Fill - Free fillable HAZARD COMMUNICATION (Department of Labor) PDF form

HAZARD COMMUNICATION

Hazard Classiﬁcation Guidance

for Manufacturers, Importers, and Employers

OSHA 3844-02 2016

Occupational Safety and Health Act of 1970

“To assure safe and healthful working conditions for

working men and women; by authorizing enforcement

of the standards developed under the Act; by assisting

and encouraging the States in their efforts to assure

safe and healthful working conditions; by providing for

research, information, education, and training in the ﬁeld

of occupational safety and health.”

This guidance document is not a standard or regulation, and it creates no new legal obligations. It contains

recommendations as well as descriptions of mandatory safety and health standards. The recommendations

are advisory in nature, informational in content, and are intended to assist employers in providing a safe

and healthful workplace. The Occupational Safety and Health Act requires employers to comply with

safety and health standards and regulations promulgated by OSHA or by a state with an OSHA-approved

state plan. In addition, the Act’s General Duty Clause, Section 5(a)(1), requires employers to provide their

employees with a workplace free from recognized hazards likely to cause death or serious physical harm.

Cover Image: Photodisc

Material contained in this publication is in the public

domain and may be reproduced, fully or partially, without

permission. Source credit is requested but not required.

This information will be made available to sensory-

impaired individuals upon request.

Voice phone: (202) 693-1999;

teletypewriter (TTY) number: 1-877-889-5627.

This publication provides a general overview of a particular

standards-related topic. This publication does not alter or

determine compliance responsibilities which are set forth

in OSHA standards, and the Occupational Safety and Health

Act. Moreover, because interpretations and enforcement

policy may change over time, for additional guidance on

OSHA compliance requirements, the reader should consult

current administrative interpretations and decisions by the

Occupational Safety and Health Review Commission and

the courts.

HAZARD COMMUNICATION

Hazard Classiﬁcation Guidance

for Manufacturers, Importers,

and Employers

Occupational Safety and Health Administration

U.S. Department of Labor

OSHA 3844-02 2016

TABLE OF CONTENTS

OVERVIEW ................................................................................................................................... 1

I. INTRODUCTION ................................................................................................................. 3

II. THE HAZARD CLASSIFICATION PROCESS .................................................................. 6

III. IDENTIFYING HAZARDOUS CHEMICALS .................................................................. 14

IV. DATA COLLECTION ........................................................................................................ 15

V. DATA ANALYSIS.............................................................................................................. 19

VI. RECORDING THE RATIONALE BEHIND THE RESULTS OBTAINED ..................... 28

VII. CLASSIFICATION OF HEALTH HAZARDS .................................................................. 32

VII.1 Acute Toxicity ............................................................................................................ 32

VII.2 Skin Corrosion/Irritation ............................................................................................. 63

VII.3 Serious Eye Damage/Eye Irritation ............................................................................ 86

VII.4 Respiratory or Skin Sensitization.............................................................................. 115

VII.5 Germ Cell Mutagenicity ........................................................................................... 135

VII.6 Carcinogenicity ......................................................................................................... 149

VII.7 Reproductive Toxicity .............................................................................................. 170

VII.8 Specific Target Organ Toxicity – Single Exposure .................................................. 189

VII.9 Specific Target Organ Toxicity – Repeated or Prolonged Exposure ........................ 210

VII.10 Aspiration Hazard ..................................................................................................... 227

VII.11 Simple Asphyxiants .................................................................................................. 237

VIII. CLASSIFICATION OF PHYSICAL HAZARDS ............................................................ 239

VIII.1 Explosives ................................................................................................................. 240

VIII.2 Flammable Gases ...................................................................................................... 258

VIII.3 Flammable Aerosols ................................................................................................. 266

VIII.4 Oxidizing Gases ........................................................................................................ 279

VIII.5 Gases under Pressure ................................................................................................ 286

VIII.6 Flammable Liquids ................................................................................................... 294

VIII.7 Flammable Solids...................................................................................................... 301

VIII.8 Self-Reactive Chemicals ........................................................................................... 307

VIII.9 Pyrophoric Chemicals ............................................................................................... 322

VIII.10 Self-Heating Chemicals ............................................................................................ 332

VIII.11 Chemicals Which, in Contact with Water, Emit Flammable Gases ......................... 339

VIII.12 Oxidizing Liquids and Solids.................................................................................... 346

VIII.13 Organic Peroxides ..................................................................................................... 358

VIII.14 Corrosive to Metals ................................................................................................... 372

VIII.15 Combustible Dust...................................................................................................... 380

IX. HAZARDS NOT OTHERWISE CLASSIFIED................................................................ 385

APPENDIX A. Glossary of Terms and Definitions .................................................................. 386

APPENDIX B. Information Sources to Assist with Hazard Classification ............................... 397

APPENDIX C. List of Substances Deemed Toxic or Hazardous by an Authoritative Process .... 406

APPENDIX D. OSHA-Designated Carcinogens ....................................................................... 419

Workers’ Rights .......................................................................................................................... 420

OSHA Assistance, Services and Programs ................................................................................. 420

NIOSH Health Hazard Evaluation Program ............................................................................... 423

OSHA Regional Offices ............................................................................................................. 423

How to Contact OSHA ............................................................................................................... 424

OVERVIEW

In March 2012, the Occupational Safety and Health Administration (OSHA) revised its Hazard

Communication Standard to align it with the United Nations Globally Harmonized System of

Classification and Labelling of Chemicals (GHS), Revision 3. The revision to the Hazard

Communication Standard (HCS) built on the existing standard, by requiring chemical

manufacturers and importers to follow specific criteria when evaluating the hazardous chemicals

and when communicating the hazards through labels and safety data sheets (SDSs).

This document is designed to help manufacturers and importers of chemicals not only identify

chemical hazards, but also to classify these hazards so that workers and downstream users can be

informed about and better understand these hazards as required by OSHA’s Hazard

Communication Standard. This guidance may also be useful to employers who decide to

conduct hazard classifications to assure the accuracy and completeness of information provided

to them by suppliers.

Understanding the hazards is the critically important first stage in the process of establishing an

effective hazard communication program. The process of hazard classification consists of four

basic steps.

 Selection of chemicals to evaluate;

 Collection of data;

 Analysis of the collected data; and

 Records of the rationale behind the results obtained.

This document provides guidance on the processes involved and identifies considerations in the

conduct of hazard classifications. Guidance on the allocation of the hazard communication label

elements is provided in an OSHA Brief on Labels and Pictograms, located on the Hazard

Communication webpage, at www.osha.gov/hazcom.

Material contained in this publication is in the public domain and may be reproduced, fully or

partially, without permission. Source credit is requested but not required.

How this Document is Organized

This guidance is organized into several chapters. Chapter I introduces the guidance. Chapter II

provides an overview of the hazard classification process. Chapter III discusses how to identify

the chemicals to be classified. Chapter IV explains the process of data collection. Chapter V

describes the process and information needed for data analysis. Chapter VI discusses the

information that may be useful to note in recording the rationale used to develop the

classification of the various hazards. Chapters VII, VIII, and IX present the guidance to classify

health hazards, physical hazards, and hazards not otherwise classified covered by the Hazard

Communication Standard, respectively.

In addition, several appendices are provided at the end of this document:

 A glossary of terms and definitions is included in Appendix A, since much of the

discussion in this document is of a technical nature.

 A list of sources is provided in Appendix B. This list is by no means exhaustive, but it

contains many useful resources.

 Appendix C contains a list of chemicals for which OSHA has adopted permissible

exposure limits. This is a helpful starting point for identifying chemicals that are toxic or

hazardous The HCS does not contain a “floor” (list) of chemicals pre-determined to be

hazardous under the standard (except for chemicals OSHA has already determined to be

carcinogens); however, there are lists of hazardous chemicals compiled by authoritative

sources that classifiers may find useful to consult. The chemicals listed in Appendix C

are an example of one such list. Classifiers should also consult the American Conference

of Governmental Industrial Hygienists’ (ACGIH’s) list of Threshold Limit Values

(TLVs) and the items identified as carcinogens by the International Agency for Research

on Cancer (IARC) Monographs on the Evaluation of Carcinogenic Risks to Humans, or

the Report on Carcinogens from the National Toxicology Program (NTP). These lists are

updated periodically, and users should check to determine whether there has been an

update.

 A list of OSHA-designated carcinogens is provided in Appendix D. Please see Chapter

VII.6, Carcinogenicity, for guidance on classification of these chemicals.

I. INTRODUCTION

OSHA's Hazard Communication Standard (HCS) is designed to protect against chemical-source

injuries and illnesses by ensuring that employers and workers are provided with sufficient

information to anticipate, recognize, evaluate, and control chemical hazards and take appropriate

protective measures. This information is provided through safety data sheets (SDSs), labels, and

employee training. In order for SDSs, labels, and training to be effective, the hazard information

they convey must be complete and accurate. Thus, it is critically important to obtain

comprehensive and correct information about the hazards associated with particular chemicals.

What is Hazard Classification?

Hazard classification is the process of evaluating the full range of available scientific evidence to

determine if a chemical is hazardous, as well as to identify the level of severity of the hazardous

effect. When complete, the evaluation identifies the hazard class(es) and associated hazard

category of the chemical.

The HCS defines hazard class as the nature of a physical or health hazard, e.g., flammable solid,

carcinogen, and acute toxicity. Hazard category means the division of criteria within each

hazard class, e.g., acute toxicity and flammable liquids each include four hazard categories

numbered from category 1 through category 4. These categories compare hazard severity within

a hazard class and should not be taken as a comparison of hazard categories more generally.

That is, a chemical identified as a category 2 in the acute toxicity hazard class is not necessarily

less toxic than a chemical assigned a category 1 of another hazard class. The hierarchy of the

categories is only specific to the hazard class. The hazard classification process provides the

basis for the hazard information that is provided in SDSs, labels, and worker training.

The hazard classification process, as provided in the Hazard Communication Standard, has

several steps, including:

 Identifying the chemical;

 Identifying the relevant data regarding the hazards of a chemical;

 Reviewing the relevant data to ascertain the hazards associated with the chemical;

 Determining whether the chemical will be classified as hazardous according to the

definition of hazardous chemical in the standard; and

 Determining the degree of the hazard, where appropriate, by comparing the data with

the criteria for health and physical hazards.

The HCS provides specific criteria for hazard classification to ensure that chemical

manufacturers, importers, and other classification experts come to similar conclusions regarding

the hazards of chemicals. The resulting classification is then used to determine appropriate

hazard warnings. This method not only provides employers and workers with more consistent

classification of hazards, but the hazard information on SDSs and labels is in a form that is more

consistent and presented in a way that facilitates the understanding of the hazards of chemicals.

This hazard information can then be used when evaluating the workplace conditions to determine

the hazards in the workplace, as well as to respond to exposure incidents.

The information and criteria provided in Appendix A to 29 CFR 1910.1200 are used to classify

the health hazards posed by hazardous chemicals. Similarly, the information and criteria

provided in Appendix B to 29 CFR 1910.1200 are used to classify the physical hazards posed by

hazardous chemicals.

Hazard classification does not involve an estimation of risk. The difference between the terms

hazard and risk is often poorly understood. Hazard refers to an inherent property of a substance

that is capable of causing an adverse effect. Risk, on the other

hand, refers to the probability that an adverse effect will occur

with specific exposure conditions. Thus, a chemical will

present the same hazard in all situations due to its innate

chemical or physical properties and its actions on cells and

tissues. However, considerable differences may exist in the

risk posed by a chemical, depending on how the chemical is contained or handled, personal

protective measures used, and other conditions that result in or limit exposure. This document

addresses only the hazard classification process, and will not discuss risk assessment, which is

not performed under the HCS.

Who Must Conduct Hazard Classifications?

Only chemical manufacturers and importers are required to perform hazard classifications on the

chemicals they produce or import. Under the HCS, an employer that manufactures, processes,

formulates, blends, mixes, repackages, or otherwise changes the composition of a hazardous

chemical is considered a "chemical manufacturer." Distributors and employers may also choose

to conduct hazard classifications if they are concerned about the adequacy of the hazard

information received for the chemicals they use in their business or distribute to others.

What Resources are Needed to Conduct a Hazard Classification?

Three primary resources are required for hazard classification. First is the complete, accurate,

most up-to-date literature and data concerning the hazardous chemical in question (discussed

below in Chapter V, Data Analysis). Second, is the ability to properly understand and interpret

the information retrieved in order to identify and document hazards. Third, is the specific

criteria for each health and physical hazard class and category defined in the Hazard

Communication Standard. As mentioned above, Appendix A to 29 CFR 1910.1200 provides the

classification criteria for health hazards, and Appendix B to 29 CFR 1910.1200 provides the

classification criteria for physical hazards.

Manufacturers and importers of hazardous chemicals are responsible for ensuring that hazard

information provided to their workers and downstream users is complete and accurate. To

achieve this, the person(s) assigned to conduct hazard classifications must have the ability to

Risk is often expressed

as the simple equation:

Hazard X Exposure = Risk.

conduct complete and effective literature research and data retrieval. They should also be able to

effectively interpret the literature and data in order to determine the nature and extent of physical

and health hazards. A lack of qualified workers does not exempt a manufacturer or importer

from compliance with the HCS.

How to Use This Guidance Document

The hazard classification requirements of the HCS are specification-oriented. That is, chemical

manufacturers, importers, and employers evaluating chemicals are required to follow specific

criteria for evaluating and classifying hazards, and they must be able to demonstrate that they

have accurately reported the hazards of the chemicals produced or imported in accordance with

the criteria set forth in the HCS.

This document provides a detailed description of the criteria used to classify a hazardous

chemical and guidance on how to apply them. In addition, a basic framework for hazard

classification is provided, along with a description of the process that can be used to comply with

the requirements of the HCS. An example using a mock chemical is also provided to illustrate

the classification process of the given hazard.

The interpretation of information relating to the physical and health hazards associated with a

chemical can be a highly technical undertaking, and should be conducted by trained staff such as

toxicologists, industrial hygienists, and safety professionals. This document will not replace the

need for such professional expertise. It is intended to serve only as useful guidance on the basic

considerations and operational aspects involved in the conduct of hazard classifications.

Once hazard classification is complete, classifiers must select the appropriate label elements for

the hazards identified. Appendix C to 29 CFR 1910.1200, Allocation of Label Elements,

identifies the proper pictogram, signal word, hazard and precautionary statements for each

hazard class and category in the HCS.

This document does not address detailed labeling requirements or SDSs. OSHA has developed

QuickCards

™

and OSHA Briefs on labels, pictograms, and SDSs, as well as other guidance.

These materials can be found on the HCS website at: www.osha.gov/hazcom.

II. THE HAZARD CLASSIFICATION PROCESS

Introduction

The purpose of the Hazard Communication Standard is to ensure that the hazards of all

chemicals produced or imported are classified, and that the information on the hazardous

chemicals is transmitted to employers and workers. The standard covers only hazardous

chemicals. During the classification process, the chemical manufacturer or importer must

determine if the chemical being evaluated is hazardous or not. With the alignment of the HCS to

the GHS, the hazard information will be consistent in format and content, making it easier for

employers and workers to understand and use. This section of the guidance clarifies what is

considered a hazardous chemical.

What is the HCS Definition of a “Chemical”?

The definition of a chemical in the HCS is much broader than that which is commonly used in

everyday speech. The HCS definition of chemical is “any substance, or mixture of substances.”

Thus, virtually any product is a “chemical.” These various types of chemicals are defined as

follows:

 Substance - chemical elements and their compounds in the natural state or obtained by

any production process, including any additive necessary to preserve the stability of the

product and any impurities deriving from the process used, but excluding any solvent

which may be separated without affecting the stability of the substance or changing its

composition.

 Element - the simplest form of matter. There are currently 118 known elements in the

periodic table. Examples of elements are aluminum, carbon, chlorine, hydrogen, mercury

and oxygen.

 Chemical compound - a substance consisting of two or more elements combined or bonded

together so that its constituent elements are always present in the same proportions.

 Mixture - a combination or a solution composed of two or more substances in which they

do not react.

Although virtually all products are considered chemicals under this definition, the HCS identifies

certain categories of chemicals that are not covered by the standard. These categories are:

 Any hazardous waste as defined by the Solid Waste Disposal Act, as amended by the

Resource Conservation and Recovery Act of 1976 (42 U.S.C. 6901 et seq.), as amended,

when subject to regulations issued under that Act by the Environmental Protection Agency;

 Any hazardous substance as defined by the Comprehensive Environmental Response,

Compensation and Liability Act (42 U.S.C. 9601 et seq.) when the hazardous substance

is the focus of remedial or removal action being conducted under that Act in

accordance with Environmental Protection Agency regulations;

 Tobacco or tobacco products;

 Wood or wood products, including lumber which will not be processed, where the

chemical manufacturer or importer can establish that the only hazard they pose to

employees is the potential for flammability or combustibility (wood or wood products

which have been treated with a hazardous chemical covered by this standard, and wood

which may be subsequently sawed or cut, generating dust, are not exempted);

 Articles, defined as a manufactured item other than a fluid or particle: (i) which is

formed to a specific shape or design during manufacture; (ii) which has end use

function(s) dependent in whole or in part upon its shape or design during end use; and

(iii) which under normal conditions of use does not release more than very small

quantities, e.g., minute or trace amounts of a hazardous chemical, and does not pose a

physical hazard or health risk to employees;

 Food or alcoholic beverages which are sold, used, or prepared in a retail establishment

(such as a grocery store, restaurant, or drinking place), and foods intended for personal

consumption by employees while in the workplace;

 Any drug, as that term is defined in the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 301 et seq.), when it is in solid, final form for direct administration to the patient

(e.g., tablets or pills); drugs which are packaged by the chemical manufacturer for sale to

consumers in a retail establishment (e.g., over-the-counter drugs); and drugs intended for

personal consumption by employees while in the workplace (e.g., first-aid supplies);

 Cosmetics which are packaged for sale to consumers in a retail establishment, and

cosmetics intended for personal consumption by employees while in the workplace;

 Any consumer product or hazardous substance, as those terms are defined in the

Consumer Product Safety Act (15 U.S.C. 2051 et seq.) and the Federal Hazardous

Substances Act (15 U.S.C. 1261 et seq.), respectively, where the employer can show that

it is used in the workplace for the purpose intended by the chemical manufacturer or

importer of the product, and the use results in a duration and frequency of exposure

which is not greater than the range of exposures that could reasonably be

experienced by consumers when used for the purpose intended;

 Nuisance particulates where the chemical manufacturer or importer can establish that

they do not pose any physical or health hazard covered under this section;

 Ionizing and nonionizing radiation; and

 Biological hazards.

The HCS also does not require labeling for certain chemicals, but hazard classification is still

needed for these chemicals to provide the required safety data sheet. The chemicals include:

 Any pesticide as such term is defined in the Federal Insecticide, Fungicide, and

Rodenticide Act (7 U.S.C. 136 et seq.), when subject to the labeling requirements of that

Act and labeling regulations issued under that Act by the Environmental Protection

Agency;

 Any chemical substance or mixture as such terms are defined in the Toxic Substances

Control Act (15 U.S.C. 2601 et seq.), when subject to the labeling requirements of that Act

and labeling regulations issued under that Act by the Environmental Protection Agency;

 Any food, food additive, color additive, drug, cosmetic, or medical or veterinary device

or product, including materials intended for use as ingredients in such products (e.g.

flavors and fragrances), as such terms are defined in the Federal Food, Drug, and

Cosmetic Act (21 U.S.C. 301 et seq.) or the Virus-Serum-Toxin Act of 1913 (21 U.S.C.

151 et seq.), and regulations issued under those Acts, when they are subject to the

labeling requirements under those Acts by either the Food and Drug Administration or

the Department of Agriculture;

 Any distilled spirits (alcoholic beverages), wine, or malt beverage intended for

nonindustrial use, as such terms are defined in the Federal Alcohol Administration Act

(27 U.S.C. 201 et seq.) and regulations issued under that Act, when subject to the labeling

requirements of that Act and labeling regulations issued under that Act by the Bureau of

Alcohol, Tobacco, Firearms and Explosives;

 Any consumer product or hazardous substance as those terms are defined in the

Consumer Product Safety Act (15 U.S.C. 2051 et seq.) and the Federal Hazardous

Substances Act (15 U.S.C. 1261 et seq.) respectively, when subject to a consumer product

safety standard or labeling requirement of those Acts, or regulations issued under those

Acts by the Consumer Product Safety Commission; and,

 Agricultural or vegetable seed treated with pesticides and labeled in accordance with the

Federal Seed Act (7 U.S.C. 1551 et seq.) and the labeling regulations issued under that

Act by the Department of Agriculture.

How to Determine if a Chemical is “Hazardous”

Under the HCS, any chemical that is classified as a physical hazard, a health hazard, a simple

asphyxiant, combustible dust, pyrophoric gas, or hazard not otherwise classified is considered a

hazardous chemical. The HCS definitions for physical hazard and health hazard are:

 Physical hazard means a chemical that is classified as posing one of the following

hazardous effects: explosive; flammable (gases, aerosols, liquids, or solids); oxidizer

(liquid, solid or gas); self-reactive; pyrophoric (liquid or solid); self-heating; organic

peroxide; corrosive to metal; gas under pressure; or in contact with water emits flammable

gas. The criteria for determining whether a chemical is classified as a physical hazard are

detailed in Appendix B to 29 CFR 1910.1200 – Physical Hazard Criteria.

 Health hazard means a chemical that is classified as posing one of the following

hazardous effects: acute toxicity (any route of exposure); skin corrosion or irritation;

serious eye damage or eye irritation; respiratory or skin sensitization; germ cell

mutagenicity; carcinogenicity; reproductive toxicity; specific target organ toxicity

(single or repeated exposure); or aspiration hazard. The criteria for determining

whether a chemical is classified as a health hazard are detailed in Appendix A to

29 CFR 1910.1200 – Health Hazard Criteria.

The definitions for each of the specific physical and health hazards identified above are the same

as those found in the GHS, Rev. 3. To maintain the coverage of those hazards that were included

in the 1994 Hazard Communication Standard, OSHA included hazard communication elements

for the following hazards that are not found in GHS Rev. 3: combustible dusts, pyrophoric gases,

and simple asphyxiants. OSHA has also created “hazards not otherwise classified”, a hazard

class to capture hazards for which criteria have not yet been created.

Each of these hazards are included in this guidance document. Guidance on classification of

simple asphyxiants is presented in Chapter VII, Classification of Health Hazards. Guidance on

classification of pyrophoric gases and combustible dusts is presented in Chapter VIII,

Classification of Physical Hazards. Guidance on classification of hazards not otherwise

classified is presented in Chapter IX, Classification of Hazards not Otherwise Classified.

Table II.1 lists the different health hazard classes and categories identified in the HCS.

Similarly, Table II.2 lists the different physical hazard classes and categories found in the HCS.

Those hazard classes listed in italicized font in these two tables are the hazard classes not

identified in GHS Rev.3, but are included in the HCS to maintain workplace coverage.

Explanations of the classification process for each of these hazard classes and their associated

hazard categories are presented in Chapters VII and VIII of this document, respectively.

Table II.1. Health Hazard Classes and Categories.

Hazard Class

Hazard Category

Acute Toxicity

Skin Corrosion/Irritation

Serious Eye Damage/

Eye Irritation

Respiratory or Skin

Sensitization

Germ Cell Mutagenicity

Carcinogenicity

Reproductive Toxicity

Lactation

STOT –

Single Exposure

STOT –

Repeated Exposure

Aspiration

Simple Asphyxiants

Single Category

Table II.2. Physical Hazard Classes and Categories.

Hazard Class

Hazard Category

Explosives

Unstable

Explosives

Div 1.1

Div 1.2

Div 1.3

Div 1.4

Div 1.5

Div 1.6

Flammable Gases

Flammable Aerosols

Oxidizing Gases

Gases under Pressure

Compressed Gases

Liquefied Gases

Refrigerated

Liquefied Gases

Dissolved Gases

Flammable Liquids

Flammable Solids

Self-Reactive

Chemicals

Type A

Type B

Type C

Type D

Type E

Type F

Type G

Pyrophoric Liquids

Pyrophoric Solid

Pyrophoric Gases

Single

category

Self-heating

Chemicals

Chemicals, which in

contact with water,

emit flammable gases

Oxidizing Liquids

Oxidizing Solids

Organic Peroxides

Type A

Type B

Type C

Type D

Type E

Type F

Type G

Corrosive to Metals

Combustible Dusts

Single

category

For a hazard classification process to be complete, one must consider all possible hazards, and

should document any hazards that are identified. In conducting the hazard classification, one

should be cognizant of all types of physical and health hazards to properly identify the nature and

severity of the chemical’s hazards.

OSHA regulates a number of chemicals as toxic and hazardous substances, which are contained

in Subpart Z of 29 CFR 1910. The classifier must refer to the regulations of these substances for

specific hazard classification requirements. For example, the Lead standard requires that at least

the hazards of reproductive/developmental toxicity, central nervous system effects, kidney

effects, blood effects, and acute toxicity effects be addressed in classification (See 29 CFR

1910.1025(m)(ii)). In addition, there are certain lists that can help the classifier identify

chemicals that have been deemed hazardous by nationally and internationally recognized

organizations, such as the American Conference of Governmental Industrial Hygienists

(ACGIH) Threshold Limit Values (TLVs), National Institute for Occupational Safety and Health

(NIOSH) Recommended Exposure Limits (RELs), National Toxicology Program (NTP) Report

on Carcinogens (RoC), and International Agency for Research on Cancer (IARC). Appendix C

of this document contains a list of those materials regulated by OSHA as toxic and hazardous

substances. Appendix D of this document contains a list of OSHA-designated carcinogens.

The classifier must evaluate all the evidence and data available for the given chemical and use

the specific criteria spelled out for each health and physical hazard to classify the chemical in

appropriate hazard classes and categories. In some cases, available data provides enough

information to classify a chemical. In other cases, classification is determined on the basis of the

total weight of evidence using expert judgment. This means that all available information

bearing on the classification of the hazard must be considered together. In the case of health

hazards, for example, this includes the results of valid in vitro tests, relevant animal data, and

human experience, such as epidemiological and clinical studies, and well-documented case

reports and observations.

If OSHA has designated a chemical as a carcinogen, then the chemical must be classified as a

carcinogen. There are also organizations that evaluate chemicals for carcinogenicity. These

organizations, such as the International Agency for Research on Cancer (IARC) and the National

Toxicology Program (NTP), publish lists of hazardous chemicals that they have determined, with

varying degrees of certainty, to be carcinogens. OSHA has provided a crosswalk table to aid

classifiers in translating the classification from NTP or IARC into the HCS classification scheme

in Chapter VII.6 of this document. The discussion on carcinogens in this guidance provides

more detail on the classification of carcinogens.

The definition for hazardous chemical in the standard is thus very broad. The standard does not

require the testing of chemicals - only the collection and analysis of currently available data.

Nevertheless, if no data is available or it is questionable, testing should be considered when

hazardous properties are suspected.

Is Hazard Classification the Same for Mixtures as for

Individual Chemicals?

Generally speaking, the chemical and physical properties and hazards of pure elements and

chemical compounds are precise and constant. For example, benzene has explicit boiling and

flashpoints of 176 °F and 12 °F (at sea level), respectively. In contrast, the properties of the

complex mixture, Stoddard Solvent, can vary considerably depending on the manufacturer and

lot received, with ranges for boiling and flashpoints of 309-396 °F and 102-110 °F, respectively.

The process for evaluating mixtures may require steps in addition to those required for single

chemical agents. The HCS has designated specific classification requirements for mixtures,

which depend upon the availability of test data. Please see Chapter V, Data Analysis, for a

detailed discussion on classification of mixtures. In addition, the chapters for the individual

hazard classes discuss the specifics necessary for classification of mixtures.

What is Involved in Conducting a Hazard Classification?

All possible physical or health hazards that might be associated with a chemical’s use must be

considered. The hazard classification process consists of four main steps:

 Selection of chemicals to evaluate;

 Collection of data;

 Analysis of the collected data using the criteria provided in the HCS; and

 Documentation of the hazard classification process and the results obtained

The Hazard Communication Standard provides the specific criteria upon which the hazard

classification for a given chemical is based, ensuring that all those evaluating data and

performing hazard classification are following the same process, resulting in similar

classification conclusions. If no hazards are found, the manufacturer, importer, or employer is

not required to take further action pertaining to the evaluated chemical. Documentation of the

results of the analysis used in the classification process may be useful for future reference.

For many chemicals, hazard information has been compiled in readily available and reliable

sources (see Appendix B of this document). The specific classification criteria for each health or

physical hazard class identified in the HCS enables manufacturers, importers, and others

performing hazard classification to collect and evaluate the available data to determine if the

chemical is hazardous and identify the associated level of severity.

In some cases, a chemical may present a single hazard. In other cases, several hazards may be

associated with exposure to a chemical. The severity of the hazardous effect can range from

mild to severe. In the HCS, for example, identified health hazards for acetic acid, as normally

Note that documentation of the hazard classification process and the results obtained is not required by the HCS;

however OSHA recommends it. See Chapter VI, Recording the Rationale Behind the Results Obtained, of this

document.

used in industry, are skin irritation/corrosion and respiratory sensitization. In contrast, exposure

to lead may involve a multitude of hazards, including reproductive/developmental toxicity,

central nervous system effects, kidney effects, and acute toxicity effects.

Hazard evaluation is a process that relies heavily on the professional judgment of the evaluator,

particularly in the area of chronic health hazards. The specification approach of the HCS requires

the chemical manufacturer, importer or employer to conduct a thorough evaluation, examining the

full range of available data and producing a scientifically defensible evaluation of the chemical

hazards.

III. IDENTIFYING HAZARDOUS CHEMICALS

The ultimate goal in the hazard classification process is to know and document the hazards of all

covered chemicals you manufacture or import. In order to achieve this, you must first determine

which chemicals require a hazard classification. The logical way to do this is to first prepare an

inventory of all the chemicals you manufacture or import, as well as a list of the ingredients in

the mixtures produced. To create the list of ingredients from the mixtures produced, consider

information found in the chemical formula, on order receipts, batch sheets, and so on.

While a single SDS must be created for the mixtures produced, you may rely upon the

information provided on the SDSs and labels for ingredients obtained from the chemical

manufacturer or importer, unless you have reason to believe the information is incorrect.

However, you may choose to conduct a hazard classification for those ingredients if there is

concern about the adequacy of the hazard information received.

All employers are required to have a list of hazardous chemicals known to be present in the

workplace under 29 CFR 1910.1200(e)(1)(i). If a chemical inventory is not already in place, a

good start would be to review purchase orders and receipts to create an initial inventory. Next,

take time to inspect the workplace to identify any additional chemicals present. It would be ideal

to note the location and quantity of each chemical found. Chemical inventories are often

maintained as computer files for ease and efficiency in keeping them current. With knowledge

of the chemicals in your possession, you can use this information to perform hazard

classifications for chemicals that you manufacture or import.

On a related safety note, the chemical inventory or survey can also be used to decide which

chemicals to dispose of, as well as to identify potentially unsafe storage areas and techniques.

Some chemicals should not be stored near each other due to incompatibilities and potential

reactions.

IV. DATA COLLECTION

The second step in the hazard classification process is data collection. There are two main

questions to be answered: (1) what type of data should be searched for and collected; and (2)

how do I go about finding sources that might contain the desired data? You should recognize

that the hazard classification process involves the identification of all of the hazards associated

with a chemical, not just some of them. OSHA expects classifiers to use reasonable efforts in

their search for available data for all hazard classes (see Chapter V, Data Analysis), for a

discussion on the use of available data). Specific types of data used for classification of a given

hazard are discussed in the individual hazard chapters of this document. Any hazard that exists

for the chemical must be identified and communicated to downstream employers and workers.

To complete the hazard identification, information is needed in three categories:

 chemical identity;

 physical and chemical properties; and

 health effects.

There are numerous sources that could be searched for this information. A list of commonly

used data sources is provided in Appendix B of this document, although other sources exist and

new sources continue to appear online and in print. For new or less commonly used chemicals,

there may not be much data available from any of these sources. While the HCS does not

require testing, you may choose to test chemicals to determine chemical and physical properties

and identify hazards.

In the sections that follow, a discussion of data needs for the three categories of information is

provided. Also, a few recommended key references for the various types of data are listed.

Complete and reliable data must be entered on SDSs and labels to meet the HCS requirements.

Before the search for hazard data can begin, the exact chemical composition of the chemical(s)

or products manufactured or imported must be identified. This chemical search includes the

name of each chemical (whether it is a substance or a mixture), including active ingredients,

inactive ingredients, impurities, and stabilizing additives.

Chemical Identity

The specific chemical identity of all chemicals on your chemical inventory should be carefully

and completely compiled. The specific chemical identity includes:

 the chemical name along with common name and synonyms;

 the Chemical Abstracts Services (CAS) Registry Number (if available); and

 any other information that reveals the precise chemical designation and composition of

the substance, such as impurities and stabilizers.

Correct identification of chemicals is critical for data retrieval. Use the precise chemical name,

where available, and Chemical Abstract Service (CAS) number when searching for information. A

problem with the use of common names or abbreviations is that they may be used for more than

one molecular entity. To avoid confusion, literature is often indexed using the CAS number or the

primary chemical name. For example, TCE is commonly used as an acronym for trichloroethylene

(CAS 79-01-6), but sometimes this same acronym is used to

refer to tetrachloroethylene (CAS 127-18-4).

Additionally, the use of trade names could cause difficulty in

finding information. An example of the type of chemical

identification data that is needed is presented for Perclene®, a

widely used industrial solvent. Perclene® is a trade name for perchloroethylene or Perc

(common name), or more specifically tetrachloroethylene (CAS Number 127-18-4). Several

databases exist that can only be searched using the CAS number or chemical name. Thus, the

most effective search of computerized databases is conducted using both the precise chemical

name (tetrachloroethylene) and the CAS number (CAS Number 127-18-4). Searches using the

trade or common name(s) or abbreviation(s) may not return information for that chemical.

The percent composition (or exact percentage) should be available in-house for all chemicals

manufactured or imported. The chemical composition information may be based on an analysis

of the final or technical grade product or product formulation. A technical grade product is not

usually a pure substance and often contains other chemicals such as stabilizers, solvents, carriers,

“inert” ingredients, or impurities. For the purposes of hazard classification, these other

chemicals must also be considered since they may have their own unique hazards and may

contribute to the hazards of the chemical.

Thus, one of the initial steps is to collect as much data as possible pertaining to the physical and

chemical properties and toxicity data for chemicals on your chemical inventory.

Key sources of information related to chemical identification are:

 Company records;

 SDSs and product safety bulletins from manufacturers or suppliers;

 OSHA Chemical Sampling Information pages;

 The Merck Index;

 ChemID; and

 Trade associations.

CAS numbers are assigned

by the Chemical Abstract

Service of the American

Chemical Society.

Physical and Chemical Properties

The physical and chemical properties of a hazardous chemical are the empirical data of the

substance or mixture. That is, this data has been gathered from observation or by tests performed

on the chemical. For many hazardous chemicals, this data has been compiled and is readily

available.

Key sources of information related to physical and chemical properties include:

 Fire Protection Guide to Hazardous Materials;

 Department of Transportation Emergency Response Guidebook, most recent version

(phmsa.dot.gov/hazmat/library/erg);

 OSHA’s Occupational Chemical Database (www.osha.gov/chemicaldata);

 Hazardous Substances Data Bank (HSDB) (toxnet.nlm.nih.gov);

 Product safety bulletins from manufacturers or suppliers;

 National Institute for Occupational Safety and Health (NIOSH) documents

(www.cdc.gov/niosh/topics/chemical.html);

 NIOSH Pocket Guide to Chemical Hazards (www.cdc.gov/niosh/npg);

 International Chemical Safety Cards (www.cdc.gov/niosh/ipcs);

 OECD eChemPortal (www.oecd.org/env/ehs/risk-

assessment/echemportalglobalportaltoinformationonchemicalsubstances.htm);

 The Merck Index;

 CRC Handbook of Chemistry and Physics;

 Sax's Dangerous Properties of Industrial Materials, latest edition;

 Bretherick's Handbook of Reactive Chemicals Hazards, latest edition; and

 Trade associations.

The HCS includes classification criteria for 17 physical hazard classes (see Table II.2) and are

discussed in detail in Chapter VIII. These physical hazard classes should not be confused with

the physical and chemical properties of a chemical.

Health Effects

The HCS includes the classification criteria for 11 health hazard classes (see Table II.1) and are

discussed in detail in Chapter VII. In many cases, a chemical may pose more than one type of

health hazard. If your company is manufacturing a new chemical you may be required to submit

pre-manufacturing health effects data to the U.S. Environmental Protection Agency (EPA) to

comply with the Toxic Substances Control Act (TSCA). Data submitted to EPA by other

companies may be available to you by contacting EPA. This data may be used to assist with

hazard classification and the preparation of SDSs and labels. The company also should seek

toxicity data from the literature, government, or private sources. Some recommended reference

sources are listed below.

 Company-sponsored research, if available;

 SDSs and product safety bulletins from manufacturers, suppliers, or Internet sites;

 OSHA’s Occupational Chemical Database (www.osha.gov/chemicaldata);

 Hazardous Substances Data Bank (HSDB) (toxnet.nlm.nih.gov);

 National Institute of Occupational Safety and Health (NIOSH) documents

(www.cdc.gov/niosh/topics/chemical.html);

 NIOSH Pocket Guide to Chemical Hazards (www.cdc.gov/niosh/npg);

 Center for Disease Control’s (CDC) Agency for Toxic Substances and Disease Registry

(ATSDR), www.atsdr.cdc.gov/toxprofiles/index.asp

 International Chemical Safety Cards (www.cdc.gov/niosh/ipcs);

 NIOSH Registry of Toxic Effects of Chemical Substances (RTECS®)

(www.cdc.gov/niosh/rtecs/RTECSaccess.html);

 OSHA Chemical Sampling Information pages;

 IARC Monographs on the Evaluation of Carcinogenic Risks to Humans

(monographs.iarc.fr);

 NTP Annual Report on Carcinogens (ntp.niehs.nih.gov/pubhealth/roc );

 TLVs and BEIs (ACGIH) (www.acgih.org/tlv-bei-guidelines/policies-procedures-

presentations/overview);

 OECD eChemPortal (www.oecd.org/env/ehs/risk-

assessment/echemportalglobalportaltoinformationonchemicalsubstances.htm);

 Hawley's Condensed Chemical Dictionary, latest edition;

 Sax's Dangerous Properties of Industrial Materials, latest edition;

 Published literature; and

 Trade associations.

V. DATA ANALYSIS

The third step in the hazard classification process is data analysis. This step is the most

demanding in terms of technical expertise. The HCS requires that chemical manufacturers and

importers conduct a hazard classification to determine whether physical hazards or health

hazards exist.

For both health and physical hazards, explicit classification criteria are provided in the HCS. For

example, criteria are given for classifying a chemical as a flammable liquid, an organic peroxide,

and for designating a chemical as acutely toxic or a carcinogen.

In some cases, the HCS establishes the criteria to be followed. For example, if a liquid has a

flashpoint of less than or equal to 93°C (199.4°F), it is by definition a “flammable liquid.” To

determine into what category of flammable liquid the chemical is classified, you also will need to

identify its initial boiling point. This involves a simple data analysis. You can rely on the

flashpoint and boiling point listed in a standard reference. In the event that your company is

manufacturing or importing a chemical for which there is no information on the flashpoint and

boiling point, you may choose to determine the flashpoint by laboratory testing. See Use of

available data, test methods and test data quality below for a more detailed discussion.

The following discusses the general considerations for analyzing data to complete the

classification process as defined in the Hazard Communication Standard.

Hazard Classification

In the Hazard Communication Standard, the term “hazard classification” is used to indicate that

only the intrinsic hazardous properties of chemicals are considered. Hazard classification

incorporates three steps:

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

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

chemical;

c) Determination of whether the chemical should be classified as hazardous and the

degree of hazard, where applicable.

For many hazard classes, the criteria are semi-quantitative or qualitative and expert judgment is

required to interpret the data for classification purposes.

Use of available data, test methods and test data quality

The criteria for determining health hazards are test-method neutral. That is, they do not specify

particular test methods, as long as the methods are scientifically validated. The term

“scientifically validated” refers to the process by which the reliability and the relevance of a

procedure are established for a particular purpose. Any test that determines hazardous

properties, which is conducted according to recognized scientific principles, can be used for

purposes of a hazard determination for health hazards. Test conditions need to be standardized

so that the results are reproducible for a given chemical, and the standardized test yields “valid”

data for defining the hazard class of concern. OSHA allows the use of existing test data for

classifying chemicals, although expert judgment also may be needed for classification purposes.

The effect of a chemical on biological systems is influenced by the physical and chemical

properties of the substance and/or ingredients of the mixture and the way in which ingredient

substances are biologically available. A chemical need not be classified when it can be shown

by conclusive experimental data from scientifically validated test methods that the chemical is

not biologically available.

For classification purposes, epidemiological data and experience on the effects of chemicals on

humans (e.g., occupational data, data from accident databases) must be considered in the

evaluation of the chemical’s human health hazards.

Testing is not required by the HCS. Therefore, if existing data is not available, you have the

option to state this on the safety data sheet. However, if you decide to test the chemical, use the

test methods specified in the appropriate health or physical hazard appendices to the HCS to

gather the data (see the Classification Procedure and Guidance section for each health hazard

class and for each physical hazard class of this guidance, and Appendix A and Appendix B to 29

CFR 1910.1200). Appropriate test methods for each physical hazard class are identified in the

standard and discussed in each physical hazard section of this guidance.

Classification based on weight of evidence (WoE)

For some hazard classes, classification results directly when the data satisfy the criteria. This is

the case for most physical hazard classes. For others, classification of a chemical may be

determined on the basis of the total weight of evidence using expert judgment. Under the GHS,

weight of evidence (WoE) means that all available information bearing on the classification of a

hazard is considered together, including the results of valid in vitro tests, relevant animal data,

and human experience, such as epidemiological and clinical studies and well-documented case

reports and observations. There are several reasons to utilize a WoE approach. First, WoE

makes use of all available information. This is important especially when there is conflicting

information between studies. Second, less reliable studies can be pooled to draw a conclusion on

the relevant endpoint. Finally, WoE allows for use of different but adequate information that is

available (e.g., data on other species, or routes of exposure).

As human experience can also provide information on the hazards of a chemical, occupational data and data from

accident databases are examples of where you can get such information.

OSHA has provided general criteria on how to perform an analysis based on weight of evidence

in Appendix A.0.3 to 29 CFR 1910.1200, as well as specific criteria in the individual health

chapters where weight of evidence is used (skin corrosion/irritation, serious eye damage/eye

irritation, respirator or skin sensitization, germ cell mutagenicity, carcinogenicity, reproductive

toxicity, specific target organ toxicity - single exposure (STOT-SE), and STOT-repeated or

prolonged exposure). See Appendices A.2-A.9 to 29 CFR 1910.1200.

When performing a WoE assessment to determine the classification of a chemical, the classifier

must determine which data or study results have the most utility and validity to support the

resulting hazard classification of the chemical. These considerations include four basic elements:

data adequacy, data reliability, data relevance, and quantity of evidence. It is also necessary to

understand how to apply this information to the data in order to make hazard classification

decisions. Information on chemicals related to the material being classified must also be

considered, as appropriate, along with site of action and mechanism or mode of action study

results. In addition, both positive and negative results must be considered together in a single

weight-of-evidence determination.

Most toxicity and epidemiology reports provide an analysis of the data and conclude whether the

results were positive or negative, or describe the adverse effects observed at specific dose levels.

Positive results mean that the exposed humans or animals were more likely to develop toxic

effects than the non-exposed population.

Positive effects which are consistent with the criteria for classification, whether seen in humans

or animals, normally justify classification. Where evidence is available from both humans and

animals and there is a conflict between the findings, the quality and reliability of the evidence

from both sources must be evaluated in order to resolve the question of classification. Reliable,

good quality human data generally has precedence over other data. However, even well-

designed and conducted epidemiological studies may lack a sufficient number of subjects to

detect relatively rare but still significant effects, or to assess potentially confounding factors.

Therefore, positive results from well-conducted animal studies are not necessarily negated by the

lack of positive human experience, but require an assessment of the robustness, quality and

statistical power of both the human and animal data.

Route of exposure, mechanistic information, and metabolism studies are used in determining the

relevance of a health effect in humans. When such information raises doubt about relevance in

humans, a lower classification may be warranted. When there is scientific evidence

demonstrating that the mechanism or mode of action is not relevant to humans, the data may not

justify classification.

Both positive and negative results are considered together in the weight of evidence

determination. However, a single positive study performed according to established scientific

principles and with statistically and biologically significant positive results may justify

classification.

Statistical significance is a mathematical determination of the confidence in the outcome of a

test. The usual criterion for establishing statistical significance is the p-value (probability value).

A statistically significant difference in results is generally indicated by p<0.05, meaning there is

less than a 5% probability that the toxic effects observed were due to chance and were not caused

by the chemical. Another way of looking at it is that there is a 95% probability that the effect is

real, i.e., the effect seen was the result of the chemical exposure.

The other major measure of statistical significance is the 95% confidence level for a specific data

point. Most reports of toxicity testing will include some information on the confidence in the

data. For example, a study with a stated confidence level of 95% and an LD

with a listed

value of 9.5 ± 1.2 indicates that if the same study were to be repeated many times, the LD

would be expected to be within the range of 8.3 - 10.7 on 95 out of every 100 times.

Hazard evaluation relies on professional judgment, particularly in the area of chronic hazards.

The specific and detailed orientation of the HCS does not diminish the duty of the chemical

manufacturer, importer or employer to conduct a thorough evaluation, examining all relevant

data and producing a scientifically defensible classification.

Considerations for the classification of mixtures

Classification of mixtures is based on the following sequence for most hazard classes:

1. If the mixture has been tested as a whole and test data are available for the complete

mixture, these results are used to classify the mixture.

2. If a mixture has not been tested as a whole or test data are not available for the

complete mixture, the bridging principles designated in each health hazard chapter of

Appendix A of the Hazard Communication Standard are used to classify the mixture.

3. If test data are not available for the mixture itself, and the available information is

not sufficient to allow application of the above-mentioned bridging principles, then the

method(s) described in each chapter for estimating the hazards based on the information

known will be applied to classify the mixture (e.g., application of cut-off values/

concentration limits).

An exception to the above order of precedence is made for Carcinogenicity, Germ Cell

Mutagenicity, and Reproductive Toxicity (CMR). For these three hazard classes, mixtures are

classified based upon information on the ingredient substances, unless on a case-by-case basis,

justification can be provided for classifying based upon the mixture as a whole. Mixture rules

for these three hazard classes are presented in Chapters VII.5, VII.6, and VII.7 of this document.

See also chapters A.5, A.6, and A.7 in the Hazard Communication Standard for further

information.

(Lethal Dose 50) is the amount of a chemical, given all at once, which causes the death of 50% (one half) of a

group of test animals.

Bridging principles for the classification of mixtures where test data

are not available for the complete mixture

Where the mixture itself has not been tested to determine its toxicity, but there are sufficient data on

both the individual ingredients and similar tested mixtures to adequately characterize the

hazards of the mixture, the following bridging principles are used, subject to any specific provisions

for mixtures for each hazard class. These principles ensure that the classification process uses the

available data to the greatest extent possible in characterizing the hazards of the mixture.

Dilution

For mixtures classified in accordance with all the health hazard classes of the HCS (see

Appendices A.1 through A.10 to 29 CFR 1910.1200), if a tested mixture is diluted with a diluent

that has an equivalent or lower toxicity classification than the least toxic original ingredient, and

which is not expected to affect the toxicity of other ingredients, then:

(a) The new diluted mixture is classified as equivalent to the original tested mixture; or

(b) For classification of acute toxicity, the additivity formula must be applied (see

A.1.3.6 in Appendix A to 29 CFR 1910.1200).

Batching

The toxicity of a tested production batch of a mixture can be assumed to be substantially

equivalent to that of another untested production batch of the same mixture, when produced by

or under the control of the same chemical manufacturer, unless there is reason to believe there

is significant variation such that the toxicity of the untested batch has changed. If the latter

occurs, a new classification is necessary. The batching approach is used for mixtures classified

in accordance with all the health hazard classes of the HCS (see Appendices A.1 through A.10 to

29 CFR 1910.1200).

Concentration of mixtures

The concentration of ingredients may be used to classify mixtures for the following hazard

classes: acute toxicity, skin corrosion/irritation, serious eye damage/eye irritation, specific target

organ toxicity - single exposure (STOT-SE), STOT-repeated or prolonged exposure, or

aspiration (see Appendices A.1, A.2, A.3, A.8, A.9, or A.10 to 29 CFR 1910.1200). In these

cases, if a tested mixture is classified in Category 1, and the concentration of the ingredients of

the tested mixture that are in Category 1 is increased, the resulting untested mixture is classified

in Category 1.

Interpolation within one toxicity category

For three mixtures (A, B and C) with identical ingredients, where mixtures A and B have been

tested and are in the same toxicity category, and where untested mixture C has the same

toxicologically active ingredients as mixtures A and B but has concentrations of toxicologically

active ingredients intermediate to the concentrations in mixtures A and B, then mixture C is

assumed to be in the same toxicity category as A and B. This approach to interpolating data

within one toxicity category is used for mixtures classified in accordance with the classification

criteria for the following hazard classes in the HCS: acute toxicity, skin corrosion/irritation,

serious eye damage/eye irritation, specific target organ toxicity - single exposure (STOT-SE),

STOT-repeated or prolonged exposure, or aspiration (see Appendices A.1, A.2, A.3, A.8, A.9, or

A.10 to 29 CFR 1910.1200).

Substantially similar mixtures

For mixtures classified in accordance with all health hazard categories of the HCS (see

Appendices A.1 through A.10 to 29 CFR 1910.1200), given the following set of conditions:

(a) Where there are two mixtures:

(i) A + B;

(ii) C + B;

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

mixture (ii);

(d) And data on toxicity for A and C are available and substantially equivalent; i.e.,

they are in the same hazard category and are not expected to affect the toxicity of

B; then

If mixture (i) or (ii) is already classified based on test data, the other mixture can be assigned the

same hazard category.

Aerosols

For mixtures classified in accordance with the classification criteria for acute toxicity, skin

corrosion/irritation, serious eye damage/eye irritation, respiratory or skin sensitization, specific

target organ toxicity - single exposure (STOT-SE), or STOT-repeated or prolonged exposure

(see Appendices A.1, A.2, A.3, A.4, A.8, or A.9 to 29 CFR 1910.1200), an aerosol form of a

mixture is classified in the same hazard category as the tested, non-aerosolized form of the

mixture, provided the added propellant does not affect the toxicity of the mixture when spraying.

Use of cut-off values/concentration limits

When classifying an untested mixture based on the hazards of its ingredients, cut-off

values/concentration limits

for the classified ingredients of the mixture are used for several

hazard classes. While the adopted cut-off values/concentration limits adequately identify the

hazard for most mixtures, there may be some that contain hazardous ingredients at lower

concentrations than the specified cut-off values/concentration limits that still pose an identifiable

hazard. There may also be cases where the cut-off value/concentration limit is considerably

lower than the established non-hazardous level for an ingredient.

For the purposes of the HCS, the terms “cut-off values” and “concentration limits” mean the same thing.

If the chemical manufacturer, importer or other hazard classifier has information that the hazard

of an ingredient will be evident (i.e., it presents a health risk) below the specified cut-off

value/concentration limit, the mixture containing that ingredient must be classified accordingly.

In exceptional cases, conclusive data may demonstrate that the hazard of an ingredient will not

be evident (i.e., it does not present a health risk) when present at a level above the specified cut-

off value/concentration limit(s). In these cases the mixture may be classified according to those

data. The data must exclude the possibility that the ingredient will behave in the mixture in a

manner that would increase the hazard over that of the pure substance. Furthermore, the mixture

must not contain ingredients that would affect that determination.

The HCS has established specific cut-off values for different health hazards. Table V.1 presents

these cut-off values. When a substance in a specified hazard class is present in a mixture at or

above the cut-off level, the mixture must be classified in that hazard class.

Table V.1. Cut-off Values for Health Hazards

Hazard class

Label Cut-Off

Values

SDS Cut-Off

Values

Respiratory/Skin sensitization

 0.1%

Germ cell mutagenicity (Category 1)

 0.1%

Germ cell mutagenicity (Category 2)

 1.0%

Carcinogenicity

 0.1%

Reproductive toxicity

 0.1%

Specific target organ toxicity (single exposure)

 1.0%

Specific target organ toxicity (repeated exposure)

 1.0%

Specific target organ toxicity Category 3

≥20%

Synergistic or antagonistic effects

When performing an assessment in accordance with the requirements of the Hazard

Communication Standard, the evaluator must take into account all available information about

the potential occurrence of synergistic effects among the ingredients of the mixture. Lowering

the classification of a mixture to a less hazardous category on the basis of antagonistic effects

may be done only if the determination is supported by sufficient data.

Synergistic effects result when the overall effect of the ingredients is greater than the sum of any

of the individual effects, while antagonistic effects result from the contrasting actions or negative

effect from two (or more) ingredients, so that the overall effect is less than the sum of any of the

individual effects.

Hazard Classification of Petroleum Streams

To classify the health hazards of petroleum streams, follow the guidance presented below in

conjunction with the general guidance found in Appendix A.0.1-A.0.3 to 29 CFR 1910.1200, and

the classification criteria provided for the health hazards presented in Appendix A to 29 CFR

1910.1200.

1. For hazard classes other than carcinogenicity, germ cell mutagenicity, and reproductive

toxicity (“CMR”), classify a petroleum stream as follows:

a) Where test data are available for the petroleum stream, the classification of the stream

will always be based on those data.

b) Where test data are not available for the stream itself, the classification may be based on

a toxicologically appropriate read across from test results of a substantially similar

stream. A substantially similar stream is one that has a similar starting material,

production process, and range of physico-chemical properties (e.g., boiling point and

carbon number) and similar constituent compositions.

c) If test data are not available either for the stream itself or a substantially similar stream,

then apply the method(s) described in each chapter of Appendix A to 29 CFR 1910.1200

for estimating the hazards based on the information known to classify the stream (i.e.,

application of cut-off values/concentration limits).

2. For the CMR hazard classes:

a) When reliable and good quality data are available to classify a petroleum stream, based

on testing of the stream or the toxicologically appropriate read-across to a substantially

similar stream, a weight of evidence analysis supported by that data may be relied upon

for classification regardless of whether a CMR constituent is present in the stream. A

substantially similar stream is one that has a similar starting material, production process,

and range of physico-chemical properties (e.g., boiling point and carbon number) and

similar constituent compositions.

b) To be reliable and good quality test data, the data must be from one or more tests that

reflect appropriate study design and performance. The study or studies must appropriately

take into account dose and other factors such as duration, observations, and analysis (e.g.,

statistical analysis, test sensitivity) so as to conclusively exclude the possibility that the

lack of effect(s) is due to a poor study design, e.g., insufficient dose or number of

subjects. A study (or studies) is conclusive in this sense if, when viewed in conjunction

with all relevant information about the chemical, its results are consistent with the

relevant information and allow a strong inference that the lack of effects is not due to a

poor study design.

c) Where reliable and good quality data are not available on the stream or a substantially

similar stream, then apply the method(s) described in each chapter of Appendix A of 29

CFR 1910.1200 for estimating the hazards based on the information known to classify the

stream (i.e., application of cut-off values/concentration limits).

Interface Between the HCS and U.S. Department of Transportation

(DOT) labeling

As mentioned earlier, the purpose of the HCS is to ensure that the hazards of all chemicals

produced or imported are classified, and that information concerning the hazards is transmitted to

employers and workers. This information is transmitted by means of a comprehensive hazard

communication program, which includes container labeling and other forms of warning, safety

data sheets, and worker training.

With the alignment of the HCS to the GHS, one will find that there is generally a correlation

between the DOT packing group and the HCS physical hazard class category. If the chemical

being classified is the same chemical that has previously undergone classification to meet DOT’s

Hazardous Materials Regulations, you may use this data to classify the physical hazards of the

chemical to meet the requirements of OSHA’s Hazard Communication Standard. You may find

the information contained in DOT’s Hazardous Materials Regulations is another useful

reference, in particular the Hazardous Materials Table, located in 49 CFR 172.101.

DOT labeling (referred to as placarding) applies to chemicals that are transported by means of

rail car, aircraft, motor vehicle, and vessel. These placards must follow certain size and color

requirements. The labels for the transport of dangerous goods are those prescribed by DOT’s

Hazardous Materials Regulations (49 CFR Parts 100-185). The classification criteria and testing

procedures found in the DOT Hazardous Materials Regulations are aligned with the UN

Recommendations on the Transport of Dangerous Goods – Model Regulations.

VI. RECORDING THE RATIONALE BEHIND THE

RESULTS OBTAINED

The fourth and final step in the hazard classification process is also important. All the other

steps will be wasted if findings are not recorded carefully. If a chemical is found to be

hazardous, OSHA recommends that the findings and the rationale used to arrive at these findings

be documented.

The HCS no longer requires documentation of the procedures used to determine the hazards of a

chemical since this is now provided through the classification procedures specified in

Appendices A and B of the HCS, and all those performing hazard classification must follow the

same process. However, OSHA still recommends the data, the rationale used, and other results

gathered during the classification process be maintained for future reference and use.

To assist in this, OSHA recommends that a structured approach to data retrieval and compilation

be adopted. This structured approach also applies to the preparation of SDSs and labels. If you

decide to take such an approach, this section provides some guidelines you may wish to consider.

Compilations of three types of data are considered essential:

 Initial chemical inventory;

 Specific data retrieved for each chemical; and

 List of hazardous chemicals.

Chemical Inventory

The chemical inventory

should consist of all chemicals that are imported or produced by the

company, and those chemicals that are ingredients used in a mixture produced by the company.

Classifiers may find it helpful if the chemical inventory includes the following information for

future reference:

 chemical name;

 CAS Number;

 common name;

 synonyms;

 product/mixture name (if applicable); and

 percentage of ingredients in product/mixture (if applicable).

The chemical inventory is different than the list of hazardous chemicals required under paragraph (e) of the HCS

(29 CFR 1910.1200). The chemicals listed on the chemical inventory would be required to appear on the list of

hazardous chemicals required under paragraph (e) of the HCS if they are present in the workplace.

As discussed in Chapter III, Identifying Hazardous Chemicals, it is recommended that this

chemical inventory be computerized for future sorting, additions, deletions, and status reports.

Specific Data Retrieved for Each Chemical

OSHA recommends that the data retrieved be organized to facilitate the preparation of SDSs and

labels. Listing all the hazard classes and categories, and the relevant data obtained for each

hazard will also facilitate the gathering of data to document the effectiveness and completeness

of the classification process. When data are not located for a specific type of hazard or when a

specific hazard would not occur due to the chemical or physical form of the chemical, this should

be indicated.

The data retrieved should be listed in the basic format of the SDS to facilitate preparation of

SDSs and labels, as well as to allow for future updating as the need arises. As you would expect,

OSHA recommends that the data be computerized and archived in a secure location for future

use. A commonly used phrase for hazard data compilations for specific chemicals is hazards

profile. A suggested organization for the documentation is provided in Table VI.1.

Table VI.1. LIST OF DATA RECOMMENDED FOR INCLUSION IN THE HAZARDS

PROFILE FOR A CHEMICAL

(Reference source should be included for each item, where appropriate. In the event that no

information on an item is known or it is not applicable, this should be so indicated.)

TYPE OF INFORMATION

DATA

category

ATE

mix

to decision

logic #1

ATE

mix

to decision

logic #1

Yes

Acute Toxicity Classification Examples

The following examples are provided to demonstrate the acute toxicity calculation and

classification process.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Acute Toxicity - Corrosive Substance

Test Data

HCS 2012

Classification

Rationale

Toxicity data:

In a GLP-compliant acute toxicity

study in rats the following results

were observed:

At a test dose of 200 mg/kg bw:

no mortality, only transient

symptoms and no necropsy

findings

At a test dose of 500 mg/kg:

100% mortality, symptoms: poor

general state; necropsy findings:

hyperemia in stomach (due to

local irritation/corrosivity), no

other organs affected

Acute Toxicity

Oral Category 4

Since at a dose of 200 mg/kg bw no

mortality and only slight transient

symptoms without necropsy findings

were observed, and at 500 mg/kg bw

the high amount/concentration of the

corrosive substance caused serious

effect only at the site of action and

mortality, based on expert judgment

it can be assumed that the likely

is > 300 mg/kg bw. Therefore,

the Acute Toxicity Estimate (ATE)

value for classification purpose is

between 300 and 500 mg/kg bw,

corresponding to Category 4

classification for acute toxicity.

Substance Example #2

Acute Toxicity Use of Human Data

Test Data

HCS 2012

Classification

Rationale

Toxicity Data:

Animal test data: LD

(rat) >

5,000 mg/kg bw (several values)

Human experience: lethal in

relatively low dose range (ca.

300-1,000 mg/kg)

Acute Toxicity

Oral Category 3

Valid human data from a large data

base (case studies) have precedence

over animal data; the rat in this case

is not the appropriate test species.

Substance Example #3

Acute Toxicity - Dermal

Test Data

HCS 2012

Classification

Rationale

Toxicity Data:

Aromatic Amine

Animal test data: LD

(rat) >

2,000 mg/kg bw

Human experience: many lethal

intoxications at relatively low

doses after dermal exposure (dose

range of 200 to 1000 mg/kg bw)

Acute Toxicity

Dermal Category 3

Human experience (valid) has

precedence over experimental data;

the rat is not an appropriate species

for this substance class.

Substance Example #4

Acute Toxicity - Dermal

Test Data

HCS 2012

Classification

Rationale

Animal data:

A study to evaluate the acute

dermal toxicity was performed in

rabbits. The following test data

results were reported:

- At the dose level of 50 mg/kg

bw: no mortality was observed

- At 200 mg/kg bw: 100%

mortality

Therefore, LD

was estimated to

be between 50 mg/kg bw and 200

mg/kg bw

Acute Toxicity

Dermal Category 2

Since the dermal LD

is above 50

mg/kg bw and less than 200 mg/kg

bw, Category 2 classification is

warranted.

Substance Example #5

Acute Toxicity – Inhalation/dust

Test Data

HCS 2012

Classification

Rationale

Toxicity Data:

The acute inhalation toxicity was

studied in rats in a GLP-

compliant study performed

according to OECD test guideline

403. The LC

(1-hr.) = 3 mg/l.

Acute Toxicity

Inhalation

Category 3

The classification criteria for acute

inhalation toxicity refer to a 4-hour

exposure time. Therefore to classify

a substance, existing inhalation

toxicity data generated from 1-hour

exposure should be converted

accordingly: LC

values with 1hour

have to be converted by dividing by

The LC

(4-hr.) = 0.75 mg/l which

is Category 3.

Substance Example #6

Acute Toxicity – Inhalation/gas

Test Data

HCS 2012

Classification

Rationale

Animal data:

A GLP-compliant test for acute

inhalation toxicity (gaseous form)

was performed in accordance

with OECD test guideline 403 in

rats. The LC

was 4500 ppm/4h.

Acute Toxicity

Inhalation

Category 4

= 4500 ppm is considered an

Acute Toxicity Estimate (ATE) for

classification purposes. According to

the classification criteria for acute

inhalation toxicity for gases, this

value corresponds to Category 4.

Substance Example #7

Acute Toxicity – Oral

Test Data

HCS 2012

Classification

Rationale

Oral LD

: 300 mg/kg bw

(observed in a GLP-compliant

study in rats)

Acute Toxicity

Oral Category 3

= 300 mg/kg bw is considered

an Acute Toxicity Estimate (ATE)

for classification purposes;

according to the classification

criteria for acute oral toxicity, 300

mg/kg bw is the upper value for

Category 3. Therefore, it is assigned

Category 3 Acute Oral Toxicity

classification.

Examples of substances not fulfilling the criteria for classification:

Substance Example #8

Acute Toxicity – Inhalation/Vapors

Test Data

HCS 2012

Classification

Rationale

Toxicity Data:

Three values for acute inhalation

toxicity of TS10 (vapor form) in

rats were described. Two studies

were performed in accordance

with OECD test guideline 403.

One study was determined not to

be scientifically valid. The LC

values were reported as follows:

LC 50 (4-h): 19 mg/l (not

scientifically valid)

LC 50 (4-h): 23 mg/l (TG 403)

LC 50 (4-h): 28 mg/l (TG 403)

HCS- No Acute

Toxicity

Classification

With 3 different available LC

values, a validity check proved that

the 1

study with 19 mg/l is not

scientifically valid in contrast to the

two others; thus, with an ATE> 20

mg/l the criteria for Category 4 are

not fulfilled.

Substance Example #9

Acute Toxicity – Oral

Test Data

HCS 2012

Classification

Rationale

Tested in rats in accordance with

OECD Test Guideline 423. In a

limit test at a value of 2000 mg/kg

bw no mortality or signs of

toxicity were observed.

No Acute Toxicity

classification

There was no mortality nor signs of

toxic effects at the outer limit of

category 4. Therefore there is no

acute toxicity classification.

Substance Example #10

Acute Toxicity – Oral

Test Data

HCS 2012

Classification

Rationale

Oral LD

> 2,000 mg/kg (no

further details available)

Further information from SDS:

NOAEL (No Adverse Effect

Level) in a 90 day oral study >

3,000 mg/kg bw

No Acute Toxicity

classification

Does not fulfill criteria for

classification:

 Oral LD

> 2,000 mg/kg

 At 3,000 mg/kg after daily

administration (90 times) of

3,000 mg/kg no adverse health

effects (i.e., no toxicity) were

observed.

Example of a mixture fulfilling the criteria for classification

Mixture Example #1

Acute Toxicity – Dermal

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 5%, Dermal LD

= 40 mg/kg

Component 2: 44%, Dermal LD

> 200 < 1,000

Component 3: 48%, Dermal LD

= 90 mg/kg

Component 4: 3%, Acute Dermal

Toxicity Category 4

Acute Toxicity

Dermal Category 2

The LD

data for Components 1 and

3 are used in the ATE

mixture

calculation since data are available.

For Components 1 and 2, apply the

guidance in Note (b) to Table A.1.1:

 The Dermal LD

> 200 < 1,000

range estimate for Component 2

is converted to the acute toxicity

point estimate of 300 mg/kg

using Table A.1.2. of the HCS.

 The classification category for

Component 4 is converted to the

acute toxicity point estimate of

1,100 using Table A.1.2.





mixture

ATEi

ATE

100

100,1

300

5100



mixture

ATE

Dermal ATE

mixture

= 123 mg/kg,

Category 2

Mixture Example #2

Acute Toxicity – Oral

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 16%, oral LD

1,600 mg/kg

Component 2: 4%, oral LD

200 < 2,000

Component 3: 80%, oral LD

3,450 mg/kg

Acute Oral

Toxicity

Category 4

Per A.1.3.6.1 (a) include ingredients

with a known acute toxicity, which

fall into any of the acute toxicity

categories, or have an oral LD

2000 ≤5000 mg/kg body weight.

The LD

data for Components 1 and

3 are used in the ATE

mixture

calculation since data are available.

For Component 2, apply the

guidance in Note (b) to Table A.1.1:

The use of expert judgment is needed

to determine what value to use in the

ATE

mixture

calculation for Component

2. The oral LD

> 200 < 2,000

range for Component 2 does not

match up with the ranges provided in

Table A.1.2. The lower end of the

range falls within the Category 3

range of 50 – 300 mg/kg and the

converted acute toxicity point

estimate for an Oral Category 3

ingredient is 100. Given that the

converted point estimate is lower

than the experimentally determined

value of > 200 mg/kg it does not

make sense to use the converted

point estimate. In this case, one

should apply the known information,

and 200 mg/kg should be used in the

ATE

mixture

calculation.





mixture

ATEi

ATE

100

Oral ATE

mixture

= 1,880 mg/kg,

Category 4

450,3

200

600,1

16100



mixture

ATE

Mixture Example #3

Acute Toxicity – Oral

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 4%, oral LD

= 125

mg/kg

Component 2: 92%, No data

available

Component 3: 3%, oral LD

1500 mg/kg

Component 4: 0.9%, No data

available

Component 5: 0.1%, oral LD50 =

10 mg/kg, Oral Category 2

Acute Oral Toxicity

Category 3

Components 1 and 3 are included in

the ATE

mixture

calculation because they

have data that fall within an acute

toxicity category.

The total concentration of relevant

ingredients with unknown acute

toxicity (i.e., Component 2) is 92%.

Therefore, the ATE

mixture

equation that

corrects for ingredients with unknown

acute toxicity above 10% of the

mixture must be used.

Component 2 does not have any

useable information for the oral route

ATE

mixture

calculation and is in the

mixture at a concentration  1% so an

additional statement is included on the

label and SDS.

The “relevant ingredients” concept

means that Component 4 could be

excluded from both the ATE

mixture

calculations. This same reasoning

could also apply to Component 5, as it

is below the “relevant ingredients”

threshold; however, the use of expert

judgment is necessary to make this

decision for Component 5 as it is

classified in Category 2. For this

example, since the percentage of this

ingredient is well below the 1%

threshold (i.e., 0.1%) and the

ingredient is classified in Category 2

rather than Category 1, it may be

excluded from the ATE calculation.

ATE

mixture

= 235 mg/kg, Category 3

“92% of the mixture consists of an

ingredient of unknown acute oral

toxicity.”

 







mixture

unknown

ATE

ifC %10100

1500

125

4)92(100





mixture

ATE

Mixture Example #4

Acute Toxicity – Multiple Routes

Components

Wt%

Acute toxicity test data

Oral

Dermal

Inhalation

Vapors

Component 1

: 2,737

mg/kg

: 6,480 mg/kg

: 11 mg/l

Component 2

: 4,500

mg/kg

:> 6,000 mg/kg

: 19 mg/l

Component 3

50:

5,000 mg/kg

No data available

No data

available

Component 4

: 400

mg/kg

Dermal limit dose > 2,000

mg/kg (No signs of toxicity)

: 4 mg/l

Oral route





mixture

ATEi

ATE

100

400

4,500

2,737

ATE

100

mixture



ATE

mixture

= 873 mg/kg, Acute Oral Toxicity Category 4

Inhalation route

 







mixture

unknown

ATE

10%if C100

ATE

)11(100

mixture





ATE

mixture

= 6.6 mg/l, Acute inhalation toxicity Category 3 and “11% of the

mixture consists of an ingredient of unknown acute inhalation toxicity”

HCS 2012 Classification

Rationale

Acute Oral Toxicity

Category 4

Acute Inhalation Toxicity

Category 3

Review of the component test data show there is relevant

evidence to suggest acute toxicity via the oral and inhalation

routes so the ATE

mixture

calculation was applied to the oral and

inhalation routes

Oral route

 Data is available for all ingredients via the oral route

 Components 1 and 4 are included in the ATE

mixture

calculation because they have data that fall within an acute

toxicity category

 Component 2: per A.1.3.6.1(a) include ingredients with a

known acute toxicity, which fall into any of the acute

toxicity categories, or have an oral LD

> 2000 ≤5000

mg/kg body weight.

 Component 3 is excluded because it does not fall within

acute toxicity categories 1-4 and its LD

> 5000 mg/kg.

 Apply the guidance in Note (a) to Table A.1.1 for

Components 1, 2 and 4 in the ATE

mixture

calculation since

data is available.

Inhalation route

 The total concentration of ingredients with unknown

inhalation acute toxicity (i.e., Component 3) is 11%.

Therefore, the ATE

mixture

equation that corrects for

ingredients with unknown acute toxicity above 10% of

the mixture must be used for the inhalation route.

 Components 1, 2 and 4 are included in the ATE

mixture

calculation because they have data that fall within an

acute toxicity category.

 Apply the guidance in Note (a) to Table A.1.1 for

Components 1, 2 and 4 in the ATE

mixture

calculation since

data is available.

 Component 3 does not have any useable information for

the inhalation route ATE

mixture

calculation and is in the

mixture at a concentration  1% so an additional

statement is included.

Dermal route

None of the ingredient test data for the dermal route show a

< 5000 mg/kg bodyweight and so a dermal ATE

mixture

calculation was not performed. See A.1.3.6.1(a).

References

29 CFR 1910.1200, Hazard Communication, Appendix A.1 Acute Toxicity.

29 CFR 1910.1200, Hazard Communication. Appendix C, Allocation of Label Elements.

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

The Organization for Economic Co-operation and Development (OECD) Guidelines for the

Testing of Chemicals.

United States Environmental Protection Agency (EPA) Office of Prevention, Pesticides, and

Toxic Substances (OPPTS) Health Effects Test Guidelines.

VII.2 Skin Corrosion/Irritation

Introduction

Changes at the site of first contact (e.g., skin, eye) can be caused regardless of whether a

chemical can become systemically available. These changes are considered local effects.

Chemicals causing local effects after a single exposure can be further distinguished as irritant or

corrosive chemicals, depending on the reversibility of the effects observed.

Corrosive chemicals are those which can destroy living tissues with which they come into

contact. In toxicology, the term ”corrosive” normally means causing visible destruction of the

skin, eyes, or the lining of the respiratory tract or the gastrointestinal tract on contact. Corrosion

is manifested by ulcers, cell death, and scar formation. Generally speaking, corrosive materials

have a very low pH (acids) or a very high pH (bases). Strong bases are usually more corrosive

than acids. Examples of corrosive materials are sodium hydroxide (lye) and sulfuric acid.

Irritant chemicals are non-corrosive chemicals which, through immediate contact with the

tissue under consideration, may cause inflammation. Dermal irritation is a skin reaction resulting

from a single or multiple exposures to a physical or chemical entity at the same site,

characterized by the presence of inflammation.

The difference between an irritant and a corrosive is the ability of the body to repair the tissue

reaction. With irritants, the inflammatory reaction can be reversed, whereas with corrosive

damage it is permanent and irreparable.

Appendix A.2 of the HCS addresses the classification of those chemicals which present a

corrosion or irritation hazard to the skin.

General Considerations

Classification for skin corrosion/irritation should be conducted using a tiered weight-of-evidence

approach. In the tiered approach, emphasis should be placed upon existing human data, followed

by existing animal data, followed by in vitro data, and then other sources of information.

Classification results directly when the data satisfy the criteria. However, in some cases,

classification of a substance or a mixture is made on the basis of the weight of evidence within a

tier. If no decision can be made about classification after following the tiered approach, then a

total weight-of-evidence approach to classification should be used. In a total weight-of-evidence

approach all available information bearing on the determination of skin corrosion/irritation is

considered together, including the results of appropriate validated in vitro tests, relevant animal

data, and human data, such as epidemiological and clinical studies and well-documented case

reports and observations.

Classification Criteria for Substances

There are two categories assigned for skin effects in the HCS. In addition, the category for skin

corrosion is subdivided into three subcategories according to specific criteria outlined below.

(a) Category 1 (skin corrosion)

This category is further divided into three sub-categories (1A, 1B and 1C)

(b) Category 2 (skin irritation)

Classification criteria for substances using animal test data

Skin Corrosion (Category 1)

Skin corrosion is the production of irreversible damage to the skin; namely, visible necrosis

through the epidermis and into the dermis, following the application of a test substance for up to

4 hours. Corrosive reactions are typified by ulcers, bleeding, bloody scabs, and, by the end of

observation at 14 days, by discoloration due to blanching of the skin, complete areas of alopecia,

and scars. Histopathology should be considered to evaluate questionable lesions.

A substance is classified as corrosive to skin when it produces destruction of skin tissue, namely,

visible necrosis through the epidermis and into the dermis, in at least one tested animal after

exposure for up to 4 hours.

Table VII.2.1. Skin corrosion category and sub-categories

Category

Criteria

Category 1

Destruction of skin tissue, namely, visible necrosis through the

epidermis and into the dermis, in at least one tested animal after

exposure ≤ 4 hours

Sub-category 1A

Corrosive responses in at least one animal following exposure ≤ 3

minutes during an observation period ≤ 1 hour

Sub-category 1B

Corrosive responses in at least one animal following exposure > 3

minutes and ≤ 1 hour and observations ≤ 14 days

Sub-category 1C

Corrosive responses in at least one animal after exposures > 1 hour and

≤ 4 hours and observations ≤ 14 days

Skin Irritation (Category 2)

Skin irritation is the production of reversible damage to the skin following the application of a

test substance for up to 4 hours.

Animal irritant responses within a test can be variable, as they are with corrosion. A separate

irritant criterion accommodates cases where there is a significant irritant response but less than

the mean score criterion for a positive test. For example, a test material might be designated as

an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study,

including lesions persisting at the end of an observation period (normally 14 days). Other

responses could also fulfill this criterion. However, it should be ascertained that the responses are

the result of chemical exposure. Addition of this criterion increases the sensitivity of the

classification system.

Reversibility of skin lesions is another consideration in evaluating irritant responses. When

inflammation persists to the end of the observation period in two or more test animals, taking

into consideration alopecia (limited area), hyperkeratosis, hyperplasia, and scaling, then a

chemical should be considered to be an irritant.

The classification criteria for skin irritation (Category 2) are presented in Table VII.2.2. The

major criterion for the irritation category is that at least 2 of 3 tested animals have a mean score

of  2.3 and  4.0.

Table VII.2.2. Skin irritation categories

a, b

category

Does the mixture contain ≥ 1% of an ingredient which is

corrosive when the additivity approach does not apply?

Does the mixture contain  3% of an ingredient which is irritant

and when the additivity approach does not apply?

Can bridging principles be applied?

Yes

Category 1

Danger

Category 2

Warning

Does the mixture contain one or more corrosive ingredients when

the additivity approach applies and where the sum of

concentrations of ingredients classified as skin Category 1  5%?

Category 1

Danger

Are there data on similar tested mixtures to evaluate skin

corrosion/irritation?

Yes

Skin Corrosion/Irritation Classification Examples

The following examples are provided to walk you through the skin corrosion/irritation

calculation and classification processes.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Skin Irritation

Test Data

HCS 2012

Classification

Rationale

According to OECD Test

Guideline 404 test substance was

applied for 1 hour and three

minutes. No scars or other

irreversible effects were found.

The scoring results obtained after

4 hours application time are

 Erythema/Eschar: 2.7, 3, 0.66

 Edema: 1.7, 2, 1

Skin Irritant

Category 2

Fulfills criteria

 The classification is made on the

basis of 2 of 3 animals exceeding

a 2.3 mean score for erythema.

Not

classified

Does the mixture contain one or more corrosive or irritant

ingredients when the additivity approach applies and where the sum

of concentrations of ingredients classified as:

(a) skin Category 1 ≥ 1% but < 5%, or

(b) skin Category 2 ≥ 10%, or

Yes

Category 2

Warning

Substance Example #2

Skin Corrosion

Test Data

HCS 2012

Classification

Rationale

In OECD Test 404 full

necrosis/irreversible skin damage

after 4-hour exposure within 14

days were observed in one animal

Skin Corrosion

Category 1C

Fulfills criteria

 According to the classification

criteria the production of

irreversible damage to the skin

after 4-hour exposure in at least

one animal warrants

classification in Category 1C.

Substance Example #3

Skin Corrosion

Test Data

HCS 2012

Classification

Rationale

The material is a new aliphatic

tertiary amine. No data is

available. The test substance has

Structure Activity Relationships

(SAR) to substances with similar

structure known to be corrosive.

Skin Corrosion

Category 1

Using expert judgment and SAR

information the classifier of this

mixture concluded that Category 1 is

justified, since there is much

information indicating that aliphatic

amines are corrosive. According to

the criteria, the classifier of this

mixture concluded that classification

as corrosive Category 1 is warranted.

Substance Example #4

Skin Irritation

Test Data

HCS 2012

Classification

Rationale

OECD Test Guidelines 404

test results:

 Erythema/Eschar: mean value

2.2 (in 2 of 3 animals)

 Edema: 2.4 (in all animals)

Skin Irritation

Category 2

Fulfills criteria

 The criteria for Category 2

classification are fulfilled, since

the mean value for edema over

24, 48, and 72 hours in 2 of 3

animals is > 2.3.

Examples of mixtures fulfilling the criteria for classification:

Mixture Example #1

Skin Corrosion/Irritation

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 4%, Skin

Category 1, pH = 1.8

Component 2: 5%, Skin

Category 2

Component 3: 5%, not classified

Component 4: 86%, No data

available

Mixture pH = 4.0

Skin Corrosion

Category 1

For this mixture, the classification

was assigned as a Category 1

because component 1 (Category 1) is

in the mixture at  1%

Rationale:

 The overall mixture pH of 4.0

does not result in classification in

Category 1 since this does not

fall within the criteria of pH  2

or pH  11.5

 Component 1 with a pH = 1.8 is

an ingredient for which additivity

might not apply. Expert judgment

would be needed to determine

whether or not additivity applies.

Knowledge of the components is

important. Given the limited

information in this example, the

classifier of this mixture chose to

apply non-additivity for a

conservative approach. Without

information on the mode of

action of component 1, the

mixture could be corrosive

regardless of the overall pH.

Therefore, the criteria described

in 29 CFR 1910.1200 paragraph

A.2.4.3.4 were applied (i.e., “A

mixture containing corrosive or

irritant ingredients that cannot be

classified based on the additivity

approach shown in [Table

VII.2.3], due to chemical

characteristics that make this

approach unworkable, should be

classified as Skin Category 1 if it

contains ≥ 1% of a corrosive

ingredient and as Skin Category

2 when it contains ≥ 3% of an

irritant ingredient”).

Mixture Example #2

Skin Corrosion/Irritation

Data

HCS 2012

Classification

Rationale

Tested mixture information

Animal 1: Mean Erythema/eschar

3.8, Mean Edema: 2.5

Animal 2: Mean Erythema/eschar

3.5, Mean Edema: 2.9

Animal 3: Mean Erythema/eschar

4.0, Mean Edema: 3.2

Based on the test data the mixture

is classified as Skin Irritant

Category 2. The tested mixture is

aerosolized using a 50/50 mixture

of propane/butane as the

propellant.

Aerosolized untested mixture

information

Component 1: 50%, Tested

mixture = Skin Category 2

Component 2: 25%, Liquefied

propane

Component 3: 25%, Liquefied

butane

Skin Irritation

Category 2

Applying the aerosols bridging

principle, the aerosolized untested

mixture can be classified as

Skin Irritant Category 2 without

additional testing.

Rationale:

 Classification via application of

bridging principles can be

considered since there are

sufficient data on both the

individual ingredients and a

similar tested mixture

 The aerosols bridging principle

can be applied because:

(i) The non-aerosolized mixture

has been tested, and

(ii) The propellant (i.e., 50/50

mixture of liquefied

propane/butane) is not corrosive

or an irritant, and

(iii) The propellant will not

affect the irritation properties of

the mixture upon spraying.

Mixture Example #3

Skin Corrosion/Irritation

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 91%, no data

available

Component 2: 5%, Skin

Category 2

Component 3: 3%, Skin

Category 2

Component 4: 0.9%, Skin

Category 1

Component 5: 0.1%, no data

available

Skin Irritation

Category 2

Use equations from Table VII.2.3

Category 1 calculation:

a) ∑%Skin Category 1 = 0.9 which

is not ≥ 5%

Category 2 calculations:

b) ∑%Skin Category 1= 0.9 which

is not ≥ 1% but < 5%

c) ∑%Skin Category 2 = 5 + 3 = 8

which is not ≥ 10%

d) ∑(10 x %Skin Category 1) +

∑%Skin Category 2 = (10 x 0.9)

+ (5 + 3) = 17 which is ≥ 10%

Rationale

 Classification of the mixture

based on ingredient data can be

considered

 In the exercise of expert

judgment in applying the

“relevant ingredient” concept, the

classifier took a conservative

approach since component 4

(Skin Category 1) is only slightly

below 1% (i.e., 0.9%) and

application of the additivity

approach includes a weighting

factor for Category 1 ingredients.

References

29 CFR 1910.1200, Hazard Communication, Appendix A.2 Skin Corrosion/Irritation.

29 CFR 1910.1200, Hazard Communication. Appendix C, Allocation of Label Elements.

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

The Organization for Economic Co-operation and Development (OECD) Guidelines for the

Testing of Chemicals.

United States Environmental Protection Agency (EPA) Office of Prevention, Pesticides, and

Toxic Substances (OPPTS) Health Effects Test Guidelines.

VII.3 Serious Eye Damage/Eye Irritation

Introduction

Changes at the site of first contact (e.g., skin, eye) can be caused regardless of whether a

chemical can become systemically available. These changes are considered local effects.

Chemicals causing local effects after a single exposure can be further distinguished as irritant or

corrosive chemicals, depending on the reversibility of the effects observed.

Corrosive chemicals are those which can destroy living tissues with which they come into

contact. In toxicology, the term “corrosive” normally means causing visible destruction of the

skin, eyes, or the lining of the respiratory tract or the gastrointestinal tract on contact. Corrosion

is manifested by ulcers, cell death, and scar formation. Generally speaking, corrosive materials

have a very low pH (acids) or a very high pH (bases). Strong bases are usually more corrosive

than acids. Examples of corrosive materials are sodium hydroxide (lye) and sulfuric acid.

Irritant chemicals are non-corrosive substances which, through immediate contact with the

tissue under consideration, may cause inflammation. Dermal irritation is a skin reaction resulting

from a single or multiple exposures to a physical or chemical entity at the same site,

characterized by the presence of inflammation.

The difference between an irritant and a corrosive is the ability of the body to repair the tissue

reaction. With irritants the inflammatory reaction can be reversed, whereas with corrosive

damage it is permanent and irreparable.

Appendix A.3 of the HCS addresses the classification of those chemicals which present a

corrosion or irritation hazard to the eye.

General Considerations

Classification for serious eye damage/eye irritation should be conducted using a tiered weight–

of-evidence approach. In the tiered approach, emphasis should be placed upon existing human

data, followed by existing animal data, followed by in vitro data and then other sources of

information. Classification results directly when the data satisfy the criteria. However, in some

cases, classification of a chemical is made on the basis of the weight-of-evidence within a tier. If

no decision can be made about classification after following the tiered approach, then a total

weight-of-evidence approach to classification should be used. In a total weight-of-evidence

approach all available information bearing on the determination of serious eye damage /eye

irritation is considered together, including the results of appropriate validated in vitro tests,

relevant animal data, and human data such as epidemiological and clinical studies and well-

documented case reports and observations.

Classification Criteria for Substances

There are two categories assigned for eye effects in the HCS. In addition, the category for eye

irritation is subdivided into two subcategories according to specific criteria outlined below.

Substances are allocated to one of the categories within this hazard class, Category 1 (serious eye

damage) or Category 2 (eye irritation), as follows:

(a) Category 1 (serious eye damage/irreversible effects on the eye): Substances that have

the potential to seriously damage the eyes (see Table VII.3.1);

(b) Category 2 (eye irritation/reversible effects on the eye): Substances that have the

potential to induce reversible eye irritation (see Table VII.3.2). Category 2 has two

subcategories, Category 2A and Category 2B, which are differentiated by the time it

takes for the eye effects to reverse.

Classification criteria for substances using animal test data

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

Serious eye damage is the production of tissue damage in the eye, or serious physical decay of

vision, following application of a test substance to the anterior surface of the eye, which is not

fully reversible within 21 days of application.

The criteria include animals with grade 4 cornea lesions and other severe reactions (e.g.,

destruction of cornea) observed at any time during the test, as well as persistent corneal opacity,

discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the

function of the iris or other effects that impair sight. In this context, persistent lesions are

considered those which are not fully reversible within an observation period of normally 21 days.

Hazard classification as Category 1 also includes substances fulfilling the criteria of corneal

opacity ≥3 and/or iritis > 1.5 detected in a Draize eye test with rabbits, because severe lesions

like these usually do not reverse within a 21-day observation period.

Table VII.3.1. Serious eye damage/Irreversible eye effects category

a,b

Category

Criteria

Category 1:

Serious eye

damage/Irreversible

eye effects

A substance that produces:

(a) in at least one 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) in at least 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 test material.

Grading criteria correspond to those described in OECD Test Guideline 405.

Criteria for evaluation of a 4, 5 or 6-animal study are provided below under the heading “Guidance on evaluation

of data from studies with more than three animals.”

Eye irritation (Category 2)/Reversible effects on the eye

Eye irritation is the production of changes in the eye following the application of test substance

to the anterior surface of the eye, which are fully reversible within 21 days of application.

Substances that have the potential to induce reversible eye irritation should be classified in

Category 2. When data are sufficient, substances may be classified in Category 2A or 2B in

accordance with the criteria in Table VII.3.2. For substances inducing eye irritant effects

reversing within an observation time of normally 21 days, Category 2A applies. For substances

inducing eye irritant effects reversing within an observation time of 7 days, Category 2B applies.

If there is insufficient data to subdivide into category 2B then the classifier may use the generic

term of Category 2. The criteria for the generic Category 2 are equivalent to Category 2A.

For those substances where there is pronounced variability among animal responses, this

information may be taken into account in determining the classification.

Table VII.3.2. Reversible eye effects categories

a,b

Criteria

Substances that have the potential to induce reversible eye irritation

Category

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a) corneal opacity  1; and/or

(b) iritis  1; and/or

(d) conjunctival edema (chemosis)  2

calculated as the mean scores following grading at 24, 48 and 72 hours after

instillation of the test material, and which fully reverses within an observation

period of normally 21 days.

Category

Within Category 2A an eye irritant is considered mildly irritating to eyes

(Category 2B) when the effects listed above are fully reversible within 7 days of

observation.

Grading criteria correspond to those described in OECD Test Guideline 405.

Criteria for evaluation of a 4, 5 or 6-animal study are provided below under the heading “Guidance on evaluation

of data from studies with more than three animals.”

Classification in a tiered approach

A tiered approach to the evaluation of initial information must be used, where applicable (Figure

VII.3.1), recognizing that not all elements may be relevant.

The tiered approach provides guidance on how to organize existing information on a substance

and to make a weight-of-evidence decision about hazard assessment and hazard classification

(ideally without conducting new animal tests). Although information might be gained from the

evaluation of single parameters within a tier, consideration should be given to the totality of

existing information and making an overall weight-of-evidence determination. This is especially

true when there is conflict in information available on some parameters.

Existing human and animal data should be the first line of evaluation, as they give information

directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to

consideration of any testing for serious eye damage/eye irritation in order to avoid testing for

local effects on eyes with skin corrosive substances.

In vitro alternatives that have been scientifically validated and accepted must be used to make

classification decisions.

Likewise, pH extremes such as  2 and  11.5 may indicate serious eye damage, especially when

associated with significant acid/alkaline reserve (buffering capacity).

Generally, such

substances are expected to produce significant effects on the eyes. In the absence of any other

information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤

2 or ≥ 11.5. However, if consideration of acid/alkaline reserve suggests the substance may not

cause serious eye damage despite the low or high pH value, then further evaluation may be

necessary. Data from an appropriate scientifically validated in vitro test is the preferred method

for validation.

In some cases sufficient information may be available from structurally related substances to

make classification decisions.

Figure VII.3.1. Tiered evaluation for serious eye damage/eye irritation

(see also Tiered evaluation for skin corrosion and irritation)

Step

Parameter

Finding

Conclusion

1a:

Existing human or animal serious eye

damage/eye irritation data

Serious eye damage

Category 1

Eye irritant

Category 2

Negative data/Insufficient data/No data

1b:

Existing human or animal data, skin

corrosion

Skin corrosion

Category 1

Negative data /Insufficient data/No data

1c:

Existing human or animal serious eye

damage/eye irritation data

Existing data showing

that substance does not

cause serious eye

damage or eye irritation

Not classified

No/Insufficient data

Other, existing skin/eye data in

animals

Yes; other existing data

showing that substance

may cause serious eye

damage or eye irritation

Category 1 or Category 2

No/Insufficient data

Existing ex vivo/in vitro eye data

Positive: serious eye

damage

Category 1

Positive: eye irritant

Category 2

No/Insufficient data/Negative response

For further information concerning acid/alkaline reserve, see (1) Young et al. 1988, “Classification as corrosive or

irritant to skin of preparations containing acidic or alkaline substances, without test on animals,” Toxicology in Vitro

2, 19-26 and (2) Young and How, 1994, “Product classification as corrosive or irritant by measuring pH and acid /

alkali reserve,” Alternative Methods in Toxicology vol. 10 - In Vitro Skin Toxicology: Irritation, Phototoxicity,

Sensitization, 23-27.

Figure VII.3.1. Tiered evaluation for serious eye damage/eye irritation

(see also Tiered evaluation for skin corrosion and irritation)

Step

Parameter

Finding

Conclusion

pH-based assessment (with

consideration of acid/alkaline reserve

of the chemical)

pH ≤ 2 or ≥ 11.5 with

high acid/alkaline

reserve or no data for

acid/alkaline reserve

Category 1

Not pH extreme, no pH data or extreme

pH with data showing low/no

acid/alkaline reserve

Severe damage to eyes

Category 1

Validated Structure Activity

Relationship (SAR) methods

Eye irritant

Category 2

Skin corrosive

Category 1

No/Insufficient data

Consideration of the total weight of

evidence

Serious eye damage

Category 1

Eye irritant

Category 2

Not classified

Existing human or animal data could be derived from single or repeated exposure(s), for example in occupational,

consumer, transport, or emergency response scenarios; from ethically conducted human clinical studies; or from

purposely generated data from animal studies conducted according to validated and internationally accepted test

methods. Although human data from accident or poison center databases can provide evidence for classification,

absence of incidents is not itself evidence for no classification.

Classify in the appropriate category/sub-category, as shown in Tables VII.3.1 and VII.3.2.

Existing animal data should be carefully reviewed to determine if sufficient serious eye damage/eye irritation

evidence is available through other, similar information. It is recognized that not all skin irritants are eye irritants.

Expert judgment should be exercised prior to making such a determination.

Evidence from studies using validated protocols with isolated human/animal tissues or other non-tissue-based,

validated protocols should be assessed. Examples of scientifically validated test methods for identifying eye

corrosives and severe irritants (i.e., Serious Eye Damage) include OECD TG 437 (Bovine Corneal Opacity and

Permeability (BCOP)) and 438 (Isolated Chicken Eye (ICE)). Presently there are no scientifically validated and

internationally accepted in vitro test methods for identifying eye irritation. A positive test result from a scientifically

validated in vitro test on skin corrosion would lead to the conclusion to classify as causing serious eye damage.

Measurement of pH alone may be adequate, but assessment of acid or alkali reserve (buffering capacity) would be

preferable. Presently, there is no scientifically validated method for assessing this parameter.

All information that is available on a substance should be considered and an overall determination made on the

total weight of evidence. This is especially true when there is conflict in information available on some parameters.

The weight of evidence including information on skin irritation may lead to classification for eye irritation. Negative

results from applicable validated in vitro tests are considered in the total weight of evidence evaluation.

Classification criteria for mixtures

It should be noted that the classification criteria for the health hazards of mixtures usually

include a tiered scheme (i.e., stepwise procedure based on a hierarchy principle) in which test

data available on the complete mixture are considered as the first tier in the evaluation, followed

by the applicable bridging principles, and lastly, cut-off values/concentration limits or additivity.

Tier 1: Classification of mixtures when data are available for the complete mixture

When serious eye damage /eye irritation test data on the mixture itself is available, these data are

used to classify the mixture using the criteria for substances and taking into account the tiered

weight-of-evidence approach illustrated in Figure VII.3.1.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight-of-

evidence approach as included in the criteria for classification of substances for skin corrosion

and serious eye damage/eye irritation to help ensure an accurate classification. In the absence of

any other information, a mixture is considered to cause serious eye damage (Eye Category 1) if it

has a pH ≤ 2 or ≥ 11.5. However, if consideration of alkali/acid reserve suggests the mixture may

not cause serious eye damage despite the low or high pH value, then further evaluation may be

necessary.

If appropriate test data for the mixture are not available, then the classifier must consider the

application of the Bridging Principle criteria in Tier 2, if appropriate, or if application of bridging

principles are not appropriate, use the classification resulting from the application of criteria in

Tier 3.

Tier 2: Classification of mixtures when data are not available for the complete mixture -

bridging principles

Where the mixture itself has not been tested to determine its skin corrosivity or serious eye

damage/eye irritation potential, but there are sufficient data on BOTH the individual ingredients

AND similar tested mixtures to adequately characterize the hazards of the mixture, these data are

used in accordance with the bridging principles below.

The bridging principles that are applicable to the serious eye damage/eye irritation hazard class

include:

 Dilution,

 Batching,

 Concentration of mixtures,

 Interpolation within one toxicity category,

 Substantially similar mixtures,

 Aerosols.

The application of bridging principles ensures that the classification process uses the available

data to the greatest extent possible in characterizing the potential skin corrosion/irritation hazard.

Dilution

If a tested mixture is diluted with a diluent which has an equivalent or lower

classification for serious eye damage/eye irritation classification than the least seriously

eye damaging/eye irritant original ingredient and which is not expected to affect the

serious eye damage/eye irritancy of other ingredients, then the new diluted mixture must

be classified as equivalent to the original tested mixture. Alternatively, the cut-off

values/concentration limits or additivity method could be applied.

Batching

The serious eye damage/eye irritation potential of a tested production batch of a mixture

can be assumed to be substantially equivalent to that of another untested production batch

of the same commercial product when produced by or under the control of the same

manufacturer, unless there is reason to believe there is significant variation such that the

serious eye damage/eye irritation potential of the untested batch has changed. If the latter

occurs, a new classification is necessary.

Concentration of mixtures

If a tested mixture classified for serious eye damage (Category 1) is concentrated, the

more concentrated untested mixture is classified for serious eye damage (Category 1)

without additional testing. If a tested mixture classified for eye irritation (Category 2 or

2A) is concentrated and does not contain serious eye damage ingredients, the more

concentrated untested mixture should be classified in the same category (Category 2 or

2A) without additional testing.

Interpolation within one hazard category

For three mixtures (A, B and C) with identical ingredients, where mixtures A and B have

been tested and are in the same serious eye damage/eye irritation hazard category, and

where untested mixture C has the same toxicologically active ingredients as mixtures A

and B but has concentrations of toxicologically active ingredients intermediate to the

concentrations in mixtures A and B, then mixture C is assumed to be in the same serious

eye damage/eye irritation category as A and B.

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

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

mixture (ii);

(d) Data on serious eye damage/eye irritation for A and C are available and

substantially equivalent, i.e., they are in the same hazard category and are not

expected to affect the serious eye damage/eye irritation potential of B.

If mixture (i) or (ii) is already classified by testing, then the other mixture can be

classified in the same hazard category.

Aerosols

An aerosol form of a mixture must be classified in the same hazard category as the tested

non-aerosolized form of the mixture provided that the added propellant does not affect

the serious eye damage/eye irritation properties of the mixture upon spraying. Bridging

principles apply for the intrinsic hazard classification of aerosols. However, the need to

evaluate the potential for “mechanical” eye damage from the physical force of the spray

is recognized.

If appropriate data is not available to apply the above bridging principles then the classifier

applies the criteria in Tier 3.

Tier 3: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

Cut-off values/concentration limits: Additivity

In general, the approach to classifying a mixture for serious eye damage/eye irritation in Tier 3 is

based on the theory of additivity, where each corrosive or irritant ingredient is considered to

contribute to the overall corrosive or irritant properties of the mixture. The ingredients are

summed in proportion to their concentration and potency (i.e., corrosives carry more weight in

the irritation calculations).

Table VII.3.3 provides the cut-off value/concentration limits to be used to determine if the

mixture is considered to be corrosive or irritant to the eyes. Six potential additivity calculations

are given in the first column. Each calculation has specific concentration cut-offs that will trigger

the classification specified in columns 2 and 3 which correspond to Category 1 and Category 2,

respectively.

To better illustrate the order in which the equations should be evaluated an arrow has been added

to the table. Following the arrow, the first calculation that exceeds the percentage cut-off trigger

determines which classification is assigned to the mixture. If none of the sums exceed the cut-off

triggers then the mixture is not classified.

Table VII.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 mixture as hazardous to

the eye (Category 1 or 2)

Sum of ingredients classified as

Concentration triggering

classification of a mixture as

Serious eye damage

Eye irritation

Category 1

Category 2

Eye Category 1 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 2

 10%

If an ingredient is classified as both skin Category 1 and eye Category 1 its concentration is considered only once

in the calculation.

Note: A mixture is classified as eye Category 2B when all relevant ingredients are classified as eye

Category 2B.

The Nine Serious Eye Damage/Eye Irritation Mixture Additivity Calculations

There are nine possible calculations that may need to be performed to determine if the mixture

should be classified.

Sum of ingredients classified as

Concentration triggering

classification of a mixture as

Serious eye

damage

Eye irritation

Category 1

Category 2

Eye Category 1

 3% (1)

 1% but < 3% (4)

Skin Category 1

 3% (2)

 1% but < 3% (5)

Eye Category 2

 10% (6)

(10 × Eye Category 1) + Eye Category 2

 10% (7)

Skin Category 1 + Eye Category 1

 3% (3)

 1% but < 3% (8)

10  (Skin Category 1 + Eye Category 1)

Eye Category 2

 10% (9)

Revision 6 of the GHS contains a similar table that may be easier to understand. See GHS Table 3.3.3.

If an ingredient is classified as both skin Category 1 and eye Category 1 its concentration is considered only once

in the calculation

Note: A mixture is classified as eye Category 2B when all relevant ingredients are classified as eye

Category 2B.

Serious eye damage Category 1 classification calculations:

(1) Add the percentages of all ingredients classified as Eye Category 1.

If the sum is ≥ 3% the mixture is classified as Category 1 Serious Eye Damage.

∑ % Eye Category 1 ingredients ≥ 3%

(2) Add the percentages of all ingredients classified as Skin Category 1.

If the sum is ≥ 3% the mixture is classified as Category 1 Serious Eye Damage.

∑ % Skin Category 1 ingredients ≥ 3%

(3) First add the percentages of all ingredients classified as Eye Category 1.

Then add the percentages of all ingredients classified as Skin Category 1.

Add these two numbers together. If the sum is ≥ 3%, the mixture is classified as

Category 1 Serious Eye Damage.

∑ % Skin Category 1 ingredients + ∑ % Eye Category 1 ingredients ≥ 3%

Eye irritation Category 2 classification calculations:

For Category 1 ingredients:

(4) Add the percentages of all ingredients classified as Eye Category 1.

If the sum is ≥ 1% but < 3%, the mixture is classified as Category 2 Eye Irritation.

∑ % Eye Category 1 ingredients ≥ 1% but < 3%

(5) Add the percentages of all ingredients classified as Skin Category 1.

If the sum is ≥ 1% but < 3%, the mixture is classified as Category 2 Eye Irritation.

∑ % Skin Category 1 ingredients ≥ 1% but < 3%

For Category 2 ingredients:

(6) Add the percentages of all ingredients classified as Eye Category 2.

If the sum is ≥ 10% the mixture is classified as Category 2 Eye Irritation.

∑ % Eye Category 2 ingredients ≥ 10%

For Category 1 & 2 ingredients:

(7) First add the percentages of all ingredients classified as Eye Category 1 and multiply

this sum by 10.

Then add the percentages of all ingredients classified as Eye Category 2.

Add these two numbers together. If the sum is ≥ 1% but < 3%, the mixture is classified as

Category 2 Eye Irritation.

10 (∑ % Eye Category 1 ingredients) + ∑ % Eye Category 2 ingredients ≥ 1% but < 3%

For Skin & Eye Category 1 ingredients:

(8) First add the percentages of all ingredients classified as Skin Category 1.

Then add the percentages of all ingredients classified as Eye Category 1.

(If an ingredient is classified as both skin Category 1 and eye Category 1 its

concentration is considered only once in the calculation.)

Add these two numbers together. If the sum is ≥ 1% but < 3%, the mixture is

classified as Category 2 Eye Irritation.

∑ % Skin Category 1 ingredients + ∑ % Eye Category 1 ingredients ≥ 1% but < 3%

For Skin & Eye Category 1 & Eye 2 ingredients:

(9) Add the percentages of all ingredients classified as Skin Category 1.

Add the percentages of all ingredients classified as Eye Category 1.

Add these two numbers. Multiply that sum by 10. This is calculation one.

In calculation two add the percentages of all ingredients classified as Eye

Category 2.

In calculation three add the numbers from calculation one and calculation two together.

If the number in calculation 3 is ≥ 10%, the mixture is classified as Category 2 Eye

Irritation.

10 (∑ % Skin Category 1 ingredients + ∑ % Eye Category 1 ingredients) + ∑ % Eye

Category 2 ingredients ≥ 10%

Reminder:

A mixture may be classified as eye Category 2B when all relevant ingredients are classified as

eye Category 2B. Category 2A is equivalent to Category 2.

Shortcut Serious Eye Damage/Eye Irritation Mixture Additivity Calculations

Shortcut

For those doing the calculations manually, a shortcut that leads to the same classification is to

only do the worst-case calculations for the Serious Eye Damage Category 1 classification and the

Eye Irritation Category 2 classification. In the shortcut there are only two calculations. The first

sum that exceeds the percentage cut-off trigger determines which classification is assigned to the

mixture. If neither exceeds the cut-off triggers then the mixture is not classified.

Sum of ingredients classified as

Concentration triggering

classification of a mixture as

Serious eye damage

Eye irritation

Category 1

Category 2

Eye Category 1

 3%

 1% but < 3%

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 2

 10%

If an ingredient is classified as both skin Category 1 and eye Category 1 its concentration is considered only once

in the calculation

Note: A mixture is classified as eye Category 2B when all relevant ingredients are classified as eye

Category 2B.

Shortcut Serious eye damage Category 1 classification calculation:

(3) First add the percentages of all ingredients classified as Eye Category 1.

Then add the percentages of all ingredients classified as Skin Category 1.

Add these two numbers together. If the sum is ≥ 3%, the mixture is classified as

Category 1 Serious Eye Damage.

∑ % Skin Category 1 ingredients + ∑ % Eye Category 1 ingredients ≥ 3%

Shortcut Eye irritation Category 2 classification calculation:

(9) Add the percentages of all ingredients classified as Skin Category 1.

Add the percentages of all ingredients classified as Eye Category 1.

Add these two numbers. Multiply that sum by 10. This is calculation one.

In calculation two add the percentages of all ingredients classified as Eye

Category 2.

In calculation three add the numbers from calculation one and calculation two together.

If the number in calculation 3 is ≥ 10%, the mixture is classified as Category 2 Eye

Irritation.

10 (∑ % Skin Category 1 ingredients + ∑ % Eye Category 1 ingredients) + ∑ % Eye

Category 2 ingredients ≥ 10%

Cut-off values/concentration limits: when the additivity approach does not apply

Particular care must be taken when classifying certain types of chemicals such as acids and

bases, inorganic salts, aldehydes, phenols, and surfactants. The additivity approach might not

work because many such chemicals are seriously damaging or irritating to the eye at

concentrations < 1% and additivity may underestimate the overall corrosive or irritant properties

of the mixture.

For mixtures containing strong acids or bases, the pH should be used as the classification

criterion since pH will be a better indicator of serious eye damage (subject to consideration of

acid/alkali reserve) than the concentration limits in Table VII.3.3. A mixture containing

corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the

additivity approach applied in Table VII.3.3 due to chemical characteristics that make this

approach unworkable should be classified using the more conservative cut-off/concentration

limit approach summarized below:

 Mixture is Eye Category 1 if it contains ≥ 1% of a corrosive ingredient, and

 Mixture is Eye Category 2 if it contains ≥ 3% of an irritant ingredient.

The cut-off value/concentration limits approach is summarized in HCS Table VII.3.4.

Table VII.3.4. Concentration of ingredients of a mixture when the additivity approach does

not apply, that would trigger classification of the mixture as hazardous to the eye

Ingredient

Concentration

Mixture classified as:

Eye

Acid with pH  2

 1%

Category 1

Base with pH  11.5

 1%

Category 1

Other corrosive (Eye Category 1) ingredient

 1%

Category 1

Other eye irritant (Eye Category 2) ingredient

for which additivity does not apply , including

acids and bases

 3%

Category 2

100

Cut-off values/concentration limits: Important Points to Consider

To ensure consistent application of both the additivity and cut-off/concentration limit approaches

to classification for Serious Eye Damage/Eye Irritation, the following principles need to be

applied where appropriate:

 Classification Above or Below Cut-Off Values/Concentration Limits

On occasion, reliable data may show that the irreversible/reversible eye effects of an

ingredient will not be evident when present at a level above the cut-off

values/concentration limits mentioned in Tables VII.3.3 and VII.3.4. In these cases the

mixture could be classified according to those data (see also HCS 2012 A.0.4.3). Testing

of the mixture may be considered. If testing is not performed, the tiered weight-of-

evidence approach should be applied.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously

damaging to the eye/eye irritating at a concentration of  1% (corrosive to the skin or

seriously damaging to the eye) or  3% (eye irritant), the mixture should be classified

accordingly.

 “Relevant Ingredient” Concept

For the purpose of applying the cut-off values in Tables VII.3.3 and VII.3.4, only

“relevant ingredients” need to be included in the calculation.

The “relevant ingredients” of a mixture are those which are present in concentrations ≥

1% (w/w for solids, liquids, dusts, mists and vapors and v/v for gases), unless there is a

presumption (e.g., in the case of corrosive ingredients) that an ingredient present at a

concentration < 1% can still be relevant for classifying the mixture for serious eye

damage/eye irritation. If the classifier suspects that the ingredient could be relevant for

classifying the mixture at < 1%, then the classifier must use expert judgment to determine

at what concentration below 1% the corrosive Category 1 ingredient(s) should be

included in the calculation.

Classification Procedure and Guidance

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

In classification the data are compared to the serious eye damage/eye irritation classification

criteria. If valid data on serious eye damage/eye irritation of a substance or mixture are available,

these data should be used for classification. To find the necessary data, a classifier is advised to

try the following:

 ask the manufacturer or supplier for the serious eye damage/eye irritation data for the

product; or

101

 check if the serious eye damage/eye irritation data is available in the SDS or any other

documentation accompanying the product; or

 find the data available in the open literature, if the chemical identity of the product is

known (for a single-component chemical).

Data generated in accordance with internationally recognized scientific principles are acceptable

under the HCS.

Examples of scientifically validated test methods

There are a number of methods that use recognized scientific principles for investigation of

serious eye damage/eye irritation effects:

 OECD Test Guideline 405: Acute Eye Irritation/Corrosion

 USEPA OTS code: 798.4500;

 USEPA OPP code: 81-4;

 USEPA OPPTS code: 870.2400;

 EEC Directive 92/32/EEC (B.5);

 OECD Test Guideline 437: In Vitro Bovine Corneal Opacity and Permeability (BCOP);

 OECD Test Guideline 438: In Vitro Isolated Chicken Eye (ICE).

In the in vivo test, the substance is applied in a single dose to one of the eyes of an experimental

animal (usually a healthy young albino rabbit) while the untreated eye serves as the control.

Internationally accepted, validated in vivo test methods for identifying eye corrosives and severe

irritants (i.e., Serious Eye Damage) include OECD TG 437 - Bovine Corneal Opacity and

Permeability (BCOP) and OECD TG 438 - Isolated Chicken Eye (ICE). Presently there are no

validated and internationally accepted in vitro test methods for identifying eye irritation.

Guidance on evaluation of data from studies with more than three animals

The classification criteria for serious eye damage/eye irritation are given in terms of a 3-animal

test. Some older test methods may have used up to 6 animals. However, the serious eye

damage/eye irritation criteria do not specify how to classify based on existing data from tests

with more than 3 animals.

Criteria for the evaluation of a 4, 5 or 6-animal study are provided in the paragraphs below,

depending on the number of animals tested. Scoring is done at 24, 48 and 72 hours after

instillation of the test material.

In the case of a study with 6 animals the following principles apply:

(a) The substance or mixture is classified as serious eye damage Category 1 if:

(i) at least in one animal effects on the cornea, iris or conjunctiva are not expected

to reverse or have not fully reversed within an observation period of normally

21 days; and/or

102

(ii) at least 4 out of 6 animals show a mean score per animal of  3 for corneal

opacity and/or > 1.5 for iritis.

(b) The substance or mixture is classified as eye irritation Category 2/2A if at least 4 out

of 6 animals show a mean score per animal of:

(i) ≥ 1 for corneal opacity; and/or

(ii) ≥ 1 for iritis; and/or

(iii) ≥ 2 for conjunctival redness; and/or

(iv) ≥ 2 for conjunctival oedema (chemosis)

and which fully reverses within an observation period of normally 21 days.

listed in sub-paragraph (b) above are fully reversible within 7 days of observation.

In the case of a study with 5 animals the following principles apply:

(a) The substance or mixture is classified as serious eye damage Category 1 if:

(i) at least in one animal effects on the cornea, iris or conjunctiva are not expected

to reverse or have not fully reversed within an observation period of normally 21

days; and/or

(ii) at least 3 out of 5 animals show a mean score per animal of  3 for corneal

opacity and/or > 1.5 for iritis.

(b) The substance or mixture is classified as eye irritation Category 2/2A if at least 3 out

of 5 animals show a mean score per animal of:

(i) ≥ 1 for corneal opacity; and/or

(ii) ≥ 1 for iritis; and/or

(iii) ≥ 2 for conjunctival redness; and/or

(iv) ≥ 2 for conjunctival oedema (chemosis)

and which fully reverses within an observation period of normally 21 days.

listed in sub-paragraph (b) above are fully reversible within 7 days of observation.

In the case of a study with 4 animals the following principles apply:

(a) The substance or mixture is classified as serious eye damage Category 1 if:

(i) at least in one animal effects on the cornea, iris or conjunctiva are not expected

to reverse or have not fully reversed within an observation period of normally 21

days; and/or

(ii) at least 3 out of 4 animals show a mean score per animal of  3 for corneal

opacity and/or > 1.5 for iritis.

103

(b) Classification as eye irritation Category 2/2A if at least 3 out of 4 animals show a

mean score per animal of:

(i) ≥ 1 for corneal opacity; and/or

(ii) ≥ 1 for iritis; and/or

(iii) ≥ 2 for conjunctival redness; and/or

(iv) ≥ 2 for conjunctival oedema (chemosis)

and which fully reverses within an observation period of normally 21 days.

listed in sub-paragraph (b) above are fully reversible within 7 days of observation.

Decision logic

Two decision logics for classifying Serious Eye Damage/Eye Irritation are provided. The first

decision logic is for substances and for mixtures with data on the mixture as a whole. Use the

second decision logic for classifying mixtures on the basis of information/data on similar tested

mixtures and/or ingredients. The decision logics are provided as additional guidance. It is

strongly recommended that the person responsible for classification study the criteria before and

during use of the decision logic.

These decision logics are essentially flowcharts for classifying substances and mixtures

regarding serious eye damage/eye irritation. They present questions in a sequence that walks you

through the classification steps and criteria for classifying serious eye damage/eye irritation.

Once you answer the questions provided, you will arrive at the appropriate classification.

104

Decision logic for serious eye damage/eye irritation

(Cont’d on next page)

Yes

Does the

substance or mixture

have potential to cause

irreversible eye

damage

(

serious eye damage

)

considering

(

total weight of evidence as

needed

)

(a)

Existing human experience,

(b)

Existing animal observations including single or repeated exposure,

(c)

In vitro data,

(d)

Information available from structurally related compounds,

(e)

pH extremes of





11.5

(taking into account acid/alkaline reserve)

(f)

Irreversible eye damage in one or more test animals?

(see Table A.3.1

for

for criteria and sub-categorization)

See next decision logic

for use with ingredients

Substance:

Are there data/information to evaluate serious eye

damage/eye irritation?

Classification

not possible

Mixture:

Does the mixture as a whole or its ingredients

have data/information to evaluate serious eye

damage/eye irritation?

Yes

Mixture:

Does the mixture as a whole have

data/information to evaluate serious eye

damage/eye irritation?

ategory 1

Danger

Yes

Classification

not possible

105

Is the

substance or mixture

eye irritant

considering

(

total weight of

evidence as needed)

(a)



Existing human experience and data, single or repeated exposure,

(b)

Existing animal observations including single or repeated exposure,

(c)

In vitro data,

(d)

Information available from structurally related compounds,

(e)

Eye irritation data from an animal study (see Table A.3.2 for

criteria for Category 2A)?

Yes

Category 2A

Warning

Not classified

Yes

ategory 2B

No symbol

Warning

Is the

substance or mixture

a mild irritant, Category 2B, considering

criteria in Table A.3.2?

106

Mixtures decision logic for serious eye damage/eye irritation

Classification of mixtures on the basis of information/data on ingredients

Cont’d on next page)

Does the mixture contain ≥ 1% of an ingredient which causes

irreversible eye damage & for which additivity may not apply,

such as:

(a) Acids and bases with extreme pHs

 2 or  11.5

(considering acid/alkaline reserve), or

(b) Inorganic salts, or

(d) Phenols, or

(e) Surfactants, or

(f) Other ingredients?

Can bridging principles be applied?

Does the mixture contain  3% of an ingredient

which is irritant

and for which additivity may not apply, including acids and

bases?

Yes

Classify in

appropriate

category

Yes

Category 1

Danger

Yes

Category 2

Warning

Does the mixture contain one or more corrosive or irritant

ingredients for which additivity applies, and where the sum of

concentrations of ingredients classified as:

(a) eye or skin Category 1:

 3% or

(b) skin Category 1 + eye Category 1:

 3%?

Yes

Category 1

Danger

107

Not classified

Does the mixture

contain one or more corrosive or irritant

ingredients for which additivity applies, and where the sum of

concentrations of ingredients classified as

(a)

eye or skin Category 1:



1% but < 3%,

(b)

eye Category 2A/2B:



10%,

(c)

(10 × eye Category

1) + eye Category 2A/2B:



10%,

(d)

skin Category 1 + eye Category 1:



1% but < 3%,

(e)

10 × (skin Category 1 + eye Category 1) + eye Category

2A/2B



10%?

Yes

Category 2

Warning

108

Serious Eye Damage/Eye Irritation Classification Examples

The following examples are provided to walk you through the serious eye damage/eye irritation

calculation and classification processes.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Serious Eye Damage

Test Data

HCS 2012

Classification

Rationale

Toxicity data: neither in vivo data

nor in vitro data available

Other relevant information: pH

1.9; no info on buffering capacity

Serious Eye

Damage

Category 1

Based on a pH < 2, the substance is a

Serious Eye Damage Category 1

according to Figure VII.3.1 Tiered

evaluation for serious eye

damage/eye irritation, Step 4.

Substance Example #2

Eye Irritation

Test Data

HCS 2012

Classification

Rationale

In an OECD Test Guideline 405

study the test substance was

applied on the eyes of three

rabbits. The scoring results are

 Corneal opacity: 2, 2, 1.3

 Iritis: 1, 1, 1

 Conjunctival redness: 2, 1, 1

 Conjunctival edema

(chemosis): 3, 1.7, 2.3

 Reversibility: The effects

were reversible.

Eye Irritation

Category 2

Fulfills criteria

 The test results show:

Cornea ≥ 1 (in all animals)

Iritis ≥ 1 (in all animals)

Conjunctival redness ≥ 2 (in 1

animal)

Conjunctival edema ≥2 (in 2 of 3

animals)

 The Category 2 criteria are

fulfilled by the Cornea,

Conjunctiva and Iris scores.

109

Substance Example #3

Serious Eye Damage

Test Data

HCS 2012

Classification

Rationale

The material is a new aliphatic

secondary amine. No data is

available. The test substance has

Structure Activity Relationships

(SAR) to substances with similar

structure known to be corrosive to

the skin.

Serious Eye

Damage

Category 1

Based on expert judgment using

SAR information the classifier

concluded that Category 1 is

justified, since there is much data on

aliphatic amines which are skin

corrosives Category 1 and thus

deemed to cause irreversible eye

effects resulting in Serious Eye

Damage Category 1 according to

Figure VII.3.1 Tiered evaluation for

serious eye damage/eye irritation,

Step 5.

Substance Example #4

Eye Irritation

Test Data

HCS 2012

Classification

Rationale

OECD Test Guideline 405: Acute

Eye Irritation/Corrosion test

results:

 Corneal opacity: mean score

0.6

 Iritis: mean score 1.3

 Conjunctival redness: mean

score 2.4 (from 2 of 3

animals)

 Conjunctival edema

(chemosis): mean score 1.4

 Reversibility: The effects

were fully reversible after 7

days.

Eye Irritation

Category 2B

Fulfills criteria

 the mean score for redness over

24, 48, and 72 hours in 2 of 3

animals is 2.4 and therefore >

2.3,

 the effects are fully reversible in

7 days,

 the criteria for classification in

Category 2B are fulfilled.

110

Examples of a mixture fulfilling the criteria for classification:

Mixture Example #1

Eye Irritation

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 0.5%, Eye

Category 1

Component 2: 3.5%, Eye

Category 2, surfactant

Component 3: 15%, No data

available

Component 4: 15%, No data

available

Component 5: 66%, No data

available

Eye Irritation

Category 2

Mixture is Eye Irritation Category 2

because

 Mixture contains 0.5% of an Eye

Category 1 which is not ≥ 1% so

the mixture is not Category 1;

 Mixture contains 3.5% of an Eye

Category 2 surfactant which is ≥

3.0% so the mixture is Category

 Classification of the mixture

based on ingredient data can be

considered.

 Component 2 (Surfactant) is a

component for which additivity

might not apply. Expert judgment

would be needed to determine

whether or not additivity applies.

Knowledge of the components is

important. Given the limited

information in this example, the

classifier of this mixture chose to

apply non-additivity for a

conservative approach.

Therefore, the criteria described

in 29 CFR 1910.1200 paragraph

A.3.4.3.4 apply (i.e., “A mixture

containing corrosive or irritant

ingredients that cannot be

classified based on the additivity

approach shown in [Table

VII.3.3], due to chemical

characteristics that make this

approach unworkable, should be

classified as Eye Category 1 if it

contains ≥ 1% of a corrosive

ingredient and as Eye Category

2/3 when it contains ≥ 3% of an

irritant ingredient”).

111

Mixture Example #2

Serious Eye Damage

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 22.06%, Eye

Category 1

Component 2: 4%, Eye

Category 1

Component 3: 5.5%, Eye

Category 2A

Component 4: 8%, not classified

based on test data

Component 5: 0.05%, not

classified based on test data

Component 5: 0.2%, not

classified based on test data

Water: 60.19%, %, not classified

pH of mixture (neat liquid): 7 – 8

Mixture BCOP test data:

Mean opacity value = 15

Mean permeability OD490

value = 5

In Vitro Irritancy Score

(IVIS) = 90

Serious Eye

Damage

Category 1

IVIS = mean opacity value + (15 x

mean permeability OD490 value)

A test sample that induces an IVIS ≥

55.1 is defined as a corrosive or

severe irritant to eyes.

Applying the Tiered evaluation for

serious eye damage/eye irritation

approach using serious eye

damage/eye irritation in vitro data

from a Bovine Corneal Opacity and

Permeability (BCOP) test, the mixture

is classified as Serious Eye Damage

Category 1 based on test data.

 Test results derived using the

BCOP test method indicate the

mixture is a corrosive or severe

eye irritant.

112

Mixture Example #3

Eye Irritation

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 4%, Eye Irritation

Category 2A

Component 2: 5%, Eye Irritation

Category 2A

Component 3: 5%, Eye Irritation

Category 2A

Component 4: 86%, no data

available

Eye Irritation

Category 2A

Use equations from Table VII.3.3

Category 1 calculation:

a) ∑% Eye Category 1 = 0 which is

not ≥ 3%

b) ∑ % Skin Category 1 = 0 which

is not ≥ 3%

c) ∑ % Skin Category 1 + ∑ % Eye

Category 1 = 0 which is not ≥ 3%

Category 2 calculations:

d) ∑% Eye Category 1 = 0 which is

not ≥ 1% but < 3%

e) ∑ % Skin Category 1 = 0 which is

not ≥ 1% but < 3%

f) ∑ % Eye Category 2/2A = 4% +

5% + 5% = 14% which is ≥ 10%

 Classification of the mixture

based on ingredient data can be

considered

 Apply the calculations in Table

VII.3.3

 The mixture is classified as

Category 2A since all the

classified components were

Category 2A.

113

Example of a substance not fulfilling the criteria for classification:

Substance Example #5

Eye Irritation

Test Data

HCS 2012

Classification

Rationale

Toxicity data: Old non-guideline

study in rabbits

 After 24 hours: questionable

redness

 Reversibility: full after 8 days

Not classified

According to the classification

criteria the slight irritating effect

with full reversibility does not justify

classification in this hazard class.

114

References

29 CFR 1910.1200, Hazard Communication, Appendix A.3 Serious Eye Damage/Eye Irritation.

29 CFR 1910.1200, Hazard Communication. Appendix C, Allocation of Label Elements.

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

The Organization for Economic Co-operation and Development (OECD) Guidelines for the

Testing of Chemicals.

United States Environmental Protection Agency (EPA) Office of Prevention, Pesticides, and

Toxic Substances (OPPTS) Health Effects Test Guidelines.

115

VII.4 Respiratory or Skin Sensitization

Introduction

A sensitizer (allergen) causes little or no reaction in humans or test animals on first exposure.

The problem arises on subsequent exposures when a marked immunological response occurs.

The response is not necessarily limited to the contact site as it may be a generalized body

condition. Skin sensitization is common in industry. Respiratory sensitization and generalized

hyperallergy to a few chemicals have also been known to occur. Well-known examples of

sensitizers are toluene diisocyanate, nickel compounds, and poison ivy.

A sensitizer is an agent that can cause an allergic response in susceptible individuals. The

consequence of this is that following an initial exposure which sensitizes the individual,

subsequent exposures via the skin or by inhalation provoke the characteristic adverse health

effects of allergic contact dermatitis or asthma (and related respiratory symptoms such as

rhinitis), respectively. Although asthma and rhinitis are generally thought to be a result of an

allergic reaction, the understanding, in recent years, that other, non-immunological, mechanisms

may occur, makes it more appropriate to use a term based on disease rather than mechanism.

Thus, the term “respiratory hypersensitivity” is a term that is used to describe asthma and other

related respiratory conditions, irrespective of the mechanism by which they are caused.

The term skin sensitization specifies an allergic mechanism of action, while respiratory

hypersensitivity does not. For this reason, the two health hazards have been approached

differently.

For the purpose of this chapter, sensitization includes two phases:

 induction of specialized immunological memory in an individual by exposure to an

allergen; and

 elicitation, i.e., production of a cell-mediated or antibody-mediated allergic response by

exposure of a sensitized individual to an allergen.

For respiratory sensitization, the pattern of induction followed by elicitation phases is shared in

common with skin sensitization. For skin sensitization, an induction phase is required in which

the immune system learns to react; clinical symptoms can then arise when subsequent exposure

is sufficient to elicit a visible skin reaction (elicitation phase). Respiratory sensitization may be

induced not only by inhalation but also by skin contact.

Tests for sensitization usually follow the same pattern in which there is an induction phase, and

then a response, which is measured by a standardized elicitation phase, typically involving a patch

test. The local lymph node assay is the exception, directly measuring the induction response.

Evidence of skin sensitization in humans normally is assessed by a diagnostic patch test.

Usually, for both skin and respiratory sensitization, lower levels are necessary for elicitation than

are required for induction.

116

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

(a) Respiratory sensitization and

(b) Skin sensitization.

Respiratory Sensitizers

Definition and General Considerations

Respiratory sensitizer means a chemical that will lead to hypersensitivity of the airways

following inhalation of the chemical.

Respiratory Sensitizer Classification Criteria for Substances

Effects seen in either humans or animals will normally justify classification using a weight-of-

evidence approach for respiratory sensitizers. Substances may be allocated to one of the two sub-

categories, 1A or 1B, using a weight-of-evidence approach in accordance with the criteria

indicated below and on the basis of reliable and good quality evidence from human cases or

epidemiological studies and/or observations from appropriate studies in experimental animals.

Where data are not sufficient for sub-categorization, respiratory sensitizers shall be classified in

Category 1.

Table VII.4.1. Hazard category and sub-categories for respiratory sensitizers

Category

Respiratory Sensitizer Criteria

Category 1

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.

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.

Severity of reaction may also be considered.

Sub-category 1B

Substances showing a low to moderate frequency of occurrence

humans; or a probability of occurrence of a low to moderate

sensitization rate in humans based on animal or other tests.

Severity

of reaction may also be considered.

At this writing, recognized and validated animal models for the testing of respiratory hypersensitivity are not

available. Under certain circumstances, data from animal studies may provide valuable information in a weight-of-

evidence assessment

With regard to the criteria for respiratory sensitization, the frequency of occurrence in humans is a matter of

expert judgment.

117

Human evidence

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based

on human experience. In this context, hypersensitivity is normally seen as asthma, but other

hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The

condition will have the clinical character of an allergic reaction. However, immunological

mechanisms do not have to be demonstrated.

When considering the human evidence, it is necessary that in addition to the evidence from the

cases, the following factors should be taken into account:

(a) The size of the population exposed;

(b) The extent of exposure.

The evidence referred to above could be:

(a) Clinical history and data from appropriate lung function tests related to exposure to

the substance, confirmed by other supportive evidence which may include:

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

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

(iii) Studies that may indicate other specific hypersensitivity reactions where

immunological mechanisms of action have not been proven, e.g., repeated low-

level irritation, pharmacologically mediated effects

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

hypersensitivity;

(b) Data from positive bronchial challenge tests with the substance conducted according

to accepted guidelines for the determination of a specific hypersensitivity reaction.

Clinical history should include both medical and occupational history to determine a relationship

between exposure to a specific substance and development of respiratory hypersensitivity.

Relevant information includes aggravating factors both in the home and workplace, the onset and

progress of the disease, family history and medical history of the patient in question. The

medical history should also include details of other allergic or airway disorders from childhood

and smoking history.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for

classification on their own. It is, however, recognized that in practice many of the examinations

listed above will already have been carried out.

118

Animal studies

Data from appropriate animal studies which may be indicative of the potential of a substance to

cause sensitization by inhalation in humans may include:

(a) Measurements of Immunoglobulin E (IgE) and other specific immunological

parameters, for example in mice

(b) Specific pulmonary responses in guinea pigs.

At this writing, recognized and validated animal models for the testing of respiratory

hypersensitivity are not available. Under certain circumstances, data from animal studies may

provide valuable information in a weight-of-evidence assessment.

The mechanisms by which substances induce symptoms of asthma are not yet fully known. For

preventive measures, these substances are considered respiratory sensitizers. However, if on the

basis of the evidence, it can be demonstrated that these substances induce symptoms of asthma

by irritation only in people with bronchial hyperactivity, they should not be considered as

respiratory sensitizers.

Classification Procedure and Guidance

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

Classification procedure

In classification, the data are compared to the respiratory sensitizer classification criteria. Data

can be found in literature, on SDSs, or be determined by testing, (which is not required by the

HCS). For classification of mixtures, follow the three-tier approach discussed below.

To assess the respiratory sensitization hazard of a chemical, identify the relevant data. Effects

seen in either humans or animals will normally justify classification using a weight-of-evidence

approach for respiratory sensitizers. The weight-of-evidence approach uses expert judgment. All

available information bearing on the respiratory sensitizer hazard classification is considered

together, including the results of relevant animal data, and human experience, such as

epidemiological and clinical studies and well-documented case reports and observations.

The quality and consistency of the data should be considered. Information on chemicals related

to the material being classified should be considered, as appropriate. Both positive and negative

results shall be considered together in a weight-of-evidence determination. However, positive

effects which are consistent with the respiratory sensitizer classification criteria, whether seen in

humans or animals, normally justify classification.

Where evidence is available from both humans and animals and there is a conflict between the

findings, evaluate the quality and reliability of the evidence from both sources. Reliable, good

119

quality human data generally takes precedence over other data. Positive results from well-

conducted animal studies are not necessarily negated by the lack of positive human experience

but require an assessment of the robustness, quality and statistical power of both the human and

animal data.

If the data are available, then you must classify the chemical into the appropriate respiratory

sensitization sub-category, i.e., category 1A or category 1B. If the data does not allow

classification into a sub-category, then you must classify the chemical in respiratory sensitization

category 1.

Skin Sensitizers

Definition and General Considerations

Skin sensitizer means a chemical that will lead to an allergic response following skin contact.

Skin Sensitizer Classification Criteria for Substances

Effects seen in either humans or animals will normally justify classification using a weight-of-

evidence approach for skin sensitizers. Substances may be allocated to one of the two sub-

categories, 1A or 1B, using a weight-of-evidence approach in accordance with the criteria given

below, and on the basis of reliable and good quality evidence from human cases or

epidemiological studies and/or observations from appropriate studies in experimental animals.

Where data are not sufficient for sub-categorization, skin sensitizers shall be classified in

Category 1.

Table VII.4.2. Hazard category and sub-categories for skin sensitizers

Category

Skin Sensitizer Criteria

Category 1

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

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.

With regard to the criteria for respiratory sensitization, the frequency of occurrence in humans is a matter of

expert judgment.

120

Human evidence

Human evidence for sub-category 1A may include:

(a) Positive responses at ≤ 500 μg/cm

(Human Repeat Insult Patch Test (HRIPT),

Human Maximization Test (HMT) – induction threshold);

(b) Diagnostic patch test data where there is a relatively high and substantial incidence of

reactions in a defined population in relation to relatively low exposure;

incidence of allergic contact dermatitis in relation to relatively low exposure.

Human evidence for sub-category 1B may include:

(a) Positive responses at > 500 μg/cm

(HRIPT, HMT – induction threshold);

(b) Diagnostic patch test data where there is a relatively low but substantial incidence of

reactions in a defined population in relation to relatively high exposure;

incidence of allergic contact dermatitis in relation to relatively high exposure.

Animal studies

Two types of in vivo methods to investigate skin sensitization tests have been developed: an

adjuvant test in which sensitization is potentiated by the injection of Freunds Complete Adjuvant

(FCA), and non-adjuvant tests. There are three animal test methods used to evaluate skin

sensitization for substances: the mouse local lymph node assay (LLNA), the guinea pig

maximization test (GPMT), and the Buehler occluded patch test. The Organization for Economic

Cooperation and Development (OECD) Guidelines describe test methods for skin sensitization:

Guideline 406, the Guinea Pig Maximization test and the Buehler guinea pig test and Guideline

429, the Local Lymph Node Assay. Other methods may be used provided that they are

scientifically validated. The Mouse Ear Swelling Test (MEST), appears to be a reliable screening

test to detect moderate to strong sensitizers, and can be used, in accordance with professional

judgment, as a first stage in the assessment of skin sensitization potential.

121

Animal test results for Skin Sensitization Category 1 include data with values indicated below:

Table VII.4.3. Animal test results for Skin Sensitization Category 1

Assay

Criteria

Adjuvant type test method for skin

sensitization

Response in at least 30% of the animals is considered

positive.

Non-adjuvant Guinea pig test method

Response in at least 15% of the animals is considered

positive.

Local lymph node assay

Stimulation index of three or more is considered a

positive response.

Animal test results for Skin Sensitization sub-category 1A can include data with values indicated

below:

Table VII.4.4. Animal test results for Skin Sensitization 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 the test chemical required to induce a

stimulation index of 3 in the local lymph node assay.

Animal test results for Skin Sensitization sub-category 1B can include data with values indicated

below:

Table VII.4.5. Animal test results for Skin Sensitization 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

122

Note: EC3 refers to the estimated concentration of the test chemical required to induce a

stimulation index of 3 in the local lymph node assay.

Immunological contact urticaria

Substances which cause immunological contact urticaria with or without meeting the criteria for

respiratory sensitizers shall be considered for classification as skin sensitizers.

There is no recognized animal model available to identify substances which cause

immunological contact urticaria. Therefore, classification will normally be based on human

evidence, similar to that for skin sensitization.

Classification procedure

In classification, the data are compared to the skin sensitizer classification criteria. Data can be

found in literature, on SDSs, or be determined by testing (which is not required by the HCS). For

mixtures, follow the three-tier approach discussed below.

For classification of a substance, evidence shall include one or more of the following conditions

using a weight-of-evidence approach:

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

clinic;

(b) Epidemiological studies showing allergic contact dermatitis caused by the substance;

Situations in which a high proportion of those exposed exhibit characteristic symptoms

are to be looked at with special concern, even if the number of cases is small;

(d) Positive data from experimental studies in humans;

(e) Well-documented episodes of allergic contact dermatitis, normally obtained in more

than one dermatology clinic;

(f) Severity of reaction.

Evidence from animal studies is usually much more reliable than evidence from human

exposure. However, in cases where evidence is available from both sources, and there is conflict

between the results, the quality and reliability of the evidence from both sources must be

assessed in order to resolve the question of classification on a case-by-case basis. Normally,

human data are not generated in controlled experiments with volunteers for the purpose of hazard

classification but rather as part of risk assessment to confirm lack of effects seen in animal tests.

Consequently, positive human data on skin sensitization are usually derived from case-control or

other, less defined studies. Evaluation of human data must, therefore, be carried out with caution

as the frequency of cases reflect, in addition to the inherent properties of the substances, factors

such as the exposure situation, bioavailability, individual predisposition and preventive measures

123

taken. Negative human data should not normally be used to negate positive results from animal

studies. For both animal and human data, consideration should be given to the impact of the

vehicle used.

If none of the above-mentioned conditions ((a)-(f) above) are met, the substance need not be

classified as a skin sensitizer. However, a combination of two or more indicators of skin

sensitization, as listed below, may alter the decision. This shall be considered on a case-by-case

basis.

(a) Isolated episodes of allergic contact dermatitis;

(b) Epidemiological studies of limited power, e.g., where chance, bias or confounders

have not been ruled out fully with reasonable confidence;

meet the criteria for a positive result described in 29 CFR 1910.1200 Paragraph

A.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) Positive data from non-standard methods;

(e) Positive results from close structural analogues.

If the data is available, then you must classify into the appropriate skin sensitization sub-

category, i.e., category 1A or category 1B. If the data does not allow classification into a sub-

category, then you must classify in skin sensitization category 1.

Sensitizer Classification Criteria for Mixtures

The approach to classifying mixtures for both skin and respiratory sensitizers incorporates a

tiered approach (i.e., stepwise procedure based on a hierarchy).

Tier 1: Classification of mixtures when data are available for the complete mixture

When reliable and good evidence from human experience or appropriate animal studies is

available for the mixture then it should be used in a weight-of-evidence approach using the same

criteria as those specified for substances. Care should be exercised in evaluating such data to

ensure the dose used does not render the results inconclusive. If test data for the mixture is not

available, then the classifier should consider the application of the criteria in Tier 2 or 3, as

appropriate.

124

Tier 2: Classification of mixtures when data are not available for the complete mixture –

bridging principles

Where the mixture itself has not been tested to determine its sensitizing properties, but there are

sufficient data on BOTH the individual ingredients AND similar tested mixtures to adequately

characterize the hazard of the mixture, these data can be used in accordance with the following

bridging principles.

All six bridging principles are applicable to the skin and respiratory sensitization classes:

 Dilution,

 Batching,

 Concentration of mixtures,

 Interpolation within one toxicity category,

 Substantially similar mixtures, and

 Aerosols.

The application of bridging principles ensures that the classification process uses the available

data to the greatest extent possible in characterizing the potential skin or respiratory sensitization

hazard.

Dilution

If a tested mixture is diluted with a diluent which is not a sensitizer and which is not

expected to affect the sensitization of other ingredients, then the new diluted mixture may

be classified as equivalent to the original tested mixture.

Batching

The sensitizing properties of a tested production batch of a mixture can be assumed to be

substantially equivalent to that of another untested production batch of the same

commercial product when produced by or under the control of the same manufacturer,

unless there is reason to believe there is significant variation such that the sensitization

potential of the untested batch has changed. If the latter occurs, a new classification is

necessary.

Concentration of mixtures

If a tested mixture is classified in Category 1 or sub-category 1A, and the concentration

of the ingredients of the tested mixture that are in Category 1 and sub-category 1A is

increased, the resulting untested mixture should be classified in Category 1 or sub-

category 1A without additional testing.

125

Interpolation within one category/sub-category

For three mixtures (A, B and C) with identical ingredients, where mixtures A and B have

been tested and are in the same sensitizer category/sub-category, and where untested

mixture C has the same sensitization toxicologically active ingredients as mixtures A and

B but has concentrations of sensitization toxicologically active ingredients intermediate

to the concentrations in mixtures A and B, then mixture C is assumed to be in the same

sensitizer category/sub-category as A and B.

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

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

mixture (ii);

(d) Ingredient B is a sensitizer and ingredients A and C are not sensitizers;

(e) A and C are not expected to affect the sensitizing properties of B.

If mixture (i) or (ii) is already classified by testing for sensitization, then the other

mixture can be assigned the same hazard category.

Aerosols

An aerosol form of the mixture may be classified in the same hazard category as the

tested non-aerosolized form of the mixture provided that the added propellant does not

affect the sensitizing properties of the mixture upon spraying.

If appropriate data is not available to apply the above bridging principles then the classifier

should consider the application of the cut-off value/concentration limit approach described in

Tier 3.

Tier 3: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

If there are not sufficient data to apply the bridging principles, then the third tier for sensitizers is

to classify the mixture using the cut-off/concentration limit approach.

126

The mixture shall be classified as a respiratory sensitizer when at least one ingredient has been

classified as a respiratory sensitizer and is present at or above the appropriate respiratory

sensitizer cut-off value/concentration limit for a solid/liquid or gas. See table below.

Table VII.4.6. Cut-off values/concentration limits of ingredients of a mixture classified as

respiratory sensitizers that would trigger classification of the mixture

Ingredient classified as:

Cut-off values/concentration limits

triggering classification of a mixture as:

Respiratory sensitizer Category 1

Solid/Liquid

Gas

Respiratory sensitizer Category 1

 0.1%

Respiratory sensitizer Sub-category 1A

 0.1%

Respiratory sensitizer Sub-category 1B

 1.0%

 0.2%

The mixture shall be classified as a skin sensitizer when at least one ingredient has been

classified as a skin sensitizer and is present at or above the appropriate skin sensitizer cut-off

value/concentration limit. See table below.

Table VII.4.7. Cut-off values/concentration limits of ingredients of a mixture classified as

skin sensitizers that would trigger classification of the mixture

Ingredient classified as:

Cut-off values/concentration limits

triggering classification of a mixture as:

Skin sensitizer Category 1

All physical states

Skin sensitizer Category 1

 0.1%

Skin sensitizer Sub-category 1A

 0.1%

Skin sensitizer Sub-category 1B

 1.0%

The respiratory and skin sensitization assessments are carried out separately.

Some chemicals that are classified as sensitizers may elicit a response, when present in a mixture

in quantities below the cut-offs established in the above tables in individuals who are already

sensitized to the chemical. 29 CFR 1910.1200 paragraph A.0.4.3.2 states that if the classifier has

information that the hazard of an ingredient will be evident (i.e., it presents a health risk) below

the above cut-off values/concentration limits, then the mixture should be classified according to

those lower cut-off values.

 If the classifier has reliable data that show the respiratory or skin sensitization potential of

an ingredient will not be evident above the cut-off values/concentration limits then the

mixture may be classified according to those higher substance specific cut-off values.

127

Decision logic

Decision logics for classifying respiratory and skin sensitizers are provided. The decision logics

are for both substances and mixtures and are provided as additional guidance. It is strongly

recommended that the person responsible for classification study the criteria before and during

use of the decision logics.

The decision logics are essentially flowcharts for classifying substances and mixtures regarding

sensitization. It presents questions in a sequence that walks you through the classification steps

and criteria for classifying respiratory and skin sensitizers. Once you answer the questions

provided, you will arrive at the appropriate classification.

128

Decision logic for respiratory sensitization

Substance: Does the substance have respiratory sensitization data?

Mixture: Does the mixture as a whole or its

ingredients have respiratory sensitization data?

Can bridging principles be applied?

Classification

not possible

Yes

(a) Is there evidence in humans that the

substance/mixture can lead to specific

respiratory hypersensitivity, and/or

(b) are there positive results from an appropriate

animal test?

Yes

Category 1

Danger

Not classified

Yes

Classify in

appropriate

category

Does the mixture contain one or more ingredients classified

as a respiratory sensitizer at:

(a)

 0.1% w/w (solid/liquid)?

(b)

 1.0% w/w (solid/liquid)?

(c)

 0.1% v/v (gas)?

(d)  0.2% v/v (gas)?

Yes

Not classified

Category 1

Danger

Classification

not possible

Does the mixture as a whole have

respiratory sensitization data?

Yes

129

Decision logic for skin sensitization

Substance: Does the substance have skin sensitization data?

Mixture: Does the mixture as a whole or its

ingredients have skin sensitization data?

Classification

not possible

Yes

(a) Is there evidence in humans that the

substance/mixture can lead to sensitization

by skin contact in a substantial number of

persons, or

(b) Are there positive results from an appropriate

animal test?

Yes

Category 1

Warning

Not classified

Yes

Classification

not possible

Does the mixture as a whole have skin

sensitization data?

Yes

Can bridging principles be applied?

Yes

Classify in

appropriate

category

Does the mixture contain one or more ingredients classified

as a skin sensitizer at:

(a)

 0.1% ?

(b)  1.0%?

Yes

Not classified

Category 1

Warning

130

Respiratory and Skin Sensitization Classification Examples

The following examples are provided to walk you through respiratory and/or skin sensitization

classification.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Respiratory and Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

The material is a new isocyanate.

No data are available for the new

material. The test substance has

Structure Activity Relationships

(SAR) to substances with similar

structure known to be respiratory

and skin sensitizers in humans

(e.g., methyl isocyanate).

Respiratory

Sensitizer

Category 1

Skin Sensitizer

Category 1

(cannot

differentiate sub-

categories since

this is not based on

data for the actual

substance)

Fulfills criteria.

Based on expert judgment using

SAR information the classifier

concluded that classification as a

Category 1 Respiratory Sensitizer

and Category 1 Skin Sensitizer is

justified, since there is ample

available data on isocyanates that are

respiratory and skin sensitizers in

humans.

Substance Example #2

Respiratory Sensitization

Test Data

HCS 2012

Classification

Rationale

The material is an enzyme with

many well-documented human

case studies for respiratory

sensitization occurring in workers

exposed during the manufacturing

process.

Respiratory

Sensitizer

Category 1

Fulfills criteria.

Because of the clear evidence from

valid human studies, classification

for respiratory sensitization is

warranted.

131

Substance Example #3

Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

In an OECD Test Guideline 406

Skin Sensitization study, 4

animals out of 10 had a positive

response.

In a Freund’s Complete Adjuvant

test in guinea pigs, 4 animals out

of 8 showed a positive reaction.

Skin Sensitizer

Category 1

Fulfills Category 1 criteria.

The criteria for Skin Sensitizer

Category 1 classification are

fulfilled, since in two independent

adjuvant tests the response was ≥

30% positive.

Substance Example #4

Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

Toxicity data: A high frequency

of well documented human case

reports on contact sensitization at

very low concentrations (≤ 500

µg/cm

) and in addition positive

animal study results showing a

high potency

Skin Sensitizer,

Category 1A

Fulfills Category 1A criteria.

The classification criteria are

fulfilled based both on human and

animal evidence.

Substance Example #5

Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

Substance X gave a positive

result in the Local Lymph Node

Assay (LLNA) with an EC3-

value of 10.4%.

Skin Sensitizer

Category 1B

Fulfills Category 1B criteria.

This EC3-value is above the

Category 1A criteria cut-off of 2%

and meets the Category 1B criteria.

132

Substance Example #6

Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

Substance Y tested positive in

the LLNA with an EC3-value of

0.5%.

In the Guinea Pig Maximization

Test (GPMT) a dermal induction

concentration of 0.375%

produced a positive response in

70% of the animals.

Skin Sensitizer

Category 1A

Fulfills Category 1A criteria

on the basis of the EC3-value and the

response in the GPMT.

Example of a mixture fulfilling the criteria for classification:

Mixture Example #1

Skin Sensitization

Data

HCS 2012

Classification

Rationale

Component data:

Component 2: 20%, Skin

Sensitization Category 1B

Skin Sensitization

Category 1B

Fulfills cutoff value criteria.

Component 2 is 20% which is ≥1%

Skin Sensitization Category 1B

criteria are fulfilled.

133

Examples of mixtures and substances not fulfilling the criteria for classification:

Mixture Example #2

Skin Sensitization

Data

HCS 2012

Classification

Rationale

Component data:

Component 3: 0.8%, Skin

Sensitization Category 1B

Not classified for

skin sensitization

While a component meets the criteria

for Skin Sensitization Category 1B,

the component is present in the

mixture at less than the cutoff value

for Skin Sensitization Category 1B.

The mixture criteria for Skin

Sensitization Category 1B are not

fulfilled.

Substance Example #7

Skin Sensitization

Test Data

HCS 2012

Classification

Rationale

In the LLNA a maximum

stimulation index of 2.2 was

reported.

Not classified for

skin sensitization

The criteria for Skin Sensitization

Category 1 is not met since the

maximum stimulation index is less

than 3.

134

References

29 CFR 1910.1200, Hazard Communication, Appendix A.4, Respiratory or Skin Sensitization

29 CFR 1910.1200, Hazard Communication, Appendix C, Allocation of Label Elements

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

135

VII.5 Germ Cell Mutagenicity

Introduction

Genotoxicity is a toxic end-point which may be associated with somatic mutation and germ cell

mutation. A chemical’s ability to induce germ cell mutations, which may continue to affect

future generations, is an important consideration in the protection of human health.

Genetic effects result from damage to DNA and altered genetic expression. This process is

known as mutagenesis. The genetic change is referred to as a mutation and the agent causing the

change as a mutagen.

There are several types of genetic change: Gene mutation is a change in DNA sequence within a

gene. Chromosome aberrations are changes in the chromosome structure. Aneuploidy/polyploidy

is an increase or decrease in the number of chromosomes.

Mutagenicity refers to the ability of some chemicals to modify the genetic material in the nucleus

of cells in ways that allow the changes to be transmitted during cell division. Germ cell

mutations occur in germinal cells – (sperm and ova) – where there is no effect on the exposed

person; rather the effect is passed on to future generations. Somatic mutations occur in other cell

types (all body cells except sperm and ova), and may result in cell death (e.g., teratogenesis) or

the transmission of a genetic defect to other cells in the same tissue. Current genotoxicity tests

are aimed largely at detecting somatic cell mutations and are used as predictive indicators of

carcinogenic potential. Relatively few genotoxic agents have been demonstrated to affect germ

cells in vivo.

Definition and General Considerations

A mutation is defined as a permanent change in the amount or structure of the genetic material in

a cell. The term mutation applies both to heritable genetic changes that may be manifested at the

phenotypic level and to the underlying DNA modifications when known (including, for example,

specific base pair changes and chromosomal translocations). The terms mutagenic and mutagen

will be used for agents giving rise to an increased occurrence of mutations in populations of cells

and/or organisms.

The more general terms genotoxic and genotoxicity apply to agents or processes which alter the

structure, information content, or segregation of DNA, including those which cause DNA

damage by interfering with normal replication processes, or which in a non-physiological

manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators

for mutagenic effects.

This hazard class is primarily concerned with chemicals that may cause mutations in the germ

cells of humans that can be transmitted to the progeny. However, mutagenicity/genotoxicity tests

in vitro and in mammalian somatic cells in vivo are also considered in classifying substances and

mixtures within this hazard class.

136

Classification Criteria for Substances

There are two hazard categories for germ cell mutagens to accommodate the weight-of-evidence

available. Category 1 is subdivided into two subcategories according to specific criteria outlined

below.

Table VII.5.1. Hazard categories for germ cell mutagens

Category

Criteria

CATEGORY 1

Substances known to induce heritable mutations or to be regarded

as if they induce heritable mutations in the germ cells of humans

Category 1A

Substances known to induce heritable mutations in

germ cells of humans

Positive evidence from human epidemiological studies.

Category 1B

Substances which should be regarded as if they induce heritable

mutations in the germ cells of humans

(a) Positive result(s) from in vivo heritable germ cell mutagenicity tests

in mammals; or

(b) Positive result(s) from in vivo somatic cell mutagenicity tests in

mammals, in combination with some evidence that the substance has

potential to cause mutations to germ cells. This supporting evidence

may, for example, be derived from mutagenicity/genotoxicity tests in

germ cells in vivo, or by demonstrating the ability of the substance or its

metabolite(s) to interact with the genetic material of germ cells; or

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 a chemical structure activity

relationship to known germ cell mutagens, should be considered for

classification as Category 2 mutagens.

137

Specific considerations for classification of substances as germ cell mutagens

The HCS is hazard-based, classifying chemicals on the basis of their intrinsic ability to induce

mutations in germ cells. The HCS criteria are not meant for the quantitative risk assessment of

chemical substances.

For classification, test results are considered from experiments determining mutagenic and/or

genotoxic effects in germ and/or somatic cells of animals. Mutagenic and/or genotoxic effects

determined in in vitro tests shall also be considered. Examples of various tests for mutagenic

effects are given later in this chapter.

Classification for heritable effects in human germ cells is made on the basis of scientifically

validated tests. Evaluation of the test results shall be done using expert judgment and all the

available evidence shall be weighed for classification.

The classification of substances shall be based on the total weight-of-evidence available, using

expert judgment. In those instances where a single well-conducted test is used for classification,

it shall provide clear and unambiguously positive results. The relevance of the route of exposure

used in the study of the substance compared to the route of human exposure should also be taken

into account.

Classification criteria for mixtures

It should be noted that the HCS classification criteria for health hazards often include a tiered

scheme in which test data available on the complete mixture are considered as the first tier in the

evaluation, followed by the applicable bridging principles, and lastly, cut-off

values/concentration limits or additivity. However, this approach is not used for Germ Cell

Mutagenicity. The criteria for Germ Cell Mutagenicity consider the cut-off values/concentration

limits as the primary tier and allow the classification to be modified only on a case-by-case

evaluation based on available test data for the mixture as a whole.

Tier 1: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

The mixture will be classified as a mutagen when at least one ingredient has been classified as a

Category 1A, Category 1B or Category 2 mutagen and is present at or above the appropriate cut-

off value/concentration limit specified below for Category 1 and Category 2, respectively.

An assessment is carried out separately for each Category 1A, Category1B or Category 2

ingredient in the mixture. In the case where the mixture has Category 1A, Category 1B and

Category 2 ingredients above the cut-off/concentration limit the mixture is classified in the most

severe category.

138

Table VII.5.2. Cut-off values/concentration limits of ingredients of a mixture classified as

germ cell mutagens that would trigger classification of the mixture

Ingredient

classified as:

Cut-off/concentration limits triggering

classification of a mixture as:

Category 1 mutagen

Category 2 mutagen

Category 1A

Category 1B

Category 1A mutagen

 0.1%

Category 1B 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).

Tier 2: Classification of mixtures when data are available for the complete mixture

On a case-by-case basis the Germ Cell Mutagenicity classification, which normally considers

results obtained with the individual ingredients, may be modified using available test data for the

mixture as a whole.

The concern with using test data for the mixture as a whole is that as the concentration of a germ

cell mutagen is reduced in a mixture, the dilution effect may result in a misleading test result

(i.e., false negative) if the study was not appropriately designed to factor in the concentration of

the germ cell mutagen in the mixture. In these cases, mixtures that could cause Germ Cell

Mutation would not be classified and labeled. Accordingly, the HCS states that the test results

for the mixture as a whole must be conclusive taking into account dose, and other factors such as

duration, observations and analysis (e.g., statistical analysis, test sensitivity) of germ cell

mutagenicity test systems. If appropriate test data for the mixture is not available then the

classifier can consider the application of the Bridging Principle criteria in Tier 3, if appropriate,

or as stated above use the classification resulting from the application of criteria in Tier 1.

Tier 3: Classification of mixtures when data are not available for the complete mixture -

bridging principles

Where the mixture itself has not been tested to determine its germ cell mutagenicity hazard, but

there are sufficient data on BOTH the individual ingredients AND similar tested mixtures to

adequately characterize the hazards of the mixture, these data can be used in accordance with the

below bridging principles. If data on another mixture are used in the application of the bridging

principles, the data on that mixture must be conclusive as discussed above in Tier 2.

139

Only the following bridging principles are applicable to the Germ Cell Mutagenicity

hazard class:

 Dilution,

 Batching,

 Substantially similar mixtures.

Dilution

If a tested mixture is diluted with a diluent which is not expected to affect the germ cell

mutagenicity of other ingredients, then the new diluted mixture may be classified as

equivalent to the original tested mixture.

Batching

The germ cell mutagenic potential of a tested production batch of a mixture can be

assumed to be substantially equivalent to that of another untested production batch of the

same commercial product, when produced by or under the control of the same

manufacturer, unless there is reason to believe there is significant variation in

composition such that the germ cell mutagenic potential of the untested batch has

changed. If the latter occurs, a new classification is necessary.

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

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

mixture (ii);

(d) Data on toxicity for A and C are available and substantially equivalent, i.e.

they are in the same hazard category and are not expected to affect the germ cell

mutagenicity of B.

If mixture (i) or (ii) is already classified by testing, then the other mixture can be

classified in the same hazard category.

140

Classification Procedure and Guidance

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

Examples of scientifically validated test methods

There are a number of scientifically recognized methods for investigation of mutagenic effects.

Examples of in vivo heritable germ cell mutagenicity tests are:

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

(b) Mouse heritable translocation assay (OECD 485)

Examples of in vivo somatic cell mutagenicity tests are:

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

(b) Mouse spot test (OECD 484)

Examples of mutagenicity/genotoxicity tests in germ cells are:

(a) Mutagenicity tests:

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

(ii) Spermatid micronucleus assay

(b) Genotoxicity tests:

(i) Sister chromatid exchange analysis in spermatogonia

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

Examples of genotoxicity tests in somatic cells are:

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

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

Examples of in vitro mutagenicity tests are:

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

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

As new, scientifically validated tests arise, these may also be used in the total weight-of-evidence

to be considered.

Classification procedure

In classification, the data are compared to the germ cell mutagenicity classification criteria. Data

can be found in literature, on SDSs, or be determined by testing (which is not required by the

HCS). For mixtures, follow the above modified three-tier approach.

141

Classification is made on the basis of the appropriate criteria and an assessment of the total

weight-of-evidence. The validity and usefulness of each of the data sets to the overall assessment

of mutagenicity should be individually assessed, taking account of protocol design (including

route of administration) and current expert views on the value of the test systems. See

considerations below.

If the data is available, then you must classify into the appropriate germ cell mutagenicity sub-

category, i.e., Category 1A or Category 1B. If the data does not allow classification into a sub-

category, then you must classify in germ cell mutagenicity category 1.

Currently, there is no example of a substance classified in germ cell mutagen category 1A. To

date, epidemiological studies have not provided evidence to classify a substance as a Category

1A mutagen. Hereditary diseases in humans for the most part have an unknown origin and show

a varying distribution in different populations. Due to the random distribution of mutations in the

genome it is not expected that one particular substance would induce one specific genetic

disorder. It is unlikely that epidemiological studies will provide evidence for classifying a

substance as a Category 1A mutagen.

Considerations

Considerations When Evaluating Negative Test Results

Doses or concentrations

Were the doses or concentrations of test substance used high

enough?

Sensitivity of test system

Was the test system used sensitive to the nature of

the genotoxic changes that might have been expected?

Volatility of the test

substance

Were the concentrations maintained in tests conducted in vitro?

Metabolism

Was the metabolic activation suitable in the test systems in vitro?

Exposure to target organ

Was the substance reaching the target organ, for studies in vivo?

(taking also toxicokinetic data into consideration)

Reactivity of the substance

Was the test substance reactive? (e.g., rate of hydrolysis,

electrophilicity, presence or absence of structural alerts and other

available indications)

Response in the control

What was the response of the positive and negative controls?

142

Considerations When Evaluating Positive/Contradictory Test Results

Conflicting results

Conflicting results obtained in non-mammalian systems and in

mammalian cell tests may be addressed by considering possible

differences in substance uptake, metabolism or in the

organization of genetic material. The results of mammalian tests

may be considered of higher significance.

Positive in the in vitro

SCE assay

Positive results in the in vitro SCE assay should be viewed with

caution, as this assay is associated with a relatively high

incidence of false positive results. Thus, a positive result in this

assay would not be considered to be evidence of a significant

clastogenic potential in vitro if negative results were available in

an in vitro chromosome aberration assay.

Positive in the DNA

binding assay

Interpretation of results from DNA binding assays should be

viewed with caution as these assays are only considered to be

indicators of DNA damage. Consequently, the observance of in

vivo DNA adducts alone in the absence of positive findings from

in vitro assays is generally not considered sufficient evidence of

a significant genotoxic potential in vivo.

Contradiction between in

vitro and in vivo

If contradictory findings are obtained in vitro and in vivo, in

general, the results of in vivo tests indicate a higher degree of

reliability. However, for evaluation of negative results in vivo, it

should be considered whether there is adequate evidence of

target tissue exposure.

Sensitivity and specificity

of test systems

The sensitivity and specificity of different test systems varies for

different classes of substances. If available testing data for other

related substances permits assessment of the performance of

difference assays for the class of substance under evaluation, the

result from the test system known to produce more accurate

responses would be given higher priority.

Positive in high toxic

concentration

The consequences of “positive” findings only at highly

toxic/cytotoxic concentrations, and the presence or absence of a

dose-response relationship should be considered. The default

assumption for genotoxic chemicals, in the absence of

mechanistic evidence to the contrary, is that they have a linear

dose response relationship. However, both direct and indirect

mechanisms of genotoxicity can be non-linear or threshold, and

sometimes this default assumption may be inappropriate. When

interpreting positive results, considerations of the dose-response

relationship and of possible mechanisms of action are important

components of a hazard assessment.

143

Considerations When Evaluating Positive/Contradictory Test Results

Expert judgment

Conflicting results may also be available from the same test,

performed by different laboratories or on different occasions. In

this case, expert judgment should be used to reach an overall

evaluation of the data. In particular, the quality of each of the

studies and of the data provided should be evaluated, with

special consideration of the study design, reproducibility of data,

dose-effect relationships, and biological relevance of the

findings. The purity of the test substance may also be a factor to

take into account. In the case where an OECD guideline is

available for a test method, the quality of a study using the

method is regarded as being higher if it was conducted in

compliance with the requirements stated in the guideline.

Furthermore, studies compliant with Good Laboratory Practices

(GLP) may be regarded as being of a higher quality.

Decision Logic

Two decision logics for classifying germ cell mutagenicity are provided. The first decision logic

is for substances. Use the second decision logic for classifying mixtures. The decision logics are

provided as additional guidance. It is strongly recommended that the person responsible for

classification study the criteria before and during use of the decision logics.

These decision logics are essentially flowcharts for classifying substances and mixtures

regarding germ cell mutagenicity. They present questions in a sequence that walks you through

the classification steps and criteria for classifying germ cell mutagenicity. Once you answer the

questions provided, you will arrive at the appropriate classification.

144

Substance decision logic for germ cell mutagenicity

Continued on next page

Substance: Does the substance have data on mutagenicity?

Classification

not possible

Yes

According to the criteria, is the substance:

(a)

Known

to induce heritable mutations in germ cells of humans, or

(b) Should it be

regarded as if it induces heritable mutations in the

germ cells of humans?

Application of the criteria needs expert judgment in a weight-of-

evidence approach.

Yes

Category 1

Danger

Category 2

Warning

Not classified

According to the criteria, does the substance cause concern for

humans owing to the possibility that it

may induce heritable

mutations in the germ cells of humans?

Application of the criteria needs expert judgment in a weight-of-

evidence approach.

Yes

145

Mixtures decision logic for germ cell mutagenicity

Mixture:

Classification of mixtures will be based on the available test data for the

individual ingredients

of the

mixture, using cut-off values/concentration limits for those ingredients. The classification may be

modified on a case-by-case basis based on the available test data for the mixture itself or based on

bridging principles. See modified classification on a case-by-case basis below.

Yes

Does the mixture contain one or more ingredients classified as

a Category 2 mutagen at:

 1.0%?

Does the mixture contain one or more ingredients classified

as a Category 1 mutagen at:

 0.1%?

Not classified

Yes

Category 2

Warning

Classification based on individual ingredients of the mixture

Category 1

Danger

Are test data available

for the mixture itself?

Yes

Can bridging principles be applied? If data on another

mixture are used, data on that mixture must be conclusive.

Are the test results on the mixture

conclusive taking into account dose

and other factors such as duration,

observations and analysis (e.g.

statistical analysis, test sensitivity) of

germ cell mutagenicity test systems?

Classify in

appropriate

category

Danger

Warning

classification

Classification based on individual

ingredients of the mixture (see above).

Yes

Classification based on a case-by-case basis

146

Germ cell mutagenicity Classification Examples

The following examples are provided to walk you through germ cell mutagenicity classification.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Germ Cell Mutagenicity

Test Data

HCS 2012

Classification

Rationale

Positive result in the Rodent

Dominant Lethal Mutation Test

(OECD Test Guideline 478)

Germ Cell

Mutagenicity

Category 1B

The test result fulfills the Germ Cell

Mutagenicity Category 1B

classification criteria of a positive

result from an in vivo heritable germ

cell mutagenicity test in mammals.

Substance Example #2

Germ Cell Mutagenicity

Test Data

HCS 2012

Classification

Rationale

Positive result in the Mammalian

Bone Marrow Chromosome

Aberration Test (OECD Test

Guideline 475)

Germ Cell

Mutagenicity

Category 2

The test result fulfills the Germ Cell

Mutagenicity Category 2

classification criteria of positive

evidence obtained from a somatic

cell mutagenicity test in vivo in

mammals

147

Example of a mixture fulfilling the criteria for classification:

Mixture Example #1

Germ Cell Mutagenicity

Data

HCS 2012

Classification

Rationale

Component data:

Component 1:0.09%, GCM

Category 1B

Component 2: 3%, GCM

Category 2

Component 3: 2%, GCM

Category 1B

Germ Cell

Mutagenicity

Category 1B

The GCM cut-off

values/concentration limits are used

for classification.

 Component 1 is not ≥ 0.1% so the

mixture does not meet the

Category 1B criteria.

 Component 2 is ≥ 1.0% so the

mixture meets the Category 2

criteria.

 Component 3 is ≥ 0.1% so the

mixture meets the Category 1B

criteria.

When the criteria are satisfied by

more than one ingredient for more

than one category the most severe

category is used to classify the

mixture. Therefore, this mixture is

classified as Germ Cell Mutagen

Category 1B.

148

References

29 CFR 1910.1200, Hazard Communication, Appendix A.5 Germ Cell Mutagenicity

29 CFR 1910.1200, Hazard Communication, Appendix C, Allocation of Label Elements

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

149

VII.6 Carcinogenicity

Introduction

The terminology used to describe cancer may be confusing. Cancer is a type of tumor. A tumor

(also known as a neoplasm) is simply an uncontrolled growth of cells. Tumors may be benign or

malignant. Benign tumors grow only at the site of origin, and do not invade adjacent tissues or

go to distant sites in the body (known as “metastasis”). Except for those that develop deep in

vital organs (such as the brain), benign tumors can be successfully treated (usually by surgical

removal) and the potential for causing death is low. Malignant tumors are cancers and can grow

outside their original site in an organ, invade surrounding tissue, or metastasize to distant organs

where they can start new growths of the cancerous tissue. Cancers vary greatly in type and

behavior in the body. Some cancers grow slowly and rarely metastasize. Others are highly

invasive and metastasize rapidly. Cancers are usually named for the specific cell type or organ of

origination. For example, squamous cell carcinoma of the lung is a cancer that arose from a

squamous cell in the lung. A hepatocellular carcinoma is a cancer arising from a liver cell

(hepatocyte). Sometimes the name given to a cancer also reflects its nature. For example, chronic

lymphocytic leukemia is a cancer involving lymphocytes (a type of blood cell) in which the

leukemia is chronic or long-lasting in nature. OSHA, NTP, and IARC list the specific chemicals

they consider to be carcinogens. These lists will be discussed later in this chapter.

Definition and General Considerations

Carcinogen means a substance or a mixture of substances which induces cancer or increases its

incidence. Substances and mixtures which have induced benign and malignant tumors in well-

performed experimental studies on animals are considered also to be presumed or suspected

human carcinogens unless there is strong evidence that the mechanism of tumor formation is not

relevant for humans.

Classification of a substance or mixture as posing a carcinogenic hazard is based on its inherent

properties and does not provide information on the level of the human cancer risk which the use

of the substance or mixture may represent.

Classification Criteria for Substances

For the purpose of classification for carcinogenicity, substances are allocated to one of two

categories based on strength of evidence and additional weight-of-evidence considerations. In

certain instances, route-specific classification may be warranted.

150

Table VII.6.1 Hazard categories for carcinogens

Category

Criteria

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.

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. 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.

151

Where OSHA has included cancer as a health hazard to be considered by classifiers for a

chemical covered by 29 CFR part 1910, Subpart Z, Toxic and Hazardous Substances, chemical

manufacturers, importers, and employers shall classify the chemical as a carcinogen. See the

table below for the substance-specific OSHA standards listing cancer as a health effect.

Table VII.6.2 Standards listing cancer as a health effect

Standard Number

Substance

1910.1001

Asbestos

1910.1003

4-Nitrobiphenyl

1910.1004

alpha-Naphthylamine

1910.1006

Methyl chloromethyl ether

1910.1007

3,'-Dichlorobenzidine (and its salts)

1910.1008

bis-Chloromethyl ether

1910.1009

beta-Naphthylamine

1910.1010

Benzidine

1910.1011

4-Aminodiphenyl

1910.1012

Ethyleneimine

1910.1013

beta-Propiolactone

1910.1014

2-Acetylaminofluorene

1910.1015

4-Dimethylaminoazobenzene

1910.1016

N-Nitrosodimethylamine

1910.1017

Vinyl chloride

1910.1018

Inorganic arsenic

1910.1026

Chromium VI

1910.1027

Cadmium

1910.1028

Benzene

1910.1029

Coke oven emissions

1910.1044

1,2-dibromo-3-chloropropane

1910.1045

Acrylonitrile

1910.1047

Ethylene oxide

1910.1048

Formaldehyde

1910.1050

Methylenedianiline

1910.1051

1,3-Butadiene

1910.1052

Methylene chloride

Specific considerations for classification of substances as carcinogens

Classification as a carcinogen is made on the basis of evidence from reliable and acceptable

methods, and is intended to be used for substances which have an intrinsic property to produce

such toxic effects. The evaluations are to be based on all existing data, peer-reviewed published

studies and additional data accepted by regulatory agencies.

152

Carcinogen classification is a one-step, criterion-based process that involves two interrelated

determinations: evaluations of strength of evidence and consideration of all other relevant

information to place substances with human cancer potential into hazard categories.

Strength of evidence involves the enumeration of tumors in human and animal studies and

determination of their level of statistical significance. Sufficient human evidence demonstrates

causality between human exposure and the development of cancer, whereas sufficient evidence

in animals shows a causal relationship between the agent and an increased incidence of tumors.

Limited evidence in humans is demonstrated by a positive association between exposure and

cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when

data suggest a carcinogenic effect, but are less than sufficient to demonstrate causation.

(Guidance on consideration of important factors in the classification of carcinogenicity and a

more detailed description of the terms “limited” and “sufficient” have been developed by the

International Agency for Research on Cancer (IARC) and are provided in non-mandatory

Appendix F to the HCS. See below detailed discussion.)

Weight-of-evidence: Beyond the determination of the strength of evidence for carcinogenicity, a

number of other factors should be considered that influence the overall likelihood that an agent

may pose a carcinogenic hazard in humans. These factors will be discussed later in this chapter.

Sources for establishing that a substance is a carcinogen or potential carcinogen

The following sources may be treated as establishing that a substance is a carcinogen or potential

carcinogen for hazard communication purposes in lieu of applying the criteria described in Table

VII.6.1:

 National Toxicology Program (NTP), “Report on Carcinogens” (latest edition)

 International Agency for Research on Cancer (IARC) “Monographs on the Evaluation of

Carcinogenic Risks to Humans” (latest editions).

When performing classifications, the HCS provides classifiers with the option of relying on the

classification listings of IARC and NTP to make classification decisions regarding

carcinogenicity, rather than applying the criteria themselves. This will make classification easier,

as well as lead to greater consistency in carcinogen classification. In addition, the HCS has

provided guidance on hazard classification for carcinogenicity in non-mandatory Appendix F to

29 CFR 1910.1200. Part A of Appendix F includes background guidance provided by the GHS

based on the Preamble of the IARC “Monographs on the Evaluation of Carcinogenic Risks to

Humans” (2006). Part B provides IARC classification information. Part C provides background

guidance from the National NTP “Report on Carcinogens” (RoC), and Part D is a table that

compares HCS carcinogen hazard categories to carcinogen classifications under IARC and NTP,

allowing classifiers to be able to use information from IARC and NTP RoC carcinogen

classifications to complete their classifications under the HCS. The table relating carcinogen

classification information from IARC and NTP to the HCS is provided below.

153

Table VII.6.3 Approximate Equivalences Among Carcinogen Classification Schemes

Approximate Equivalences Among Carcinogen Classification Schemes

IARC

HCS

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:

1. Limited evidence of carcinogenicity from studies in humans (corresponding to IARC

2A/HCS 1B);

2. Sufficient evidence of carcinogenicity from studies in experimental animals (again,

essentially corresponding to IARC 2A/HCS 1B);

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

a. The agent, substance, or mixture belongs to a well-defined, structurally-related class of

substances whose members are listed in a previous RoC as either ‘‘Known’’ or

‘‘Reasonably Anticipated’’ to be a human carcinogen, or

b. There is convincing relevant information that the agent acts through mechanisms

indicating it would likely cause cancer in humans.

OSHA considers the determinations of IARC and NTP as sufficient evidence in establishing the

classification of a carcinogen. If the classifier uses the determinations of IARC or NTP then they

do not have to conduct their own weight-of-evidence evaluation with regards to carcinogenicity.

However, if the classifier does perform their own hazard evaluation and their determination

differs from that of IARC and/or NTP, they would need to justify with evidence why their

classification result differs from that of IARC and/or NTP.

In addition, the National Institute for Occupational Safety and Health (NIOSH) has revised its

policy for classifying carcinogens. The updated policy evaluates the carcinogen hazard

assessments made by NTP, IARC, and the Environmental Protection Agency (EPA) and aligns

their cancer designations into the appropriate HCS carcinogen categories. The classification

scheme developed by NIOSH is an acceptable alternative to using Table VII.6.3.

Classification Procedure and Guidance

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

154

Examples of scientifically validated test methods

There are a number of scientifically validated methods for investigation of carcinogenic effects:

 OECD Test Guideline 451: Carcinogenicity Studies

 OECD Test Guideline 453: Combined Chronic Toxicity/Carcinogenicity Studies

Other test methodologies that meet the requirements for testing carcinogenicity potential include:

Carcinogenicity Studies:

 USEPA OTS code: 798.3300;

 USEPA OPP code: 83-2;

 USEPA OPPTS code: 870.4200;

Combined Chronic Toxicity and Carcinogenicity Studies:

 USEPA OTS code: 798.3320;

 USEPA OPP code: 83-5;

 USEPA OPPTS code: 870.4300;

The objective of a long-term carcinogenicity study is to observe test animals for a major portion

of their life span for the development of neoplastic lesions during or after exposure to various

doses of a test substance by an appropriate route of administration.

Carcinogenicity Studies (also known as Oncogenicity Studies) are performed to determine the

carcinogenic potential and dose-response relationships of the test chemical. They produce data

on the production of tumors as well as pre-neoplastic lesions and other indications of chronic

toxicity that may provide evidence of treatment-related effects and insights into the mechanism

of carcinogenesis. Given that development of tumors is age-related and that large groups are

required to detect increases in treated animals, carcinogenicity studies are normally conducted in

small rodents (usually mice and rats) over most of their life span.

Combined Chronic Toxicity/Carcinogenicity Studies encompass both neoplastic effects and

general toxicity, including neurological, physiological, biochemical, hematological and

pathological effects. Typically, rats are used for combined chronic toxicity/carcinogenicity

assessment except in respect of the dermal route, for which mice are preferred. The study design

incorporates groups of treated and control animals scheduled for interim sacrifice after 12

months of study for investigation of pathological abnormalities that are uncomplicated by age-

related changes. OECD Test Guideline 453 and US EPA Health Effects Test Guidelines

870.4300 specify the same duration of exposure as in carcinogenicity studies.

155

Classification procedure

In classification, the data are compared to the carcinogenicity classification criteria. Data can be

found in literature, on SDSs, or be determined by testing (which is not required by the HCS). For

mixtures follow the modified three-tier approach discussed below.

If the data is available, then you must classify into the appropriate carcinogenicity sub-category,

i.e., category 1A or category 1B. If the data does not allow classification into a sub-category,

then you must classify in carcinogenicity category 1.

This guidance discusses some additional considerations in classification and an approach to

analysis, rather than hard-and-fast rules. It is consistent with 29 CFR 1910.1200 Appendix A.6,

and should help in evaluating information to determine carcinogenicity.

The terms “sufficient” and “limited” evidence are used in the HCS as they have been defined by

IARC and are outlined below.

Carcinogenicity in humans

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

following 2 categories:

Sufficient evidence of

carcinogenicity in humans:

A causal relationship has been established between exposure to

the agent and human cancer. That is, a positive relationship has

been observed between the exposure and cancer in studies in

which chance, bias and confounding could be ruled out with

reasonable confidence.

Limited evidence of

carcinogenicity in humans:

A positive association has been observed between exposure to the

agent and cancer for which a causal interpretation is considered

by the Working Group to be credible, but chance, bias or

confounding could not be ruled out with reasonable confidence.

156

Carcinogenicity in experimental animals

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

following 2 categories:

Sufficient evidence of

carcinogenicity in

experimental animals:

A causal relationship has been established between the agent and

an increased incidence of malignant neoplasms or of an

appropriate combination of benign and malignant neoplasms in

two or more species of animals or two or more independent

studies in one species carried out at different times or in different

laboratories or under different protocols. An increased incidence

of tumors in both sexes of a single species in a well-conducted

study, ideally conducted under Good Laboratory Practices, can

also provide sufficient evidence.

Exceptionally, a single study in one species and sex might be

considered to provide sufficient evidence of carcinogenicity when

malignant neoplasms occur to an unusual degree with regard to

incidence, site, type of tumor or age at onset, or when there are

strong findings of tumors at multiple sites.

Limited evidence of

carcinogenicity in

experimental animals:

The data suggest a carcinogenic effect but are limited for making

a definitive evaluation because, e.g., the evidence of

carcinogenicity is restricted to a single experiment; there are

unresolved questions regarding the adequacy of the design,

conduct or interpretation of the studies; the agent increases the

incidence only of benign neoplasms or lesions of uncertain

neoplastic potential; or the evidence of carcinogenicity is

restricted to studies that demonstrate only promoting activity in a

narrow range of tissues or organs.

Guidance on how to consider important factors in classification of carcinogenicity

Carcinogenicity classification is based on strength of evidence and additional weight-of-evidence

considerations. The weight-of-evidence analysis called for in the HCS is an integrative approach

that considers important factors in determining carcinogenic potential along with the strength of

evidence analysis.

The full list of factors that influence this determination is very lengthy, but some of the important

ones are considered here. Factors can be viewed as either increasing or decreasing the level of

concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon

the amount and coherence of evidence bearing on each. Generally there is a requirement for

more complete information to decrease than to increase the level of concern.

Additional considerations (weight-of-evidence) should be used in evaluating the tumor findings

and the other factors in a case-by-case manner. Some important factors which may be taken into

consideration, when assessing the overall level of concern are summarized below.

157

Factors that increase concerns

Tumor type and

background incidence

A carcinogen that increases the incidence of a neoplastic disease

that is rare in the test species or strain is of greater concern than a

carcinogen that increases the incidence of a neoplasm having a

high spontaneous incidence.

Unusual tumor types or tumors occurring with reduced latency

may add to the weight-of-evidence for the carcinogenic potential

of a substance, even if the tumors are not statistically significant.

Reduced tumor latency

Unusual tumor types or tumors occurring with reduced latency

may add to the weight-of-evidence for the carcinogenic potential

of a substance, even if the tumors are not statistically significant.

Progression of lesions to

malignancy

At first, it may appear logical that a carcinogen that increases

only benign tumors in experimental animals is of lesser

significance to human health than a test chemical that causes

malignancies. However, it should never be assumed that an agent

that causes benign tumors in animals will not cause malignancy

in humans. In any case, benign tumors are potentially serious,

even lethal, depending on their size, growth rate and site of

origin.

Multiple responses

The formation of tumors at several sites is viewed with greater

concern than tumor formation at a single site.

Whether responses are in

single or both sexes

It is worth observing that a carcinogenic response in experimental

animals is more significant for human health if it occurs in more

than one species and/or in both sexes.

If tumors are seen only in one sex of an animal species, the mode

of action should be carefully evaluated to see if the response is

consistent with the postulated mode of action. Effects seen only

in one sex in a test species may be less convincing than effects

seen in both sexes, unless there is a clear patho-physiological

difference consistent with the mode of action to explain the single

sex response.

Whether responses are in a

single species or several

species

Positive responses in several species add to the weight-of-

evidence that a chemical is a carcinogen.

Responses in multiple

animal experiments

A carcinogenic response confined to one species assumes greater

human significance if it is seen in two or more studies conducted at

different times, in different laboratories or under different protocols.

158

Factors that increase concerns

Taking into account all of the factors discussed here, chemicals

with positive outcomes in two or more species would be

provisionally considered to be classified in Category 1B until

human relevance of animal results are assessed in their entirety. It

should be noted, however, that positive results for one species in

at least two independent studies, or a single positive study

showing unusually strong evidence of malignancy may also lead

to Category 1B.

Structural similarity to a

chemical(s) for which there

is good evidence of

carcinogenicity

Mode of action and its

relevance to humans, such

as mutagenicity,

cytotoxicity with growth

stimulation, mitogenesis,

immunosuppression

A chemical that has not been tested for carcinogenicity may in

certain instances be classified for carcinogenicity based on tumor

data from a structural analogue together with substantial support

from consideration of other important factors such as formation

of common significant metabolites (e.g., for benzidine congener

based dyes)

Animal carcinogens that are genotoxic, or structurally similar to

known human carcinogens, also assume greater significance.

It is recognized that genetic events are central in the overall

process of cancer development. Therefore evidence of mutagenic

activity in vivo may indicate that a chemical has a potential for

carcinogenic effects.

Factors that reduce concerns

Comparison of absorption,

distribution, metabolism

and excretion between test

animals and humans

Routes of exposure

If a metabolism and toxicokinetic behavior of a chemical in

humans is fundamentally different from its behavior in the

species in which it is carcinogenic, or if the animal study employs

an inappropriate route of administration, or demonstrates

carcinogenic activity only at doses that causes excessive toxicity.

Certain tumor types in animals may be associated with

toxicokinetics or toxicodynamics that are unique to the animal

species tested and may not be predictive of carcinogenicity in

humans (e.g., the lack of human relevance of kidney tumors in

male rats associated with compounds causing α2υ-globulin

nephropathy). Even when a particular tumor type may be

discounted, expert judgment must be used in assessing the total

tumor profile in any animal experiment.

159

Factors that reduce concerns

The possibility of a

confounding effect of

excessive toxicity at test

doses

Localized effects

Tumors occurring only at excessive doses associated with severe

toxicity generally have doubtful potential for carcinogenicity in

humans.

In addition, tumors occurring only at sites of contact and/or only

at excessive doses need to be carefully evaluated for human

relevance for carcinogenic hazard (e.g., forestomach tumors,

following administration by gavage of an irritating or corrosive,

non-mutagenic chemical, may be of questionable relevance).

However, such determinations must be evaluated carefully in

justifying the carcinogenic potential for humans; any occurrence

of other tumors at distant sites must also be considered.

Mode of action not

relevant to humans

One must look closely at any mode of action in animal

experiments taking into consideration comparative

toxicokinetics/toxicodynamics between the animal test species

and humans to determine the relevance of the results to humans.

This may lead to the possibility of discounting very specific

effects of certain types of chemicals. Life-stage-dependent effects

on cellular differentiation may also lead to qualitative differences

between animals and humans. Only if a mode of action of tumor

development is conclusively determined not to be operative in

humans may the carcinogenic evidence for that tumor be

discounted. However, a weight-of-evidence evaluation for a

substance calls for any other tumorigenic activity to be evaluated,

as well.

In addition to the factors listed above, another important consideration with regard to carcinogen

classification is the significance of a single positive study. In evaluating the weight-of-evidence,

the carcinogen classification criteria indicate that one positive study conducted according to good

scientific principles and with statistically and biologically significant positive results may justify

classification. OSHA expects classification of a chemical if one positive study is available.

However, if following the evaluation of available scientific data, the classifier deems non-

classification to be the appropriate result, the one positive carcinogen study must still be

communicated on the SDS.

Classification criteria for mixtures

It should be noted that the classification criteria for health hazards often include a tiered scheme

in which test data available on the complete mixture are considered as the first tier in the

evaluation, followed by the applicable bridging principles, and lastly, cut-off

160

values/concentration limits or additivity. However, this approach is not used for Carcinogenicity.

The criteria for Carcinogenicity consider the cut-off values/concentration limits as the primary

tier and allow the classification to be modified only on a case-by-case evaluation based on

available test data for the mixture as a whole.

Tier 1: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

The approach to classifying a mixture for carcinogenicity in Tier 1 is to use a cut-

off/concentration limit. An assessment is carried out separately for each Category 1A, Category

1B or Category 2 ingredient in the mixture. In the case where the mixture has Category 1A,

Category 1B and Category 2 ingredients above the cut-off/concentration limit the mixture is

classified in the most severe category.

The mixture will be classified as a carcinogen when at least one ingredient has been classified as

a Category 1A, Category 1B or Category 2 Carcinogen and is present at or above the appropriate

cut-off value/concentration limit specified below for Category 1 and Category 2, respectively.

Table VII.6.4. Cut-off values/concentration limits of ingredients of a mixture classified as a

carcinogen that would trigger classification of the mixture

Ingredient classified as:

Cut-off/concentration limits triggering

classification of a mixture as:

Category 1 carcinogen

Category 2 carcinogen

Category 1A

Category 1B

Category 1A carcinogen

 0.1 %

Category 1B carcinogen

 0.1 %

Category 2 carcinogen

 0.1% (Note)

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 the mixture. 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 are required and the information must be included on each.

Tier 2: Classification of mixtures when data are available for the complete mixture

On a case-by-case basis the classification which normally considers results obtained with the

individual ingredients may be modified using available test data for the mixture as a whole.

The concern with using test data for the mixture as a whole is that as the concentration of a

carcinogenic ingredient is reduced in a mixture the dilution effect may result in misleading test

results (i.e., false negative) if the study was not appropriately designed to factor in the

concentration of the carcinogenic ingredient in the mixture. In these cases, mixtures that would

161

cause cancer would not be classified and labeled. Accordingly, the GHS provides guidance that

the test results for the mixture as a whole must be conclusive taking into account dose, and other

factors such as duration, observations and analysis (e.g., statistical analysis, test sensitivity) of

carcinogenicity test systems. If appropriate test data for the mixture is not available then the

classifier can consider the application of the Bridging Principle criteria in Tier 3, if appropriate,

or as stated above use the classification resulting from the application of criteria in Tier 1.

Tier 3: Classification of mixtures when data are not available for the complete mixture -

bridging principles

Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are

sufficient data on BOTH the individual ingredients AND similar tested mixtures to adequately

characterize the hazards of the mixture, these data can be used in accordance with the below

bridging principles. If data on another mixture are used in the application of the bridging

principles, the data on that mixture must be conclusive as discussed above in Tier 2.

Only the following bridging principles are applicable to the Carcinogenicity hazard class:

 Dilution,

 Batching,

 Substantially similar mixtures.

Dilution

If a tested mixture is diluted with a diluent that is not expected to affect the

carcinogenicity of other ingredients, then the new diluted mixture may be classified as

equivalent to the original tested mixture.

Batching

The carcinogenic potential of a tested production batch of a mixture can be assumed to be

substantially equivalent to that of another untested production batch of the same

commercial product, when produced by or under the control of the same manufacturer

unless there is reason to believe there is significant variation in composition such that the

carcinogenic potential of the untested batch has changed. If the latter occurs, a new

classification is necessary.

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

162

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

mixture (ii);

(d) Data on toxicity for A and C are available and substantially equivalent, i.e.,

they are in the same hazard category and are not expected to affect the

carcinogenicity of B.

If mixture (i) or (ii) is already classified by testing, then the other mixture can be

classified in the same hazard category.

Decision Logic

Two decision logics for classifying carcinogenicity are provided. The first decision logic is for

substances. Use the second decision logic for classifying mixtures. The decision logics are

provided as additional guidance. It is strongly recommended that the person responsible for

classification study the criteria before and during use of the decision logic.

These decision logics are essentially flowcharts for classifying substances and mixtures

regarding carcinogenicity. They present questions in a sequence that walks you through the

classification steps and criteria for classifying carcinogenicity. Once you answer the questions

provided, you will arrive at the appropriate classification.

163

Substance decision logic for carcinogenicity

According to the criteria, is the substance:

(a)

Known to have carcinogenic potential for humans, or

(b)

Presumed

to have carcinogenic potential for humans?

Application of the criteria needs expert judgment in a

strength and weight-of-evidence approach.

Yes

Category 1

Danger

Not classified

According to the criteria, is the substance a suspected

human carcinogen?

Application of the criteria needs expert judgment in a

strength and weight-of-evidence approach

Substance: Does the substance have carcinogenicity data?

Yes

Classification

not possible

Yes

Category 2

Warning

164

Mixtures decision logic for carcinogenicity

Between 0.1% and 1% information is required on the SDS and a label warning is optional. At

≥ 1% both an SDS and a label are required.

Classification based on individual ingredients of the mixture

Modified classification on a case-by-case basis

Mixture:

Classification of mixtures will be based on the available test data for the

individual ingredients of the

mixture, using cut-off values/concentration limits for those ingredients. The classification may be

modified on a case-by-case basis

based on the available test data for the mixture as a whole or based

on bridging principles. See modified classification on a case-by-case basis below.

Does the mixture contain one or more ingredients

classified as a Category 1 carcinogen at:

 0.1%?

Yes

Does the mixture contain one or more ingredients

classified as a Category 2 carcinogen at:

 0.1%?

Yes

Not classified

Are test data available

for the mixture itself?

Yes

Are the test results on the mixture

conclusive taking into account

dose and other factors such as

duration, observations and analysis

(e.g., statistical analysis, test

sensitivity) of carcinogenicity test

systems?

Yes

Classify in

appropriate

category

Danger

Warning

No classification

Can bridging principles be applied? If data on

another mixture are used, data on that mixture

must be conclusive.

Classification based on individual

ingredients of the mixture (see above).

Category 1

Danger

Category 2

Warning

Yes

165

Carcinogenicity Classification Examples

The following examples are provided to walk you through carcinogenicity classification.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1: S32

Carcinogenicity

Test Data

HCS 2012

Classification

Rationale

Occupational exposure has been strongly

associated with bladder cancer in numerous

case reports from many countries. The

association has also been observed in several

epidemiological studies. In one extreme

instance, all five of a group of workers

continuously employed in S32 manufacture

for 15 years or more developed bladder

cancer.

S32 was tested in mice, rats and hamsters by

oral administration, in mice and rats by

subcutaneous administration and in rats by

inhalation and intraperitoneally. Following its

oral administration to mice of different

strains, both sexes, newborn and adult, and

following its subcutaneous administration, it

significantly increased the incidence of liver-

cell tumors (benign and malignant). In female

rats, it markedly increased the incidence of

mammary tumors; and in male and female

hamsters, it increased the incidence of liver

tumors following its oral administration. S32

induced bladder carcinomas in dogs.

The subcutaneous administration of S32 to

rats produced a high incidence of Zymbal-

gland tumors; colonic tumors were also

reported. The results of the inhalation study in

rats could not be interpreted. The

intraperitoneal administration of S32 to rats

resulted in a marked increase in the incidence

of mammary and Zymbal-gland tumors. It

was also tested in dogs by oral administration,

producing bladder carcinomas. Studies in fish,

rabbits and frogs could not be evaluated.

No data were available on the genetic and

related effects of S32 in humans.

Carcinogenicity

Category 1A

Fulfills criteria

 There is sufficient evidence

that S32 is carcinogenic to

mice, rats, hamsters and dogs

and there is sufficient

evidence that S32 is

carcinogenic to humans

 Sufficient human evidence

demonstrates causality

between human exposure and

the development of cancer,

and sufficient evidence in

animals shows a causal

relationship between S32 and

an increased incidence of

tumors fulfills HCS criteria

166

Substance Example #2: S33

Carcinogenicity

Test Data

HCS 2012

Classification

Rationale

Five S33 samples all produced skin tumors,

including carcinomas, when applied to the

skin of mice. One of the S33 samples also

produced lung tumors in mice after skin

application. In two limited studies, a basic

fraction of S33 was not carcinogenic for the

skin of mice.

S33 was mutagenic in S. typhimurium and

was positive in the mouse lymphoma

L5178Y system, in the presence of an

exogenous metabolic system. The urine from

rats administered S33 was mutagenic in S.

typhimurium in the presence of an

exogenous metabolic system.

A mortality analysis of many occupations

indicated an increased risk of mortality from

scrotal cancer for S33-exposed workers.

Malignant epitheliomas, about a third of

which were of the scrotum, have been

reported in several case reports of workers

exposed to S33.

A cohort study of workers in Norway and

Sweden who had been exposed to S33

reported a statistically significant excess

incidence of non-melanoma skin cancer. A

study of workers in Norway did not report

any statistically significant increase in the

incidence of cancer, although the risk for

non-melanoma cancer was slightly increased.

A nested case–control study of lung cancer

among a cohort of workers in France

reported an increased risk for exposure to

S33. A cohort study of workers in the USA

who had used S33 indicated the possibility of

an increase in mortality from lung cancer; a

nested case–control study found no evidence

of an exposure–response relationship

between exposure to S33 and cancer. A study

that applied a job–exposure matrix to job

titles in the Swedish census and linked this to

cancer incidence found an increase in the

incidence of urinary bladder cancer that was

related to S33.

Carcinogen Category 1B

Fulfills criteria

 There is sufficient

evidence for the

carcinogenicity in

experimental animals of

S33. There is limited

evidence that S33 is

carcinogenic in humans.

The data indicate that S33

is probably carcinogenic

to humans.

 The category 1B criteria

are fulfilled by evidence

from animal experiments

for which there is

sufficient evidence to

demonstrate animal

carcinogenicity

(presumed human

carcinogen) and limited

evidence in humans.

167

Substance Example #3

Carcinogenicity

Test Data

HCS 2012

Classification

Rationale

NTP listed as Reasonably

Anticipated to be Human

Carcinogen

IARC listed as Group 2B:

Possibly Carcinogenic to Humans

ACGIH listed as Category A3:

Confirmed Animal Carcinogen

with Unknown Relevance to

Humans

Listed in EU CLP Table 3.1 as

Category 2/Table 3.2 Category 3

Carcinogen

Category 2

Fulfills criteria

 Due to the fact that the substance

is listed by NTP as Reasonably

Anticipated to be Human

Carcinogen and by IARC as

Group 2B

 Per 29 CFR 1910.1200 A.6.4,

NTP and IARC may be treated

as establishing that a substance

is a carcinogen or potential

carcinogen for hazard

communication purposes in lieu

of applying the criteria

 Per 29 CFR 1910.1200 Annex F

Part D, IARC Group 2B is

Carcinogen Category 2

Substance Example #4

Carcinogenicity

Test Data

HCS 2012

Classification

Rationale

Listed by NTP as Reasonably

Anticipated to be Human

Carcinogen)

Listed by IARC as Group 2A:

Probably Carcinogenic to Humans

Listed as 2A: Probably

Carcinogenic to Humans by the

Japan Society for Occupational

Health

Carcinogen

Category 1B

Fulfills criteria

 Due to the fact that the substance

is listed by NTP as Reasonably

Anticipated to be Human

Carcinogen and by IARC as

Group 2A

 Per 29 CFR 1910.1200 A.6.4,

NTP and IARC may be treated as

establishing that a substance is a

carcinogen or potential

carcinogen for hazard

communication purposes in lieu

of applying the criteria

 Per 29 CFR 1910.1200 Annex F

Part D, IARC Group 2A is

Carcinogen Category 1B

168

Example of a substance not fulfilling the criteria for classification:

Substance Example #5

Carcinogenicity

Test Data

HCS 2012

Classification

Rationale

Listed by IARC as Group 3: Not

Classifiable as to Carcinogenicity

to Humans

Listed by ACGIH as Category

A4: Not Classifiable as a Human

Carcinogen

Listed by EPA as Category D:

Not Classifiable as to Human

Carcinogenicity

Not classified for

Carcinogenicity

Does not fulfill criteria

 The substance is listed by IARC

as Group 3

 Per 29 CFR 1910.1200 A.6.4,

NTP and IARC may be treated as

establishing that a substance is a

carcinogen or potential

carcinogen for hazard

communication purposes in lieu

of applying the criteria

 Per 29 CFR 1910.1200 Annex F

Part D, IARC Group 3 is not an

equivalent cancer HCS 2012

classification

Example of a mixture fulfilling the criteria for classification:

Mixture Example #1

Carcinogenicity

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 0.05%, Carcinogen

Category 1B

Component 2: 0.5%, Carcinogen

Category 2

Carcinogen

Category 2

Fulfills the criteria

 Component 1 is not ≥ 0.1% so

the mixture does not meet the

Carcinogen Category 1B criteria.

 Component 2 is ≥ 0.1% so the

mixture meets the Carcinogen

Category 2 criteria.

This mixture is classified as

Carcinogen Category 2 and a label

warning is optional.

169

References

29 CFR 1910.1200, Hazard Communication, Appendix A.6 Carcinogenicity

29 CFR 1910.1200, Hazard Communication, Appendix F Guidance for Hazard Classifications

Re: Carcinogenicity (Non-Mandatory)

29 CFR 1910.1200, Hazard Communication, Appendix C, Allocation of Label Elements

National Toxicology Program (NTP), “Report on Carcinogens” (latest edition)

International Agency for Research on Cancer (IARC) “Monographs on the Evaluation of

Carcinogenic Risks to Humans” (latest editions).

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

170

VII.7 Reproductive Toxicity

Introduction

The term “reproductive toxicity” is used to describe the adverse effects induced by a chemical on

any aspect of mammalian reproduction. It covers all phases of the reproductive cycle, including

impairment of male or female reproductive organs and/or function or capacity and the induction

of non-heritable adverse effects in the progeny such as death, growth retardation, structural and

functional effects.

Definition and General Considerations

Reproductive toxicity includes adverse effects on sexual function and fertility in adult males and

females, as well as adverse effects on development of the offspring. Some reproductive toxic

effects cannot be clearly assigned to either impairment of sexual function and fertility or to

developmental toxicity. Nonetheless, chemicals with these effects shall be classified as

reproductive toxicants.

For classification purposes, the known induction of genetically based inheritable effects in the

offspring is addressed in the Germ cell mutagenicity hazard class (see Chapter VII.5).

Adverse effects on sexual function and fertility means any effect of a chemical that interferes

with reproductive ability or sexual capacity. This includes, but is not limited to, alterations to the

female and male reproductive system; adverse effects on onset of puberty, gamete production

and transport, reproductive cycle normality, sexual behavior, fertility, parturition, or pregnancy

outcomes; premature reproductive senescence; or modifications in other functions that are

dependent on the integrity of the reproductive systems.

Adverse effects on development of the offspring means any effect of a chemical that interferes

with normal development of the conceptus either before or after birth, which is induced during

pregnancy or results from parental exposure. These effects can be manifested at any point in the

life span of the organism. The major manifestations of developmental toxicity include death of

the developing organism, structural abnormality, altered growth and functional deficiency. A

term often used to describe effects manifested as malformations of the newborn is teratogenicity.

Adverse effects on or via lactation are also included in reproductive toxicity, but for

classification purposes, such effects are treated in a separate hazard category.

Classification Criteria for Substances

For the purpose of classification for reproductive toxicity, substances shall be classified in one of

two categories. Category 1, known or presumed human reproductive toxicant, is subdivided into

two subcategories according to specific criteria outlined below. Category 2 includes criteria for

suspected human reproductive toxicants. Effects on sexual function and fertility, and on

development, shall also be considered. In addition, effects on or via lactation shall be classified

in a separate hazard category.

171

Table VII.7.1. Hazard categories for reproductive toxicants

Category

Criteria

CATEGORY 1

Known or presumed human reproductive toxicant

A substance shall be classified in Category 1 for reproductive toxicity

when it is known to have produced an adverse effect on sexual function

and fertility or on development in humans or when there is evidence

from animal studies, possibly supplemented with other information, to

provide a strong presumption that the substance has the capacity to

interfere with reproduction in humans. The classification of a substance

is further distinguished on the basis of whether the evidence for

classification is primarily from human data (Category 1A) or from

animal data (Category 1B).

Category 1A

Known human reproductive toxicant

The classification of a substance in this category is largely based on

evidence from humans.

Category 1B

Presumed human reproductive toxicant

The classification of a substance in this category is largely based on

evidence from experimental animals. Data from animal studies shall

provide sufficient evidence of an adverse effect on sexual function and

fertility or on development in the absence of other toxic effects, or if

occurring together with other toxic effects the adverse effect on

reproduction is considered not to be a secondary non-specific

consequence of other toxic effects. However, when there is mechanistic

information that raises doubt about the relevance of the effect for

humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected human reproductive toxicant

A substance shall be classified in Category 2 for reproductive toxicity

when there is some evidence from humans or experimental animals,

possibly supplemented with other information, of an adverse effect on

sexual function and fertility, or on development, in the absence of other

toxic effects, or if occurring together with other toxic effects the adverse

effect on reproduction is considered not to be a secondary non-specific

consequence of the other toxic effects, and where the evidence is not

sufficiently convincing to place the substance in Category 1. For

instance, deficiencies in the study may make the quality of evidence less

convincing, and in view of this, Category 2 would be the more

appropriate classification.

172

Table VII.7.2. Hazard category for effects on or via lactation

Category

Criteria

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.

Classification for effects via lactation 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

period.

Basis of classification for Reproductive Toxicity

Classification for reproductive toxicity is on the basis of the criteria, an assessment of the total

weight-of-evidence, and the use of expert judgment. Classification as a reproductive toxicant is

intended to be used for chemicals that have an intrinsic, specific property to produce an adverse

effect on reproduction; chemicals should not be so classified if such an effect is produced solely

as a non-specific secondary consequence of other toxic effects.

In the evaluation of toxic effects on the developing offspring, it is important to consider the

possible influence of maternal toxicity.

CATEGORY 1

Classification in Category 1A is largely based on evidence from humans. Evidence used for

classification shall be from well-conducted epidemiological studies, if available, which include

the use of appropriate controls, balanced assessment, and consideration of bias or confounding

factors. Less rigorous data from studies in humans may be sufficient for a Category 1A

classification if supplemented with adequate data from studies in experimental animals, but

classification in Category 1B may also be considered.

In Figure A.7.1(b) of Appendix A of 29 CFR 1910.1200 this sentence ends with the phrase “hazardous to

breastfed babies.” The inclusion of that language renders the sentence grammatically incorrect, and incorrect as a

matter of substance, because classification can also be based on effects on lactation, rather than only effects via

lactation. OSHA intends to correct the sentence in the standard.

The words “for effects via lactation” do not appear in Figure A.7.1.(b) of Appendix A of 29 CFR 1910.1200, but

the words are inserted here to make clear that the stated criteria only apply to that effect, and do not apply to exclude

classification for effects on lactation. OSHA intends to correct the sentence in the standard.

173

Weight-of-evidence

Classification as a reproductive toxicant is made on the basis of an assessment of the total

weight-of-evidence using expert judgment. This means that all available information that bears

on the determination of reproductive toxicity is considered together. Included is information such

as epidemiological studies and case reports in humans and specific reproduction studies along

with sub-chronic, chronic and special study results in animals that provide relevant information

regarding toxicity to reproductive and related endocrine organs. Evaluation of substances

chemically related to the material under study may also be included, particularly when

information on the material is scarce. The weight given to the available evidence will be

influenced by factors such as

 the quality of the studies;

 consistency of results;

 nature and severity of effects;

 level of statistical significance for intergroup differences;

 number of endpoints affected;

 relevance of route of administration to humans; and

 freedom from bias.

Both positive and negative results are considered together in a weight-of-evidence determination.

However, a single, positive study performed according to good scientific principles and with

statistically or biologically significant positive results should be enough to justify classification

unless the classifier shows that there is no relevance to humans or exposure as discussed below.

Considerations When Evaluating Weight-of-Evidence

Factors

Weight-of-Evidence Evaluation

Experimental

data quality/

adequacy:

A number of internationally accepted test methods are available; these

include methods for developmental toxicity testing, methods for peri-

natal and post-natal toxicity testing and methods for one- or two-

generation toxicity testing.

Results obtained from screening tests can also be used to justify

classification, although it is recognized that the quality of this evidence is

less reliable than that obtained through full studies.

Adverse effects or changes, seen in short- or long-term repeated dose

toxicity studies, which are judged likely to impair reproductive function

and which occur in the absence of significant generalized toxicity, may

be used as a basis for classification, e.g., histopathological changes in

the gonads.

174

Factors

Weight-of-Evidence Evaluation

Evidence from in vitro assays, or non-mammalian tests, and from

analogous substances using structure-activity relationship (SAR), can

contribute to the procedure for classification. In all cases of this nature,

expert judgment must be used to assess the adequacy of the data.

Inadequate data should not be used as a primary support for

classification. A single, positive study performed according to good

scientific principles and with statistically or biologically significant

positive results should justify classification.

Toxicokinetics/

mode of action:

If it can be conclusively demonstrated that the clearly identified

mechanism or mode of action has no relevance for humans or when the

toxicokinetic differences are so marked that it is certain that the

hazardous property will not be expressed in humans, then a substance

that produces an adverse effect on reproduction in experimental animals

should not be classified.

Routes of

administration:

It is preferable that animal studies are conducted using appropriate routes

of administration which relate to the potential route of human exposure.

However, in practice, reproductive toxicity studies are commonly

conducted using the oral route, and such studies will normally be suitable

for evaluating the hazardous properties of the substance with respect to

reproductive toxicity.

Studies involving routes of administration such as intravenous or

intraperitoneal injection, which may result in exposure of the

reproductive organs to unrealistically high levels of the test substance, or

which elicit local damage to the reproductive organs, (e.g., by irritation)

must be interpreted with extreme caution, such studies on their own

would not normally be the basis for classification.

Limit dose:

There is general agreement about the concept of a limit dose, above

which the production of an adverse effect may be considered to be

outside the criteria which lead to classification. Some test guidelines

specify a limit dose; other test guidelines qualify the limit dose with a

statement that higher doses may be necessary if anticipated human

exposure is sufficiently high that an adequate margin of exposure would

not be achieved. Also, due to species differences in toxicokinetics,

establishing a specific limit dose may not be adequate for situations

where humans are more sensitive than the animal model.

175

Factors

Weight-of-Evidence Evaluation

In principle, adverse effects on reproduction seen only at very high dose

levels in animal studies (for example, doses that induce prostration,

severe inappetence, excessive mortality) would not normally lead to

classification, unless other information is available, e.g., toxicokinetics

information indicating that humans may be more susceptible than

animals, to suggest that classification is appropriate.

Specification of the actual “limit dose” will depend upon the test method

that has been used to provide the test results (e.g., in the OECD Test

Guideline for repeated dose toxicity studies by the oral route, an upper

dose of 1000 mg/kg) unless expected human response indicates the need

for a higher dose level to be used as a limit dose.

Effects of

minimal or low

toxicological

significance:

In some reproductive toxicity studies in experimental animals the only

effects recorded may be considered of low or minimal toxicological

significance and classification may not necessarily be the outcome.

These include, for example, small changes in semen parameters or in the

incidence of spontaneous defects in the fetus, small changes in the

proportions of common fetal variants such as are observed in skeletal

examinations, or in fetal weights, or small differences in postnatal

developmental assessments.

Maternal

toxicity:

If developmental toxicity occurs together with other toxic effects in the

dam (mother), the potential influence of the generalized adverse effects

should be assessed to the extent possible. The preferred approach is to

consider adverse effects in the embryo/fetus first, and then evaluate

maternal toxicity, along with any other factors, which are likely to have

influenced these effects. Generally, the presence of maternal toxicity

should not be used to negate findings of embryo/fetal effects, unless it

can be clearly demonstrated that the effects are secondary non-specific

effects (e.g., maternal stress, disruption of homeostasis).

Developmental effects, which occur even in the presence of maternal

toxicity, are considered to be evidence of developmental toxicity, unless

it can be unequivocally demonstrated on a case-by-case basis that the

developmental effects are secondary to maternal toxicity. Moreover,

classification should be considered where there is significant toxic effect

in the offspring, e.g., irreversible effects such as structural

malformations, embryo/fetal lethality, or significant post-natal functional

deficiencies.

176

Factors

Weight-of-Evidence Evaluation

Classification should not automatically be discounted for chemicals that

produce developmental toxicity only in association with maternal

toxicity, even if a specific maternally-mediated mechanism has been

demonstrated. In such a case, classification in Category 2 may be

considered more appropriate than Category 1. However, when a

chemical is so toxic that maternal death or severe inanition results, or

when the dams (mothers) are prostrate and incapable of nursing the pups,

it may be reasonable to assume that developmental toxicity is produced

solely as a secondary consequence of maternal toxicity and discount the

developmental effects. Classification may not necessarily be the outcome

in the case of minor developmental changes (e.g., small reduction in

fetal/pup body weight, or retardation of ossification when seen in

association with maternal toxicity).

Maternal toxicity

Maternal toxicity deserves careful consideration. Development of the offspring throughout

gestation and during the early postnatal stages can be influenced by toxic effects in the mother

either through non-specific mechanisms related to stress and the disruption of maternal

homeostasis, or by specific maternally-mediated mechanisms. So, in the interpretation of the

developmental outcome that is used to decide classification for developmental effects, it is

important to consider the possible influence of maternal toxicity. This is a complex issue because

of uncertainties surrounding the relationship between maternal toxicity and developmental

outcome. Expert judgment and a weight-of-evidence approach, using all available studies, shall

be used to determine the degree of influence to be attributed to maternal toxicity when

interpreting the criteria for classification for developmental effects. As weight-of-evidence to

help reach a conclusion about classification, the adverse effects in the embryo/fetus shall be first

considered; and then maternal toxicity, along with any other factors which are likely to have

influenced these effects.

Based on pragmatic observation, it is believed that maternal toxicity may, depending on severity,

influence development via non-specific secondary mechanisms, producing effects such as

depressed fetal weight, retarded ossification, and possibly resorptions and certain malformations

in some strains of certain species. However, the limited number of studies which have

investigated the relationship between developmental effects and general maternal toxicity have

failed to demonstrate a consistent, reproducible relationship across species.

Some of the endpoints used to assess maternal toxicity are provided below. Data on these

endpoints, if available, shall be evaluated in light of their statistical or biological significance and

dose-response relationship.

177

(a) Maternal mortality: An increased incidence of mortality among the treated dams over

the controls shall be considered evidence of maternal toxicity if the increase occurs in a

dose-related manner and can be attributed to the systemic toxicity of the test material.

Maternal mortality greater than 10% is considered excessive and the data for that dose

level shall not normally be considered to need further evaluation.

(b) Mating index (Number of animals with seminal plugs or sperm/Number of matings ×

100)

(d) Gestation length (If allowed to deliver)

(e) Body weight and body weight change: Consideration of the maternal body weight

change and/or adjusted (corrected) maternal body weight shall be included in the

evaluation of maternal toxicity whenever such data are available. The calculation of an

adjusted (corrected) mean maternal body weight change, which is the difference between

the initial and terminal body weight minus the gravid uterine weight (or alternatively, the

sum of the weights of the fetuses), may indicate whether the effect is maternal or

intrauterine. In rabbits, the body weight gain may not be a useful indicator of maternal

toxicity because of normal fluctuations in body weight during pregnancy.

(f) Food and water consumption (if relevant): The observation of a significant decrease in

the average food or water consumption in treated dams (mothers) compared to the control

group may be useful in evaluating maternal toxicity, particularly when the test material is

administered in the diet or drinking water. Changes in food or water consumption must

be evaluated in conjunction with maternal body weights when determining if the effects

noted are reflective of maternal toxicity or, more simply, unpalatability of the test

material in feed or water.

(g) Clinical evaluations (including clinical signs, markers, and hematology and clinical

chemistry studies): The observation of increased incidence of significant clinical signs of

toxicity in treated dams (mothers) relative to the control group is useful in evaluating

maternal toxicity. If this is to be used as the basis for the assessment of maternal toxicity,

the types, incidence, degree and duration of clinical signs shall be reported in the study.

Clinical signs of maternal intoxication include, but are not limited to: coma, prostration,

hyperactivity, loss of righting reflex, ataxia, or labored breathing.

(h) Post-mortem data: Increased incidence and/or severity of post-mortem findings may

be indicative of maternal toxicity. This can include gross or microscopic pathological

findings or organ weight data, including absolute organ weight, organ-to-body weight

ratio, or organ-to-brain weight ratio. When supported by findings of adverse

histopathological effects in the affected organ(s), the observation of a significant change

178

in the average weight of suspected target organ(s) of treated dams (mothers), compared to

those in the control group, may be considered evidence of maternal toxicity.

Classification criteria for mixtures

It should be noted that the classification criteria for health hazards often include a tiered scheme

in which test data available on the complete mixture are considered as the first tier in the

evaluation, followed by the applicable bridging principles, and lastly, cut-off

values/concentration limits or additivity. However, this approach is not used for Reproductive

Toxicity. The criteria for Reproductive Toxicity consider the cut-off values/concentration limits

as the primary tier and allow the classification to be modified only on a case-by-case evaluation

based on available test data for the mixture as a whole.

Tier 1: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

The approach to classifying a mixture for reproductive toxicity in Tier 1 is to use a cut-

off/concentration limit. An assessment is carried out separately for each Category 1A, Category

1B or Category 2 ingredient in the mixture. In the case where the mixture has Category 1A,

Category 1B and Category 2 ingredients above the cut-off/concentration limit, the mixture is

classified in the most severe category.

The mixture will be classified as a reproductive toxicant when at least one ingredient has been

classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present at or

above the appropriate cut-off value/concentration limit specified below for Category 1 and

Category 2, respectively.

Additionally, a separate evaluation will be made to determine if the mixture will be classified for

effects on or via lactation. If at least one ingredient in the mixture is classified in the category for

effects on or via lactation and is present at or above the appropriate cut-off/concentration limit,

then the mixture will be classified for effects on or via lactation.

179

Table VII.7.3. Cut-off values/concentration limits of ingredients of a mixture classified as

reproductive toxicants or for effects on or via lactation that would trigger classification of

the mixture

Ingredient

classified as:

Cut-off/concentration limits triggering classification of a mixture as:

Category 1 reproductive

toxicant

Category 2

reproductive

toxicant

Additional

category for

effects on or via

lactation

Category 1A

Category 1B

Category 1A

reproductive

toxicant

 0.1%

Category 1B

reproductive

toxicant

 0.1%

Category 2

reproductive

toxicant

 0.1%

Additional

category for

effects on or via

lactation

 0.1%

Tier 2: Classification of mixtures when data are available for the complete mixture

On a case-by-case basis the Reproductive Toxicity classification, which normally considers

results obtained with the individual ingredients, may be modified using available test data for the

mixture as a whole.

The concern with using test data for the mixture as a whole is that as the concentration of a

reproductive toxicant is reduced in a mixture the dilution effect may result in a misleading test

results (i.e., false negative) if the study was not appropriately designed to factor in the

concentration of the reproductive toxicant in the mixture. In these cases, mixtures that would

cause Reproductive Toxicity would not be classified and labeled. Accordingly, the HCS

provides guidance that the test results for the mixture as a whole must be conclusive, taking into

account dose, and other factors such as duration, observations and analysis (e.g., statistical

analysis, test sensitivity) of reproduction test systems.

If appropriate test data for the mixtures is not available, then the classifier can consider the

application of the Bridging Principle criteria in Tier 3, if appropriate, or use the classification

resulting from the application of the criteria in Tier 1.

180

Tier 3: Classification of mixtures when data are not available for the complete mixture -

bridging principles

Where the mixture itself has not been tested to determine its reproductive toxicity, but there are

sufficient data on BOTH the individual ingredients AND similar tested mixtures to adequately

characterize the hazards of the mixture, then these data can be used in accordance with the

bridging principles below. If data on another mixture are used in the application of the bridging

principles, the data on that mixture must be conclusive as discussed in Tier 2 above.

Only the following bridging principles are applicable to the Reproductive Toxicity hazard class:

 Dilution,

 Batching,

 Substantially similar mixtures.

The application of bridging principles ensures that the classification process uses the available

data to the greatest extent possible in characterizing the potential reproductive toxicity hazard.

Dilution

If a tested mixture is diluted with a diluent which is not expected to affect the

reproductive toxicity of other ingredients, then the new diluted mixture may be classified

as equivalent to the original tested mixture.

Batching

The reproductive toxicity potential of a tested production batch of a mixture can be

assumed to be substantially equivalent to that of another untested production batch of the

same commercial product, when produced by or under the control of the same

manufacturer, unless there is reason to believe there is significant variation in

composition such that the reproductive toxicity potential of the untested batch has

changed. If the latter occurs, a new classification is necessary.

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

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

mixture (ii);

181

(d) Data on toxicity for A and C are available and substantially equivalent (i.e.,

they are in the same hazard category and are not expected to affect the

reproductive toxicity of B).

If mixture (i) or (ii) is already classified by testing, then the other mixture can be

classified in the same hazard category.

Classification Procedure and Guidance

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

Data generated in accordance with internationally recognized scientific principles are acceptable

under the HCS.

Examples of scientifically validated test methods

There are a number of internationally recognized methods for investigation of reproductive

toxicity effects:

 Prenatal Developmental Toxicity Study (OECD Test Guideline 414)

 One-Generation Reproduction Toxicity Study (OECD Test Guideline 415)

 Two-Generation Reproduction Toxicity Study (OECD Test Guideline 416)

 Reproduction/Developmental Toxicity Screening Test (OECD Test Guideline 421)

 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity

Screening Test (OECD Test Guideline 422)

Other test methodologies that meet the requirements for testing of reproductive toxicity include:

 Preliminary developmental toxicity screen (EPA 798.4420/870.3500)

 Inhalation developmental toxicity study (EPA 798.4350/870.3600)

 Prenatal developmental toxicity study (EPA 798.4900/ 870.3700)

 Prenatal developmental toxicity study (EEC Directive 92/32/EEC B.31)

 Reproduction and fertility effects (EPA 798.4700/870.3800)

 Onegeneration reproduction toxicity test study (EEC Directive 92/32/EEC B.34)

 Twogeneration reproduction toxicity study (EEC Directive 92/32/EEC B.35)

182

Classification procedure

In classification, the data are compared to the reproductive toxicity classification criteria. If valid

data on the reproductive toxicity of a substance or mixture are available, then these data should

be used for classification. To find the necessary data, a classifier is advised to try the following:

 ask the manufacturer or supplier for the reproductive toxicity data for the product; or

 check to see if the reproductive toxicity data is available in the SDS or any other

documentation accompanying the product; or

 find the data available in the open literature if the chemical identity of the product is

known (for a single-component chemical).

For mixtures follow the three-tier approach discussed above.

Considerations

Classification is made on the basis of the appropriate HCS criteria and an assessment of the total

weight-of-evidence. The validity and usefulness of each test data set to the overall assessment of

reproductive toxicity should be individually assessed, taking account of protocol design

(including route of administration) and current expert views on the value of the test systems.

If the data are available, then you must classify into the appropriate reproductive toxicity sub-

category (i.e., category 1A or category 1B). If the data does not allow classification into a sub-

category, then you must classify in reproductive toxicity category 1.

Decision logic

Three decision logics for classifying reproductive toxicity are provided. The first decision logic

is for reproductive toxic substances. Use the second decision logic for classifying reproductive

toxic mixtures. There is an additional decision logic for classifying effects on or via lactation for

both substances and mixtures. The decision logics are provided as additional guidance. It is

strongly recommended that the person responsible for classification study the criteria before and

during use of the decision logic.

These decision logics are essentially flowcharts for classifying substances and mixtures

regarding reproductive toxicity. They present questions in a sequence that walks you through the

classification steps and criteria for classifying reproductive toxicity. Once you answer the

questions provided, you will arrive at the appropriate classification.

183

Substance decision logic for reproductive toxicity

According to the criteria, is the substance:

(a)

Known human reproductive toxicant, or

(b)

Presumed human reproductive toxicant?

Application of the criteria needs expert judgment in a

weight-of-evidence approach.

Yes

Category 1

Danger

Not classified

According to the criteria, is the substance a suspected

human reproductive toxicant?

Application of the criteria needs expert judgment in a

strength and weight-of-evidence approach.

Substance: Does the substance have data on reproductive

toxicity?

Yes

Classification

not possible

Yes

Category 2

Warning

184

Mixtures decision logic for reproductive toxicity

Classification based on individual ingredients of the mixture

Modified classification on a case-by-case basis

Mixture: Classification of mixtures will be based on the available test data for the individual

ingredients of the mixture, using cut-off values/concentration limits for those ingredients. The

classification may be

modified on a case-by-case basis

based on the available test data for the mixture

as a whole or based on bridging principles. See modified classification on a case-by-case basis below.

For further details see criteria (See 3.7.3.1, 3.7.3.2 and 3.Does the substance according to the criteria

cause concern for the health of breastfed children?

Does the mixture contain one or more ingredients classified

as a Category 1 reproductive toxicant at

 0.1%?

Yes

Category 1

Danger

Does the mixture contain one or more ingredients

classified as a Category 2 reproductive toxicant at



0.1%?

Yes

Category 2

Warning

Not Classified

Are test data available for

the mixture itself?

Yes

Are the test results on the

mixture conclusive, taking into

account dose and other factors

such as duration, observations

and analysis (e.g., statistical

analysis, test sensitivity) of

reproduction test systems?

Classify in

appropriate

category

Danger

Warning

No classification

Yes

Classification based on individual

ingredients of the mixture (See above).

Can bridging principles be applied? If data on another

mixture are used in the application of bridging principles,

the data on that mixture must be conclusive. See criteria.

Yes

Mixture: Classification of mixtures will be based on the available test data for the individual

ingredients

of the mixture, using cut-off values/concentration limits for those ingredients. The

classification may be

modified on a case-by-case basis based on the available test data for the mixture

as a whole or based on bridging principles. See modified classification on a case-by-case basis below.

For further details see criteria.

185

Decision logic for effects on or via lactation

Decision logic for substances

Decision logic for mixtures

Does the substance according to the criteria cause concern

for the health of breastfed children or interfere with

lactation?

Yes

Additional category

for effects on or via

lactation

No symbol

No signal word

Not classified

Mixture: Classification of mixtures will be based on the available test data for the individual

ingredients of the mixture, using cut-off values/concentration limits for those ingredients. The

classification may be modified on a case-by-case basis

based on the available test data for the mixture

as a whole or based on bridging principles. See modified classification on a case-by-case basis below.

For further details see criteria.

Does the mixture contain one or more ingredients classified for

effects on or via lactation at

 0.1%?

Yes

Not classified

Are test data available for

the mixture itself?

Yes

Are the test results on the mixture

conclusive taking into account dose

and other factors such as duration,

observations and analysis (e.g.,

statistical analysis, test sensitivity)

of reproduction test systems?

Yes

Classification based on individual

ingredients of the mixture (See above).

Can bridging principles be applied? If data on another

mixture are used in the application of bridging principles,

the data on that mixture must be conclusive. See criteria.

Additional category

for effects on or via

lactation

No symbol

No signal word

Additional

category for

effects on or

via lactation

No symbol

No signal

word

classification

Yes

Classification based on individual ingredients of the mixture

Modified classification on a case-by-case basis

186

Reproductive Toxicity Classification Examples

The following examples are provided to walk you through reproductive toxicity classification.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Reproductive Toxicity

Test Data

HCS 2012

Classification

Rationale

Evidence of decreased number of fetuses

per brood, decline in the ability of males

to impregnate females, increased

incidence of preimplantation embryo

death, etc. at dosing levels causing no

general toxicity.

Reproductive

Toxicity

Category 1B

Fulfills criteria

 Data from animal studies providing

clear evidence of an adverse effect

on sexual function and fertility or on

development in the absence of other

toxic effects.

Substance Example #2

Reproductive Toxicity

Test Data

HCS 2012

Classification

Rationale

Human epidemiological studies in IRIS

Toxicological review (2005) and

ATSDR (2000), describe increased

incidence of natural abortion after

exposure, abnormal development and

malformation of newborns caused by

prenatal abuse and decreased plasma

concentrations of luteinizing hormone

and testosterone after exposure.

Increased risk of late spontaneous

abortions associated with exposure at

levels around 88 ppm (range 50-150

ppm).

Evidence of increased incidences of fetal

death and delayed ossification, a

decrease and unossification of

sternebrae, a shift in rib profile, excess

ribs, retarded skeletal development,

delayed reflex response, learning

disability and early vaginal opening and

testes descent at dosing levels not toxic

to dams from rat and mouse

teratogenicity tests.

Reproductive

Toxicity

Category 1A

Fulfills criteria

 Evidence of adverse effects on

development in humans and in

animal studies.

187

Example of a mixture fulfilling the criteria for classification:

Mixture Example #1

Reproductive Toxicity

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 0.05%, Category 1B

Component 2: 2%, Category 2

Component 3: 0.2%, Effect on or

via lactation

Component 4: 97.75%

Reproductive

Toxicity

Category 2 and

Additional

category for effects

on or via lactation

The Reproductive Toxicity cut-off

values/concentration limits are used

for classification.

Fulfills criteria

 Component 1 is not ≥ 0.1% so

the mixture does not meet the

Category 1B criteria.

 Component 2 is ≥ 0.1% so the

mixture meets the Category 2

criteria.

 Component 3 is ≥ 0.1% so the

mixture meets the effect on or via

lactation criteria.

188

References

29 CFR 1910.1200, Hazard Communication, Appendix A.7 Reproductive Toxicity

29 CFR 1910.1200, Hazard Communication, Appendix C Allocation of Label Elements

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

The Organization for Economic Co-operation and Development (OECD) Guidelines for the

Testing of Chemicals.

United States Environmental Protection Agency (EPA), Office of Prevention, Pesticides, and

Toxic Substances (OPPTS) Health Effects Test Guidelines.

189

VII.8 Specific Target Organ Toxicity – Single Exposure

Introduction

Chemical exposures can potentially result in adverse effects on one or more of the body’s organ

systems such as the renal or nervous systems. The HCS provides criteria for the evaluation of

data related to a specific target organ or type of effect.

The specific target organ toxicity (STOT) classification addresses chemicals that affect various

target organ systems of the body after either a single or repeated exposure. These criteria address

those target organ systems that are not covered by the HCS criteria for acute toxicity, skin

corrosion/irritation, serious eye damage/eye irritation, respiratory or skin sensitization, germ cell

mutagenicity, carcinogenicity, reproductive toxicity and aspiration toxicity. Specific target organ

toxicity criteria apply to significant health effects that can impair function, both reversible and

irreversible, which can be immediate and/or delayed. Specific target organ toxicity can occur by

any route that is relevant for human exposures (i.e., principally oral, dermal or inhalation).

The HCS addresses two different types of STOT hazards: toxicity that occurs after a single

exposure to a chemical, and toxicity that occurs after repeated exposures to a chemical. To

conform to the HCS, this guidance addresses the two STOT hazard classes separately: STOT –

single exposure in Chapter VII.8 and STOT – repeated exposure in Chapter VII.9.

Substances and mixtures shall be classified for either or both single and repeated dose toxicity

independently.

Definition and General Considerations

Specific target organ toxicity - single exposure (STOT-SE) means specific, non-lethal target

organ toxicity arising from a single exposure to a chemical. All significant health effects that can

impair function, both reversible and irreversible, immediate and/or delayed and not specifically

addressed in Chapters VII.1 to VII.7 and VII.10 are included. Specific target organ toxicity

following repeated exposure is classified in accordance with Specific Target Organ Toxicity –

Repeated Exposure and is not included here but is discussed in the next chapter, VII.9.

The adverse health effects produced by a single exposure include consistent and identifiable

toxic effects in humans; or, in experimental animals, toxicologically significant changes which

have affected the function or morphology of a tissue/organ, or have produced serious changes to

the biochemistry or hematology of the organism, and these changes are relevant for human

health. Human data is the primary source of evidence for this hazard class.

Assessment shall take into consideration not only significant changes in a single organ or

biological system but also generalized changes of a less severe nature involving several organs.

Specific target organ toxicity can occur by any route that is relevant for humans (i.e., principally

oral, dermal or inhalation).

190

The classification criteria for specific organ systemic toxicity – single exposure are organized as

criteria for substances Categories 1 and 2, criteria for substances Category 3 and criteria for

mixtures.

Classification Criteria for Substances

Substances of Category 1 and Category 2

Substances shall be classified for immediate or delayed effects separately, by the use of expert

judgment on the basis of the weight of all evidence available, including the use of recommended

guidance values. Substances shall then be classified in Category 1 or 2, depending upon the

nature and severity of the effect(s) observed.

Figure VII.8.1. Hazard categories for specific target organ toxicity following single exposure

Category

Criteria

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 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 in order to help in

classification.

In exceptional cases, human evidence can also be used to place a

substance in Category 2.

191

Category

Criteria

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 includes only narcotic effects and respiratory tract irritation.

Substances are classified specifically for these.

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).

Specific considerations for classification of substances as specific target organ toxicity – single

exposure

Classification is determined by expert judgment, on the basis of the weight of all evidence

available.

Weight-of-evidence of all available data, including human incidents, epidemiology, and studies

conducted in experimental animals is used to substantiate specific target organ toxic effects that

merit classification.

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

identified.

The information required to evaluate specific target organ toxicity comes either from single

exposure in humans (e.g., exposure at home, in the workplace or environmentally), or from

studies conducted in experimental animals. The standard animal studies in rats or mice that

provide this information are acute toxicity studies which can include clinical observations and

detailed macroscopic and microscopic examination to enable the toxic effects on target

tissues/organs to be identified. Results of acute toxicity studies conducted in other species may

also provide relevant information.

In most cases chemicals with human evidence of target organ toxicity will be classified in

Category 1. Only in exceptional cases, based on expert judgment, it may be appropriate to place

certain substances with human evidence of target organ toxicity in Category 2: (a) when the

weight of human evidence is not sufficiently convincing to warrant Category 1 classification,

and/or (b) based on the nature and severity of effects. However, the following considerations

should be kept in mind when applying this concept. Dose/concentration levels in humans shall

not be considered in the classification. Additionally, any available evidence from animal studies

192

shall be consistent with the Category 2 classification. In other words, if there are also animal data

available on the substance that warrant Category 1 classification, the chemical shall be classified

as Category 1.

Effects considered to support classification for Categories 1 and 2

Classification is supported by evidence associating single exposure to the substance with a

consistent and identifiable toxic effect.

Evidence from human experience/incidents is usually restricted to reports of adverse health

consequences, often with uncertainty about exposure conditions, and may not provide the

scientific detail that can be obtained from well-conducted studies in experimental animals.

Therefore, evidence from appropriate studies in experimental animals can furnish much more

detail, in the form of clinical observations and macroscopic and microscopic pathological

examination; this can often reveal hazards that may not be life-threatening but could indicate

functional impairment. Consequently, all available evidence, including evidence relevant to

human health, must be taken into consideration in the classification process. Relevant toxic

effects in humans and/or animals include, but are not limited to:

(a) Morbidity resulting from single exposure;

(b) Significant functional changes, more than transient in nature, in the respiratory

system, central or peripheral nervous systems, other organs or other organ systems,

including signs of central nervous system depression and effects on special senses (e.g.,

sight, hearing and sense of smell);

or urinalysis parameters;

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

confirmed at microscopic examination;

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

regenerative capacity;

(f) Morphological changes that are potentially reversible but provide clear evidence of

marked organ dysfunction; and

(g) Evidence of appreciable cell death (including cell degeneration and reduced cell

number) in vital organs incapable of regeneration.

193

Effects considered not to support classification for Categories 1 and 2

Effects may be seen in humans and/or animals that do not justify classification. Such effects

include, but are not limited to:

(a) Clinical observations or small changes in body weight gain, food consumption or

water intake that may have some toxicological importance but that do not, by themselves,

indicate “significant” toxicity;

(b) Small changes in clinical biochemistry, hematology or urinalysis parameters and/or

transient effects, when such changes or effects are of doubtful or of minimal toxicological

importance;

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

(e) Substance-induced species-specific mechanisms of toxicity, i.e., demonstrated with

reasonable certainty to be not relevant for human health.

Guidance values to assist with classification based on the results obtained from studies

conducted in experimental animals for Categories 1 and 2

In order to help reach a decision about whether a substance shall be classified or not, and to what

degree it shall be classified (Category 1 vs. Category 2), dose/concentration “guidance values”

are provided for consideration of the dose/concentration which has been shown to produce

significant health effects. The principal argument for proposing such guidance values is that all

chemicals are potentially toxic and there has to be a reasonable dose/concentration above which

a degree of toxic effect is acknowledged.

Thus, in animal studies, when significant toxic effects are observed that indicate classification,

consideration of the dose/concentration at which these effects were seen, in relation to the

suggested guidance values, provides useful information to help assess the need for classification

(since the toxic effects are a consequence of the hazardous property(ies) and also the

dose/concentration).

The guidance value ranges for single-dose exposure which has produced a significant non-lethal

toxic effect apply to acute toxicity testing, as shown in the table below.

194

Table VII.8.1. Guidance value ranges for single-dose exposures

Route of exposure

Units

Guidance values (dose/concentration)

Category 1

Category 2

Category 3

Oral (rat)

mg/kg

body weight

< 300

> 300 and  2000

Guidance

values do not

apply

Dermal

(rat or rabbit)

mg/kg

body weight

< 1000

> 1000 and  2000

Inhalation (rat) gas

ppm

< 2500

> 2500 and  5000

Inhalation (rat) vapor

mg/1

< 10

> 10 and  20

Inhalation (rat)

dust/mist/fume

mg/l/4h

< 1.0

> 1.0 and  5.0

The guidance values and ranges mentioned in the above table are intended only for guidance

purposes, i.e., to be used as part of the weight-of-evidence approach, and to assist with decisions

about classification. They are not intended as strict demarcation values. Guidance values are not

provided for Category 3 since this classification is primarily based on human data; animal data

may be included in the weight-of-evidence evaluation.

It is possible that even where a specific profile of toxicity occurs at a dose/concentration below

the guidance value, e.g., < 2000 mg/kg body weight by the oral route, the nature of the effect

may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen

in animal studies occurring at above a guidance value, e.g., ≥ 2000 mg/kg body weight by the

oral route, and in addition there is supplementary information from other sources, e.g., other

single dose studies, or human case experience, which supports a conclusion that, in view of the

weight-of-evidence, classification is the prudent action to take.

Other considerations when classifying using animal data

When a substance is characterized only by use of animal data, the classification process must

include reference to dose/concentration guidance values as one of the elements that contribute to

the weight-of-evidence approach.

Evidence in humans

When well-substantiated human data are available showing a specific target organ toxic effect

that can be reliably attributed to a single exposure to a substance, the substance shall be

classified. Positive human data, regardless of probable dose, predominates over animal data.

Thus, if a substance is unclassified because specific target organ toxicity observed was

considered not relevant or significant to humans, if subsequent human incident data become

available showing a specific target organ toxic effect, the substance shall be classified.

195

Non-test data

A substance that has not been tested for specific target organ toxicity shall, where appropriate, be

classified on the basis of data from a scientifically validated structure activity relationship and

expert judgment-based extrapolation from a structural analogue that has previously been

classified together with substantial support from consideration of other important factors such as

formation of common significant metabolites.

Substances of Category 3

Criteria for respiratory tract irritation

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

(a) Respiratory irritant effects (characterized by localized redness, edema, pruritus and/or

pain) that impair function with symptoms such as cough, pain, choking, and breathing

difficulties are included. It is recognized that this evaluation is based primarily on human

data;

(b) Subjective human observations supported by objective measurements of clear

respiratory tract irritation (RTI) (e.g., electrophysiological responses, biomarkers of

inflammation in nasal or bronchoalveolar lavage fluids);

produced in the exposed population rather than being an isolated idiosyncratic reaction or

response triggered only in individuals with hypersensitive airways. Ambiguous reports

simply of “irritation” should be excluded as this term is commonly used to describe a

wide range of sensations including those such as smell, unpleasant taste, a tickling

sensation, and dryness, which are outside the scope of classification for respiratory tract

irritation;

(d) There are currently no scientifically validated animal tests that deal specifically with

RTI; however, useful information may be obtained from the single and repeated

inhalation toxicity tests. For example, animal studies may provide useful information in

terms of clinical signs of toxicity (dyspnea, rhinitis, etc.) and histopathology (e.g.,

hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible

and may reflect the characteristic clinical symptoms described above. Such animal

studies can be used as part of the weight-of-evidence evaluation; and

(e) This special classification will occur only when more severe organ effects including

the respiratory system are not observed, as those effects would require a higher

classification.

196

Criteria for narcotic effects

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

(a) Central nervous system depression including narcotic effects in humans such as

drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo

are included. These effects can also be manifested as severe headache or nausea, and can

lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function,

deficits in perception and coordination, reaction time, or sleepiness; and

(b) Narcotic effects observed in animal studies may include lethargy, lack of coordination

righting reflex, narcosis, and ataxia. If these effects are not transient in nature, then they

shall be considered for classification as Category 1 or 2.

Classification criteria for mixtures

Mixtures are classified using the same criteria that are used to classify substances; or

alternatively, as described below. As with substances, mixtures may be classified for specific

target organ toxicity following single exposure, repeated exposure, or both.

The approach to classifying mixtures for specific target organ toxicity – single exposure

incorporates the tiered approach (i.e., stepwise procedure based on a hierarchy).

Tier 1: Classification of mixtures when data are available for the complete mixture

When reliable and good evidence from human experience or appropriate animal studies is

available for the mixture, then the mixture can be classified by use of a weight-of-evidence

approach using the same criteria as specified for substances. Specifically for mixtures, care

should be exercised in evaluating data so that the dose, duration of exposure, observation or

analysis, does not render the results inconclusive. If test data for the mixture is not available then

the classifier should consider application of the criteria in Tier 2 or Tier 3 below, as appropriate.

Tier 2: Classification of mixtures when data are not available for the complete mixture -

bridging principles

Where the mixture itself has not been tested to determine its specific target organ toxicity, but

there are sufficient data on BOTH the individual ingredients AND similar tested mixtures to

adequately characterize the hazards of the mixture, these data can be used in accordance with the

below bridging principles.

All six bridging principles are applicable to the specific target organ toxicity-single exposure

hazard class:

 Dilution,

 Batching,

197

 Concentration of mixtures,

 Interpolation within one toxicity category,

 Substantially similar mixtures,

 Aerosols.

The application of bridging principles ensures that the classification process uses the available

data to the greatest extent possible in characterizing the potential specific target organ toxicity-

single exposure hazard.

Dilution

If a tested mixture is diluted with a diluent which has the same or a lower toxicity

classification as the least toxic original ingredient and which is not expected to affect the

specific target organ toxicity of other ingredients, then the new diluted mixture may be

classified as equivalent to the original tested mixture.

Batching

The specific target organ toxicity of a tested production batch of a mixture can be

assumed to be substantially equivalent to that of another untested production batch of the

same commercial product when produced by or under the control of the same

manufacturer, unless there is reason to believe there is significant variation such that the

specific target organ toxicity of the untested batch has changed. If the latter occurs, a new

classification is necessary.

Concentration of mixtures

If in a tested mixture of STOT-SE Category 1, the concentration of a specific target organ

toxic ingredient is increased, the resulting concentrated mixture should be classified in

STOT-SE Category 1 without additional testing.

Interpolation within one toxicity category

For three mixtures (A, B and C) with identical ingredients, where mixtures A and B have

been tested and are in the same STOT-SE category, and where untested mixture C has the

same specific target organ toxicologically active ingredients as mixtures A and B but has

concentrations of specific target organ toxicologically active ingredients intermediate to

the concentrations in mixtures A and B, then mixture C is assumed to be in the same

STOT-SE category as A and B.

198

Substantially similar mixtures

Given the following:

(a) Two mixtures: (i) A + B;

(ii) C + B;

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

mixture (ii);

(d) Data on toxicity for A and C are available and substantially equivalent, i.e.,

they are in the same hazard category and are not expected to affect the specific

target organ toxicity of B.

If mixture (i) or (ii) is already classified by testing, then the other mixture can be

classified in the same hazard category.

Aerosols

An aerosol form of a mixture may be classified in the same hazard category as the tested,

non-aerosolized form of the mixture for oral and dermal specific target organ toxicity

provided the added propellant does not affect the toxicity of the mixture on spraying.

Classification of aerosolized mixtures for specific target organ toxicity by the inhalation

route should be considered separately.

If appropriate data is not available to apply the above bridging principles then the classifier

should consider application of the criteria in Tier 3.

Tier 3: Classification of mixtures when data are available for all ingredients or only for some

ingredients of the mixture

The approach to classifying a mixture for specific target organ toxicity in Tier 3 is to use a cut-

off/concentration limit.

Where there is no reliable evidence or test data for the specific mixture itself, and the bridging

principles cannot be used to enable classification, then classification of the mixture is based on

the classification of the ingredient substances. In this case, the mixture shall be classified as a

specific target organ toxicant (specific organ specified), following a single exposure when at

least one ingredient has been classified as a Category 1 or Category 2 specific target organ

toxicant and is present at or above the appropriate cut-off value/concentration limit specified in

the below table for Categories 1 and 2, respectively.

199

Table VII.8.2. Cut-off values/concentration limits of ingredients of a mixture classified as a

specific target organ toxicant that would trigger classification of the mixture as Category 1

or 2

Ingredient Classified as:

Cut-off/concentration limits

triggering classification of a mixture as:

Category 1

Category 2

Category 1

Target organ toxicant

≥ 1.0%

Category 2

Target organ toxicant

≥ 1.0%

Care shall be exercised when toxicants affecting more than one organ system are combined that

the potentiation or synergistic interactions are considered, because certain substances can cause

target organ toxicity at < 1% concentration when other ingredients in the mixture are known to

potentiate its toxic effect.

Additionally, a mixture can also be classified in STOT – Single Exposure Category 3 for

respiratory tract irritation and/or narcotic effects using a cut off/concentration limit of 20%, as

appropriate.

Table VII.8.3. 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 3

Sum of Ingredients Classified as:

Cut-off/concentration limits triggering

classification of a mixture as STOT SE:

Category 3

Respiratory Tract Irritant

Category 3

Narcotic Effects

STOT SE Category 3 -

Respiratory Tract Irritant

20%

STOT SE Category 3 -

Narcotic Effects

20%

Care shall be exercised when extrapolating the toxicity of a mixture that contains Category 3

ingredient(s). A cut-off value/concentration limit of 20%, considered as an additive of all Category

3 ingredients for each hazard endpoint, is appropriate; however, this cut-off value/concentration

limit may be higher or lower depending on the Category 3 ingredient(s) involved and the fact that

some effects such as respiratory tract irritation may not occur below a certain concentration while

other effects such as narcotic effects may occur below this 20% value. Expert judgment shall be

200

exercised. Respiratory tract irritation and narcotic effects are to be evaluated separately. When

conducting classifications for these hazards, the contribution of each ingredient should be

considered additive, unless there is evidence that the effects are not additive.

Since the mixture criteria for STOT-SE Category 3 ingredients are generally additive, the

concept of relevant ingredients can be considered. The “relevant ingredients” of a mixture are

those which are present in concentration ≥ 1% (w/w for solids, liquids, dusts, mists and vapors

and v/v for gases), unless there is a reason to suspect that an ingredient present at a concentration

< 1% can still be relevant for classifying the mixture for respiratory tract irritation or narcotic

effects.

Note that the additivity approach does NOT apply when classifying mixtures for STOT-SE

categories 1 and 2.

Mixtures containing from 1% to less than 10% of Category 1 STOT-SE ingredients may be

classified as Category 2 STOT-SE under the limited following circumstances. The criteria allow

for the classification of mixtures under the criteria as used for substances. Where the

classification of the ingredients is based on animal data only, the use of the guidance values in

Table VII.8.1 is appropriate as a part of the total weight-of-evidence approach. It may be

appropriate, in light of the guidance values, to classify a mixture containing from 1% to less than

10% of Category 1 STOT-SE substances as a Category 2 STOT-SE hazard, where warranted by

the weight of evidence. Such a classification must be consistent with all of the criteria in 29 CFR

1910.1200 A.8.2.1 ("Substances of Category 1 and Category 2"), including consideration of the

severity of the effect observed. However, OSHA would not accept a determination not to classify

a mixture based on this approach.

Classification Procedure and Guidance

Test data

There is no requirement in the HCS to test a chemical to classify its hazards. The HCS requires

collecting and evaluating the best available existing evidence on the hazards of each chemical.

Old-style acute toxicity tests on animals use death as the main observational endpoint, usually in

order to determine LD

or LC

values. These tests will generally not provide useful information

for STOT-SE categories 1 and 2. Findings of narcosis and respiratory tract irritation are

sometimes reported in clinical observations in standard acute toxicity tests.

Some of the current acute toxicity tests, such as the fixed dose and up-down procedures (e.g.,

OECD Test Guideline 420 Acute oral toxicity – Fixed dose procedure and OECD Test Guideline

425 Acute oral toxicity – Up-and-down procedure), have observations on signs of non-lethal

toxicity and may provide useful information for STOT-SE.

201

Classification procedure

Specific target organ toxicity after a single exposure addresses effects on the body other than

death (which is addressed by acute toxicity criteria). These effects may be reversible or

irreversible, and immediate or delayed. The criteria specifically note that, if available, human

data will be the primary source of evidence for this hazard class.

Relevant information with respect to toxicity after a single exposure may be available from case

reports, epidemiological studies, medical surveillance and poison centers.

Classification for STOT-SE Category 1 and 2 is based on findings of “significant” or “severe”

toxic effects. Significant effects mean changes which clearly indicate functional disturbance or

morphological changes which are toxicologically relevant. Severe effects are generally more

profound or serious than significant effects and are of a considerably adverse nature with

substantial impact on health. Both factors have to be evaluated by weight-of-evidence and expert

judgment.

Considerations

The STOT criteria are applied independently for STOT – single exposure and STOT – repeated

exposure (RE). Substances and mixtures can be classified into both hazard classes and either

Category 1 or Category 2 for each hazard class, as well as the additional STOT - SE Category 3

where respiratory tract irritation and/or narcotic effects are evaluated separately.

If the chemical is classified into more than one STOT hazard class and/or category, then all

relevant classifications should be communicated on the Safety Data Sheet in Section 2 and all

appropriate hazard statements should be communicated along with the specific affected organs

on the label.

Classification for STOT-SE and acute toxicity are independent of each other and both may be

assigned to a chemical if the respective criteria are met. However, it is not necessary to classify

in both classes for the same toxic effect. See Substance Example #5 at the end of this chapter.

Classification for STOT-SE is warranted where there is clear evidence of specific organ toxicity

especially in absence of lethality which then may be classified under a separate hazard class such

as acute toxicity.(e.g., methanol and tricresylphosphate).

The specific target organ(s) should be identified for both substances and mixtures whenever

known. All known specific target organs should be identified for mixtures classified by any of

the three tiers. If the mixture is classified on the basis of ingredients, then the target organs

effects from the ingredients should be identified. This information should be provided on SDSs

and labels.

202

Decision Logic

Two decision logics for classifying specific target organ toxicity – single exposure are provided.

The first decision logic is for substances and tested mixtures. The second decision logic is for

classifying mixtures not tested as a whole. The decision logics are provided as additional

guidance. It is strongly recommended that the person responsible for classification study the

criteria before and during use of the decision logic.

These decision logics are essentially flowcharts for classifying substances and mixtures

regarding specific target organ toxicity – single exposure. They present questions in a sequence

that walks you through the classification steps and criteria for classifying specific target organ

toxicity – single exposure. Once you answer the questions provided, you will arrive at the

appropriate classification.

203

Decision logic for specific target organ toxicity – single exposure

Substances and tested mixtures

Substance: Does the substance have data and/or information to evaluate specific

target organ toxicity following single exposure?

Classification

not possible

Mixture: Does the mixture as a whole or its ingredients have

data/information to evaluate specific target organ toxicity

following single exposure?

Yes

Following single exposure,

(a) Can the substance or mixture produce significant toxicity in humans,

(b) Can it be presumed to have the potential to produce significant

toxicity in humans on the basis of evidence from studies in

experimental animals?

See criteria and guidance values. Application of the criteria needs expert

judgment in a weight of evidence approach.

Yes

Category 2

Warning

Following single exposure,

Can the substance or mixture be presumed to have the potential to

be harmful to human health on the basis of evidence from studies in

experimental animals?

See criteria and guidance values. Application of the criteria needs

expert judgment in a weight-of-evidence approach.

Yes

Classification

not possible

See decision

logic #2

Category 1

Danger

Does the mixture as a whole have data/information to

evaluate specific target organ toxicity following single

exposure?

Yes

Following single exposure,

Can the substance or mixture produce transient narcotic effects or

respiratory tract irritation or both? Classification in Category 3 would

only occur when classification into Category 1 or 2 (based on more

severe respiratory effects or narcotic effects that are not transient) is not

warranted

See criteria. Application of the criteria needs expert judgment in a weight-of-

evidence approach.

Yes

Category 3

Warning

Not classified

Yes

204

Decision logic for specific target organ toxicity – single exposure

Mixtures not tested as a whole

Category 3

Warning

Can bridging principles be applied?

Yes

Category 2

Warning

Does the mixture contain one or more ingredients classified as a

Category 2 specific target organ toxicant at a concentration of



1.0%?

See Table for explanation of cut-off values.

Yes

Does the mixture contain one or more ingredients classified as a

Category 1 specific target organ toxicant at a concentration of



1.0%?

See Table for explanation of cut-off values.

Is the sum of the ingredients classified as a Category 3 specific target

organ toxicant at a concentration

 20%?

Care should be exercised when classifying such mixtures. See criteria.

Yes

Not classified

Classify in

appropriate

category

Yes

Category 1

Danger

205

Specific Target Organ Toxicity – Single Exposure Classification Examples

The following examples are provided to walk you through the specific target organ toxicity –

single exposure classification.

Examples of a substance fulfilling the criteria for classification:

Substance Example #1

Specific Target Organ Toxicity – Single Exposure

Test Data

HCS 2012

Classification

Rationale

There is broad human experience

from many case reports of

blindness following oral

ingestion.

Acute oral toxicity in rats is low

(LD50 values > 7,000 mg/kg

body weight with no evidence of

specific target organ toxicity

observed in rats).

STOT – SE

Category 1

Fulfills criteria

 The classification criteria for

STOT-SE Category 1 are

fulfilled, as there is clear human

evidence of a specific target

organ toxicity effect.

 The rat is the standard animal

species for single exposure tests

and is not sensitive as it did not

predict the specific target organ

toxicity potential seen in humans.

Substance Example #2

Specific Target Organ Toxicity – Single Exposure

Test Data

HCS 2012

Classification

Rationale

Human experience: There are

well-documented case reports of

strong neurotoxic effects

(peripheral neuropathy; cramps in

calves, paresthesia in feet or

hands; weak feet, wrist drop,

paralysis).

Animal data: Serious neurotoxic

effects (Paralysis) were observed

after single exposure of doses <

200 mg/kg body weight.

STOT–SE

Category 1

Fulfills criteria

 The classification criteria for

STOT-SE Category 1 are

fulfilled based on human

experience as well as on results

of animal studies, with the same

target organ toxicity being

observed in humans and

experimental animals.

206

Substance Example #3

Specific Target Organ Toxicity – Respiratory Tract Irritation

Test Data

HCS 2012

Classification

Rationale

There is broad well-documented

human experience on irritating

effect to the respiratory system

following inhalation.

STOT – SE

Category 3

respiratory tract

irritation

Fulfills criteria

 The classification criteria for

respiratory tract irritation STOT

Category 3 are fulfilled based on

well-documented experience in

humans.

Substance Example #4

Specific Target Organ Toxicity – Narcotic Effects

Test Data

HCS 2012

Classification

Rationale

In valid animal experiments

narcotic effects (transient effect

on the nervous system including

lethargy, lack of coordination and

narcosis) were observed

following a single inhalation

exposure at ≥ 8 mg/l.

STOT – SE

Category 3

Narcotic effects

Fulfills criteria

 The classification criteria for

narcotic effects STOT Category 3

are fulfilled based on results in an

animal experiment.

207

Example of a mixture fulfilling the criteria for classification:

Mixture Example #1

Specific Target Organ Toxicity – Single Exposure

Data

HCS 2012

Classification

Rationale

Component data:

Component 1: 0.5%

Component 2: 3.5%, Category 3 -

Respiratory Tract Irritation

Component 3: 15%, Category 3 -

Narcotic effects

Component 4: 15%, Category 3 -

Narcotic effects

Component 5: 66%

STOT – SE

Category 3

Narcotic effects

Respiratory tract irritation and

narcotic effects are evaluated

separately

∑%Category 3 – Narcotic effects =

15% + 15% = 30% which is > 20%,

therefore classify as Category 3 –

Narcotic Effects

∑%Category 3 – Respiratory

Irritation = 3.5%, which is < 20%,

not classified for Respiratory

Irritation

Expert judgment is necessary. A cut-

off value of 20% is appropriate, but

the cut-off value at which effects

occur may be higher or lower

depending on the Category 3

ingredient(s). In this case, the

classifiers judged that 30% is

sufficient to classify.

208

Example of a substance not fulfilling the criteria for classification:

Substance Example #5

Specific Target Organ Toxicity – Single Exposure

Data

HCS 2012

Classification

Rationale

In a study in rats after single

exposure at 2,000mg/kg body

weight severe liver damage

together with mortality was

observed in 6/10 animals.

Not classified for

STOT – SE

Though specific target organ toxicity

was observed in experimental

animals, the substance will be

classified as Acute Oral Toxicity

(Cat 4), since the lethality was due to

the target organ toxicity, i.e., liver

impairment. The substance would be

classified as Acute Oral Toxicity

Category 4 as it is assumed that the

LD50 is >300 and ≤ 2,000 mg/kg.

Thus, classification for STOT single

exposure is not required as this

would result in double classification

for the same effect/mechanism.

Death is not generally an effect that

supports classification as STOT

single exposure.

209

References

29 CFR 1910.1200, Hazard Communication, Appendix A.8 Specific Target Organ Toxicity-

Single Exposure

29 CFR 1910.1200, Hazard Communication, Appendix C Allocation of Label Elements

United Nations Globally Harmonized System of Classification and Labelling of Chemicals,

Third Revised Edition, 2009.

The Organization for Economic Co-operation and Development (OECD). Guidelines for the

Testing of Chemicals.

210

VII.9 Specific Target Organ Toxicity – Repeated or

Prolonged Exposure

Introduction

Chemical exposures can potentially result in adverse effects on one or more of the body’s target

organ systems such as the renal or nervous systems. The HCS provides criteria for the evaluation

of data related to a specific target organ or type of effect.

Specific target organ toxicity (STOT) classification addresses chemicals that affect various target

organ systems of the body after either a single or repeated exposure. These criteria address those

target organ systems that are not covered by the HCS criteria for acute toxicity, skin

corrosion/irritation, serious eye damage/eye irritation, respiratory or skin sensitization, germ cell

mutagenicity, carcinogenicity, reproductive toxicity and aspiration toxicity. Specific target organ

toxicity criteria apply to significant health effects that can impair function, both reversible and

irreversible, which can be immediate and/or delayed. Specific target organ toxicity can occur by

any route that is relevant for human exposures, i.e., principally oral, dermal or inhalation.

The HCS addresses two different types of STOT hazards: toxicity that occurs after a single

exposure to a chemical, and toxicity that occurs after repeated exposures to a chemical. To

conform to the HCS, this guidance addresses the two STOT hazard classes separately: STOT –

single exposure in Chapter VII.8 and STOT – repeated exposure in Chapter VII.9.

Substances and mixtures shall be classified for either or both single and repeated dose toxicity

independently.

Definition and General Considerations

Specific target organ toxicity - repeated exposure (STOT-RE) means specific target organ

toxicity arising from repeated exposure to a chemical. All significant health effects that can

impair function, both reversible and irreversible, immediate and/or delayed and not specifically

addressed in VII.1 to VII.7 and VII.10 are included. Specific target organ toxicity following a

single-event exposure is classified in accordance with Specific Target Organ Toxicity – Single

Exposure and is therefore not included here but discussed in the previous chapter, VII.8.

The adverse health effects produced by a repeated exposure include consistent and identifiable

toxic effects in humans; or, in experimental animals, toxicologically significant changes which

have affected the function or morphology of a tissue/organ, or have produced serious changes to

the biochemistry or hematology of the organism, and these changes are relevant for human

health. Human data is the primary source of evidence for this hazard class.

Assessment shall take into consideration not only significant changes in a single organ or

biological system but also generalized changes of a less severe nature involving several organs.

211

Specific target organ toxicity can occur by any route that is relevant for humans, i.e., principally

oral, dermal or inhalation.

The classification criteria for specific organ systemic toxicity – repeated exposure are organized

as criteria for substances Categories 1 and 2 and criteria for mixtures.

Classification Criteria for Substances

Substances shall be classified as STOT - RE by expert judgment on the basis of the weight of all

evidence available, including the use of recommended guidance values which take into account the

duration of exposure and the dose/concentration which produced the effect(s). Substances shall be

placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

Figure VII.9.1. Hazard categories for specific target organ toxicity following

repeated exposure

Category

Criteria

Category 1

Substances that have produced significant toxicity in humans, or

that, on the basis of evidence from studies in experimental animals

can be presumed to have the potential to produce significant toxicity

in humans following repeated or prolonged

exposure

Substances are classified in Category 1 for STOT-RE 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 to be used

as part of weight-of-evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in

experimental animals can be presumed to have the potential to be

harmful to human health following repeated or prolonged exposure

Substances are classified in Category 2 for STOT-RE 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 in order to help in classification.

In exceptional cases, human evidence can also be used to place a

substance in Category 2.

Significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals.

212

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).

Specific considerations for classification of substances as specific target organ toxicity –

repeated exposure

Classification is determined by expert judgment, on the basis of the weight of all evidence

available.

Weight-of-evidence of all available data, including human incidents, epidemiology, and studies

conducted in experimental animals is used to substantiate specific target organ toxic effects that

merit classification.

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

identified.

The information required to evaluate specific target organ toxicity comes either from repeated

exposure in humans, (e.g., exposure at home, in the workplace or environmentally), or from

studies conducted in experimental animals. The standard animal studies in rats or mice that

provide this information are 28-day, 90-day or lifetime studies (up to 2 years) that include

hematological, clinico-chemical and detailed macroscopic and microscopic examination to

enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies

performed in other species may also be used. Other long-term exposure studies, e.g., for

carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific

target organ toxicity that could be used in the assessment of classification.

In most cases chemicals with human evidence of target organ toxicity will be classified in

Category 1. Only in exceptional cases, based on expert judgment, it may be appropriate to place

certain substances with human evidence of target organ toxicity in Category 2: (a) when the

weight of human evidence is not sufficiently convincing to warrant Category 1 classification,

and/or (b) based on the nature and severity of effects. However, the following considerations

should be kept in mind when applying this concept. Dose/concentration levels in humans shall

not be considered in the classification. Additionally, any available evidence from animal studies

shall be consistent with the Category 2 classification criteria. In other words, if there are also

animal data available on the substance that warrant Category 1 classification, the chemical shall

be classified as Category 1.

Effects considered to support classification for Categories 1 and 2

Classification is supported by reliable evidence associating repeated exposure to the substance

with a consistent and identifiable toxic effect.

213