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



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ternal 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. 

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## 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 • People TM

## iii 

# Foreword

Since the establishment of the original Immediately Dangerous to Life or Health (IDLH) val

ues in 1974, the National Institute for Occupational Safety and Health (NIOSH) has con

tinued 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 charac

terize the health risks of occupational exposures to high concentrations of airborne contami

nants. The methodology for deriving IDLH values presented in the CIB incorporates the ap

proach 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. Depart

ment 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 in

crease the transparency behind their derivation. The increased transparency will provide occupational health professionals, risk managers, and emergency response personnel ad

ditional 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 man

agement 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

## 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 air

borne 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, se

vere irreversible health effects, impairment of the ability to escape from the exposure en

vironment, 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 ex

plosions), 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 Danger

ous to Life or Health (IDLH) values, which are intended to characterize these high-risk con

ditions. 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 con

taminated 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, provid

ing 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 Cur

rent 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 The IDLH methodology outlined in this CIB reflects the modern principles and under

standing 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 as

sessment practices. According to this protocol, IDLH values are based on health effects con

siderations 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 characteriza

tion 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 con

centrations 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 methodol

ogy 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 ex

trapolation 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, includ

ing 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 avail

able 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,

## vii 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 po

tential 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 stud

ies 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 chemi

cal 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 interspe

cies 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 alter

native 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 re

duces visibility, preventing escape from the hazardous environment

• The airborne concentration of a gas or vapor is greater than 10% of the lower explo

sive limit (LEL) and represents an explosive hazard. In such cases, it is important that safety hazards or other considerations be taken into ac

count. Information on the safety hazards will be incorporated in the support documenta

tion ( 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 mini

mum explosive concentration (MEC). However, determining the combustibility of dusts is

## viii complicated and dictated by the relationship between multiple dust-specific factors includ

ing, but not limited to, particle size distribution, minimum ignition energy, explosion in

tensity, and dispersal in the air [Cashdollar 2000]. The ability to quantify dust-specific con

centrations 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 consider

ations 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 scientifi

cally based approach for the selection of the UF during the derivation of IDLH values. In addi

tion, 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.

## ix 

# Contents

Foreword

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii Executive Summary

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Abbreviations and Acronyms

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi Glossary

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Acknowledgements

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xxiii 1 Intro duction

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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 Cr it eria 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 U se o f 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 Ref erenc es
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Appe ndix 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 Appe ndix B: ID LH Value Development Prioritization

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

## x References

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Appendix C: C ritical 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

## xi 

# Abbreviations and Acronyms

ACGIH A merican Conference of Governmental Industrial Hygienists AIHA A merican Industrial Hygiene Association AEGL A cute Exposure Guideline Level (published by NRC) AUC a rea under the curve ATSDR A gency for Toxic Substances and Disease Registry BBDR b iologically based dose response BMC b enchmark concentration BMCL b enchmark concentration lower-bound confidence limit BMD b enchmark dose BMDS B enchmark Dose Software (developed by USEPA) “C” cei ling value CA carcinogen Cal/EPA C alifornia Environmental Protection Agency CAS# C hemical Abstracts Service Registry Number CDC C enters for Disease Control and Prevention CFATS C hemical Facility Anti-Terrorism Standards (developed by DHS) CFR C ode of Federal Regulations CHEMID o nline chemical identification database (developed by NLM) CIB C urrent Intelligence Bulletin (developed by NIOSH) C max p eak (maximum) concentration CNS cen tral 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 de velopmental toxicant EC eff ective concentration

## xii EEGL Em ergency and Continuous Exposure Guidance Levels (p ublished by NRC) EINECS E uropean IN ventory of E xisting C ommercial chemical S ubstances EMBASE o nline biomedical journal abstract and indexing database (s ubscription based) EPP Em ergency Preparedness Plan ERPG Em ergency Response Planning Guidelines (developed by AIHA) ERG Em ergency Response Guidebook (developed by DOT) EU E uropean Union FEL f rank effect level FACA F ederal Advisory Committee Act GI gastrointestinal GLP G ood Laboratory Practices HAZARDTEXT® o nline hazardous substance database (subscription based) HazMap o nline occupational exposure to hazardous agents database (de veloped by NLM) HCN h ydrogen cyanide hr hour HPV hig h production volume HSDB H azardous Substance Data Bank (developed by NLM) HSEES H azardous Substance Emergency Events Surveillance (de veloped by ATSDR) IARC I nternational Agency for Research on Cancer ICSC I nternational Chemical Safety Cards (developed by IPCS) IDLH I mmediately Dangerous to Life or Health (developed by NIOSH) i.p. in traperitoneal IPCS I nternational Programme on Chemical Safety IRIS I ntegrated Risk Information System (developed by USEPA) IRR irritant ITER I nternational Toxicity Estimates for Risk database (de veloped by TERA) JSC J ohnson Space Center (division of NASA) k a constant reflected in equations expressing “conc × time” relationships kg kilogram L liter LC let hal concentration

## xiii LD let hal dose LEL lo wer explosive limit L/min li ters per minute LOAEL lo west observed adverse effect level LOEL lo west observed effect level

m 3 c ubic meter MEC minim um explosive concentration MEDITEXT® o nline medical and toxicology database (subscription based) mg/m 3 mi lligrams per cubic meter of air mg/m 3 -min mi lligrams per cubic meter of air per minute min minute MOA m ode of action MSHA M ine Safety and Health Administration NAC/AEGL N ational Advisory Committee for Acute Exposure Guideline L evels for Hazardous Substances NASA N ational Aeronautics and Space Administration NAS/NRC N ational Academy of Sciences/National Research Council NIOSH N ational Institute for Occupational Safety and Health NIOSHTIC2 b ibliographic database of NIOSH-supported occupational safety
a nd health publications NJ-HSFS N ew Jersey Hazardous Substance Fact Sheets NLM N ational Library of Medicine NOAEL n o observed adverse effect level NOEL n o observed effect level NRC N ational Research Council NTP N ational Toxicology Program OECD Or ganisation for Economic Co-operation and Development OEL o ccupational exposure limit OSHA O ccupational Safety and Health Administration PAL P rovisional Advisory Levels (developed by DHS) PBPK p hysiologically based pharmacokinetic PEL P ermissible Exposure Limit (developed by OSHA and MSHA) ppm p arts per million POD p oint of departure PUBMED o nline biomedical literature citation database (developed by NLM)

## xiv RD r espiratory depression REL R ecommended Exposure Limit (developed by NIOSH) RfC in halation reference concentration RIVM N etherlands National Institute for Public Health
a nd the Environment RMP R isk Management Plan R-phrases r isk phrases (developed by EU) RTECS R egistry of Toxic Effects of Chemical Substances SCAPA S ubcommittee on Consequence Assessment and Protective Actions SCBA s elf-contained breathing apparatus SCP S tandards Completion Program (developed by NIOSH and OSHA) SMAC S pacecraft Maximum Allowable Concentration (developed by N ASA, published by NRC) SOP S tanding Operating Procedures SPEGL S hort-term Public Emergency Guidance Levels (developed by NRC) STEG s hort-term exposure guidelines STEL S hort Term Exposure Limit ST s hort-term exposure limit TEEL T emporary Emergency Exposure Limit (developed by DOE) TERA T oxicology Excellence for Risk Assessment TIH t oxic inhalation hazard (developed by DOT) TLV 

## ® Thr eshold Limit Value (developed by ACGIH) TOXLINE o nline toxicology literature database (developed by NLM) TWA t ime-weighted average UF un certainty factor USEPA U .S. Environmental Protection Agency WEEL W orkplace Environmental Exposure Limits (developed by AIHA) WHO W orld Health Organization

## 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 min

utes, 1 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of sever

ity 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 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. Com

mon defaults for the BMR are 10% or 5%, reflecting study design, data variability, and sen

sitivity 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 de

fine 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 expo

sure 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 bio

logical agents. Ceiling Value (“C”) : U.S. term in occupational exposure indicating the airborne concen

tration of a potentially toxic substance that should never be exceeded in a worker’s breath

ing zone. Chronic Exposure : Repeated exposure for an extended period of time. Typically expo

sures 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/m 3 ) or the volume of test article per unit volume (e.g., ppm, mL/L). Concentration-response Curve : Graph of the relationship between the exposure concen

tration 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 quantita

tive assessment of risk [USEPA 2010].

## xvii 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 develop

mental 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; deter

mination of respiratory tract region deposition fractions.
ECt 50 : A combination of the effective concentration of a substance in the air and the ex

posure 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 oc

cupational 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 concentra

tions below which nearly all individuals can be exposed without experiencing health ef

fects 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 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 prob

ability 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 dura

tion (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 non

cancer health assessments. Internal Dose : A dose denoting the amount absorbed without respect to specific absorp

tion 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 environmen

tal 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).
LC 01 : The statistically determined concentration of a substance in the air that is estimated to cause death in 1% of the test animals.
LC 50 : 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.
LC LO : The lowest lethal concentration of a substance in the air reported to cause death, usu

ally for a small percentage of the test animals.

## xix LD 50 : 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.
LD LO : 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 concentra

tion 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 sub

stance 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 repre

sent 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 pe

riod 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 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 hazard

ous 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, distri

bution among target organs and tissues, metabolism, and excretion. Point of Departure (POD) : The point on the dose–response curve from which dose ex

trapolation is initiated. This point can be the lower bound on dose for an estimated inci

dence 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 expo

sure 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 inci

dents [US DHS 2009].
RD 50 : 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 pre

vent adverse health effects based on human and animal studies and established for occu

pational (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 reproduc

tive 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 sub

stances 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 be

tween 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.

## xxi Short-Term Exposure Limit (STEL) : A worker’s 15-minute time-weighted average expo

sure 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 un

predicted, 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 ac

cidental releases, and long-term guidelines (up to 180 days) apply to low levels of contami

nants 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 appropri

ate adjustments for differences in potency, to apply to an entire chemically and toxicologi

cally 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 com

munities 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 Indus

trial Hygienists (ACGIH). TLVs refer to airborne concentrations of chemical substances and represent conditions under which it is believed that nearly all workers may be repeat

edly 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 aver

age 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 ex

posed organism.

## xxii Toxicology : Scientific discipline involving the study of the actual or potential danger pre

sented 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 uncon

trolled 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 hu

mans), or whether an effect occurs at a specific exposure level. Workplace Environmental Exposure Levels (WEELs) : Exposure levels that provide guid

ance for protecting most workers from adverse health effects related to occupational chemi

cal exposures expressed as a TWA or ceiling limit.

## xxiii 

# 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 ac

knowledgment 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 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

## 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

## 1 

# 1 Introduction

Occupational exposures to chemicals have long been recognized as having the potential to ad

versely 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” situ

ations 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 re

lease 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 ex

posure 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 develop

ing acute exposure guidelines. This document re

flects 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 avail

able 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 B ackground The concept of using respirators to protect work

ers 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. Depart

ment of Labor (DOL) bulletin: The situations for which respiratory protec

tion is required may be designated as, (1) non

emergency 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, per

manent harm, or death after a prolonged expo

sure or with repeated exposure. Emergency sit

uations 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 The Occupational Safety and Health Administra

tion (OSHA) defines an IDLH concentration in the hazardous waste operations and emergency re

sponse regulation as follows: An atmospheric concentration of any toxic, cor

rosive or asphyxiant substance that poses an im

mediate 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 de

layed threat to life or that would cause irrevers

ible 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 con

sidered 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 appli

cation of respirators in IDLH conditions. Specific information that is provided in the respiratory pro

tection standard requires:

• A trained standby person be present with suit

able rescue equipment when self-contained breathing apparatus or hose masks with blow

ers are used in IDLH atmospheres; and • Persons using air-line respirators in IDLH at

mospheres must be equipped with safety har

nesses 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 de

fines “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, immedi

ate 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 T he Standards Completion Program In 1974, NIOSH and OSHA jointly initiated the de

velopment of occupational health standards consis

tent with Section 6(b) of the Occupational Safetyand Health Act of 1970 for substances with thenexisting OSHA permissible exposure limits (PELs). This joint effort was called the Standards Comple

tion Program (SCP) and resulted in the develop

ment of 387 substance-specific draft standards with supporting documentation that contained techni

cal information and recommendations needed for the promulgation of occupational health regula

tions. 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 deter

mined 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 pro

vide guidance on respirator selection and to estab

lish a maximum exposure concentration in which workers, in the event of respiratory protection fail

ure (e.g., contaminant breakthrough in a cartridge

## 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 ex

posure. 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 B asis 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 hu

mans 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 es

timated on the basis of an equivalent exposure to a 70-kilogram (kg) worker breathing 10 cubic meters (m 3 ) of air for an 8-hour period. Because chronic exposure data may have little relevance to acute ef

fects, 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 val

ues 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 ob

tained 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 (Chemi

cal Abstracts Service number [CAS#] 50-29-3) and triphenyl phosphate (CAS# 115-86-6)—showed no evidence that an acute exposure to high concentra

tions would impede escape or cause any irrevers

ible health effects following a 30-minute exposure, and the designation “NO EVIDENCE” was used in the listing of IDLH values. For all of these sub

stances, respirators were selected on the basis of assigned protection factors. For some (e.g., cop

per 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” respira

tors were permitted. However, for most particu

late 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 encoun

tered 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 re

view and revision of the IDLH values) that for such

## 4 particulate substances, only the “most protective” respirators would be permitted for use in concen

trations 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 con

centrations 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 protec

tive” 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 val

ues determined during the SCP were greater than the concentrations permitted on the basis of as

signed respiratory protection factors. In most in

stances the IDLH values for these substances were set at concentrations 2,000 times the PEL.


## 1.4 Up date 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 ex

posure is likely to cause death or immediate or de

layed 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 respi

rators) would be selected for emergency situations, firefighting, exposure to carcinogens, entry into oxygen-deficient atmospheres, entry into atmo

spheres 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” res

pirators include either a self-contained breathing apparatus (SCBA) that has a full face piece and isoperated in a pressure-demand or other positivepressure mode or else a supplied-air respirator thathas a full face piece and is operated in a pressuredemand or other positive-pressure mode in com

bination 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 re

quested information on the uses of IDLH values in the workplace and on the scientific adequacy of the criteria and procedures originally used for estab

lishing them [Federal Register, Volume 58, Num

ber 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 re

view the original IDLH values and revise them as appropriate [NIOSH 1994]. The update was com

pleted in 1994. The 1994 update also included revi

sions 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 occu

pational 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 protec

tive” respirators be worn by workers exposed at concentrations above the NIOSH REL, or at any detectable concentration when there is no REL. For

## 5 ethylene oxide and crystalline silica, NIOSH rec

ommends that the “most protective” respirators be worn in concentrations exceeding 5 parts per mil

lion (ppm) and milligrams per cubic meter of air (mg/m 3 ), respectively [NIOSH 1987, 2004].


## 1.5 P urpose and Objectives of the IDLH Values IDLH values have traditionally been identified as a key component of the decision logic for the selec

tion 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 provid

ing maximum worker protection is permitted. Ad

ditionally, IDLH values are based on a 30-minute exposure duration. Since the inception of IDLH values as part of the SCP, occupational health pro

fessionals have employed these values beyond their initial purpose as a component of the NIOSH Res

pirator Selection Logic . Examples of such applica

tions 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 devel

opment 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 devel

opment of RMPs and EPPs. The scientific rationale and derivation process out

lined 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 repre

sents a high-risk situation that may endanger work

ers’ 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 re

sponse 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 as

sociated 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 rou

tine occupational exposure conditions (see Section 2.3 ). A situation resulting in airborne concentra

tions at or near the IDLH value should be consid

ered a non-routine event, and exposure duration should not exceed 30 minutes. All available precau

tions 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 work

place hazards, such as safety concerns and con

siderations. Situations and conditions that might preclude the use of a health-based IDLH value in

clude 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 nitro

gen (CAS# 7727-37-9).

• Where the IDLH value based on health effects considerations is higher than a particulate

## 6 concentration that generates significant haz

ards 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 caus

ing 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 ef

fects 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 ef

fects data, the most protective respiratormay not be adequately protective for fullshift exposures at this concentration. Exam

ples 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. In

formation on safety hazards will be incorporated into the derivation of an IDLH value when appro

priate. 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 addi

tion, the notation (>10% LEL) will appear be

side 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 Na

tional Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/ AEGL Committee) [NAS 2001]. Additional infor

mation on the establishment of IDLH values based on safety hazards can be located in Section 3.6.

## 7 

# 2 C omparison of IDLH Values to Alternative S hort-term Exposure Limits/Values

An important step in the development of IDLH values is the review of alternative short-term ex

posure 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 de

veloping 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 andselected 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, de

pending on availability. Although IDLH values may rely on much of the same acute health effects information used to de

rive alternative short-term exposure limits/values, there are underlying differences in the intended use of the various acute exposure values. Therefore, re

view 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 A cute Exposure Guideline Levels AEGLs are threshold exposure limits for the gen

eral public intended to be guideline levels used during rare events or single once-in-a-lifetime ex

posures 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 ex

posure 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 fre

quent 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 de

grees of severity of toxic effects. The three AEGLs are defined as follows [NAS 2001]:

• AEGL-1 is the airborne concentration (ex

pressed as ppm or mg/m 3 ) of a substance above which it is predicted that the general

## 8 population, including susceptible individu

als, could experience notable discomfort, irri

tation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and reversible upon cessa

tion of exposure.

• AEGL-2 is the airborne concentration (ex

pressed as ppm or mg/m 3 ) of a substance above which it is predicted that the general population, including susceptible individu

als, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.

• AEGL-3 is the airborne concentration (ex

pressed as ppm or mg/m 3 ) of a substance above which it is predicted that the general population, including susceptible individu

als, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 repre

sent 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 suscepti

ble 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 experi

ence 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 dura

tion 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

## 9 is that the AEGL-2 is designed to protect the gen

eral population, including potentially sensitive sub

populations (i.e., children, elderly, and individuals with pre-existing health impairments). IDLH values are designed for worker populations, which tradi

tionally 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 se

lection 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 dif

ferent 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 es

tablish AEGL values and IDLH values for a chemi

cal. 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 thresh

old. 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 heav

ily on the overall weight of evidence, with limited use of default procedures. The extensive AEGL documentation for each chemical has been thor

oughly reviewed by expert committees and is often a useful resource for de novo analyses. In addition, the AEGL documentation includes detailed analy

sis 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 Commit

tee Act (FACA) committee established to identify, review, and interpret relevant toxicologic and other scientific data and to develop AEGLs for high pri

ority, 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 Protec

tion Agency [USEPA], U.S. Department of Trans

portation [DOT], U.S. Department of Defense [DOD], U.S. Department of Energy [DOE], Agency for Toxic Substances and Disease Regis

try [ATSDR], Canadian Government, Netherlands National Institute for Public Health and the En

vironment [RIVM], state agencies and environ

mental organizations, academia, private industry, and international and nonprofit organizations). Interim AEGLs prepared by the AEGL Commit

tee, after stakeholder comment, are reviewed by the National Academy of Sciences (NAS)/Nation

al Research Council (NRC) AEGL Committee be

fore finalization.


## 2.2 Emer gency 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 concentra

tions 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 pre

vention and emergency response plans, including transportation emergency planning, and for devel

oping community emergency response plans. As with AEGLs, there are three ERPG guidance con

centration levels designed for community protec

tion [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 concentra

tion below which it is believed that nearly all individuals could be exposed for up to one hour without experiencing other than mild,

## 10 transient adverse health effects or without per

ceiving 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 ormild irritation. In the event that a small, nonthreatening release has occurred, the commu

nity could be notified that they may notice an odor or slight irritation but that concentrations are below those which could cause unac

ceptable health effects. For some materials, because of their properties, there may not be an ERPG-1. Such cases would include sub

stances 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 concentra

tion below which it is believed that nearly all individuals could be exposed for up to one hour without experiencing or developing ir

reversible 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 ad

verse 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 re

spiratory irritation, muscular weakness, cen

tral nervous system (CNS) impairments, or serious adverse health effects.

• ERPG-3 : The maximum airborne concentra

tion below which it is believed that nearly all individuals could be exposed for up to onehour 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 organiza

tion, ERPGs are more like the AEGLs in that they are designed to protect the general population, and thus susceptible populations are more of a consid

eration for ERPGs than for IDLH values.


## 2.3 Oc cupational Exposure Limits OELs are derived by various governmental, nongov

ernmental, 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 orga

nizations and their respective OEL values include; NIOSH RELs, OSHA PELs, MSHA PELs, ACGIH TLVs®, and AIHA WEELs®. Although the exact def

inition 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

## 11 human data (such as results from epidemiologic studies or controlled human exposure studies), animal toxicologic data, or a combination of hu

man and animal data. The health basis on which exposure limits are established may differ from sub

stance to substance; protection against impairment of health may be a guiding factor for some, whereas reasonable freedom from irritation, narcosis, nui

sance, 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 re

sisting other toxic substances or disease processes, or impair reproductive function or developmental processes. Alternative considerations, such as tech

nological 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 con

trol 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 un

interrupted exposures or other exposure scenarios involving extended work periods, or as proof of ex

isting disease or physical conditions. OELs neither clearly delineate between safe and dangerous con

centrations 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 con

centration 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, eco

nomic 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 catego

ry 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 in

jury, 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 ceil

ing OELs and designated by ACGIH with a “C” pre

ceding the value, are the concentrations that should not be exceeded during any part of the working ex

posure, unless otherwise noted [ACGIH 2009]. Like the IDLH values, OELs are aimed at worker populations, and therefore consideration of sus

ceptible 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 air

borne 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 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 O ther Acute Exposure Limits/Values A number of other governmental agencies and orga

nizations also develop, or have developed, acute in

halation exposure limits/values intended to address various applications, exposed populations, and du

rations. 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 in

sights that impact the development or interpreta

tion of the IDLH value. For example, acute expo

sure limits/values from other government agencies and organizations might be included in the docu

mentation 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]

## 13 

# 3 C riteria 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 sci

entific 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) ap

proach, 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 over

all 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. Over

all, 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 deter

mine 30-minute-equivalent exposure concen

trations, as well as other dosimetry adjustments as needed • Application of a UF for each potential POD or critical adverse-effect concentration iden

tified 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 tox

icity), 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 ap

proach, 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 simi

lar to that used in other risk assessment applica

tions, 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.

## 14Figure 3–1.Key steps in the derivation of IDLH values.

## 15 As illustrated in the remainder of this CIB, deriva

tion of IDLH values uses a systematic data evalu

ation 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 weigh

ing various lines of evidence, with vetting by multi

ple scientists through a rigorous peer review process. Thus, although the following sections describe gen

eral 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 I mportance of Mode ofAction and Weight-ofEvidence Approach The mode of action (MOA), meaning a general de

scription 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 chemi

cal 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 re

spiratory irritation and CNS effects. Some of the more common classes of MOA that are encoun

tered 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 irri

tants 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 com

monly 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 re

active 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 depres

sion. Clinical signs reported in humans may include fatigue, weakness, and headaches. Endpoints commonly reported in animals or humans include sedation and reduced per

formance in specialized neurological testing. Certain classes of pesticides (e.g., organophos

phates 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 (con

striction 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 • Target Organ Toxicants: Certain organs or organ systems, such as the liver or kidney, arethe 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 evalu

ation of histopathology or clinical chemistry for certain organ systems. Also, acute poison

ing incidents in humans may indicate that the liver or kidney is a target. These organ systems are frequently the most sensitive systemic tar

gets 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, nau

sea, and shortness of breath. A number of halogenated hydrocarbons (e.g., vinyl chlo

ride [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 ef

fects. 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 oxy

gen. Chemical asphyxiants (e.g., carbon mon

oxide [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 symp

toms 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 differ

ences. Below are some examples of how MOA af

fects 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 sup

port 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 dura

tion of exposure.

• MOA information indicating that the chem

ical targets the route of entry, with resulting effects such as eye, nose, and throat irrita

tion, would indicate that the route-to-route extrapolation is not appropriate.

• MOA information may suggest the use of surrogates when information on the chemi

cal of interest is limited or when a breakdown product is identified as being the primary cause of toxicity. For example, HCN is com

monly used as a surrogate for acetocyanohy

drin (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., hu

midity) to form hydrogen chloride and silan

ols. 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 po

tential refinements to the dose–response analysis. For example, carbon monoxide toxicity is due to the formation of carboxy

hemoglobin (COHb), and the IDLH value for carbon monoxide is based on calculated COHb levels.

## 17 

## 3.2 P rocess for Prioritization of Chemicals In addition to serving as a crucial factor in the se

lection of respiratory protection equipment, IDLH values play an important role in planning workpractices 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 chemi

cals 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 im

pact 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 sim

ple 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 ap

proach would not meet the primary objective to quickly and effi ciently identify chemicals of great

est 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 re

lated to toxicity or exposure potential. The develop

ment and use of a documented prioritization pro

cess 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 Lit erature Search Strategy NIOSH performs in-depth literature searches to ensure that all relevant data from human and ani

mal 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 conduct

ed with limitations on search dates. The databases are searched for studies pertinent to acute inhala

tion toxicity, with use of the search terms summa

rized 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 re

views are also examined, including those identi

fied by searching the databases and organization websites, as noted in Table 3–1. Toxicology reviews that are routinely used to identify pertinent litera

ture 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 documenta

tion), OSHA (i.e., PEL documentation), WHO (i.e., Environmental Health Criteria) and USEPA (i.e., IRIS Toxicological Reviews). Other key unpub

lished 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 dur

ing the external and stakeholder review process.


## 3.4 Det ermining 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 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, LC 50 values)

• Duration of the exposure for the study. Once this information is compiled, critical ef

fect 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, E uropean IN ventory of E xisting C ommercial chemical S ubstances (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

## 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 quantita

tive 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 se

lection 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 S tudy 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 ex

posure 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 qual

ity 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 Or

ganisation for Economic Co-operation and Devel

opment [OECD] test guidelines), and whether good laboratory practices (GLPs) were followed. These considerations are evaluated for each study accord

ing 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 stud

ies 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 consid

erations. 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 LC 50 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 LC 50 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 S tudy Relevance Considerations The weight-of-evidence approach requires a criti

cal 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 se

vere, irreversible or escape impairing effects. The methodology for developing IDLH values follows a hierarchical approach based on the following pref

erence 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 fol

lows similar principles but is based more on an over

-

## 20 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 ob

tained directly from original studies and reports, whereas secondary data refers to information sum

marized 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 informa

tion. 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 informa

tion contained within the secondary data source. Some secondary sources provide greater value than other sources. For example, authoritative second

ary sources might include robust toxicity profiles that have undergone extensive review, such as the ATSDR Toxicological Profiles or EPA IRIS Toxico

logical Reviews. Peer reviewed data are generally preferred as the basis of an IDLH value, over data obtained fromnon-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 aredetermined 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 standard

ized or guideline-compliant protocols, butavailable 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 bet

ter biological and statistical significance due to increased sample size, selection of test spe

cies, 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 R elevance of the Type and Severity of the Effect
3.4.2.1.1 G eneral 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 de

velop a high-confidence estimate of the 30-minute human threshold concentration for severe, irre

versible, 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 ob

served 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 ob

served adverse effect level (NOAEL) for severe or escape-impairing effects. In some cases, concentra

tion modeling can be used to further refine such es

timates 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 onmortality, 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

## 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 accuratelydetermined 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 concen

tration 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 consid

ered 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 C onsideration of lethality data Datasets for acute toxicity are often limited to stud

ies 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 thresh

old for lethality is the preferred basis for an IDLH value, rather than an estimate of median lethal con

centration (i.e., the LC 50 ). Lethality thresholds can be estimated from LC LO values (the lowest concen

tration in the study that caused lethality) if the mor

tality 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 wheth

er the estimate is the maximum likelihood estimate or a lower confidence limit. For example, a com

monly reported model value such as an LC 01 value (the statistically derived air concentration that caused lethality in 1% of test animals) is the model estimated maximum likelihood concentration as

sociated 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 con

centrations. 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 estimate or the 95% lower-bound confidence limit on the BMC (BMCL). Thus, a BMCL 05 is the esti

mated 95% lower confidence bound on the con

centration associated with a 5% increased lethality response above controls. Such model-calculated values are preferred over LC LO 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 tak

ing into account the uncertainty in the data and sta

tistical power of the study. Frequently, the BMCL 05 (i.e., the lower 95% confidence limit on the concen

tration associated with a 5% response) and BMC 01 (i.e., the central tendency estimate of the concentra

tion associated with a 1% response) are both calcu

lated for lethality data, and the lower value is used as the lethality threshold. The lower value is often the BMCL 05 , 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 LC 50 values has been ap

plied in the AEGL methodology [NAS 2001; Rusch et al., 2009]. This approach uses 1/3 of the LC 50 value as the POD to estimate the boundary between the lethality threshold and a non-lethal exposure level. When compared to LC 01 values and BMCL 05 values for selected chemicals, in general, 1/3 of the LC 50 value resulted in lower estimates of a non-lethalthreshold [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 LC 50 values as a POD. Although estimates of a lethality threshold are pre

ferred over other measures of lethal concentrations, in many cases, the only available data from acute lethality studies are LC 50 values (i.e., concentrations associated with a 50% mortality incidence). † If LC 50 value estimates are available for multiple species, then the lowest reliable LC 50 value in the most rele

vant animal species is used for extrapolation to pre

dict 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 consid

ering study quality. Multiple LC 50 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 dif

ference exists, the LC 50 from the more sensitive sex is used. If there is no clear difference, the combined LC 50 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 dif

ferent measures of lethality are available from the rat study: the LC 50 , LC LO , and BMCL 05 . The selected POD for deriving the IDLH value would be the rat BMCL 05 , 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 BMCL 05 resulted in the lowest derived value, but the BMCL 05 would gener

ally be preferred, even if it was somewhat higher than the LC LO , due to statistical variability related to the LC LO and because the BMCL 05 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 in

terest. Because the goal is to estimate the threshold for the severe responses, a larger UF is applied to the LC 50 value than is applied to measures around

† LC 50 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 usu

ally fits acute data well, particularly for lethality data (e.g., Fowles et al. [1999]).

## 23 the threshold for lethality, such as the BMCL 05 (see Chapter 4 for additional discussion of UF).

3.4.2.1.3 C onsideration of escape-impairing effects For effects other than mortality, reported health ef

fects in both human and animal studies are classified as severe, irreversible, or escape-impairing. Identify

ing which effects may be escape-impairing is compli

cated 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 dis

charge, 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 irrevers

ible 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 com

monly 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, moder

ate, or severe. The severity and the type of the ef

fect are considered in determining whether escape impairment is likely. For example, moderate to se

vere eye irritation, but not mild irritation, is gener

ally considered an appropriate basis for an IDLH value based on escape impairment. For effects on the CNS, narcosis or moderate dizziness is consid

ered sufficiently adverse to impair escape, whereas effects such as headache are generally not consid

ered 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 screen

ing assays, such as the respiratory depression 50% (RD 50 ) assay and cardiac sensitization tests. The RD 50 assay is a sensitive measure of sensory irrita

tion, which occurs due to stimulation of trigemi

nal nerve endings in the cornea and nasal mucosa. These effects frequently are due to a decrease in respiratory frequency that occurs in some labora

tory animals when exposed to chemical irritants. The RD 50 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 LC 50 /1000 30 30 33 Males and females combined
Rat LC LO /400 30 10 40 1/10 died
Rat BMCL 05 /240 30 10 24 Modeling done by the authors
Mouse LC 50 /2000 30 30 66 Males only
Abbreviations: BMCL 05 = lower 95% confidence limit on the concentration associated with a 5% response; IDLH = immediately

dangerous to life or health; LC 50 value = median lethal concentration; ppm = parts per million; UF = uncertainty factor.

## 24 weight of evidence and can be used to support the selection of a POD from other studies that iden

tified 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 RD 50 value can also be used as the POD if no reliable LOAEL is available. However, the LOAEL is preferred over the RD 50 value as a POD because of uncertainties in relating the respi

ratory 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. Car

diac 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 arrhyth

mias and, in some cases, can lead to sudden death [Reinhardt et al. 1971]. The arrhythmia results from the hydrocarbon potentiating the effect of endog

enous epinephrine (adrenalin), rather than a direct effect of exposure to the hydrocarbon. As described by NAS [2002], “the mechanism of action of car

diac sensitization is not completely understood but appears to involve a disturbance in the normal con

duction 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 epi

nephrine during exposure to the chemical of inter

est. 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 ap

proximately 10 times the blood concentrations that would be achieved endogenously in dogs [Chenge

lis 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 sen

sitization is relevant to humans, but because of the conditions of the assay, which focuses on the mea

surement 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 selec

tion of the UF.

3.4.2.1.4 C onsideration 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 im

mediately 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 im

portant to evaluate the design of the study to ensure that adequate time was allowed, following comple

tion 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 fur

ther in the following paragraphs, data on irreversible effects of special interest (e.g., reproductive and de

velopmental toxicity) or effects that have significant latency (e.g., cancer) are generally considered as anadequate basis for the IDLH value only when singleexposure studies have been conducted that evaluated

## 25 these endpoints. For example, if reproductive or de

velopmental 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 regard

ing 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 de

scribed in the following paragraphs. Standard developmental toxicity studies are not used directly because they typically involve re

peated exposures (e.g., during all of gestation or from implantation through one day prior to ex

pected parturition), and extrapolation from stud

ies that involve long exposure periods thereby resulting in an unacceptable level of uncertainty. However, it is also recognized that some devel

opmental effects can result from exposure dur

ing 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 areevaluated 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, be

cause the exposure duration of repeated days is much longer than the duration of interest—asingle 30-minute exposure. Use of repeatedexposure studies in this manner can provide per

spective 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 de

velopmental toxicity data. Table 3–5 shows how developmental toxicity datacan 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 LC 50 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 ad

justment for durations other than 30 minutes and UF used to calculate the derived value.) A devel

opmental 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 LC 50 -based IDLH value to be lower than the derived value from a repeat-exposure study for non-lethal effects. The IDLH derived from the LC 50 is somewhat higher than from the repeated-exposure developmental toxicity study; thus, the overall findings are consis

tent with expectations and the overall dataset pro

vides 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 re

productive toxicity studies that report irrevers

ible 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 hor

monal control) may suggest the use of an increased UF, if the available acute toxicity data are insuffi

cient to evaluate the concentration–duration re

sponse for such effects.

## 26 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 supple

mental 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 usu

ally 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 with

out the supplemental UF is below 1 in 1,000, then the supplemental UF is not used.



### 3.4.2.2 R elevance 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 ef

fects 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, theyare 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 dur

ing the derivation of an IDLH value will consist of high-quality 30-minute inhalation studies with ef

fects in the severity range of interest. In most cases, such datasets are unavailable. Thus, when selecting among less-than-optimal study designs to iden

tify 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 LC 50 /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: LC 50 = median lethal concentration; LOAEL = lowest observed adverse effect level; ppm = parts per million;

UF = uncertainty factor.

## 27 is given to high-quality studies of the duration of interest (30 minutes) or involving minimal dura

tion extrapolation (e.g., 20-minute exposure du

ration is preferred over a 4-hour exposure dura

tion). However, the relative merits of a well-done study of longer duration versus a poorly conducted 30-minute study must be considered. A well-docu

mented weight-of-evidence decision is even more important when there are no adequate acute inha

lation 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 in

halation (e.g., oral or direct-injection dosing), and studies with other (usually structurally related) chemicals. MOA understanding is particularly im

portant in such situations and can determine such issues as whether route-to-route extrapolation is appropriate, the impact of using data from repeat

ed-exposure studies, and which structurally related chemicals are appropriate to use by analogy. The fol

lowing examples illustrate the impact of MOA on extrapolation decisions.
1. For route-to-route extrapolation : It is inappro

priate to conduct route-to-route extrapolation for irritants, because they target the route of entry. 2. For duration extrapolation : It may be appropri

ate to extrapolate from repeated-exposure stud

ies for irritants, since concentration is often a more important determinant of irritation than exposure duration. Irritation effects observedon the first day of exposure during a repeatedexposure study may be used as the basis of an IDLH value. Repeated-exposure studies that identify subchronicor 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 exam

ple, 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 RD 50 study and one LC 50 . 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. Clinicalsigns reported at 4.9 ppm were limited to eyes halfclosed during exposure, an indication of eye irri

tation, 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 clini

cal 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 applica

tion 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 RD 50 . A slightly higher IDLH value would have been calculated from the LC 50 , but that value was not used, since it involves more extrapolation due to the severity of the response (lethality). Di

rect observations from the initial exposure during the repeated-exposure study were considered more reliable than using the RD 50 value directly, based on the uncertainties in interpreting the RD 50 assay.


### 3.4.2.3 R elevance 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 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 rel

evant 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 addi

tional stress, because of their being restrained dur

ing exposure. There is no default preference for one exposure scenario over the other. Instead, the stud

ies and results should be examined to determine whether the limitations of either method preclude the use of certain studies. For example, the obser

vation of overt gastrointestinal (GI) effects from whole-body exposure suggests the potential forconfounding by ingestion. In general, both noseonly and whole-body exposures are considered to

gether in the overall weight-of-evidence evaluation. Well-conducted inhalation studies generally report both nominal concentrations (the concentration ex

pected on the basis of the amount of chemical intro

duced 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 differ

ence should be determined. Large differences may reflect difficulty in maintaining the exposure atmo

sphere (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 be

ginning of the experiment), as opposed to dynamic studies (where the chemical is continuously cir

culated and the chemical concentration is actively maintained at the target level). Because the analyti

cal concentration reflects the actual concentration to which the animals were exposed, the analytical concentration is usually used in IDLH value cal

culations. However, in some cases, the nominal concentration may more appropriately reflect the exposure conditions. For example, substances, such as trichloromethylsilane (CAS# 75-79-6), sul

fur trioxide (CAS# 7446-11-9), uranium hexafluo

ride (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 as

sociated with the previously listed substances. Be

cause the observed toxicity is due to both the par

ent 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 de

pends 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/m 3 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/m 3 using the ideal gas law. At 1 atmosphere of pressure and room temperature (25 ̊ C), the conversion is as follows: mg/m 3 = ppm × molecular weight/24.45 Difficulties in the determination of exposure concen

trations 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 rea

sonable to assume that toxicity is due to the total mass of the chemical. However, it should be recog

nized that vapors and aerosols (e.g., solid particles and liquid droplets) are deposited differently in the respiratory tract on the basis of many fac

tors, including the physiochemical properties of the chemical [USEPA 1994]. For this reason, the

## 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 RD 50 /10.4 30 10.4 3 3.5

— Rat LC 50 /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; LC 50 value = median lethal concentration; LOAEL = lowest

observed adverse effect level; NOAEL = no observed adverse effect level; ppm = parts per million; RD 50 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 toxicity related to vapor exposure and aerosol ex

posure to the same concentration (e.g., mg/m 3 ) 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 documen

tation when sufficient data are available. The most appropriate size fraction is driven by the nature of acute toxicity observed. If such data are not avail

able, the chemical-specific IDLH support docu

mentation 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 O ther 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 consid

ered, depending on the understanding of the MOA and availability of data. Available information on surrogates, or related compounds, primary metab

olites, 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 inter

est. 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 simi

larities, bromine pentafluoride can be used as a sur

rogate 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 toxic

ity 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 pri

mary 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 ac

cording to the respective amounts of chlorine at

oms 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 under

stood for the surrogate than for the chemical of in

terest, 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 uncertain

ties 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 ac

etone. 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 sur

rogate and basis of an IDLH value for acetone cya

nohydrin [NAS 2002, 2005]. Use of such surrogates is not necessary when adequate information on the primary chemical is available. In addition, if a sur

rogate 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

## 31 addressed by the surrogate. For example, acetone cyanohydrin causes irritant effects that are not seenwith 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 inha

lation, such as oral or intraperitoneal (i.p.) dosing studies. As noted above, this route-to-route ex

trapolation is appropriate only if the effect of in

terest 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 ex

trapolation, but it is rare that such data would exist (particularly for a chemical for which the inhala

tion 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 m 3 ] = oral or i.p. dose [mg/kg] × 70 kg 1.5 m 3 This conversion is a health-protective estimate of the air concentration that would result in the sys

temic dose, since a worker breathing at a rate of 50 liters per minute (L/min) for 30 minutes would inhale 1.5 m 3 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 metabo

lism. First-pass metabolism, also known as pre

systemic 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 metab

olism by the liver generally decreases systemic expo

sure 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 alter

native 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 in

volved 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 charac

teristics 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 consider

ations for conducting route-to-route extrapolations are described in several guidance documents (e.g., [USEPA 1994; NAS 2001]).


## 3.5 T ime Scaling A critical consideration in developing IDLH val

ues is accounting for exposure duration and the extrapolation from the experimental exposure du

ration to the duration of interest (i.e., 30 minutes).

## 32 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 evalua

tion 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 cal

culating n in the ten Berge modification to Haber’s rule. These issues are discussed briefly in the follow

ing 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 respi

ratory 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. Histori

cally, particularly for extended exposure durations, toxicity was described as the simple product of con

centration (Conc) and time, so that Conc × time = k, a constant. In other words, if Conc 1 × time 1 = Conc 2 × time 2 , 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 pro

tective tissue response) is irreversible and, there

fore, 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 asphyxi

ants (e.g., argon or nitrogen) is related to the peak concentration of the chemical, rather than the cu

mulative dose. Sensory irritation and transient acute CNS effects may also be influenced more by the ex

posure concentration than the exposure duration. Further investigation into the relationship between concentration, duration, and toxicity was con

ducted by ten Berge et al. [1986], who proposed the following relationship between Conc and du

ration (time, t): Conc n × t = k. These investigators examined the data on 20 irritant and systemically acting gases and vapors; the results of this inves

tigation 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 . Further

more, 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 inter

est involved exposure for 30 minutes; the em

pirical 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 docu

ments), 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 di

rectly 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 differentspecies 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 deri

vation 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 du

ration 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 es

timates for the 30-minute equivalent POD, as shown in Appendix E–2.

## 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 equiv

alent value via the ten Berge correction, the ra

tionale for this decision will be described in the documentation of the IDLH value. Additional information and illustration on the ap

plication of time scaling within the IDLH method

ology are included in Appendix E–2.


## 3.6 I nclusion 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 va

por to be achieved at toxicologically relevant air concentrations. Maintaining safety considerations in the process for this methodology update is con

sistent 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 concentra

tions 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 concentra

tion will become the default IDLH value. The fol

lowing 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 consid

erations related to the potential hazard of explo

sion 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 publica

tions. For dust, the equivalent default approach would be using 10% of the minimum explosive concentra

tion (MEC). However, determining the combusti

bility of dusts is too complex to assign a single de

fault 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 find

ings 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 state

ment: “Dust may represent an explosive hazard. Safety considerations related to hazard of explo

sion must be taken into account.” In addition, the notation (Combustible Dust) will appear beside the IDLH value in the NIOSH Pocket Guide to Chemi

cal 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/).

## 35 

# 4 U se of Uncertainty Factors

4.1 A pplication of Uncertainty Factors As noted in prior sections of this CIB, the first step in the development of an IDLH value is to deter

mine 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 frompotential lethal, severe or irreversible, or escapeimpairing health effects. Thus the IDLH value can be represented as:

IDLH Value = POD (e.g., 30-min-equivalent LC 50 value, LC LO value, 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 LC 50 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 LC 50 value in this example, by an ad

ditional UF would then reduce the IDLH value to a lower concentration well below the LC 50 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 av

erage 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 toxi

cology 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 determina

tion and its relevance to the duration of in

terest. 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 da

tasets 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 ap

propriate 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 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 flex

ibility to fully use the limited data from multiple lines of evidence often encountered in IDLH devel

opment. 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 consider

ation 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 T he NIOSH IDLH Value Uncertainty Factor Approach As discussed regarding the overall UF approach, the analysis focuses on the weight-of-evidence ap

proach 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 chemi

cal 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 in

crements 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*

LC 50 (in an animal study) 10 to 100 LC 01 , LC Lo , or BMCL 10 for lethality in animals 3 to 30 LC Lo 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 RD 50 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: BMCL 10 = lower confidence limit on the concentration associated with a 10% response; IDLH = immediately

dangerous to life or health; LC 01 = the statistically derived air concentration that caused lethality in 1% of test animals; LC 50 = median lethal concentration; LC LO = 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.

## 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 w ill 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 move

ment 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 ef

fects data that serve as the POD are from hu

man studies, then the UF would not need to address this area of uncertainty.

• Human variability in sensitivity: If chem

ical-specific data are available to help deter

mine the magnitude of the variability in hu

man 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 sensi

tive human group (e.g., non-smoking, young adult females for a clinical study of nasal irri

tation [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 vari

ability that needs to be covered in applying the UF is expected to be less than for develop

ment of exposure values/limits meant to pro

tect 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 ob

served at the POD. This is reflected in the pre

liminary 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 LC 50 value and the IDLH value than would be needed in between a BMCL 05 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 shal

low concentration–response curve. Thus, if the concentration–response curve is very steep, a factor of 10 (rather than the prelimi

nary UF of 30) may be applied to an LC 50 value, based on consideration of the overall database. This is because there is less than a factor of 3 between the LC 50 and the (actual or estimated) LC 01 value.

• Duration of exposure: For most acute lim

its, including IDLH values, acute studies are typically used directly as the basis for the POD. Thus, the available studies are gener

ally representative of the overall duration of interest (exposure for a single day or less). Further refinements to account for uncer

tainties 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 in design or outside the immediate durationrange of interest. For example, if only repeatexposure studies were available for a chemi

cal to serve as the POD, and the observed ef

fects 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 uncer

tainties 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 consid

erations 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 indi

cate that the chemical is a sensory irritant and the data are insufficient to derive an IDLH value (e.g., due to inappropriate exposure du

rations) 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 Resear ch 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 es

tablish 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 ac

counted for in determining the appropriate value of the final UF. Although the NIOSH approach does not assign an individual factor for each area of un

certainty, there is generally good agreement between the NIOSH UF and the UF embedded in deriva

tion of AIHA ERPG values and the cumulative UF used for derivation of the AEGL values. As expected, there is not complete alignment between these val

ues, 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 es

tablishment of community-based acute exposure limits, such as the ERPG and AEGL. The IDLH values do not take into consideration the poten

tially sensitive members of the general population because it is assumed that they will not be sub

stantially represented in the workforce for the pur

poses 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 ap

propriate for defining the POD as the basis for de

riving an IDLH value. To further verify that the preliminary ranges of the UF are supported by existing data, NIOSH con

ducted an analysis of acute toxicity data to deter

mine the appropriate size of the UF for extrapolat

ing from various points of departure to derive IDLH values that would be expected to protect from le

thal, 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

## 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., LC 50 values) and the effect level for lethality or other non-lethal effects in humans were determined for each chemical. The distribu

tion of these ratios was analyzed, and the median value and 95 th percentile value for each comparison were derived (see Appendix D). The resulting me

dian values and upper-bound estimates for these case study chemicals were used to verify that the range of total UFs adopted in the IDLH methodol

ogy 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 concentra

tions and human effect thresholds (both LC LO val

ues and LOAELs for severe or escape-impairing effects) were generally correlated, such that chem

icals with low animal LC 50 values tended to have low human lethality thresholds and cause severe or escape-impairing effects in humans at low con

centrations. This finding was important to support the approach of developing preliminary UF rangesthat 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 devel

oping a preliminary UF to address effect severity by MOA category has not been applied for IDLH deri

vation. 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.

## 41 

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## 45 

# APPENDIX A: Example of the Derivation of an IDLH Value

This appendix illustrates the IDLH value deriva

tion 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 ap

plication of the derivation process outlined in this CIB. For this reason, the proposed IDLH value for chlorine presented in this CIB should not be con

strued as official NIOSH policy.


## A.1 Supp ort Documentation for the Revised IDLH Value for Chlorine
Revised IDLH value: 2.8 ppm (8.1 mg/m 3 ) 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 hu

man volunteers exposed to 2 ppm for 1 hour [An

glen 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 thresh

old 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/m 3 ), 15-minute ceiling [NIOSH 2005] Current OSHA PEL: 1 ppm (3 mg/m 3 ), ceiling [OSHA 2010] 1989 OSHA PEL: ‡ 0.5 ppm (1.5 mg/m 3 ), TWA; 1 ppm (3 mg/m 3 ), 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 A nimal 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 [Bar

row and Smith 1975], and dogs [Underhill 1920; Withers and Lees 1985a]. The lowest LC 50 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 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/m 3 0.5 ppm 1.5 mg/m 3 0.5 ppm 1.5 mg/m 3 0.5 ppm 1.5 mg/m 3 0.5 ppm 1.5 mg/m 3 AEGL-2 2.8 ppm 8.1 mg/m 3 2.8 ppm 8.1 mg/m 3 2.0 ppm 5.8 mg/m 3 1.0 ppm 2.9 mg/m 3 0.71 ppm 2.0 mg/m 3 AEGL-3 50.0 ppm 145.0 mg/m 3 28.0 ppm 81.0 mg/m 3 20.0 ppm 58.0 mg/m 3 10.0 ppm 29.0 mg/m 3 7.1 ppm 21.0 mg/m 3 Abbreviation: mg/m 3 = 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 LC 50 (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; LC 50 value = median lethal concentration; ppm = parts per million; UF = uncertainty factor. *No time adjustment was made to LC 50 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 (C n × 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.

## 47 summarized in Table A–2, along with time adjust

ments, 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 pas

sages 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 RD 50 studies have also been conducted in mice [Barrow et al. 1977; Barrow and Steinhagen 1982; Chang and Barrow1984; 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 Da ta Deaths have been reported after inhalation expo

sures to chlorine, but specific exposure concentra

tions 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 LC 50 value and LC 10 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 Ver

berk 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 ex

posed to 2 ppm for 30 minutes [Anglen 1981]. Multiple accidental exposures to non-lethal con

centrations of chlorine have been reported, but specific exposure conditions and durations are not available. Symptoms of dyspnea, cough, and irrita

tion 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 ef

fects (such as headache, vomiting, giddiness, chest

Table A–4. Acute toxicity data and 30-minute-equivalent lethal concentration values for chlorine

Species Reference LC LO (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; LC LO = 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 LC LO 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 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 V alue Rationale Summary Among the acute lethality studies, the mouse provides the lowest LC 50 value of 127 ppm for a 30-minute exposure period [Schlagbauer and Hen

schler 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 vol

unteers 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 hu

man 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, Pajan

kar 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 Oc

cup Med 39 :131–132. ACGIH [2010]. TLV s 

## ® (threshold limit values) and BEI s 

## ® (biological exposure indices). Cincinnati, OH: American Conference of Governmental Industrial Hygienists Signature Publications. AIHA [2010]. Annual ERPG (emergency response planning guidelines) and WEEL (workplace envi

ronmental 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 (C n × 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.

## 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]. Re

classification 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 irri

tation 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 En

viron Health 32 :68–76. Bitron MD, Aharonson EF [1978]. Delayed mor

tality of mice following inhalation of acute doses of formaldehyde, sulfur dioxide, chlorine and bro

mine. Am Ind Hyg Assoc J 39 :129–138. Chang JCF, Barrow CS [1984]. Sensory tolerance and cross-tolerance in F-344 rats exposed to chlo

rine 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 nonspe

cific airway hyperreactivity. Chest 109 :331–337. Demanti R, Fraser R, Plaa G, Malo JL [1995]. His

topathological 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 re

sponse in mice to chlorine and nitrogen trichlo

ride. J Appl Toxicol 14 :405–409. ILO [1971]. Chlorine and compounds. In: Ency

clopaedia of occupational health and safety. 4th ed. Vol. 1 (A–K). Geneva, Switzerland: International Labour Office. ILO [1998]. Chlorine and compounds. In: Ency

clopaedia of occupational health and safety. 4th ed. Vol. 1 (A–K). Geneva, Switzerland: International Labour Office. Jiang XZ, Buckley LA, Morgan KT [1983]. Pathol

ogy of toxic responses to the RD 50 concentration of chlorine gas in the nasal passages of rats and mice. Toxicol Appl Pharmacol 71 :225–236. Joosting P, Verberk M [1974]. Emergency popula

tion 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. AM

RL-TR-72-62. Dayton, OH: Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base; Springfield, VA: National Technical Informa

tion Service. Mrvos R, Dean BS, Krenzelok EP [1993]. Home ex

posures to chlorine/chloramine gas: review of 216 cases. South Med J 86 :654–657. NAS [2004]. Interim acute exposure guideline lev

els (AEGLs): chlorine, CAS# 7782-50-5. Washing

ton, DC: National Academy of Sciences, Commis

sion on Life Sciences, National Research Council. NIOSH [1994]. Documentation for Immediate

ly Dangerous to Life or Health Concentrations (IDLHs): Chlorine. Cincinnati, OH: Centers for

## 50 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. Cincin

nati, OH: Centers for Disease Control and Preven

tion, National Institute for Occupational Safety and Health, http://www.cdc.gov/niosh/npg/default.html. O’Neil CE [1991] Immune responsiveness in chlo

rine exposed rats. PB92-124478. Cincinnati, OH: Centers for Disease Control and Prevention, Na

tional 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: Oc

cupational 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 inha

lation. Int Arch Gewerbepathol Gewerbehyg 23 :91. Shroff CP, Khade MV, Srinivasan M [1988]. Re

spiratory cytopathology in chlorine gas toxicity: a study in 28 subjects. Diagn Cytopathol 4 :28–32. Shusterman DJ, Murphy MA, Balmes JR [1998]. Sub

jects 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]. Chlo

rine median lethal concentration data for mice. DATR 373. Aberdeen, MD: Edgewood Arsenal. ten Berge WF, Zwart A, Appelman LM [1986]. Concentration-time mortality response relation

ship of irritant and systematically acting vapors and gases. J Haz Mat 13 :301–309. Underhill FP [1920]. The lethal war gases: physi

ology 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: Ani

mals. 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 inhalationtoxicity of chlorine in rats and mice: timeconcentration-mortality relationships and effects on respiration. J Hazard Mater 19 :195–208.

## 51 

# APPENDIX B: IDLH Value Development Prioritization

This appendix identifies how NIOSH will deter

mine the priorities for developing IDLH values. The guidance values play an important role in plan

ning 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 expo

sure 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 chemi

cals currently available in commerce. Therefore, a prioritization process is used by NIOSH to ensure that resources are allocated to yield the greatest im

pact on risk reduction in the event that control mea

sures fail (including respiratory protection devices). This process takes into account both toxicity and ex

posure potential, and it is applied to a broad pool of relevant chemicals (e.g., chemical warfare agents, in

dustrial 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 rank

ing. This process is intended only to provide tenta

tive guidance based on a simple approach that uses readily available sources of information. The result

ing 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 docu

mented prioritization process allows for frequent updating of both input data and prioritization cri

teria 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 uncon

trolled releases (and thus having greater opportu

nities 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., spe

cial 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 chemi

cals of interest that are nominated by interested stakeholders or the subject of new emphasis pro

grams. 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 con

tains self-reported incidents of accidental chemical releases. The database was created by the Agency for Toxic Substances and Dis

ease 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) chemi

cals 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 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 ac

cidents 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 confi

dence 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 chemi

cals 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 ascore 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 follow

ing approach and resources are used to score toxic

ity 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 haz

ardous chemical releases and emergency re

sponder 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/m 3 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 Eu

ropean 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 chem

icals 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

## 53 of “very toxic” or “toxic” are scored as 1; oth

erwise, chemicals are scored as 0.

• Chemicals that have not been evaluated by means of these systems are judged on the ba

sis of the lowest reliable LC 50 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/devel

opmental toxicants are scored as 0.5; other

wise, 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 carcino

gens 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 consid

erations include the following:

• Availability of other acute exposure guid

ance—Such guidance includes existing IDLH, AEGL, or ERPG values. The availabili

ty 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 meth

ods —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 ana

lytical 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 mate

rial as a high priority, then the IDLH value may be useful to other agencies. This type of lever

aging 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 compari

son 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 

## Appendix B: References ACGIH [2008]. Threshold limit values (TLVs 

## ® ) and biological exposure indices (BEIs 

## ® ). Cincin

nati, 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, Cen

ters 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 toxic

ity. August 1, 2008. Sacramento, CA: California Environmental Protection Agency, Office of En

vironmental Health Hazard Assessment, http:// www.oehha.org/prop65/prop65_list/files/P65sin

gle080108.pdf. CCOHS [2008]. RTECS: Registry of Toxic Effects of Chemical Substances. Ontario, Canada: Cana

dian Centre for Occupational Health and Safety. CDC [2008]. Emergency preparedness and re

sponse 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: In

ternational 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. De

partment of Homeland Security, http://www.dhs. gov/xlibrary/assets/chemsec_appendixa-chemi

calofinterestlist.pdf. US DOT [2008]. Emergency response guidebook. Washington, DC: U.S. Department of Transporta

tion, 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. Pre

vention, pesticides and toxic substances, pollution prevention and toxics. Washington, DC: U.S. Envi

ronmental Protection Agency, http://www.epa.gov/ chemrtk/pubs/general/opptsrch.htm.

## 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 per

manent adverse health effects or prevent escape from such an environment.” In other words, the most ap

propriate 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 determin

ing which ones are irreversible, but guidance is avail

able from a number of different sources. Severe adverse effects that are not necessarily im

mediately escape-impairing are judged on a caseby-case basis weighing considerations such as the need for medical treatment, the potential for alteredfunction 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 signifi

cant acute organ damage (hepatitis, decreased kid

ney 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 be

tween exposure and evaluation of the endpoint. Guidance on evaluating and ranking the sever

ity 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 develop

mental toxicity. The Agency for Toxic Substances and Disease Registry (ATSDR) includes the follow

ing five severity rankings [Pohl and Abadin 1995]:

• No Observed Effect Level (NOEL)

• No Observed Adverse Effect Level (NOAEL)

• Minimal Lowest Observed Adverse Effect Level (LOAEL 1 )

• Moderate Lowest Observed Adverse Effect Level (LOAEL 2 )

• Frank Effect Level (FEL) ATSDR applies this approach from acute expo

sures (defined as exposures up to 14 days) through chronic exposures, and a number of publications are available on applying this approach to vari

ous 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 hu

man clinical study or case report, but may manifest

## 56 as changes in respiration rate, nasal discharge, or al

tered activity level in an acute toxicity test in animals. For this reason, guidance was developed that allows for more consistent assigning of comparative sever

ity of observed effects (i.e., escape-impairing versus non-escape-impairing) for commonly observed ad

verse 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 spe

cialized testing, and some histopathology evaluation that can be conducted non-invasively (e.g., for the nasal cavity), or can be inferred from other evalua

tions (e.g., pulmonary edema).

## 57Table C–1. Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposuresClinical sign(s)Escapeimpairing?HumansAnimalsCommentsIrritation—OcularSigns and symptoms—OcularEye irritation (subjective description)YesXIf moderate or severeLacrimation (excessive tearing, clear or colored)YesXXIf severe (assumes will be accompanied by other severeirritation responses)Blepharospasm (eye squinting and shutting)YesXXIf severeReduced or poor visionYesXIf severeMouth- or face-pawing activityNoXMay be observed even during mild irritationEye blink rate/frequencyNoXXDifficult to use as a correlate of irritation, although someinvestigators assert that it may be useful as a marker ofmoderate to severe eye irritationOcular examination findingsSwelling of eyelidsYesXXIf eyelids are closed (more than half-closed)Scattered or diffuse areas of opacity (other thanslight dulling of normal luster), details of irisclearly visibleNoXXAssuming no significant impairment of visionEasily discernible translucent area, details of irisslightly obscuredNoXXNacreous (lustrous) area, no details or iris visible,size of pupil barely discernibleYesXXOpaque cornea, iris not discernible through the opacityYesXXIf severe, assumes will significantly impair vision(Continued)

## 58Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsMarkedly deepened rugae (folds or wrinkles),congestion, swelling, moderate circumcornealhyperemia, or injection, or any of these orcombination of any thereof, iris still reactingto light (sluggish reaction is positive)YesXXNo reaction to light, hemorrhage, grossdestruction (any or all of these)YesXXOcular hyperemia (blood vessels hyperemiccausing red eye)NoXXCornea, inflammation or abrasionYesXXCataractYesXXInflammation of the eyesYesXXIf inflammation severe, assumes this correlates to severeirritation; large changes in some sensitive biomarkers maynot necessarily indicate severe irritation responses.Irritation - RespiratoryNasal signs and symptomsNasal irritation or pain (subjective description)NoXNasal localizationNoXEndpoint differentiates sharp smell from irritationSneezingYesXXIf severeNasal congestionNoXXNostril discharges: red or colorlessNoXXTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 59Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsThickness/swelling of nasal mucosa (decreasednasal cross-sectional area)NoXXMethods measuring mucosal thickness not directly relatedto sensory irritation effectsIncreased nasal airway resistanceNoXRespiratory tract symptomsDry coughYesXIf severeCough with mucus or bloodYesXIf severeChest wheezingYesXIf severe, assumes may impair breathingRales (rapid series of short, loud sounds)NoXBreathing rate/volume measured by pulmonaryfunction test resultsYesXXIf severe in humans, assumes may impair breathing;concentrations in the range of the RD50in rodentsDyspnea (difficult or labored breathing observedas abdominal breathing or gasping)YesXIf severe in humans, assumes may impair breathingPainful breathingYesXIf severe in humans, assumes sufficient to impair breathingApnea (a transient cessation of breathingfollowing a forced respiration)YesXXIndication of sufficient irritation to modify breathingTachypnea (quick and usually shallow respiration)YesXXIndication of sufficient irritation to modify breathingCyanosis (bluish appearance of tail, mouth, footpads, skin or mucous membranes)YesXXIf severe, assumes sufficient to impair respirationLaryngoconstrictionYesXXIf severe, assumes may impair breathingBronchoconstrictionYesXXIf moderate or severe, assumes may impair breathingTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 60Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsRespiratory tract histopathologyNasopharynx inflammationNoXXNasopharynx erosion or necrosisNoXXLarynx inflammationYesXXIf severe, assumes may impair breathingLarynx erosion or necrosisYesXIf moderate or severe, assumes may impair breathingTracheal or bronchial inflammationYesXIf severe, assumes may impair breathingTracheal or bronchial erosion or necrosisYesXIf moderate or severe, assumes may impair breathingAlveolar hemorrhage or necrosisYesXIf observed, assumes may impair breathingPulmonary edemaYesXXIf observed, assumes may impair breathingNeurologicalSigns and symptomsArousal stateNoXXIf sluggish with some exploratory movements with periodsof immobility, or hyperalert, excited, sudden bouts ofrunning or body movements, or changes in rearingHeadacheYesXOnly if described in study as debilitatingLightheadedness, dizziness/faintnessYesXIf moderate or severeLassitude/lethargy (feeling low in energy or slowed)NoXAssume if severe, lassitude would be seen as extremedrowsiness/fatigueExtreme drowsiness, fatigue or sleepiness (somnolence)YesXIf severeNarcosis (stupor)YesXXIf observedTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 61Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsFrank effects (including postural observations—excessive sway, lying on side, limbs in the air, lossof balance, stupor, convulsions, seizure, coma)YesXXIf observedExhilaration (unusual)NoXEuphoria (a feeling of exaggerated elation)NoXLoss of concentrationYesXXIf severeLoss of recent memoryYesXXLong-term memory lossNoXXUnstable moodsNoXCNS excitabilityClonic movements (marked by alternatecontraction and relaxation of muscles)YesXXIf moderate-severe body tremors and myoclonic jerksTonic movements (marked by continuousmuscular contractions)YesXXIf head and body rigidly forward or backwardAutonomic effectsPalpebral closure, ptosis or relaxation ofnictating membranesYesXXIf eyelids or nictating membranes drooping; drooping ofnictating membranes would not be observed in humansUrinationYesXXCommon effects of nerve agents and accompanied bychanges that impair escapeDefecationYesXXCommon effects of nerve agents and accompanied bychanges that impair escapeTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 62Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsPiloerection (contraction of erectile tissue of hairfollicles, resulting in rough fur)NoXHypo- or hyperthermiaYesXXIf severeExcessive perspiration/sweating/pantingNoXXCommon effects of nerve agents that accompanyother effects considered to be escape impairingSalivationNoXXCommon effects of nerve agents that accompanyother effects considered to be escape impairingSyncope (loss of consciousness)YesXXIf observedBlurred visionYesXIf severeMydriasis (reflex pupillary dilation)YesXXIf severeMiosis (constriction of pupil, regardless of light)YesXXIf severePtosis (drooping of upper eyelids)YesXXChromodacryorrhea (red lacrimation)NoXLoss of libidoNoXMuscle tone/equilibriumAbnormal gait or postural observationsYesXXIf sufficient to impair balance or locomotionMobilityYesXXIf severely impairedRightingYesXIf moderately or severely impairedForelimb grip strengthYesXIf severely impairedLanding foot splayYesXIf significantly increased a measure of posturalinstabilityTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 63Clinical sign(s)Escapeimpairing?HumansAnimalsCommentsFasciculation (muscular twitching)YesXIf severeMuscle weakness of extremities (foot drop)YesXIf severeDecreased manual dexterityYesXIf severeDecreased nerve conduction velocityYesXIf accompanied by changes that affectlocomotionSensorimotor reactivityClick responseNoXSensitive responseTouch responseNoXSensitive responseTail pinch responseYesXIf no or limited reaction, indicates decreasedsensory ability and CNS impairmentParesthesia (numbness/tingling body parts)YesXIf impairs locomotion or ability to graspPerception speedNoXXSensitive responseReaction time (simple or choice)NoXXSensitive responseAuditory vigilanceNoXXSensitive responseVisual time discriminationNoXXSensitive responseDepth and form perceptionNoXXSensitive responseTinnitus (ear ringing)NoXPressure in the earsNoXReduced hearing acuityNoXInsomnia or wake frequentlyNoXXTable C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposures(Continued)

## 64Table C–1 (Continued). Common clinical signs, symptoms, and histopathological abnormalities observed during acute exposuresClinical sign(s)Escapeimpairing?HumansAnimalsCommentsNervous system histopathologyCentral nervous system lesionsYesXIf degenerative change observedPeripheral nervous system lesionsYesXIf degenerative change observedOtherGI tract signs and symptomsStomach acheYesXIf severe—e.g., causes involuntary doubling overNauseaNoXMay be accompanied by weakness or dizzinessthat will be considered escape-impairingDiarrheaNoXVomitingYesXXIf severeCardiovascular changesChange in blood pressureYesXXIf severe, assumes may induce faintness ordizziness (extreme hypotension)Changes in heart rate (tachycardia or bradycardia)YesXXIf severe or accompanied by other impairingcardiovascular changeTightness in the chestYesXIf severe or accompanied by other impairingcardiovascular changePains in heart or chestYesXIf severe or accompanied by other impairingcardiovascular changeArrhythmiasYesXXAssumes sufficient to impair systemic blood flowVentricular fibrillationYesXIf observed

## 65 

## Appendix C: References Abadin H, Murray H, Wheeler J [1998]. The use of hematological effects in the development of mini

mal 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 mini

mal risk levels: Immunological effects. Regul Toxi

col 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. Toxi

col Ind Health 1 (4):177–192. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Bur

gos 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 strat

egies 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 Toxi

col 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 mini

mal risk levels: Reproductive and endocrine effects. Regul Toxicol Pharmacol 42 :209–217. US EPA (United States Environmental Protection Agency) [1994]. Methods for derivation of inha

lation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F.

## 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., LC 50 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 typi

cally applied. The rationale for this decision was neither described in the 1994 update methodology [NIOSH 1994] nor specified in the support docu

mentation 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 con

ducted several analyses in preparation of the IDLH methodology to determine if the approach used in the 1994 update needed to be revised. Numer

ous datasets were evaluated to identify the typi

cal 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 analy

sis [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 A nalysis for Selected Approach To derive a scientifically based approach for the use of UFs in the derivation of IDLH values, several analy

ses 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 de

scribed 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 identi

fied 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 LC 50 and LC 01 val

ues based on the mortality incidence data for each of the animal studies of adequate quality. All of the animal LC 50 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 val

ues 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 lethal

ity (e.g., irritation or signs of CNS depression). It should be noted that the default ten Berge adjust

ment approach would also be most appropriate for less than lethal effects. However, since this analy

sis 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 hu

man studies was deemed an unnecessary refinement for this particular analysis. The default ten Berge ap

proach 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 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 concentra

tions and human effect thresholds were generally correlated for this limited dataset. Additional anal

yses were conducted by MOA category (e.g., irri

tant, CNS depressant, or “other”). Group means for each MOA category were not significantly dif

ferent when comparing animal lethal concentra

tions (LC 50 and LC 01 values) to human lethality thresholds (human LC LO values). However, group means for the three MOA categories did differ sig

nificantly for the ratios of animal lethal concen

trations (LC 50 and LC 01 values) versus the human LOELs for the 20 case-study chemicals. The mean LC 50 /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 ani

mal RD 50 values to IDLH values suggests that, on average, the RD 50 corresponds to a human severe irritation threshold, since the IDLH values used in the analysis were based on irritant effects in hu

mans. This interpretation is consistent with study findings [Schaper 1993] that suggested that ex

posure at the RD 50 would likely cause intolerable sensory irritation. However, it is noteworthy that the RD 50 would have been considered in the over

all 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 95 th Percentile

LC 50 /LOEL * 25 330 LC 01 /LOEL 15 130 LC 50 /LC LO 2 13 LC 01 /LC LO 1.5 11 LC 50 /IDLH value † 8 67 RD 50 /IDLH value † 1 9 Abbreviation: IDLH = immediately dangerous to life or health; LC 01 = the statistically derived air concentration that

caused lethality in 1% of test animals; LC 50 = median lethal concentration; LC LO = 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.

## 69 The second approach used data directly from cur

rent 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 LC 50 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 LC 50 value, the current IDLH value, and the MOA for which the current IDLH value was set. As for the first ap

proach, 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 cho

linesterase. 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 ef

fects 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 RD 50 estimates (the con

centration of the chemical that results in a 50% de

crease in respiratory rate in a standardized rodent test) for these same chemicals. The distribution of the LC 50 /IDLH value ratios is shown in Figure D–1. Results of the LC 50 /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. Dis

tribution of RD 50 /IDLH value ratios for 26 chemi

cals yielded a median ratio of 1, suggesting that exposure at the RD 50 would generally result in sen

sory irritation of sufficient severity to be judged as escape-impairing. This interpretation is consistent with study results [Schaper 1993] suggesting that exposure at the RD 50 would likely cause intolerable sensory irritation. Overall, no clear pattern regard

ing MOA was evident when comparing LC 50 /IDLH value ratios and its primary MOA for the 94 chemi

cals or comparing RD 50 /IDLH value ratios for the 26 chemicals. This analysis hypothesized that potent irritants may have a greater difference between the LC 50 and the threshold for serious effects in humans, as com

pared 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 LC 50 for such chemicals would re

quire a greater UF than would be needed for chem

icals with other modes of action. The analysis pro

duced 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 recom

mend a different UF by MOA category.


## D.2 Rec ommendation for Deriving IDLH Values Three primary methods are traditionally applied during the development of acute emergency lim

its, 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 ap

proach, 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 hav

ing 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 nu

meric value.

## 70 

## Lowest LC 50 

## /Current IDLH <1 1–<3 3–<10 10–<30 30–<100 100–300Number of Chemicals

0 10 20 30 40 

### Central Nervous System Irritant Other Pesticide

LC 50 —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 LC 50 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.

## 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 ap

proach provides a data-informed starting point for the analysis, supported by empiri

cal analysis (see Section D.2). The approach is intended to provide flexibility in UF selection by accounting for typical overlaps in individ

ual UF and data hierarchies at the beginning of the UF selection process. This provides anincrease in transparency over the weight-ofevidence approach, without requiring signifi

cant effort to explain departures from pre

scribed defaults. This is the approach that has been included in the IDLH methodology.

• Method 3—Apply a set of default UFs and re

vise 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 uncer

tainty that pertain to a specific dataset. The final UF is derived by multiplying the individual fac

tors. 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 inappropri

ate values from one potential critical study to another. The end result of such data con

flicts 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 dif

ferences focusing on the level of transparency of

fered 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 incor

porate 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, with

out the rigid application of default values that may require extensive post-hoc explanations. Multi

plication 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 respira

tory protection selection. 

## Appendix D: References Fowles JR, Alexeeff GV, Dodge D [1999]. The use of benchmark dose methodology with acute in

halation 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 Hu

man Services, Centers for Disease Control and Pre

vention, National Institute for Occupational Safety and Health. NTIS Publication No. PB-94-195047. Rusch GM, Bast CB, Cavender FL [2009]. Estab

lishing a point of departure for risk assessment us

ing 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 occu

pational exposure limits. Am Ind Hyg Assoc J 54 (9):488–544. ten Berge WF, Zwart A, Appelman LM [1986]. Concentration-time mortality response relation

ship of irritant and systematically acting vapors and gases. J Haz Mat 13 :301–309.

## 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 consid

erations 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 I nhalation Volume Adjustments Approach for Route-to-Route Extrapolation During the 1994 update of the IDLH values, a vol

ume of 10 m 3 for inhaled air was included in the methodology as the basis for calculating the inhala

tion 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 methodol

ogy uses an alternative approach that takes into ac

count that IDLH values are intended to be based on a maximum exposure duration of 30 minutes. As

suming 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
m 3 . This volume corresponds with dosimetry guide

lines recommended by the International Commis

sion on Radiological Protection [ICRP 1994]. Use of the value 1.5 m 3 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 useof the 1994 methodology is built on more healthprotective assumptions (yields a lower IDLH value) than the IDLH methodology, and it may have re

sulted 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 ap

proach that used 10 m 3 and the IDLH methodology presented in the CIB that uses 1.5 m 3

. Because the impact of the selected default is sig

nificant (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 com

pared 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 m 3 as

sumption is likely to be adequate. The level of con

cern about the degree to which the 1.5 m 3 value is likely to be protective can be summarized for differ

ent scenarios. If the MOA is based on the peak con

centration, then the differences in absorption and

## 74 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 LD 50 value (mg/kg) Body weight (kg) Inhaled air volume (m 3 ) UF* Derived IDLH value † (mg/m 3 ) 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; LD 50 = median lethal dose; mg/kg = milligrams per kilograms of

body weight; m 3 = 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 LD 50 value * Body weight)/Inhaled

Air Volume)]/(UF)

## 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 m 3 is viewed as an adequate default approach. However, there are scenarios based on chemical ki

netics or non-inhalation study designs that may im

pact the level of protection afforded by the default adjustment. For this reason, the IDLH methodol

ogy has been modified to further communicate the potential conditions where additional kinetic-based adjustments may be needed.


## E.2 T ime Scaling Adjustments
In most cases IDLH values are derived from studies having exposures for periods shorter than or lon

ger 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 con

centration (Conc) and duration (time, t): (Conc n × 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 concentra

tion 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 con

centration 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 concentra

tion at 4 hours, whereas the calculated concentra

tion at 30 minutes is substantially higher when n = 1. Thus, using n = 3 for extrapolating from longer durations to 30 minutes results in lower concentra

tions, a more health-protective approach. Figure E–2 shows the converse situation, extrapo

lating 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 concentra

tion at 30 minutes, compared with the value calcu

lated 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 dura

tions, and a default value of n = 3 is used for ex

trapolation 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 con

centrations 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 concen

trations 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 LC 50 and LOAEL values for 1,1-dimethylhydrazine correlated to exposure durations of 5 or 15 minutes. No empir

ically derived n values were identified within the

## 76 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 4.0Concentration (ppm)

0 20 40 60 80 100 120 140 160 180

n=1 n=2 n=3

30-minute extrapola ti on

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]

## 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. Fig

ure E–3 provides a visual representation of the data for 1,1-dimethylhydrazine. In comparison, the selected LC 50 and LOAEL values for vinyl ac

etate 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 du

rations. 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 tetrachlo

ride (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 expo

sure 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 correspond

ing to exposure durations less than 30 minutes, the resulting extrapolated concentrations were approximately 5% to 50% of the original LC 50 and LOAEL values. Substantial changes in the extrapo

lated 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 scal

ing may greatly affect the resulting 30-minuteequivalent concentrations.

## 78 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) LC 50 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: LC 50 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 6Concentration(ppm)

Stud y number St ud y concen tration Du ration adjusted con centra tio n

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.

## 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. LC 50 (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: LC 50 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 5Concentration(ppm)

Stud y number St ud y concen tration Du ration adjusted con centra tio n

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 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. LC 50 (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: LC 50 = 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 7Concentration(ppm)

Stud y number St ud y Concen tration

Du ration Adjusted Con cen trati on

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.

## 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 epi

thelium. Inhal Toxicol 9 :331–350. Gardner RJ [1980]. Rat sensory irritation study: TiCl 4 . 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 tita

nium tetrachloride. Haskell Laboratory report no. 658–80, October 31, 1980. Wilmington, DE: E.I. du Pont de Nemours and Company, Haskell Labora

tory 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, Kus

tova 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 submis

sion: 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 relation

ship 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.

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