Derivation of Immediately Dangerous 

to Life or Health (IDLH) Values

CURRENT INTELLIGENCE BULLETIN 66

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health
Cover photo: Courtesy of Dupont
Derivation of Immediately Dangerous 

to Life or Health (IDLH)Values

Current Intelligence Bulletin 66

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Centers for Disease Control and Prevention

National Institute for Occupational Safety and Health
ii NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

This document is in the public domain and may be freely copied or reprinted.

Disclaimer

Mention of any company or product does not constitute endorsement by the National Institute for Occupational Safety and Health (NIOSH). In addition, citations to websites external to NIOSH do not constitute NIOSH endorsement of the sponsoring organizations 

or their programs or products. Furthermore, NIOSH is not responsible for the content of 

these websites. All Web addresses referenced in this document were accessible as of the 

publication date.

Ordering Information

To receive documents or other information about occupational safety and health topics, 

contact NIOSH:

Telephone: 1–800–CDC–INFO (1–800–232–4636)

TTY: 1–888–232–6348

CDC INFO: www.cdc.gov/info

or visit the NIOSH website at www.cdc.gov/niosh.

For a monthly update on news at NIOSH, subscribe to NIOSH eNews by visiting 

www.cdc.gov/niosh/eNews.

Suggested Citation

NIOSH [2013]. Current intelligence bulletin 66: derivation of immediately dangerous to life 

or health (IDLH) values. Cincinnati, OH: US Department of Health and Human Services, 

Centers for Disease Control and Prevention, National Institute for Occupational Safety and 

Health, DHHS (NIOSH) Publication 2014–100.

DHHS (NIOSH) Publication No. 2014–100

November 2013

Safer • Healthier • PeopleTM
NIOSH CIB 66 iii • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Foreword

Since the establishment of the original Immediately Dangerous to Life or Health (IDLH) values in 1974, the National Institute for Occupational Safety and Health (NIOSH) has continued to review available scientific data to improve the methodology used to derive acute 

exposure guidelines, in addition to the chemical-specific IDLH values. The primary objective 

of this Current Intelligence Bulletin (CIB) is to present a methodology, based on the modern 

principles of risk assessment and toxicology, for the derivation of IDLH values, which characterize the health risks of occupational exposures to high concentrations of airborne contaminants. The methodology for deriving IDLH values presented in the CIB incorporates the approach established by the National Advisory Committee on Acute Exposure Guideline Levels 

(AEGLs) for Hazardous Substances—consisting of members from the U.S. Environmental 

Protection Agency, U.S. Department of Defense, U.S. Department of Energy, U.S. Department of Transportation, other federal and state government agencies, the chemical industry, 

academia, labor, and other organizations from the private sector—during the derivation of 

community-based acute exposure limits. The inclusion of the AEGL methodology has helped 

ensure that the IDLH values derived with use of the guidance provided in this document are 

based on validated scientific rationale.

The intent of this document is not only to update the IDLH methodology used by NIOSH 

to develop IDLH values based on contemporary risk assessment practices, but also to increase the transparency behind their derivation. The increased transparency will provide 

occupational health professionals, risk managers, and emergency response personnel additional information that can be applied to improve characterization of the hazards of 

high concentrations of airborne contaminants. This will also facilitate a more informed 

decision-making process for the selection of respirators and establishment of risk management plans for non-routine work practices and emergency preparedness plans capable 

of better protecting workers. 

John Howard, M.D.

Director, National Institute for Occupational 

 Safety and Health 

Centers for Disease Control and Prevention
This page intentionally left blank.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values v

Executive Summary

Chemicals are a ubiquitous component of the modern workplace. Occupational exposures 

to chemicals have long been recognized as having the potential to adversely affect the lives 

and health of workers. Acute or short-term exposures to high concentrations of some airborne chemicals have the ability to quickly overwhelm workers, resulting in a spectrum 

of undesirable outcomes that may include irritation of the eyes and respiratory tract, severe irreversible health effects, impairment of the ability to escape from the exposure environment, and, in extreme cases, death. Airborne concentrations of chemicals capable of 

causing such adverse health effects or of impeding escape from high-risk conditions may 

arise from a variety of non-routine workplace situations affecting workers, including special 

work procedures (e.g., in confined spaces), industrial accidents (e.g., chemical spills or explosions), and chemical releases into the community (e.g., during transportation incidents 

or other uncontrolled-release scenarios). 

Since the 1970s, the National Institute for Occupational Safety and Health (NIOSH) has been 

responsible for the development of acute exposure guidelines called Immediately Dangerous to Life or Health (IDLH) values, which are intended to characterize these high-risk conditions. Used initially as key components of the NIOSH Respirator Selection Logic [NIOSH 

2004], IDLH values are established (1) to ensure that the worker can escape from a given contaminated environment in the event of failure of the respiratory protection equipment and (2) 

to indicate a maximum level above which only a highly reliable breathing apparatus, providing maximum worker protection, is permitted. In addition, occupational health professionals 

have employed these acute exposure guidelines beyond their initial purpose as a component 

of the NIOSH Respirator Selection Logic. Examples of such applications of the IDLH values 

include the development of Risk Management Plans (RMPs) for non-routine work practices 

governing operations in high-risk environments (e.g., confined spaces) and the development 

of Emergency Preparedness Plans (EPPs), which provide guidance for emergency response 

personnel and workers during unplanned exposure events. 

Since the establishment of the IDLH values in the 1970s, NIOSH has continued to review 

available scientific data to improve the protocol used to derive acute exposure guidelines, 

in addition to the chemical-specific IDLH values. The information presented in this Current Intelligence Bulletin (CIB) represents the most recent update of the scientific rationale 

and the methodology (hereby referred to as the IDLH methodology) used to derive IDLH 

values. The primary objectives of this document are to

• Provide a brief history of the development of IDLH values 

• Update the scientific bases and risk assessment methodology used to derive IDLH 

values from quality data

• Provide transparency behind the rationale and derivation process for IDLH values

• Demonstrate how scientifically credible IDLH values can be derived from available 

data resources.
vi NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

The IDLH methodology outlined in this CIB reflects the modern principles and understanding in the fields of risk assessment, toxicology, and occupational health and provides 

the scientific rationale for the derivation of IDLH values based on contemporary risk assessment practices. According to this protocol, IDLH values are based on health effects considerations determined through a critical assessment of the toxicology and human health 

effects data. This approach ensures that the IDLH values reflect an airborne concentration 

of a substance that represents a high-risk situation that may endanger workers’ lives or 

health. Relevant airborne concentrations are typically addressed through the characterization of inhalation exposures; however, airborne chemicals can also contribute to toxicity 

through other exposure routes, such as the skin and eyes. In this document, airborne concentrations are referred to as acute inhalation limits or guidelines to adhere to commonly 

used nomenclature. 

The emphasis on health effects is consistent with both the traditional use of IDLH values as 

a component of the respirator selection logic and the growing applications of IDLH values 

in RMPs for non-routine work practices governing operations in high-risk environments 

(e.g., confined spaces) and the development of EPPs. Incorporated in the IDLH methodology are the standing guidelines and procedures [NAS 2001] used for the development of 

community-based acute exposure limits called Acute Exposure Guideline Levels (AEGLs). 

The inclusion of the AEGL methodology has helped ensure that the health-based IDLH 

values derived with use of the guidance provided in this document are based on validated 

scientific rationale. 

The IDLH methodology is based on a weight-of-evidence approach that applies scientific 

judgment for critical evaluation of the quality and consistency of scientific data and in extrapolation from the available data to the IDLH value. The weight-of-evidence approach 

refers to critical examination of all available data from diverse lines of evidence and the 

derivation of a scientific interpretation on the basis of the collective body of data, including its relevance, quality, and reported results. This is in contrast to a purely hierarchical or 

strength-of-evidence approach, which relies on rigid decision criteria for selecting a critical 

adverse effect, a point of departure (POD), or the point on the dose–response curve from 

which dose extrapolation is initiated and for applying default uncertainty factors (UFs) to 

derive the IDLH value. Conceptually, the derivation process for IDLH values is similar to 

that used in other risk-assessment applications, including these steps:

• Hazard characterization 

• Identification of critical adverse effects 

• Identification of a POD 

• Application of appropriate UFs, based on the study and POD 

• Determination of the final risk value. 

However, the use of a weight-of-evidence approach allows for integration of all available data that may originate from different lines of evidence into the analysis and the 

subsequent derivation of an IDLH value. Ideally, this ensures that the analysis is not 

restricted to a limited dataset or a single study for a specific chemical. In particular, 
NIOSH CIB 66 vii • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

application of the appropriate UFs to each potential POD allows for consideration of 

the impact of the overall dataset as well as the uncertainties associated with each potential key study in determining the final IDLH value. 

The primary steps (see Figure 3–1) applied in the establishment of an IDLH value include 

the following:

• Critical review of human and animal toxicity data to identify potential relevant studies and characterize the various lines of evidence that can support the derivation of 

the IDLH value 

• Determination of a chemical’s mode of action (MOA) or description of how a chemical exerts its toxic effects 

• Application of duration adjustments (time scaling) to determine 30-minute-equivalent 

exposure concentrations and the conduct of other dosimetry adjustments, as needed 

• Selection and application of a UF for POD or critical adverse effect concentration, 

identified from the available studies to account for issues associated with interspecies and intraspecies differences, severity of the observed effects, data quality, or data 

insufficiencies 

• Development of the final recommendation for the IDLH value from the various alternative lines of evidence, with use of a weight-of-evidence approach to all of the data.

NIOSH recognizes that in some cases a health-based IDLH value might not account for all 

workplace hazards, such as safety concerns or considerations. Here are some examples of 

situations and conditions that might preclude the use of a health-based IDLH value: 

• The airborne concentration of a substance is sufficient to cause oxygen deprivation 

(oxygen concentration <19.5%), a life-threatening condition

• The concentration of particulate matter generated during a process significantly reduces visibility, preventing escape from the hazardous environment 

• The airborne concentration of a gas or vapor is greater than 10% of the lower explosive limit (LEL) and represents an explosive hazard.

In such cases, it is important that safety hazards or other considerations be taken into account. Information on the safety hazards will be incorporated in the support documentation (see Appendix A) for an IDLH value, to aid occupational health professionals in the 

development of RMPs for non-routine work practices governing operations in high-risk 

environments (e.g., confined spaces) and EPPs. In the event that the derived health-based 

IDLH value exceeds 10% of the LEL concentration for a flammable gas or vapor, the air 

concentration that is equal to 10% of the LEL will become the default IDLH value for the 

chemical. The following hazard statement will be included in the support documentation: 

“The health-based IDLH value is greater than 10% of the LEL (>10% LEL) of the chemical 

of interest in the air. Safety considerations related to the potential hazard of explosion must 

be taken into account.” In addition, the notation “>10% LEL” will appear beside the IDLH 

value in the NIOSH Pocket Guide to Chemical Hazards [NIOSH 2005] and other NIOSH 

publications. The equivalent default approach for dust would be based on 10% of the minimum explosive concentration (MEC). However, determining the combustibility of dusts is 
viii NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

complicated and dictated by the relationship between multiple dust-specific factors including, but not limited to, particle size distribution, minimum ignition energy, explosion intensity, and dispersal in the air [Cashdollar 2000]. The ability to quantify dust-specific concentrations that could represent explosive hazards for risk assessment purposes is limited 

and often not possible given the absence of critical data, such as chemical-specific MEC and 

other previously identified factors. Despite the absence of specific guidance, NIOSH will 

critically assess the explosive nature of a dust when sufficient technical data are available. 

If determined to be appropriate, the findings of this assessment will be incorporated into 

the derivation process to ensure that the IDLH value is protective against both health and 

safety hazards. When an explosive hazard is identified for an aerosol, NIOSH will include 

the following hazard statement: “Dust may represent an explosive hazard. Safety considerations related to hazard of explosion must be taken into account.” In addition, the notation 

(Combustible Dust) will appear in other NIOSH publications. 

Supplemental information is included in this CIB to provide insight into (1) the literature 

search strategy, (2) the scheme used to prioritize and select chemicals for which an IDLH value 

will be established, and (3) an overview of the analysis applied by NIOSH to develop a scientifically based approach for the selection of the UF during the derivation of IDLH values. In addition, Appendix A presents an example of the derivation of an IDLH value for chlorine (CAS# 

7782-50-5), based on the scientific rationale and process outlined in this CIB. The example 

highlights the primary steps in establishment of an IDLH value, including a critical review 

of the identified human and animal data, discussion of the selection of the POD and UF, and 

extrapolation of the 30-minute-equivalent exposure concentration from animal toxicity data.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values ix

Contents

Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

Executive Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Abbreviations and Acronyms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Glossary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv

Acknowledgements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

 1.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

 1.2 The Standards Completion Program . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

 1.3 Basis of the Original IDLH Values . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

 1.4 Update of the IDLH Values in 1994 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

 1.5 Purpose and Objectives of the IDLH Values. . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2 Comparison of IDLH Values to Alternative Short-term Exposure Limits/Values . . . 7

 2.1 Acute Exposure Guideline Levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

 2.2 Emergency Response Planning Guidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

 2.3 Occupational Exposure Limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

 2.4 Other Acute Exposure Limits/Values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

3 Criteria for Determining IDLH Values. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

 3.1 Importance of Mode of Action and Weight-of-Evidence Approach. . . . . . . . . 15

 3.2 Process for Prioritization of Chemicals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

 3.3 Literature Search Strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

 3.4 Determining the Critical Study and Endpoint. . . . . . . . . . . . . . . . . . . . . . . . . . . 17

 3.4.1 Study Quality Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

 3.4.2 Study Relevance Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

 3.5 Time Scaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

 3.6 Inclusion of Safety Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4 Use of Uncertainty Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

 4.1 Application of Uncertainty Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

 4.2 The NIOSH IDLH Value Uncertainty Factor Approach. . . . . . . . . . . . . . . . . . . 36

 4.3 Research Support for the NIOSH Uncertainty Factor Approach. . . . . . . . . . . 38

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Appendix A: Example of the Derivation of an IDLH Value. . . . . . . . . . . . . . . . . . . . . . . . . 45

 A.1 Support Documentation for the Revised IDLH Value for Chlorine . . . . . . . . 45

 A.2 Animal Toxicity Data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

 A.3 Human data. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

 A.4 IDLH Value Rationale Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Appendix B: IDLH Value Development Prioritization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
x NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Appendix C: Critical Effect Determination for IDLH Value Development—

 Consideration of Severity, Reversibility, and Impact on Escape Impairment . . . . . . . . 55

 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Appendix D: Analyses Supporting the Development of Uncertainty 

 Factor Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

 D.1 Analysis for Selected Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

 D.2 Recommendation for Deriving IDLH Values. . . . . . . . . . . . . . . . . . . . . . . . . . . 69

 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Appendix E: Quantitative Adjustments during the Derivation of IDLH Values. . . . . . . . 73

 E.1 Inhalation Volume Adjustments Approach for 

 Route-to-Route Extrapolation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

 E.2 Time Scaling Adjustments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
NIOSH CIB 66 xi • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Abbreviations and Acronyms

ACGIH American Conference of Governmental Industrial Hygienists 

AIHA American Industrial Hygiene Association

AEGL Acute Exposure Guideline Level (published by NRC)

AUC area under the curve 

ATSDR Agency for Toxic Substances and Disease Registry

BBDR biologically based dose response 

BMC benchmark concentration

BMCL benchmark concentration lower-bound confidence limit

BMD benchmark dose

BMDS Benchmark Dose Software (developed by USEPA)

“C” ceiling value 

CA carcinogen 

Cal/EPA California Environmental Protection Agency

CAS# Chemical Abstracts Service Registry Number

CDC Centers for Disease Control and Prevention

CFATS Chemical Facility Anti-Terrorism Standards (developed by DHS)

CFR Code of Federal Regulations

CHEMID online chemical identification database (developed by NLM)

CIB Current Intelligence Bulletin (developed by NIOSH)

Cmax peak (maximum) concentration

CNS central nervous system

COHb carboxyhemoglobin

Conc concentration

DHHS U.S. Department of Health and Human Services

DHS U.S. Department of Homeland Security

DOD U.S. Department of Defense

DOE U.S. Department of Energy

DOL U.S. Department of Labor

DOT U.S. Department of Transportation

DT developmental toxicant

EC effective concentration
xii NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

EEGL Emergency and Continuous Exposure Guidance Levels 

 (published by NRC)

EINECS European INventory of Existing Commercial chemical Substances

EMBASE online biomedical journal abstract and indexing database 

 (subscription based)

EPP Emergency Preparedness Plan

ERPG Emergency Response Planning Guidelines (developed by AIHA)

ERG Emergency Response Guidebook (developed by DOT)

EU European Union

FEL frank effect level

FACA Federal Advisory Committee Act

GI gastrointestinal

GLP Good Laboratory Practices

HAZARDTEXT® online hazardous substance database (subscription based)

HazMap online occupational exposure to hazardous agents database 

 (developed by NLM)

HCN hydrogen cyanide

hr hour

HPV high production volume 

HSDB Hazardous Substance Data Bank (developed by NLM)

HSEES Hazardous Substance Emergency Events Surveillance 

 (developed by ATSDR)

IARC International Agency for Research on Cancer 

ICSC International Chemical Safety Cards (developed by IPCS)

IDLH Immediately Dangerous to Life or Health (developed by NIOSH)

i.p. intraperitoneal 

IPCS International Programme on Chemical Safety

IRIS Integrated Risk Information System (developed by USEPA)

IRR irritant

ITER International Toxicity Estimates for Risk database 

 (developed by TERA)

JSC Johnson Space Center (division of NASA)

k a constant reflected in equations expressing “conc × time” relationships

kg kilogram

L liter

LC lethal concentration
NIOSH CIB 66 xiii • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

LD lethal dose

LEL lower explosive limit

L/min liters per minute

LOAEL lowest observed adverse effect level

LOEL lowest observed effect level

m3 cubic meter

MEC minimum explosive concentration 

MEDITEXT® online medical and toxicology database (subscription based)

mg/m3 milligrams per cubic meter of air

mg/m3-min milligrams per cubic meter of air per minute

min minute

MOA mode of action

MSHA Mine Safety and Health Administration

NAC/AEGL National Advisory Committee for Acute Exposure Guideline 

 Levels for Hazardous Substances 

NASA National Aeronautics and Space Administration

NAS/NRC National Academy of Sciences/National Research Council 

NIOSH National Institute for Occupational Safety and Health

NIOSHTIC2 bibliographic database of NIOSH-supported occupational safety 

 and health publications 

NJ-HSFS New Jersey Hazardous Substance Fact Sheets

NLM National Library of Medicine

NOAEL no observed adverse effect level

NOEL no observed effect level

NRC National Research Council

NTP National Toxicology Program 

OECD Organisation for Economic Co-operation and Development

OEL occupational exposure limit

OSHA Occupational Safety and Health Administration 

PAL Provisional Advisory Levels (developed by DHS)

PBPK physiologically based pharmacokinetic 

PEL Permissible Exposure Limit (developed by OSHA and MSHA)

ppm parts per million

POD point of departure 

PUBMED online biomedical literature citation database (developed by NLM)
xiv NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

RD respiratory depression 

REL Recommended Exposure Limit (developed by NIOSH)

RfC inhalation reference concentration

RIVM Netherlands National Institute for Public Health 

 and the Environment

RMP Risk Management Plan

R-phrases risk phrases (developed by EU)

RTECS Registry of Toxic Effects of Chemical Substances

SCAPA Subcommittee on Consequence Assessment and Protective Actions

SCBA self-contained breathing apparatus

SCP Standards Completion Program (developed by NIOSH and OSHA)

SMAC Spacecraft Maximum Allowable Concentration (developed by 

 NASA, published by NRC)

SOP Standing Operating Procedures

SPEGL Short-term Public Emergency Guidance Levels (developed by NRC)

STEG short-term exposure guidelines

STEL Short Term Exposure Limit

ST short-term exposure limit

TEEL Temporary Emergency Exposure Limit (developed by DOE)

TERA Toxicology Excellence for Risk Assessment

TIH toxic inhalation hazard (developed by DOT)

TLV® Threshold Limit Value (developed by ACGIH)

TOXLINE online toxicology literature database (developed by NLM)

TWA time-weighted average

UF uncertainty factor

USEPA U.S. Environmental Protection Agency

WEEL Workplace Environmental Exposure Limits (developed by AIHA)

WHO World Health Organization
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values xv

Glossary*

Acute Exposure: Exposure by the oral, dermal, or inhalation route for 24 hours or less.

Acute Exposure Guideline Levels (AEGLs): Threshold exposure limits for the general 

public applicable to emergency exposure periods ranging from 10 minutes to 8 hours. 

AEGL-1, AEGL 2, and AEGL-3 are developed for five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects ranging from transient, reversible effects to life-threatening effects 

[NAS 2001]. AEGLs are intended to be guideline levels used during rare events or single 

once-in-a-lifetime exposures to airborne concentrations of acutely toxic, high-priority 

chemicals [NAS 2001]. The threshold exposure limits are designed to protect the general 

population, including the elderly, children or other potentially sensitive groups that are 

generally not considered in the development of workplace exposure recommendations 

(additional information available at http://www.epa.gov/oppt/aegl/).

Acute Reference Concentration (RfC): An estimate (with uncertainty spanning perhaps 

an order of magnitude) of a continuous inhalation exposure for an acute duration (24 

hours or less) of the human population (including sensitive subgroups) that is likely to be 

without an appreciable risk of deleterious effects during a lifetime. It can be derived from 

a NOAEL, LOAEL, or benchmark concentration, with uncertainty factors (UFs) generally 

applied to reflect limitations of the data used. Generally used in USEPA noncancer health 

assessments [USEPA 2010]. 

Acute Toxicity: Any poisonous effect produced within a short period of time following 

an exposure, usually 24 to 96 hours.

Acute Toxicity Test: Experimental animal study to determine what adverse effects occur in 

a short time (usually up to 14 days) after a single dose of a chemical or after multiple doses 

given in up to 24 hours.

Adverse Effect: A substance-related biochemical change, functional impairment, or 

pathologic lesion that affects the performance of an organ or system or alters the ability 

to respond to additional environmental challenges. 

Analytical (Actual) Concentration: The test article concentration to which animals are 

exposed (i.e., the concentration in the animals’ breathing zone), as measured by analytical 

(GC, HPLC, etc.) or gravimetric methods. The analytical or gravimetric concentration (not 

the nominal concentration) is usually used for concentration response assessment.

Assigned Protection Factor (APF): The minimum anticipated protection provided by a 

properly functioning respirator or class of respirators to a given percentage of properly 

*Except where specific references are given, glossary definitions are from numerous sources such as AIHA 

[2008], Hayes [2008], IUPAC [2007], NAS [1986, 2001], NASA [1999], NIOSH [2005], OSHA [2003], 

US DHS [2007], US DOE [2008], and US DOT [2008].
xvi NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

fitted and trained users. For example, an APF of 10 for a respirator means that a user could 

expect to inhale no more than one tenth of the airborne contaminant present.

Benchmark Dose/Concentration (BMD/BMC): A dose or concentration that produces 

a predetermined change in response rate of an effect (called the benchmark response, 

or BMR) compared to background [USEPA 2010] (additional information available at 

http://www.epa.gov/ncea/bmds/). 

Benchmark Response (BMR): A predetermined change in response rate of an effect. Common defaults for the BMR are 10% or 5%, reflecting study design, data variability, and sensitivity limits used.

BMCL: A statistical lower confidence limit on the concentration at the BMC [USEPA 2010].

Biologically Based Dose Response (BBDR) model: A predictive model that describes 

biological processes at the cellular and molecular level, linking the target organ dose to the 

adverse effect [USEPA 2010].

Bolus Exposure: A single, relatively large dose. 

Bounding: A process of identifying estimates of exposure, dose, or risk that are clearly 

higher than or lower than the exposure, dose, or risk of interest. Bounding can help to define the practical uncertainty associated with the estimate of a derived risk value, such as 

an IDLH value. 

Cancer Risk: The likelihood of developing cancer, given a specific exposure (i.e., during a 

working lifetime). Individual cancer risks are determined by multiplying a specific exposure by the cancer potency. A 10-3 risk level is often characterized as a 1 in 1,000 chance of 

developing cancer in occupational risk assessment.

Carcinogen: An agent capable of causing cancer.

Carcinogenicity: Process of induction of malignant tumors by chemical, physical, or biological agents.

Ceiling Value (“C”): U.S. term in occupational exposure indicating the airborne concentration of a potentially toxic substance that should never be exceeded in a worker’s breathing zone.

Chronic Exposure: Repeated exposure for an extended period of time. Typically exposures are more than approximately 10% of life span for humans and >90 days to 2 years for 

laboratory species.

Concentration (Conc): The mass of test article per unit volume of air (e.g., mg/L, mg/m3

) 

or the volume of test article per unit volume (e.g., ppm, mL/L).

Concentration-response Curve: Graph of the relationship between the exposure concentration and the incidence or other measure of response of a defined biological effect in an 

exposed population or animal study.

Critical Study: The study that contributes most significantly to the qualitative and quantitative assessment of risk [USEPA 2010].
NIOSH CIB 66 xvii • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Cumulative Toxicity: Toxicity that is related to the cumulative, or total, dose to an organ or 

the body of an individual, up to a specified date or time. 

Developmental Toxicity: Adverse effects on the developing organism that may result from 

exposure prior to conception (either parent), during prenatal development, or postnatally 

until the time of sexual maturation [USEPA 2010]. The major manifestations of developmental toxicity include death of the developing organism, structural abnormality, altered 

growth, and functional deficiency.

De Novo: Referring to an analysis that does not build on prior analyses.

Dose: The amount of a substance available for interactions with metabolic processes 

or biologically significant receptors after crossing the outer boundary of an organism 

[USEPA 2010].

Dosimetry: Estimating or measuring the quantity of material at specific target sites; determination of respiratory tract region deposition fractions. 

ECt50: A combination of the effective concentration of a substance in the air and the exposure duration that is predicted to cause an effect in 50% (one half) of the experimental 

test subjects.

Emergency and Continuous Exposure Guidance Level (EEGL): A ceiling guidance level 

for unpredicted, single, short-term, emergency exposures (1 to 24 hours) of a defined occupational group. EEGLs are developed at the request of the U.S. Department of Defense by 

the National Research Council’s Committee on Toxicology [NAS 1996, 2008]. 

Emergency Response Planning Guidelines (ERPGs): Maximum airborne concentrations below which nearly all individuals can be exposed without experiencing health effects for 1-hour exposure. ERPGs are presented in a tiered fashion with health effects 

ranging from mild or transient to serious, irreversible, or life threatening (depending 

on the tier). ERPGs are developed by the American Industrial Hygiene Association 

[AIHA 2006].

Endpoint: An observable or measurable biological event or sign of toxicity ranging from 

biomarkers of initial response to gross manifestations of clinical toxicity.

Exposure: Contact made between a chemical, physical, or biological agent and the outer 

boundary of an organism. Exposure is quantified as the amount of an agent available at the 

exchange boundaries of the organism (e.g., skin, lungs, gut).

Extrapolation: An estimate of the response at a point outside the range of the experimental 

data, generally through the use of a mathematical model, although qualitative extrapolation 

may also be conducted. The model may then be used to extrapolate to response levels that 

cannot be directly observed.

Fetal Toxicity: An adverse effect occurring in the fetus from exposure to a substance. These 

effects can occur through direct interaction with the fetus or indirectly from the effects of 

maternal toxicity.
xviii NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Gestation: Pregnancy, the period of development in the uterus from conception until birth.

Hazard: A potential source of harm. Hazard is distinguished from risk, which is the probability of harm under specific exposure conditions.

Healthy Worker Effect: Epidemiological phenomenon observed initially in studies 

of occupational diseases: workers usually exhibit lower overall disease and death rates 

than the general population, due to the fact that elderly individuals and those with 

significant pre-existing illness are less likely to be active in the workforce than healthy 

adults. Death rates in the general population may be inappropriate for comparison with 

occupational death rates, if this effect is not taken into account.

Immediately Dangerous to Life or Health (IDLH) condition: A situation that poses a 

threat of exposure to airborne contaminants when that exposure is likely to cause death 

or immediate or delayed permanent adverse health effects or prevent escape from such 

an environment [NIOSH 2004]. 

IDLH value: A maximum (airborne concentration) level above which only a highly reliable 

breathing apparatus providing maximum worker protection is permitted [NIOSH 2004]. 

IDLH values are based on a 30-minute exposure duration.

Implantation: The process by which a fertilized egg implants in the uterine lining, typically 

several days following conception, depending on the species.

Inhalation Reference Concentration (RfC): An estimate (with uncertainty spanning 

perhaps an order of magnitude) of a continuous inhalation exposure for a chronic duration (up to a lifetime) of the human population (including sensitive subgroups) that is 

likely to be without an appreciable risk of deleterious effects during a lifetime [USEPA 

2010]. It can be derived from a NOAEL, LOAEL, or benchmark concentration, with UF 

generally applied to reflect limitations of the data used. Generally used in USEPA noncancer health assessments.

Internal Dose: A dose denoting the amount absorbed without respect to specific absorption barriers or exchange boundaries.

International Toxicity Estimates for Risk Database (ITER): A free Internet database of 

human health risk values and cancer classifications for over 600 chemicals of environmental concern, from multiple organizations worldwide (additional information available at 

http://www.tera.org/iter/).

Intraperitoneal: Within the peritoneal cavity (the area that contains the abdominal organs).

LC01: The statistically determined concentration of a substance in the air that is estimated to 

cause death in 1% of the test animals.

LC50: The statistically determined concentration of a substance in the air that is estimated to 

cause death in 50% (one half) of the test animals; median lethal concentration.

LCLO: The lowest lethal concentration of a substance in the air reported to cause death, usually for a small percentage of the test animals.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values xix

LD50: The statistically determined lethal dose of a substance that is estimated to cause death 

in 50% (one half) of the test animals; median lethal concentration.

LDLO: The lowest dose of a substance that causes death, usually for a small percentage of the 

test animals.

LEL: The minimum concentration of a gas or vapor in air, below which propagation of a 

flame does not occur in the presence of an ignition source.

Lethality: Pertaining to or causing death; fatal; referring to the deaths resulting from acute 

toxicity studies. May also be used in lethality threshold to describe the point of sufficient 

substance concentration to begin to cause death.

Lowest Observed Adverse Effect Level (LOAEL): the lowest tested dose or concentration of a substance that has been reported to cause harmful (adverse) health effects in 

people or animals. 

Malignant: A growth with a tendency to invade and destroy nearby tissue and spread to 

other parts of the body.

Maternal Toxicity: Adverse effects occurring in the mother during a developmental study. 

Maternal toxicity can result in adverse effects to the fetus.

Maximum Likelihood Concentration: A statistical estimate of the concentration that was 

most likely to cause the desired effect.

Mode of Action: The sequence of significant events and processes that describe how a substance causes a toxic outcome. Mode of action is distinguished from the more detailed 

mechanism of action, which implies a more detailed understanding on a molecular level.

Nominal Concentration: The concentration of test article introduced into a chamber. It is 

calculated by dividing the mass of test article generated by the volume of air passed through 

the chamber. The nominal concentration does not necessarily reflect the concentration to 

which an animal is exposed. 

No Observed Adverse Effect Level (NOAEL): The highest tested dose or concentration of 

a substance that has been reported to cause no harmful (adverse) health effects in people 

or animals. 

Occupational Exposure Limit (OEL): Workplace exposure recommendations developed 

by governmental agencies and non-govermental organizations. OELs are intended to represent the maximum airborne concentrations of a chemical substance below which workplace 

exposures should not cause adverse health effects. OELs may apply to ceiling, short-term 

(STELs), or time-weighted average (TWA) limits.

Parturition: The act or process of giving birth.

Peak Concentration: Highest concentration of a substance recorded during a certain period of observation.

Permissible Exposure Limit (PEL): Occupational exposure limits developed by OSHA (29 

CFR 1910.1000) or MSHA (30 CFR 57.5001) for allowable occupational airborne exposure 

concentrations. PELs are legally enforceable and may be designated as ceiling, STEL, or 

TWA limits. 
xx NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Permit-Required Confined Spaces: OSHA defines a confined space as one that has one or 

more of the following characteristics: (1) contains or has the potential to contain a hazardous atmosphere; (2) contains a material that has the potential to engulf an entrant; (3) has 

walls that converge inward or floors that slope downward and taper into a smaller area 

which could trap or asphyxiate an entrant; (4) or contains any other recognized safety or 

health hazard, such as unguarded machinery, exposed live wires, or heat stress.

Physiologically Based Pharmacokinetic (PBPK) Model: A model that estimates the dose 

to a target tissue or organ by taking into account the rate of absorption into the body, distribution among target organs and tissues, metabolism, and excretion. 

Point of Departure (POD): The point on the dose–response curve from which dose extrapolation is initiated. This point can be the lower bound on dose for an estimated incidence or a change in response level from a concentration-response model (BMC), or it can 

be a NOAEL or LOAEL for an observed effect selected from a dose evaluated in a health 

effects or toxicology study. 

Promulgation: To make known (a decree, for example) by public declaration; 

announce officially.

Provisional Advisory Level (PAL): A tiered set of air and drinking water threshold exposure values for high priority chemical, biological, and radiological agents intended for the 

general public, including susceptible and sensitive subpopulations. Developed by USEPA to 

inform risk-based decision-making during a response to terrorist or natural disaster incidents [US DHS 2009].

RD50: The statistically determined concentration of a substance in the air that is estimated 

to cause a 50% (one half) decrease in the respiratory rate.

Recommended Exposure Limit (REL): Recommended maximum exposure limit to prevent adverse health effects based on human and animal studies and established for occupational (up to 10-hour shift, 40-hour week) inhalation exposure by NIOSH. RELs may be 

designated as ceiling, STEL, or TWA limits.

Reproductive Toxicology: The study of adverse effects on male and/or female reproductive function, capacity, or associated endocrine system components. Common adverse 

effects include altered sexual behavior, fertility, pregnancy outcomes, or modifications 

in other functions that depend on reproductive integrity of the system.

Risk Phrases: A European system of hazard codes and phrases for labeling dangerous substances and compounds, consisting of the letter R followed by a series of numbers. Each 

number corresponds to a specific hazard phrase. For example, R-34 means “causes burns,” 

regardless of any language translations.

Sensory Irritation: Immediate irritation to the eyes and nose, due to an interaction between the substance and receptors in the trigeminal nerve endings. Often an endpoint for 

OEL derivation.

Short-Term Exposure: Repeated exposure by the oral, dermal, or inhalation route for more 

than 24 hours, up to 30 days.
NIOSH CIB 66 xxi • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Short-Term Exposure Limit (STEL): A worker’s 15-minute time-weighted average exposure concentration that shall not be exceeded at any time during a work day.

Short-Term Public Emergency Guidance Level (SPEGL): A ceiling guidance level for unpredicted, single, short-term, emergency exposures (1 to 24 hours) for the general public. 

SPEGLs are developed at the request of the U.S. Department of Defense by the National 

Research Council’s Committee on Toxicology [NAS 1986]. 

Spacecraft Maximum Allowable Concentration (SMAC): Guideline values set to protect 

astronauts from spacecraft contaminants. Short-term guidelines (1 to 24 hours) apply to accidental releases, and long-term guidelines (up to 180 days) apply to low levels of contaminants aboard a spacecraft. These guidelines are set by the NASA/JSC in cooperation with 

the National Research Council’s Committee on Toxicology [NASA 1999]. 

Surrogate: Relatively well studied chemical whose properties are assumed, with appropriate adjustments for differences in potency, to apply to an entire chemically and toxicologically related class; for example, benzo(a)pyrene data are assumed to be toxicologically 

equivalent to those for all carcinogenic polynuclear aromatic hydrocarbons or are used 

as a basis for extrapolating to these other chemicals.

Systemic Concentration: The concentration in a blood or tissue arising from exposure to 

a substance that is absorbed and distributed throughout the body. 

Target Organ: Organ in which the toxic injury manifests in terms of dysfunction or overt 

disease.

Temporary Emergency Exposure Limits (TEELs): Tiered temporary guidance values 

that are used by DOE until AEGL or ERPG values are available. TEELs are derived by the 

Subcommittee on Consequence Assessment and Protective Actions (SCAPA) to aid in 

emergency preparedness hazard analysis of DOE facilities, employees, and adjacent communities in the event of an accidental chemical release [US DOE 2008].

Threshold Limit Values (TLVs®): Recommended guidelines for occupational exposure to 

airborne contaminants, published by the American Conference of Governmental Industrial Hygienists (ACGIH). TLVs refer to airborne concentrations of chemical substances 

and represent conditions under which it is believed that nearly all workers may be repeatedly exposed, day after day, over a working lifetime, without adverse effects. TLVs may be 

designated as ceiling, short-term (STELs), or 8-hr TWA limits. 

Time-Weighted Average (TWA): A worker’s 8-hour (or up to 10-hour) time-weighted average exposure concentration that shall not be exceeded during an 8-hour (or up to 10-hour) 

work shift of a 40-hour week. The average concentration is weighted to take into account the 

duration of different exposure concentrations. 

Toxic Inhalation Hazard (TIH): Gases or volatile liquids that are known or presumed on 

the basis of tests to be so toxic to humans as to pose a hazard to health in the event of a 

release during transportation, determined by DOT.

Toxicity: The degree to which a substance is able to cause an adverse effect on an exposed organism.
xxii NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Toxicology: Scientific discipline involving the study of the actual or potential danger presented by the harmful effects of substances (poisons) on living organisms and ecosystems, 

of the relationship of such harmful effects to exposure, and of the mechanisms of action, 

diagnosis, prevention, and treatment of intoxications.

Tumor: An abnormal mass of tissue that results from excessive cell division that is uncontrolled and progressive. Tumors perform no useful body function. Tumors can be either 

benign (not cancerous) or malignant (cancerous).

Uncertainty Factors: Mathematical adjustments applied to the POD when developing 

IDLH values. The UFs for IDLH value derivation are determined by considering the study 

and effect used for the POD, with further modification based on the overall database.

Weight of Evidence (Toxicity): Extent to which the available biomedical data support a 

conclusion, such as whether a substance causes a defined toxic effect (e.g., cancer in humans), or whether an effect occurs at a specific exposure level.

Workplace Environmental Exposure Levels (WEELs): Exposure levels that provide guidance for protecting most workers from adverse health effects related to occupational chemical exposures expressed as a TWA or ceiling limit.
NIOSH CIB 66 xxiii • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Acknowledgements

This document was developed by the Education and Information Division (Paul Schulte, 

Ph.D., Director). G. Scott Dotson, Ph.D., was the project officer and lead NIOSH author for 

this CIB, assisted in great part by Richard Niemeier, Ph.D. The basis for this document was a 

report contracted by NIOSH and prepared by Andrew Maier, Ph.D., Ann Parker, and Lynne 

Haber, Ph.D. (Toxicology Excellence for Risk Assessment [TERA]).

For their contribution to the technical content and review of this document, special acknowledgment is given to the following NIOSH personnel:

Division of Applied Research and Technology

Leonid A. Turkevich, Ph.D. 

Division of Respiratory Disease Studies 

Chris Coffey, Ph.D. 

Division of Survelliance, Hazard Evaluations, and Field Studies

Dave Sylvain

Doug Trout, M.D.

Education and Information Division 

David Dankovic, Ph.D. 

Charles L. Geraci, Ph.D. 

Thomas J. Lentz, Ph.D. 

Chris Sofge, Ph.D. 

Ralph Zumwalde, M.Sc. 

National Personal Protective Technology Laboratory

Heinz Ahlers, M.Sc., J.D.

Leslie Boord, Ph.D. 

NIOSH Office of the Director

K. Ann Berry, Ph.D., M.B.A. 

A. Yvonne Boudreau, M.D.

Lisa Delaney, M.Sc.

Ted Katz, M.P.A. 

Office of Mine Safety and Health Research

Pamela Drake, M.P.H. 
xxiv NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Additional NIOSH contributors to the document include:

Devin S. Baker, Seleen Collins, Sarah Earl, John Lechiter, Rachel Thieman, and Vanessa 

B. Williams.

In addition, special appreciation is expressed to the following individuals for serving as 

independent, external reviewers and providing critical comments that contributed to the 

refinement of the document:

Rebecca Adams

Army Institute of Public Health (AIPA; formerly US Army Center 

 for Health Promotion and Preventive Medicine)

US Army Public Health Command

Aberdeen Proving Grounds, Maryland

Christopher Carroll M.S.E.S., AIPA

US Army Public Health Command

Aberdeen Proving Grounds, Maryland

Ernest V. Falke Ph.D.

US Environmental Protection Agency (USEPA)

Acute Exposure Guideline Levels Program

Washington, District of Columbia 

Veronique Hauschild M.P.H., AIPA

US Army Public Health Command

Aberdeen Proving Grounds, Maryland

James Holler, Ph.D.

Agency for Toxic Substances and Disease Registry (ATSDR)

Division of Toxicology and Environmental Medicine, Prevention, 

 Response, and Medical Support Branch

Atlanta, Georgia

Glenn Millner, Ph.D.

Center for Toxicology and Environmental Health (CTEH), LLC

Little Rock, Arkansas 

John S. Morawetz, M.Sc.

ICWUC Center for Worker Health & Safety Education

Cincinnati, Ohio

Mattias Öberg, Ph.D.

Unit for Work Environment Health

Institute of Environmental Medicine, Karolinska Institutet

Stockholm, Sweden

Irene L. Richardson, M.Sc., R.S., AIPA

US Army Public Health Command

Aberdeen Proving Grounds, Maryland
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values xxv

Laurie Roszell, Ph.D., AIPA

US Army Public Health Command

Aberdeen Proving Grounds, Maryland

John J. Resta, M.C.E., AIPA

US Army Public Health Command

Aberdeen Proving Grounds, Maryland

George Rusch, Ph.D., DABT, ATS

Risk Assessment and Toxicology Services

Bridgewater, New Jersey

Richard B. Schlesinger, Ph.D.

Dyson College of Arts and Sciences

Pace University

New York

Public Review

NIOSH greatly appreciates the public comments on the December 2010 draft document 

that were submitted to the NIOSH docket. The comments and responses to them can be 

seen at: http://www.cdc.gov/niosh/docket/archive/docket156.html
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 1

1 Introduction 

Occupational exposures to chemicals have long 

been recognized as having the potential to adversely affect the lives and health of workers. Acute 

or short-term exposures to high concentrations of 

some airborne chemicals have the ability to quickly 

overwhelm workers, resulting in a wide spectrum 

of undesirable health outcomes that may include 

irritation of the eyes and respiratory tract, severe 

irreversible health effects, impairment of the ability 

to escape from the exposure environment, and, in 

extreme cases, death. Airborne concentrations of 

chemicals capable of causing such adverse health 

effects or impeding escape from “high risk” situations or conditions may arise from a variety of 

situations affecting workers, including special work 

procedures (e.g., in confined spaces), industrial 

accidents (e.g., chemical spills or explosions), or 

chemical releases into the community (e.g., during 

transportation incidents or other uncontrolled release scenarios). Many organizations develop acute 

inhalation limits or guidelines. These are typically 

presented as airborne concentrations. However, 

airborne chemicals can also contribute to toxicity 

through other exposure routes, such as the skin 

and eyes.

The “immediately dangerous to life or health air 

concentration values (IDLH values)” developed by 

the National Institute for Occupational Safety and 

Health (NIOSH) characterize these high-risk exposure concentrations and conditions and are used 

as a component of the respirator selection criteria 

first developed in the mid-1970s [NIOSH 1994]. 

Since the development of the original IDLH values 

in the 1970s and their subsequent revision in 1994, 

NIOSH has continued to review relevant scientific 

data and conduct research on methods for developing acute exposure guidelines. This document reflects continuing enhancements in risk assessment 

approaches and provides a detailed description of 

the methodology used to derive IDLH values. The 

documentation for specific IDLH values is available as separate NIOSH publications and on the 

NIOSH website (http://www.cdc.gov/niosh/idlh/

default.html).

The primary objectives of this Current Intelligence 

Bulletin (CIB) are:

1. To provide a brief history of the development of 

IDLH values, 

2. To update the scientific bases and risk assessment 

methodology used to derive IDLH values from 

quality toxicity and human health effects data,

3. To provide transparency behind the rationale 

and derivation process for IDLH values, and

4. To demonstrate how scientifically credible IDLH 

values can be derived from available data resources.

1.1 Background 

The concept of using respirators to protect workers in situations that are immediately dangerous to 

life or health was discussed at least as early as the 

1940s. The following is from a 1944 U.S. Department of Labor (DOL) bulletin:

The situations for which respiratory protection is required may be designated as, (1) nonemergency and (2) emergency. Nonemergency 

situations are the more or less normal ones that 

involve exposure to atmospheres that are not 

immediately dangerous to health and life, but 

will produce marked discomfort, sickness, permanent harm, or death after a prolonged exposure or with repeated exposure. Emergency situations are those that involve actual or potential 

exposure to atmospheres that are immediately 

harmful and dangerous to health or life after 

comparatively short exposures. [Yant 1944] 
2 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

The Occupational Safety and Health Administration (OSHA) defines an IDLH concentration in 

the hazardous waste operations and emergency response regulation as follows: 

An atmospheric concentration of any toxic, corrosive or asphyxiant substance that poses an immediate threat to life or would interfere with an 

individual’s ability to escape from a dangerous 

atmosphere [29 CFR 1910.120]. 

In the OSHA regulation on “permit-required for 

confined spaces,” an IDLH condition is defined 

as follows: 

Any condition that poses an immediate or delayed threat to life or that would cause irreversible adverse health effects or that would interfere 

with an individual’s ability to escape unaided 

from a permit space [29 CFR 1910.146]. Note: 

Some materials (e.g., hydrogen fluoride gas 

and cadmium vapor) may produce immediate 

transient effects that, even if severe, may pass 

without medical attention, but are followed by 

sudden, possibly fatal collapse ~ 6 to 24 hours 

after exposure. The victim “feels normal” from 

recovery from transient effects until collapse. 

Such materials in hazardous quantities are considered to be “immediately dangerous to life or 

health.” [29 CFR 1910.146] 

In the current respiratory protection standard, 

OSHA states that an IDLH condition is as follows: 

An atmosphere that poses an immediate threat to 

life, would cause irreversible adverse health effects, 

or would impair an individual’s ability to escape 

from a dangerous atmosphere [29 CFR 1910.134]. 

As part of this standard, additional guidance is 

provided by OSHA that dictates the type and application of respirators in IDLH conditions. Specific 

information that is provided in the respiratory protection standard requires:

• A trained standby person be present with suitable rescue equipment when self-contained 

breathing apparatus or hose masks with blowers are used in IDLH atmospheres; and 

• Persons using air-line respirators in IDLH atmospheres must be equipped with safety harnesses and safety lines for lifting or removing 

workers from hazardous atmospheres.

The Mine Safety and Health Administration 

(MSHA) defines IDLH as “immediately harmful 

to life” [30 CFR 56/57/5005(c)]. The standard defines “immediately harmful to life” as that used by 

NIOSH to define “immediately dangerous to life or 

health,” which is “acute respiratory exposure that 

poses an immediate threat of loss of life, immediate or delayed irreversible adverse health effects, or 

acute eye exposure that would prevent escape from 

a hazardous atmosphere.” IDLH values are based 

on a 30-minute exposure duration. 

1.2 The Standards 

Completion Program 

In 1974, NIOSH and OSHA jointly initiated the development of occupational health standards consistent with Section 6(b) of the Occupational Safety 

and Health Act of 1970 for substances with thenexisting OSHA permissible exposure limits (PELs). 

This joint effort was called the Standards Completion Program (SCP) and resulted in the development of 387 substance-specific draft standards with 

supporting documentation that contained technical information and recommendations needed for 

the promulgation of occupational health regulations. Although standards were not promulgated at 

that time, these data became the original basis for 

the NIOSH/OSHA Occupational Health Guidelines 

for Chemical Hazards [NIOSH/OSHA 1981]. 

As part of the respirator selection process for each 

draft technical standard, an IDLH value was determined for each chemical. The definition used for 

IDLH values that was derived during the SCP was 

based on the definition stipulated in 30 CFR 11.3(t). 

The purpose of deriving an IDLH value was to provide guidance on respirator selection and to establish a maximum exposure concentration in which 

workers, in the event of respiratory protection failure (e.g., contaminant breakthrough in a cartridge 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 3

respirator or stoppage of air flow in a supplied-air 

respirator), could escape safely when the exposure 

was below the IDLH value. In determining IDLH 

values, the ability of a worker to escape without loss 

of life or irreversible health effects was considered, 

along with severe eye or respiratory tract irritation 

and other deleterious effects (e.g., disorientation or 

incoordination) that could prevent escape. Although 

in most cases, egress from a particular worksite 

could occur in much less than 30 minutes, as a safety 

margin, IDLH values were based on the effects that 

might occur as a consequence of a 30-minute exposure. However, the 30-minute period was NOT 

meant to imply that workers should stay in the work 

environment any longer than necessary following 

the failure of respiratory protection equipment; in 

fact, EVERY EFFORT SHOULD BE MADE TO 

EXIT IMMEDIATELY! 

1.3 Basis of the Original 

IDLH Values 

IDLH values were determined for each substance 

during the SCP on a case-by-case basis, taking 

into account the toxicity data available at the time. 

Whenever possible, IDLH values were determined 

with use of health effects data from studies of humans exposed for short durations. However, in 

most instances, a lack of human data necessitated 

the use of animal toxicity data. When the findings 

of inhalation studies of animals exposed for short 

durations (i.e., 30 minutes to 4 hours) were the only 

health effects data available, IDLH values were based 

on the lowest exposure causing death or irreversible 

health effects in any species. When lethal dose (LD) 

data from animals were used, IDLH values were estimated on the basis of an equivalent exposure to a 

70-kilogram (kg) worker breathing 10 cubic meters 

(m3

) of air for an 8-hour period. Because chronic 

exposure data may have little relevance to acute effects, these types of data were used in determining 

IDLH values only when no acute toxicity data were 

available and only in conjunction with competent 

scientific judgment. In a number of instances when 

no relevant human or animal toxicity data were 

available, IDLH values were based on analogies 

with other substances with similar toxic effects.

The basis for each of the 387 original IDLH values determined during the SCP was reviewed and 

paraphrased from the individual draft technical 

standards for the publication of the original list of 

IDLH values. Also included is a complete listing of 

references cited in the SCP; in many cases where 

only secondary references were cited, the original 

sources have also been added. Whenever available, 

the references (secondary and primary) were obtained to verify the information cited in the SCP. 

However, a few of the original references, such as 

personal communications and foreign reports, 

could not be located. 

Although 387 substances were originally included 

in the SCP, IDLH values were not determined for 

all of them. The published data at that time for 40 

of these substances—for example, DDT (Chemical Abstracts Service number [CAS#] 50-29-3) and 

triphenyl phosphate (CAS# 115-86-6)—showed no 

evidence that an acute exposure to high concentrations would impede escape or cause any irreversible health effects following a 30-minute exposure, 

and the designation “NO EVIDENCE” was used 

in the listing of IDLH values. For all of these substances, respirators were selected on the basis of 

assigned protection factors. For some (e.g., copper fume (CAS# 7440-50-8) and tetryl (CAS #479-

45-8), an assigned protection factor of 2,000 times 

the PEL was used to determine the concentration 

above which only the “most protective” respirators were permitted. However, for most particulate substances for which evidence for establishing 

an IDLH value did not exist (e.g., ferbam [CAS# 

14484-64-1] and oil mist [CAS# 8012-95-1]), the 

use of an assigned protection factor of 2,000 would 

have resulted in the assignment of respirators at 

concentrations that were not likely to be encountered in the occupational environment. In addition, 

exposure concentrations greater than 500 times the 

PEL for many airborne particulates could result in 

exposures that would hamper vision. Therefore, it 

was decided as part of the SCP (and during the review and revision of the IDLH values) that for such 
4 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

particulate substances, only the “most protective” 

respirators would be permitted for use in concentrations exceeding 500 times the PEL. 

IDLH values could not be determined during the 

SCP for 22 substances (e.g., bromoform [CAS# 75-

25-2] and calcium oxide [CAS# 1305-78-8]) because 

of a lack of relevant toxicity data, and therefore, the 

designation “UNKNOWN” was used in the IDLH 

value listing. For most of these substances, the concentrations above which only the “most protective” 

respirators were allowed were based on assigned 

protection factors that ranged from 10 to 2,000 

times the PEL, depending on the substance. There 

were also 10 substances (e.g., n-pentane [CAS# 

109-66-0] and ethyl ether [CAS# 60-29-7]) for 

which it was determined only that the IDLH values 

were in excess of the lower explosive limits (LELs). 

Therefore, the LEL was selected as the IDLH value, 

with the designation “LEL” added in the IDLH value 

listing. For these substances, only the “most protective” respirators were permitted above the LEL in 

the SCP draft technical standards. 

For 14 substances (e.g., beryllium [CAS# 7440-

41-7] and endrin [CAS# 72-20-8]), the IDLH values determined during the SCP were greater than 

the concentrations permitted on the basis of assigned respiratory protection factors. In most instances the IDLH values for these substances were 

set at concentrations 2,000 times the PEL.

1.4 Update of the IDLH 

Values in 1994 

The NIOSH definition for an IDLH condition, 

as given in the NIOSH Respirator Decision Logic 

[NIOSH 2004], is a situation “that poses a threat of 

exposure to airborne contaminants when that exposure is likely to cause death or immediate or delayed permanent adverse health effects or prevent 

escape from such an environment.” It is also stated 

that the purpose of establishing an IDLH value 

is to “ensure that the worker can escape from a 

given contaminated environment in the event of 

failure of the respiratory protection equipment.” 

The respirator decision logic uses an IDLH value as 

one of several respirator selection criteria. “Highly 

reliable” respirators (i.e., the most protective respirators) would be selected for emergency situations, 

firefighting, exposure to carcinogens, entry into 

oxygen-deficient atmospheres, entry into atmospheres that contain a substance at a concentration 

greater than 2,000 times the NIOSH recommended 

exposure limit (REL) or OSHA PEL, and entry 

into IDLH conditions. These “highly reliable” respirators include either a self-contained breathing 

apparatus (SCBA) that has a full face piece and is 

operated in a pressure-demand or other positivepressure mode or else a supplied-air respirator that 

has a full face piece and is operated in a pressuredemand or other positive-pressure mode in combination with an auxiliary SCBA operated in a 

pressure-demand or other positive-pressure mode. 

When the IDLH values were developed in the mid1970s, only limited toxicological data were available 

for many of the substances. In 1993, NIOSH requested information on the uses of IDLH values in 

the workplace and on the scientific adequacy of the 

criteria and procedures originally used for establishing them [Federal Register, Volume 58, Number 229, p. 63379, Wednesday, December 1, 1993]. 

The information received in response to the Federal 

Register announcement was evaluated and used to 

establish future actions concerning IDLH values. 

While new methodology research efforts were 

planned and initiated, NIOSH also decided to review the original IDLH values and revise them as 

appropriate [NIOSH 1994]. The update was completed in 1994. The 1994 update also included revisions or derivation of IDLH values for 85 substances 

(e.g., benzene [CAS# 71-43-2] and methylene 

chloride [CAS# 75-09-2]) determined by NIOSH 

to meet the OSHA definition of “potential occupational carcinogen,” as given in 29 CFR 1990.103. 

For all of these substances, except ethylene oxide 

(CAS#75-21-8) and crystalline silica (CAS# 14808-

60-7), NIOSH recommends that the “most protective” respirators be worn by workers exposed at 

concentrations above the NIOSH REL, or at any 

detectable concentration when there is no REL. For 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 5

ethylene oxide and crystalline silica, NIOSH recommends that the “most protective” respirators be 

worn in concentrations exceeding 5 parts per million (ppm) and milligrams per cubic meter of air 

(mg/m3

), respectively [NIOSH 1987, 2004].

1.5 Purpose and Objectives 

of the IDLH Values

IDLH values have traditionally been identified as a 

key component of the decision logic for the selection of respiratory protection devices. For example, 

the NIOSH Respirator Selection Logic [NIOSH 2004] 

states that the purpose of establishing an IDLH value 

is (1) to ensure that the worker can escape from a 

given contaminated environment in the event of 

failure of the respiratory protection equipment and 

(2) to determine a maximum level above which 

only a highly reliable breathing apparatus providing maximum worker protection is permitted. Additionally, IDLH values are based on a 30-minute 

exposure duration. Since the inception of IDLH 

values as part of the SCP, occupational health professionals have employed these values beyond their 

initial purpose as a component of the NIOSH Respirator Selection Logic. Examples of such applications of the IDLH values include the development 

of Risk Management Plans (RMPs) for non-routine 

work practices governing operations in high-risk 

environments (e.g., confined spaces) and the development of Emergency Preparedness Plans (EPPs), 

which provide guidance for emergency response 

personnel and workers during unplanned exposure 

events. This CIB presents the methodology used to 

derive IDLH values capable of being used in both 

the traditional role of respirator selection and in 

non-traditional applications, including the development of RMPs and EPPs. 

The scientific rationale and derivation process outlined in this CIB have been established to ensure 

that a consistent approach is used for development 

of IDLH values. According to this protocol, IDLH 

values are based on health effects considerations 

determined through a critical assessment of the 

toxicology and human health effects data. This 

approach ensures that the IDLH values reflect an 

airborne concentration of a substance that represents a high-risk situation that may endanger workers’ life or health. The emphasis on health effects 

is consistent with both the traditional use of IDLH 

values as a component of the respirator selection 

logic and the growing applications of IDLH values 

in guiding accident prevention and emergency response planning. It is important to note that IDLH 

values are concentrations that may cause adverse 

effects, and thus, they are not intended to be used 

as surrogates for occupational exposure limits 

(OELs). OELs, such as NIOSH RELs, are intended 

to protect workers from adverse health effects associated with repeated chemical exposure for up to 

10-hour shifts during a 40-hour work week for a 

working lifetime. The IDLH values should not be 

used as comparative indices of toxicity or to infer 

a “safe” level for exposures to chemicals under routine occupational exposure conditions (see Section 

2.3). A situation resulting in airborne concentrations at or near the IDLH value should be considered a non-routine event, and exposure duration 

should not exceed 30 minutes. All available precautions should be taken to ensure that workers exit 

the environment immediately if exposures are at or 

near concentrations equivalent to IDLH values.

NIOSH recognizes that in some cases a healthbased IDLH value might not account for all workplace hazards, such as safety concerns and considerations. Situations and conditions that might 

preclude the use of a health-based IDLH value include but are not limited to these: 

• Where the IDLH value based on health effects 

considerations is above the concentration that 

would result in oxygen deprivation (oxygen 

concentration of less than 19.5%). Chemicals 

capable of causing such conditions include 

inert gases such as argon (CAS# 7440–37–1), 

carbon dioxide (CAS# 124-38-9), and nitrogen (CAS# 7727-37-9).

• Where the IDLH value based on health effects 

considerations is higher than a particulate 
6 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

concentration that generates significant hazards from reduced visibility. Such conditions 

may occur in processes that generate dust 

plumes in enclosed areas or confined spaces 

(e.g., grinding, milling, or mining operations) 

and structural fires. 

• Where the IDLH value based on health-effects 

considerations is greater than 10% of the LEL 

concentration or the minimum concentration 

of gas or vapor in air below which propagation 

of a flame does not occur in the presence of 

an ignition source. Chemicals capable of causing such conditions include flammable gases 

or vapors such as acetone (CAS# 67-64-1), 

ethyl acetate (CAS# 64-17-5), and n-pentane 

(CAS#109-66-0). 

• Where the IDLH value based on health effects considerations is greater than the timeweighted average (TWA) OEL multiplied by 

the assigned protection factor for the most 

protective respirator. Because IDLH values 

are based on acute exposure and health effects data, the most protective respirator 

may not be adequately protective for fullshift exposures at this concentration. Examples of substances where this situation may 

occur include chromic acid and chromates 

(CAS# 1333–82–0) and lead compounds 

(CAS# 7439–92–1, metal). 

In such cases, it is important that safety hazards 

or other considerations be taken into account. Information on safety hazards will be incorporated 

into the derivation of an IDLH value when appropriate. For example, in the event that the derived 

health-based IDLH value exceeds 10% of the LEL 

concentration for a flammable gas or vapor, the 

airborne concentration that is equal to 10% of the 

LEL will become the IDLH value for the chemical. 

The following hazard statement will be included in 

the support documentation: “The health-based 

IDLH value is greater than 10% of the LEL (>10% 

LEL) of the chemical of interest in the air. Safety 

considerations related to the potential hazard of 

explosion must be taken into account.” In addition, the notation (>10% LEL) will appear beside the IDLH value in the NIOSH Pocket Guide 

to Chemical Hazards [NIOSH 2005] and other 

NIOSH publications. Similar statements will be 

developed as needed for other safety hazards and 

considerations. The use of hazard statements and 

notations to provide supplemental information on 

safety hazards and considerations aligns with the 

protocols used to derive the AEGLs by the National Advisory Committee for Acute Exposure 

Guideline Levels for Hazardous Substances (NAC/

AEGL Committee) [NAS 2001]. Additional information on the establishment of IDLH values based 

on safety hazards can be located in Section 3.6.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 7

2 Comparison of IDLH Values to Alternative 

Short-term Exposure Limits/Values 

An important step in the development of IDLH 

values is the review of alternative short-term exposure limits/values developed by other agencies 

and organizations. The review of such information 

serves several purposes: 

• It is useful for verifying that all key data 

and scientific issues are considered and thus 

serves as one step in verifying that a robust 

literature search has been completed. 

• It assists in identifying critical issues with 

study design, methodology, or results for 

critical studies that must be considered in developing an IDLH value. 

• In some cases, alternative exposure limits/

values may aid in determining a potential 

range for the IDLH value (after taking into 

account the methodology differences used to 

develop various short-term limits/values), as 

described later in this section. 

Because the documentation for the IDLH values 

is intended to be a concise summary document, 

NIOSH incorporates in the IDLH documentation 

information on the acute effects of chemicals and 

selected short-term limits/values from other indepth peer-reviewed assessments, for comparison 

purposes. Table 2–1 summarizes several of the 

short-term exposure limits/values most commonly 

evaluated during the derivation of IDLH values. 

There are numerous other sources of short-term 

exposure limits/values, which may be reviewed on 

a case-by-case basis for a particular chemical, depending on availability. 

Although IDLH values may rely on much of the 

same acute health effects information used to derive alternative short-term exposure limits/values, 

there are underlying differences in the intended use 

of the various acute exposure values. Therefore, review of documentation for these alternative shortterm limits/values provides information to guide 

IDLH value development, but the actual proposed 

values are not directly comparable. The remaining 

sections of Chapter 2 discuss the different purposes 

and populations protected by commonly reviewed 

alternative short-term exposure limits/values.

2.1 Acute Exposure 

Guideline Levels 

AEGLs are threshold exposure limits for the general public intended to be guideline levels used 

during rare events or single once-in-a-lifetime exposures to airborne concentrations of acutely toxic, 

high-priority chemicals [NAS 2001]. The threshold 

exposure limits are designed to protect the general 

population, including the elderly, children or other 

potentially sensitive groups that are generally not 

considered in the development of workplace exposure recommendations [NAS 2001]. AEGLs are 

based primarily on acute toxicology data and not 

subchronic or chronic data and therefore do not 

reflect the health effects that could result from frequent exposures.

Three levels, referred to as AEGL-1, AEGL-2, and 

AEGL-3, are developed for each of five exposure 

periods (10 minutes, 30 minutes, 1 hour, 4 hours, 

and 8 hours) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs 

are defined as follows [NAS 2001]:

• AEGL-1 is the airborne concentration (expressed as ppm or mg/m3

) of a substance 

above which it is predicted that the general 
8 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory 

effects. However, the effects are not disabling 

and are transient and reversible upon cessation of exposure.

• AEGL-2 is the airborne concentration (expressed as ppm or mg/m3

) of a substance 

above which it is predicted that the general 

population, including susceptible individuals, could experience irreversible or other 

serious, long-lasting adverse health effects or 

an impaired ability to escape.

• AEGL-3 is the airborne concentration (expressed as ppm or mg/m3

) of a substance 

above which it is predicted that the general 

population, including susceptible individuals, could experience life-threatening health 

effects or death. 

Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and 

progressively increasing irritation or asymptomatic, 

non-sensory effects, such as non-disabling odor 

and taste. With increasing airborne concentrations 

above each AEGL, there is a progressive increase 

in the likelihood of occurrence and the severity of 

effects described for each corresponding AEGL. 

Although the AEGL values represent threshold 

levels for the general public, including susceptible subpopulations, such as infants, children, the 

elderly, persons with asthma, and those with other 

illnesses, it is recognized that individuals, subject 

to unique or idiosyncratic responses, could experience the effects described at concentrations below 

the corresponding AEGL.

Like the IDLH value, the AEGL-2 is designed to 

protect from irreversible or other serious effects 

and escape-impairing effects. Thus, the effects that 

are the basis for the AEGL-2 closely match those of 

interest for the IDLH value. In addition, the AEGLs 

include a 30-minute value, which is the same duration of interest for the IDLH values. One significant 

difference between the IDLH value and the AEGL-2 

Table 2–1. Short-term exposure limits/values by other agencies and organizations

Purpose of short-term exposure limit Agency or organization designation

Acute exposure guidelines for protection of the 

general public during emergency or rare releases

Acute Exposure Guidelines Levels (AEGLs)

Emergency Response Planning Guidelines (ERPGs)

Other values as appropriate 

Acute exposure guidelines for potential routine 

acute exposures in the workplace such as short-term 

exposure limits (STELs) 

or Ceiling Limits (“C”).

National Institute for Occupational Safety and Health 

(NIOSH) Recommended Exposure Limits (RELs)

Occupational Safety and Health Administration (OSHA) 

Permissible Exposure Limits (PELs)

American Conference of Governmental Industrial 

Hygienists (ACGIH) Threshold Limit Values (TLVs)®

American Industrial Hygiene Association (AIHA) 

Workplace Environmental Exposure Levels (WEELs)

Other values as appropriate 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 9

is that the AEGL-2 is designed to protect the general population, including potentially sensitive subpopulations (i.e., children, elderly, and individuals 

with pre-existing health impairments). IDLH values 

are designed for worker populations, which traditionally exclude the most sensitive subpopulations. 

This assumption is based on the consideration that 

there would be a smaller likelihood for significant 

inclusion of specific sensitive subpopulations in the 

population of working adults. In addition, the selection of the critical effect (health endpoint) and 

interpretation of the severity of the health impact 

to the population of interest (in this case a worker 

population in a high-risk environment) may be different than that used for the AEGL-2. This means 

that given the same set of data, the IDLH value will 

often be in the range of the 30-minute AEGL-2 but 

will vary somewhat because of the fundamental 

differences between the approaches applied to establish AEGL values and IDLH values for a chemical. The IDLH value is usually below the 30-minute 

AEGL-3, since, for most chemicals, serious or 

escape-impairing effects relevant for IDLH values 

occur at concentrations below the lethality threshold. In light of these considerations, recent AEGL-2 

and AEGL-3 values can provide a rough gauge for 

identifying a potential range for the IDLH value. 

Exceptions may occur, partially because the AEGL 

process follows fairly strict methodology guidelines 

[NAS 2001], including the use of default approaches 

in the absence of chemical-specific data, whereas 

the process for developing IDLH values relies heavily on the overall weight of evidence, with limited 

use of default procedures. The extensive AEGL 

documentation for each chemical has been thoroughly reviewed by expert committees and is often 

a useful resource for de novo analyses. In addition, 

the AEGL documentation includes detailed analysis of all key studies, often including calculation of 

the value of the ten Berge exponent n [ten Berge et 

al. 1986]; for a detailed description of the ten Berge 

exponent, see Section 3.5—Time Scaling. 

The AEGL values are derived by the NAC/AEGL 

Committee, which is a Federal Advisory Committee Act (FACA) committee established to identify, 

review, and interpret relevant toxicologic and other 

scientific data and to develop AEGLs for high priority, acutely toxic chemicals (available online at: 

http://www.epa.gov/oppt/aegl/). The NAC/AEGL 

includes members from federal and international 

agencies (e.g., NIOSH, U.S. Environmental Protection Agency [USEPA], U.S. Department of Transportation [DOT], U.S. Department of Defense 

[DOD], U.S. Department of Energy [DOE], 

Agency for Toxic Substances and Disease Registry [ATSDR], Canadian Government, Netherlands 

National Institute for Public Health and the Environment [RIVM], state agencies and environmental organizations, academia, private industry, 

and international and nonprofit organizations). 

Interim AEGLs prepared by the AEGL Committee, after stakeholder comment, are reviewed by 

the National Academy of Sciences (NAS)/National Research Council (NRC) AEGL Committee before finalization. 

2.2 Emergency Response 

Planning Guidelines

Emergency Response Planning Guidelines (ERPGs) 

are developed by the American Industrial Hygiene 

Association (AIHA) for emergency planning and 

are intended as health-based guideline concentrations for single exposures to chemicals [AIHA 2006, 

2008]. These guidelines (i.e., the ERPG documents 

and ERPG values) are intended for use as planning 

tools for assessing the adequacy of accident prevention and emergency response plans, including 

transportation emergency planning, and for developing community emergency response plans. 

As with AEGLs, there are three ERPG guidance concentration levels designed for community protection [AIHA 2006]. However, ERPGs are derived for 

only single-exposure durations of 1 hour. Each of the 

three levels is defined and briefly discussed below:

• ERPG-1: The maximum airborne concentration below which it is believed that nearly all 

individuals could be exposed for up to one 

hour without experiencing other than mild, 
10 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

transient adverse health effects or without perceiving a clearly defined objectionable odor.

The ERPG-1 identifies a level that does not 

pose a health risk to the community but that 

may be noticeable because of slight odor or 

mild irritation. In the event that a small, nonthreatening release has occurred, the community could be notified that they may notice an 

odor or slight irritation but that concentrations 

are below those which could cause unacceptable health effects. For some materials, 

because of their properties, there may not be 

an ERPG-1. Such cases would include substances for which sensory perception levels 

are higher than the ERPG-2 level. In those 

cases, the ERPG-1 level would be given as 

“Not Appropriate.” It is also possible that no 

valid sensory perception data are available for 

the chemical. In these cases, the ERPG-1 level 

would be given as “Insufficient Data.”

• ERPG-2: The maximum airborne concentration below which it is believed that nearly all 

individuals could be exposed for up to one 

hour without experiencing or developing irreversible or other serious health effects or 

symptoms that could impair an individual’s 

ability to take protective action.

Above ERPG-2, there may be significant adverse health effects, signs, or symptoms for 

some members of the community that could 

impair their ability to take protective action. 

These effects might include severe eye or respiratory irritation, muscular weakness, central nervous system (CNS) impairments, or 

serious adverse health effects.

• ERPG-3: The maximum airborne concentration below which it is believed that nearly all 

individuals could be exposed for up to one 

hour without experiencing or developing lifethreatening health effects.

The ERPG-3 level is a worst-case planning 

level, above which there is the possibility 

that some members of the community may 

develop life-threatening health effects. This 

guidance level could be used to determine 

the airborne concentration of a chemical that 

could pose life-threatening consequences 

should an accident occur. This concentration 

could be used in planning stages to project 

possible levels in the community. Once the 

distance from the release to the ERPG-3 level 

is known, the steps to mitigate the potential 

for such a release can be established.

Like the IDLH value, the ERPG-2 is designed to 

protect from irreversible or other serious and 

escape-impairing effects and therefore is based on 

effects similar to those considered as the basis for 

IDLH values. Like the IDLH values, ERPGs are 

for acute exposure, but they are based on a 1-hour 

rather than 30-minute exposure. All other things 

being equal, this would mean that ERPG-2 values 

will generally be lower than the corresponding 

IDLH values, since the potential exposure time for 

the ERPG is higher. Moreover, even though ERPGs 

are developed by an occupational health organization, ERPGs are more like the AEGLs in that they 

are designed to protect the general population, and 

thus susceptible populations are more of a consideration for ERPGs than for IDLH values.

2.3 Occupational 

Exposure Limits 

OELs are derived by various governmental, nongovernmental, and private organizations for application 

to repeated or daily worker exposure situations. For 

example, in the United States, OELs are developed 

by several organizations. Examples of such organizations and their respective OEL values include; 

NIOSH RELs, OSHA PELs, MSHA PELs, ACGIH 

TLVs®, and AIHA WEELs®. Although the exact definition varies among organizations (see Glossary), 

the general intent of OELs is to identify airborne 

concentrations of substances in the air to which all 

or nearly all workers can be exposed on a repeated 

basis for a working lifetime without adverse health 

effects. OELs are developed on the basis of available 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 11

human data (such as results from epidemiologic 

studies or controlled human exposure studies), 

animal toxicologic data, or a combination of human and animal data. The health basis on which 

exposure limits are established may differ from substance to substance; protection against impairment 

of health may be a guiding factor for some, whereas 

reasonable freedom from irritation, narcosis, nuisance, or other forms of stress may form the basis 

for others. For most OELs, health impairment refers 

to effects that shorten life expectancy, compromise 

physiological function, impair the capability of resisting other toxic substances or disease processes, 

or impair reproductive function or developmental 

processes. Alternative considerations, such as technological feasibility, analytical achievability and 

economic impact, are often included during the 

establishment of an OEL based on the mandate of 

the organization deriving the exposure limit. For 

this reason, it is important to review the support 

documentation for any OEL to determine its basis 

(i.e., health endpoint versus alternative endpoint) 

and intended purpose.

OELs are guidelines (or regulatory standards, if 

mandated by OSHA and MSHA) intended for use 

in the practice of industrial hygiene, for the control of potential workplace hazards. OELs are not 

intended for use in other situations, such as the 

evaluation or control of ambient air pollution, or 

for estimating the toxic potential of continuous uninterrupted exposures or other exposure scenarios 

involving extended work periods, or as proof of existing disease or physical conditions. OELs neither 

clearly delineate between safe and dangerous concentrations nor serve as a relative index of toxicity. 

There are three primary categories of OELs, each 

with a different exposure duration comparison. 

The first category defines the TWA exposure concentration for up to a 10-hour workday (NIOSH 

REL) or a conventional 8 hour workday (OSHA 

PEL, MSHA PEL, ACGIH TLV®, or AIHA WEEL) 

during a 40-hour work week, to which it is believed 

that all workers (for the REL and PEL), nearly all 

workers (for the TLV®), or most workers (WEEL) 

may be repeatedly exposed daily without adverse 

effects. It should be noted that because alternative 

considerations (i.e., technical achievability, economic impact and analytical feasibility) are often 

included during the derivation of an OEL they may 

reflect an airborne concentration of a chemical for 

which there is residual risk of experiencing adverse 

health effects for some workers. The second category of OEL, called short-term exposure limit (STEL) 

and designated by ST preceding the value for 

NIOSH RELs, is a TWA concentration that should 

not be exceeded during any 15-minute period of a 

workday. ACGIH describes the TLV-STEL as the 

concentration to which it is believed that workers 

can be exposed continuously for a short period of 

time without suffering from irritation, chronic or 

irreversible tissue damage, or narcosis of sufficient 

degree to increase the likelihood of accidental injury, to impair self-rescue, or to materially reduce 

work efficiency [ACGIH 2009]. Exposures above 

the TLV-TWA and up to the TLV-STEL should 

not be longer than 15 minutes and should not occur 

more than four times per day, with a minimum of 60 

minutes between exposures in this range [ACGIH, 

2009]. The last category of OELs, referred to as ceiling OELs and designated by ACGIH with a “C” preceding the value, are the concentrations that should 

not be exceeded during any part of the working exposure, unless otherwise noted [ACGIH 2009].

Like the IDLH values, OELs are aimed at worker 

populations, and therefore consideration of susceptible populations is of less significance than for 

general population values. STELs and ceiling OELs 

are acute exposure values, whereas the TWA OELs 

are for repeated, chronic exposure. STELs are for 

a shorter duration (15 minutes), compared with 

30-minute IDLH values, and repeated exposures 

are permitted during the work shift at these airborne concentrations. STELs can be based on some 

endpoints similar to those that are of concern for 

IDLH values (e.g., chronic or irreversible tissue 

damage, narcosis that would impair self-rescue). 

For other endpoints, the severity for the basis of 

STELs may be less than that for the IDLH value. 

For example, mild irritation that would not be 

escape-impairing and mild narcosis that affects 

work efficiency but is not escape-impairing could 
12 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

be the bases for a STEL but would be considered 

below the threshold of interest for an IDLH value. 

Thus, depending on the nature of the effect caused 

by the chemical, the IDLH value may or may not be 

comparable to a STEL value for the same substance. 

2.4 Other Acute Exposure 

Limits/Values

A number of other governmental agencies and organizations also develop, or have developed, acute inhalation exposure limits/values intended to address 

various applications, exposed populations, and durations. These include acute exposure limits/values 

listed in Table 2–2.

Documentation for acute exposure limits/values 

from these selected organizations is reviewed and 

considered if it is deemed to provide specific insights that impact the development or interpretation of the IDLH value. For example, acute exposure limits/values from other government agencies 

and organizations might be included in the documentation for IDLH values if they are more recent 

or have unique data not available in other sources. 

Table 2–2. Other sources of acute inhalation exposure limits/values

Governmental agencies 

and organizations

Acute inhalation exposure

limits/values Sources

Department of Energy (DOE) Temporary Emergency Exposure 

Limits (TEELs)

Craig et al. [2000]; US DOE [2008]

State agencies (California, Texas, 

Minnesota, New York, New Jersey, etc.)

State Exposure Limits MDH [2010]; TCEQ [2010]; Cal/

EPA [2010]; NJ RTK [2010] 

National Academy of Sciences/National 

Research Council (NAS/NRC)

Emergency and Continuous Exposure 

Guidance Levels (EEGLs)

NAS [1986, 2008]

National Academy of Sciences/National 

Research Council (NAS/NRC)

Short-term Public Emergency 

Guidance Levels (SPEGLs)

NAS [1986]

NAS/NRC Spacecraft Maximum Allowable 

Concentration (SMAC)

NASA [1999]

U.S. Environmental Protection 

Agency (USEPA)

Acute reference concentrations (RfCs) USEPA [2010] 

USEPA’s homeland security 

program (DHS)

Provisional Advisory Levels (PALs) 

for Hazardous Agents

US DHS [2009]; Young et al. [2009]
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 13

3 Criteria for Determining IDLH Values

A weight-of-evidence approach based on scientific 

judgment is used in the IDLH methodology, both 

for evaluating the quality and consistency of the scientific data and in extrapolating from the available 

data to the IDLH value. The weight-of-evidence 

approach refers to the critical examination of all 

the available data from diverse lines of evidence 

and deriving a scientific interpretation based on 

the collective body of data, including its relevance, 

quality, and reported results. This is in contrast to 

a purely hierarchical (or strength-of-evidence) approach, which would use rigid decision criteria 

for selecting a critical adverse effect concentration 

and applying default uncertainty factors (UFs) to 

derive the IDLH value. The documentation of the 

IDLH value for each chemical is not intended to be 

a comprehensive review of all the available studies; 

instead, it focuses on the key data, decisions points, 

and scientific rationale integrated into the overall weight of evidence applied to derive the IDLH 

value for a chemical of interest. An example of the 

documentation for development of an IDLH value 

is provided in Appendix A, which explains the logic 

and rationale behind the derivation of the IDLH 

values for chlorine (CAS# 7782-50-5). 

Because IDLH values are often developed from 

limited data, the process for developing a value 

often applies data from multiple lines of evidence 

rather than a single key high-quality study. Overall, the following approach is used for deriving 

IDLH values:

• Critical review of human and animal toxicity 

data to identify potential relevant studies and 

characterize the various lines of evidence that 

can support the derivation of the IDLH value 

• Application of duration adjustments to determine 30-minute-equivalent exposure concentrations, as well as other dosimetry adjustments 

as needed 

• Application of a UF for each potential POD 

or critical adverse-effect concentration identified from the available studies to account 

for issues associated with interspecies and 

intraspecies differences, the severity of the 

observed effects (including concern about 

cancer or reproductive or developmental toxicity), and data quality or data insufficiencies 

• Developing the final recommendation for the 

IDLH value from the various alternative lines 

of evidence, using a weight-of-evidence approach, from all of the data.

Figure 3–1 provides a detailed summary of the key 

steps in derivation of IDLH values.

This process (see Figure 3–1) is conceptually similar to that used in other risk assessment applications, including these steps:

• Hazard characterization 

• Identification of critical effects 

• Identification of a POD 

• Application of an appropriate UF based 

 on the study and POD 

• Determination of the final risk value. 

The use of a weight-of-evidence approach allows 

for the integration of all available data that may 

originate from different lines of evidence into the 

analysis and the subsequent derivation of an IDLH 

value. Ideally, this ensures that the analysis is not 

restricted to a limited dataset or a single study for 

a specific chemical. In particular, application of the 

appropriate UF to each potential POD allows for 

consideration of the impact of the overall dataset 

as well as the uncertainties associated with each 

potential key study in determining the final IDLH 

value. See Appendix A for an example of how a 

typical dataset is evaluated to derive an IDLH value. 
14 NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) ValuesFigure 3–1. Key steps in the derivation of IDLH values.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 15

As illustrated in the remainder of this CIB, derivation of IDLH values uses a systematic data evaluation process that gives preference for data that 

provide the greatest degree of confidence in the 

assessment. The approach describes some overall 

preferences that define a general data hierarchy, 

but the methodology allows for all of the data to 

be evaluated by means of a weight-of-evidence 

approach to develop a toxicologically meaningful 

IDLH value that is consistent with the dataset as 

a whole. Implementing such a procedure requires 

considerable expertise and relies heavily on weighing various lines of evidence, with vetting by multiple scientists through a rigorous peer review process. 

Thus, although the following sections describe general processes and priorities for use of the data, these 

approaches are provided as general guidance, and 

the focus is on interpretation of the overall database.

3.1 Importance of Mode of 

Action and Weight-ofEvidence Approach

The mode of action (MOA), meaning a general description of how a chemical exerts its toxic effects, 

is an important part of the evaluation of chemical 

data and development of IDLH values. MOA can 

be thought of as a general category of how a chemical acts to cause adverse effects. Note that the MOA 

is a general description of the biological basis for 

toxicity and does not require the detailed level of 

understanding implied by mechanism of action. 

The MOA for a chemical is identified on the basis 

of the observed toxic effects, any mechanistic data, 

structure-activity data, and information on related 

chemicals; many chemicals act by more than one 

MOA. For example, many solvents cause both respiratory irritation and CNS effects. Some of the 

more common classes of MOA that are encountered in developing IDLH values, and examples of 

chemicals that fall into these classes, include:

• Irritants: All chemicals in this group induce 

sensory irritation that is caused by trigeminal 

nerve stimulation and manifests as pain 

within the mucous membranes at the sites of 

contact. Chemicals such as capsaicin (CAS# 

618-92-8) act in this manner without causing 

tissue damage. However, most sensory irritants can cause cytotoxicity (i.e., inflammation 

and tissue damage), with severity increasing in 

proportion to airborne concentrations. These 

types of irritants include highly reactive 

and/or corrosive chemicals, including acids, 

bases, and halogen gases. Endpoints commonly reported include eye, nose, and throat 

irritation, with higher concentrations typically 

leading to irritation and tissue damage lower 

in the respiratory tract. Chemicals in this class 

include organic solvents (e.g., vinyl acetate 

[CAS# 108-05-4]), organic acids (e.g., acrylic 

acid [CAS# 79-10-7]), halogens and other reactive gases (e.g., bromine [CAS# 7726-95-6]), 

and some metal compounds (e.g., titanium 

tetrachloride [CAS# 7550-45-0]).

• Nervous System Effects:Chemicals can cause 

nervous system effects by different MOAs. 

Many solvents (e.g., chloroform [CAS# 67-66-

3] and 1,1,1-trichloroethane [CAS# 71-55-6]), 

as well as other chemicals, cause CNS depression. Clinical signs reported in humans may 

include fatigue, weakness, and headaches. 

Endpoints commonly reported in animals or 

humans include sedation and reduced performance in specialized neurological testing. 

Certain classes of pesticides (e.g., organophosphates and carbamates) and nerve agents (e.g., 

sarin [CAS# 107-44-8]) inhibit the action of 

the enzyme acetylcholinesterase. Early signs of 

exposures to such agents include miosis (constriction of the eye pupil), excessive salivation, 

and muscle twitching. 

• Metabolic Toxicants: This class of chemicals 

acts by interfering with the cell’s ability to 

generate and store energy and includes, for 

example, cyanides and azides. Initial effects 

of these chemicals are CNS symptoms (some 

similar to those noted previously for CNS 

depressants) and toxicity, ultimately leading 

to respiratory failure. 
16 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

• Target Organ Toxicants: Certain organs or 

organ systems, such as the liver or kidney, are 

the site of toxicity for many chemicals. Organspecific effects are typically not evaluated in 

acute lethality studies. In-depth study of a 

single inhalation exposure may include evaluation of histopathology or clinical chemistry 

for certain organ systems. Also, acute poisoning incidents in humans may indicate that the 

liver or kidney is a target. These organ systems 

are frequently the most sensitive systemic targets because of the high blood flow to these 

organs and their capacity for metabolizing 

chemicals to more reactive forms. 

In addition, some chemicals target specific 

organs or have unique systematic effects. For 

example, arsine (CAS# 7784-42-1) causes 

hemolysis (breakage of red blood cells), with 

accompanying symptoms of headache, nausea, and shortness of breath. A number of 

halogenated hydrocarbons (e.g., vinyl chloride [CAS# 75-01-4], HFC-134a [CAS# 811-

87-2], and HCFC-141b [CAS# 1717-00-6]) 

cause cardiac sensitization. Chemicals, such 

as hexafluoroacetone (CAS# 684-16-2) and 

1-bromopropane (CAS# 106-94-5), cause 

reproductive toxicity and development effects. Also, hormonally-mediated effects 

can be suggested by direct observations of 

effects on reproductive function or toxicity 

studies evaluating fetal development.

• Asphyxiants: Inert gases (e.g., nitrogen 

[CAS# 7727-37-9] and argon [CAS# 7440-

37-1]) cause health effects by displacing oxygen. Chemical asphyxiants (e.g., carbon monoxide [CAS# 630-08-0], hydrogen cyanide 

[HCN; CAS# 74-90-8], and hydrogen sulfide 

[CAS# 7783-06-4]) can interfere with the 

body’s ability to use oxygen. Some early symptoms of asphyxiation include headache, rapid 

breathing, heart palpitations, and lethargy.

MOA is considered as part of the evaluation of 

need for and adequacy of UF in extrapolation 

from various points of departure. The MOA of a 

substance is used during the derivation of IDLH 

values to determine UF, time extrapolation, choice 

of POD, and consideration of interspecies differences. Below are some examples of how MOA affects these considerations. 

• A smaller UF is used when the endpoint 

is known to be very sensitive (e.g., cardiac 

sensitization in response to an epinephrine 

challenge, which is considered a sensitive 

marker of a severe effect). 

• MOA information may also be used to support a flatter time extrapolation curve for 

sensory irritants, based on the observation 

that effects from such chemicals (after the 

first few minutes of exposure) are driven 

primarily by concentration and less by duration of exposure. 

• MOA information indicating that the chemical targets the route of entry, with resulting 

effects such as eye, nose, and throat irritation, would indicate that the route-to-route 

extrapolation is not appropriate. 

• MOA information may suggest the use of 

surrogates when information on the chemical of interest is limited or when a breakdown 

product is identified as being the primary 

cause of toxicity. For example, HCN is commonly used as a surrogate for acetocyanohydrin (CAS# 78-97-7), which spontaneously 

forms acetone and HCN. Another example 

is the use of hydrogen chloride (CAS# 7647-

01-0) as a surrogate for chlorosilanes, which 

decomposes when exposed to water (i.e., humidity) to form hydrogen chloride and silanols. In both cases, the surrogates (i.e., HCN 

and hydrogen chloride) are directly linked to 

the severity of the toxic effect. 

• Finally, MOA information may suggest potential refinements to the dose–response 

analysis. For example, carbon monoxide 

toxicity is due to the formation of carboxyhemoglobin (COHb), and the IDLH value 

for carbon monoxide is based on calculated 

COHb levels. 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 17

3.2 Process for Prioritization 

of Chemicals

In addition to serving as a crucial factor in the selection of respiratory protection equipment, IDLH 

values play an important role in planning work 

practices surrounding potential emergency highexposure environments in the workplace and in 

guiding actions by emergency response personnel 

during unplanned exposure events. Ideally, such 

guidance values would be available for all chemicals that might be present under high-exposure 

situations. However, the development of IDLH 

values is not necessary for many chemicals, such 

as those with very low exposure potential or those 

that do not exhibit significant acute toxicity via the 

inhalation route. A prioritization process is used 

by NIOSH to ensure that resources allocated to 

IDLH value development yield the greatest impact on risk reduction. This process takes into 

account both toxicity and exposure potential and 

is applied to a broad range of potentially hazardous 

chemicals (e.g., chemical warfare agents, industrial 

chemicals, or agrochemicals) subject to emergency 

or uncontrolled releases. A qualitative algorithm is 

used to generate a priority ranking. This process 

provides initial priority rankings based on a simple approach that uses readily available sources 

of information. More sophisticated hazard- or 

risk-based ranking schemes could be used, but 

gathering and analyzing the data would require 

the same approximate effort required to actually 

derive an IDLH value. A complex ranking approach would not meet the primary objective to 

quickly and efficiently identify chemicals of greatest concern. The resulting priorities are further 

modified according to NIOSH emphasis areas. For 

example, chemicals can be added or removed from 

the priority list on the basis of new information related to toxicity or exposure potential. The development and use of a documented prioritization process allows for more frequent updating by NIOSH 

of both input data and prioritization criteria to 

meet changing needs. The prioritization approach 

is described more fully in Appendix B. 

3.3 Literature Search Strategy 

NIOSH performs in-depth literature searches to 

ensure that all relevant data from human and animal studies with acute exposures to the substance 

are identified. An initial literature search is done, 

including searches for information from the sources 

listed in Table 3–1.

Electronic searches of these databases are conducted with limitations on search dates. The databases 

are searched for studies pertinent to acute inhalation toxicity, with use of the search terms summarized in Table 3–2. 

The electronic literature searches are screened for 

relevant articles, and a bibliography of relevant 

literature is compiled that identifies studies for 

retrieval and review. Peer-reviewed toxicology reviews are also examined, including those identified by searching the databases and organization 

websites, as noted in Table 3–1. Toxicology reviews 

that are routinely used to identify pertinent literature for developing the IDLH value include those 

published by ACGIH (i.e., TLV® and Biological 

Exposure Indices), AIHA (i.e., ERPG and WEEL 

documentation), ATSDR (i.e., Toxicology Profiles), 

National Toxicology Program (NTP), NIOSH (i.e., 

REL documentation), NRC (i.e., AEGL documentation), OSHA (i.e., PEL documentation), WHO (i.e., 

Environmental Health Criteria) and USEPA (i.e., 

IRIS Toxicological Reviews). Other key unpublished literature, such as toxicological reports on 

file with the USEPA as part of the Toxic Substance 

Control Act Section 8D, may become available 

from stakeholders and other interested parties during the external and stakeholder review process. 

3.4 Determining the Critical 

Study and Endpoint

Development of an IDLH value begins with the 

critical evaluation and array of the available animal 

toxicity and human health effects data. In order to 

effectively evaluate the data, it is useful to array the 

following information: 
18 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Table 3–2. Literature search key words

Search terms

Acute Irritation

Inhalation Respiratory

Lethal RD

Lethal concentration Threshold

LC Case study

Fatal Poisoning

Fatality Chemical identifiers

• Description of the test species 

• Health endpoints evaluated

• Exposure concentrations

• Critical effect levels (e.g., NOAELs, LOAELs, 

LC50 values) 

• Duration of the exposure for the study. 

Once this information is compiled, critical effect levels are adjusted to a 30-minute-equivalent 

concentration to derive a POD estimate for each 

Table 3–1. Literature search sources

Database Link

Centers for Disease Control and Prevention (CDC)/

Agency for Toxic Substance and Disease Registry 

(ATSDR) ToxProfiles

http://www.atsdr.cdc.gov/toxprofiles/index.asp

ChemIDplus http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp

EU, European INventory of Existing Commercial 

chemical Substances (EINECS)

http://ihcp.jrc.ec.europa.eu/our_labs/predictive_

toxicology/information-sources/ec_inventory

EMBASE http://www.embase.com/

National Library of Medicine (NLM), Haz-Map http://hazmap.nlm.nih.gov/

NLM, Hazardous Substance Data Bank (HSDB) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

International Agency for Research on Cancer (IARC) http://www.iarc.fr/

Environmental Protection Agency (EPA) Toxic 

Substance Control Act (TSCA) Section 8(e) Notices

http://www.epa.gov/oppt/tsca8e/index.html

World Health Organization (WHO)/IPCS International 

Chemical Safety Card (ICSC)

http://www.ilo.org/public/english/protection/safework/

cis/products/icsc/dtasht/index.htm

International Toxicity Estimates for Risk (ITER) http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?iter

New Jersey Hazardous Substance Fact Sheets (NJ-HSFS) http://web.doh.state.nj.us/rtkhsfs/indexfs.aspx

NIOSHTIC2 http://www2a.cdc.gov/nioshtic-2/default.asp

NLM, PUBMED http://www.ncbi.nlm.nih.gov/pubmed/

National Institute for Occupational Safety and Health 

(NIOSH)/Registry of Toxic Effects of Chemical 

Substances (RTECS)

http://www.cdc.gov/niosh/rtecs/

NLM, Toxicology Literature Online (TOXLINE) http://toxnet.nlm.nih.gov/cgi-bin/sis/

htmlgen?TOXLINE

Web of Science http://thomsonreuters.com/products_services/

science/science_products/scholarly_research_analysis/

research_discovery/web_of_science
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 19

study or study endpoint. Through the application 

of the weight-of-evidence approach described in 

this document, the critical study that contributes 

most significantly to the qualitative and quantitative assessment of risk is selected as the basis of an 

IDLH value. Appendix A provides an example of 

how such information is compiled and used in the 

derivation of the IDLH value for chlorine (CAS# 

7782-50-5). The weight given to each study in selection of a final POD is based on the reliability 

of the reported findings (as determined from an 

assessment of study quality), the relevance of the 

study type for predicting human effects from acute 

inhalation exposure, and the estimated 30-minute 

adjusted effect level. 

3.4.1 Study Quality Considerations

For toxicology studies, quality considerations that 

affect the reliability of each study include the key 

elements of the study design and the adequacy of 

study documentation. For example, such aspects of 

study quality might include the following:

• Relevance of the exposure regimen to a single 

30-minute inhalation exposure 

• Quality of atmosphere generation system 

and analytical techniques used to assess exposure conditions

• Degree of evaluation of toxic endpoints

• Number of animals used and relevance of the 

test species to humans. 

Other considerations for evaluation of study quality include the reliability of the cited data source, 

whether the study adhered to or was equivalent to 

current standards of practice (e.g., USEPA or Organisation for Economic Co-operation and Development [OECD] test guidelines), and whether good 

laboratory practices (GLPs) were followed. These 

considerations are evaluated for each study according to the general concepts outlined by Klimish et 

al. [1997]. Although a single authoritative guide 

to such study quality evaluation for epidemiology 

studies is not available, human effects data studies are judged on the basis of current standards of 

practice for conducting epidemiology or clinical 

studies [USEPA 1994; Federal Focus Inc. 1995; 

Lewandowski and Rhomberg 2005]. Consistency 

of effects across studies and consistency based on 

other information available about the chemical 

(e.g., oral data, structure-activity data) are used to 

assess the quality of individual studies.

Selection of the critical study to serve as the basis 

for the IDLH relies heavily on study quality considerations. A high-quality study might be chosen as 

the basis for the IDLH value, even if a lower IDLH 

value could be generated from a low-quality study, 

where the evaluation of quality casts doubt on the 

reliability of the study results. An LC50 value derived 

from a USEPA or OECD guideline–compliant acute 

lethality study with robust atmosphere generation 

and measurement systems may be selected over a 

lower LC50 value from an older study that used a 

static exposure chamber system and reported only 

nominal air concentrations or that used a small 

number of animals or non-standard test species. 

3.4.2 Study Relevance 

Considerations

The weight-of-evidence approach requires a critical evaluation of each study as to its relevance to 

the ultimate goal of the IDLH value derivation—

to develop a scientifically-based estimate of the 

30-minute human threshold concentration for severe, irreversible or escape impairing effects. The 

methodology for developing IDLH values follows a 

hierarchical approach based on the following preference for data: 

• Acute human inhalation toxicity data 

• Acute animal inhalation toxicity data 

• Data for longer-term inhalation studies 

• Inhalation data for analogous chemicals 

(i.e., toxicological surrogates)

• Acute animal oral toxicity data.

The IDLH methodology described in this CIB follows similar principles but is based more on an over-
20 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

all weight-of-evidence approach that considers study 

reliability, quality (as discussed in Section 3.4.1), 

relevance, and the magnitude of the observed effect 

levels. The evaluation of study relevance includes 

the type and severity of the effects observed, study 

duration, and route of exposure.

Other considerations that will be addressed during 

the selection of the key data include the following:

• Primary versus secondary sources.

• Peer-reviewed versus non-peer-reviewed studies.

The term primary data refers to information obtained directly from original studies and reports, 

whereas secondary data refers to information summarized within reviews and monographs. Primary 

data are given more weight within the derivation 

of IDLH values, whereas secondary data are used 

to provide background and supporting information. An exception to this may occur when critical 

primary data are unobtainable and an IDLH value 

cannot be derived without being based on data 

contained in a secondary source. In such cases, 

the IDLH value may be based on the information contained within the secondary data source. 

Some secondary sources provide greater value than 

other sources. For example, authoritative secondary sources might include robust toxicity profiles 

that have undergone extensive review, such as the 

ATSDR Toxicological Profiles or EPA IRIS Toxicological Reviews. 

Peer reviewed data are generally preferred as the 

basis of an IDLH value, over data obtained from 

non-peer-reviewed sources. For this reason, peerreviewed data take precedent over non-peer-reviewed 

data within the IDLH methodology. Exceptions are 

made when issues with the peer-reviewed data are 

identified or if non-peer-reviewed studies are 

determined to be of higher quality. Non-peerreviewed data may take precedent over peer-reviewed 

data in circumstances such as these:

• Non-peer-reviewed studies used standardized or guideline-compliant protocols, but 

available peer-reviewed studies used nonstandardized protocols.

• The toxic effects reported in non-peer-reviewed 

studies align better with the health endpoints 

of interest (e.g., escape-impairing effects, 

irreversible effects, or lethality) than do the 

effects reported in peer-reviewed studies 

(e.g., mild irritation). 

• Non-peer-reviewed studies demonstrate better biological and statistical significance due 

to increased sample size, selection of test species, or overall study design, in comparison 

with peer-reviewed studies.

Ultimately, the basis of an IDLH value will result 

from the weight-of-evidence approach incorporated 

into the CIB that reflects the relative strengths and 

weaknesses of all the data. 

3.4.2.1 Relevance of the Type 

and Severity of the Effect

3.4.2.1.1 General considerations in identifying 

the severity of effects for IDLH derivation

Relevance of the effect is evaluated in the context 

of the goal for deriving an IDLH value (i.e., to develop a high-confidence estimate of the 30-minute 

human threshold concentration for severe, irreversible, or escape-impairing effects). Studies that 

identify with good precision the actual threshold 

for such effects are rare; therefore, usually it is 

necessary either to extrapolate from an effect level 

that is above a threshold, by relying on a lowest observed adverse effect level (LOAEL) for severe or 

escape-impairing effects, or to use a lower-bound 

estimate of the threshold by relying on a no observed adverse effect level (NOAEL) for severe or 

escape-impairing effects. In some cases, concentration modeling can be used to further refine such estimates on the basis of actual study concentrations. 

All of the data for effects relevant to the IDLH are 

evaluated and used in this effort, including data on 

mortality, severe or irreversible effects, and escapeimpairing effects. Data on exposure levels causing 

less severe effects, which are below the threshold 

of interest, are useful as estimates of the NOAEL 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 21

for severe effects or escape-impairment. Together, 

these data can describe the exposure–response 

relationship for the chemical of interest, which 

compares the estimated exposure concentration 

to the reported effects. Having an understanding 

of this relationship allows the potential region of 

the threshold concentration to be more accurately 

determined for the most-sensitive severe or escapeimpairing effects. 

Table 3–3 illustrates how the severity of effect is 

taken into account in determining the POD and 

IDLH value. In this case, human data are available 

for a 30-minute exposure that describe the concentration response, from no effects at 10 ppm to mild 

irritation at 20 ppm and severe irritation that was 

considered escape-impairing at 30 ppm. Thus, the 

threshold for an escape-impairing effect in humans 

is between 20 and 30 ppm for a 30-minute exposure, 

and the POD for the IDLH value would be 20 ppm. 

In this case, no concentration–response modeling 

was available to estimate the threshold for severe 

lacrimation and coughing. Application of a typical 

UF of 3 (see Chapter 4) to the NOAEL concentration 

of 20 ppm for mild irritation and coughing would 

generate an IDLH value of 7 ppm, which would be 

lower than appropriate on the basis of the absence of 

any irritant effects at 10 ppm. Thus, in this case, since 

the severity of the effects at 20 ppm was not considered escape-impairing, the appropriate IDLH value 

would be approximately 20 ppm or less on the basis 

of balancing consideration of the human effect level 

and variability in human sensitivity.

3.4.2.1.2 Consideration of lethality data

Datasets for acute toxicity are often limited to studies reporting mortality experience in acute animal 

toxicology studies or from case reports describing 

accidental human exposures that include estimates 

of the lethal concentration. Lethality data from 

acute toxicology studies in animals are commonly 

available, and many IDLH values are derived from 

such data. In such cases, information on the threshold for lethality is the preferred basis for an IDLH 

value, rather than an estimate of median lethal concentration (i.e., the LC50). Lethality thresholds can 

be estimated from LCLO values (the lowest concentration in the study that caused lethality) if the mortality incidence is relatively low (i.e., 10% or less) or 

can be based on concentration-response models. 

These models can be used to indicate the estimated 

response incidence (percent response) and whether the estimate is the maximum likelihood estimate 

or a lower confidence limit. For example, a commonly reported model value such as an LC01 value 

(the statistically derived air concentration that 

caused lethality in 1% of test animals) is the model 

estimated maximum likelihood concentration associated with an increased mortality incidence 

of 1% over control values. More recently, studies 

report lethality estimates with use of software that 

provides lower confidence estimates of the concentrations. For example, the USEPA provides free 

software for this purpose (available at http://www.

epa.gov/ncea/bmds/). The output from the USEPA 

software is commonly reported as the benchmark 

concentration (BMC) for the maximum likelihood 

Table 3–3. Consideration of severity of effect

Species Endpoint—effect level, ppm Duration, minutes Comments

Human NOAEL—10 30 No irritation

Human NOAEL—20 30 Mild irritation and coughing

Human LOAEL—30 30 Severe lacrimation and coughing

Abbreviations: LOAEL = lowest observed adverse effect level; NOAEL = no observed adverse effect level; ppm = parts per million. 
22 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

estimate or the 95% lower-bound confidence limit 

on the BMC (BMCL). Thus, a BMCL05 is the estimated 95% lower confidence bound on the concentration associated with a 5% increased lethality 

response above controls.

Such model-calculated values are preferred over 

LCLO values, because they are not dependent on the 

actual concentrations tested and reflect the response 

at each concentration. Use of a lower confidence 

limit (i.e., the BMCL) also has the advantage of taking into account the uncertainty in the data and statistical power of the study. Frequently, the BMCL05

(i.e., the lower 95% confidence limit on the concentration associated with a 5% response) and BMC01

(i.e., the central tendency estimate of the concentration associated with a 1% response) are both calculated for lethality data, and the lower value is used as 

the lethality threshold. The lower value is often the 

BMCL05, due to the relatively wide confidence limits 

associated with the small sample size. An extensive 

discussion on the application of benchmark dose 

(BMD) within the development of acute emergency 

response guidelines has been included in the AEGL 

SOP [NAS 2001]. This includes key considerations, 

shortcomings, and uncertainty within the process. 

An alternative approach used for estimating a nonlethal exposure level from LC50 values has been applied in the AEGL methodology [NAS 2001; Rusch 

et al., 2009]. This approach uses 1/3 of the LC50 value 

as the POD to estimate the boundary between the 

lethality threshold and a non-lethal exposure level. 

When compared to LC01 values and BMCL05 values 

for selected chemicals, in general, 1/3 of the LC50

value resulted in lower estimates of a non-lethal 

threshold [Rusch et al. 2009]; thus, this is a healthprotective approach. Although the use of lethality 

data as the basis of an IDLH value is not ideal, the 

absence of concentration-response data may require 

the use of LC50 values as a POD. 

Although estimates of a lethality threshold are preferred over other measures of lethal concentrations, 

in many cases, the only available data from acute 

lethality studies are LC50 values (i.e., concentrations 

associated with a 50% mortality incidence).†

 If LC50

value estimates are available for multiple species, 

then the lowest reliable LC50 value in the most relevant animal species is used for extrapolation to predict human response. If no data are available that 

favor the use of one animal species over another, 

then the most sensitive species is used after considering study quality. Multiple LC50 values may also 

be available from a single study, including values 

for both sexes individually and for the two sexes 

combined. In such cases, the data are evaluated for 

any clear difference between the sexes. If a clear difference exists, the LC50 from the more sensitive sex 

is used. If there is no clear difference, the combined 

LC50 value is used, since the combined data provide 

a higher statistical power.

Table 3–4 illustrates different lethality data that 

may be available. In the example cited, three different measures of lethality are available from the 

rat study: the LC50, LCLO, and BMCL05. The selected 

POD for deriving the IDLH value would be the rat 

BMCL05, because this value represents a defined 

response near the threshold for lethality and the 

data show that the rat is more sensitive than the 

mouse. In this case, the BMCL05 resulted in the 

lowest derived value, but the BMCL05 would generally be preferred, even if it was somewhat higher 

than the LCLO, due to statistical variability related 

to the LCLO and because the BMCL05 reflects the 

variability in the data. The derived IDLH values 

reflect the application of UFs, addressing how far 

the data and endpoints are from the endpoint of interest. Because the goal is to estimate the threshold 

for the severe responses, a larger UF is applied to 

the LC50 value than is applied to measures around 

†

LC50 and BMC values are conceptually similar, although 

the BMC approach is a more recent innovation. Both 

values are determined by fitting a flexible mathematical 

curve to the data, and determining the concentration 

corresponding to a specified response. While various 

mathematical models can be fit to the data, the probit 

model is frequently used, as a flexible model that usually fits acute data well, particularly for lethality data 

(e.g., Fowles et al. [1999]).
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 23

the threshold for lethality, such as the BMCL05 (see 

Chapter 4 for additional discussion of UF).

3.4.2.1.3 Consideration of escape-impairing effects 

For effects other than mortality, reported health effects in both human and animal studies are classified 

as severe, irreversible, or escape-impairing. Identifying which effects may be escape-impairing is complicated by the fact that observed signs and symptoms 

in animals may differ from those expected to occur 

in humans. For example, the same underlying MOA 

that manifests as changes in respiration rate, nasal discharge, or altered activity level in an acute toxicity test 

in animals may be reported as intolerable irritation in 

humans. For this reason, guidance was developed that 

allows for more consistent assigning of comparative 

severity of observed effects (i.e., severe and irreversible versus non-severe; escape-impairing versus nonescape-impairing) for commonly observed adverse 

effects used as the basis of IDLH values. Appendix 

C provides the guidelines for classifying effects commonly seen in acute animal studies.

Generally, basing IDLH values on effects that can 

impair escape relates to consideration of irritation 

responses (e.g., severe eye burning or coughing) 

or impacts on the nervous system (e.g., headache, 

dizziness, drowsiness), although other effects (e.g., 

cardiovascular or gastrointestinal tract effects) may 

also be considered, when warranted. To facilitate 

a consistent approach, qualitative descriptions of 

severity have been developed with study results 

assigned to one of three categories: mild, moderate, or severe. The severity and the type of the effect are considered in determining whether escape 

impairment is likely. For example, moderate to severe eye irritation, but not mild irritation, is generally considered an appropriate basis for an IDLH 

value based on escape impairment. For effects on 

the CNS, narcosis or moderate dizziness is considered sufficiently adverse to impair escape, whereas 

effects such as headache are generally not considered as an adequate basis for the IDLH value unless 

described in the study as debilitating or occurring 

with other symptoms that directly impaired vision 

or mobility. 

Additional consideration is needed for screening assays, such as the respiratory depression 50% 

(RD50) assay and cardiac sensitization tests. The 

RD50 assay is a sensitive measure of sensory irritation, which occurs due to stimulation of trigeminal nerve endings in the cornea and nasal mucosa. 

These effects frequently are due to a decrease in 

respiratory frequency that occurs in some laboratory animals when exposed to chemical irritants. 

The RD50 value is considered as part of the overall 

Table 3–4. Consideration of lethality effects

Species

Endpoint/effect 

level (ppm)

Duration 

(minutes) UF

Derived 

IDLH value 

(ppm) Comments

Rat LC50/1000 30 30 33 Males and females combined

Rat LCLO/400 30 10 40 1/10 died

Rat BMCL05/240 30 10 24 Modeling done by

the authors

Mouse LC50/2000 30 30 66 Males only

Abbreviations: BMCL05 = lower 95% confidence limit on the concentration associated with a 5% response; IDLH = immediately 

dangerous to life or health; LC50 value = median lethal concentration; ppm = parts per million; UF = uncertainty factor.
24 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

weight of evidence and can be used to support the 

selection of a POD from other studies that identified the concentration that caused clinical signs 

of irritation or generated histopathologic changes 

consistent with moderate or severe irritant effects 

[Alarie 1981; ASTM 1984; Schaper 1993; Nielsen 

et al. 2007]. The RD50 value can also be used as the 

POD if no reliable LOAEL is available. However, 

the LOAEL is preferred over the RD50 value as a 

POD because of uncertainties in relating the respiratory depression response in rodents to potential 

clinical or tissue changes in humans that would be 

correlated with severe irritation in humans [Bos et 

al. 1992, 2002]. 

Cardiac sensitization is another sensitive endpoint 

[Brock et al. 2003; ECETOC 2009] that serves as the 

basis of some IDLH values. This endpoint reflects a 

serious effect in humans, which is characterized by 

the sensitization of the heart to arrhythmias. Cardiac sensitization can occur from exposure to some 

hydrocarbons and hydrocarbon derivatives which 

make the mammalian heart abnormally sensitive to 

epinephrine. This can result in ventricular arrhythmias and, in some cases, can lead to sudden death 

[Reinhardt et al. 1971]. The arrhythmia results from 

the hydrocarbon potentiating the effect of endogenous epinephrine (adrenalin), rather than a direct 

effect of exposure to the hydrocarbon. As described 

by NAS [2002], “the mechanism of action of cardiac sensitization is not completely understood but 

appears to involve a disturbance in the normal conduction of the electrical impulse through the heart, 

probably by producing a local disturbance in the 

electrical potential across cell membranes.”

Cardiac sensitization is determined by injecting 

the test animal (usually dogs, but rodents are also 

used) with epinephrine to establish a background 

(control) response, followed by an injection of epinephrine during exposure to the chemical of interest. Different doses of epinephrine are often tested 

for the initial injection, and the dose of epinephrine 

chosen is the maximum dose that does not cause 

a serious arrhythmia [NAS 1996]. The test is very 

conservative, because the levels of epinephrine 

administered result in blood concentrations approximately 10 times the blood concentrations that 

would be achieved endogenously in dogs [Chengelis 1997] or humans [NAS 1996], even under highly 

stressful situations. Thus, even though scenarios 

where IDLH values would apply would be highly 

stressful, the cardiac sensitization test is considered 

a sensitive measure of a severe effect. Cardiac sensitization is relevant to humans, but because of the 

conditions of the assay, which focuses on the measurement of the response to a challenge injection 

with epinephrine, the assay itself is very sensitive 

[Brock et al. 2003; ECETOC 2009]. The sensitivity 

of the assay is considered in the weight-of-evidence 

approach when selecting the POD and in the selection of the UF.

3.4.2.1.4 Consideration of severe and 

irreversible effects

A variety of health effects may result from acute 

exposures that do not immediately impair escape 

(although over an extended time period these effects 

may be lethal). Severe adverse effects that are not immediately escape-impairing are evaluated on a caseby-case basis, by weighing considerations such as the 

need for medical treatment, the potential for altered 

function or disability, the potential for long-term 

deficits in function, and the likelihood for secondary 

symptoms that would be escape-impairing. These 

include severe, but reversible, acute effects such as 

hemolysis, chemical asphyxia, delayed pulmonary 

edema, or significant acute organ damage (e.g., 

hepatitis, decreased kidney function). If a chemical 

is suspected of generating such effects, then it is important to evaluate the design of the study to ensure 

that adequate time was allowed, following completion of the exposure period, to determine whether 

such latent effects of interest were assessed.

Irreversible target organ effects (e.g., permanent

functional respiratory impairment or permanent 

neurological impairment) are also considered a 

sufficient basis for an IDLH value. As discussed further in the following paragraphs, data on irreversible 

effects of special interest (e.g., reproductive and developmental toxicity) or effects that have significant 

latency (e.g., cancer) are generally considered as an 

adequate basis for the IDLH value only when singleexposure studies have been conducted that evaluated 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 25

these endpoints. For example, if reproductive or developmental studies involving short-term exposures 

(i.e., 1 day or less) are available and have adequately 

long observation periods to observe delayed effects, 

then they are considered in the development of the 

IDLH value; such studies can be informative regarding the potential for irreversible reproductive or 

developmental effects. These effects are considered 

in the overall weight-of-evidence analysis to ensure 

that the derived IDLH value is sufficiently protective 

against the most sensitive health endpoint, as described in the following paragraphs.

Standard developmental toxicity studies are not 

used directly because they typically involve repeated exposures (e.g., during all of gestation or 

from implantation through one day prior to expected parturition), and extrapolation from studies that involve long exposure periods thereby 

resulting in an unacceptable level of uncertainty. 

However, it is also recognized that some developmental effects can result from exposure during a critical window of development, and that 

the time in which the exposure is administered 

may be more important than exposure duration. 

Therefore, data from developmental studies are 

evaluated in the context of the overall weight-ofevidence analysis. For example, if developmental 

effects are seen, the data on MOA and the relative 

concentration response for maternal toxicity and 

fetal toxicity are evaluated to determine whether 

an increased UF is needed. Conversely, a potential 

IDLH value derived from systemic toxicity in the 

pregnant female can provide a health-protective, 

lower-bound estimate for the IDLH value, because the exposure duration of repeated days 

is much longer than the duration of interest—a 

single 30-minute exposure. Use of repeatedexposure studies in this manner can provide perspective to potential IDLH values derived from very 

high concentration acute studies where a large UF 

leads to relatively low IDLH values that are more 

than adequately protective. Information relating to 

key issues in the use of developmental toxicity data 

during the assessment of the health risks of acute 

exposure scenarios has been published [van Raaij 

et al. 2003; Davis et al. 2009]. These publications 

provide supplemental resources that will be used to 

refine the derivation of IDLH values based on developmental toxicity data.

Table 3–5 shows how developmental toxicity data 

can be used to help evaluate an appropriate lowerbound estimate for the IDLH value. In this case, the 

IDLH value is derived from the 60-minute LC50

value, as the lowest acute lethality value from the 

studies of relevant duration. (See Section 3.5 and 

Chapter 4.0, respectively, for discussion of the adjustment for durations other than 30 minutes and 

UF used to calculate the derived value.) A developmental toxicity study is also available, in which 

exposure was for 6 hours/day on gestation days 6 to 

20. Because the developmental effect of decreased 

fetal body weight may have resulted from a single 

exposure during a critical window, the exposure 

duration is listed as 6 hours. Because this is a very 

health-protective assumption, the developmental 

toxicity study is not used as the basis for the IDLH 

value, since confidence in the actual acute exposure 

effect level is highly uncertain. However, the derived 

IDLH value does provide a lower-bound estimate, 

since we would not expect the LC50-based IDLH 

value to be lower than the derived value from a 

repeat-exposure study for non-lethal effects. The 

IDLH derived from the LC50 is somewhat higher 

than from the repeated-exposure developmental 

toxicity study; thus, the overall findings are consistent with expectations and the overall dataset provides reasonable confidence in the selected value. 

Like developmental toxicity studies, reproductive 

toxicity studies tend to involve repeated exposures 

and therefore usually are not used as the basis for 

an IDLH value. However, single-exposure reproductive toxicity studies that report irreversible or slowly reversible effects are considered 

in the development of IDLH values. In addition, 

findings of reproductive toxicity coupled with 

MOA data (e.g., data suggesting an effect on hormonal control) may suggest the use of an increased 

UF, if the available acute toxicity data are insufficient to evaluate the concentration–duration response for such effects. 
26 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

As noted above, acute animal toxicity studies rarely 

include sufficient post-exposure monitoring to be 

useful for cancer assessment. Even when a study is 

sufficient for evaluating carcinogenicity following 

a single exposure (e.g., Hehir et al. [1981]), such 

as following vinyl chloride exposure, the data are 

usually insufficient for a quantitative calculation of 

cancer risk. Therefore, concern for carcinogenicity 

is addressed by consideration of adding a supplemental UF (see Chapter 4). The cancer risk at the 

potential IDLH value can also be estimated and 

compared with a chosen risk level (i.e., a 1 in 1,000 

excess cancer risk) [NAS 2001]. The concentration 

corresponding to a specified risk level is not usually used as the basis for the IDLH value, because of 

the considerable uncertainty in extrapolating from 

a chronic study to a single exposure. However, if 

the estimated cancer risk at the IDLH value without the supplemental UF is below 1 in 1,000, then 

the supplemental UF is not used. 

3.4.2.2 Relevance of the Exposure 

Duration for Acute Studies

Acute animal inhalation studies reviewed for the 

derivation of the IDLH value may use treatment 

regimens ranging from an exposure duration as 

short as a few minutes (e.g., <10 minutes) to several 

hours (e.g., 8 hours or more). Because the intended 

use of the IDLH value is for the prevention of 

adverse effects that may occur as a result of a single 

exposure for 30 minutes, the derivation of an IDLH 

value is ideally based on:

• Studies involving exposure for 30 minutes 

• Studies that have information on the threshold 

for rapidly occurring escape-impairing effects 

• Studies that include a sufficient observation 

period for potential severe delayed effects. 

Acute studies of durations other than 30 minutes 

that provide information on escape-impairing effects and severe adverse effects are also desirable 

and used. Although inhalation studies of durations 

other than 30 minutes introduce uncertainties in 

extrapolating effects to a 30-minute duration, they 

are still used after being adjusted to a 30-minuteequivalent exposure duration, as discussed in detail 

in Section 3.5 on Time Scaling. 

It is recognized that the ideal dataset applied during the derivation of an IDLH value will consist of 

high-quality 30-minute inhalation studies with effects in the severity range of interest. In most cases, 

such datasets are unavailable. Thus, when selecting 

among less-than-optimal study designs to identify the most appropriate critical study and POD, 

a weight-of-evidence approach is used to select the 

critical study. For example, within a given category 

of studies (e.g., acute lethality studies), preference 

Table 3–5. Consideration of developmental toxicity data

Species

Endpoint/effect 

level (ppm)

Duration 

(minutes)

Adjusted to 

30 minutes 

(ppm) UF

Derived 

value (ppm) Comments

Rat LC50/1800 60 2268 30 75.6 2/4 died—not a 

calculated value

Rat LOAEL/200 360 458 10 45.8 1/21 dams died; fetal 

weight decreased; 

significant reabsorptions 

at 300 ppm; 6 hours/day 

on days 6–20 of gestation

Abbreviations: LC50 = median lethal concentration; LOAEL = lowest observed adverse effect level; ppm = parts per million;

UF = uncertainty factor.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 27

is given to high-quality studies of the duration of 

interest (30 minutes) or involving minimal duration extrapolation (e.g., 20-minute exposure duration is preferred over a 4-hour exposure duration). However, the relative merits of a well-done 

study of longer duration versus a poorly conducted 

30-minute study must be considered. A well-documented weight-of-evidence decision is even more 

important when there are no adequate acute inhalation studies in humans or animals. In such cases, 

consideration of all other available data is needed, 

including MOA information, repeated-exposure 

studies, studies of exposure routes other than inhalation (e.g., oral or direct-injection dosing), and 

studies with other (usually structurally related) 

chemicals. MOA understanding is particularly important in such situations and can determine such 

issues as whether route-to-route extrapolation is 

appropriate, the impact of using data from repeated-exposure studies, and which structurally related 

chemicals are appropriate to use by analogy. The following examples illustrate the impact of MOA on 

extrapolation decisions.

1. For route-to-route extrapolation: It is inappropriate to conduct route-to-route extrapolation for 

irritants, because they target the route of entry. 

2. For duration extrapolation: It may be appropriate to extrapolate from repeated-exposure studies for irritants, since concentration is often a 

more important determinant of irritation than 

exposure duration. Irritation effects observed 

on the first day of exposure during a repeatedexposure study may be used as the basis of an 

IDLH value.

Repeated-exposure studies that identify subchronic 

or chronic systemic toxicity (rather than rapidonset clinical signs) are not used quantitatively as 

the basis for deriving the IDLH value. However, 

considerations of these other toxicity metrics are 

included in overall database evaluation during the 

consideration of UF and to assess the reliability of 

estimates derived from acute studies. For example, if a well-conducted repeated-exposure study 

shows no adverse effect at a given concentration, 

then such a finding can help to determine the lower 

range of potential values for an IDLH value, since 

single acute exposures will usually identify a higher 

POD. In this way, repeated-exposure studies can 

provide a lower bound on the range of potential 

IDLH values for a chemical if the databases of acute 

studies are limited or of marginal quality. 

Table 3–6 illustrates how scientific judgment is 

used in considering duration. In this example, only 

limited acute data are available for the chemical, 

including an RD50 study and one LC50. However, 

some information on the effects of acute exposure 

can be extracted from clinical signs reported for a 

subchronic exposure study in which exposure was 

for 6 hours/day, 5 days/week, for 13 weeks. Clinical 

signs reported at 4.9 ppm were limited to eyes halfclosed during exposure, an indication of eye irritation, but at a level that is not escape-impairing. 

However, at the next higher exposure level (15.3 

ppm), the authors reported burning of the nose 

and eyes, as well as olfactory lesions. Although 

the lesions may have been related to the repeated 

exposure, it is reasonable to assume that the clinical signs of burning eyes and nose were observed 

during the first exposure, and that these effects 

would be escape-impairing. After consideration 

of time adjustments (see Section 3.5) and application of the appropriate UF (see Chapter 4.0), the 

LOAEL from the repeated-exposure study was 

used as the basis for the IDLH value, supported 

by the RD50. A slightly higher IDLH value would 

have been calculated from the LC50, but that value 

was not used, since it involves more extrapolation 

due to the severity of the response (lethality). Direct observations from the initial exposure during 

the repeated-exposure study were considered more 

reliable than using the RD50 value directly, based on 

the uncertainties in interpreting the RD50 assay.

3.4.2.3 Relevance of the 

Exposure Measurements

Animal inhalation studies are typically conducted 

using either whole-body or nose-only exposure. 

Both methods have strengths and limitations. 
28 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Whole-body exposure more closely simulates the 

situation for occupational exposure and includes 

the potential for exposure both via inhalation and 

via dermal exposure to the chemical in the air. 

However, in rodent studies, whole-body exposure 

may also involve ingestion exposure that is not relevant to humans, due to grooming of fur on which 

the chemical has deposited. Nose-only exposure 

avoids the potential for ingestion exposure, but also 

eliminates the potential for human-relevant dermal 

exposure, and may place the animals under additional stress, because of their being restrained during exposure. There is no default preference for one 

exposure scenario over the other. Instead, the studies and results should be examined to determine 

whether the limitations of either method preclude 

the use of certain studies. For example, the observation of overt gastrointestinal (GI) effects from 

whole-body exposure suggests the potential for 

confounding by ingestion. In general, both noseonly and whole-body exposures are considered together in the overall weight-of-evidence evaluation.

Well-conducted inhalation studies generally report 

both nominal concentrations (the concentration expected on the basis of the amount of chemical introduced into the exposure system) and the analytical 

concentration (the amount actually measured). The 

two values should be similar; if they are markedly 

different, the reasons and implications for the difference should be determined. Large differences may 

reflect difficulty in maintaining the exposure atmosphere (e.g., the chemical may be adhering to the 

exposure chamber walls) or other issues, and may 

indicate uncertain study quality. Larger differences 

between nominal and analytical concentrations 

may be seen with static exposure studies (where the 

chemical is introduced into the chamber at the beginning of the experiment), as opposed to dynamic 

studies (where the chemical is continuously circulated and the chemical concentration is actively 

maintained at the target level). Because the analytical concentration reflects the actual concentration 

to which the animals were exposed, the analytical 

concentration is usually used in IDLH value calculations. However, in some cases, the nominal 

concentration may more appropriately reflect the 

exposure conditions. For example, substances, 

such as trichloromethylsilane (CAS# 75-79-6), sulfur trioxide (CAS# 7446-11-9), uranium hexafluoride (CAS# 7783-81-5), and acetone cyanohydrin 

(CAS# 75-86-5), react with the moisture in air to 

produce a variety of hydrolysis products. Table 

3–7 provides examples of hydrolysis products associated with the previously listed substances. Because the observed toxicity is due to both the parent chemical and the hydrolysis products, nominal 

concentration is a better indicator of toxicity, since 

it reflects the total burden of toxic constituents, 

whereas analytical concentration would reflect 

only the concentration of the parent compound 

[NAS 2009]. In such cases, the decision of whether 

to use nominal or analytical concentrations depends on the approach that would be used for air 

monitoring and whether it would capture only the 

parent compound or the parent compound and its 

hydrolysis products. 

Care should also be used in considering the

exposure units. For example, it is appropriate to use 

ppm only for gases and vapors because ppm in air 

refers to molecules of the chemical in air (rather 

than being on a weight basis). The units of mg/m3

can be used for particulates and aerosols, as well as 

gases and vapors. Although exposures to gases and 

vapors are usually reported in ppm, care is needed 

to ensure that units are not confused. Units of ppm 

can be converted to mg/m3

 using the ideal gas law. 

At 1 atmosphere of pressure and room temperature 

(25 ̊ C), the conversion is as follows:

mg/m3 = ppm × molecular weight/24.45

Difficulties in the determination of exposure concentrations may arise because, at high concentrations, 

some vapors may condense into liquid droplets, 

resulting in exposures to a mixture of vapor and 

aerosol. Under such conditions, it is generally reasonable to assume that toxicity is due to the total 

mass of the chemical. However, it should be recognized that vapors and aerosols (e.g., solid particles 

and liquid droplets) are deposited differently in 

the respiratory tract on the basis of many factors, including the physiochemical properties of 

the chemical [USEPA 1994]. For this reason, the 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 29

Table 3–6. Use of scientific judgment

Species

Endpoint/effect level 

(ppm)

Duration 

(minutes)

Adjusted to 

30 minutes 

(ppm) UF

Derived IDLH value 

(ppm) Comments

Mouse RD50/10.4 30 10.4 3 3.5 —

Rat LC50/125 240 250 30 8.3 —

Rat NOAEL/4.9 360 11.2

3

3.7

6 hours/day, 5 days/

week, 13 weeks; eyes 

half-closed during 

exposure

Rat LOAEL/15.3 360 35.0

10

3.5

6 hours/day, 5 days/

week, 13 weeks; 

olfactory lesions, 

burning nose and eyes

Abbreviations: IDLH = immediately dangerous to life or health; LC50 value = median lethal concentration; LOAEL = lowest 

observed adverse effect level; NOAEL = no observed adverse effect level; ppm = parts per million; RD50 value = median 

respiratory depression value; UF = uncertainty factor.

Table 3–7. Examples of hydrolysis products associated with selected chemicals

Chemical names CAS# Hydrolysis products Health effects of hydrolysis products

Trichloromethylsilane 75-79-6 Hydrochloric acid 

(CAS# 7647-01-0) 

Respiratory tract and eye irritation

Sulfur trioxide 7446-11-9 Sulfuric acid 

(CAS# 7664-93-9)

Respiratory tract and eye irritation 

Acetone cyanohydrin 75-86-5 Hydrogen cyanide 

(CAS# 74-90-8); 

Acetone (CAS# 67-64-1) 

Respiratory tract and eye irritation 

Uranium hexafluoride 7783-81-5 Uranyl fluoride 

(CAS# 13536-84-010); 

Hydrogen fluoride 

(CAS# 7664-39-3)

Respiratory tract and eye irritation 

Abbreviation: CAS # = chemical abstract service number
30 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

toxicity related to vapor exposure and aerosol exposure to the same concentration (e.g., mg/m3

) of a 

substance may be somewhat different if respiratory 

tract effects are of concern. 

IDLH values derived for aerosols will reflect the 

relevant size fraction. Specific recommendations 

relating to size fractions for aerosols are included 

in the chemical-specific IDLH support documentation when sufficient data are available. The most 

appropriate size fraction is driven by the nature of 

acute toxicity observed. If such data are not available, the chemical-specific IDLH support documentation for the aerosol will note that the size 

fraction that represents the greatest hazard could 

not be determined. In such cases, total inhalable 

particulate is used as the basis for the IDLH value. 

3.4.2.4 Other Issues of Study 

Relevance—Use of Surrogates 

and Route Extrapolation

When neither human nor animal acute inhalation 

data are sufficient to derive an IDLH value for a 

chemical of interest, other approaches are considered, depending on the understanding of the MOA 

and availability of data. Available information on 

surrogates, or related compounds, primary metabolites, or key breakdown products (e.g., secondary 

chemical products formed from hydrolysis due to 

moisture in the air) that are closely related to the 

chemical of interest can be used when inadequate 

information is available for the chemical of interest. As an example of the use of a related compound 

during the derivation of an IDLH value, bromine 

pentafluoride (CAS# 7789-30-2) and chlorine 

pentafluoride (CAS# 13637-63-3) differ only in 

the primary halogen atom. Because of their similarities, bromine pentafluoride can be used as a surrogate for chlorine pentafluoride, and the limited 

toxicity data available for bromine pentafluoride 

indicate that its toxicity is comparable to or slightly 

less than that of the chlorine compound. Another 

example is the assessment of the acute inhalation 

hazard of an entire chemical class on the basis of the 

data for a single compound; the NAS/NRC drafted 

AEGL values for multiple chlorosilanes and metal 

phosphides with use of this approach [NAS 2007, 

2009]. This approach takes advantage of knowledge 

about the MOA and the actual form of the toxicity of related chemicals to use the entirety of the 

data for the class of chemicals to develop exposure 

values. For example, for the chlorosilanes the primary cause of the acute effect of interest (irritation) 

is hydrolysis in moist air to form hydrochloric acid. 

Thus, for the series of related chlorosilanes, the 

IDLH value can be derived from actual testing data 

for the most data-rich member of the family and 

by adjusting the IDLH value for other members according to the respective amounts of chlorine atoms produced during hydrolysis. A refinement of 

the use of surrogate chemicals or information on 

classes of related chemicals is to use data on the 

relative potency, when adequate data are available 

to quantitatively compare the chemical of interest 

with the surrogate but data for the chemical itself 

are not sufficient to develop an IDLH value. In such 

cases, the toxicity threshold is much better understood for the surrogate than for the chemical of interest, but the threshold for the chemical of interest 

can be adjusted on the basis of relative potency. 

When a surrogate or relative-potency approach 

is used, it is necessary to consider the uncertainties associated with using a limited database for 

the chemical of interest versus the uncertainties 

associated with extrapolation from a surrogate 

chemical. An example of extrapolation from a 

breakdown product is the chemical reaction that 

causes acetone cyanohydrin to form HCN and acetone. The acute toxicity of acetone cyanohydrin is 

driven by exposure to an equimolar (i.e., having an 

equal number of moles) equivalent to HCN. Thus, 

the acute toxicity data for HCN can serve as a surrogate and basis of an IDLH value for acetone cyanohydrin [NAS 2002, 2005]. Use of such surrogates 

is not necessary when adequate information on the 

primary chemical is available. In addition, if a surrogate is being considered as the basis for the IDLH 

value, it is important to consider whether other 

aspects of toxicity are associated with the parent 

chemical and whether these aspects are adequately 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 31

addressed by the surrogate. For example, acetone 

cyanohydrin causes irritant effects that are not seen 

with exposure to HCN, but the most potent escapeimpairing effects are secondary to cyanide action as 

a metabolic toxicant. This results in HCN being the 

most valid surrogate for acetone cyanohydrin.

If no adequate inhalation data are available for the 

chemical of interest or for a potential surrogate, an 

IDLH value may be derived by extrapolation from 

studies that used exposure routes other than inhalation, such as oral or intraperitoneal (i.p.) dosing 

studies. As noted above, this route-to-route extrapolation is appropriate only if the effect of interest is systemic (i.e., involves absorption into the 

systemic blood circulation for distribution to an 

internal target tissue). Route extrapolation (e.g., 

from oral or i.p. dosing studies) is not appropriate 

if the chemical’s primary relevant effects for IDLH 

development are as an irritant, or if it is expected 

to target the route of entry (i.e., respiratory tract) 

as the most sensitive end point. The ideal approach 

is to use a physiologically based pharmacokinetic 

(PBPK) model to conduct the route-to-route extrapolation, but it is rare that such data would exist 

(particularly for a chemical for which the inhalation data are insufficient to directly derive an IDLH 

value). In the absence of such a PBPK model, the 

approach is to estimate the concentration to which 

a 70-kg worker could be exposed in order to receive 

the equivalent systemic dose to that delivered in the 

oral or i.p. study. The 30-minute concentration is 

estimated by multiplying the animal dose data by 

the worker body weight (to reach a systemic dose), 

and dividing by the volume of air inhaled per work 

day, as shown in this equation:

Systemic dose equivalent [mg/10 m3] = 

oral or i.p. dose [mg/kg] × 70 kg 

 1.5 m3

This conversion is a health-protective estimate of 

the air concentration that would result in the systemic dose, since a worker breathing at a rate of 

50 liters per minute (L/min) for 30 minutes would 

inhale 1.5 m3

 of air. The basis for this decision is 

discussed in greater detail in Appendix E. 

A second consideration in applying route-to-route 

extrapolation is the impact of first-pass metabolism. First-pass metabolism, also known as presystemic metabolism, refers to the metabolism of a 

chemical delivered from the GI tract directly to the 

liver via hepatic blood flow, before distribution to 

the general systemic circulation. First-pass metabolism by the liver generally decreases systemic exposure to the parent chemical following oral exposure 

when compared with inhalation exposure. More 

precisely, first-pass metabolism via the respiratory 

tract tends to be of smaller magnitude than for the 

liver resulting in increased systemic exposure to the 

parent chemical and decreased exposure to alternative organ systems to metabolites formed in the 

lungs. Quantitatively addressing the implications of 

first-pass metabolism is often difficult, and use of 

a surrogate for which inhalation data are available 

is considered to provide greater weight of evidence 

for chemicals where first-pass metabolism plays an 

important role. Comparing IDLH values derived 

from different approaches (e.g., using a surrogate 

versus using route-to-route extrapolation) can 

provide information on possible uncertainties involved and may help to set the range of reasonable 

IDLH values. Finally, since this approach is based 

on systemic dose, it assumes equal absorption via 

both routes (unless a separate correction is made) 

and ignores issues related to the physical characteristics of the chemical (e.g., gas/vapors versus 

particulate) and implications of particle size and 

dosimetry (i.e., determination of respiratory tract 

region deposition fractions). Where quantitative 

adjustments for differing routes of exposure are 

uncertain, this issue is further considered in the 

selection of additional UFs. Additional considerations for conducting route-to-route extrapolations 

are described in several guidance documents (e.g., 

[USEPA 1994; NAS 2001]).

3.5 Time Scaling

A critical consideration in developing IDLH values is accounting for exposure duration and the 

extrapolation from the experimental exposure duration to the duration of interest (i.e., 30 minutes). 
32 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

The methods used for these extrapolations in the 

development of IDLH values are similar in many 

ways to the Standing Operating Procedures (SOPs) 

outlined by the NAS for the development of AEGLs 

[NAS 2001]. Issues to be considered include evaluation of the chemical’s MOA and how that is reflected 

in key drivers of toxicity (concentration vs. time); 

modifications to Haber’s rule; and methods for calculating n in the ten Berge modification to Haber’s 

rule. These issues are discussed briefly in the following paragraphs and in more detail in NAS [2001]. 

The toxicity of airborne chemicals depends on both 

exposure concentration and exposure duration, as 

well as physiochemical properties that affect respiratory deposition and systemic absorption. Ideally, 

information from validated PBPK or biologically 

based dose–response (BBDR) models is used for 

time extrapolation, but such information is rarely 

available. In the absence of such models, simpler 

concentration–time relationships are used. Historically, particularly for extended exposure durations, 

toxicity was described as the simple product of concentration (Conc) and time, so that Conc × time = k, 

a constant. In other words, if Conc1

 × time1 = Conc2

× time2

, then the toxicity would be the same. This 

relationship is described as Haber’s law, or Haber’s 

rule [Haber 1924]. 

The key assumption embedded in the relationship 

of Haber’s rule is that damage (or depletion of protective tissue response) is irreversible and, therefore, that toxicity is cumulative, related to the total 

dose of the chemical [NAS 2001]. This assumption 

is generally not true for single acute exposures 

[NAS 2001]. For example, toxicity due to asphyxiants (e.g., argon or nitrogen) is related to the peak 

concentration of the chemical, rather than the cumulative dose. Sensory irritation and transient acute 

CNS effects may also be influenced more by the exposure concentration than the exposure duration.

Further investigation into the relationship between 

concentration, duration, and toxicity was conducted by ten Berge et al. [1986], who proposed 

the following relationship between Conc and duration (time, t): Concn

 × t = k. These investigators 

examined the data on 20 irritant and systemically 

acting gases and vapors; the results of this investigation indicated that n was ≤3 for lethality data 

from 18 of the 20 chemicals. This study is one of the 

primary published sources for values of n. Furthermore, based on the finding in this study that an n

of 3 covers 90% of the chemicals in the dataset, the 

default value of an n for extrapolating from longer 

durations to shorter durations was chosen to be 3, 

as a health-protective approach.

The following approach is used in extrapolating 

across durations within the IDLH methodology:

1. No extrapolation is needed if the study of interest involved exposure for 30 minutes; the empirical data are used directly.

2. If information on the value of n is available from 

the original paper of ten Berge et al. [1986] or 

from authoritative reviews (e.g., AEGL documents), then that value is used. Note, however, 

there are caveats to the use of the ten Berge data, 

and other considerations in the choice of n. In 

general, a published value of n will be used directly only for studies reporting the same effect 

or effects related to the same underlying toxic 

mode of action. Use of the published values of n 

for application to studies conducted in different 

species or for different effects is done on a caseby-case basis, with rationale provided. 

3. If no value of n is available in the literature, n 

can be mathematically derived directly from the 

key studies of interest and applied with the same 

caveats as noted in item 2.

4. If the data are not available to support the derivation of n, then a default of 1 is used if the 

duration of the study of interest is less than 30 

minutes, in which case the ten Berge equation 

defaults to Haber’s rule. Conversely, if the duration of the study of interest is more than 30 

minutes, then the default of 3 is used for n. This 

approach generally yields health-protective estimates for the 30-minute equivalent POD, as 

shown in Appendix E–2.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 33

5. In limited cases, the overall dose–response data 

and the mode of action information may suggest 

that the observed acute effects are independent 

(or nearly independent) of exposure duration, 

and that exposure concentration can be used 

with no further duration adjustment. If the POD 

is used from studies of durations other than 30 

minutes without adjusting to a 30-minute equivalent value via the ten Berge correction, the rationale for this decision will be described in the 

documentation of the IDLH value. 

Additional information and illustration on the application of time scaling within the IDLH methodology are included in Appendix E–2.

3.6 Inclusion of Safety 

Considerations 

Safety hazards are considered during the derivation 

of IDLH values to ensure the protection of worker 

safety and health. One particular consideration in 

the derivation of IDLH values is the potential for 

explosive concentrations of a flammable gas or vapor to be achieved at toxicologically relevant air 

concentrations. Maintaining safety considerations 

in the process for this methodology update is consistent with the prior method used to develop IDLH 

values. For gases and vapors, NIOSH has adopted 

a threshold of 10% of the LEL as a default basis for 

the IDLH values based on explosivity concerns. 

This threshold aligns with the airborne concentrations of a flammable gas, vapor or mist identified 

by OSHA as a hazardous explosive condition [29 

CFR 1910.146(b)]. In such events, when the air 

concentration that corresponds with 10% of the 

LEL is less than the health-based value using the 

approach outlined in Chapter 3, this air concentration will become the default IDLH value. The following hazard statement will be included in the 

support documentation: “The health-based IDLH 

value is greater than 10% of the LEL (>10% LEL) 

of the chemical of interest in the air. Safety considerations related to the potential hazard of explosion must be taken into account.” In addition, the 

notation (>10% LEL) will appear beside the IDLH 

value within the NIOSH Pocket Guide to Chemical 

Hazards [NIOSH 2005] and other NIOSH publications. 

For dust, the equivalent default approach would be 

using 10% of the minimum explosive concentration (MEC). However, determining the combustibility of dusts is too complex to assign a single default measure. Dust combustibility and explosivity 

are dictated by the relationships among substance 

and scenario-specific factors including (1) particle 

size distribution, (2) minimum ignition energy, (3) 

moisture content, (4) explosion intensity and (5) 

dispersal in air [Cashdollar 2000]. The ability to 

quantify combustible dust specific concentrations 

for application of an IDLH is often not possible 

given the absence of critical chemical-specific data, 

such as the MEC or the other previously identified 

factors. NIOSH will critically assess the explosive 

nature of a dust when sufficient technical data are 

available. If determined to be appropriate, the findings of this assessment will be incorporated in the 

derivation process to ensure that the IDLH value 

protects against both health and safety hazards. 

When a dust has been identified as combustible, 

NIOSH will include the following hazard statement: “Dust may represent an explosive hazard. 

Safety considerations related to hazard of explosion must be taken into account.” In addition, the 

notation (Combustible Dust) will appear beside the 

IDLH value in the NIOSH Pocket Guide to Chemical Hazards [NIOSH 2005] and in other NIOSH 

publications. Supplemental information on the 

combustibility of dust can be located on the OSHA 

Combustible Dust webpage (http://www.osha.gov/

dsg/combustibledust/). 
This page intentionally left blank.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 35

4 Use of Uncertainty Factors 

4.1 Application of 

Uncertainty Factors

As noted in prior sections of this CIB, the first step 

in the development of an IDLH value is to determine POD estimates adjusted to a 30-minuteequivalent exposure. However, in many cases the 

available POD values need to be further adjusted to 

develop an IDLH value that protects workers from 

potential lethal, severe or irreversible, or escapeimpairing health effects. Thus the IDLH value can 

be represented as:

IDLH Value =

 POD (e.g., 30-min-equivalent LC50

 value, LCLOvalue, LOAEL, or NOAEL) 

Total UF

The application of UFs is needed to account for 

uncertainties related to extrapolation from the 

concentration that caused effects in the selected 

toxicity study to those that would be expected to 

be below the threshold for such effects in workers 

exposed for up to 30 minutes. For example, if the 

most appropriate POD was an LC50 value in rats 

from a 30-minute exposure study, then use of this 

value directly as the IDLH value would clearly not 

be acceptable since a sub-threshold concentration 

for humans is needed. Dividing the selected POD, 

such as the LC50 value in this example, by an additional UF would then reduce the IDLH value to a 

lower concentration well below the LC50 value. 

In general, the UFs need to address all key areas of 

uncertainty that result from extrapolating from the 

available studies. Most organizations that develop 

exposure values/limits consider the following key 

areas of uncertainty:

• Interspecies variability in sensitivity: This 

area addresses differences in sensitivity between 

the test species (e.g., mouse, rat, etc.) and the average human for the population of interest (i.e., 

in the context of IDLH application, workers). 

• Human variability in sensitivity: This area 

addresses differences in sensitivity between 

the average human from the population of 

interest to the sensitive component of the 

population of interest. 

• Severity of effect: Because the IDLH value 

is intended to be below a concentration that 

will cause death or severe, irreversible, or 

escape-impairing effects, the UF needs to 

account for extrapolation from a POD that 

caused such responses in the selected toxicology study to a concentration below the 

threshold for these effects. 

• Duration of exposure: Some organizations 

that develop exposure values/limits include 

consideration of the duration of the study 

that served as the POD in the UF determination and its relevance to the duration of interest. In the context of IDLH development, 

this area of uncertainty is addressed through 

duration adjustments of the POD rather than 

the explicit application of a UF. 

• Other database deficiencies: When datasets available to develop IDLH values are 

very limited, it is necessary to account for the 

possibility that the available studies did not 

identify the most sensitive endpoint relevant 

to IDLH development. In such cases it is appropriate to increase the UF to account for 

this uncertainty. 

An approach used by many organizations, such as 

by USEPA for developing reference concentrations 

[USEPA 1994] and for the AEGL process [NAS 

2001], involves consideration of these separate 
36 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

areas of uncertainty and the multiplication of UFs for 

each of these areas to derive the final cumulative UF. 

The IDLH methodology is a modification of this 

approach that blends the rigor of full consideration 

of the relevant areas of uncertainty embedded in 

the USEPA and AEGL approaches with the flexibility to fully use the limited data from multiple 

lines of evidence often encountered in IDLH development. Overall, the assignment of UFs for IDLH 

derivation includes two steps: 

1. Selection of an appropriate preliminary UF range

2. Modification of this preliminary range to select 

a final value. 

The preliminary UF ranges are based on consideration of the study design and the adverse health effect 

occurring at the POD. Use of a preliminary range of 

values helps to ensure consistency in application of 

UFs within the IDLH development effort for diverse 

chemicals. However, modification of the UF is often 

required on the basis of unique issues arising from 

the review of the database for each unique chemical. 

Thus, the IDLH methodology captures the need to 

use a consistent approach for UF application while 

maximizing the ability to make informed decisions 

based on weight-of-evidence considerations.

4.2 The NIOSH IDLH

Value Uncertainty

Factor Approach

As discussed regarding the overall UF approach, 

the analysis focuses on the weight-of-evidence approach using all the relevant data. Thus, a range of 

preliminary UFs is shown for each of the typical 

types of effect levels that are available as a POD. 

However, the final UF applied is determined from 

the weight-of-evidence evaluation for each chemical that allows for modifying the preliminary UF on 

the basis of additional considerations unique to the 

dataset. The preliminary UF ranges are shown in 

Table 4–1. The most common UFs for a given data 

type are shown, but the range indicates how this 

value is commonly adjusted up or down according 

to the entirety of the database, as described further 

in this section. The preliminary UFs are applied as 

multiples of 1 or 10, with use of an intermediate 

value of 3. The value of 3 represents one half of the 

log10 unit (3.16 rounded to 3) as the minimum increments that are used for the UF adjustments to 

reflect the level of precision for such an approach. 

Although the value of 3 is used in place of 3.16 

during the discussion of UFs, caution should be 

applied when multiplying UFs of 3 together. For 

Table 4–1. Typical UF ranges

Point of departure Typical UF range*

LC50 (in an animal study) 10 to 100

LC01, LCLo, or BMCL10 for lethality in animals 3 to 30

LCLo in humans 1 to 10

LOAEL for an escape-impairing or irreversible effect in animals 3 to 30

NOAEL for an escape-impairing or irreversible effect in animals, or animal RD50 1 to 10

LOAEL for an escape-impairing or irreversible effect in humans 1 to 10

NOAEL for an escape-impairing or irreversible effect in humans 1 to 3

Abbreviations: BMCL10 = lower confidence limit on the concentration associated with a 10% response; IDLH = immediately 

dangerous to life or health; LC01 = the statistically derived air concentration that caused lethality in 1% of test animals; LC50

= median lethal concentration; LCLO = lowest concentration of a substance in the air reported to cause death; LOAEL = lowest 

observed adverse effect level; NOAEL = no observed adverse effect level; UF = uncertainty factor.

*Typical UF Range is based on the information presented in Appendix D.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 37

example, when multiplying two UFs of 3 together 

(e.g., 3 × 3), the product will be 10, not 9. This is 

also illustrated by the multiplication of three UFs of 

3, that is, 3 × 3 × 3 will equal 30, not 27. 

Selection of values other than the preliminary UF 

for deriving an IDLH value is common, reflecting 

the use of a weight-of-evidence approach and the 

sometimes-conflicting data from multiple lines of 

evidence. Common situations that lead to movement away from the preliminary UF value relate to 

evaluation of data for the areas of uncertainty and 

extrapolation noted in the prior section. 

• Interspecies variability in sensitivity: If 

chemical-specific data are available to help 

determine the magnitude of the differences in 

species sensitivity, then such data are used to 

refine the size of the final UF. For example, if 

information about specific sensitivity due to 

differences in species metabolism is available, 

the UF applied to the POD from an animal 

study is adjusted accordingly (either up or 

down, depending on the data). If health effects data that serve as the POD are from human studies, then the UF would not need to 

address this area of uncertainty.

• Human variability in sensitivity: If chemical-specific data are available to help determine the magnitude of the variability in human sensitivity, then such data are used to 

refine the size of the final UF. If health effects 

data that serve as the POD are from a sensitive human group (e.g., non-smoking, young 

adult females for a clinical study of nasal irritation [Shusterman et al. 2003]), then the UF 

would be smaller in addressing this area of 

uncertainty. Because IDLH values are used in 

occupational applications, the range of variability that needs to be covered in applying 

the UF is expected to be less than for development of exposure values/limits meant to protect sensitive members of the general public. 

Conversely, if additional data do not include 

sensitive populations (e.g., asthmatics who 

may be exposed to respiratory irritants), then 

a larger UF may be selected. 

• Severity of effect: The size of the adjustment 

needed would reflect the severity of effect observed at the POD. This is reflected in the preliminary UF ranges shown in Table 4–1. For 

example, as shown in the table, to derive an 

IDLH value that protects from severe effects, 

a larger margin would be needed between an 

LC50 value and the IDLH value than would be 

needed in between a BMCL05 for an escapeimpairing effect and the IDLH value. The 

range of preliminary values incorporates this 

consideration of effect severity.

The consideration of the severity of effect also 

addresses the slope of the concentration–

response curve. Steep concentration–response 

curves and high-quality data may result 

in UFs at the lower end of the range. Steep 

concentration–response curves represent 

estimates of responses that decrease rapidly 

with decreasing exposure concentrations, so 

that a smaller UF may be warranted to reach 

the response level in the concentration–

response curve, compared with a more shallow concentration–response curve. Thus, if 

the concentration–response curve is very 

steep, a factor of 10 (rather than the preliminary UF of 30) may be applied to an LC50

value, based on consideration of the overall 

database. This is because there is less than a 

factor of 3 between the LC50 and the (actual 

or estimated) LC01 value.

• Duration of exposure: For most acute limits, including IDLH values, acute studies are 

typically used directly as the basis for the 

POD. Thus, the available studies are generally representative of the overall duration of 

interest (exposure for a single day or less). 

Further refinements to account for uncertainties in duration extrapolation, such as 

between a 4-hour study and the 30-minute 

duration of interest for IDLH development, 

are addressed in the time-scaling adjustment 

to the POD (see Section 3.5), rather than as 

a consideration for the UF value. However, 

significant uncertainties may need additional 

consideration if the available study is limited 
38 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

in design or outside the immediate duration 

range of interest. For example, if only repeatexposure studies were available for a chemical to serve as the POD, and the observed effects were not clearly due only to initial acute 

exposures, then the use of such a POD might 

justify a smaller UF.

• Other database deficiencies: A UF at the 

higher end of the typical range (e.g., a UF of 

10 instead of 3) is often used if major uncertainties or additional significant concerns are 

identified. If a database is very deficient, then 

the UF might be increased. This approach is 

often used if the only reliable data are lethality 

data from a single acute study. Other considerations for database deficiency relate to the 

potential for effects that were not evaluated in 

the available studies. For example, the higher 

end of the range may be used if the data indicate that the chemical is a sensory irritant and 

the data are insufficient to derive an IDLH 

value (e.g., due to inappropriate exposure durations) but indicate a large margin between 

concentrations causing severe irritation and 

those causing death. Other data gaps that may 

affect the size of the final UF reflect specific 

endpoints of concern. For example, a UF from 

the higher end of the range may be used if a 

chemical is a known or likely carcinogen or 

a developmental toxicant, with evidence that 

acute exposures may be of concern. 

The examples in Appendix A highlight how these 

weight-of-evidence considerations are applied to 

select UFs and derive potential IDLH values. 

4.3 Research Support for 

the NIOSH Uncertainty 

Factor Approach

The UF approach used for deriving IDLH values 

is based on a review of NIOSH research efforts, 

approaches used by other organizations that establish acute exposure limits/values, and other 

independent research. 

The NIOSH approach is similar to that of other 

agencies in terms of the areas of uncertainty accounted for in determining the appropriate value of 

the final UF. Although the NIOSH approach does 

not assign an individual factor for each area of uncertainty, there is generally good agreement between 

the NIOSH UF and the UF embedded in derivation of AIHA ERPG values and the cumulative UF 

used for derivation of the AEGL values. As expected, 

there is not complete alignment between these values, because of differences in application of IDLH 

values versus other types of acute exposure limits. 

In particular, the UF applied to the IDLH value is 

often smaller than for deriving the ERPG or AEGL 

values, which results in a larger final exposure limit 

for IDLH values compared to these other guidelines. 

For example, differences often arise because of the 

explicit inclusion of potentially sensitive members 

of the general population (e.g., children, elderly, and 

individuals with health impairments) during the establishment of community-based acute exposure 

limits, such as the ERPG and AEGL. The IDLH 

values do not take into consideration the potentially sensitive members of the general population 

because it is assumed that they will not be substantially represented in the workforce for the purposes of considering average population responses. 

However, in some cases such populations may be 

considered when a chemical has specific effects on 

a target population that is well-represented in the 

expected worker population. An example would be 

an agent that has significant impacts on asthmatics. 

In such cases, health effects data from asthmatics 

that have been exposed to the agent would be appropriate for defining the POD as the basis for deriving an IDLH value.

To further verify that the preliminary ranges of the 

UF are supported by existing data, NIOSH conducted an analysis of acute toxicity data to determine the appropriate size of the UF for extrapolating from various points of departure to derive IDLH 

values that would be expected to protect from lethal, severe, irreversible, or escape-impairing effects 

in humans. Two approaches were used: one based 

on a detailed evaluation of acute toxicity data for 

20 chemicals, and the second based on data for 94 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 39

chemicals taken from the documentation for IDLH 

values and consideration of MOA. 

From these data compilations for chemicals with 

robust datasets, the ratios between animal lethality 

values commonly used as the POD for developing 

the IDLH value (e.g., LC50 values) and the effect level 

for lethality or other non-lethal effects in humans 

were determined for each chemical. The distribution of these ratios was analyzed, and the median 

value and 95th percentile value for each comparison 

were derived (see Appendix D). The resulting median values and upper-bound estimates for these 

case study chemicals were used to verify that the 

range of total UFs adopted in the IDLH methodology adequately accounts for the value that should 

be applied to an animal-based endpoint to protect 

from severe or escape-impairing effects in humans. 

The analysis found that animal lethal concentrations and human effect thresholds (both LCLO values and LOAELs for severe or escape-impairing 

effects) were generally correlated, such that chemicals with low animal LC50 values tended to have 

low human lethality thresholds and cause severe 

or escape-impairing effects in humans at low concentrations. This finding was important to support 

the approach of developing preliminary UF ranges 

that could be used to address protection from nonlethal effects when extrapolating from data from 

acute animal studies. Additional analyses were 

conducted by MOA category (e.g., irritant, CNS 

depressant, or “other”) to determine if different UF 

ranges could be applied on the basis of a chemical’s 

MOA. However, statistically significant differences 

were not found among the MOA categories. Thus, 

this further refinement to the approach for developing a preliminary UF to address effect severity by 

MOA category has not been applied for IDLH derivation. Overall, comparison of the median values 

to the UF ranges in Table 4–1 showed that the most 

common value is typically above or in the range 

of the median value for the comparison dataset. 

This result is also consistent with other evaluations 

that analyzed effect-level ratios from acute toxicity 

studies (e.g., Rusch et al. 2009). Additional results, 

as well as the results of the second approach, are 

presented in Appendix D.
This page intentionally left blank.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 41

References 

ACGIH [2009]. Threshold limit values (TLVs®) 

and biological exposure indices (BEIs®). Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists.

AIHA [2006]. AIHA Emergency Response Planning 

(ERP) Committee procedures and responsibilities. 

Fairfax, VA: American Industrial Hygiene Association, http://www.aiha.org/get-involved/AIHAGuidelineFoundation/EmergencyResponsePlanningGuidelines/Documents/ERP-SOPs2006.pdf.

AIHA [2008]. Emergency response planning guidelines (ERPG) and workplace environmental exposure levels (WEEL) handbook. Fairfax, VA: American Industrial Hygiene Association Press. 

Alarie Y [1981]. Dose-response analysis in animal 

studies: prediction of human responses. Environ 

Health Perspect 42:9–13.

ASTM [1984]. E981-84: standard test method for 

estimating sensory irritancy of airborne chemicals. 

Vol. 11.04. Philadelphia, PA: American Society for 

Testing and Materials.

Bos PM, Zwart G, Reuzel PG, Bragt P [1992]. 

Evaluation of the sensory irritation test for the 

assessment of occupational health risk. Crit Rev 

Toxicol 21:423–450.

Bos PM, Busschers M, Arts JH [2002]. Evaluation 

of the sensory irritation test (Alarie test) for the 

assessment of respiratory tract irritation. J Occup 

Environ Med 44:968–975.

Brock WJ, Rusch GM, Trochimowicz HJ [2003]. 

Cardiac sensitization: methodology and interpretation in risk assessment. Regul Toxicol Pharmacol 

38(1):78–90.

Cal/EPA [2010]. Toxicity criteria database. Sacramento, CA: California Environmental Protection 

Agency, Office of Environmental Health Hazard 

Assessment, http://oehha.ca.gov/risk/ChemicalDB/index.asp.

Cashdollar KL [2000]. Overview of dust explosibility characteristics. J Loss Prev Process Ind 

13:183–199. 

Chengelis CP [1997]. Epinephrine sensitivity of the 

canine heart: a useful test. In Snyder R, Bakshi KS, 

Wagner BM. Abstracts of the Workshop on Toxicity of Alternatives to Chlorofluorocarbons. Inhal 

Toxicol 9:775–810.

Craig DK, Davis JS, Hansen DJ, Petrocchi AJ, Powell TJ, Euccinardi TE Jr [2000]. Derivation of temporary emergency exposure limits (TEELs). J Appl 

Toxicol 20:11–20.

Davis A, Gift JS, Woodall GM, Narotsky MG, 

Foureman GL [2009]. The role of development toxicity studies in acute exposure assessments: Analysis 

of single-day vs. multiple-day exposure regimens. 

Regul Toxicol Pharmcol 54(2):134–142. 

ECETOC [2009]. Technical report no. 105: evaluation of cardiac sensitization test methods. Brussels, 

Belgium: European Centre for Ecotoxicology and 

Toxicology of Chemicals [ISSN-0773-8072-105]. 

Federal Focus Inc. [1995] Principles for evaluating 

epidemiologic data in regulatory risk assessment. 

Developed by an expert panel at a conference in 

London, England, October 1995. Washington, DC: 

Federal Focus Inc.

Fowles JR, Alexeeff GV, Dodge D [1999]. The use of 

benchmark dose methodology with acute inhalation 

lethality data. Regul Toxicol Pharmacol 29(3):262–278.

Haber F [1924]. Zur Geschichte des Gaskrieges. In: 

Fünf Vorträge aus den Jahren 1920–1923. Berlin: 

Springer-Verlag, pp. 76–92.
42 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Hayes AW, ed [2008]. Principles and methods of 

toxicology. 5th ed. Boca Raton, FL: CRC Press.

Hehir RM, McNamara BP, McLaughlin J, Willigan 

DA, Bierbower G, Hardisty JF [1981]. Cancer induction following single and multiple exposure to a 

constant amount of vinyl chloride monomer. Environ Health Perspect 41:63–72.

IUPAC [2007]. International Union of Pure and 

Applied Chemistry glossary of terms used in toxicology. 2nd ed. Pure Appl Chem 79(7):1153–1344, 

http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html. 

Klimish H-J et al. [1997]. A systematic approach for 

evaluating the quality of experimental toxicological 

and ecotoxicological data. Regul Toxicol Pharmacol 25:1–5.

Lewandowski TA, Rhomberg LR [2005]. A proposed methodology for selecting a trichloroethylene inhalation unit risk value for use in risk assessment. Regul Toxicol Pharmacol 41:39–54.

MDH [2010]. Health risk values (HRVs) for chemicals in ambient air. St. Paul, MN: Minnesota Department of Health, Environmental Health Division, www.health.state.mn.us/divs/eh/risk/rules/

hrvrule.html. 

NAS [1986]. Criteria and methods for preparing 

emergency exposure guidance level (EEGL), shortterm public emergency guidance level (SPEGL), 

and continuous exposure guidance level (CEGL). 

National Academy of Science, Committee on Toxicology, Board of Environmental Studies and Toxicology, National Research Council. Washington, 

DC: National Academy Press, http://www.nap.edu/. 

NAS [1996]. Toxicity of alternatives to chlorocarbons: HFC-134a and HCFC-123. National Academy 

of Science, Committee on Toxicology, Board of Environmental Studies and Toxicology, National Research Council. Washington, DC: National Academy Press, http://www.nap.edu/. 

NAS [2001]. Standing operating procedures for 

developing acute exposure guideline levels for 

hazardous chemicals. National Academy of Science, Committee on Toxicology, Board of Environmental Studies and Toxicology, National Research 

Council. Washington, DC: National Academy Press, 

http://www.nap.edu/. 

NAS [2002]. Final acute exposure guideline levels 

for selected airborne chemicals. Vol. 2. National 

Academy of Science, Committee on Toxicology, 

Board of Environmental Studies and Toxicology, 

National Research Council. Washington, DC: National Academy Press, www.nap.edu/. 

NAS [2005]. Final acute exposure guideline levels 

(AEGLs) for acetone cyanohydrin, CAS# 75-86-5. 

National Academy of Science, Committee on Toxicology, Board of Environmental Studies and Toxicology, National Research Council. Washington, 

DC: National Academy Press, http://www.nap.edu/. 

NAS [2007]. Interim acute exposure guideline levels (AEGLs) for selected metal phosphides. National 

Academy of Science, Committee on Toxicology, 

Board of Environmental Studies and Toxicology, 

National Research Council. Washington, DC: National Academy Press, http://www.nap.edu/. 

NAS [2008]. Emergency and continuous exposure 

guidance levels for selected submarine contaminants. Vol. 2. National Academy of Science, Committee on Emergency and Continuous Exposure 

Guidance Levels for Selected Submarine Contaminants, Committee on Toxicology, National Research 

Council. Washington, DC: National Academy Press, 

http://www.nap.edu/. 

NAS [2009]. Interim acute exposure guideline levels (AEGLs) for 25 selected chlorosilanes. National 

Academy of Science, Committee on Toxicology, 

Board on Environmental Studies and Toxicology, 

National Research Council. Washington, DC: National Academy Press, http://www.nap.edu/. 

NASA [1999]. Spacecraft maximum allowable concentrations for airborne contaminants. JSC 20584. 

Houston, TX: National Aeronautics and Space Administration, Johnson Space Center, http://hefd.jsc.

nasa.gov/toxeg.htm. 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 43

Nielsen GD, Wolkoff P, Alarie Y [2007]. Sensory 

irritation: risk assessment approaches. Regul Pharmacol Toxicol 48(1):6–18.

NIOSH [1987]. NIOSH respirator decision logic. 

Cincinnati, OH: U.S. Department of Health and 

Human Services, Centers for Disease Control, National Institute for Occupational Safety and Health. 

NIOSH Publication No. 87–108 (NTIS Publication 

No. PB-88-149612).

NIOSH [1994]. Documentation for immediately 

dangerous to life or health concentrations (IDLH). 

Cincinnati, OH: U.S. Department of Health and 

Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational 

Safety and Health. NTIS Publication No. PB-94-

195047.

NIOSH [2004]. NIOSH respirator selection logic. 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety 

and Health, NIOSH Publication No. 2005–100. 

NIOSH [2005]. NIOSH pocket guide to chemical hazards. Cincinnati, OH: U.S. Department of 

Health and Human Services, Centers for Disease 

Control and Prevention, National Institute for Occupational Safety and Health. NIOSH Publication 

No. 2005–149. 

NIOSH/OSHA [1981]. Occupational health guidelines for chemical hazards. Cincinnati, OH: U.S. Department of Health and Human Services, Centers 

for Disease Control and Prevention, National Institute for Occupational Safety and Health. NIOSH 

Publication No. 81–123 (NTIS Publication No. PB83-154609).

NJ RTK [2010]. Right to know hazardous substance 

fact sheets. Trenton, NJ: Department of Health and 

Senior Services, New Jersey Right to Know, http://

web.doh.state.nj.us/rtkhsfs/indexfs.aspx. 

OSHA [2003]. Department of Labor: 29 CFR 1910. 

134. In: Code of Federal Regulations. Washington, 

DC: U.S. Government Printing Office, Office of the 

Federal Register.

Reinhardt CF, Azar A, Maxfield ME, Smith PE, 

Mullin LS [1971]. Cardiac arrhythmias and aerosol 

“sniffing.” Arch Environ Health 22:265–279.

Rusch GM, Bst CB, Cavender FL [2009]. Establishing a point of departure for risk assessment using 

acute inhalation toxicity data. Regul Toxicol Pharmacol 54(3):247–255.

Schaper M [1993]. Development of a database for 

sensory irritants and its use in establishing occupational exposure limits. Am Ind Hyg Assoc J 

54(9):488–544.

Shusterman D, Murphy MA, Balmes J [2003]. Differences in nasal irritant sensitivity by age, gender, 

and allergic rhinitis status. Int Arch Occup Environ 

Health 76:577–583.

TCEQ [2010]. Effects screening levels. Austin, TX: 

Texas Commission on Environmental Quality, 

Toxicology Branch, http://www.tceq.state.tx.us/

nav/data/effectsscreeninglevels.html. 

ten Berge WF, Zwart A, Appelman LM [1986]. 

Concentration-time mortality response relationship of irritant and systematically acting vapors 

and gases. J Haz Mat 13:301–309.

US DHS [2007]. Chemical facility anti-terrorism standards: interim final rule. U.S. Department of Homeland Security. Federal Register 72(67):17688–17745.

US DHS [2009]. Provisional advisory levels (PALs) 

for hazardous agents: research highlights. Washington, DC: U.S. Department of Homeland Security, Office of Research and Development, http://

www.epa.gov/nhsrc/news/news121208.html. 

US DOE [2008]. Temporary emergency exposure limits for chemicals: methods and practice. Washington, 

DC: U.S. Department of Energy, Technical Standards 

Program [DOE-HDBK-1046-2008], http://orise.orau.

gov/emi/scapa/files/doe-hdbk-1046-2008_ac.pdf.

US DOT [2008]. Emergency response guidebook 

(ERG). Washington, DC: U.S. Department of 

Transportation, Homeland Security & Emergency 

Management Agency.
44 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

US EPA [1994] Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. Washington, DC: U.S. Environmental Protection Agency.

US EPA [2010]. Integrated risk information system 

(IRIS): glossary. Washington, DC: U.S. Environmental Protection Agency, National Center for Environmental Assessment, http://www.epa.gov/iris/

index.html. 

van Raaij MTM, Janssen PAH, Piersma AH [2003]. 

The relevance of developmental toxicology endpoints 

for acute limit setting. The Netherlands: National 

Institute for Public Health and the Environment 

(RIVM). RIVM report 60190004/2003, http://www.

epa.gov/opptintr/aegl/pubs/meetings/mtg35b.pdf. 

Yant WP [1944]. Protecting workers against temporary and emergency exposures. In: Protecting plant 

manpower through the control of air contaminants. 

Special Bulletin No. 14. Washington, DC: U.S. Department of Labor, Division of Labor Standards.

Young RA, Bast CB, Wood CS, Adeshina F [2009]. 

Overview of the standing operating procedure 

(SOP) for the development of provisional advisory 

levels (PALs). Inhal Toxicol 21(Suppl)(3):1–11.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 45

APPENDIX A: Example of the Derivation

of an IDLH Value

This appendix illustrates the IDLH value derivation on the basis of the scientific criteria outlined in 

this document. This profile contains the proposed 

IDLH value and draft support documentation for 

chlorine (CAS# 7782-50-5). It should be noted 

that the information presented in this appendix is 

intended to serve only as an illustration of the application of the derivation process outlined in this 

CIB. For this reason, the proposed IDLH value for 

chlorine presented in this CIB should not be construed as official NIOSH policy.

A.1 Support Documentation 

for the Revised IDLH 

Value for Chlorine 

Revised IDLH value: 2.8 ppm (8.1 mg/m3)

Basis for revised IDLH value: The IDLH value is 

based on the human LOAEL for severe effects, on 

the basis of respiratory irritation and cough in human volunteers exposed to 2 ppm for 1 hour [Anglen 1981]. The LOAEL was adjusted to a 30-minute 

duration equivalent value of 3 ppm. A UF of 1 was 

applied to account for extrapolation from a threshold for severe effects in humans, yielding an IDLH 

value of 2.8 ppm rounded to 3 ppm.

1994 IDLH value: 10 ppm

Basis for 1994 IDLH value: The 1994 IDLH value 

for chlorine is 10 ppm, based on acute inhalation 

toxicity data in humans [NIOSH 1994]. 

NIOSH REL: 0.5 ppm (1.45 mg/m3

), 15-minute ceiling 

[NIOSH 2005]

Current OSHA PEL: 1 ppm (3 mg/m3

), ceiling 

[OSHA 2010]

1989 OSHA PEL:‡

 0.5 ppm (1.5 mg/m3), TWA; 

1 ppm (3 mg/m3

), STEL [OSHA 1989]

2010 ACGIH TLV: 0.5 ppm, TWA; 1 ppm, STEL 

[ACGIH 2010]

2010 AIHA ERPG: ERPG-1: 1 ppm; ERPG-2: 

3 ppm; ERPG-3: 20 ppm [AIHA 2010]

2010 AIHA WEEL: Not available

Description of substance: A greenish yellow gas 

with a pungent, irritating odor [NAS 2004]

LEL: Not available

NAC AEGL: Summarized in Table A–1. National 

Advisory Committee [2004] Final AEGLs: Chlorine. 

A.2 Animal Toxicity Data

The available acute lethality database consists of 

multiple studies in mice [Lipton and Rotariu 1941; 

Silver et al. 1942; Schlagbauer and Henschler 1967; 

Bitron and Aharonson 1978; Alarie 1980; Jiang et al. 

1983; O’Neil 1991], rats [Weedon et al. 1940; Back 

et al. 1972; MacEwen and Vernot 1972; Vernot et 

al. 1977; Zwart and Woutersen 1988], rabbits [Barrow and Smith 1975], and dogs [Underhill 1920; 

Withers and Lees 1985a]. The lowest LC50 value in 

animals was identified from a study that exposed 

mice to 127 ppm for 30 minutes [Schlagbauer and 

Henschler 1967]. Critical animal lethality data are

‡

1989 PELS are no longer legally enforced by federal 

OSHA, but many of these PELs were adopted by state 

OSHA plans, thus the 1989 PELs may still be in force 

in various states.
46 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Table A–1. Summary of the AEGL values for chlorine

Classification 10 minutes 30 minutes 1 hour 4 hours 8 hours

AEGL-1 0.5 ppm

1.5 mg/m3

0.5 ppm

1.5 mg/m3

0.5 ppm

1.5 mg/m3

0.5 ppm

1.5 mg/m3

0.5 ppm

1.5 mg/m3

AEGL-2 2.8 ppm

8.1 mg/m3

2.8 ppm

8.1 mg/m3

2.0 ppm

5.8 mg/m3 

1.0 ppm

2.9 mg/m3

0.71 ppm

2.0 mg/m3

AEGL-3 50.0 ppm

145.0 mg/m3

28.0 ppm

81.0 mg/m3

20.0 ppm

58.0 mg/m3

10.0 ppm

29.0 mg/m3

7.1 ppm

21.0 mg/m3

Abbreviation: mg/m3 = milligrams per cubic meter; ppm = parts per million

Table A–2. Acute toxicity data and 30-minute-equivalent lethal concentration values for chlorine 

Species Reference

LC50

(ppm)

Time

(minutes)

Adjusted 

30-minute LC* UF†

30-minute

derived value

(ppm)‡

Mouse Schlagbauer and Henschler [1967] 127 30 127 30 4.2

Mouse Zwart and Woutersen [1988] 504 30 504 30 17

Rat Zwart and Woutersen [1988] 703 30 703 30 23

Abbreviation: LC = lethal concentration; LC50 value = median lethal concentration; ppm = parts per million; UF = uncertainty factor.

*No time adjustment was made to LC50 values. †

The selection of the UF for chlorine was based on Chapter 4.0: Use of Uncertainty Factors. The UF of 30 was selected on the basis 

of (1) the extrapolation from a concentration that is lethal to animals, (2) animal to human differences, and (3) human variability.

‡

Derived values are calculated by dividing the Adjusted 30-minute LC by the UF.

Table A–3. Acute toxicity data and 30-minute-equivalent

non-lethal concentration values for chlorine 

Species Reference

LOAEL

(ppm)

Time

(minutes)

Adjusted 

30 minute 

LC* UF†

30-minute

derived value

(ppm)‡

Mouse Jiang et al. [1983] 9.1 360 32 10 3.2

Rat Jiang et al. [1983] 9.1 360 32 10 3.2

Abbreviation: LOAEL = lowest observed adverse effect level; ppm = parts per million; UF = uncertainty factor.

*For exposures other than 30 minutes, the ten Berge et al. [1986] relationship is used for duration adjustment (Cn

 × t = k); no 

empirically estimated n values were available; therefore, the default values were used: n = 3 for exposures greater than 30 

minutes and n = 1 for exposures less than 30 minutes. †

The selection of the UF for chlorine was based on Chapter 4.0: Use of Uncertainty Factors. The UF of 10 was selected on the 

basis of (1) animal to human differences, and (2) human variability.

‡

Derived values are calculated by dividing the Adjusted 30-minute LC by the UF.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 47

summarized in Table A–2, along with time adjustments, UF, and potential derived IDLH values. 

Non-lethal effects in mice, rabbits, and rats consisted 

of ocular and nasal irritation, transient changes in 

lung function, bronchitis, lesions in the nasal passages and lung, and mild edema [Barrow and Smith 

1975; Jiang et al. 1983; Zwart and Woutersen 1988; 

Demnati et al. 1995]. Nasal lesions appear to be the 

most sensitive effect, as they occur at the lowest 

tested concentrations of chlorine in both rats and 

mice [Jiang et al. 1983]. Multiple RD50 studies have 

also been conducted in mice [Barrow et al. 1977; 

Barrow and Steinhagen 1982; Chang and Barrow 

1984; Gagnaire et al. 1994]. Critical animal nonlethality data are summarized in Table A–3 along 

with time adjustments, UFs, and potential derived 

IDLH values. 

A.3 Human Data

Deaths have been reported after inhalation exposures to chlorine, but specific exposure concentrations are not available from reports of accidental 

releases. Withers and Lees [1985b] estimated 

lethal concentrations to humans using a probit 

analysis of available information. They estimated 

a 30-minute LC50 value and LC10 value of 100 and 

50 ppm, respectively, for vulnerable populations. 

Critical human lethality data are summarized in 

Table A–4, along with time adjustments, UFs, and 

potential derived IDLH values.

Experimental exposure to non-lethal concentrations 

of chlorine has caused changes in nasal air resistance 

[D’Alessandro et al. 1996; Shusterman et al. 1998], 

transient changes in pulmonary function [Anglen 

1981; Rotman et al. 1983; D’Alessandro et al. 1996], 

irritation [Joosting and Verberk 1974; Anglen 1981; 

Rotman et al. 1983], and cough [Joosting and Verberk 1974; Anglen 1981]. The lowest concentration 

at which mild discomfort due to irritation or cough 

was reported is at 1 ppm for durations of 4 hours or 

greater [Anglen 1981; Rotman et al. 1983]; however, 

irritation was not significant among volunteers exposed to 2 ppm for 30 minutes [Anglen 1981].

Multiple accidental exposures to non-lethal concentrations of chlorine have been reported, but 

specific exposure conditions and durations are not 

available. Symptoms of dyspnea, cough, and irritation are most commonly reported in the literature 

[Shroff et al. 1988; Abhyankar et al. 1989; Mrvos et 

al. 1993; ILO 1998], but other severe systemic effects (such as headache, vomiting, giddiness, chest 

Table A–4. Acute toxicity data and 30-minute-equivalent 

lethal concentration values for chlorine

Species Reference

LCLO 

(ppm)

Time

(minutes)

Adjusted 

30-minute

LC* UF†

30-Minute derived value

(ppm)‡

Human Withers and Lees [1985b] 50 30 50 3 17

Abbreviation: LC = Lethal concentration; LCLO = lowest lethal concentration of a substance in the air reported to cause death; 

ppm = parts per million; UF = uncertainty factor.

*No time adjustment was made to the LCLO value. †

The selection of the UF for chlorine was based on Chapter 4.0: Use of Uncertainty Factors. The UF of 3 was selected 

on the basis of human variability.

‡

Derived values are calculated by dividing the Adjusted 30-minute LC by the UF.
48 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

pain, and abdominal discomfort) have also been 

reported [Shroff et al. 1988; Abhyankar et al. 1989]. 

Critical human non-lethality data are summarized 

in Table A–5, along with time adjustments, UFs, 

and potential derived IDLH values. 

A.4 IDLH Value 

Rationale Summary

Among the acute lethality studies, the mouse 

provides the lowest LC50 value of 127 ppm for a 

30-minute exposure period [Schlagbauer and Henschler 1967]. A UF of 30 was applied to account for 

extrapolation from a concentration that is lethal to 

animals, animal to human differences, and human 

variability, resulting in a potential IDLH value of 

4.2 ppm. Anglen [1981] reported a LOAEL of 2 

ppm for throat irritation and cough in human volunteers exposed to chlorine for 1 hour. The LOAEL 

was duration-adjusted to a 30-minute-equivalent 

value of 2.8 ppm. A safety factor of 1 was applied 

to account for extrapolation from a threshold for 

irritant effects in humans, resulting in an IDLH 

value of 3 ppm rounded to 3 ppm.. This value is 

supported by the presence of irritant effects in human volunteers exposed to 1 ppm of chlorine for 

4 hours [Anglen 1981; Rotman et al. 1983], which 

would also result in a similar IDLH value.

Appendix A: References

Abhyankar AN, Bhambure N, Kamath NN, Pajankar SP, Nabar ST, Shrenivas A, Shah AC, Deshmukh 

SN [1989]. Six month follow-up of fourteen victims 

with short-term exposure to chlorine gas. J Soc Occup Med 39:131–132.

ACGIH [2010]. TLVs® (threshold limit values) and 

BEIs® (biological exposure indices). Cincinnati, OH: 

American Conference of Governmental Industrial 

Hygienists Signature Publications.

AIHA [2010]. Annual ERPG (emergency response 

planning guidelines) and WEEL (workplace environmental exposure levels) handbook. Fairfax, VA: 

American Industrial Hygiene Association Press.

Table A–5. Acute toxicity data and 30-minute-equivalent 

non-lethal concentration values for chlorine 

Species Reference

NOAEL 

(ppm)

LOAEL 

(ppm)

Time 

(minutes)

Adjusted 

30-minute

LC* UF†

30-minute 

derived value

(ppm)‡

Human Anglen [1981] 2.0 30 2.0 1 2.0

Human Anglen [1981] 2.0 60 2.8 1 2.8

Human Rotman et al. [1983] 1.0 240 2.8 1 2.8

Human ILO [1971] 40.0 30 40 3 13

Abbreviation: LC =lethal concentration; LOAEL = lowest observed adverse effect level; NOAEL = no observed adverse effect level; 

ppm = parts per million; UF = uncertainty factor

*For exposures other than 30 minutes, the ten Berge et al. [1986] relationship is used for duration adjustment (Cn

 × t = k); no 

empirically estimated n values were available; therefore, the default values were used: n = 3 for exposures greater than 30 

minutes and n = 1 for exposures less than 30 minutes. †

The selection of the UF for chlorine was based on Chapter 4: Use of Uncertainty Factors. The UF of 1 or 3 was selected on the basis 

of (1) severe effects or (2) human variability.

‡

Derived values are calculated by dividing the Adjusted 30-minute LC by the UF.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 49

Alarie Y [1980]. Toxicological evaluation of airborne 

chemical irritants and allergens using respiratory 

reflex reactions. In: Proceedings, Symposium on 

Inhalation Toxicology and Technology, Ann Arbor, 

MI: Ann Arbor Science, pp 207–231.

Anglen DM [1981]. Sensory response of human 

subjects to chlorine in air [dissertation]. Ann Arbor, 

MI: University of Michigan.

Back KC, Thomas AA, MacEwen JD [1972]. Reclassification of materials listed as transportation 

health hazards. Report no. TSA-20-72-3. Dayton, 

OH: Aerospace Medical Research Laboratory, 

Wright-Patterson AFB.

Barrow CS, Smith RG [1975]. Chlorine induced 

pulmonary function changes in rabbits. Am Ind 

Hyg Assoc J 36:398–403.

Barrow CS, Steinhagen WH [1982]. Sensory irritation tolerance development to chlorine in F-344 

rats following repeated inhalation. Toxicol Appl 

Pharmacol 65:383–389.

Barrow CS, Alarie Y, Warrick JC, Stock MF [1977]. 

Comparison of the sensory irritation response in 

mice to chlorine and hydrogen chloride. Arch Environ Health 32:68–76.

Bitron MD, Aharonson EF [1978]. Delayed mortality of mice following inhalation of acute doses 

of formaldehyde, sulfur dioxide, chlorine and bromine. Am Ind Hyg Assoc J 39:129–138.

Chang JCF, Barrow CS [1984]. Sensory tolerance 

and cross-tolerance in F-344 rats exposed to chlorine or formaldehyde gas. Toxicol Appl Pharmacol 

76:319–327.

D’Alessandro A, Kuschner W, Wong H, Boushey 

HA, Blanc PD [1996]. Exaggerated responses to 

chlorine inhalation among persons with nonspecific airway hyperreactivity. Chest 109:331–337.

Demanti R, Fraser R, Plaa G, Malo JL [1995]. Histopathological effects of acute exposure to chlorine 

gas on Sprague-Dawley rat lungs. J Environ Pathol 

Toxicol Oncol 14:15–19.

Gagnaire F, Azim S, Bonnet P, Hecht G, Hery M 

[1994]. Comparison of the sensory irritation response in mice to chlorine and nitrogen trichloride. J Appl Toxicol 14:405–409.

ILO [1971]. Chlorine and compounds. In: Encyclopaedia of occupational health and safety. 4th ed. 

Vol. 1 (A–K). Geneva, Switzerland: International 

Labour Office.

ILO [1998]. Chlorine and compounds. In: Encyclopaedia of occupational health and safety. 4th ed. 

Vol. 1 (A–K). Geneva, Switzerland: International 

Labour Office.

Jiang XZ, Buckley LA, Morgan KT [1983]. Pathology of toxic responses to the RD50 concentration of 

chlorine gas in the nasal passages of rats and mice. 

Toxicol Appl Pharmacol 71:225–236.

Joosting P, Verberk M [1974]. Emergency population exposure: a methodological approach. Recent 

Adv Assess Health Eff Environ Pollut 4:2005–2029.

Lipton MA, Rotariu GJ [1941]. In: EMK Gelling, 

McLean FC, eds. Progress report on toxicity of 

chlorine gas for mice. Report no. 286. Washington, 

DC: U.S. National Defense Committee, Office of 

Science Research and Development.

MacEwen JD, Vernot EH [1972]. Toxic hazards 

research unit annual technical report: 1972. AMRL-TR-72-62. Dayton, OH: Aerospace Medical 

Research Laboratory, Wright-Patterson Air Force 

Base; Springfield, VA: National Technical Information Service.

Mrvos R, Dean BS, Krenzelok EP [1993]. Home exposures to chlorine/chloramine gas: review of 216 

cases. South Med J 86:654–657.

NAS [2004]. Interim acute exposure guideline levels (AEGLs): chlorine, CAS# 7782-50-5. Washington, DC: National Academy of Sciences, Commission on Life Sciences, National Research Council. 

NIOSH [1994]. Documentation for Immediately Dangerous to Life or Health Concentrations 

(IDLHs): Chlorine. Cincinnati, OH: Centers for 
50 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Disease Control and Prevention, National Institute 

for Occupational Safety and Health, http://www.

cdc.gov/niosh/idlh/7782505.html. 

NIOSH [2005]. NIOSH pocket guide to chemical 

hazards. NIOSH publication no. 2005–149. Cincinnati, OH: Centers for Disease Control and Prevention, National Institute for Occupational Safety and 

Health, http://www.cdc.gov/niosh/npg/default.html. 

O’Neil CE [1991] Immune responsiveness in chlorine exposed rats. PB92-124478. Cincinnati, OH: 

Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health.

OSHA [1989]. OSHA PEL project documentation, 

1988. NIOSH databases, http://www.cdc.gov/

niosh/pel88/pelstart.html. 

OSHA [2010]. Occupational Safety and Health 

Standards. 29 CFR 1910. Subpart Z: Toxic and 

Hazardous Substances. Washington, DC: Occupational Safety and Health Administration, 

http://www.osha.gov/pls/oshaweb/owadisp.show_

document?p_table=standards&p_id=9992. 

Rotman HH, Fliegelman MJ, Moore T, Smith RG, 

Anglen DM, Kowalski CJ, Weg JG [1983]. Effects of 

low chlorine and bromine concentrations on man. 

Int Arch Gewerbepathol 23:79–90.

Schlagbauer M, Henschler D [1967]. Toxicity of 

chlorine and bromine with single and repeated inhalation. Int Arch Gewerbepathol Gewerbehyg 23:91.

Shroff CP, Khade MV, Srinivasan M [1988]. Respiratory cytopathology in chlorine gas toxicity: a 

study in 28 subjects. Diagn Cytopathol 4:28–32.

Shusterman DJ, Murphy MA, Balmes JR [1998]. Subjects with seasonal allergic rhinitis and nonrhinitic 

subjects react differentially to nasal provocation with 

chlorine gas. J Allergy Clin Immunol 101:732–740.

Silver SD, McGrath FP, Ferguson RL [1942]. Chlorine median lethal concentration data for mice. 

DATR 373. Aberdeen, MD: Edgewood Arsenal.

ten Berge WF, Zwart A, Appelman LM [1986]. 

Concentration-time mortality response relationship of irritant and systematically acting vapors 

and gases. J Haz Mat 13:301–309.

Underhill FP [1920]. The lethal war gases: physiology and experimental treatment. New Haven, 

CT: Yale University Press, p. 20.

Vernot EH, MacEwen JD, Haun CC, Kinkead 

ER [1977]. Acute toxicity and skin corrosion 

data for some organic and inorganic compounds 

and aqueous solutions. Toxicol Appl Pharmacol 

42:417–423.

Weedon FR, Hartzell A, Setterstrom C [1940]. 

Toxicity of ammonia, chlorine, hydrogen cyanide, 

hydrogen sulfide and sulfur dioxide gases. V: Animals. Contrib Boyce Thompson Inst 11:365–386.

Withers RMJ, Lees FP [1985a]. The assessment 

of major hazards: the lethal toxicity of chlorine. 

Part 1: review of information on toxicity. J Hazard 

Mater 12:231–282.

Withers RMJ, Lees FP [1985b]. The assessment 

of major hazards: the lethal toxicity of chlorine. 

Part 2: model of toxicity to man. J Hazard Mater 

12:283–302.

Zwart A, Wouterson RA [1988]. Acute inhalation 

toxicity of chlorine in rats and mice: timeconcentration-mortality relationships and effects 

on respiration. J Hazard Mater 19:195–208.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 51

APPENDIX B: IDLH Value 

Development Prioritization

This appendix identifies how NIOSH will determine the priorities for developing IDLH values. 

The guidance values play an important role in planning work practices surrounding potential highexposure environments in the workplace and in 

guiding actions by emergency response personnel 

during unplanned exposure events. Ideally, IDLH 

values would be available for all chemicals that 

might be present under high exposure situations. 

However, this breadth of coverage of IDLH values 

is not practical and might not even be necessary for 

many chemicals, such as those with very low exposure potential or those that are not acutely toxic. In 

addition, the absence of data and limited resources 

makes it difficult to evaluate the multitude of chemicals currently available in commerce. Therefore, a 

prioritization process is used by NIOSH to ensure 

that resources are allocated to yield the greatest impact on risk reduction in the event that control measures fail (including respiratory protection devices). 

This process takes into account both toxicity and exposure potential, and it is applied to a broad pool of 

relevant chemicals (e.g., chemical warfare agents, industrial chemicals, high-production-volume [HPV] 

chemicals, or agrochemicals subject to emergency 

or uncontrolled releases). A qualitative algorithm is 

used to generate a tentative relative priority ranking. This process is intended only to provide tentative guidance based on a simple approach that uses 

readily available sources of information. The resulting priorities are further modified on the basis of 

NIOSH emphasis areas. For example, chemicals 

can be added or removed from the list on the basis 

of new information related to toxicity or exposure 

potential. The development and use of a documented prioritization process allows for frequent 

updating of both input data and prioritization criteria to meet changing needs. 

Substances considered in the ranking process are 

compiled from existing databases of chemicals 

identified by other agencies as “of concern” because 

of use in chemical terrorism or as chemicals with 

the potential for exposure due to other uncontrolled releases (and thus having greater opportunities for high, acute exposures). Existing lists of 

agents of concern may not be fully representative 

of industrial chemicals for which acute exposures 

may occur during planned activities (e.g., special maintenance activities) or unplanned-release 

events. However, IDLH values for many of these 

sorts of chemicals were included in the original 

IDLH value development process and in the 1994 

updates. Moreover, NIOSH adds additional chemicals of interest that are nominated by interested 

stakeholders or the subject of new emphasis programs. Chemicals from the following databases 

(as supplemented by NIOSH chemicals of interest) 

were included in the ranking process: 

• Hazardous Substances Emergency Events 

Surveillance (HSEES)—This database contains self-reported incidents of accidental 

chemical releases. The database was created 

by the Agency for Toxic Substances and Disease Registry (ATSDR) [ATSDR 2008].

• Emergency Preparedness and Response—

This list of specific agents and other threat 

agents was created by the Centers for Disease 

Control and Prevention (CDC) [CDC 2008].

• Emergency Response Guidebook (ERG)—

This list of toxic by inhalation (TIH) chemicals and water-reactive TIH chemicals was 

created by the DOT [US DOT 2008]. 

• Chemical Facility Anti-Terrorism Standards 

(CFATS), Appendix A—This list of chemicals 
52 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

of interest to national security was created 

by the Department of Homeland Security 

(DHS) [US DHS 2007].

Exposure-related parameters can be divided into two 

categories: 1) those that provide a direct indication 

of exposure potential (e.g., number of recorded accidents or spills involving a chemical) and 2) data 

that provide indirect indication of exposure potential 

(e.g., volume produced). In weighing such metrics, a 

balance needs to be struck between the greater confidence provided by direct-release data based on the 

obvious relevance to exposure potential, and the 

need to have data on exposure potential that are 

available for most chemicals. Information on direct 

exposure indicators was obtained from the HSEES 

database [ATSDR 2008]. Although only 14 states 

participate in the program, the data are useful as 

an exposure indicator. Evidence of frequent past 

incidents involving uncontrolled releases receives 

a score of 1, and the absence of reporting of prior 

releases is scored 0. 

Chemical production volume is used as an indirect 

indication of exposure potential [USEPA 2008]. The 

USEPA classifies HPV chemicals as those chemicals produced or imported in the United States in 

quantities of 1 million pounds or more per year; 

medium-production chemicals are quantities of 

25,000 to less than 1 million pounds per year; and 

low-production chemicals are quantities less than 

25,000 pounds per year. HPV chemicals receive a 

score of 1, whereas low-and medium-productionvolume chemicals receive a score of 0.

Because the aim of the prioritization process is the 

development of guidance for protection from acute 

inhalation exposures, endpoints that best inform 

the potential for life-threatening, irreversible, or 

escape-impairing effects following acute inhalation 

exposures receive the greatest weight. The following approach and resources are used to score toxicity considerations:

1. Direct indication of exposure potential (e.g., 

number of recorded accidents or spills involving 

a chemical).

• Evidence of frequent past incidents involving 

uncontrolled releases

• HSEES—collects and analyzes actual hazardous chemical releases and emergency responder injuries

• Chemicals with uncontrolled releases (URs) 

are scored as a 1, and lack of reported data is 

scored as a 0.

2. Indirect indication of exposure potential (e.g., 

volume produced)

• Indicative of the potential for exposure from 

the amount of chemical that is produced

• USEPA classifies chemicals as low, medium, 

or high production volume (HPV)

• Chemicals classified as HPV are scored as a 1, 

whereas low- and medium-volume chemicals 

are scored as a 0.

3. Short-term exposure limits (STELs)—NIOSH 

RELs, OSHA PELs, AIHA WEELs, and ACGIH 

TLVs® [ACGIH 2008; AIHA 2008; NIOSH 2007]

• STEL values below 20 ppm for vapors and 

gases or 2 mg/m3 for particulates provide a 

reasonable cut point for identifying the most 

significantly acutely toxic substances.

• Substances with a STEL below these cut points 

receive a score of 1, whereas substances with a 

STEL equal to or greater than these values or 

that have no available STEL receive a score of 0.

4. Irritant Potential (IRR)—NIOSH Pocket Guide 

to Chemical Hazards [NIOSH 2005] or the European Union (EU) Risk Phrases (R-phrases) 

[EU 2008] for irritation 

• Irritants receive a score of 0.5 and corrosive 

chemicals receive a score of 1; all other chemicals receive a score of 0.

5. Acute toxicity (AT) (e.g., lethal concentration 

resulting in 50% mortality in exposed animals 

[LC50])—Registry of Toxic Effects of Chemical 

Substances (RTECS) [CCOHS 2008]

• Chemicals classified as extremely or highly 

hazardous in RTECS or with an EU R-phrase 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 53

of “very toxic” or “toxic” are scored as 1; otherwise, chemicals are scored as 0. 

• Chemicals that have not been evaluated by 

means of these systems are judged on the basis of the lowest reliable LC50 compared to the 

EU R-phrase criteria.

6. Developmental toxicant (DT)—NIOSH Pocket 

Guide to Chemical Hazards [NIOSH 2005] or 

California Environmental Protection Agency 

(Cal/EPA) Proposition 65 list [Cal/EPA 2008].

• Chemicals identified as reproductive/developmental toxicants are scored as 0.5; otherwise, chemicals are scored 0.

7. Carcinogenicity (CA)—EPA, International Agency 

for Research on Cancer (IARC) [IARC 2008], 

ACGIH [2008], NIOSH Pocket Guide to Chemical 

Hazards [NIOSH 2005], Cal/EPA Proposition 65 

List [Cal/EPA 2008], or other sources

• Chemicals classified by recognized systems 

as probable, likely, or known human carcinogens are scored as 0.5; otherwise, chemicals 

are scored as 0.

8. Other considerations are used qualitatively to 

further refine priorities among chemicals with 

the same risk-based score. These Tier II considerations include the following:

• Availability of other acute exposure guidance—Such guidance includes existing 

IDLH, AEGL, or ERPG values. The availability of such guidance decreases the urgency for 

developing (or revising) IDLH values.

• Availability of toxicity data—the absence of 

adequate data precludes the development of 

an IDLH value. The lack of toxicity data for a 

chemical with high exposure potential is used 

to identify research needs.

• Availability of exposure monitoring methods —The availability of a validated sampling 

and analytical method increases the likely 

near-term utility of a derived IDLH value. 

The absence of a validated sampling and analytical method for high-priority chemicals 

could be used to identify research needs. 

• Presence on existing lists of high priority 

agents—If other agencies have listed the material as a high priority, then the IDLH value may 

be useful to other agencies. This type of leveraging of resources is desirable and also helps to 

harmonize levels of worker health protection 

among agencies with related missions.

• Degree of safety hazard—If potential risk for 

two or more chemicals as determined on the 

basis of chemical toxicity is equal, then agents 

that have a greater degree of safety-related risk 

(e.g., flammability) are given greater weight. 

This consideration allows for easier comparison of overall risk profiles and selection of the 

most appropriate basis for risk management 

(e.g., developing entry criteria or emergency 

plans on the basis of whichever is the greater 

concern, safety or health risk).

The overall priority score is the sum of the exposure 

score and toxicity score: 

• Tier I: Risk Priority Score = Exposure Score 

[ranges from 0 to 2] + Toxicity Score [ranges 

from 0 to 3]

Risk Priority Score = 

 [UR + PV] + [STEL + IRR + AT + DT + CA]

Where:

 AT = acute toxicant

 CA = carcinogenicity

 DT = developmental toxicant 

 IRR = irritant

 PV = production volume

 STEL = short-term exposure limit

 UR = uncontrolled release 

• Tier II: Used qualitatively to make an overall 

judgment on priorities among chemicals with 

the same risk priority score.
54 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Appendix B: References

ACGIH [2008]. Threshold limit values (TLVs®) 

and biological exposure indices (BEIs®). Cincinnati, OH: American Conference of Governmental 

Industrial Hygienists.

AIHA [2008]. The emergency response planning 

guidelines (ERPG) and workplace environmental 

exposure levels (WEEL) handbook. Fairfax, VA: 

American Industrial Hygiene Association.

ATSDR [2008]. Hazardous substances emergency 

events surveillance (HSEES) system. Atlanta, GA: 

Department of Health and Human Services, Centers for Disease Control and Prevention, Agency 

for Toxic Substances and Disease Registry, http://

www.atsdr.cdc.gov/HS/HSEES/index.html. 

Cal/EPA [2008]. Proposition 65: chemicals known 

to the state to cause cancer or reproductive toxicity. August 1, 2008. Sacramento, CA: California 

Environmental Protection Agency, Office of Environmental Health Hazard Assessment, http://

www.oehha.org/prop65/prop65_list/files/P65single080108.pdf. 

CCOHS [2008]. RTECS: Registry of Toxic Effects 

of Chemical Substances. Ontario, Canada: Canadian Centre for Occupational Health and Safety.

CDC [2008]. Emergency preparedness and response chemical emergencies: agents, diseases and 

other threats. Atlanta, GA: Department of Health 

and Human Services, Centers for Disease Control 

and Prevention, http://www.bt.cdc.gov/chemical/. 

EU [2008]. ESIS (European Chemical Substances 

Information System): EU risk phrases. Brussels, 

Belgium: European Union, Joint Research Centre, 

European Commission, http://ecb.jrc.it/esis/. 

IARC [2008]. IARC monographs on the evaluation 

of carcinogenic risks to humans. Lyon, France: International Agency for Research on Cancer, http://

monographs.iarc.fr/. 

NIOSH [2005]. Pocket guide to chemical hazards. 

Cincinnati, OH: U.S. Department of Health and 

Human Services, Centers for Disease Control and 

Prevention, National Institute for Occupational 

Safety and Health, http://www.cdc.gov/niosh/npg/

default.html. 

US DHS [2007]. Chemical facility anti-terrorism 

standards: appendix A. Washington, DC: U.S. Department of Homeland Security, http://www.dhs.

gov/xlibrary/assets/chemsec_appendixa-chemicalofinterestlist.pdf. 

US DOT [2008]. Emergency response guidebook. 

Washington, DC: U.S. Department of Transportation, Office of Hazardous Materials Initiatives and 

Training, Pipeline and Hazardous Materials Safety 

Administration, http://hazmat.dot.gov/pubs/erg/

erg2008_eng.pdf. 

US EPA [2008]. High production volume list. Prevention, pesticides and toxic substances, pollution 

prevention and toxics. Washington, DC: U.S. Environmental Protection Agency, http://www.epa.gov/

chemrtk/pubs/general/opptsrch.htm.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 55

APPENDIX C: Critical Effect Determination for IDLH 

Value Development—Consideration of Severity, 

Reversibility, and Impact on Escape Impairment 

As discussed in the main document, the intent of the 

IDLH value is to protect against exposures that are 

“likely to cause death or immediate or delayed permanent adverse health effects or prevent escape from 

such an environment.” In other words, the most appropriate effects to use as the basis of the IDLH value 

derivation are those that are severe, irreversible, or 

escape-impairing. Scientific judgment is an important 

aspect in evaluating severity of effects and determining which ones are irreversible, but guidance is available from a number of different sources. 

Severe adverse effects that are not necessarily immediately escape-impairing are judged on a caseby-case basis weighing considerations such as the 

need for medical treatment, the potential for altered 

function or disability, and the potential for longterm deficits in function. These include severe, but 

reversible, acute effects such as hemolysis, chemical 

asphyxia, delayed pulmonary edema, and significant acute organ damage (hepatitis, decreased kidney function, etc.). If these effects could be caused 

by the chemical, it is important that the available 

toxicity studies evaluated the development of such 

effects by, for example, allowing sufficient time between exposure and evaluation of the endpoint.

Guidance on evaluating and ranking the severity of toxic effects is available from a number of 

organizations. DeRosa et al. [1985] developed 

a 10-category scheme for evaluating noncancer 

toxicity in the evaluation of Reportable Quantities 

under the USEPA Superfund legislation. Although 

designed for the context of chronic exposures, this 

approach provides insight into the relative severity 

of different types of histopathology and developmental toxicity. The Agency for Toxic Substances 

and Disease Registry (ATSDR) includes the following five severity rankings [Pohl and Abadin 1995]:

• No Observed Effect Level (NOEL)

• No Observed Adverse Effect Level (NOAEL) 

• Minimal Lowest Observed Adverse Effect 

Level (LOAEL1

) 

• Moderate Lowest Observed Adverse Effect 

Level (LOAEL2

) 

• Frank Effect Level (FEL)

ATSDR applies this approach from acute exposures (defined as exposures up to 14 days) through 

chronic exposures, and a number of publications 

are available on applying this approach to various types of effects (e.g., Abadin et al. 1998, 2007; 

Chou and Pohl 2005; Pohl and Chou 2005; Pohl 

et al. 2005). Although intended for a different 

purpose, these analyses can provide insights into 

the evaluation of effect severity. In particular, the 

“moderate” LOAEL category used by ATSDR is 

more likely to be considered severe or irreversible, 

and thus relevant to IDLH value development. 

Guidance on evaluation of the severity of effects 

is also available from the USEPA RfC guidelines 

[USEPA 1994] and from the American Thoracic 

Society (e.g., Pellegrino et al. 2005). 

Determining which effects are escape-impairing is 

complicated both by the limited guidance available 

from other sources and by the fact that reporting of 

signs and symptoms for similar underlying effects 

may differ across human and animal studies. For 

example, the same underlying mechanism may be 

described as inducing intolerable irritation in a human clinical study or case report, but may manifest 
56 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

as changes in respiration rate, nasal discharge, or altered activity level in an acute toxicity test in animals. 

For this reason, guidance was developed that allows 

for more consistent assigning of comparative severity of observed effects (i.e., escape-impairing versus 

non-escape-impairing) for commonly observed adverse effects used as the basis of IDLH values. Table 

C–1 provides guidance for classification of many 

effects commonly seen in acute studies. Because of 

the nature of the evaluation methods, endpoints that 

can be evaluated in humans are generally limited to 

clinical signs and symptoms, along with some specialized testing, and some histopathology evaluation 

that can be conducted non-invasively (e.g., for the 

nasal cavity), or can be inferred from other evaluations (e.g., pulmonary edema).
NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values 57

Table C–1. Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Irritation—Ocular 

Signs and symptoms—Ocular

Eye irritation (subjective description) Yes X If moderate or severe Lacrimation (excessive tearing, clear or colored) Yes X X If severe (assumes will be accompanied by other severe 

irritation responses)

Blepharospasm (eye squinting and shutting) Yes X X If severeReduced or poor vision Yes X If severeMouth- or face-pawing activity No X May be observed even during mild irritationEye blink rate/frequency No X X Difficult to use as a correlate of irritation, although some 

investigators assert that it may be useful as a marker of moderate to severe eye irritation

Ocular examination findingsSwelling of eyelids Yes X X If eyelids are closed (more than half-closed)Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible

No X X Assuming no significant impairment of vision

Easily discernible translucent area, details of iris slightly obscured

No X X

Nacreous (lustrous) area, no details or iris visible, size of pupil barely discernible

Yes X X

Opaque cornea, iris not discernible through the opacity Yes X X If severe, assumes will significantly impair vision

(Continued)
58 NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Markedly deepened rugae (folds or wrinkles), congestion, swelling, moderate circumcorneal hyperemia, or injection, or any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)

Yes X X

No reaction to light, hemorrhage, gross destruction (any or all of these)

Yes X X

Ocular hyperemia (blood vessels hyperemic causing red eye)

No X X

Cornea, inflammation or abrasion Yes X X

Cataract Yes X X

Inflammation of the eyes Yes X X If inflammation severe, assumes this correlates to severe 

irritation; large changes in some sensitive biomarkers may not necessarily indicate severe irritation responses.

Irritation - Respiratory

Nasal signs and symptoms

Nasal irritation or pain (subjective description) No X

Nasal localization No X Endpoint differentiates sharp smell from irritation

Sneezing Yes X X If severeNasal congestion No X X

Nostril discharges: red or colorless No X X

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values 59

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Thickness/swelling of nasal mucosa (decreased nasal cross-sectional area)

No X X Methods measuring mucosal thickness not directly related 

to sensory irritation effects

Increased nasal airway resistance No X

Respiratory tract symptomsDry cough Yes X If severeCough with mucus or blood Yes X If severeChest wheezing Yes X If severe, assumes may impair breathingRales (rapid series of short, loud sounds) No X

Breathing rate/volume measured by pulmonary function test results

Yes X X If severe in humans, assumes may impair breathing; 

concentrations in the range of the RD50 in rodents 

Dyspnea (difficult or labored breathing observed as abdominal breathing or gasping)

Yes X If severe in humans, assumes may impair breathing

Painful breathing Yes X If severe in humans, assumes sufficient to impair breathingApnea (a transient cessation of breathing following a forced respiration)

Yes X X Indication of sufficient irritation to modify breathing

Tachypnea (quick and usually shallow respiration) Yes X X Indication of sufficient irritation to modify breathingCyanosis (bluish appearance of tail, mouth, foot pads, skin or mucous membranes)

Yes X X If severe, assumes sufficient to impair respiration 

Laryngoconstriction Yes X X If severe, assumes may impair breathingBronchoconstriction Yes X X If moderate or severe, assumes may impair breathing

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
60 NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Respiratory tract histopathologyNasopharynx inflammation No X X

Nasopharynx erosion or necrosis No X X

Larynx inflammation Yes X X If severe, assumes may impair breathingLarynx erosion or necrosis Yes X If moderate or severe, assumes may impair breathingTracheal or bronchial inflammation Yes X If severe, assumes may impair breathingTracheal or bronchial erosion or necrosis Yes X If moderate or severe, assumes may impair breathingAlveolar hemorrhage or necrosis Yes X If observed, assumes may impair breathingPulmonary edema Yes X X If observed, assumes may impair breathing

Neurological

Signs and symptoms

Arousal state No X X If sluggish with some exploratory movements with periods 

of immobility, or hyperalert, excited, sudden bouts of running or body movements, or changes in rearing

Headache Yes X Only if described in study as debilitatingLightheadedness, dizziness/faintness Yes X If moderate or severeLassitude/lethargy (feeling low in energy or slowed) No X Assume if severe, lassitude would be seen as extreme 

drowsiness/fatigue

Extreme drowsiness, fatigue or sleepiness (somnolence) Yes X If severeNarcosis (stupor) Yes X X If observed

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values 61

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Frank effects (including postural observations—excessive sway, lying on side, limbs in the air, loss of balance, stupor, convulsions, seizure, coma) 

Yes X X If observed 

Exhilaration (unusual) No X

Euphoria (a feeling of exaggerated elation) No XLoss of concentration Yes X X If severe 

Loss of recent memory Yes X X

Long-term memory loss No X X

Unstable moods No X

CNS excitabilityClonic movements (marked by alternate contraction and relaxation of muscles)

Yes X X If moderate-severe body tremors and myoclonic jerks

Tonic movements (marked by continuous muscular contractions)

Yes X X If head and body rigidly forward or backward 

Autonomic effectsPalpebral closure, ptosis or relaxation of nictating membranes

Yes X X If eyelids or nictating membranes drooping; drooping of 

nictating membranes would not be observed in humans

Urination Yes X X Common effects of nerve agents and accompanied by 

changes that impair escape

Defecation Yes X X Common effects of nerve agents and accompanied by 

changes that impair escape

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
62 NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Clinical sign(s)

Escapeimpairing? Humans Animals Comments

Piloerection (contraction of erectile tissue of hair follicles, resulting in rough fur)

No X

Hypo- or hyperthermia Yes X X If severe

Excessive perspiration/sweating/panting No X X Common effects of nerve agents that accompany 

other effects considered to be escape impairing

Salivation No X X Common effects of nerve agents that accompany 

other effects considered to be escape impairing

Syncope (loss of consciousness) Yes X X If observed

Blurred vision Yes X If severe

Mydriasis (reflex pupillary dilation) Yes X X If severe

Miosis (constriction of pupil, regardless of light) Yes X X If severe

Ptosis (drooping of upper eyelids) Yes X X

Chromodacryorrhea (red lacrimation) No XLoss of libido No X

Muscle tone/equilibrium Abnormal gait or postural observations Yes X X If sufficient to impair balance or locomotion

Mobility Yes X X If severely impaired

Righting Yes X If moderately or severely impaired

Forelimb grip strength Yes X If severely impaired

Landing foot splay Yes X If significantly increased a measure of postural 

instability

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values 63 Clinical sign(s)

Escapeimpairing? Humans Animals Comments 

Fasciculation (muscular twitching) Yes X If severe 

Muscle weakness of extremities (foot drop) Yes X If severe

Decreased manual dexterity Yes X If severe

Decreased nerve conduction velocity Yes X If accompanied by changes that affect 

locomotion

Sensorimotor reactivity Click response No X Sensitive responseTouch response No X Sensitive responseTail pinch response Yes X If no or limited reaction, indicates decreased 

sensory ability and CNS impairment 

Paresthesia (numbness/tingling body parts) Yes X If impairs locomotion or ability to grasp

Perception speed No X X Sensitive responseReaction time (simple or choice) No X X Sensitive responseAuditory vigilance No X X Sensitive responseVisual time discrimination No X X Sensitive responseDepth and form perception No X X Sensitive responseTinnitus (ear ringing) No X

Pressure in the ears No X

Reduced hearing acuity No X

Insomnia or wake frequently No X X

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

(Continued)
64 NIOSH CIB 66 

• Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures

Clinical sign(s)

Escapeimpairing? Humans Animals Comments 

Nervous system histopathology

Central nervous system lesions Yes X If degenerative change observedPeripheral nervous system lesions Yes X If degenerative change observed

Other 

GI tract signs and symptoms

Stomach ache Yes X If severe—e.g., causes involuntary doubling over

Nausea No X May be accompanied by weakness or dizziness 

that will be considered escape-impairing

Diarrhea No X

Vomiting Yes X X If severe

Cardiovascular changesChange in blood pressure Yes X X If severe, assumes may induce faintness or 

dizziness (extreme hypotension)

Changes in heart rate (tachycardia or bradycardia) Yes X X If severe or accompanied by other impairing 

 cardiovascular change

Tightness in the chest Yes X If severe or accompanied by other impairing 

 cardiovascular change

Pains in heart or chest Yes X If severe or accompanied by other impairing 

 cardiovascular change

Arrhythmias Yes X X Assumes sufficient to impair systemic blood flowVentricular fibrillation Yes X If observed
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 65

Appendix C: References

Abadin H, Murray H, Wheeler J [1998]. The use of 

hematological effects in the development of minimal risk levels. Reg Toxicol Pharm 28:61–66.

Abadin H, Chou C, Llados F [2007]. Health effects 

classification and its role in the derivation of minimal risk levels: Immunological effects. Regul Toxicol Pharmacol 47:249–256.

Chou C, Pohl H [2005] Health effects classification 

and its role in the derivation of minimal risk levels: 

Renal effects. Regul Toxicol Pharmacol 42:202–208.

DeRosa CT, Stara JF, Durkin PR [1985]. Ranking of 

chemicals based upon chronic toxicity data. Toxicol Ind Health 1(4):177–192. 

Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der Grinten CPM, 

Gustafsson P, Hankinson J, Jensen R, Johnson DC, 

MacIntyre N, McKay R, Miller MR, Navajas D, 

Pedersen OR, Wanger J [2005]. Interpretative strategies for lung function tests. ATS/ERS task force: 

Standardisation of lung function testing. Eur Respir 

J American Thoracic Society 26:948–968.

Pohl H, Abadin H [1995]. Utilizing uncertainty 

factors in minimal risk levels derivation. Reg Toxicol Pharm 22:180–188.

Pohl H, Chou C [2005]. Health effects classification 

and its role in the derivation of minimal risk levels: 

Hepatic effects. Regul Toxicol Pharmacol 42:161–171.

Pohl H, Luukinen B, Holler J [2005]. Health effects 

classification and its role in the derivation of minimal risk levels: Reproductive and endocrine effects. 

Regul Toxicol Pharmacol 42:209–217.

US EPA (United States Environmental Protection 

Agency) [1994]. Methods for derivation of inhalation reference concentrations and application of 

inhalation dosimetry. EPA/600/8-90/066F. 
This page intentionally left blank.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 67

APPENDIX D: Analyses Supporting the 

Development of Uncertainty Factor Approach

During the 1994 update to the IDLH values, NIOSH 

chose to use an approach for extrapolation from a 

duration-adjusted LC value (e.g., LC50 value) that 

included the use of a default UF (or safety factor) of 

10. When data on effects other than lethality were 

available, an unspecified UF less than 10 was typically applied. The rationale for this decision was 

neither described in the 1994 update methodology 

[NIOSH 1994] nor specified in the support documentation for the IDLH values derived from such 

data. This has resulted in the need to re-examine 

this practice to verify its efficacy in the derivation 

of health-protective IDLH values. 

To evaluate the assignment of UFs, NIOSH conducted several analyses in preparation of the IDLH 

methodology to determine if the approach used 

in the 1994 update needed to be revised. Numerous datasets were evaluated to identify the typical ratio between the IDLH and the POD derived 

from different types of studies. The results of these 

analyses are presented in Section D.1. In arriving at 

the final methodology presented in this CIB, the 

empirical analysis discussed in this appendix was 

supplemented by previously published data analysis [Fowles et al. 1999; Rusch et al. 2010]. Current 

risk assessment principles related to the rationale 

and concepts for UF application for setting exposure 

guidelines of different types were also considered, in 

particular the process used by the AEGL committee.

D.1 Analysis for 

Selected Approach

To derive a scientifically based approach for the use of 

UFs in the derivation of IDLH values, several analyses were conducted to determine the appropriate size 

of the UF for extrapolating from various points 

of departure, taking into account the weight-ofevidence approach and MOA considerations described previously. Two approaches were used. 

Approach 1 involved a detailed evaluation of 

acute toxicity data for a selection of 20 chemicals, 

whereas Approach 2 evaluated the MOAs identified from a larger dataset of 94 chemicals. 

For Approach 1, 20 case-study compounds with 

high-quality animal lethality studies and adequate 

human effects data to estimate lethality thresholds 

were identified. The Log-Probit model of USEPA’s 

BMDS was used to calculate the LC50 and LC01 values based on the mortality incidence data for each 

of the animal studies of adequate quality. All of the 

animal LC50 values and human lethality threshold 

data were adjusted to 30-minute-equivalent values 

via the method of ten Berge and colleagues [ten 

Berge et al. 1986], by using chemical-specific values of n for lethality whenever possible or standard 

defaults (i.e., n = 1 for extrapolation from shorter to 

longer durations and n = 3 for extrapolation from 

longer to shorter durations), and using an n of 1 for 

time correction of human effects other than lethality (e.g., irritation or signs of CNS depression). It 

should be noted that the default ten Berge adjustment approach would also be most appropriate for 

less than lethal effects. However, since this analysis was intended as one of several range-finding 

approaches for uncertainty selection explored by 

NIOSH, the additional analysis required to make 

the adjustments from the poorly documented human studies was deemed an unnecessary refinement 

for this particular analysis. The default ten Berge approach is specified for lethal and non-lethal effects 

within the IDLH methodology outlined in this CIB. 

The correct approach for extrapolation is uncertain 

for less-than-lethal effects. Adequate quantitative 
68 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

data are rarely available for severe adverse effects 

in humans to support concentration–response 

modeling. In particular, thresholds for lethality 

are difficult to estimate from the very limited 

available case report information. However, 

available effect levels in humans gleaned from 

peer-reviewed secondary sources were arrayed by 

concentration (Conc), duration of exposure (time, 

t), the concentration × duration product (Conc × 

t = k), and severity of effect for each study that 

provided human response data.

Results of this analysis are shown in Table D–1. 

The analysis found that animal lethal concentrations and human effect thresholds were generally 

correlated for this limited dataset. Additional analyses were conducted by MOA category (e.g., irritant, CNS depressant, or “other”). Group means 

for each MOA category were not significantly different when comparing animal lethal concentrations (LC50 and LC01 values) to human lethality 

thresholds (human LCLO values). However, group 

means for the three MOA categories did differ significantly for the ratios of animal lethal concentrations (LC50 and LC01 values) versus the human 

LOELs for the 20 case-study chemicals. The mean 

LC50/human LOEL ratio was greatest for irritants, 

followed by chemicals that induce CNS effects, 

and then chemicals that had other MOAs.

As shown below in Table D–1, comparison of animal RD50 values to IDLH values suggests that, on 

average, the RD50 corresponds to a human severe 

irritation threshold, since the IDLH values used 

in the analysis were based on irritant effects in humans. This interpretation is consistent with study 

findings [Schaper 1993] that suggested that exposure at the RD50 would likely cause intolerable 

sensory irritation. However, it is noteworthy that 

the RD50 would have been considered in the overall weight of evidence in setting the IDLH values 

used in our analysis, which might have biased the 

results toward a value of 1. 

Table D–1. Ratio of lethal concentrations from 

animal studies and observed or estimated human effect levels

Comparison Median 95th Percentile

LC50/LOEL* 25 330

LC01/LOEL 15 130

LC50/LCLO 2 13

LC01/LCLO 1.5 11

LC50/IDLH value† 8 67

RD50/IDLH value† 1 9

Abbreviation: IDLH = immediately dangerous to life or health; LC01 = the statistically derived air concentration that 

caused lethality in 1% of test animals; LC50 = median lethal concentration; LCLO = lowest lethal concentration of a 

substance in the air reported to cause death; LOEL = lowest observed effect level; RD = respiratory depression.

*

Based on analysis of 20 case study substances. The numerator is the value from animal studies and the denominator 

is the human effect level or value of the IDLH value.

†

Based on analysis of IDLH values.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 69

The second approach used data directly from current IDLH value documentation to analyze all of 

the chemicals in the current list of IDLH values 

that are based on human effects data and had at 

least one reported LC50 value, resulting in a list of 

94 chemicals for further examination. For each of 

these chemicals, the analysis identified the value of 

the lowest adequate 30-minute adjusted LC50 value, 

the current IDLH value, and the MOA for which 

the current IDLH value was set. As for the first approach, three MOA categories were used:

1. Irritation

2. Neurological effects 

3. “Other” 

It was noted that the “other” category included 

several pesticides that act via inhibition of cholinesterase. Although this group was not analyzed 

separately, it does form a potential fourth group for 

additional analysis. The cholinesterase inhibitors 

were not included in the general neurological effects category, since they have a specific underlying 

mechanism that might yield significant differences 

in lethality to non-lethal-effect ratios, as compared 

with other organics that act via the more general 

mechanisms of CNS depression. Published data 

were also used to compile RD50 estimates (the concentration of the chemical that results in a 50% decrease in respiratory rate in a standardized rodent 

test) for these same chemicals. 

The distribution of the LC50/IDLH value ratios is 

shown in Figure D–1. Results of the LC50/IDLH 

value ratio analysis (shown in Figure D–1) indicate 

that a factor of 10 would account for human effect 

thresholds for effects such as severe irritation and 

neurological effects, for approximately half of the 

chemicals reviewed, although a factor as high as 

100 may be needed to cover 95% of chemicals. Distribution of RD50/IDLH value ratios for 26 chemicals yielded a median ratio of 1, suggesting that 

exposure at the RD50 would generally result in sensory irritation of sufficient severity to be judged as 

escape-impairing. This interpretation is consistent 

with study results [Schaper 1993] suggesting that 

exposure at the RD50 would likely cause intolerable

sensory irritation. Overall, no clear pattern regarding MOA was evident when comparing LC50/IDLH 

value ratios and its primary MOA for the 94 chemicals or comparing RD50/IDLH value ratios for the 

26 chemicals.

This analysis hypothesized that potent irritants 

may have a greater difference between the LC50 and 

the threshold for serious effects in humans, as compared with chemicals that cause toxicity via other 

modes of action. If this hypothesis was true, then 

the implication would be that deriving an IDLH 

value from an LC50 for such chemicals would require a greater UF than would be needed for chemicals with other modes of action. The analysis produced mixed results, with a significant MOA effect 

observed for a subset of 20 chemicals, but not in a 

broader analysis of current IDLH values. Based on 

these results, the data are not adequate to recommend a different UF by MOA category.

D.2 Recommendation for 

Deriving IDLH Values

Three primary methods are traditionally applied 

during the development of acute emergency limits, such as the IDLH values, ERPGs, and AEGLs, 

to account for uncertainty in extrapolating from a 

key study to arrive at the final value. In developing 

the IDLH methodology, three possible approaches 

were considered. 

• Method 1—Use a weight-of-evidence approach, without specifying any default UF 

values. This would be an approach consistent 

with many volunteer groups that set acute 

occupational values (e.g., the AIHA ERPG 

committee). This approach provides for the 

greatest degree of flexibility in integrating 

all the complexities of the data, without having to explain departures from defaults that 

might not be very meaningful in the context 

of a specific dataset. However, this approach 

generally has limitations in that it is not 

highly transparent—i.e., it is often difficult 

to “back-calculate” the basis for the final numeric value.
70 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Lowest LC50 /Current IDLH

<1 1–<3 3–<10 10–<30 30–<100 100–300

Number of Chemicals

0

10

20

30

40

Central Nervous System

Irritant

Other

Pesticide

LC50—Concentration to cause a 50% mortality rate in an acute toxicity study.

Irritants—The critical effect that would be the basis for an IDLH value is irritation.

CNS Depressants—The critical effect that would be the basis for an IDLH value is CNS system depression.

Other—The critical effect that would be the basis for an IDLH value arises from an MOA other than irritation or 

CNS depression.

Pesticide—The critical effect that would be the basis for an IDLH value is cholinesterase inhibition.

Figure D–1. The distribution of ratios of the lowest 30-minute adjusted LC50 value to the current 

IDLH value is shown for 94 substances, representing four MOA categories, to evaluate the potential 

uncertainty value that provides adequate coverage for each MOA. 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 71

• Method 2—Use a preliminary composite UF 

as a starting point, based on the nature of 

the overall dataset, and communicate areas 

of uncertainty that impacted the final IDLH 

value in the rationale statement. This approach provides a data-informed starting 

point for the analysis, supported by empirical analysis (see Section D.2). The approach is 

intended to provide flexibility in UF selection 

by accounting for typical overlaps in individual UF and data hierarchies at the beginning 

of the UF selection process. This provides an 

increase in transparency over the weight-ofevidence approach, without requiring significant effort to explain departures from prescribed defaults. This is the approach that has 

been included in the IDLH methodology.

• Method 3—Apply a set of default UFs and revise post-hoc on the basis of the dataset. This 

would be an approach similar to that used to 

derive the AEGL values. This approach assigns 

default values for well-defined areas of uncertainty that pertain to a specific dataset. The final 

UF is derived by multiplying the individual factors. This approach is the most clear in terms of 

transparency (i.e., ability to back-calculate the 

derived value). However, because of the nature 

of the datasets involved, application of default 

values often yields conflicting or inappropriate values from one potential critical study 

to another. The end result of such data conflicts is the application of a post-hoc weightof-evidence evaluation, in which the final UF 

or critical study selected might be changed to 

align better with the overall dataset.

Application of the three methods outlined above 

should yield similar results, with the primary differences focusing on the level of transparency offered by each approach versus the need for posthoc modifications. There has been a history of 

successful application of methods 1 and 3, in the 

context of acute emergency limit-setting. Method 

2 is a hybrid of the methods that attempts to incorporate previous data and experience tailored to the 

unique needs of the IDLH Program. Method 2 is 

recommended as a reasonable blend of providing 

transparency in the basis for an assessment, without the rigid application of default values that may 

require extensive post-hoc explanations. Multiplication of default UF values may also tend to 

yield IDLH values that are more than adequately 

protective. In developing the approach, it was 

considered that setting IDLH values lower than 

needed can present new safety risks in the context 

of the intended application as a tool for respiratory protection selection. 

Appendix D: References

Fowles JR, Alexeeff GV, Dodge D [1999]. The use 

of benchmark dose methodology with acute inhalation lethality data. Regul Toxicol Pharmacol 

29(3):262–278.

NIOSH [1994]. Documentation for immediately 

dangerous to life or health concentrations (IDLH). 

Cincinnati, OH: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety 

and Health. NTIS Publication No. PB-94-195047. 

Rusch GM, Bast CB, Cavender FL [2009]. Establishing a point of departure for risk assessment using acute inhalation toxicity data. Regul Toxicol 

Pharmacol 54(3):247–255.

Schaper M [1993]. Development of a database for 

sensory irritants and its use in establishing occupational exposure limits. Am Ind Hyg Assoc J 

54(9):488–544.

ten Berge WF, Zwart A, Appelman LM [1986]. 

Concentration-time mortality response relationship of irritant and systematically acting vapors 

and gases. J Haz Mat 13:301–309.
This page intentionally left blank.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 73

APPENDIX E: Quantitative Adjustments during 

the Derivation of IDLH Values

This appendix provides supplemental information 

on quantitative adjustments applied within the 

IDLH methodology. Section E.1 discusses considerations applied when route-to-route extrapolation 

is conducted during the derivation of an IDLH 

value. Section E.2 provides supplemental detail 

pertaining to adjustments made during the time 

scaling of data.

E.1 Inhalation Volume 

Adjustments Approach 

for Route-to-Route 

Extrapolation

During the 1994 update of the IDLH values, a volume of 10 m3

 for inhaled air was included in the 

methodology as the basis for calculating the inhalation equivalent concentration from an oral toxicity 

study dose. This value represents the volume of air 

assumed to be inhaled over the course of a typical 

8-hour shift at light work load. The IDLH methodology uses an alternative approach that takes into account that IDLH values are intended to be based on 

a maximum exposure duration of 30 minutes. Assuming a worker breathing rate of 50 L/min for 30 

minutes, the corresponding total inhaled volume of 

air for a scenario relevant to the IDLH would be 1.5 

m3

. This volume corresponds with dosimetry guidelines recommended by the International Commission on Radiological Protection [ICRP 1994]. Use of 

the value 1.5 m3

 in the calculation of the inhalation 

equivalent concentration from an oral toxicity study 

dose has been applied in the IDLH method as the 

default for route-to-route calculations, as discussed 

in Section 3.4.2.4. 

The inhalation concentration calculated with use 

of the 1994 methodology is built on more healthprotective assumptions (yields a lower IDLH value) 

than the IDLH methodology, and it may have resulted in IDLH values that are more than adequately 

protective in some cases. The impact of this change 

in the assumed inhaled volume can be highlighted in 

the context of a typical example for a chemical with 

an IDLH value based on systemic toxicity derived 

from a single-oral-dose acute lethality study. Table 

E–1 illustrates the differences between the 1994 approach that used 10 m3

 and the IDLH methodology 

presented in the CIB that uses 1.5 m3

. 

Because the impact of the selected default is significant (roughly 7-fold), additional insight into 

the conditions under which each possibility is most 

scientifically appropriate is needed. Factors that 

impact this judgment include these:

• The toxicokinetic profile associated with the 

dosing regimen for the critical study compared to the IDLH acute inhalation scenario. 

Key considerations include 1) differences 

in absorption kinetics and 2) differences in 

clearance or elimination kinetics.

• The MOA and its associated dose metric for 

the adverse effect, commonly based on either 

peak (maximum) concentration (Cmax) or 

total dose (represented by the area under the 

curve [AUC]).

Under the most common scenarios and datasets 

available for setting IDLH values, the 1.5 m3

 assumption is likely to be adequate. The level of concern about the degree to which the 1.5 m3

 value is 

likely to be protective can be summarized for different scenarios. If the MOA is based on the peak concentration, then the differences in absorption and 
74 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

elimination rate kinetics for the dosing regimen used 

in the non-inhalation study can impact the selection 

of an inhalation volume. Simplifying assumptions 

related to the absorption rates of alternative dosing 

routes and methods can be applied to generalize the 

decision process:

• Low Concern:

ȣ If the underlying MOA for the critical 

effect is based on total systemic dose 

(AUC) and dose is sufficiently low that 

absorption and elimination rates are not 

severely saturated. In this case the total 

systemic dose (e.g., total mg dose) is the 

driver for the response, not the rate of 

uptake, and thus the most appropriate 

calculation of an IDLH yields an air 

concentration associated with achieving 

the total mass dose (mg) over the 30-min 

IDLH duration.

ȣ If the underlying MOA is based on peak 

concentration, an IDLH based on oral 

gavage dosing regimen should ensure 

that the chemical-specific kinetics allow 

for rapid absorption in the GI tract (short 

Tmax). In this case, the peak concentration 

achieved from a 30-min exposure by 

either route is approximately equal.

ȣ AUC or peak concentration is correct 

dose metric and the critical acute study is 

based on IV or IP injection data. Uptake is 

considered immediate and would parallel 

assumed rapid uptake via inhalation; 

thus, peak doses would be roughly similar 

across routes.

• Moderate Concern:

ȣ AUC is the correct dose metric and an 

oral dosing study was used. In most cases, 

since total dose is the driver for the onset 

of toxicity, use of the acute inhalation 

volume will be appropriate. An exception 

is the absorption or elimination rate is 

severely saturated, such that the orally 

administered dose does not represent 

well the total dose that would be received 

following an acute inhalation exposure 

at the IDLH. Under such conditions, the 

actual internal dose received by the test 

animals is lower than estimated by the 

administered oral dose, and the percentage 

of systemic bioavailability of the toxic form 

of the chemical (parent or metabolite) 

would need to be considered. Direct 

adjustment of the animal dose would be 

the best approach under these conditions. 

However, using some greater inhalation 

intake time to account for higher systemic 

doses across the two routes could also be 

considered in the absence of quantitative 

kinetic adjustments based on equivalent 

systemic doses across routes.

ȣ Peak concentration is the correct dose 

metric and the chemical has slow 

Table E–1. Illustration of the impact of various inhaled air volumes on derived IDLH values 

Approach

Oral LD50 value 

(mg/kg)

Body weight 

(kg)

Inhaled air volume 

(m3) UF*

Derived IDLH value† 

(mg/m3)

1994 Approach 50 70 10 100 3.5

IDLH Methodology 50 70 1.5 100 23.3

Abbreviation: IDLH = immediately dangerous to life or health; LD50 = median lethal dose; mg/kg = milligrams per kilograms of 

body weight; m3

 = cubic meters; UF = uncertainty factor

*The UF of 100 is included as an example only and is not a default value used during the derivation of IDLH values 

based on oral data.

†

Derived IDLH values were calculated with use of the following equation: IDLH value = [(Oral LD50 value * Body weight)/Inhaled 

Air Volume)]/(UF) 
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 75

absorption kinetics in an oral gavage 

dosing study, or the critical oral study 

used serial dosing or continuous 

dosing protocols. In these cases the 

peak concentration in the critical 

study would not represent the likely 

peak concentration reached for the 

inhalation study, and the currently 

proposed extrapolation method would 

not necessarily be adequately protective. 

The toxicokinetic considerations for route-to-route 

extrapolation are complex. In most cases, because 

of the nature of the acute systemic effects involved 

in IDLH derivation, rapid absorption kinetics and 

rapid onset of effects are expected. Thus, under the 

most likely conditions, the 30-min inhalation volume 

of 1.5 m3

 is viewed as an adequate default approach. 

However, there are scenarios based on chemical kinetics or non-inhalation study designs that may impact the level of protection afforded by the default 

adjustment. For this reason, the IDLH methodology has been modified to further communicate the 

potential conditions where additional kinetic-based 

adjustments may be needed. 

E.2 Time Scaling Adjustments 

In most cases IDLH values are derived from studies 

having exposures for periods shorter than or longer than 30 minutes. Thus, the PODs derived from 

such studies are adjusted to 30-minute-equivalent 

values. This adjustment is made by using the ten 

Berge et al. [1986] modification to Haber’s Rule that 

assumes the following relationship between concentration (Conc) and duration (time, t): (Concn

 × 

t = k). The impact of the value of n on the shape of 

the concentration–time–response curve is shown 

in Figures E–1 and E–2. As shown in these figures, 

larger values of n result in flatter curves, meaning 

that, for a given degree of toxicity, the concentration varies less with changes in duration. This is 

particularly apparent in Figure E–1, which shows 

the extrapolation from 4 hours to 30 minutes. This 

figure shows the impact of using different values of 

n to extrapolate to shorter durations from a concentration of 10 ppm at 4 hours. In this example, 

an n of 3 results in a concentration at 30 minutes 

that is not much higher than the test concentration at 4 hours, whereas the calculated concentration at 30 minutes is substantially higher when n = 

1. Thus, using n = 3 for extrapolating from longer 

durations to 30 minutes results in lower concentrations, a more health-protective approach. 

Figure E–2 shows the converse situation, extrapolating from an exposure to 10 ppm for 15 minutes 

to longer durations. In this case, the steeper curve 

associated with n = 1 results in a lower concentration at 30 minutes, compared with the value calculated using n = 3. Thus, using n = 1 is a more healthprotective approach in extrapolating from shorter 

durations to 30 minutes.

Based on these considerations, a default value of 

n = 1 is used for extrapolation from shorter durations, and a default value of n = 3 is used for extrapolation from longer durations to the 30-minute 

duration of interest. In both cases, a calculated n

specific to the chemical and species of interest is 

preferred when data are available to calculate the 

value. 

The data used to construct Figure E–1 are shown 

in Table E–2. Table E–2 shows the calculated concentrations when extrapolating from 10 ppm at 4 

hours, using n values of 1, 2, or 3.

The data used to construct Figure E–2 are shown in 

Table E–3. Table E–3 shows the calculated concentrations when extrapolating from 10 ppm at 0.25 

hours, using n values of 1, 2, or 3.

The following paragraph illustrates the effects of time 

scaling on inhalation toxicity data evaluated during 

the development of IDLH values for three chemicals: 

• 1,1-Dimethylhydrazine (CAS# 57-41-7)

• Vinyl acetate (CAS# 108-05-04)

• Titanium tetrachloride (CAS# 7550-45-0). 

In the first example, the identified LC50 and LOAEL 

values for 1,1-dimethylhydrazine correlated to 

exposure durations of 5 or 15 minutes. No empirically derived n values were identified within the 
76 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Figure E–2. ten Berge extrapolation from shorter (15 minute) to longer (30 minute) durations

Time (hours)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Concentration (ppm)

0

20

40

60

80

100

120

140

160

180

n=1

n=2

n=3

 30-minute

extrapolation

Figure E–1. ten Berge Extrapolation from longer (4 hour) to shorter (30 minute) durations

*n = exponent applied within ten Berge equation [1986]

*n = exponent applied within ten Berge equation [1986]
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 77

Table E–3. Time scaling for 

10 ppm at 15 minutes (0.25 hours)

Time n* = 1 n = 2 n = 3

0.25 10 10 10

0.5 5 7 8

1 3 5 6

1.5 2 4 6

2 1 4 5

2.5 1 3 5

3 1 3 4

3.5 1 3 4

4 1 3 4

n* = exponent applied within ten Berge equation [1986]

Table E–2. Time scaling for 10 ppm at 4 hours

Time, hours n* = 1 n = 2 n = 3

0.25 160 40 25

0.5 80 28 20

1 40 20 16

1.5 27 16 14

2 20 14 13

2.5 16 13 12

3 13 12 11

3.5 11 11 10

4 10 10 10

n* = exponent applied within ten Berge equation [1986]

reviewed literature for 1,1-dimethylhydrazine. 

Because the selected data were associated with 

exposure times less than 30 minutes, a default value 

of 1 for n within the ten Berge equation was applied 

on the basis of the rationale discussed in the previous 

paragraphs to extrapolate the most health-protective 

estimate. Time scaling resulted in a reduction of the 

exposure concentrations to approximately 17% to 

50% of the original exposure concentrations for the 

5- and 15-minute durations, respectively. Table E–4 

provides the extrapolated 30-minute-equivalent 

concentration for 1,1-dimethylhydrazine. Figure E–3 provides a visual representation of the 

data for 1,1-dimethylhydrazine. In comparison, 

the selected LC50 and LOAEL values for vinyl acetate were associated with exposure durations of 2 

to 6 hours. Because no empirically derived value of 

n was available, a default value of 3 for n was used 

for time scaling in the ten Berge equation to adjust 

the data points from longer to shorter exposure durations. As noted earlier, this is a health-protective 

default. The resulting extrapolated concentrations 

were approximately double the original exposure 

concentrations and can be found in Table E–5 and 

Figure E–4. The last example, titanium tetrachloride (see Table E–6 and Figure E–5), demonstrates 

the effects of the use of an empirically derived n

to calculate the 30-minute equivalents for exposure concentrations associated with durations both 

shorter and longer than 30 minutes. A value of 0.88 

has previously been calculated by the NAS during 

the development of the AEGL values for titanium 

tetrachloride [NAS 2007]. For data corresponding to exposure durations less than 30 minutes, 

the resulting extrapolated concentrations were 

approximately 5% to 50% of the original LC50 and 

LOAEL values. Substantial changes in the extrapolated 30-minute-equivalent concentrations were 

also observed when extrapolating from longer to 

shorter durations, with the relative increases being 

in a range of 2 to 10 times higher than the original 

value. As evident by the three previous examples, 

selection of the appropriate n during time scaling may greatly affect the resulting 30-minuteequivalent concentrations. 
78 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Table E–4. Time scaling of toxicity data from shorter to longer 

durations, using the ten Berge equation: 1,1-dimethylhydrazine (CAS# 57-41-7)

Study no. Species

Toxicological endpoint

Exposure duration 

(minute) n

30-minute equivalent value 

(ppm)

LC50 value 

(ppm)

LOAEL

(ppm)

1 Rat 8,230 15 1 4,115

2 Rat 24,500 5 1 4,083

3 Dog 3,580 15 1 1,790

4 Dog 22,300 5 1 3,717

5 Dog 360 15 1 180

6 Dog 1,550 5 1 258

Abbreviations: LC50 value = median lethal concentration; LOAEL = lowest observed adverse effect level; ppm = parts per million;

n = exponent applied in ten Berge equation [1986]. The study data are from Weeks et al. [1963].

0

5000

10000

15000

20000

25000

30000

0 12345 6

Concentration (ppm)

Study number

 

Study concentration

Duration adjusted concentration

Figure E–3. Time scaling of toxicity data from shorter to longer durations, using the ten Berge 

equation: 1,1-dimethylhydrazine (CAS# 57-41-7)*

Abbreviation: ppm = parts per million

*All 30-minute data points are duration-adjusted values.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 79

Table E–5. Time scaling of toxicity data from shorter to longer durations, 

using the ten Berge equation: vinyl acetate (CAS# 108-05-04)

Species Reference

Toxicological 

endpoint

Exposure 

duration 

(minute) n

30-minuteequivalent

value

(ppm)

Study 

no.

LC50

(ppm)

LOAEL 

(ppm)

1 Rat Bogdanffy et al. [1997] 1,000 360 3 2,289

2 Rat Roumiantsev et al. [1981] 3,238 240 3 6,476

3 Mouse Smyth and Carpenter [1973] 1,460 240 3 2,920

4 Dog Smyth and Carpenter [1973] 3,280 240 3 6,274

5 Guinea pig Smyth and Carpenter [1973] 5,210 240 3 10,420

Abbreviations: LC50 value = median lethal concentration; LOAEL = lowest observed adverse effect level; n = exponent applied in 

ten Berge equation [1986]; ppm = parts per million.

0

2000

4000

6000

8000

10000

12000

0 1234 5

Concentration (ppm)

Study number

Study concentration

Duration adjusted concentration

Figure E–4. Time scaling of toxicity data from shorter to longer durations, using the ten Berge 

equation: vinyl acetate (CAS# 108-05-04)*

Abbreviation: ppm = parts per million

*All 30-minute data points are duration-adjusted values.
80 NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values

Table E–6. Effects of an empirically-derived n on time adjustments, 

using the ten Berge equation: titanium tetrachloride (CAS# 7550-45-0) 

Species Reference

Toxicological 

endpoint

Exposure duration

(minute) n

30-minuteequivalent value

(ppm)

Study 

no.

LC50

(ppm)

LOAEL 

(ppm)

1 Rat Kelly [1980] 13,940 2 0.88 642

2 Rat Kelly [1980] 4600 5 0.88 600

3 Rat Kelly [1980] 713 15 0.88 324

4 Rat Kelly [1980] 171 60 0.88 376

5 Rat Kelly [1980] 143 120 0.88 691

6 Rat Kelly [1980] 59 240 0.88 627

7 Rat Gardner [1980] 26 20 0.88 16

Abbreviations: LC50 = statistically determined median concentration of a substance in the air that is estimated to cause death in 

50% (one half) of the test animals; LOAEL = lowest observed adverse effect level; n = exponent applied in ten Berge equation 

[1986; NAS 2007]; ppm= parts per million.

0

2,000

4,000

6,000

8,000

10,000

12,000

14,000

16,000

012 3 456 7

Concentration (ppm)

Study number

Study Concentration

Duration Adjusted

Concentration

Figure E–5. Effects of an empirically derived n on time adjustments, using the ten Berge equation: 

titanium tetrachloride (CAS# 7550-45-0)*

Abbreviation: ppm = parts per million.

*All 30-minute data points are duration-adjusted values.
NIOSH CIB 66 • Derivation of Immediately Dangerous to Life or Health (IDLH) Values 81

Appendix E: References 

Bogdanffy MS, Gladnick NL, Kegelman T, Frame 

SR [1997]. Four-week inhalation cell proliferation 

study of the effects of vinyl acetate on rat nasal epithelium. Inhal Toxicol 9:331–350.

Gardner RJ [1980]. Rat sensory irritation study: 

TiCl4

. Haskell report no. 593-80, August 11, 1980. 

Wilmington, DE: E.I. du Pont de Nemours and 

Company, Haskell Laboratory for Toxicology and 

Industrial Medicine. 

ICRP [1994]. Human respiratory tract model for 

radiological protection. ICRP publication 66. Ann 

ICRP 24(1–3).

Kelly DP [1980]. Acute inhalation studies with titanium tetrachloride. Haskell Laboratory report no. 

658–80, October 31, 1980. Wilmington, DE: E.I. du 

Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. 

NAS [2007]. Interim acute exposure guideline 

levels (AEGLs) for selected metal phosphides. 

Committee on Toxicology, Board on Environmental 

Studies and Toxicology, National Research Council, 

National Academy of Science. Washington, DC: 

National Academy Press [http://www.nap.edu/]. 

Roumiantsev AP, Tiunova LV, Astapova CA, Kustova ZR, Lobanova IA, Ostroumova NA, Petushkov 

NM, Chernikova VV [1981]. Information from the 

Soviet Toxicology Center: toxicometric parameters 

of vinyl acetate. Gig Tr Prof Zabol 11:57–60.

Smyth HF, Carpenter CP [1973]. Initial submission: vinyl acetate: single animal inhalation and 

human sensory response, with cover letter dated 

082792. Doc. no. 88-920010328. Pittsburgh, PA: 

Carnegie-Mellon Institute. 

ten Berge WF, Zwart A, Appelman LM [1986]. 

Concentration-time mortality response relationship of irritant and systematically acting vapors 

and gases. J Haz Mat 13:301–309.

Weeks MH, Maxey GC, Sicks ME, Greene EA [1963]. 

Vapor toxicity of UDMH in rats and dogs from short 

exposures. Am Ind Hyg Assoc J 24:137–143. 
This page intentionally left blank. 
This page intentionally left blank.
To receive NIOSH documents or more information about occupational safety and health topics, contact NIOSH:

1–800–CDC–INFO (1–800–232–4636)

TTY: 1–888–232–6348

CDC INFO: www.cdc.gov/info

or visit the NIOSH website at http://www.cdc.gov/niosh.

For a monthly update on news at NIOSH, subscribe to 

NIOSH eNews by visiting www.cdc.gov/niosh/eNews.

DHHS (NIOSH) Publication No. 2014–100

safer • healthier • peopleTM

Delivering on the Nation’s promise:

safety and health at work for all people

through research and prevention