 1–11 and 16. If no relevant information is found for any given subheading with- A safety data sheet (SDS) shall include the in a section, the SDS shall clearly indicate information specified in Table D.1 under the

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that no applicable information is available. Sections 12–15 may be included in the SDS, but are not mandatory.

TABLE D.1—MINIMUM INFORMATION FOR AN SDS

Heading Subheading

1. Identification ...... (a) Product identifier used on the label; (b) Other means of identification; (c) Recommended use of the chemical and restrictions on use; (d) Name, address, and telephone number of the chemical manufacturer, importer, or other responsible party; (e) Emergency phone number. 2. Hazard(s) identification ...... (a) Classification of the chemical in accordance with paragraph (d) of § 1910.1200; (b) Signal word, hazard statement(s), symbol(s) and precautionary statement(s) in accordance with paragraph (f) of § 1910.1200. (Hazard symbols may be provided as graphical reproductions in black and white or the name of the symbol, e.g., flame, skull and crossbones); (c) Describe any hazards not otherwise classified that have been identified during the classification process; (d) Where an ingredient with unknown acute toxicity is used in a mixture at a concentration ≥1% and the mixture is not classified based on testing of the mixture as a whole, a statement that X% of the mixture consists of ingredient(s) of unknown acute toxicity is required. 3. Composition/information on ingredients Except as provided for in paragraph (i) of § 1910.1200 on trade secrets: For Substances (a) Chemical name; (b) Common name and synonyms; (c) CAS number and other unique identifiers; (d) Impurities and stabilizing additives which are themselves classified and which contribute to the classification of the substance. For Mixtures In addition to the information required for substances: (a) The chemical name and concentration (exact percentage) or concentration ranges of all ingredients which are classified as health hazards in accordance with paragraph (d) of § 1910.1200 and (1) Are present above their cut-off/concentration limits; or (2) Present a health risk below the cut-off/concentration limits. (b) The concentration (exact percentage) shall be specified unless a trade secret claim is made in accordance with paragraph (i) of § 1910.1200, when there is batch-to-batch variability in the production of a mixture, or for a group of substantially similar mixtures (See A.0.5.1.2) with similar chemical composition. In these cases, concentration ranges may be used. For All Chemicals Where a Trade Secret is Claimed Where a trade secret is claimed in accordance with paragraph (i) of § 1910.1200, a statement that the specific chemical identity and/or exact percentage (concentration) of composition has been withheld as a trade secret is required. 4. First-aid measures ...... (a) Description of necessary measures, subdivided according to the different routes of exposure, i.e., inhalation, skin and eye contact, and ingestion; (b) Most important symptoms/effects, acute and delayed. (c) Indication of immediate medical attention and special treatment needed, if necessary. 5. Fire-fighting measures ...... (a) Suitable (and unsuitable) extinguishing media. (b) Specific hazards arising from the chemical (e.g., nature of any hazardous combustion products). (c) Special protective equipment and precautions for fire-fighters. 6. Accidental release measures ...... (a) Personal precautions, protective equipment, and emergency procedures. (b) Methods and materials for containment and cleaning up. 7. Handling and storage ...... (a) Precautions for safe handling. (b) Conditions for safe storage, including any incompatibilities. 8. Exposure controls/personal protection ... (a) OSHA permissible exposure limit (PEL), American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Value (TLV), and any other exposure limit used or recommended by the chemical manufacturer, importer, or employer preparing the safety data sheet, where available. (b) Appropriate engineering controls. (c) Individual protection measures, such as personal protective equipment. 9. Physical and chemical properties ...... (a) Appearance (physical state, color, etc.); (b) Odor; (c) Odor threshold; (d) pH; (e) Melting point/freezing point; (f) Initial boiling point and boiling range; (g) Flash point; (h) Evaporation rate; (i) Flammability (solid, gas);

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TABLE D.1—MINIMUM INFORMATION FOR AN SDS—Continued

Heading Subheading

(j) Upper/lower flammability or explosive limits; (k) Vapor pressure; (l) Vapor density; (m) Relative density; (n) Solubility(ies); (o) Partition coefficient: n-octanol/water; (p) Auto-ignition temperature; (q) Decomposition temperature; (r) Viscosity. 10. Stability and reactivity ...... (a) Reactivity; (b) Chemical stability; (c) Possibility of hazardous reactions; (d) Conditions to avoid (e.g., static discharge, shock, or vibration); (e) Incompatible materials; (f) Hazardous decomposition products. 11. Toxicological information ...... Description of the various toxicological (health) effects and the available data used to identify those effects, including: (a) Information on the likely routes of exposure (inhalation, ingestion, skin and eye contact); (b) Symptoms related to the physical, chemical and toxicological characteristics; (c) Delayed and immediate effects and also chronic effects from short- and long- term exposure; (d) Numerical measures of toxicity (such as acute toxicity estimates). (e) Whether the hazardous chemical is listed in the National Toxicology Program (NTP) Report on Carcinogens (latest edition) or has been found to be a potential carcinogen in the International Agency for Research on Cancer (IARC) Mono- graphs (latest edition), or by OSHA. 12. Ecological information (Non-mandatory) (a) Ecotoxicity (aquatic and terrestrial, where available); (b) Persistence and degradability; (c) Bioaccumulative potential; (d) Mobility in soil; (e) Other adverse effects (such as hazardous to the ozone layer). 13. Disposal considerations (Non-manda- Description of waste residues and information on their safe handling and methods tory). of disposal, including the disposal of any contaminated packaging. 14. Transport information (Non-mandatory) (a) UN number; (b) UN proper shipping name; (c) Transport hazard class(es); (d) Packing group, if applicable; (e) Environmental hazards (e.g., Marine pollutant (Yes/No)); (f) Transport in bulk (according to Annex II of MARPOL 73/78 and the IBC Code); (g) Special precautions which a user needs to be aware of, or needs to comply with, in connection with transport or conveyance either within or outside their premises. 15. Regulatory information (Non-manda- Safety, health and environmental regulations specific for the product in question. tory). 16. Other information, including date of The date of preparation of the SDS or the last change to it. preparation or last revision.

APPENDIX E TO § 1910.1200—DEFINITION OF events in the conduct of the business, as, for ‘‘TRADE SECRET’’ (MANDATORY) example, the amount or other terms of a secret bid for a contract or the salary of cer- The following is a reprint of the Restate- tain employees, or the security investments ment of Torts section 757, comment b (1939): made or contemplated, or the date fixed for b. Definition of trade secret. A trade secret the announcement of a new policy or for may consist of any formula, pattern, device bringing out a new model or the like. A trade or compilation of information which is used in one’s business, and which gives him an op- secret is a process or device for continuous portunity to obtain an advantage over com- use in the operations of the business. Gen- petitors who do not know or use it. It may be erally it relates to the production of goods, a formula for a chemical compound, a proc- as, for example, a machine or formula for the ess of manufacturing, treating or preserving production of an article. It may, however, re- materials, a pattern for a machine or other late to the sale of goods or to other oper- device, or a list of customers. It differs from ations in the business, such as a code for de- other secret information in a business (see termining discounts, rebates or other conces- s759 of the Restatement of Torts which is not sions in a price list or catalogue, or a list of included in this Appendix) in that it is not specialized customers, or a method of book- simply information as to single or ephemeral keeping or other office management.

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Secrecy. The subject matter of a trade se- ther use of it and is required to account for cret must be secret. Matters of public knowl- the profits derived from his past use. If, on edge or of general knowledge in an industry the other hand, the secret consists of me- cannot be appropriated by one as his secret. chanical improvements that a good me- Matters which are completely disclosed by chanic can make without resort to the se- the goods which one markets cannot be his cret, the wrongdoer’s liability may be lim- secret. Substantially, a trade secret is ited to damages, and an injunction against known only in the particular business in future use of the improvements made with which it is used. It is not requisite that only the aid of the secret may be inappropriate. the proprietor of the business know it. He may, without losing his protection, commu- APPENDIX F TO § 1910.1200—GUIDANCE FOR nicate it to employees involved in its use. He HAZARD CLASSIFICATIONS RE: CARCINO- may likewise communicate it to others GENICITY (NON-MANDATORY) pledged to secrecy. Others may also know of The mandatory criteria for classification it independently, as, for example, when they of a chemical for carcinogenicity under HCS have discovered the process or formula by (§ 1910.1200) are found in Appendix A.6 to this independent invention and are keeping it se- section. This non-mandatory Appendix pro- cret. Nevertheless, a substantial element of secrecy must exist, so that, except by the vides additional guidance on hazard classi- use of improper means, there would be dif- fication for carcinogenicity. Part A of Ap- ficulty in acquiring the information. An pendix F includes background guidance pro- exact definition of a trade secret is not pos- vided by GHS based on the Preamble of the sible. Some factors to be considered in deter- International Agency for Research on Cancer mining whether given information is one’s (IARC) ‘‘Monographs on the Evaluation of trade secret are: (1) The extent to which the Carcinogenic Risks to Humans’’ (2006). Part information is known outside of his business; B provides IARC classification information. (2) the extent to which it is known by em- Part C provides background guidance from ployees and others involved in his business; the National Toxicology Program (NTP) (3) the extent of measures taken by him to ‘‘Report on Carcinogens’’ (RoC), and Part D guard the secrecy of the information; (4) the is a table that compares GHS carcinogen value of the information to him and his com- hazard categories to carcinogen classifica- petitors; (5) the amount of effort or money tions under IARC and NTP, allowing classi- expended by him in developing the informa- fiers to be able to use information from tion; (6) the ease or difficulty with which the IARC and NTP RoC carcinogen classifica- information could be properly acquired or tions to complete their classifications under duplicated by others. the GHS, and thus the HCS. Novelty and prior art. A trade secret may be 1 a device or process which is patentable; but PART A: BACKGROUND GUIDANCE it need not be that. It may be a device or As noted in Footnote 6 of Appendix A.6. to process which is clearly anticipated in the this section, the GHS includes as guidance prior art or one which is merely a mechan- for classifiers information taken from the ical improvement that a good mechanic can Preamble of the International Agency for make. Novelty and invention are not req- Research on Cancer (IARC) ‘‘Monographs on uisite for a trade secret as they are for pat- the Evaluation of Carcinogenic Risks to Hu- entability. These requirements are essential mans’’ (2006), providing guidance on the eval- to patentability because a patent protects uation of the strength and evidence of car- against unlicensed use of the patented device cinogenic risks to humans. This guidance or process even by one who discovers it prop- also discusses some additional consider- erly through independent research. The pat- ations in classification and an approach to ent monopoly is a reward to the inventor. analysis, rather than hard-and-fast rules. But such is not the case with a trade secret. Part A is consistent with Appendix A.6, and Its protection is not based on a policy of re- should help in evaluating information to de- warding or otherwise encouraging the devel- termine carcinogenicity. opment of secret processes or devices. The Carcinogenicity in humans: protection is merely against breach of faith The evidence relevant to carcinogenicity and reprehensible means of learning an- from studies in humans is classified into one other’s secret. For this limited protection it of the following categories: is not appropriate to require also the kind of novelty and invention which is a requisite of patentability. The nature of the secret is, 1 The text of Appendix F, Part A, on the IARC however, an important factor in determining Monographs, is paraphrased from the 2006 Pre- the kind of relief that is appropriate against amble to the ‘‘Monographs on the Evaluation of one who is subject to liability under the rule Carcinogenic Risks to Humans’’; the Classifier is stated in this Section. Thus, if the secret referred to the full IARC Preamble for the com- consists of a device or process which is a plete text. The text is not part of the agreed novel invention, one who acquires the secret GHS text on the harmonized system developed wrongfully is ordinarily enjoined from fur- by the OECD Task Force-HCL.

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(a) Sufficient evidence of carcinogenicity: ysis. The IPCS ‘‘Conceptual Framework for A causal relationship has been established Evaluating a Mode of Action for Chemical Car- between exposure to the agent and human cinogenesis’’ (2001), International Life cancer. That is, a positive relationship has Sciences Institute (ILSI) ‘‘Framework for been observed between the exposure and can- Human Relevance Analysis of Information on cer in studies in which chance, bias and con- Carcinogenic Modes of Action’’ (Meek, et al., founding could be ruled out with reasonable 2003; Cohen et al., 2003, 2004), and Preamble to confidence. the IARC Monographs (2006; Section B.6. (b) Limited evidence of carcinogenicity: A (Scientific Review and Evaluation; Evalua- positive association has been observed be- tion and Rationale)) provide a basis for sys- tween exposure to the agent and cancer for tematic assessments that may be performed which a causal interpretation is considered in a consistent fashion. The IPCS also con- by the Working Group to be credible, but vened a panel in 2004 to further develop and chance, bias or confounding could not be clarify the human relevance framework. ruled out with reasonable confidence. However, the above documents are not in- In some instances, the above categories tended to dictate answers, nor provide lists may be used to classify the degree of evi- of criteria to be checked off. dence related to carcinogenicity in specific organs or tissues. Mode of Action Carcinogenicity in experimental animals: Various documents on carcinogen assess- The evidence relevant to carcinogenicity ment all note that mode of action in and of in experimental animals is classified into itself, or consideration of comparative me- one of the following categories: tabolism, should be evaluated on a case-by- (a) Sufficient evidence of carcinogenicity: case basis and are part of an analytic evalua- A causal relationship has been established tive approach. One must look closely at any between the agent and an increased inci- mode of action in animal experiments, tak- dence of malignant neoplasms or of an appro- ing into consideration comparative priate combination of benign and malignant toxicokinetics/toxicodynamics between the neoplasms in two or more species of animals animal test species and humans to determine or two or more independent studies in one the relevance of the results to humans. This species carried out at different times or in may lead to the possibility of discounting different laboratories or under different pro- very specific effects of certain types of sub- tocols. An increased incidence of tumors in stances. Life stage-dependent effects on cel- both sexes of a single species in a well-con- lular differentiation may also lead to quali- ducted study, ideally conducted under Good tative differences between animals and hu- Laboratory Practices, can also provide suffi- mans. Only if a mode of action of tumor de- cient evidence. velopment is conclusively determined not to Exceptionally, a single study in one species be operative in humans may the carcino- and sex might be considered to provide suffi- genic evidence for that tumor be discounted. cient evidence of carcinogenicity when ma- However, a weight of evidence evaluation for lignant neoplasms occur to an unusual degree with regard to incidence, site, type of a substance calls for any other tumorigenic tumor or age at onset, or when there are activity to be evaluated, as well. strong findings of tumors at multiple sites. Responses in Multiple Animal Experiments (b) Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but Positive responses in several species add to are limited for making a definitive evalua- the weight of evidence that a substance is a tion because, e.g. the evidence of carcino- carcinogen. Taking into account all of the genicity is restricted to a single experiment; factors listed in A.6.2.5.2 and more, such there are unresolved questions regarding the chemicals with positive outcomes in two or adequacy of the design, conduct or interpre- more species would be provisionally consid- tation of the studies; the agent increases the ered to be classified in GHS Category 1B incidence only of benign neoplasms or le- until human relevance of animal results are sions of uncertain neoplastic potential; or assessed in their entirety. It should be noted, the evidence of carcinogenicity is restricted however, that positive results for one species to studies that demonstrate only promoting in at least two independent studies, or a sin- activity in a narrow range of tissues or or- gle positive study showing unusually strong gans. evidence of malignancy may also lead to Category 1B. Guidance on How To Consider Important Fac- tors in Classification of Carcinogenicity (See Responses Are in One Sex or Both Sexes Reference Section) Any case of gender-specific tumors should The weight of evidence analysis called for be evaluated in light of the total in GHS and the HCS (§ 1910.1200) is an inte- tumorigenic response to the substance ob- grative approach that considers important served at other sites (multi-site responses or factors in determining carcinogenic poten- incidence above background) in determining tial along with the strength of evidence anal- the carcinogenic potential of the substance.

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If tumors are seen only in one sex of an Group 1: The agent is carcinogenic to hu- animal species, the mode of action should be mans carefully evaluated to see if the response is This category is used when there is suffi- consistent with the postulated mode of ac- cient evidence of carcinogenicity in humans. tion. Effects seen only in one sex in a test Exceptionally, an agent may be placed in species may be less convincing than effects this category when evidence of carcino- seen in both sexes, unless there is a clear genicity in humans is less than sufficient but patho-physiological difference consistent there is sufficient evidence of carcinogenicity with the mode of action to explain the single in experimental animals and strong evidence sex response. in exposed humans that the agent acts through a relevant mechanism of carcino- Confounding Effects of Excessive Toxicity or genicity. Localized Effects Group 2: Tumors occurring only at excessive doses This category includes agents for which, at associated with severe toxicity generally one extreme, the degree of evidence of car- have doubtful potential for carcinogenicity cinogenicity in humans is almost sufficient, in humans. In addition, tumors occurring as well as those for which, at the other ex- only at sites of contact and/or only at exces- treme, there are no human data but for sive doses need to be carefully evaluated for which there is evidence of carcinogenicity in human relevance for carcinogenic hazard. experimental animals. Agents are assigned For example, forestomach tumors, following to either Group 2A (probably carcinogenic to administration by gavage of an irritating or humans) or Group 2B (possibly carcinogenic to corrosive, non-mutagenic chemical, may be humans) on the basis of epidemiological and of questionable relevance. However, such de- experimental evidence of carcinogenicity terminations must be evaluated carefully in and mechanistic and other relevant data. justifying the carcinogenic potential for hu- The terms probably carcinogenic and possibly mans; any occurrence of other tumors at dis- carcinogenic have no quantitative signifi- tant sites must also be considered. cance and are used simply as descriptors of different levels of evidence of human car- Tumor Type, Reduced Tumor Latency cinogenicity, with probably carcinogenic sig- Unusual tumor types or tumors occurring nifying a higher level of evidence than pos- with reduced latency may add to the weight sibly carcinogenic. of evidence for the carcinogenic potential of Group 2A: The agent is probably carcino- a substance, even if the tumors are not sta- genic to human. tistically significant. This category is used when there is limited Toxicokinetic behavior is normally as- evidence of carcinogenicity in humans and suf- sumed to be similar in animals and humans, ficient evidence of carcinogenicity in experi- at least from a qualitative perspective. On mental animals. In some cases, an agent may the other hand, certain tumor types in ani- be classified in this category when there is mals may be associated with toxicokinetics inadequate evidence of carcinogenicity in hu- or toxicodynamics that are unique to the mans and sufficient evidence of carcinogenicity animal species tested and may not be pre- in experimental animals and strong evidence dictive of carcinogenicity in humans. Very that the carcinogenesis is mediated by a few such examples have been agreed inter- mechanism that also operates in humans. nationally. However, one example is the lack Exceptionally, an agent may be classified in of human relevance of kidney tumors in this category solely on the basis of limited male rats associated with compounds caus- evidence of carcinogenicity in humans. An ing a2u-globulin nephropathy (IARC, Sci- agent may be assigned to this category if it entific Publication N° 147 2). Even when a clearly belongs, based on mechanistic con- particular tumor type may be discounted, siderations, to a class of agents for which expert judgment must be used in assessing one or more members have been classified in the total tumor profile in any animal experi- Group 1 or Group 2A. ment. Group 2B: The agent is possibly carcinogenic to humans. PART B: INTERNATIONAL AGENCY FOR This category is used for agents for which RESEARCH ON CANCER (IARC) 3 there is limited evidence of carcinogenicity in IARC Carcinogen Classification Categories: humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate 2 While most international agencies do not evidence of carcinogenicity in humans but α consider kidney tumors coincident with 2u- there is sufficient evidence of carcinogenicity globulin nephropathy to be a predictor of risk in in experimental animals. In some instances, humans, this view is not universally held. (See: Doi et al., 2007). 3 Preamble of the International Agency for Re- Evaluation of Carcinogenic Risks to Humans’’ search on Cancer (IARC) ‘‘Monographs on the (2006).

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an agent for which there is inadequate evi- there is less than sufficient evidence of car- dence of carcinogenicity in humans and less cinogenicity in humans or laboratory ani- than sufficient evidence of carcinogenicity in mals; however, the agent, substance, or mix- experimental animals together with sup- ture belongs to a well-defined, structurally- porting evidence from mechanistic and other related class of substances whose members relevant data may be placed in this group. are listed in a previous Report on Carcino- An agent may be classified in this category gens as either known to be a human car- solely on the basis of strong evidence from cinogen or reasonably anticipated to be a mechanistic and other relevant data. human carcinogen, or there is convincing relevant information that the agent acts PART C: NATIONAL TOXICOLOGY PROGRAM (NTP), ‘‘REPORT ON CARCINOGENS’’, BACK- through mechanisms indicating it would GROUND GUIDANCE likely cause cancer in humans. Conclusions regarding carcinogenicity in NTP Listing Criteria 4: humans or experimental animals are based The criteria for listing an agent, sub- on scientific judgment, with consideration stance, mixture, or exposure circumstance in given to all relevant information. Relevant the Report on Carcinogens (RoC) are as fol- information includes, but is not limited to, lows: dose response, route of exposure, chemical Known To Be A Human Carcinogen: There structure, metabolism, pharmacokinetics, is sufficient evidence of carcinogenicity from sensitive sub-populations, genetic effects, or studies in humans 5 that indicates a causal other data relating to mechanism of action relationship between exposure to the agent, or factors that may be unique to a given sub- substance, or mixture, and human cancer. stance. For example, there may be sub- Reasonably Anticipated To Be A Human stances for which there is evidence of car- Carcinogen: There is limited evidence of carcinogenicity in laboratory animals, but cinogenicity from studies in humans that in- there are compelling data indicating that dicates that a causal interpretation is cred- the agent acts through mechanisms that do ible, but that alternative explanations, such not operate in humans and would therefore as chance, bias, or confounding factors, could not reasonably be anticipated to cause cannot adequately be excluded, cer in humans. or PART D: TABLE RELATING APPROXIMATE there is sufficient evidence of carcino- EQUIVALENCES AMONG IARC, NTP ROC, AND genicity from studies in experimental ani- GHS CARCINOGENICITY CLASSIFICATIONS mals that indicates there is an increased incidence of malignant and/or a combination of The following table may be used to per- malignant and benign tumors in multiple form hazard classifications for carcino- species or at multiple tissue sites, or by mul- genicity under the HCS (§ 1910.1200). It re- tiple routes of exposure, or to an unusual de- lates the approximated GHS hazard cat- gree with regard to incidence, site, or type of egories for carcinogenicity to the classifica- tumor, or age at onset, tions provided by IARC and NTP, as de- or scribed in Parts B and C of this Appendix.

APPROXIMATE EQUIVALENCES AMONG CARCINOGEN CLASSIFICATION SCHEMES

IARC GHS NTP RoC

Group 1 ...... Category 1A ...... Known. Group 2A ...... Category 1B ...... Reasonably Anticipated (See Note 1). Group 2B ...... Category 2 ...... Reasonably Anticipated (See Note 1).

Note 1: 3. Less than sufficient evidence of carcino- 1. Limited evidence of carcinogenicity from genicity in humans or laboratory animals; how- studies in humans (corresponding to IARC 2A/ ever: GHS 1B); a. The agent, substance, or mixture belongs to 2. Sufficient evidence of carcinogenicity from a well-defined, structurally-related class of sub- studies in experimental animals (again, essen- stances whose members are listed in a previous tially corresponding to IARC 2A/GHS 1B); RoC as either ‘‘Known’’ or ‘‘Reasonably Antici- pated’’ to be a human carcinogen, or

4 See: http://ntp.niehs.nih.gov/go/15209. cells from humans exposed to the substance in 5 This evidence can include traditional cancer question that can be useful for evaluating epidemiology studies, data from clinical studies, whether a relevant cancer mechanism is oper- and/or data derived from the study of tissues or ating in people.

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b. There is convincing relevant information § 1910.1201 Retention of DOT mark- that the agent acts through mechanisms indi- ings, placards and labels. cating it would likely cause cancer in humans. (a) Any employer who receives a *REFERENCES package of hazardous material which is Cohen, S.M., J. Klaunig, M.E. Meek, R.N. required to be marked, labeled or plac- Hill, T. Pastoor, L. Lehman-McKeeman, arded in accordance with the U. S. De- J. Bucher, D.G. Longfellow, J. Seed, V. partment of Transportation’s Haz- Dellarco, P. Fenner-Crisp, and D. Patton. ardous Materials Regulations (49 CFR 2004. Evaluating the human relevance of Parts 171 through 180) shall retain chemically induced animal tumors. those markings, labels and placards on Toxicol. Sci. 78(2):181–186. the package until the packaging is suf- Cohen, S.M., M.E. Meek, J.E. Klaunig, D.E. ficiently cleaned of residue and purged Patton, P.A. Fenner-Crisp. 2003. The of vapors to remove any potential haz- human relevance of information on carcinogenic modes of action: Overview. ards. Crit. Rev. Toxicol. 33(6):581–9. (b) Any employer who receives a Meek, M.E., J.R. Bucher, S.M. Cohen, V. freight container, rail freight car, Dellarco, R.N. Hill, L. Lehman- motor vehicle, or transport vehicle McKeeman, D.G. Longfellow, T. Pastoor, that is required to be marked or plac- J. Seed, D.E. Patton. 2003. A framework arded in accordance with the Haz- for human relevance analysis of informa- ardous Materials Regulations shall re- tion on carcinogenic modes of action. tain those markings and placards on Crit. Rev. Toxicol. 33(6):591–653. the freight container, rail freight car, Sonich-Mullin, C., R. Fielder, J. Wiltse, K. motor vehicle or transport vehicle Baetcke, J. Dempsey, P. Fenner-Crisp, D. Grant, M. Hartley, A. Knapp, D. Kroese, until the hazardous materials which re- I. Mangelsdorf, E. Meek, J.M. Rice, and quire the marking or placarding are M. Younes. 2001. The conceptual frame- sufficiently removed to prevent any po- work for evaluating a mode of action for tential hazards. chemical carcinogenesis. Reg. Toxicol. (c) Markings, placards and labels Pharm. 34:146–152. shall be maintained in a manner that International Programme on Chemical Safe- ensures that they are readily visible. ty Harmonization Group. 2004. Report of (d) For non-bulk packages which will the First Meeting of the Cancer Working Group. World Health Organization. Re- not be reshipped, the provisions of this port IPCS/HSC–CWG–1/04. Geneva. section are met if a label or other ac- International Agency for Research on Can- ceptable marking is affixed in accord- cer. IARC Monographs on the Evaluation ance with the Hazard Communication of Carcinogenic Risks to Human. Pre- Standard (29 CFR 1910.1200). ambles to Volumes. World Health Orga- (e) For the purposes of this section, nization. Lyon, France. the term ‘‘hazardous material’’ and Cohen, S.M., P.A. Fenner-Crisp, and D.E. any other terms not defined in this sec- Patton. 2003. Special Issue: Cancer Modes tion have the same definition as in the of Action and Human Relevance. Critical Hazardous Materials Regulations (49 Reviews in Toxicology, R.O. McClellan, ed., Volume 33/Issue 6. CRC Press. CFR Parts 171 through 180). Capen, C.C., E. Dybing, and J.D. Wilbourn. [59 FR 36700, July 19, 1994] 1999. Species differences in thyroid, kidney and urinary bladder carcinogenesis. § 1910.1450 Occupational exposure to International Agency for Research on hazardous chemicals in labora- Cancer, Scientific Publication N° 147. tories. Doi, A.M., G. Hill, J. Seely, J.R. Hailey, G. Kissling, and J.R. Buchera. 2007. a2u- (a) Scope and application. (1) This sec- Globulin nephropathy and renal tumors tion shall apply to all employers en- in National Toxicology Program studies. gaged in the laboratory use of haz- Toxicol. Pathol. 35:533–540. ardous chemicals as defined below. [59 FR 6170, Feb. 9, 1994, as amended at 59 FR (2) Where this section applies, it shall 17479, Apr. 13, 1994; 59 FR 65948, Dec. 22, 1994; supersede, for laboratories, the require- 61 FR 9245, Mar. 7. 1996; 77 FR 17785, Mar. 26, ments of all other OSHA health stand- 2012; 78 FR 9313, Feb. 8, 2013] ards in 29 CFR part 1910, subpart Z, except as follows:

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