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Graphical Arrays of Chemical-Specific
Health Effect Reference Values for
Inhalation Exposures
Includes Errata Sheet created on 4/6/2010
September 2009
U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC
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DISCLAIMER
This document has been prepared by staff from the Hazardous Pollutant Assessment Group,
National Center for Environmental Assessment, U.S. Environmental Protection Agency. Any
opinions, findings, conclusions, or recommendations are those of the authors and do not
necessarily reflect the views of the EPA. For questions concerning this document, please contact
Dr. George Woodall (919-541-3896; woodall.george@epa.gov).
September 2009 ii
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Errata Sheet Created 4/6/2010
for the document titled
Graphical Arrays of Chemical-Specific Health Effect Reference Values for Inhalation
Exposures, Final
Table
or Page
Figure
Erratum
133
Changed "values" to "value," deleted "and OSHA," and added "OSHA
PEL" before "ACGIH " in the first sentence of the second paragraph.
Added the following sentence at the end of the second paragraph: "It
should also be noted that the original documentaion for the OSHA PEL
cited it as a Ceiling Value (OSHA, 1996, 192249) but OSHA later
clarified in a memo that the value was a time-weighted average
(OSHA, 1996. 598129)"
Figure
2.15
133
Replaced Figure 2.15
Table
2.15
137
Replaced "OSHA-Ceiling" with "OSHA-PEL (TWA)" in the first
column of Table 2.15. Replaced "10 min" with "8 hr TWA" in the
second column. Added reference in last column.
140
Added reference "OSHA (1996). Mercury vapor. Retrieved 11-JUN-
09, from
http://www.osha.gov/SLTC/healthguidelines/mercuryvapor/recognition
.html. 192249 OSHA (1996). PEL (permissible exposure limit) for
inorganic mercury is a time-weighted average, not a ceiling (Sept 3,
1996), with June 2, 2005 correction. Retrieved 06-APR-10, from
http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=I
NTERPRETATIONS&p_id=23866. 598129
September 2009
in
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ACKNOWEDGEMENTS
Author:
George M. Woodall, Jr.
Office of Research and Development
National Center for Environmental Assessment
United Stated Environmental Protection Agency
Research Triangle Park, NC
Reviewers and Contributors:
Janine Dinan
Office of Solid Waste and Emergency Response
Office of Emergency Management
United States Environmental Protection Agency
Washington, DC
Nicole Hagan
Oak Ridge Institute for Science and Education
Predoctoral Trainee with the
National Center for Environmental Assessment
Research Triangle Park, NC
Deborah McKean
Office of Research and Development
National Homeland Security Research Center
United States Environmental Protection Agency
Cincinnati, OH
Jayne Michaud
Office of Solid Waste and Emergency Response
Office of Superfund Remediation & Technology
Innovation
United States Environmental Protection Agency
Washington, DC
Molly Rosett
Student Services Contractor with the
National Center for Environmental Assessment
United States Environmental Protection Agency
Research Triangle Park, NC
Reeder Sams
Office of Research and Development
National Center for Environmental Assessment
United States Environmental Protection Agency
Research Triangle Park, NC
John Vandenberg
Office of Research and Development
National Center for Environmental Assessment
United States Environmental Protection Agency
Research Triangle Park, NC
Debra Walsh
Office of Research and Development
National Center for Environmental Assessment
United States Environmental Protection Agency
Research Triangle Park, NC
William P. Ashman
Senior Research Scientist
Battelle
Department of Homeland Security
Aberdeen Proving Ground, MD
Michele Burgess
Office of Solid Waste and Emergency Response
Office of Emergency Management
United States Environmental Protection Agency
Washington, DC
Deborah Burgin
Agency for Toxic Substances and Disease
Registry
Division of Regional Operations, Liaison Office
to EPA HQ
Washington, DC
Stan Durkee
Office of Research and Development
Office of Science Policy
United States Environmental Protection Agency
Washington, DC
Ernest Falke
Office of Prevention, Pesticides, and Toxic
Substances
Office of Pollution Prevention and Toxics
United States Environmental Protection Agency
Washington, DC
September 2009
IV
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Schatzi Fitz-James
Office of Solid Waste and Emergency Response
Office of Emergency Management
United States Environmental Protection Agency
Washington, DC
Sarah Mazur
Office of Research and Development
Office of Science Policy
United States Environmental Protection Agency
Washington, DC
Jess Rowland
Office of Prevention, Pesticides, and Toxic
Substances
Office of Pesticide Programs
United States Environmental Protection Agency
Washington, DC
Roy Smith
Office of Air and Radiation
Office of Air Quality Planning and Standards
United States Environmental Protection Agency
Research Triangle Park, NC
Editorial Support
Deborah Wales
Office of Research and Development
National Center for Environmental Assessment
United States Environmental Protection Agency
Research Triangle Park, NC
September 2009
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TABLE OF CONTENTS
Disclaimer ii
ACKNOWEDGEMENTS iv
Section 1: Introduction 1
1.1. Purpose 1
1.2. Overview 1
1.2.1 Document Organization 7
1.3.4 Uncertainty and Variability 10
1.4. Duration 10
1.5. Available Health Effect Reference Values 11
1.5.1 Emergency Response Reference Values 11
1.5.2 Occupational Reference Values 14
1.5.3 General Public Reference Values 16
Section 2: Chemical-Specific Reference Value Arrays 23
2.1 Chemical-Specific Reference Values for Acrolein (CASRN 107-02-8) 26
2.2 Chemical-Specific Reference Values for Ammonia (CASRN 7664-41-7) 34
2.3. Chemical-Specific Reference Values for Arsine (CASRN 7784-42-1) 44
2.4. Chemical-Specific Reference Values for Chlorine (CASRN 7782-50-5) 52
2.5. Chemical-Specific Reference Values for Chromium VI (CASRN 18540-29-9) 61
2.6 Chemical-Specific Reference Values for Cyanogen Chloride (CASRN 506-77-4) 70
2.7 Chemical-Specific Reference Values for Ethylene Glycol Monomethyl Ether (EGME)
(CASRN 109-86-4) 74
2.8 Chemical-Specific Reference Values for Ethylene Oxide (CASRN 75-21-8) 81
2.9 Chemical-Specific Reference Values for Formaldehyde (CASRN 50-00-0) 89
2.10 Chemical-Specific Reference Values for Soman (Agent GD) and Cyclosarin (Agent
GF) (CASRN 96-64-0 and 329-99-7) 97
2.11 Chemical-Specific Reference Values for Hydrogen Cyanide (CASRN 74-90-8) 104
2.12 Chemical-Specific Reference Values for Hydrogen Fluoride (CASRN 7664-39-3). 111
2.13 Chemical-Specific Reference Values for Hydrogen Sulfide (CASRN 7783-06-4)... 119
2.14 Chemical-Specific Reference Values for Lewisite 128
2.15 Chemical-Specific Reference Values for Elemental Mercury Vapor
(CASRN 7439-97-6) 133
2.16 Chemical-Specific Reference Values for Methylene Chloride (CASRN 75-09-2)... 142
2.17 Chemical-Specific Reference Values for Perchloroethylene (CASRN 127-18-4).... 150
2.18 Chemical-Specific Reference Values for Phosgene (CASRN 75-44-5) 159
2.19 Chemical-Specific Reference Values for Phosphine (CASRN 7803-51-2) 168
2.20. Chemical-Specific Reference Values for Sarin (GB) (CASRN 107-44-8) 176
2.21. Chemical-Specific Reference Values for Styrene (CASRN 100-42-5) 182
2.22. Chemical-Specific Reference Values for Sulfur Mustard (CASRN 505-60-2) 190
2.23. Chemical-Specific Reference Values for Tabun (GA) (CASRN 77-81-6) 196
2.24. Chemical-Specific Reference Values for Agent VX (CASRN 50782-69-9) 203
Appendix A: Summary of the Client Workshop for Reference Value Arrays A-1
Appendix B: Procedures for Developing Arrays of Health Effect Reference Values B-l
Appendix C: Queries of ATHED C-l
September 2009 vi
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ACRONYMS
ACGIH American Conference of Governmental Industrial Hygienists
AEGL Acute Exposure Guideline Level
AIHA American Industrial Hygiene Association
ATSDR Agency for Toxic Substances and Disease Registry
BEI Biological Exposure Indices
BMC Benchmark Concentration
BMCL Benchmark Concentration Limit
BMD Benchmark Dose
BMDL Benchmark Dose Level
CASRN CAS Registry Number
CDC Centers for Disease Control
ERPG Emergency Response Planning Guideline
GPL General Population Limit
HEAST Health Effects Assessment Summary Tables
IARC International Agency for Research on Cancer
IDLH Immediately Dangerous to Life or Health
IRIS Integrated Risk Information System
LC Lethal Concentration
LD Lethal Dose
LOAEL Lowest Observed Adverse Effect Level
MRL Minimal Risk Level
NAC National Advisory Committee
NIOSH National Institute for Occupational Safety and Health
NOAEL No Observed Adverse Effect Level
NR Not Reported
OSHA Occupational Safety and Health Administration
PEL Permissible Exposure Limit
POD Point of Departure
ppm parts per million
REL Recommended Exposure Limit
RfC Reference Concentration
STEL Short Term Exposure Limit
TEEL Temporary Emergency Exposure Limit
TLV Threshold Limit Value
TSD Technical Support Document
TWA Time-weighted Average
UF Uncertainty Factor
WHO World Health Organization
WPL Worker Protection Limit
September 2009
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SECTION 1:
INTRODUCTION
1.1. Purpose
The purpose of this document is to provide graphical arrays that compare human
inhalation health effect reference values (e.g., RfCs (Reference Concentrations), AEGLs (Acute
Exposure Guideline Levels) for specific chemicals across durations, populations (e.g., general
public vs. healthy workers), and intended use (e.g., general public vs. emergency response vs.
repeated occupational exposure vs. occupational ceiling values). A number of program offices
within the Agency, as well as other Federal, State, and International agencies, have a need for
these types of arrays to be readily available (See Appendix A). These arrays are intended to
assist risk assessors, decision makers (risk managers), toxicologists, and may be useful in
communication with the general public. Clients of this project have indicated that the graphical
data arrays will be most useful in communicating the risks and relevant information to non-
toxicologists. The data arrays will also be useful for clients in selecting action levels during
response situations. Specifically, the data arrays could serve to support the Office of Emergency
Management and Office of Water in exercises that prepare responders for emergency situations.
Additionally, the Office of Air and Radiation has indicated that the data arrays will improve risk
communication among risk managers and with the general public in assessments of hazardous air
pollutants (HAPs) emitted from industrial sources. The 24 data arrays presented below have
been refined to present the most relevant information regarding the available inhalation reference
values and are in response to client need.
1.2. Overview
This document provides a brief summary of the types of available inhalation health effect
reference value systems, the purpose and population for which the various types of health effect
reference values were designed to be applied, and some rudimentary comparisons between
reference values on a chemical-specific basis. This summary presents only information regarding
the inhalation health effect reference values, providing key background information relevant to
how the values were derived, and where appropriate, highlighting some considerations on the use
of individual values. An earlier, more general discussion can be found in a review article by
Woodall (2005, 088790) which compares reference values, especially for acute exposure
durations, and the different types of reference values developed for specific purposes. This
document builds upon that earlier work and expands the scope to include the health effect
reference values derived for longer durations up to chronic (potentially lifetime) exposures.
Inhalation reference values are developed by various Federal, State, or professional
organizations and are derived from data drawn from the epidemiologic and toxicological
literature. Standard uncertainty factors are often used in the derivation of these reference values
to ensure that they are protective of the population for which they were intended and to account
for unknown differences between the population studied and the population to be protected.
Other adjustments may also be applied to account for differences in duration of exposure or other
variables or to account for known or unknown information. Additionally, more rigorous
Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database
(Health and Environmental Research Online) at http://epa. gov/hero. HERO is a database of scientific literature used
by U.S. EPA in the process of developing science assessments.
September 2009 1
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analytical methods (e.g., benchmark dose) have been developed and may be applied to arrive at a
starting basis or point of departure (POD) differently than simply choosing a no-effect or effect
level from the exposure concentrations tested in a study.
Table 1-1, below, provides a quick introduction to the health effect reference value
systems available for chemical exposures in general; however, not all systems are specifically
represented. The Emergency Response values are shown with light red shading, the Occupational
values with light tan shading, and the General Public values are shown with light green shading.
More detail on each of the available reference value systems and the values derived within them
is provided in Section 1.5.
Chemical-specific inhalation reference value arrays for 24 chemicals are presented in
Section 2. For each chemical, a brief description is provided with details on the chemical
properties and uses, as well as a discussion of the available reference values. Graphical arrays for
each chemical include inhalation reference values for Emergency Response, Occupational, and
General Public values. The reference value arrays are accompanied by a table with additional
information regarding the derivation of the reference values.
The first arrays comparing inhalation reference values were developed in support of a
draft document developed by an interagency work group dealing with chemical decontamination
and focused on chemical warfare agents. Later arrays were developed on an as-needed basis for
additional chemicals, and as a result, the format changed over time to incorporate the needs of
various programs. The final list of 24 chemicals included in this document took advantage of this
previous work; no other priority or implied importance was placed on this list of chemicals.
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Table 1.1. General descriptions of the health effect reference values.
Reference
Value
Definition
Originating
Organization
Level of Review
Emergency Response
AEGL
Acute
Exposure
Guideline
Level
Three severity levels (10-min up to 8-hrs) (NRC, 2001, 192042)
1 = Mild, reversible effects;
2 = Irreversible effects or impairs ability to escape;
3 = Lethal
National Advisory
Committee for AEGLs
(NAC/AEGL)
Federal Advisory
Committee Peer
Review
Public Comment
NAS Panel Review
ERPG
Emergency
Response and
Planning
Guidelines
Three severity levels (one-hour only) (AIHA, 2002, 192051)
1 = Mild, transient effects;
2 = Irreversible effects or impairs ability to escape;
3 = Lethal
American Industrial
Hygiene Association
(AIHA)
Expert Panel Review
TEEL
Temporary
Emergency
Exposure
Limits
Four severity levels (one-hour only) (DOE, 2008, 192182)
0 = No adverse health effects;
1 = Mild, transient effects;
2 = Irreversible effects or impairs ability to escape;
3 = Life threatening health effects or death
Department of Energy
Subcommittee on
Consequence
Assessment and
Protective Actions
(SCAPA)
Internal Process Review
Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these refernce values to any Occupational or General Public reference values. These values are designed for coverage of the general public, including
susceptible (e.g., children) but not hyper-susceptible individuals.
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Reference
Value
Definition
Originating
Organization
Level of Review
Occupational
IDLH
Immediately
Dangerous to
Life and Health
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." Exposure durations of 30 minutes or less. (NIOSH,
1994, 192183)
National Institute for
Occupational Safety
and Health (NIOSH)
Public Comment Period
TLV
Threshold
Limit Value
"Determinations made by a voluntary body of independent
knowledgeable individuals that represent the opinion of the scientific
community that has reviewed the data described in the
Documentation. Exposure at or below the level of the TLVฎ or
BEIฎ does not create an unreasonable risk of disease or injury."
Exposure durations usually based on an 8-hour time weighted
average (TWA) or short duration ceiling value. (ACGIH, 2007,
192024)
American Conference
of Governmental
Industrial Hygienists
(ACGIH)
Expert Panel Review
PEL
Permissible
Exposure Limit
"PELs are regulatory limits on the amount or concentration of a
substance in the air. They may also contain a skin designation.
OSHA PELs are based on an 8-hour time weighted average (TWA)
exposure." (OSHA. 2006. 192276)
Occupational Safety
and Health
Administration
(OSHA)
Federal Register
REL
Recommended
Exposure Limit
"NIOSH develops and periodically revises recommended exposure
limits (RELs) for hazardous substances or conditions in the
workplace." Usually developed for 8- or 10-hour TWAs. (NIOSH,
2006, 192177)
NIOSH
Public Comment Period
CDC WPL
Worker
Population
Limit
"An airborne exposure limit designed to protect workers. It is
expressed as a time-weighted average (TWA) for exposure over an
8-hour work shift." (CDC, 2003, 192190: CDC, 2004, 192193)
Centers for Disease
Control and Prevention
(CDC)
Federal Register, Public
Meeting and Public
Comment Period
STEL
Short-Term
Exposure Limit
An excursion level above the relevant TWA exposure limit for a
specified period of time, usually 15 or 30 minutes. (NIOSH, 2006,
192177)
ACGIH
Expert Panel Review
NIOSH
Dublic Comment Period
OSHA
"ederal Register
Others
Ceiling
"Level of exposure that should not be exceeded at any time."
(NIOSH, 2006, 192177)
ACGIH
Expert Panel Review
NIOSH
Dublic Comment Period
OSHA
"ederal Register
Others
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Reference
Value
Definition
Originating
Organization
Level of Review
General Public
RfC
Reference
Concentration
"An estimate (with uncertainty spanning perhaps an order of
magnitude) of a continuous inhalation exposure estimate to the
human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime.
The inhalation RfC considers toxic effects for both the respiratory
system (portal-of-entry) and for effects peripheral to the respiratory
system (extrarespiratory or systemic effects)." Developed for
continuous chronic exposure scenarios. (EPA, 2009, 192196)
Environmental
Protection Agency
(EPA)
Agency Work Group
Review
Public Comment
Interagency
Consultation/
Discussion
External Peer Review
MRL
Minimal Risk
Level
"An estimate of the daily human exposure to a hazardous substance
that is likely to be without appreciable risk of adverse noncancer
health effects over a specified duration of exposure. These substance
specific estimates, which are intended to serve as screening levels,
are used by ATSDR health assessors and other responders to identify
contaminants and potential health effects that may be of concern at
hazardous waste sites." Developed for acute (1-14 days),
intermediate (15-365 days), and chronic (>365 days) durations.
(ATSDR, 2009, 192154)
Agency for Toxic
Substance and Disease
Registry (ATSDR)
Expert Panel Review
Public Comment
Period
CA-REL
Reference
Exposure Level
"The concentration level at or below which no adverse health effects
are anticipated for a specified exposure duration is termed the
reference exposure level (REL). RELs are based on the most
sensitive, relevant, adverse health effect reported in the medical and
toxicological literature. RELs are designed to protect the most
sensitive individuals in the population by the inclusion of margins of
safety. Since margins of safety are incorporated to address data gaps
and uncertainties, exceeding the REL does not automatically indicate
an adverse health impact." Acute 1-hour and/or 8-hour values, and
chronic duration values, developed based on available data.
(OEHHA, 2008, 192197)
Office of
Environmental Health
Hazard Assessment
(OEHHA), State of
California
External Peer Review
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Reference
Value
Definition
Originating
Organization
Level of Review
CDC GPL
General
Population
Limit
"An airborne exposure limit designed to protect the general public."
Developed for continuous exposures for up to several years. (CDC,
2003, 192190)
CDC
Federal Register, Public
Meeting and Public
Comment Period
WHO Air
Quality
Guideline
"The primary aim of these guidelines is to provide a basis for
protecting public health from adverse effects of air pollution and for
eliminating, or reducing to a minimum, those contaminants of air that
are known or likely to be hazardous to human health and wellbeing."
Developed for continous chronic exposure scenarios. (WHO, 2000,
180143)
World Health
Organization
Internal Peer Review
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1.2.1 Document Organization
This review is organized in two major sections. Section 1 is this introductory section that
provides the background information on the various reference value systems, purposes and
limitations of the derived health effect reference values, and additional chemical-specific
information. Section 2 provides summaries on the available inhalation health effect reference
values on a chemical-by-chemical basis, also providing the details of the derivation of these
reference values. The key element of each summary is a graphical array that compares the
available reference values for each specific chemical. Tables are also provided as a companion to
each chemical-specific array and provide more details related to the derivation of the reference
values and the purposes for which they are designed. A similar shading scheme as was applied in
Table 1-1 is also used in these chemical specific tables.
In the graphical array of each chemical-specific reference value summary, those values
that were designed for use in an occupational setting are shown with an asterisk in the legend
noting that caution and expert judgment be exercised prior to applying these values to the general
public. This caution is provided to clearly state that the occupational values are designed for
application to a presumed healthy work force of prime working age (e.g., 18-65 years of age,
working 40 hours/week). Although some susceptibilities (e.g., pregnancy in female workers)
may be a consideration, many other potential susceptibilities are not taken into account (e.g.,
greater susceptibility in children) that would apply to the general population.
Similarly, caution should be exercised in applying the Emergency Response values
(AEGL and ERPG values) in that they are designed with an assumption that exposures are
limited to a short duration (less than 8-hours) and that such exposures would occur on an
extremely rare basis (i.e., once-in-a-lifetime). The Emergency Response values may not be
adequately protective for exposures that would occur for a longer duration or in situations where
increases of exposures for a short duration may be more routinely experienced (e.g., weekly).
These Emergency Response values are developed as frank effect levels and not as indicators of
safe exposure. If exceeded, these values may indicate cause for concern.
Additional introductory material is provided below on duration and uncertainty factors to
aid in describing aspects that should be considered in choosing an appropriate reference value by
a user of this document.
1.3. Reference Value Derivation
In general, two types of health-based reference values may be available: reference values
in units of concentration that may be used as is - this is usually the case for inhalation noncancer
reference values; and reference values that are expressed in terms of dose (e.g., milligrams per
kilograms of body weight per day) and concentrations in different media that will need to be
derived based on assumptions of level of exposure using risk-based calculations. All reference
values described in this document are reported in units of concentration, preferably as milligrams
per cubic meter (mg/m3).
Derivation of a reference value involves a number of steps, which are listed below. All of
these steps are applied only after a thorough evaluation of the available toxicological data for the
chemical has been conducted to determine the appropriate endpoint for the reference value.
Determination of the Point of Departure (POD)
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Dosimetry Adjustments: Calculation of the Human Equivalent Concentration (HEC)
Duration Extrapolations
Application of Uncertainty Factors
The final reference value is the result of application of adjustments HEC (Human Equivalent
Concentration) and duration extrapolations to the POD to arrive at a value (e.g., NOAELHEc)
which is then divided by the composite (i.e., total) uncertainty factor (Total UF). All of the
elements that go into this derivation have been captured in the tables for the specific chemicals in
Section 2 of this document.
1.3.1 Point of Departure (POD)
The POD is an estimate of the exposure concentration at the threshold of the chosen adverse
effect. The chosen effect will be appropriate to the reference value being derived. The approach
to estimate a predetermined effect level is based on the best available exposure-response model
and the model used would be determined largely by the availability of data. More data is
necessary to apply the benchmark concentration (BMC) approach, which is described in full
elsewhere (http://www.epa.gov/ncea/bmds/), than is required for use of the no observable
adverse effect level (NOAEL) or lowest observable adverse effect level (LOAEL). Each
approach has certain strengths and weaknesses and, depending on the data that are available, one
or more could be applied. In general, preference is given to models that use more exposure-
response information (e.g., BMC), but this is a decision based on the nature of the studies,
amount of data available to model, the agreement between the results of the models, and the size
of the confidence bounds for the applicable models. When data permit, a comparative analysis
among these approaches may be undertaken and is recommended to aid in the quantitative
analysis of uncertainty.
For the BMC approach, the critical decision is the designation of a specific adverse effect (or
risk) level. The BMCL (benchmark concentration limit), the POD for the BMC approach, is the
95% lower confidence bound on the concentration corresponding to the BMR, and the choice
varies between the various procedures. The BMCL is used like the NOAEL and implies that the
effect (or risk) level in the BMC approach is close to the onset of an adverse effect.
1.3.2 Dosimetry Adjustments
The approach taken for performing dosimetry adjustments on study results from inhalation
exposures in laboratory animals to derive exposure concentrations that are relevant to humans is
termed the HEC. The HEC can be determined for all exposures to inhaled agents, both gases and
particles, through the use of available valid models.
To accommodate species differences in inhaled dose, dosimetric adjustments are made to
exposure concentrations used in experimental animal studies to yield an HEC. The intention of
dosimetric adjustment is to provide an estimate of internal dose at the target tissue (or area of
effect) in the test species produced by a given external concentration; the corresponding external
concentration for humans that produces that same internal dose is the HEC.
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The general equation for the calculation of an HEC as developed and presented in the RfC
Method Document (U.S. EPA, 1994, 192307) is through application of a DAF to the exposure
concentration of an animal inhalation exposure, as shown in the equation below:
Exposure Concentration in animals (mg/m3) x DAF = FIEC
Procedures are included for the entire respiratory tract, for any of its regions, or for the whole
body (referred to as systemic or extrarespiratory) in response to a reactive/water-soluble gas, an
insoluble/nonreactive gas, a gas of intermediate reactivity/solubility, and particles. The
procedures are intended to be applied in a hierarchy ranging from optimal to default procedures.
An example of an optimized instance would be where sufficient data relating to dosimetry are
available and integrated into a useful PBPK model to estimate an FIEC from any given exposure
of any laboratory species. To accommodate cases most often available (i.e., where dosimetric
information is marginal) default procedures using various surrogate procedures and assumptions
are also available in the RfC Method document.
1.3.3 Duration Extrapolation
In many cases, the data available for the derivation of a reference value comes from studies
with an exposure duration other than what is desired. For example, an acute reference value for
one hour is needed but all the study data comes from observations at 4 hours. In such cases,
calculations are needed to estimate the concentration at the desired duration that would cause the
same level of effect at the observed duration.
The magnitude of response to a toxic chemical exposure by inhalation is often dependent on
both the concentration and the duration of the exposure. The internal dose of a chemical at the
site in the body where toxicity occurs also determines the magnitude of the response. A more
detailed discussion on these issues is provided in a review article (Woodall et al., 2009, 194213).
For the purposes of this document, three approaches to duration extrapolation are described:
(1) use of standard uncertainty factors (see below) when going from subchronic durations to
chronic durations; (2) use of a concentration by time relationship (Cn x T) - described more fully
below; and (3) use of physiologically-based pharmacokinetic (PBPK) models to estimate the
internal dose at the site in the body of toxic injury.
Response has often been related to the product of concentration (C) and duration of exposure
or time (T). Haber's relationship (Haber, 1924, 059334) suggests that this product is a constant
(i.e., C x T = k. Although widely viewed as an overgeneralization, this assumption is regularly
used as a default assumption. A more general version of this model advanced by ten Berge et al.
(1986, 025664) is expressed as C" x T =k, with n and b being empirically derived, and have
been determined for a series of chemicals with values ranging from 0.8 to 3.5 . The analysis
based on lethality data by ten Berge indicates that few chemicals would be expected to show a
value of n < 1, suggesting that, at least for severe effects, a value of n = 1 would be a reasonable
default for time frames longer than the observed data. In the absence of information to
extrapolate to shorter durations, the default assumption applied in the AEGL SOPs (NRC, 2001,
192042) is to use a value of n = 3.
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1.3.4 Uncertainty and Variability
Organizations that develop reference values use an approach that is intended not to
underestimate risk in the face of uncertainty and variability. When there are gaps in the available
information, uncertainty factors (UFs) are applied to derive reference values that are intended to
be protective against appreciable risk of deleterious effects. UFs are commonly standard values3
(e.g., factors of 10 or 3), used in the absence of compound-specific data. However, when data are
available, uncertainty factors may also be developed using compound-specific information.
EPA, as an example, begins the development of reference values by evaluating all of the
available relevant peer-reviewed literature to determine noncancer endpoints of concern,
evaluating the quality, strengths and limitations of the available studies. EPA typically chooses
the relevant endpoint that occurs at the lowest dose, often using statistical modeling of the
available data, and then determines the appropriate point of departure (POD) for derivation of the
toxicity value. A POD is determined by (in order of preference): (1) a statistical estimation using
the benchmark dose (BMD) approach; (2) use of the dose or concentration at which the toxic
response was not significantly elevated (no observed adverse effect level -NOAEL); or (3) use
of the lowest observed adverse effect level (LOAEL).
A series of downward adjustments using uncertainty factors is then applied to the POD to
estimate the reference value (U.S. EPA, 2002, 088824: U.S. EPA, 2004, 192199). While
collectively termed "uncertainty factors", these factors account for a number of different
quantitative considerations when utilizing observed animal (usually rodent) or human toxicity
data in a risk assessment. The uncertainty factors are to account for: (1) extrapolating from
experimental animal data to humans (i.e., interspecies differences); (2) variation in susceptibility
among the members of the human population (i.e., inter-individual variability); (3) extrapolating
from data obtained in a study with less-than-lifetime exposure (i.e., subchronic to chronic
exposure); (4) extrapolating from a LOAEL in the absence of a NOAEL; and (5) when the
database is incomplete or there are problems with applicability of available studies. When
scientifically sound, peer-reviewed assessment-specific data are not available, default adjustment
values are selected for the individual uncertainty factors. For each type of uncertainty (when
relevant to the assessment), EPA typically applies an uncertainty factor value of 10 or 3 with the
cumulative uncertainty factor value leading to a downward adjustment of 10-3,000 fold from the
selected POD. If an extrapolation step or adjustment is not relevant to an assessment (e.g., if
applying human toxicity data and an interspecies extrapolation is not required) the associated
uncertainty factor is not used. The major adjustment steps are described in greater detail below.
1.4. Duration
There is considerable variation in how organizations define the length of time associated
with different exposure durations. The definitions from the Environmental Protection Agency's
(EPA's) Risk Assessment Forum (U.S. EPA, 2002, 088824) have been adopted for use in this
document:
3 According to the NRC report Science and Judgment in Risk Assessment (NRC, 1994) "(Default) options are generic approaches, based on
general scientific knowledge and policy judgment, that are applied to various elements of the risk-assessment process when the correct scientific
model is unknown or uncertain." The 1983 NRC report Risk Assessment in the Federal Government: Managing the Process defined the standard
option as "the option chosen on the basis of risk assessment policy that appears to be the best choice in the absence of data to the contrary" (NRC,
1983a, p. 63).
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Acute exposure/duration: Exposure by the oral, dermal, or inhalation route for 24 hours
or less;
Short-term exposure/duration: Repeated exposure by the oral, dermal, or inhalation
route for more than 24 hours, up to 30 days;
Subchronic exposure/duration: Repeated exposure by the oral, dermal, or inhalation
route for more than 30 days, up to approximately 10 percent of the life span in humans
(greater than 30 days but less than 90 days in typically used laboratory animal species);
and
Chronic exposure/duration: Repeated exposure by the oral, dermal, or inhalation route
for more than approximately 10 percent of the life span in humans (greater than 90 days
to 2 years in typically used laboratory animal species).
1.5. Available Health Effect Reference Values
The following is a descriptive list of health-based reference values that may be useful to
risk assessors and decision-makers dealing with hazardous chemicals. This list is organized by
three general categories of reference values: (1) Emergency Response Values; (2) Occupational
Values; and (3) General Public Values. The applicability of each of these types of reference
values is also provided to help guide their appropriate use.
1.5.1 Emergency Response Reference Values
Emergency response values are designed for use in situations where there is a danger to
the general public from short duration exposure to high concentrations with potential serious
health effect consequences. This theme is repeated in each of the descriptions for the individual
reference value systems described below. They are designed with assumptions that exposures
will be extremely rare (e.g., once-in-a-lifetime). They are useful in determining a course of
action in planning for or to guide immediate reaction to a catastrophic release (i.e., evacuation or
shelter-in-place), but should not be misconstrued to also be levels indicating safety for any repeat
exposure (e.g., to indicate it is safe to reoccupy an affected area). For example, tier 2 levels are
thresholds for irreversible effects and tier 3 levels are thresholds for lethality.
1.5.1.1 Acute Exposure Guideline Levels (AEGLs) U.S. Environmental
Protection Agency
The AEGLs are developed through an EPA Federal Advisory Committee and reviewed
and published by the National Research Council, as specified in the Standing Operating
Procedures (SOP) document (2001, 192042). The development process includes an open peer-
review and public participation.
The SOP document states that AEGLs "represent threshold exposure limits for the
general public and are applicable to emergency exposures ranging from 10 min to 8 h." The
intended application of AEGL values is "for conducting various risk assessments to aid in the
development of emergency preparedness and prevention plans, as well as real-time emergency
response actions, for accidental chemical releases at fixed facilities and from transport carriers."
The SOP document lays out the purpose and objectives of AEGLs by stating that "the primary
purpose of the AEGL program and the NAC/AEGL Committee is to develop guideline levels for
once-in-a-lifetime, short-term exposures to airborne concentrations of acutely toxic, high-priority
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chemicals." Three health effect levels are developed for 10- and 30-minute and 1-, 4-, and 8-hour
exposures, resulting in as many as 15 different AEGL concentration values for a specific
chemical. These values are intended to protect the general public and include consideration of
sensitive and susceptible persons, including sensitive subpopulations, but not hyper-sensitive or
hyper-susceptible persons. The three AEGL health effect levels are defined below.
AEGL-1: The airborne concentration of a substance above which it is predicted that the
general population, including susceptible persons, could experience notable discomfort,
irritation, or certain asymptomatic, non-sensory effects. However, the effects are non-
disabling and are transient and reversible upon cessation of exposure.
AEGL-2: The airborne concentration of a substance above which it is predicted that the
general population, including susceptible persons, could experience irreversible or other
serious, long-lasting health effects or impaired ability to escape.
AEGL-3: The airborne concentration of a substance above which it is predicted that the
general population, including susceptible persons, could experience life-threatening
health effects or death.
The AEGLs are based primarily on acute toxicology data for vapor exposures, not
subchronic or chronic exposure data. The AEGL values include uncertainty factors to account for
variability in biological response in the human population. For carcinogens, the chemical-
specific Technical Support Document (TSD) includes an evaluation of the degree of excess
cancer risks anticipated for one-time exposure at the various AEGL levels (typically less than 1
in 1000). However, cancer as an endpoint is not used to set AEGL values. The guidance does not
consider or evaluate the effects that could result from repeated exposures.
AEGLs are not regulatory values, and the AEGL Committee does not provide specific
guidance on their implementation or use. Instead, choices made regarding how and/or which
AEGL value to use for various response decisions, such as evacuating or sheltering-in-place, are
typically left up to the Federal, State, Tribal or local officials responding to the incident.
However, it is highly recommended that the expert scientific judgment of qualified toxicologists
and/or hazard assessors be sought to help inform chemical- and site-specific decisions.
For each set of AEGLs for a chemical, an associated TSD describes the toxicological
derivation of the values (http://www.epa.gov/oppt/aegl/). Because the AEGL TSD contains a
comprehensive review of all identified acute toxicology data on the subject chemical and the
basis for the development of the AEGL values, these documents may also have general use as
toxicological references in situations involving an acute exposure scenario that goes beyond the
intended purpose of the AEGLs. Planners and risk managers should seek the advice of qualified
scientific expertise (toxicologists and/or risk assessors) who are familiar with the TSDs for
specific chemicals in order to understand the basis for the AEGL values prior to using these
values outside of their stated purpose.
Where to find AEGLs
Specific AEGL values and final Technical Support Documents
can be found at: www.epa.gov/oppt/aegl
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1.5.1.2. Emergency Response Planning Guidelines (ERPGs) American Industrial
Hygiene Association
The ERPGs are developed by the American Industrial Hygiene Association (AIHA) and
are intended for emergency planning and response operations (similar to AEGLs), but ERPGs
are only based on a 1-hour exposure duration (AIHA, 2002, 192051). ERPGs are intended to
protect the general population, but not particularly sensitive persons. They are reviewed at
regular intervals as new information becomes available. Definitions of the three levels of ERPG
values are as follows.
ERPG-1: The maximum airborne concentration below which it is believed nearly all
persons could be exposed for up to 1 hour without experiencing more than mild, transient
adverse health effects or without perceiving a clearly defined objectionable odor.
ERPG-2: The maximum airborne concentration below which it is believed nearly all
persons could be exposed for up to 1 hour without experiencing or developing
irreversible or other serious health effects or symptoms that could impair a person's
ability to take protective action.
ERPG-3: The maximum airborne concentration below which it is believed nearly all
persons could be exposed for up to 1 hour without experiencing or developing life-
threatening health effects.
Where to find ERPGs
ERPGs for various chemicals can be found at:
http ://www. aiha. org/1 documents/Committees/ERP-
erpglevels.pdf
Documentation for the individual ERPGs is available for
purchase from AIHA.
1.5.1.3. Temporary Emergency Exposure Limits (TEELs) U.S. Department of Energy
The U.S. Department of Energy (DOE) has published TEELs for about 1,200 chemicals
(DOE, 2008, 192182). TEELs adopt AEGLs and then ERPGs as their primary hierarchy for
publication of values, but they also present values obtained by other methods for use when
AEGLs or ERPGs are not available. Although the TEEL methodology has been peer-reviewed
and peer-reviewed studies are used in developing TEELs, the values derived by these other
methods are not currently peer-reviewed. In the absence of AEGL and ERPG values, TEELs are
based on the correlation between acute data (e.g., lethal concentration, LD50, LCLo, etc.) and
existing values (e.g., IDLH, STEL, TLVs and various levels of existing ERPGs). DOE thus
provides a methodology for combining hierarchy- and toxicity-based TEELs into procedure-
derived TEELs to facilitate its use by anyone requiring concentration limits for chemicals. TEEL
values, like the ERPGs, are based on a 1-hour exposure duration. The various TEEL definitions
are as follows.
TEEL-0: The threshold concentration below which most persons will experience no
appreciable risk of health effects.
TEEL-1: The maximum concentration in air below which it is believed nearly all persons
could be exposed without experiencing other than mild transient adverse health effects or
perceiving a clearly defined objectionable odor.
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TEEL-2: The maximum concentration in air below which it is believed nearly all persons
could be exposed without experiencing or developing irreversible or other serious health
effects or symptoms that could impair their abilities to take protective action.
TEEL-3: The maximum concentration in air below which it is believed nearly all persons
could be exposed without experiencing or developing life-threatening health effects.
Where to find TEEL Values
TEEL values for various substances can be found at:
http://www.hss.energy.gov/healthsafetv/wshp/chem safetv/teel.html
1.5.2 Occupational Reference Values
Occupational reference values are designed to protect the worker population from
exposures over the course of a normal work-day and work-week for a typical career (e.g., 8
hours per day, 5 days per week, for several years). Protection for this type of exposure scenario is
typically accomplished using a time-weighted average (TWA) approach. In addition to the TWA
for normal average exposures over an extended period of time, short-term exposure limits
(STELs) and/or ceiling values are also developed to protect workers from shorter-duration
excursions to the average that may be a concern for worker safety but would be lost in a multi-
hour average value. Occupational values are also often derived with an assumption that the
population is a healthy cohort of working age (e.g., 18-65 years old) and is less likely to include
susceptible subpopulations. In addition to consideration of health effects, occupational guidelines
and standards often also consider the technical feasibility of reliably monitoring and reporting for
a specific concentration, and some trade-offs (work practices, length of time at a task, etc.) may
be used to compensate for these monitoring and reporting considerations.
1.5.2.1. Occupational Exposure Limits Various Sources and Organizations
Several considerations apply to the selection of appropriate occupational exposure limits;
they include both a maximum concentration of a chemical in air and a well-defined exposure
duration. The range of available limits include: (1) 8- to 10-hour time-weighed average (TWA)
limits; (2) ceiling values, which are concentrations that should not be exceeded at anytime during
an 8-hour workday; and (3) short-term exposure limits (STELs), which are generally 15-min
exposure limits that should not be exceeded during the course of a workday. The ceiling and
STEL values are assigned to substances that exert toxic effects over a short period of time.
Chemicals may have one or more of these values. For example, the U.S. Department of
Labor, Occupational Safety and Health Administration (OSHA) has assigned carbon disulfide
both a ceiling value and a TWA. In this case, neither the ceiling value nor the TWA should be
exceeded. A worker may experience multiple peak exposures during the work shift; however,
none of these peaks may exceed the ceiling value. In addition, the average of these peaks and
other total exposures over the entire work shift may not exceed the TWA value.
The STEL, ceiling, and TWA values are concentrations to which workers may be safely
exposed daily, throughout their entire working life (up to 40 years). They are designed to protect
healthy adults. It is, however, important to note that not all workers will be protected from
adverse health effects even though their exposures are maintained below these levels. Some may
experience adverse health effects because of personal susceptibility, a preexisting medical
September 2009 14
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condition, and/or hypersensitivity (allergy). The occupational reference values are not intended
for application to community exposure or the general public.
The primary sources of occupational exposure values for the workplace are (1) NIOSH
Recommended Exposure Limits (RELs) (NIOSH, 2006, 1921771 (2) the American Conference
of Governmental Industrial Hygienists' (ACGIH) Threshold Limit Values (TLVs) and Biologic
Exposure Indices (BEIs) (2007, 1920241 and (3) OSHA's Permissible Exposure Limits (PELs),
which include TWA, ceiling and STEL values (OSHA, 2006, 192276: OSHA, 2006, 192291).
The OSHA PELs are legally enforceable exposure limits, whereas the NIOSH RELs and the
ACGIH TLVs and BEIs are recommended guidelines.
Additionally, the Centers for Disease Control and Prevention (CDC) has recommended
exposure limits for workers to protect against potential exposure to the chemical warfare agents
GA (tabun), GB (sarin), VX, L (lewisite), and HD (sulfur mustard) (CDC, 2003, 192190: CDC,
2004, 192193). These Worker Protection Limits (WPLs) are intended for use among workers
involved in chemical weapons disposal. Similar to other occupational reference values, these
worker population limits for chemical warfare agents are described in terms of 8-hour TWAs and
STEL values and are applicable to long-term, routine work in dismantling chemical weapons.
The CDC also developed General Population Limits (GPLs) which are described below.
Where to Find Occupational Exposure Limits
NIOSH RELs can be found at: www.cdc.gov/niosh/npg/npg.html
The ACGIH TLVs are published annually in the Threshold Limit
Values for Chemical Substances and Physical Agents & Biological
Exposure Indices. Additional information on the ACGIH TLVs
can be found at www.acgih.org/home.htm
OSHA PELs are listed at www.osha.gov/SLTC/pel/index.html
Information on the CDC airborne exposure limits for chemical
warfare agents can be found at:
http://www.cdc.gov/nceh/demil/reports/reports.htm.
1.5.2.2. Immediately Dangerous to Life or Health (IDLH) Concentrations National
Institute for Occupational Safety and Health
IDLH concentrations are published by NIOSH (NIOSH, 1996, 192195). which defines an
IDLH condition as 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." Furthermore, the stated purpose of establishing an
IDLH concentration is to "ensure that the worker can escape from a given contaminated
environment in the event of failure of the respiratory protection equipment." IDLH
concentrations were based on the effects that might occur as a consequence of a 30-min
exposure. However, the 30-min 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.
September 2009
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Where to find IDLH Values
The methodology for deriving IDLH concentrations and the
actual values for nearly 400 substances can be found at:
www.cdc.gov/niosh/idlh/idlh-l.html
The NIOSH respirator selection logic uses an IDLH as one of several respirator selection
criteria. Under the NIOSH respirator decision logic, highly reliable respirators (i.e., the most
protective respirators) would be selected for emergency situations, fire fighting, exposure to
carcinogens, entry into oxygen-deficient atmospheres, entry into atmospheres that contain a
substance at a concentration greater than 2,000 times the NIOSH REL or OSHA PEL, and for
entry into IDLH conditions. These highly reliable respirators include either a self-contained
breathing apparatus (SCBA) that has a full face piece and is operated in a pressure-demand or
other positive-pressure mode, or a supplied-air respirator that has a full face piece in combination
with an auxiliary SCBA, both operated in a pressure-demand or other positive-pressure mode.
1.5.3 General Public Reference Values
The general public reference values are set to protect almost all susceptible
subpopulations and tend to over-estimate rather than under-estimate potential risks from
exposures. Although the Emergency Response values are also applicable to the general public,
they are derived for more specific purposes, with attendant assumptions of frank effects and rare
"once-in-a-lifetime" exposure scenarios. The acute values derived for the general population tend
to incorporate the potential for a repeat exposure for a similar duration (e.g., one-hour) as an
uncertainty rather than the assumption of a rare event occurring, as was discussed for the
emergency response values, and including more protection for susceptible subpopulations than
are typical for the occupational values. The general public values are therefore likely to be the
best guidance values for determining safe levels of exposure for reoccupancy of a site following
clean-up or remediation.
1.5.3.1. Integrated Risk Information System (IRIS) - U.S. Environmental Protection
Agency
The Integrated Risk Information System (IRIS), prepared and maintained by EPA, is an
electronic database containing information on human health effects that may result from
exposure to various chemicals in the environment (EPA, 2009, 192196). IRIS contains
descriptive and quantitative information and includes oral reference doses (RfDs) and inhalation
reference concentrations (RfCs) for chronic noncarcinogenic health effects and oral slope factors
(CSFs) and inhalation unit risks (ITJRs) for carcinogenic effects. RfDs are usually provided in
units of mg/kg-day and RfCs in units of mg/m3. CSFs are usually provided in units of (mg/kg-
day)"1 and lURs are provided in (ug/m3) . RfDs, CSFs and lURs (dose-based reference values)
are not directly comparable to environmental concentrations. However, mathematical models
September 2009 16
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using appropriate exposure parameters can be applied to convert these dose-based reference
values into concentration-based reference values.
EPA IRIS values represent the Agency's consensus for chronic toxicity values. Many
other Federal and State agencies also make IRIS their preferred source of these dose-based
reference values. IRIS assessments are externally peer-reviewed before they are released as final
assessments.
Reference Doses (RfDs) and Inhalation Reference Concentrations (RfCs): RfDs and
RfCs are generally defined as an estimate (with uncertainty spanning perhaps an order of
magnitude) of a daily exposure to the human population (including sensitive subgroups)
that is likely to be without an appreciable risk of deleterious effects during a lifetime.
RfDs and RfCs can be derived from a NOAEL, a LOAEL, or a BMD, with standard or
data-derived uncertainty factors generally applied to reflect limitations of the data used.
Oral/Cancer Slope Factors (CSF): The Cancer Slope Factor (CSF) is defined as a
plausible upper bound on the increased cancer risk from a lifetime exposure to an agent.
This estimate is usually expressed as a dose in units of proportion (of a population)
affected per mg/kg-day.
Inhalation Unit Risk Values (IUR): ITJRs are defined as the upper-bound excess
lifetime cancer risk estimated to result from repeated exposure to an agent at a
concentration of 1 |ig/m3 in air. The interpretation of inhalation unit risk would be as
follows: if unit risk = 2 x 10"6 per |ig/m3, 2 excess cancer cases (upper bound estimate)
are expected to develop per 1,000,000 people if exposed daily for a lifetime to 1 jig of the
chemical in 1 cubic meter of air.
Where to find IRIS Values
IRIS values and background information can be accessed at:
http ://cfpub. epa.gov/ncea/iris/index.cfm.
1.5.3.2. Acute, Intermediate and Chronic Minimum Risk Levels (MRLs) Agency for
Toxic Substances and Disease Registry
The Agency for Toxic Substances and Disease Registry (ATSDR) has developed MRLs
in response to mandates under the Comprehensive Environmental Response, Compensation, and
Liability Act (CERCLA), as amended by the Superfund Amendments and Reauthorization Act
(ATSDR, 2009, 192154).
An MRL is an estimate of the daily human exposure to a hazardous substance that is
likely to be without appreciable risk of adverse noncarcinogenic health effects over a specified
duration of exposure. These values are not regulatory numbers, but are used by ATSDR health
assessors and others to identify contaminants and potential health effects that may be of concern
at hazardous waste sites.
MRLs are set below levels that, based on current information, have the potential to cause
adverse health effects in the persons most sensitive to such substance-induced effects. Most
MRLs contain some degree of uncertainty because of the lack of precise toxicological
information on persons who might be most sensitive (e.g., infants, elderly, and the nutritionally
or immunologically compromised) to the effects of hazardous substances. In deriving MRLs,
ATSDR employs uncertainty factors and modifying factors to account for uncertainty in
September 2009 17
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derivation of human health toxicity values. ATSDR states that exposure to a level above the
MRL does not necessarily mean that adverse health effects will occur.
Where to Find MRLs:
Background information and documentation for ATSDR MRLs are
publicly available in the toxicological profile information sheet at:
http://www.atsdr.cdc.gov/toxpro2.html
MRL values for various chemicals can be found at:
http ://www. atsdr. cdc. gov/mrls/index.html
MRLs are derived for exposure durations of 1 to 14 days via the oral and inhalation
routes of exposure. While ATSDR refers to this duration as acute, it corresponds to the
EPA/IRIS short-term exposure scenario described previously. In addition, ATSDR derives oral
and inhalation MRLs for longer-term exposure durations: intermediate (>14 to 364 days) and
chronic (365 days and longer). MRLs receive extensive internal and external peer-review.
1.5.3.3. California Reference Exposure Levels (CA-RELs) State of California
Environmental Protection Agency, Office of Environmental Health Hazard Assessment
The California EPA (CalEPA) Office of Environmental Health Hazard Assessment
(OEHHA) has published reviews of the acute health effects for 51 chemical contaminants and 80
chronic Reference Exposure Levels (CA-RELs)4 for individual chemicals based on the most
sensitive adverse health effect (OEHHA, 2008, 192197). The CA-RELs have a heavy emphasis
on the utilization of available human data, with two-thirds of the acute CA-RELs based on
observed human health outcomes. The final values incorporate uncertainty factors similar to
those used in deriving RfCs for chronic exposures. OEHHA derives acute (1-hour) and chronic
inhalation CA-RELs for hazardous airborne substances and has recently begun developing 8-
hour values.
The acute CA-RELs represent an exposure that is not likely to cause adverse effects in a
human population, including sensitive subgroups, exposed to that concentration for 1 hour on an
intermittent basis (OEHHA, 1999, 192198: OEHHA, 2008, 192197). Chronic CA-RELs are
concentrations or doses at or below which adverse health effects are not likely to occur. A central
assumption is that a population threshold exists below which adverse effects will not occur in a
population; however, such a threshold is not observable and can only be estimated. Areas of
uncertainty in estimating effects among a diverse human population exposed continuously over a
lifetime are addressed using extrapolation and uncertainty factors.
OEHHA's Toxicity Criteria Database provides peer-reviewed toxicity reference values
that address both cancer and non-cancer effects.
Where to find CA-RELs:
1 The CA-RELs are distinct from the NIOSH occupational RELs (Recommended Exposure Limits).
September 2009
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ปปป Acute CalEPA REL values can be found at:
http://www.oehha.ca.gov/air/acute rels/acuterel.html#download
ปปป Chronic CalEPA REL values can be found at:
http ://www. oehha. ca. gov/air/chronic_rels/index.html
*ป* A complete list of CalEPA toxicity values, including RELs, is
available on the CalEPA website at:
http: //www. oehha. ca. gov/ri sk/chemi calDB//index. asp
1.5.3.4. General Population Limits (GPLs) for Chemical Warfare Agents (CWAs)
Centers for Disease Control and Prevention
CDC recommends GPLs, which are long-term (lifetime) exposure limits for several
chemical warfare agents in air, applicable to populations surrounding chemical weapons disposal
sites. GPLs have been developed for GA (tabun), GB (sarin), VX, HD (sulfur mustard), and L
(lewisite). These values were developed specifically for CWA facilities where large amounts of
agent are handled, processed and stored continuously in bulk. These values are closely related to
the Worker Population Limits (WPLs) described in the section on occupational values.
For More Information on GPLs:
http://www.cdc.gov/nceh/demil/files/Federal%20Register%20Reprint%20-
%20October%209.pdf
http://www.cdc.gov/nceh/demil/files/Federal%20Register%20Mustard%20AEL%205 2004.pdf
1.5.3.5. World Health Organization (WHO) Air Quality Guidelines for Europe
The WHO Air Quality Guidelines for Europe were developed by the Regional Office for
Europe of the WHO (WHO, 2000, 180143). The primary aim of the WHO Air Quality guidelines
is to provide "a uniform basis for the protection of public health and of ecosystems from adverse
effects of air pollution, and to eliminate or reduce to a minimum exposure to those pollutants
that are known or are likely to be hazardous. The guidelines are based on the scientific
knowledge available at the time of their development. They have the character of
recommendations, and it is not intended or recommended that they simply be adopted as
standards." There are guidelines developed for 16 organic compounds, 12 inorganic pollutants,
and 4 pollutants considered "criteria pollutants" by the U.S. EPA (particulate matter, ozone and
other photochemical oxidants, nitrogen dioxide and sulfur dioxide).
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1.5.3.6. Other Peer-Reviewed Values or Concentration Levels
A number of other peer-reviewed published values are in existence but have not been
incorporated here. For example, the National Research Council (NRC)/National Academies
(NAS) has reviewed and published RfDs for oral exposures to six chemical warfare agents (GA,
GB, GD, VX, sulfur mustard, lewisite) and a CSF for sulfur mustard. This report is available at:
http://www.nap.edU/books/0309065984/html/l.html. Other special use reference value systems
have also been developed, such as the Spacecraft Maximum Allowable Concentration (NRC,
2008, 194182) and others, but those are not included here.
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References
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of Governmental
Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). 2002 Emergency Response Planning Guidelines (ERPG) Complete Set. Fairfax,
VA: American Industrial Hygiene Association. 192051
ATSDR. (2009). Minimal risk levels (MRLs) for hazardous substances. Retrieved 24-JUN-09,
from http://www.atsdr.cdc.gov/mrls/index.html. 192154
CDC. (2003). Final recommendations for protecting human health from potential adverse effects
of exposure to agents GA (tabun), GB (sarin), and VX. Fed Regist, 68: 58348-58351.
192190
CDC. (2004). Interim recommendations for airborne exposure limits for chemical warfare agents
H and HD (sulfur mustard). Fed Regist, 69: 24164-24168. 192193
DOE. (2008). Temporary emergency exposure limits for chemicals: methods and practice. U.S.
Department of Energy. Washington, DC. DOE-HDBK-1046-2008. 192182
EPA. (2009). Integrated risk information system (IRIS). Retrieved 24-JUN-09, from
http ://cfpub. epa.gov/ncea/iris/index. cfm. 192196
NIOSH. (1994). Introduction: documentation for immediately dangerous to life or health
concentrations (IDLH). Retrieved 02-JUL-09, from
http://www.cdc.gov/niosh/idlh/idlhintr.html. 192183
NIOSH. (1996). Documentation for immediately dangerous to life or health concentrations
(IDLH). Retrieved 15-JUN-09, from http://www.cdc.gov/niosh/idlh/intridl4.html. 192195
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National Institute for
Occupational Safety and Health. 192177
NRC. (2001). Standing operating procedures for developing acute exposure guideline levels
(AEGLs) for hazardous chemicals. Washington, DC: National Academies Press. 192042
OEHHA. (1999). Air toxics hot spots program, risk assessment guidelines part I: the
determination of acute reference exposure levels for airborne toxicants. Office of
Environmental Health Hazard Assessment, California EPA. Sacramento, CA. 192198
OEHHA. (2008). Acute, 8-hour and chronic reference exposure level (REL) summary. Retrieved
15-JUN-09, from http://www.oehha.ca.gov/air/allrels.html. 192197
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
OSHA. (2006). Table Z-2 limits for air contaminants. Retrieved , from . 192291
U.S. EPA. (2002). A review of the reference dose and reference concentration processes. 088824
U.S. EPA. (2004). An examination of EPA risk assessment principles and practices. U.S.
Environmental Protection Agency. Washington, DC. EPA/100/B-04/001. 192199
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health Organization
Regional Publications. Copenhagen. 91. 180143
September 2009 21
-------
Woodall GM. (2005). Acute health reference values: overview, perspective, and current forecast
of needs. J Toxicol Environ Health A, 68: 901-926. 088790
September 2009 22
-------
SECTION 2:
CHEMICAL-SPECIFIC REFERENCE VALUE ARRAYS
This section summarizes the available health effects reference values for inhalation
exposures for 24 chemical compounds. For each chemical, a brief description is provided with
details on the chemical properties and uses, as well as a discussion of the available reference
values. Graphical arrays for each chemical include inhalation reference values for Emergency
Response, Occupational, and General Public values. The reference value arrays are
accompanied by a table with additional information regarding the derivation of the reference
values.
Reference Value Arrays - The arrays were developed to show all available values across the
different categories of reference values (Emergency Response, Occupational, and General
Public), across all durations (acute - less than 24 hours, short-term - 1 to 30 days, subchronic -
over 30 days up to several years, and chronic - up to a lifetime), and severity of effect (lethality
down to no presumed adverse effect). The x-axis on the arrays represents hours of duration on a
logarithmic scale to allow readable inclusion of all durations on a single array. The y-axis also
shows a logarithmic scale for exposure concentration in units of milligrams per cubic meter
(mg/m3).
Standard shapes to denote related types of values and colors to denote severity of effect
were used as noted below.
Shapes:
Diamonds and Triangles for Emergency Response values5
Circles for Occupational values
Squares for General Public values
Colors
Red for defining lethality threshold values
Gold for Irreversible/Serious effects
Blue for Reversible/Mild effects
Green for values deemed without any adverse effects
Some variation in the use of colors was applied to differentiate between the occupational values,
which were all for similar severity levels6.
Derivation Details for Reference Values - Detailed information was compiled into tables to
provide the key information necessary for understanding the derivation and potential application
of the reference values shown in the graphical arrays. These tables are critical accompaniments
to the graphical arrays. Information included in the tables include final derived health effect
reference values, the critical health effect(s) for which the values were derived, the critical study
and details on the study (species, duration of exposure, etc.), the point of departure (POD) used,
5 Two shapes were used for the Emergency Response values due to the fact that all three varieties of values include
three severity levels, which are best represented by shading differences, whereas shapes more clearly depict a
different source for values.
6 Color/shading instead of shape differences were chosen for the Occupational values because all values typically
were for the same severity level, yet there were often multiple values available for the same chemical from a variety
of sources.
September 2009 23
-------
any adjustments to the observations in the study in deriving the POD, uncertainty factors used,
and finally any other important considerations not otherwise captured on derivation of the
reference value.
The 24 chemicals presented in this section, shown in the table below, were chosen based
on an inventory of existing arrays and those chemicals classified as a priority by clients
identified as primary users of the final document. Table 2.1 is a summary of the inhalation
reference values available for each chemical. An "X" indicates an available inhalation reference
value for a chemical, whereas a lack of an "X" indicates that no inhalation reference value is
available for that chemical.
September 2009 24
-------
Table 2-1. Summary of Available Inhalation Reference Values for 24 Chemicals
Acrolein
Ammonia
Arsine (SA)*
Chlorine*
Chromium VI
Cyanogen Chloride*
Etyhlene Glycol Methyl Ether
Ethylene Oxide
Formaldehyde
Soman (GD) + Cyclosarin (GF)*
Hydrogen Cyanaide (AC)*
Hydrogen Fluoride
Hydrogen Sulfide
Lewisite (L)*
Mercury
Methylene Chloride
Percholoroetyhlene
Phosgene (CG)*
Phosphine*
Sarin (GB)*
Styrene
Sulfur Mustard (HD)*
Tabun (GA)*
VX*
Emergency Response
AEGL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ERPG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TEEL
X
X
Occupational
IDLH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
TLV
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PEL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
REL
X
X
X
X
X
X
X
X
X
X
X
X
CDC
WPL
X
X
X
X
X
STEL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ceiling
X
X
X
X
X
X
X
X
X
X
X
X
General Public
RfC
X
X
X
X
X
X
X
X
X
X
X
MRL
X
X
X
X
X
X
X
X
X
X
X
X
CA-
REL
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CDC
GPL
X
X
X
X
X
WHO Air
Quality
Guideline
X
X
X
* indicates a chemical warfare agent
September 2009
25
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2.1 Chemical-Specific Reference Values for Acrolein (CASRN 107-02-8)
Acrolein is a colorless or yellowish liquid at ambient temperature and pressure and has an
acrid, pungent odor and is highly irritating to mucous membranes, especially the upper
respiratory tract and eyes. The odor threshold is <0.1 ppm (Beauchamp RO et al., 1985, 007387).
It is used as an intermediate in the production of acrylic acid; it is also used as an herbicide,
algicide, and slimicide; in the cross-linking of protein collagen in leather tanning; as a fixative of
histological samples; in the production of perfumes; and in military poison gas mixtures. The
largest sources of human exposure to acrolein are from incomplete combustion of organic
materials (such as in urban fires and forest fires), tobacco smoke, and the burning of fat-
containing foods (Beauchamp RO et al., 1985, 007387). Additional information on the nature of
acrolein and detailed summaries of health effects can be found in the AEGL Technical Support
Document (NAC/AEGL, 2006, 192187). the ATSDR Toxicological Profile (ATSDR, 2007,
192118). the IRIS Toxicological Review (U.S. EPA, 2003, 192239). the OHHEA REL
documentation (OEHHA, 2008, 192315), and other sources and is not repeated here.
As can be inferred from Figure 2.1, the occupational values for ceiling exposures and for
the time-weighted averages (TWAs) are generally very similar to the emergency response
values. As shown for the AEGL values and described in the Technical Support Document (2006,
192187), a clear concentration by time (Cn x t = k) relationship7 exists for lethality (AEGL-3),
where n = 1.2, derived from lethality data in rats exposed to acrolein from 1 to 4 hours; however,
concentration alone is the determinant for irritation (AEGL-1) and the AEGL-2 was developed
using a mixed approach to avoid values for 4 and 8 hours that were similar or lower than the
AEGL-1 values. Two data sets were used in deriving the AEGL-3 with one point used for 10-
min, 30-min and 1-hr AEGL-3 derivation from 1 hour and a separate 4-hour data point used for
4-hr and 8-hr AEGL-3 derivation.
The relatively more health protective nature of the California REL (CA-REL), ATSDR
MRL and, EPA RfC values is also readily apparent for all durations. The chronic reference
values used studies with similar points of departure (Dorman et al., 2008, 180108; Feron et al.,
1978, 007381) and differences in final values related to dose extrapolation, derivation methods
and application of uncertainty factors (see Table 2.1). The intermediate duration ATSDR MRL
and the chronic duration EPA RfC both used adjustments for duration of exposure and
differences in ventilation rates between humans and rats to derive a human equivalent
concentration (HEC) of the lowest observable adverse effect level (LOAEL).
The NIOSH values are derived by a weight of evidence approach and no particular study
was identified as the basis for the values. Following 60 seconds of exposure to 5.5 ppm, intense
irritation and marked lacrimation was noted (Henderson and Haggard, 1943, 010318).
Additionally, the background document cited slight eye irritation after 1 minute and profuse
lacrimation after 4 minutes following exposures to 1.8 ppm (NRC, 1981, 192157). In studies
with human volunteers, those exposed for 5 minutes to concentrations of 2 to 2.3 ppm produced
severe eye irritation (Darley et al., 1960, 015690), and a 10-minute exposure at 8 ppm and a 5-
minute exposure at 1.2 ppm elicited extreme eye irritation described as "only just tolerable" (Sim
andPattle, 1957, 071236).
7 Where C = concentration, t = time, n is an empirically derived value from observed data, and k = a constant This
relationship was originally developed by Haber (Haber, 1924) and later revised by ten Berge (ten Berge et al., 1986).
September 2009 26
-------
Overall, there is a full set of reference values for acrolein available. The database for this
chemical is quite well defined. The most critical issues are related to the nature of the C x t
relationship and how it changes along the severity gradient and in moving from very short
(acute) to longer durations.
September 2009 27
-------
Office of Research and Development
National Center tar Environmental An
Research Triangle Park, NC
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1.E+01
,^ 1-E+OO
E
E
^ 1.E-01
O
c
o
o
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2
o
1.E-03
1.E-04
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Acrolein: Comparison of Reference Values
ACUTE
=
o
I
2^1^0-3
" ฃ NIOSH-STEL* ^^
ACGlH-Ceiling* Vป*AEG
A ERPG-1
>
X CA-REL (Acute)
XCA-R
Short Term
t/i
1
o
-3
-1
t - - - *AT
EL (8-hour)
Subchronic
1
3DR-MRL(1-14d)
I
ATSDR-MRL (1 5-365 d)
*!---* i
Chronic
C
g
OSHA-PEL (TV\
'NIOSH-RELI
CA-REL >
^ (Chronic) '
EPA/I RIS-RfC
1 '
A)'
A)*
:
1
AEGL-3 o
c
0 AEGL-2
to
o
0 AEGL-1 K
o
A ERPG-3 g
D)
A ERPG-2 ^
UJ
A ERPG-1
O ACGIH-Ceiling*
NIOSH-STEL*
NIOSH-IDLH*
o
- - - - NIOSH-REL (TWA)* Q
O OSHA-PEL (TWA)*
X CA-REL (Acute)
X CA-REL (8-hour) .ฃ2
si
X ATSDR-MRL (1-14 d) iS
X ATSDR-MRL (15-365 d)
X CA-REL (Chronic)
: :
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.1. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Acrolein
September 2009
28
-------
Table 2.1. Details on derivation of the specific inhalation health effect reference values for acrolein.
Refe
Ty
Emergency Response1
rence Value
pe / Name
AEGL-3
AEGL-2
AEGL-1
ERPG-3
ERPG-2
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
1 hr
Reference Value
(mg/mj)
14
5.7
3.2
1.1
0.62
0.92
0.41
0.23
0.23
0.23
0.07
0.07
0.07
0.07
0.07
3.4
0.34
(ppm)
6.2
2.5
1.4
0.48
0.27
0.44
0.18
0.10
0.10
0.10
0.03
0.03
0.03
0.03
0.03
1.5
0.15
Health Effect
Concentration causing
no death in rats fora 1-
hour exposure
(10-min, 30-min, 1-hr)
(Ballantyne etal., 1989,
007753)
Concentration causing
no death in rats for a 4-
hour exposure
(4-hr, 8-hr) (Ballantyne
etal., 1989,007753)
1 0-25% decrease in
respiratory rate and
sensory irritation in
healthy
humans (Weber-
Tschopp et al., 1977,
007797)
Eye irritation and
"annoyance"/
discomfort in healthy
humans (Weber-
Tschopp et al., 1977,
007797)
Irritation (Albin, 1962,
007452; Carpenter et
al., 1949,094685;
Kruysse, 1971, 192236;
Rattle etal., 1956,
072271)
Eye and respiratory
irritation (Albin, 1962,
007452; NRC, 1981,
192157)
Point of Departure
14 ppm LC0i
(1 hour)
4.8 ppm LC01
(4 hour)
0.3 ppm NOAEL
0.09 ppm Threshold
for effects
8-25 ppm LC50
(4-6 hr)
0.5 ppm NR
Uncertainty
Factors
Total UF = 9
UFA = 3
UFH = 3
Total UF = 3
UFH=3
NR
NR
Notes on
Derivation
Duration
adjusted
via
Cnxt = k
where
n = 1.2
Duration
adjusted as
AEGL-3 to
1 hour,
then flat-
lined
No duration
adjustment
Review
Status
Proposed
(NAC/AEGL,
2006,
192187)
Final
(AIHA, 2002,
192060)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these refernce values to any Occupational or General Public reference values.
September 2009
29
-------
Refe
Ty
Occupational
rence Value
pe / Name
ERPG-1
Ceiling-
ACGIH*
NIOSH-
STEL*
NIOSH-
IDLH*
NIOSH-REL
(TWA)*
OSHA-PEL*
Duration
1 hr
Any
15 min
30 min
10 hr
(TWA)
8hr
(TWA)
Reference Value
(mg/mj)
0.12
0.23
0.8
4.6
0.25
0.25
(ppm)
0.05
0.1
0.3
2
0.1
0.1
Health Effect
Mild, transient eye and
respiratory irritation
(American Industrial
Hvaiene, 1968, 192027;
NRC, 1981, 192157)
Mucous membrane
irritation, pulmonary
edema (Beauchamp
ROetal., 1985,
007387; Henderson
and Haggard, 1943,
010318; Lyonetal.,
1970,007468; Prentiss,
1937.015303:
Schaper, 1993,
1 80252)
Intense irritation and
marked lacrimation
(Henderson and
Haggard, 1943,
010318; Sim and
Pattle, 1957,071236)
(Darley et al., 1960,
01 5690; NRC, 1981,
192157)
NR
Point of Departure
0.1 ppm NR
0.22 ppm LOAEL
(animal)
0.25 ppm LOAEL
(human)
6 ppm RD50
(mouse)
NR NR
2 ppm Effect
Level
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(NIOSH,
1996,
192195)
Final
(NIOSH,
2006,
192177)
September 2009
30
-------
Refe
Ty
General Public
rence Value
pe / Name
CA-REL
(Acute)
CA-REL
(8-hr)
ATSDR-
MRL
(1-14d)
ATSDR-MRL
(15-365d)
CA-REL
(Chronic)
RfC (IRIS)
Duration
1 hr
8hr
1 -14d
15 d-
1 yr
Chronic
Chronic
Reference Value
(mg/mj)
0.25
0.0007
0.007
0.00009
3.5 x10'4
2x10'D
(ppm)
0.1
0.0003
0.003
0.00004
1.5x10'D
8.7x10'D
Health Effect
Subjective ocular
irritation in humans
(Darley et al., 1960,
015690)
Lesions in respiratory
epithelium (Dorman et
a I., 2008, 180108)
Decrease in respiratory
rate, nose and throat
irritation (Weber-
Tschopp et al., 1977,
007797)
Nasal epithelial
metaplasia in rats
(Feron etal., 1978,
007381)
Lesions in respiratory
epithelium (Dorman et
al., 2008, 180108)
Slight nasal effects
(Feron etal., 1978,
007381)
Point of Departure
0.06 ppm LOAEL
0.2 ppm NOAEL
0.6 ppm LOAEL
0.3 ppm LOAEL
0.01 2 ppm LOAELHEc
0.2 ppm NOAEL
0.6 ppm LOAEL
0.02 mg/mj LOAELHEc
Uncertainty
Factors
Total UF = 60
UFL = 6
UFH = 10
Total UF = 200
UFS= 101/2
UFA:
TK = 2,
TD = 101/2
UFH = 10
Total UF = 100
UFL= 10
UFH = 10
Total UF = 300
UFL= 10
UFA = 3
UFH = 10
Total UF = 60
UFL = 6
UFH=10
Total UF= 1000
UFA = 3
UFH = 10
UFS= 10
UFL=3
Notes on
Derivation
Review
Status
Final
(OEHHA,
2008,
192315)
Final
(ATSDR,
2007,
192118)
Final
(OEHHA,
2008,
192315)
Final
(U.S. EPA,
2003,
192239)
September 2009
31
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Acrolein(1989). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192060
ATSDR. (2007). Toxicological profile for acrolein. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. NTIS PB2008-100001. 192118
Albin TB. (1962). Handling and toxicology. In Smith, C. W. (Ed.),AcroleinNew York,
NY: John Wiley & Sons. 007452
American Industrial Hygiene Association. (1968). Aldehydes. , 29: 505-512. 192027
Ballantyne B; Dodd DE; Pritts IM; Nachreiner DJ; Fowler EH. (1989). Acute vapour
inhalation toxicity of acrolein and its influence as a trace contaminant in 2-
methoxy-3,4-dihydro-2H-pyran. Hum Exp Toxicol, 8: 229-235. 007753
Beauchamp RO Jr; Andjelkovich DA; Kligerman AD; Morgan KT; Heck Hd'A. (1985).
A critical review of the literature on acrolein toxicity. Crit Rev Toxicol, 14: 309-
380. 007387
Carpenter CP; Smyth HF Jr; Pozzani UC. (1949). The assay of acute vapor toxicity, and
the grading and interpretation of results on 96 chemical compounds. Arch Environ
Occup Health, 31: 343-346. 094685
Darley EF; Middleton JT; Garber MJ. (1960). Plant damage and eye irritation from
ozone-hydrocarbon reactions. J Agric Food Chem, 8: 483-485. 015690
Dorman DC; Struve MF; Wong BA; Marshall MW; Gross EA; Willson GA. (2008).
Respiratory tract responses in male rats following subchronic acrolein inhalation.
Inhal Toxicol, 20: 205-216. 180108
Feron VJ; Kruysse A; Til HP; Immel HR. (1978). Repeated exposure to acrolein vapour:
subacute studies in hamsters, rats and rabbits. Toxicology, 9: 47-57. 007381
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Kruysse A. (1971). Acute inhalation toxicity of acrolein in hamsters. Central Institute for
Nutrition and Food Research. The Netherlands. R 3516. 192236
Lyon JP; Jenkins LJ Jr; Jones RA; Coon RA; Siegel J. (1970). Repeated and continuous
exposure of laboratory animals to acrolein. Toxicol Appl Pharmacol, 17: 726-732.
007468
NAC/AEGL. (2006). Acrolein - interim acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192187
September 2009 32
-------
NIOSH. (1996). Documentation for immediately dangerous to life or health
concentrations (IDLH). Retrieved 15-JUN-09, from
http://www.cdc.gov/niosh/idlh/intridl4.html. 192195
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
NRC. (1981). Formaldehyde and other aldehydes. National Research Council.
Washington, DC. 192157
OEHHA. (2008). Acute, 8-hour and chronic toxicity summary - acrolein. Office of
Environmental Health Hazard Assessment, California EPA. Sacramento, CA.
192315
Pattle RE; Burgess F; Cullumbine H. (1956). The effects of a cold environment and of
ammonia on the toxicity of sulphuric acid mist to guinea-pigs. J Med Microbiol,
72:219-232. 072271
Prentiss AM. (1937). Chemicals in war. 015303
Schaper M. (1993). Development of a database for sensory irritants and its use in
establishing occupational exposure limits. , 54: 488-544. 180252
Sim VM; Pattle RE. (1957). Effect of possible smog irritants on human subjects. JAMA,
165: 1908-1913.071236
U.S. EPA. (2003). Toxicological review of acrolein. National Center for Environmental
Assessment. Washington, DC. EPA/635/R-03/003.
http://www.epa.gov/iris/toxreviews/0364-tr.pdf. 192239
Weber-Tschopp A; Fischer T; Gierer R; Grandjean E. (1977). Experimentelle
Reizwirkungen von Akrolein auf den Menschen [Experimentally induced
irritating effects of acrolein on men]. Int Arch Occup Environ Health, 40: 117-
130. 007797
September 2009 33
-------
2.2 Chemical-Specific Reference Values for Ammonia (CASRN 7664-41-7)
Ammonia is a colorless, corrosive, alkaline gas with a sharp, intensely irritating odor. Its
odor threshold is around 5 ppm. It is lighter than air and easily liquefied by pressure. Ammonia
is used as a compressed gas and in aqueous solutions. It is used in household cleaning products,
in fertilizers, and as a refrigerant. Ammonia is very water soluble, forming ammonium hydroxide
and heat when it contacts moist surfaces, often resulting in immediate damage (severe irritation
and burns) to the eyes, skin and mucous membranes of the oral cavity and respiratory tract. More
details on the chemical nature and toxicity from exposure to ammonia are available from other
sources (AIHA, 2002, 192093: NAC/AEGL, 2002, 192201: U.S. EPA, 1991, 192219)) and are
not repeated here.
Inhalation health effect reference values for ammonia are displayed graphically in
Figure 2.2. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.2.
The Emergency Response (AEGL and ERPG) values for ammonia are in close agreement
with one another for all severity levels, and also closely follow the occupational guidelines. The
most obvious exception is that the NIOSHIDLH value is somewhat lower than the AEGL-3
value for 30 minutes; these values are often in close agreement. More details are provided in the
derivation of the AEGL values than for the ERPGs, as shown in Table 2.2. Time scaling was
performed in the derivation of the AEGL-3 values, using the Cn x t relationship described by ten
Berge (1986, 025664), where n = 2. Duration extrapolations were also performed in deriving
AEGL-2 values for 30 minutes, one hour and four hours from two hour observations (Verberk,
1977, 008111): however, the 30 minute value was adopted as the 10 minute value because to do
otherwise may have lead to values that would impair the ability to escape, and the 4 hour value
was adopted as the 8 hour value because the severity for irritation rating changed very little from
30 minutes to 2 hours and is not expected to change for exposures up to 8 hours. AEGL-1 values
were held constant across durations, as specified in the Standing Operating Procedures for the
AEGLs (NRC, 2001, 192042) when considering mild irritation effects.
The NIOSH Occupational values are derived by a weight of evidence approach and no
particular study was identified as the basis for the values. The maximum short exposure
tolerance is reported as 300 to 500 ppm for 30 minutes to 1 hour (Henderson and Haggard, 1943,
010318). Subjects exposed to 500 ppm for 30 minutes experienced moderate to severe irritation
and a change in respiration rate (Silverman et al., 1946, 063013). Fewer details were provided
for all of the other occupational values, hence the majority of the derivation fields in Table 2.2
show not reported (NR).
For the General Population values, acute values were derived by the State of California
(OEHHA, 2008, 192240) for 1 hour exposures and by ATSDR for an Acute Mimimal Exposure
Level (MRL) with exposures from 1 - 14 days (ATSDR, 2004, 192116). The acute California
Reference Exposure Level (CA-REL) was developed based on observations from several studies
at various durations and concentrations, which were adjusted to a standard 1-hour duration using
the Cn x t formula, where n = 4.6 [which varies from the value of n used in the AEGL
derivations and in studies with ammonia (ten Berge et al., 1986, 025664)]. A benchmark
concentration (BMC) analysis was conducted to calculate the 95% lower confidence limit for a
5% response (BMCLos) for the endpoint of eye and respiratory irritation to arrive at a point of
departure (POD) of 13.6 ppm, which was then divided by an uncertainty factor of 3 to derive a
September 2009 34
-------
final one hour CA-REL of 4.5 ppm (3.2 mg/m3). The acute MRL was based on an observed
LOAEL of 50 ppm, with no adjustments made for duration and application of uncertainty factors
for use of a LOAEL (UFL = 3) and for inter-individual variability (UFH = 10).
Three chronic General Public values - CA-REL, ATSDR MRL, and EPA/IRIS RfC -
were derived, all using the same study (Holness et al., 1989, 008181). The differences in the
derived values were due to variations in the uncertainty factors used and in operational methods
(e.g., when and where in the derivation process rounding and units conversions were applied).
Even with those considerations taken into account, the chronic ATSDR MRL seemed to arrive at
values that were not in keeping with the stated derivation procedure outlined in Appendix A of
the Toxicological Profile for ammonia (ATSDR, 2004, 192116).
September 2009 35
-------
^ Office of Research and Development
National Center for Environmental Ass
Research Irlangle Park, NC
Ammonia: Comparison of Reference Values
O)
1.E+04
1.E+03
1.E+02
O
C
O 1.E+01
re
'E
o
| 1.E+00
1.E-01
1.E-02
ACUTE
to
3
o
I
ซs* *
^s^
T^
A^^ป
><.
Short Term
to
>1
ra
Q
0
CO
_ Tfc AEGL-3
. ONIOSH-IDLH*
O OAEGI
NIOSH-STEL* f*\
Q ^ ^ /v ^ AEGL
V O^i O^>
ACGIH-STEL*m *-"
| CA-REL (Acute
>
-2
-1
*---* A!
Subchronic
W)
^
-J
3DR-MRL(1-14d)
^
Chronic
to
<5
>
o
i~-
1 OSHA-PEL (TO
A)*
| NIOSH-REL (TWA)
ACGIH-TLV(TWA)*
CA-REL (Chronic)
^
^ T
,1, EPA/IRIS RfC J^
[
( y)/K
,j
ป AEGL-3 a,
W)
c
O AEGL-2
Ui
01
0 AEGL-1 ^
A ERPG-3
0
O)
A ERPG-2 aj
A ERPG-1
O ACGIH-STEL*
NIOSH-STEL*
c
NIOSH-IDLH*
ro
Q.
O ACGIH-TLV (TWA)*
o
O NIOSH-REL (TWA)*
O OSHA-PEL (TWA)*
X CA-REL (Acute)
o
XATCnD MDI 11 1A r\\ ~n
A 1 OUK-IVIKL (1-14 Q) ^J
Q.
X ATSDR-MRL(>1yr)
, , i.f/\"$\? "I , |C..ปiillJ!!I|
D
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.2. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Ammonia
September 2009
36
-------
Table 2.2. Details on derivation of the specific inhalation health effect reference values for ammonia.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value
(mg/mj)
1900
1100
770
385
273
154
154
113
77
77
21
21
21
21
21
(ppm)
2700
1600
1100
550
390
220
220
160
110
110
30
30
30
30
30
Health Effect
Lethality in mice
(Kapeghian etal., 1982,
008040; MacEwen and
Vernot, 1972,041949)
Respiratory tract and eye
irritation to humans
exposed to 1 1 0 ppm for 2
hr(Verberk, 1977,
008111)
Faint or no irritation to
humans (MacEwen and
Vernot, 1972,041949)
Point of Departure
3,21 9 ppm BMDL05
3,278 ppm
(4 hours)
110 ppm Threshold
(2 hours) for effects
30 ppm Threshold
(1 0 min) for effects
Uncertainty
Factors
Total UF = 3
i ic ^
UrA - 1
UFH = 3
Total UF = 1
Notes on
Derivation
Time scaling
using Cnxt
(ten Berge et
al., 1986,
025664)
Time scaling
using Cnxt
where n = 2
(ten Berge et
al., 1986,
025664)
No time
scaling.
Review
Status
Final
(NAC/AEGL,
2002,
192201)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these refernce values to any Occupational or General Public reference values.
September 2009
37
-------
Reference Value
Type / Name
0
C
0
Q.
fli
Mr
o:
o
c
0)
M%
O)
0
E
LU
ERPG-3
ERPG-2
Duration
1 hr
1 hr
Reference Value
(mg/mj)
525
105
(ppm)
754
151
Health Effect
1-hr median lethal
concentrations in the rat
from 7340 to 16600 ppm
and from 4230 to 4840 in
the mouse, also causing
eye, nasal, and
respiratory irritation
(ACGIH, 1986, 192014:
Appelman etal., 1982,
007955; Industrial Bio-
test Laboratories, 1973,
061664; Kapeghian et al.,
1982,008040; MacEwen
etal., 1970,064655;
Silverman et al., 1949,
008092; Verberk, 1977,
0081 1 1 ; Weatherbv,
1952,008121)
Slight eye irritation in
humans exposed to 100
pm for 5 weeks; no
changes in respiratory
function in humans
exposed to 140 ppm for 2
hr
(Ferguson et al., 1977,
008010; Industrial Bio-
test Laboratories, 1973,
061664; Verberk, 1977,
0081 1 1 ; Weatherby,
1952,008121)
Point of Departure
NR NR
NR NR
Uncertainty
Factors
NR
NR
Notes on
Derivation
Review
Status
Final
(AIHA, 2002,
192093)
2 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
38
-------
Refe
"
TO
c
0
+J
(0
Q.
3
O
O
rence Value
pe / Name
ERPG-1
ACGIH TLV-
TWA*
ACGIH TLV-
STEL*
OSHA-PEL
(TWA)*
NIOSH-REL
(TWA)*
NIOSH-
STEL*
NIOSH-
IDLH*
Duration
1 hr
Any
15 min
ShrTWA
10hr
TWA
15 min
< 30 min
Reference Value
(mg/mj)
17.5
17
24
35
18
27
210
(ppm)
25
25
35
50
25
35
300
Health Effect
Mild odor perception and
mild irritation (Ferguson
etal., 1977,008010:
Industrial Bio-test
Laboratories, 1973,
061664; MacEwen et al.,
1970, 064655: Pierce,
1994, 180261)
Eye and respiratory
irritation in humans
(Stombaugh etal., 1969,
008097)
Acute sensory effects
(Stombaugh etal., 1969,
008097)
NR
Acute inhalation toxicity
data in humans
Point of Departure
25 ppm NR
NR NR
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
192195)
September 2009
39
-------
Reference Value
Type / Name
General Public
CA-REL
(Acute)
ATSDR-
MRL
(1-14 d)
Duration
1 hr
1 -14
days
Reference Value
(mg/mj)
3.2
1.2
(ppm)
4.6
1.7
Health Effect
Eye and respiratory
irritation in humans
(Industrial Bio-test
Laboratories, 1973,
061664: MacEwen et al.,
1970, 064655; Silverman
etal., 1949,008092;
Verberk, 1977,008111)
Eye, nose, and throat
irritation in humans
(Verberk, 1977,008111)
Point of Departure
13. 6 ppm BMCL05
50 ppm LOAEL
Uncertainty
Factors
Total UF = 3
UFA = 1
UFH = 3
Total UF = 30
UFL = 3
UFH = 10
Notes on
Derivation
BMC analysis
performed on
duration
adjusted
observations
using Cn x T,
where n=4.6.
Review
Status
Final
(OEHHA,
2008,
192317)
Final
(ATSDR,
2004,
192116)
September 2009
40
-------
Reference Value
Type / Name
O
^
S
0.
~5
0
c
0)
ATSDR-
MRL
(> 1yr)
Chronic RfC
(IRIS)
CA-REL
(Chronic)
Duration
Chronic
Chronic
Chronic
Reference Value
(mg/mj)
0.07
0.1
0.2
(ppm)
0.1
0.14
0.29
Health Effect
No significant alterations
in lung function in
chronically exposed
workers (Holness et al.,
1989,008181)
Decreased pulmonary
function or changes in
human subjective
syptomatology
(Holness et al., 1989,
008181)
Pulmonary function, eye,
skin, and respiratory
symptoms of irritation
(Broderson etal., 1976,
007975; Holness etal.,
1989.008181)
Point of Departure
3.0 ppm NOAEI_HEc
(9.2 ppm
x8/24
x5/7)
2.3 mg/mj NOAELHEc
(Based on
6.4 mg/m3
[9.2 ppm]
observed
x5/7
x 1 0/20)
3 ppm NOAELHEc
(Based on
9.2 ppm
observed
x5/7
x 10/20,
rounded to
3 ppm then
converted
to 2 mg/m3)
Uncertainty
Factors
Total UF = 30
UFH = 10
MF = 3
Total UF = 30
UFH = 10
UFDB = 3
Total UF = 10
UFH = 10
Notes on
Derivation
Duration
adjustments
accounting
for work
schedule
applied
(8hr/24hr,
and 5d/7d).
HEC
Adjustments
based on
5 day/wk and
1 0 m3/day
occupational
breathing
rate vs.
20 m3/d
human
average
Same HEC
adjustments
as the IRIS
RfC, but
rounding to
3 ppm as the
POD then
converting to
mg/m3 before
applying UFs.
Review
Status
Final
(ATSDR,
2004,
192116)
Final
(U.S. EPA,
1991,
192219)
Final
(OEHHA,
2000,
192318)
September 2009
41
-------
REFERENCES
ACGIH. (1986). Documentation for threshold limit values and biological exposure
indices. American Conference of Governmental Industrial Hygienists. Cincinnati,
OH. 192014
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Ammonia (2000). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192093
ATSDR. (2004). Toxicological profile for ammonia. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. PBPB2004-107331. 192116
Appelman LM; ten Berge WF; Reuzel PGJ. (1982). Acute inhalation toxicity study of
ammonia in rats with variable exposure periods. J Occup Environ Hyg, 43: 662-
665. 007955
Broderson JR; Lindsey JR; Crawford JE. (1976). The role of environmental ammonia in
respiratory mycoplasmosis of rats. Am J Pathol, 85: 115-130. 007975
Ferguson WS; Koch WC; Webster LB; Gould JR. (1977). Human physiological response
and adaption to ammonia. J Occup Environ Med, 19: 319-326. 008010
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Holness DL; Purdham JT; Nethercott JR. (1989). Acute and chronic respiratory effects of
occupational exposure to ammonia. AIHA J, 50: 646-650. 008181
Industrial Bio-test Laboratories Incorporated. (1973). One-generation reproduction and
teratology study with DMF (dimethylformamide) in albino rats [unpublished
material]. 061664
Kapeghian JC; Mincer HH; Jones AB; Verlangieri AJ; Waters IW. (1982). Acute
inhalation toxicity of ammonia in mice. , 29: 371-378. 008040
MacEwen JD; Theodore J; Vernot EH. (1970). Human exposure to EEL concentrations
of monomethylhydrazine. 064655
MacEwen JD; Vernot EH. (1972). Toxic hazards research unit annual report: 1972.
041949
NAC/AEGL. (2002). Ammonia - proposed acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192201
NIOSH. (1996). Documentation for immediately dangerous to life or health
concentrations (IDLH). Retrieved 15-JUN-09, from
http://www.cdc.gov/niosh/idlh/intridl4.html. 192195
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
September 2009 42
-------
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
OEHHA. (2000). Chronic toxicity summary - ammonia . Office of Environmental Health
Hazard Assessment, California EPA. Sacramento, CA. 192318
OEHHA. (2008). Acute toxicity summary - ammonia . Office of Environmental Health
Hazard Assessment, California EPA. Sacramento, CA. 192317
OEHHA. (2008). TSD for noncancer RELs - appendix D2. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192240
Pierce JO. (1994). Ammonia. In Patty's Industrial Hygiene and Toxicology (pp. 756-
782). New York, NY: John Wiley Sons. 180261
Silverman L; Schulte HF; First MW. (1946). Further studies on sensory response to
certain industrial solvent vapors. , 28: 262-266. 063013
Silverman L; Whittenberger JL; Muller J. (1949). Physiological response of man to
ammonia in low concentrations. ,31: 74-78. 008092
Stombaugh DP; league HS; Roller WL. (1969). Effects of atmospheric ammonia on the
pig. J Anim Sci, 28: 844-847. 008097
U.S. EPA. (1991). Ammonia. Retrieved 10-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0422.htm. 192219
Verberk MM. (1977). Effects of ammonia in volunteers. Int Arch Occup Environ Health,
39:73-81.008111
Weatherby JH. (1952). Chronic toxicity of ammonia fumes by inhalation. Exp Biol Med
(Maywood), 81: 300-301. 008121
ten Berge WF; Zwart A; Appelman LM. (1986). Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J Hazard Mater,
13:301-309.025664
September 2009 43
-------
2.3. Chemical-Specific Reference Values for Arsine
(CASRN 7784-42-1)
Arsine is a colorless, extremely flammable gas with a mild, garlic-like odor (NLM, 2005,
192329). The gas is heavier than air and accumulates close to the surface, which makes distant
ignition possible in the presence of flame or spark. Arsine is extensively used in the
semiconductor industry for epitaxial growth of gallium arsenide, as a doping agent for silicon
based solid state electronic devices and the manufacture of light emitting diodes. In humans,
arsine is absorbed via the lungs and mucosal surface of the respiratory tract. After exposure, the
concentration of arsine increases rapidly in blood, whereas the distribution to the liver, kidneys
and other organs is much slower. In humans, arsine is metabolized to trivalent and pentavalent
arsenic. Trivalent arsenic is methylated to monomethylarsonate and dimethylarsinate. Arsine
metabolites are mainly excreted via urine. Arsine in humans (and other mammals) induces
hemolysis with an increase in plasma hemoglobin, iron and potassium and subsequent anemia
and kidney damage. Myocardial and pulmonary failures are other causes of death. IARC (IARC,
1987, 192133) lists arsenic and arsenic compounds as "carcinogenic to humans" hence many of
the reference values for arsine consider cancer as well as noncancer endpoints. More details on
the chemical nature and toxicity of arsine are available elsewhere (AIHA, 2002, 192087;
American Industrial Hygiene, 1965, 192026: NAC/AEGL, 2000, 192321: U.S. EPA, 1994,
192320): (NLM, 2005, 192329) and are not repeated here.
Inhalation health effect reference values for arsine are displayed graphically in
Figure 2.3. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.3.
The Emergency Response reference values , both the AEGLs and ERPGs, depend on a
single study in mice (Peterson and Bhattacharyya, 1985, 067598) for deriving level 2 values
(irreversible adverse health effects) and level 3 values (severe effects leading to potentially
lethality). Neither the AEGL nor ERPG committees developed level 1 values due to a lack of a
margin seemingly inconsequential exposures and lethal exposures, making it inappropriate to
develop AEGL-1 or ERPG-1 values.
The NIOSH Occupational values are derived by a weight of evidence approach and no
particular study was identified as the basis for the values. The recommended exposure level
(REL) consists of only a ceiling value (a REL time-weighted average value was not established),
and was based on concern for potential carcinogenicity. For establishing the IDLH value, several
studies were noted for symptoms indicative of poisoning were noted after a few hours of
exposure to concentrations of 3 to 10 ppm (Henderson and Haggard, 1943, 010318).
Additionally, a one hour exposure to 1 to 10 ppm may be dangerous (American Industrial
Hygiene, 1965, 192026), while 6 to 30 ppm is the maximum concentration that can be inhaled in
1 hour without serious consequences (Henderson and Haggard, 1943, 010318). Minimal
disabling exposures were reported to be 1,543 ppm for 2 minutes and 62 ppm for 30 minutes
(Gates et al., 1946, 192214). The lowest LCLo of 25 ppm in humans (Teitelbaum and Kier, 1969,
068668), however, seems to be the pivotal study in derivation of the IDLH, as noted in the
documentation (NIOSH, 1996, 192331).
The ACGIH-TLV TWA Occupational value was not based on consideration of cancer
effects, with ACGIH noting in their documentation (2007, 192024) that "there are no human or
animal data that show arsine to be carcinogenic." The key effects noted in that documentation
September 2009 44
-------
focused on an occupational study in battery formation work (Landrigan et al., 1982, 005485),
with other supporting studies also noted.
The General Public values include a set of newly revised Reference Exposure Levels
from the State of California (CA-RELs) for acute (1-hour), 8-hour and chronic durations
(OEHHA, 2008, 192332). The 1-hour acute value was based on equivalents of arsenic (As) from
inhalation exposure to arsenic trioxide (As2C>3) in a developmental study in mice (Nagymajtenyi
et al., 1985, 062165). The 8-hour CA-REL was determined to be equivalent to the chronic CA-
REL, which was in turn based on developmental neurotoxicity in children from exposure to
inorganic arsenic at the parts per billion (ppb) level in drinking water (Tsai et al., 2003, 180240;
Wasserman et al., 2004, 180230). The values shown in Table 2.3 for the 8-hour and chronic CA-
RELs are based on milligrams of arsenic per cubic meter, however, the parts per million (ppm)
units were converted to arsine in the Technical Support Document (OEHHA, 2008, 192332).
The U.S. EPA's IRIS Program developed a chronic inhalation RfC (U.S. EPA, 1994,
192320) based on hemolysis, abnormal red blood cell morphology and increased spleen weight
in both rats and mice (Blair et al., 1990, 067664: Blair et al., 1990, 067665: Hong et al., 1989,
067671). Adjustments were made to account for the 6 hour per day and 5 days per week
exposures, reducing the no observed adverse effect level (NOAEL) in rodents of 0.08 mg/m3 to a
human equivalent concentration of the NOAEL (NOAELHEc) of 0.014 mg/m3. Uncertainty
factors applied included: (1) 10 to account for sensitive populations; (2) a factor of 3 to account
for interspecies extrapolation (default dosimetry adjustments and large species differences not
expected for direct hemolytic effects); and (3) a composite factor of 10 to account for both
subchronic duration extrapolation and database deficiencies, specifically the lack of a two-
generation reproductive study. A reduced uncertainty factor for subchronic-to-chronic duration is
applied because the principal studies do not suggest that duration of exposure is a key
determinant of the critical effects (14- and 28-day exposures caused similar hematologic effects
as 90-day exposures in all three species tested). The final result is a chronic RfC value of 5 x 10"5
mg/m3.
September 2009 45
-------
Office of Research and Development
National Center tor Environmental An
rch Triangle Park, NC
Arsine: Comparison of Reference Values
1.E+02
1.E+01
1.E+00
O)
.ง. 1.E-01
d
c
o
O
0)
_c
'55
1.E-02
1.E-03
1.E-04
1.E-05
ACUTE
to
3
o
I
4
0 NIOSH-IDLH*
ERPG-3
^^"""""^k
'r^EFiPG-2
^> ^V
o ^^
%AEG
o
OAEGI
C
O NIOSH-Ceiling*
X CA-REL (Acute)
XCA-R
! !
Short Term
ซ
ซ
9
8
.-3
-2
-------
EL (8-hour)
1 l
Subchronic
tซ
fi
- t
>
Chronic
to
<5
o
6
^
OSHA-PEL (TV
)ACGIH-TLV(TV
EPA/IRIS RfC,
CA-REL
^ (Chronic) '
A)'
A)'
:
AEGL-3 ซ
c
o
Q.
+ AEGL-2 $
o:
o
A ERPG-3 g
s>
0
A ERPG-2 ,ง
O NIOSH-Ceiling*
NIOSH-IDLH*
1
O ACGIH-TLV (TWA)*
O
O OSHA-PEL (TWA)*
X CA-REL (Acute)
o
X CA-REL (8-hour) "ง
Q.
"s
X CA-REL (Chronic) g
$
D EPA/IRIS RfC
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.3. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Arsine
September 2009
46
-------
Table 2.3. Details on derivation of the specific inhalation health effect reference values for arsine.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
ERPG-3
ERPG-2
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
1 hr
Reference Value
(mg/mj)
2.9
2.0
1.6
0.40
0.20
0.96
0.7
0.5
0.1
0.06
4.8
1.6
(ppm)
0.91
0.63
0.50
0.13
0.060
0.3
0.21
0.17
0.04
0.02
1.5
0.5
Health Effect
Hemolysis and
lethality in mice
(Peterson and
Bhattacharyya,
1985,067598)
Absence of
significant
hemolysis in mice
exposed for 1 h
(1985,067598)
Hemolysis and
lethality in mice
(1985,067598)
Absence of
significant
hemolysis in mice
exposed for 1 h
(1985,067598)
Point of Departure
15 ppm Threshold
(1 hour) for lethality
in mice
5 ppm NOEL
(1 hour)
15 ppm No lethality
(1 hour) or
hemolysis
in mice
5 ppm Below the
(1 hour) threshold
for
hemolysis
Uncertainty
Factors
Total UF = 30
UTA - 10
UFH-3
Total UF = 30
UFA - 10
UFH = 3
NR
NR
Notes on
Derivation
Time scaling
using
Cnxt
with default
values of n: 3
for shorter
and 1 for
longer
durations.
(NRC, 2001,
1 92042)
Although UFs
were not
reported in
the ERPG
document, it
may be
assumed a
total UF of 10
was applied.
Review Status
Final
(NAC/AEGL,
2000, 192321)
Final
(AIHA, 2002,
192087)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009 47
-------
Reference Value
Type / Name
Occupational
General Public
NIOSH-
Ceiling*
OSHA-
PEL*
NIOSH-
IDLH*
ACGIH -
TLV
(TWA)*
CA-REL
(Acute)
CA-REL
(8-hr)
CA-REL
(Chronic)
Chronic
RfC (IRIS)
Duration
15 min
8hr
TWA
30 min
8 hour
TWA
1 hr
8hr
Chronic
Chronic
Reference Value
(mg/mj)
2x10'J
0.2
9.6
0.016
2x1Q-4
(Based
on mg
As)
1.5x10"ฐ
(Based
on mg
As)
1.5x10"D
(Based
on mg
As)
5x10'D
(ppm)
6.3 x10'4
0.05
3
0.005
6.5x10"D
(Arsine)
5.0x10"D
(Arsine)
5.0x10'b
(Arsine)
2.2x10'ฐ
Health Effect
Potential
carcinogen
NR
Human acute
inhalation toxicity
(Teitelbaum and
Kier, 1969,
068668)
Peripheral
nervous system;
vascular system;
kidney and liver
damage
Decreased fetal
weight in mice
(Nagymajtenyi et
al., 1985,
062165)
Decrease in
intellectual
function,
neurobehavioral
development in
human children
(Tsai et al., 2003,
180240:
Wasserman et
al., 2004,
180230)
Increased
hemolysis,
increased spleen
weight
Point of Departure
NR
NR NR
25 ppm LCLo
0.049 NOAEL
mg/m3
(Landrigan
etal.,
1982,
005485)
0.197mg LOAEL
As/m3
0.00023 LOAEL
mg As/m3
0.00023 LOAEL
mg As/m3
0.014 NOAELHEc
mg/m3
(0.08 mg/m3
x6/24
x5/7)
Uncertainty
Factors
NR
NR
NR
NR
Total UF= 1000
UFL= 10
UFA: 10
TK=3
TD = 3
UFH: 10
TK = 3
TD = 3
Total UF = 30
UFL=3
UFH: 10
TK = 3
TD = 3
Total UF = 300
UFH = 10
UFA = 3
UFS=10
Notes on
Derivation
Based on
previous
ACGIH-TLV
UFs not
reported, but
Total UF = 3
inferred.
Derivations
based on
molar
equivalents
of arsenic
(As) from
inhalation of
As2O3.
Derivations
based on
molar
equivalents
of inorganic
arsenic (As)
in drinking
water.
Adjustments
made to
NOAEL to
account for
6 hours/day
and
Review Status
Final
(ATSDR, 2006,
192117)
Final
(NIOSH, 1996,
192331)
Final
(ACGIH, 2007,
192024)
Final
(OEHHA, 2008,
192332)
Final
(U.S. EPA, 1994,
192320)
September 2009
48
-------
Refer
Typ
ence Value
e / Name
Duration
Reference Value
(mg/mj)
(ppm)
Health Effect
(Blair etal., 1990,
067664; Blair et
al., 1990,
067665; Hong et
al., 1989,
067671)
Point of Departure
Uncertainty
Factors
Notes on
Derivation
5 days/wk in
key study.
Review Status
September 2009
49
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Arsine (1999). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192087
ATSDR. (2006). Toxicologial profile for hydrogen sulfide. Agency for Toxic Substances
and Disease Registry. Atlanta, GA. PB2007-100675. 192117
American Industrial Hygiene Association. (1965). Arsine. , 26: 438-441. 192026
Blair PC; Thompson MB; Bechtold M; Wilson RE; Moorman MP; Fowler BA. (1990).
Evidence for oxidative damage to red blood cells in mice induced by arsine gas.
Toxicology, 63: 25-34. 067665
Blair PC; Thompson MB; Morrissey RE; Moorman MP; Sloane RA; Fowler BA. (1990).
Comparative toxicity of arsine gas in B6C3F1 mice, Fischer 344 rats, and Syrian
golden hamsters: system organ studies and comparison of clinical indices of
exposure. Toxicol Sci, 14: 776-787. 067664
Gates M; Williams J; Zapp JA. (1946). Summary technical report of division 9, NRDC.
National Defense Research Committee. Washington, DC. 192214
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Hong HL; Fowler BA; Boorman GA. (1989). Hematopoietic effects in mice exposed to
arsine gas. Toxicol Appl Pharmacol, 97: 173-182. 067671
IARC. (1987). Arsenic and arsenic compounds. In Overall Evaluations of
Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42 (pp. 100-
106). Lyon, France: International Agency for Research on Cancer. 192133
LandriganPJ; CostelloRJ; Stringer WT. (1982). Occupational exposure to arsine: an
epidemiologic reappraisal of current standards. Scand J Work Environ Health, 8:
169-177. 005485
NAC/AEGL. (2000). Arsine - final acute exposure guideline levels (AEGLs). National
Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC.http://www.epa.gov/oppt/aegl/pubs/tsd2.pdf. 19232J.
NIOSH. (1996). Arsenic (inorganic compounds, as As) - IDLH documentation .
Retrieved 15-JUN-09, from http://www.cdc.gov/niosh/idlh/7440382.html. 192331
NLM. (2005). Arsine. Retrieved 15-JUN-09, from http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/f?./temp/~mbg6gw: 1. 192329
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
September 2009 50
-------
Nagymajtenyi L; Selypes A; Berencsi G. (1985). Chromosomal aberrations and fetotoxic
effects of atmospheric arsenic exposure in mice. J Appl Toxicol, 5: 61-63. 062165
OEHHA. (2008). Acute, 8-hour, and chronic reference exposure levels - inorganic
arsenic. Office of Environmental Health Hazard Assessment, California EPA.
Sacramento, CA. 192332
Peterson DP; Bhattacharyya MH. (1985). Hematological responses to arsine exposure:
quantitation of exposure response in mice. Toxicol Sci, 5: 499-505. 067598
Teitelbaum DT; Kier LC. (1969). Arsine poisoning: report of five cases in the petroleum
industry and a discussion of the indications for exchange transfusion and
hemodialysis. Arch Environ Occup Health, 19: 133-143. 068668
Tsai SY; Chou HY; The HW; Chen CM; Chen CJ. (2003). The effects of chronic arsenic
exposure from drinking water on the neurobehavioral development in
adolescence. Neurotoxicology, 24: 747-753. 180240
U.S. EPA. (1994). Arsine. Retrieved 10-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0672.htm. 192320
Wasserman GA; Liu X; Parvez F; Ahsan H; Factor-Litvak P; van Geen A; Slavkovich V;
Lolacono NJ; Cheng Z; Hussain I; Momotaj H; Graziano JH. (2004). Water
arsenic exposure and children's intellectual function in Araihazar, Bangladesh.
Environ Health Perspect, 112: 1329-1333. 180230
September 2009 51
-------
2.4. Chemical-Specific Reference Values for Chlorine
(CASRN 7782-50-5)
Chlorine (Cb) is a greenish-yellow, highly reactive halogen gas with a pungent,
suffocating odor. Like other halogens, chlorine exists in the diatomic state in nature. The vapor is
heavier than air and will form a cloud in low-lying areas adjacent to the vicinity of a spill,
potentially flowing into valleys under low wind conditions. Chlorine is extremely reactive and
rapidly combines with both inorganic and organic substances, potentially reacting explosively or
forming explosive compounds with many common substances such as acetylene, ether,
turpentine, ammonia, fuel gas, hydrogen and finely divided metals. Chlorine is used in the
manufacture of a wide variety of chemicals, as a bleaching agent in industrial and household
products, and as a biocide in water and waste treatment plants. It has been used as a chemical
warfare agent in World War I (Heller, 1984, 192322) and other more recent conflicts (Multi-
National, 2007, 192323). Additional details are provided from multiple other sources (AIHA,
2002, 192059: ATSDR, 2007, 192119: NRC, 2004, 192142) on the chemical nature of and the
health effects from exposure to chlorine gas, and is not repeated here.
Inhalation health effect reference values for chlorine are displayed graphically in
Figure 2.4. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.4.
The Emergency Response reference values (AEGLs and ERPGs) were developed for all
three severity categories (level 1 for mild transient effects; level 2 for irreversible effects or
impairment of ability to escape; and level 3 for potentially lethal effects). The one-hour AEGLs
and the ERPGs are in relatively close proximity to one another, with the ERPG-3 being
somewhat lower than the corresponding one-hour AEGL-3. The nature of this difference is
difficult to assess because fewer details are provided for the derivation of the ERPGs than is
provided for the AEGLs.
The NIOSH Occupational reference values are derived by a weight of evidence approach
and no particular study was identified as the basis for the values. Intense coughing fits were
reported with exposure to 30 ppm, while exposure to 40 to 60 ppm for 30 minutes to one hour
may cause serious damage (ILO, 1971, 192324). Exposure to 34 to 51 ppm has been reported to
be lethal when subjects were exposed for one to 1.5 hours (Freitag, 1941, 194017)It has also
been reported that exposure to 14 to 21 ppm for 30 minutes to one hour is dangerous (NPIRI,
1983. 192325).
Two acute General Public reference values are available for chlorine - an acute CA-REL
and an acute ATSDR MRL. Both use the same study (Anglen, 1981, 010298) as the basis for the
POD and perform time scaling, but using two different approaches. ATSDR (ATSDR, 2007,
192119) uses the 8-hour observations from the study and performs what amounts to application
of Haber's "rule" [C x t = k; (Haber, 1924, 059334)1 by multiplying the NOAEL by 8/24 to
account for the 8-hour exposure to arrive at a 24 hour POD. OEHHA (OEHHA, 1999, 192221)
uses the Cn x t = k formula with a value of n = 2, but reports that a 30-minute time point was
used as the starting point for the extrapolation to 1 hour while the study report notes observations
from exposures of 4 or 8 hours only. The end results are acute reference values that are identical
for both 1-hour (CA-REL) and 24-hour (ATSDR) durations.
Other General Public reference values include both intermediate (14 to 365 days) and
chronic (> 1 year) duration ATSDR MRLs, as well as a chronic CA-REL (durations up to a
September 2009 52
-------
lifetime). All of these longer duration reference values include adjustments for the experimental
exposure schedule (i.e., consideration of hours per day and days per week during exposure) and
differences in respiratory surface area and breathing rates between the experimental animals and
humans through the use of the regional gas dose ratio (RGDR). Details on the calculation of the
RGDR are not provided here and the reader is directed to the ATSDR Toxicological Profile
(2007, 192119) and the OEHHA Technical Support Document (1999, 192221) for chlorine.
The rather large and comprehensive data base of health effect data in several
experimental animal models and in human studies, coupled with the ubiquitous nature of
chlorine in commerce led to the development of a fairly comprehensive set of inhalation health
effect reference values across all types of values (emergency response, occupational, and general
public), severity of effects (presumptively safe, mild, severe, and lethal), and durations (acute,
short-term, subchronic, and chronic timeframes). There also seems to be some strong
concordance among the values, based on consideration of the nature and purpose of the different
values. The lowest level emergency response values (AEGL-1 and ERPG-1) which were
designed for once-in-a-lifetime types of exposure scenarios are in the same range of exposure
levels as the ceiling and TWA occupational values. There is also a clear stair-step decrease in the
general public reference values as duration increases, based largely on the empirical evidence
that health effects accumulate from longer duration exposures to low level concentrations of
chlorine.
September 2009 53
-------
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC
Chlorine: Comparison of Reference Values
1.E+03
1.E+02
O)
E
' 1.E+00
O
c
O
O
Q) 1.E-01
O 1.E-02
1.E-03
1.E-04
1 ACUTE
s
3
OSHA-CeilinV
Short Term
w
0
c
-3
.-. yy xi yy 6 AEGL-2
NIOSH-Ceiling*
X CA-REL (Acute) )
ATSDR-MRL(1-14d)
ATS
AT
Subchronic
to
HI
Chronic
t
t
Q
C
h
ACGIH-TLV(TW
O
)R-MRL (15-365 d)
C
UJ , , ,.,,,,! , _
A-REL (Chronic
AEGL-3
HI
to
O AEGL-2 o
Q.
to
> AEGL-1 ฃ
A ERPG-3
HI
O)
& ERPG-2 5
A ERPG-1
O NIOSH-Ceiling*
O OSHA-Ceiling*
o
O ACGIH-STEL*
3
0 NIOSH-IDI.il*
0 ACGIH-TLV (TWA)*
X CA-REL (Acute)
o
X ATSDR-MRL(1-14d) 3
Q.
X ATSDR-MRL(1 5-365 d) -g
1yr) v
O
X CA-REL (Chronic)
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.4. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Chlorine
September 2009
54
-------
Table 3.5. Details on derivation of the specific inhalation health effect reference values for chlorine.
Reference Value Type
/ Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
145
81
58
29
21
8.1
8.1
5.8
2.9
2.0
1.5
1.5
1.5
1.5
1.5
58
(ppm)
50
28
20
10
7.1
2.8
2.8
2
1
0.7
0.5
0.5
0.5
0.5
0.5
20
Health Effect
Lethality
(MacEwen and
Vernot, 1972,
041949: Zwart and
Wouterson, 1988,
010507)
Sensory irritation and
transient changes in
pulmonary function
measurements
(D'Alessandro et al.,
1996,081056:
Rotman etal., 1983,
064252)
Notable irritation and
significant changes in
pulmonary function
parameters
(Anglen, 1981,
010298:
D'Alessandro et al.,
1996,081056:
Rotman etal., 1983,
064252; Shusterman
etal., 1998,085870)
Lethality
(Schlagbauerand
Henschler, 1967,
010243; Withers and
Lees, 1985,010258;
1985,010259)
Point of Departure
200 ppm Estimated
(1 hour) mean of
nonlethal
values for the
rat and
mouse
1 ppm NOAELfor
(4 hours) AEGL-2
effects
0.5 ppm NOAEL for
(4 hours) AEGL-1
effects
NR NR
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH=3
Total UF = 1
(susceptible
human)
Total UF = 1
(susceptible
human)
NR
Notes on
Derivation
Time scaling:
Cn x t = k
where
n = 2, derived
empirically.
No time scaling
Review
Status
Final
(NRC, 2004,
192142)
Final
(AIHA, 2002,
1 92059)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
55
-------
Refere
Occupational
General
Public
nee Value Type
/ Name
ERPG-2
ERPG-1
OSHA-Ceiling
(TWA)*
NIOSH
Ceiling*
NIOSH-IDLH
(<30 min)*
ACGIH TLV-
STEL*
ACGIH TLV-
TWA*
CA-REL
(Acute)
ATSDR- MRL
(Acute)
Duration
1 hr
1 hr
15 min
15 min
30 min
15 min
ShrTWA
1 hr
1 -14d
Reference Value
(mg/mj)
8.7
3
3
1.5
29
2.9
1.5
0.21
0.2
(ppm)
3
1
1
0.5
10
1
0.5
0.07
0.07
Health Effect
Slight irritation and
discomfort
(Barrow etal., 1979,
064226; Zeilhaus,
1970, 180139)
Slight transient
effects
(Gerrity et al., 1990,
012098; Rotman et
al., 1983,064252)
Irritation and
pulmonary function
decline
Pulmonary and
ocular effects
Acute inhalation
toxicity data in
humans
Eye and mucous
membrane irritation
(Anglen, 1981,
010298; Rotman et
al., 1983,064252:
Rupp and Henschler,
1967,064253)
Itching or burning of
throat in humans
(Anglen, 1981,
010298)
Sensory irritation and
pulmonary function in
humans
(Anglen, 1981,
Point of Departure
NR NR
NR NR
NR NR
NR NR
NR NR
NR NR
NR NR
0.71 ppm NOAEL
(1 ppm at
30 min
scaled to
1 hour)
0.2 ppm NOAEI-ADJ
(0.5 ppm
x 8/24)
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
NR
Total UF = 10
UFH=10
Total UF = 3
UFH = 3
Notes on
Derivation
Time scaling
using
Cn x t = k
where
n = 2
Adjusted for
8 hour
exposure
duration
Review
Status
Final
(OSHA,
1989,
1 92326)
Final
(NIOSH,
1976,
1 92334)
Final
(NIOSH,
1996,
1 92333)
Final
(ACGIH,
2007,
192024)
Final
(OEHHA,
1999,
192221)
Draft
(ATSDR,
2007,
192119)
September 2009
56
-------
Refere
nee Value Type
/ Name
ATSDR- MRL
(Intermediate)
ATSDR- MRL
(Chronic)
CA-REL
(Chronic)
Duration
15 d-
1 yr
> 1yr
Chronic
Reference Value
(mg/mj)
5.8x10"J
1.5x10""
2x10'"
(ppm)
2 x 1 0"J
5 x 1 0'ฐ
6.9x10'ฐ
Health Effect
010298)
Tracheal lesions in
rats
(Kutzman, 1983,
094919)
Nasal lesions in
monkeys
(Klonneetal., 1987,
094918)
Upper respiratory
epithelial lesions in
rats
(Wolfetal., 1995,
076612)
Point of Departure
0.1 4 ppm LOAEI_HEc
(0.5 ppm
x6/24
x5/7
x 1.41)
1 .36 ppb BMCL10[HEC]
(20 ppb
x6/24
x5/7
x 0.34)
2.4 ppb BMCos-HEc
(140 ppb (LOAEL =
x 6/24 0.4 ppm;
x 3/7 BMC05 =
xO.16) 0.14 ppm)
Uncertainty
Factors
Total UF = 60
UFL = 3
UFA = 2
UFH = 10
Total UF = 30
UFA = 3
UFH= 10
Total UF = 30
UFA = 3
UFH = 10
Notes on
Derivation
Adjusted for
6 hr/d; 5 d/wk;
and
RGDR = 1.41
Adjusted for
6 hr/d; 5 d/wk;
and
RGDR = 0.34
Adjustments to
BMC05 for
3 d/wk; 6 h/d
and
RGDR = 0.16
Review
Status
Final
(OEHHA,
2000,
1 92223)
September 2009
57
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Chlorine (1988). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192059
ATSDR. (2007). Draft toxicological profile for chlorine. Agency for Toxic Substances
and Disease Registry. Atlanta, GA. 192119
Anglen DM. (1981). Sensory response of human subjects to chlorine in air [dissertation].
010298
Barrow CS; Kociba RJ; Rampy LW; Keyes DG; Albee RR. (1979). An inhalation
toxicity study of chlorine in Fischer 344 rats following 30 days of exposure.
Toxicol Appl Pharmacol, 49: 77-88. 064226
D'Alessandro A; Kuschner W; Wong H; Boushey HA; Blanc PD. (1996). Exaggerated
responses to chlorine inhalation among persons with nonspecific airway
hyperreactivity. , 109: 331-337. 081056
Freitag. (1941). Danger of chlorine gas. , 35: 159. 194017
Gerrity TR; Henry CJ; Bronaugh R; Clewell H; Connery J; DeRosa C; Dutton RJ;
Frederick C; Hall L; Hoang K-C; Jarabek A; Marzulli F; McConnell E; Miller F;
Rhomberg L. (1990). Summary report of the workshops on principles of route-to-
route extrapolation for risk assessment. In Gerrity, T. R.; Henry, C. J.
(Ed.),Principles of Route-to-Route Extrapolation for Risk AssessmentNew York,
NY: Elsevier. 012098
Haber F. (1924). Zur Geschichte des Gaskrieges [On the history of the gas war]. 059334
Heller CE. (1984). Chemical warfare in World War I: the American experience, 1917-
1918. Combat Studies Institute, U.S. Army Command and General Staff College.
Washington, DC.http://www-
cgsc. army. mil/carl/resources/csi/Heller/HELLER. asp. 192322
ILO. (1971). Chlorine and compounds. In Encyclopaedia of occupational health and
safety (pp. 287-288). Geneva, Switzerland: International Labour Organization.
192324
Klonne DR; Ulrich CE; Riley MG; Hamm TE Jr; Morgan KT; Barrow CS. (1987). One-
year inhalation toxicity study of chlorine in rhesus monkeys (Macaca mulatta).
Toxicol Sci, 9: 557-572. 094918
Kutzman RS. (1983). A study of Fischer-344 rats sub chronically exposed to 0, 05, 15, or
50 ppm chlorine [informal report]. 094919
MacEwen JD; Vernot EH. (1972). Toxic hazards research unit annual report: 1972.
041949
September 2009 58
-------
Multi-National Force-Iraq. (2007). Chlorine tanks destroyed, terrorists killed in raid .
Combined Press Information Office. Baghdad, Iraq.http://www.mnf-
iraq.com/index.php?option=com_content&task=view&id=11530&Itemid=128.
192323
NIOSH. (1976). Criteria for a recommended standard: occupational exposure to chlorine.
National Institutes for Occupational Health and Safety. Cincinnati, OH. DHHS
(NIOSH) Publication No. 76-170. http://www.cdc.gov/niosh/76-170.html. 192334
NIOSH. (1996). Chlorine - IDLH documentation. Retrieved 15-JUN-09, from
http://www.cdc.gov/niosh/idlh/7782505.html. 192333
NPIRI. (1983). Raw materials data handbook, physical and chemical properties, fire
hazard and health hazard data. In Organic solvents (pp. 831-857). Bethlehem, PA:
National Printing Ink Research Institute. 192325
NRC. (2004). Chlorine. In Acute exposure guideline levels for selected airborne
chemicals (pp. 13-76). Washington, DC: National Academies Press. 192142
OEHHA. (1999). Acute toxicity summary - chlorine. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD2_final.pdf#page=54
. 192221
OEHHA. (2000). Chronic toxicity summary - chlorine. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_final.pdf#page=10
6. 192223
OSHA. (1989). Chlorine, H.S. no. 1079. FedRegist, 54: 2455-2456. 192326
Rotman HH; Fliegelman MJ; Moore T; Smith RG; Anglen DM; Kowalski CJ; Weg JG.
(1983). Effects of low concentrations of chlorine on pulmonary function in
humans. J Appl Physiol, 54: 1120-1124. 064252
Rupp H; Henschler D. (1967). Wirkungen geringer Chlor- und Bromkonzentrationen auf
den Menschen [Effects of low chlorine and bromine concentrations on man]. Int
Arch Occup Environ Health, 23: 79-90. 064253
Schlagbauer M; Henschler D. (1967). Toxicitat von Chlor und Brom bei einmaliger und
wiederholter Inhalation [Toxicity of chlorine and bromine after single and
repeated inhalation]. Int Arch Occup Environ Health, 23: 91-98. 010243
Shusterman D; Murphy MA; Balmes J. (1998). Seasonal allergic rhinitic and non-rhinitic
subjects react differentially to nasal provocation with chlorine gas. 085870
Withers RMJ; Lees FP. (1985). The assessment of major hazards: the lethal toxicity of
chlorine Part 1, review of information on toxicity. J Hazard Mater, 12: 231-282.
010258
Withers RMJ; Lees FP. (1985). The assessment of major hazards: the lethal toxicity of
chlorine Part 2, model of toxicity to man. J Hazard Mater, 12: 283-302. 010259
September 2009 59
-------
Wolf DC; Morgan KT; Gross EA; Barrow C; Moss OR; James RA; Popp JA. (1995).
Two-year inhalation exposure of female and male B6C3F1 mice and F344 rats to
chlorine gas induces lesions confined to the nose. Toxicol Sci, 24: 111-131.
076612
Zeilhaus R. (1970). Tentative emergency exposure limits for sulphur dioxide, sulphuric
acid, chlorine, and phosgene. Ann Occup Hyg, 13: 171-176. 180139
Zwart A; Wouterson RA. (1988). Acute inhalation toxicity of chlorine in rats and mice:
time-concentration-mortality relationships and effects of respiration. J Hazard
Mater, 19: 195-208. 010507
September 2009 60
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2.5. Chemical-Specific Reference Values for Chromium VI
(CASRN 18540-29-9)
Chromium is a naturally occurring element present in the earth's crust. Chromium VI
[Cr(VI); Cr6+] is one of three valence states of the chromium metal ion (II, III, or VI), and is the
most toxic form. Chromium(III) is an essential trace nutrient required for normal energy
metabolism. Cr(VI) is usually found as either water-soluble or insoluble chromate compounds
(ACGIH, 2001, 192015). Water-soluble chromates include potassium chromate (K^CrC^) and
dichromate (K^C^Oy), sodium chromate (NaCrC^) and dichromate (IS^C^Oy), ammonium
chromate ((NH4)2CrOy), and chromium trioxide (chromic acid; CrOs). Insoluble chromates
include all other Cr(VI) compounds not listed as water-soluble.
The higher toxic potency of Cr(VI) compared to Cr(III) is complex (ATSDR, 2008,
192121). Cr(VI) enters cells by facilitated uptake, whereas Cr(III) crosses cell membranes by
simple diffusion; thus, cellular uptake of Cr(VI) is more effective than of Cr(III). Furthermore, in
biological systems, reduction of Cr(VI) to Cr(III) results in the generation of free radicals, which
can form complexes with intracellular targets. Health effects of chromium compounds can vary
with route of exposure, with certain effects specific for the portal of entry. Respiratory effects are
associated with inhalation of chromium compounds, but not with oral and dermal exposures, and
gastrointestinal effects are primarily associated with oral exposure. However, effects of
chromium are not limited to the portal of entry, with hematological, immunological, and
reproductive systems also identified as targets for chromium. In addition, results of occupational
exposure studies and chronic duration animal studies indicate that inhalation and oral exposures
to Cr(VI) compounds are associated with respiratory and gastrointestinal system cancers,
respectively. Cr(VI) in both water-soluble and insoluble forms have been designated as known
human carcinogens via inhalation (IARC, 1990, 192135), Classification Al - Confirmed Human
Carcinogen. More information on the toxic potential and chemical nature of chromium
compounds and Cr(VI) can be found from other sources (ATSDR, 2008, 192121: IARC, 1990,
192135: U.S. EPA, 1998, 192335) and the reader is directed to consult them for additional
details.
The remainder of this discussion focuses on the available inhalation health effect
reference values for Cr(VI). Reference values for Cr(VI) are arrayed graphically across duration
and severity level across all types of values (Emergency Response, Occupational, and General
Public) in Figure 2.5. Additional details on the derivation of those reference values are shown in
Table 2.5, including whatever information is available on the health effect used as the basis for
the value, the concentration used as the point of departure for protection against those effects,
any adjustments for duration of exposure or other considerations (e.g., animal to human or
occupational to continuous exposures), and application of uncertainty factors. One of the
complicating factors in discussing the available reference values for Cr(VI) is due to the issue of
speciation. This includes the differences between the various valence states of chromium, as well
as subcategories within the various Cr(VI) compounds; these include variations such as the
water-soluble and insoluble dichotomy, and acid mists and aerosols versus particulates. All of
the reference values shown in this summary are for Cr(VI), and are based on chromium content
(i.e., chromium compounds such as chromium trioxide are based on the equivalents of
chromium). Variations based on subcategories of Cr(VI) are noted in the column "Notes on
Derivation" in Table 2.5.
September 2009 61
-------
The only Emergency Response reference values derived for chromium and chromium
compounds were the TEELs. The TEEL values shown are based on the chromium content for the
compound chromium trioxide. Very little information is available currently on the derivation of
the TEELs for individual compounds, although the methods for developing TEELs are available
(DOE, 2008, 192182). The TEEL values shown in this summary are for chromic acid, which is
reported as Cr(VI). Values for a number of other individual Cr(VI) compounds are also included
in the table of TEEL values.
The Occupational reference values include IDLH and TWA values from ACGIH, NIOSH
and OSHA. All of the TWA values are based on concerns for cancer potential from repeated
exposures. ACGIH-TLV values were derived separately for water-soluble versus insoluble
Cr(VI) compounds, with the concentration values for water-soluble Cr(VI) being a factor of five
higher than those for the insoluble. All of the other occupational values were derived based on
exposure to chromic acid but are expressed in units of milligrams chromium per cubic meter.
There is a notable difference between the levels for the IDLH and TWA values which is due
predominantly to the cancer concern for the TWA values versus frank noncancer toxicity used in
the derivation of the IDLH value.
The General Public reference values for Cr(VI) are numerous and complicated due to
values developed for different Cr(VI) species. The only acute duration value included in this
summary is one Effects Screening Level (ESL) developed by the Texas Commission on
Environmental Quality (2009, 180241), and was developed for all Cr(VI) compounds. Very little
detail was readily available for the derivation of the acute TX-ESL value. Although a chronic
TX-ESL is also available, it is not included in this review due to the numerous, more-rigorously-
reviewed chronic values already available.
ATSDR developed two intermediate duration MRL values for Cr(VI), one for acid mists
and aerosols, and another for particulates. These are the only subchronic general public reference
values available. The intermediate MRL is identical to the chronic MRL for acid mists and
aerosols and is discussed in more detail with the other chronic values below. The MRL
developed for particulate Cr(VI) was set at approximately two orders of magnitude higher than
the MRL for acid mists and aerosols. A similar pattern emerges in comparing the EPA/IRIS RfC
values derived for those same species [acid mists and aerosols versus particulate Cr(VI)], with a
similar spread in concentrations. The chronic CA-REL values were developed using a slightly
different split in Cr(VI) species by developing values for only the water-soluble species, but
discriminating between chromium trioxide and all other water-soluble Cr(VI) species.
The same study and very similar approaches were taken with both the intermediate MRL
and chronic RfC values for particulate Cr(VI): both used the same BMC analysis performed by
the researchers (Malsch et al., 1994, 192336) as the basis for deriving a point of departure
(POD), and both used HEC adjustments using a Regional Deposited Dose Ratio (RDDR) factor;
however, the RDDR values were not the same and resulted in very different POD values. A
similar approach was also taken with the chronic CA-REL for particulate Cr(VI), which used the
same data set (Glaser et al., 1990, 004286) but instead performing their own BMC analysis to
derive a BMCLos versus the previously derived BMCLio (Malsch et al., 1994, 192336), then
used an RDDR factor more closely in keeping with the EPA derivation. The uncertainty factors
applied between these three values for particulate Cr(VI) were also similar, with an added factor
of 3 applied to the chronic RfC and CA-REL values to account for use of a subchronic study.
The same study (Lindberg and Hedenstierna, 1983, 063710) was used for all three
chronic values (MRL, RfC and CA-REL) developed for acid mists and aerosols, as well as the
September 2009 62
-------
intermediate MRL which is the same as the chronic MRL for Cr(VI) acid mists and aerosols. The
resulting reference values vary based on the application of different uncertainty factors (UFs)
and on variations on adjustments for exposure duration in the key study to continuous exposure.
As noted in Table 2.5, both the CA-REL and RfC for acid mists and aerosols used not only the
same study, but also arrived at the same POD using identical adjustments to the occupational
LOAEL to arrive at a continuous LOAEL (LOAELC). The major difference between these values
was in the application of uncertainty factors. OEHHA used a factor of 10 for the subchronic to
chronic (UFS) and EPA applied a factor of 3. Another difference was the use of a composite
(total) UF of 90 for the derivation of the RfC, when in other cases this would have been
expressed as a factor of 100; this was not well described in the IRIS Toxicological Review for
Chromium (U.S. EPA, 1998, 192335). The intermediate and chronic MRL values for chromic
acid mists and aerosols used a total uncertainty factor of 100 (10 for use of a LOAEL and 10 for
inter-individual variability), but used a duration adjustment for use of an occupational study (8
hours per 24 hour day; effectively a factor of 1/3) instead of using differences in occupational
versus average continuous breathing rates (10 m3 per day versus 20 m3 per day; effectively a
factor of 1/2), as was used in the CA-REL and RfC derivations.
The coverage of reference values for Cr(IV) is somewhat complicated by the use of
different forms of the chromate compounds, both from different classifications of which
compounds apply to a particular reference value, as well as the physical state of the emissions
(e.g., particulate versus acid mist or aerosol). The issue of speciation and which reference value
applies in a given scenario (in lieu of having accurate information) may be addressed by the use
of the most health protective (lowest concentration) reference value for the particular type of
application being considered.
September 2009 63
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Office of Research and Development
National Center tor Environmental An
Research Triangle Park, NC
1.E+02
1.E+01
1.E+00
)
=. 1.E-01
d
c
o
< 1.E-02
E
.E 1.E-03
O 1.E-04
1.E-05
1.E-06
Chromium VI: Comparison of Reference Values
ACUTE
to
TEEL-3 3
0
NIOSH-IDLH*. CM
O TEEL-2
^ TEEL-1
C
^ TEEL-0 Q
+ Acute TX-ESL
Short Term
to
1
0
CO
-------
._.._..
ATS
ATS
Subchronic
!
[!
(
(
Chronic
to
CO
o
0
. ACGIH-TLV(TWA)*
' Water-soluble
U ACGIH-TLV(TWA)*
A. ""* .
I
1 CA-REL (Chronic
JR-'MR'L (15.365^ >- other Soluble -
Particulates ^
, ,
EPA/IRIS RfC "
Particulates
/A\
lf\)
'
EPA/IRIS RfC "
DR-MRL (1 5-365 d) ^'a Mists & Aerosols
Ac d Mists & Aerosols_^ ijJ ^
* '
"^ ATSDR-MRL (>1vr) '
CA-REL (Chronic|
Chromic Acid
< )
<
:
ป TEEL-0
ป TEEL-1 |g
D) ฐ_
O TEEL-2 d> ซ
* TEEL-3
* NIOSH-IDLH*
"ro
O ACGIH-TLV(TWA)*
Water-soluble
O ACGIH-TLV(TWA)*
Insoluble
O NIOSH-REL (TWA)*
O OSHA-PEL (TWA)*
+ Acute TX-ESL
- 'X - ATSDR-MRL (15-365 d)
Particulates
X ATSDR-MRL (15-365 d) o
Acid Mists & Aerosols ^
X ATSDR-MRL (> 1yr) =
X CA-REL (Chronic)
! CA-REL (Chronic)
Othnr Soluble
! I I "PA/fRfS RfC/
Particulates
D EPA/IRIS RfC
Acid ft Anmsols
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.5. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Chromium VI
September 2009
64
-------
Table 2.5. Details on derivation of the specific inhalation health effect reference values for chromium VI.
Reference Value Type
/ Name
T-
0)
c
o
Q.
0)
ฃ
>^
o
c
0)
p
0)
E
LU
TEEL - 0
TEEL - 1
TEEL - 2
TEEL - 3
Duration
1 hr
1 hr
1 hr
1 hr
Reference Value
(mg/mj)
0.0113
0.339
6.0
34
(ppm)
1.2x10'J
7.3x10'J
0.01
3.7
Health Effect
NR
Point of Departure
NR
NR
NR
NR
NR
NR
NR
NR
Uncertainty
Factors
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(DOE,
2008,
192182)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
65
-------
Reference Value Type
/ Name
Occupational
General Public
NIOSH-IDLH
(<30 min)*
ACGIH TLV-
TWA*
NIOSH-REL
(TWA)*
OSHA-PEL
(TWA)*
Acute TX-ESL
ATSDR- MRL
(1 5-365 d)
Duration
< 30 min
8 hr TWA
10hrTWA
8 hr TWA
1 h
15d-1 yr
Reference Value
(mg/mj)
15
0.05
0.01
1 x10'J
5x10'J
1 x10'"
3x10'"
(ppm)
3.7
0.01
0.005
2.5x10""
1.2x10'J
2.5x10'ฐ
1.4x10'"
Health Effect
Cough, headache,
dyspnea, substernal
pain
(ILO, 1971, 192324;
Seileretal., 1988,
191789)
Cancer; liver; kidney
Cancer; irritation
Cancer
(NIOSH, 1975,
192337)
Cancer
NR
Lactate
dehydrogenase
(LDH) in
bronchoalveolar
lavage fluid (BALF)
(Malsch et al., 1994,
192336)
Point of Departure
NR
NR
NR
NR
NR
NR
1 0 ug/mj
(16ug/m3
x 0.63)
NR
NR
NR
NR
NR
NR
BMCL10
(HEC)
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
Total UF = 30
UFA = 3
UFH = 10
Notes on
Derivation
Based on
exposure to
chromic acid
mist.
Water-
soluble
Cr(VI)
Insoluble
Cr(VI)
Based on
exposure to
chromic acid
mist.
All Cr(VI)
compounds
Cr(VI)
participates;
HEC
adjusted for
RDDR2 =
0.63
Review
Status
Final
(NIOSH,
1996,
192338)
Final
(ACGIH,
2001,
192015)
Final
(NIOSH,
2006,
192177)
Final
(OSHA,
2006,
192188)
Under
review
(Texas
Commissio
n on
Environme
ntal, 2009,
180241)
Draft
(ATSDR,
2008,
192121)
2 RDDR = regional deposited dose ratio, for differences between humans and experimental animals
September 2009 66
-------
Refere
nee Value Type
/ Name
ATSDR- MRL
(< 1 yr)
CA-REL
(Chronic)
Chronic RfC
(IRIS)
Duration
Chronic
Chronic
Chronic
Reference Value
(mg/mj)
5x10"b
2x10'"
2x10'b
8x10'D
1 x1(T
(ppm)
1.2x10'b
4.9x10"ฐ
4.9x10''
2x10'D
4.7x10-ฐ
Health Effect
Upper respiratory
effects
(Lindberg and
Hedenstierna, 1983,
063710)
Broncho-alveolar
hyperplasia in rats
(Glaseretal., 1990,
004286)
Nasal septum
atrophy, lung toxicity
(Lindberg and
Hedenstierna, 1983,
063710)
LDH in BALF
(Malsch et al., 1994,
192336)
Point of Departure
0.5 ug/nf
(2 ug/m3
x8/24
x5/7)
24.47 ug/mj
(12.5 ug/m3
x 22/24
x2.143)
0.68 ug/nf
(1 .9 ug/m3
x 1 0/20
x5/7)
34 ug/mj
(16 ug/m3
x2.16)
LOAELADJ
BMC05
(HEC)
LOAELcJ
BMCL10
(HEC)
Uncertainty
Factors
Total UF = 100
UFL = 10
UFH = 10
Total UF = 100
UFS = 3
UFA = 3
UFH = 10
Total UF = 300
UFL = 3
UFS = 10
UFH = 10
Total UF = 90
UFL = 3
UFS = 3
UFH = 10
Total UF = 100
UFA = 3
UFS = 3
UFH = 10
Notes on
Derivation
Acid mists
and
aerosols;
Adjusted for
8h/d and
5d/wk
Cr(VI)
particulates;
Adjusted for
22h/d and
RDDR2 =
2.143.
Acid mists
and
aerosols;
Adjusted for
(5 d/week)
and breathing
rate (1 0 vs
20 m3/d)
Cr(VI)
particulates;
Adjusted for
RDDR2 =
2.16
Review
Status
Final
Final
(OEHHA,
2001,
192226)
Final
(U.S. EPA,
1998,
1 92335)
3 LOAELc = LOAEL for continuous exposure
September 2009
67
-------
REFERENCES
ACGIH. (2001). Documentation of the threshold limit values for chemical substances.
American Conference of Governmental Industrial Hygienists . Cincinnati, OH.
192015
ATSDR. (2008). Draft toxicological profile for chromium. Agency for Toxic Substances
and Disease Registry. Atlanta, GA. 192121
DOE. (2008). Temporary emergency exposure limits for chemicals: methods and
practice. U.S. Department of Energy. Washington, DC. DOE-HDBK-1046-2008.
192182
GlaserU; Hochrainer D; Steinhoff D. (1990). Investigation of irritating properties of
inhaled CrVI with possible influence on its carcinogenic action. In Seemayer, N.
H.; Hadnagy, W. (Ed.),Environmental hygiene IIBerlin, Germany: Springer-
Verlag. 004286
IARC. (1990). Chromium and chromium compounds: chromium[VI] (group 1); metallic
chromium and chromium[III] compounds (Group 3). In Chromium, nickel and
welding: summary of data reported and evaluation (pp. 49). Lyon, France:
International Agency for Research on Cancer. 192135
ILO. (1971). Chlorine and compounds. In Encyclopaedia of occupational health and
safety (pp. 287-288). Geneva, Switzerland: International Labour Organization.
192324
Lindberg E; Hedenstierna G. (1983). Chrome plating: symptoms, findings in the upper
airways, and effects on lung function. Arch Environ Occup Health, 38: 367-374.
063710
Malsch PA; Proctor DM; Finley BL. (1994). Estimation of a chromium inhalation
reference concentration using the benchmark dose method: a case study. Regul
Toxicol Pharmacol, 20: 58-82. 192336
NIOSH. (1975). Criteria for a recommended standard: occupational exposure to
chromium (VI). National Institutes for Occupational Safety and Health.
Cincinnati, OH. DHHS (NIOSH) Publication No. 76-129.
http://www.cdc.gov/niosh/76-129.html. 192337
NIOSH. (1996). Chromic acid and chromates - IDLH documentation . Retrieved 15-JUN-
09, from http://www.cdc.gov/niosh/idlh/1333820.html. 192338
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
OEHHA. (2001). Determination of noncancer chronic reference exposure levels. Office
of Environmental Health Hazard Assessment, California EPA. Sacramento, CA.
192226
OSHA. (2006). Occupational exposure to hexavalent chromium. Fed Regist, 71: 63238-
63245. 192188
September 2009 68
-------
Seller H; Sigel H; Sigel; A (Eds.). (1988). Handbook on Toxicity of Inorganic
Compounds. New York: Marcel Dekker, Inc. 191789
Texas Commission on Environmental Quality. (2009). Effects Screening Levels. Texas
Commission on Environmental Quality. Texas. 180241
U.S. EPA. (1998). Toxicological review of hexavalent chromium. National Center for
Environmental Assessment. Washington,
DC.http://www.epa.gov/ncea/iris/toxreviews/0144-tr.pdf 192335
September 2009 69
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2.6 Chemical-Specific Reference Values for Cyanogen Chloride
(CASRN 506-77-4)
Cyanogen chloride (CK; CNC1) is a highly volatile and toxic chemical asphyxiant that
interferes with the ability of the body to use oxygen (NIOSH, 2008, 192339). CK is a chemical
warfare agent but is also used commercially in chemical synthesis and fumigation. Exposure to
CK can be rapidly fatal. It has whole-body (systemic) effects, particularly affecting those organ
systems most sensitive to low oxygen levels: the central nervous system (brain), the
cardiovascular system (heart and blood vessels), and the pulmonary system (lungs). CK has
strong irritant and choking effects. Its vapors are extremely irritating and corrosive.
Very few inhalation health effect reference values are available for CK. These are
displayed graphically in Figure 2.6, with the details available on the derivation of those values
shown in Table 2.6.
ERPG values for Emergency Response were derived based on a weight of evidence
approach, noting that "exposures above the 4ppm level might cause severe respiratory irritation
and possibly edema" (AIHA, 2002, 192086) in the derivation of the ERPG-3 level, and the
ERPG-2 level was based in part on a report that 0.7 ppm was unbearable to workers. The
resulting values of 4.0 and 0.4 ppm for the ERPG-3 and ERPG-2, respectively, were designed to
be protective of susceptible subpopulations in the general population for a single exposure.
The only Occupational values (NIOSH Ceiling and ACGIH Ceiling) are for short (<15
minute) exposures only, and are for the same exposure level - 0.3 ppm (0.75 mg/m3). Very little
detail in the derivation of either value was provided, and was consistent with the literature
reviewed for the ERPGs.
A calculation error was made in the NIOSH Pocket Guide (NIOSH, 2006, 192177).
reporting that 0.3 ppm converts to 0.6 mg/m3, that has since been propagated in other documents
(USACHPPM, 2006, 192030). Using the conversion factor shown in the NIOSH Pocket guide of
1 ppm = 2.52 mg/m3, a value of 0.75 mg/m3 is derived.
No General Public values were found for cyanogen chloride.
September 2009 70
-------
National Center tor Environmental AM
Research Triangle Park, NC
Cyanogen Chloride: Comparison of Reference Values
1.E+02
O)
6
c
o
O
0)
-a
O
c
0)
O)
o
c
5,
o
1.E+01
1.E+00
1.E-01
ACUTE
to
3
4
A ERPG-3
A ERPG-2
/-\ACGIH-Ceiling*
wNIOSH-Celing*
Short Term
to
CO
9
o
CO
Subchronic
ฃ
CO
CD
r^-
Chronic
to
CO
o
o
r-
A ERPG-3 M
c
o
Q.
W)
0
IT
ONIOSH-Ceiling*
IS
Q.
O
O
O
OACGIH-Ceiling*
0.1
10 100 1000 10000 100000 1000000
Duration (hours)
Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.6. Presentation of the Available Health Effect Reference Values for Inhalation Exposure to Cyanogen Chloride
September 2009
71
-------
Table 2.6. Details on derivation of the specific inhalation health effect reference values for cyanogen chloride.
Reference Value
Type / Name
>*ซ-
O 0)
C (/)
0 c
P 2
Jr. ฐ-
o **ป
js v)
ฃ
w o:
MM ^^^
15
c
.0
,^J
(0
Q.
^M
D
O
O
ERPG-3
ERPG-2
NIOSH-
Ceiling*
ACGIH-
Ceiling*
Duration
1 hr
1 hr
15 min
Any
Reference Value
(mg/mj)
10
1
0.75
0.75
(ppm)
4
0.4
0.3
0.3
Health Effect
Lethality; severe
respiratory irritation and
pulmonary edema
(Moore and Gates,
1946, 192165)
Severe eye and
respiratory irritation in
humans
(Michigan Department
of Health, 1986,
1 92340)
NR
Irritation, cellular
metabolic interference
(ACGIH, 2007, 192024)
Point of Departure
120 ppm LC50
(30 min)
48 ppm LC01 (6 hr)
0.7 ppm NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(AIHA,
2002,
192086)
Final
(NIOSH,
2006,
192177)
Final
(ACGIH,
2007,
192024)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
72
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of Governmental
Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Cyanogen chloride (1998). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene Association.
192086
Michigan Department of Health. (1986). Communication to the TLV committee. In 1986-1987
Threshold Limit Values and Biological Exposure Indices (pp. .). Cincinnati, OH:
ACGIH. 192340
Moore S; Gates M. (1946). Hydrogen cyanide and cyanogen chloride. In Summary technical
report of division 9: chemical warfare agents and related chemical problems (pp. 7-16).
Washington, DC: NDRC. 192165
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National Institute for
Occupational Safety and Health. 192177
NIOSH. (2008). Cyanogen chloride (CK). Retrieved 16-JUN-09, from
http://www.cdc.gov/niosh/ershdb/EmergencyResponseCard_29750039.html. 192339
USACHPPM. (2006). Chemical Warfare Agent Criteria/Summary Information - March 2006.
Retrieved 16-JUN-09, from
http://usachppm.amedd.army.mil/chemicalagent/pdffiles/chemicalwarfareagentcriteria_su
mmarymar2006.pdf. 192030
September 2009 73
-------
2.7 Chemical-Specific Reference Values for Ethylene Glycol Monomethyl
Ether (EGME)
(CASRN 109-86-4)
EGME (Ethylene Glycol Monomethyl Ether; 2-methoxyethanol, methyl cellosolve;
CH3OCH2CH2OH) is a colorless liquid with a mild, pleasant odor. It has several commercial
uses, including as a solvent for cellulose acetate; in dyeing leather; and as antifreeze in jet fuel.
EGME is most toxic when inhaled, and is irritating to the eyes, nose, and throat; exposure may
also cause headache, nausea, vomiting, and disorientation. Additional information on the nature
of EGME and detailed summaries of health effects can be found in the IRIS Toxicological
Review (U.S. EPA, 1991, 192218) the CA-REL documentation (OEHHA, 2000, 1922221
(OEHHA, 2008, 192341), and other sources and is not repeated here.
Available inhalation health effect reference values for EGME are arrayed graphically in
Figure 2.7. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.7.
The only available Emergency Response reference values are provided by the
Department of Energy (DOE) in the 1-hour TEEL values for EGME (level 0 for no adverse
effects; level 1 for mild transient effects; level 2 for irreversible effects or impairment of ability
to escape; and level 3 for potentially lethal effects). No details on the derivation of chemical-
specific TEELs are provided.
The Occupational values for EGME focus more on repeated exposures, and vary over
three orders of magnitude. The time-weighted average (TWA) NIOSH REL and ACGIH TLV
values are equivalent, while the OSHA PEL is set at a considerably higher concentration. No
ceiling or STEL values are available. NIOSH developed an IDLH of 200 ppm based on a factor
of 2000 times the NIOSH REL of 0.1 ppm instead of the value of 400 ppm that would have
been the independently derived basis. The factor of 2000 is an assigned protection factor for
respirators; only the "most reliable" respirators are recommended above 2000 times the NIOSH
REL (NIOSH, 1996, 192342). EGME is readily absorbed through the skin in amounts
sufficient to elicit systemic toxicity, therefore, the "skin" notation is appropriately applied to all
the occupational values (ACGIH, 2006, 192016).
There are both acute and chronic General Public reference values available for EGME.
The acute CA-REL was based on developmental effects, which OEHHA deems to be a severe
adverse effect level, and no mild adverse effect level was established. Also, no time scaling was
applied to the 6-hour observations in deriving the acute CA-REL, hence the final value was for
a 6-hour duration. The chronic EPA/IRIS RfC and CA-REL values were derived from the same
study (Miller et al., 1983, 180119) and arrived at the same POD of 17 mg/m3 (5.4 ppm), which
was derived by adjustments to the observed NOAEL (30 ppm; 93 mg/m3) at 6 hours per day, 5
days per week. The differences in the chronic General Public values are due to variation in the
application of uncertainty factors.
EGME lacks a peer-reviewed set of Emergency Response values, and Occupational
ceiling or short-term exposure limits. This is indicative that EGME has few immediately
observable adverse health effects, and that most effects are due to an accumulation of effects
from repeated exposures.
September 2009 74
-------
National Center for Environm
Research Triangle Park, NC
EGME: Comparison of Reference Values
ACUTE
ฃ + TEEL-3 M
NIOSH-IDLH* E
I
O TEEL-2
O TEEL-1
O TEEL-0 Q3
| CA-REL
Short Term
c
c
(Acute)
Subchronic
to
r
V
CA-REL (Chronic)
EPA/IRIS RfC
Chronic
CO
o
h-
OSHA-PEL (TW
ACGIH-TLV(
NIOSH-REL (TW
\
/
r
\)"
*
0 TEELJ
0 TEEL-1
O
NIOSH-IDLH*
15
O ACGIH-TLV (TWA)* g
*)*
A)'
1
ro
Q.
O NIOSH-REL (TWA)*
O
O OSHA-PEL (TWA)*
X CA-REL (Acute) o
3
X CA-REL (Chronic) -^
01
c
D EPA/IRIS RfC fj
1.E+03
JT 1-E+02
d
ง 1.E+01
O
"5
C
re
0) 1.E+00
>
X
o
0)
ol 1.E-01
1.E-02
0.1
10 100 1000 10000 100000 1000000
Duration (hours)
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.7. Comparison of Available Health Effect Reference Values for Inhalation Exposure to EGME
September 2009
75
-------
Table 2.7. Details on derivation of the specific inhalation health effect reference values for EGME.
Reference Value
Type / Name
Emergency
Response1
TEEL-O
TEEL-1
TEEL-2
TEEL-3
Duration
1 hour
1 hour
1 hour
1 hour
Reference Value
(mg/mj)
0.3
1
7.5
622
(ppm)
0.1
0.35
2.5
200
Health Effect
NR
Point of Departure
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(DOE,
2008,
192182)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
76
-------
Reference Value
Type / Name
Occupational
NIOSH-
IDLH
(<30 min)*
ACGIH
TLV-TWA*
NIOSH-
REL
(TWA)*
OSHA-PEL
(TWA)*
Duration
<30
minutes
8 hour
TWA
10 hour
TWA
8 hour
TWA
Reference Value
(mg/mj)
622
0.3
0.3
80
(ppm)
200
0.1
0.1
25
Health Effect
Acute inhalation
toxicity data
(Union Carbide,
1969, 180239)
Hematologic and
reproductive
toxicity
(Hanley Jret al.,
1984, 180288:
Hanley Jret al.,
1984, 180112:
Nelson et al., 1984,
031 878; Shin etal.,
2003. 180246)
NR
NR
Point of Departure
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
Notes on
Derivation
2000 times
NIOSH
REL value
Review
Status
Final
(NIOSH,
1996,
1 92342)
Final
(ACGIH,
2006,
192016)
Final
(NIOSH,
2006,
192177)
Final
(OSHA,
2006,
192188)
September 2009
77
-------
Reference Value
Type / Name
General Public
CA-REL
(Acute)
CA-REL
(Chronic)
Chronic
RfC (IRIS)
Duration
6 hour
Chronic
Chronic
Reference Value
(mg/mj)
0.09
0.06
0.02
(ppm)
0.03
0.02
0.006
Health Effect
Gross soft tissue
and skeletal
teratogenic effects
and significantly
decreased fetal
body weights in
rabbits
(Hanley Jret al.,
1984, 180288)
Testicular effects
(Miller etal., 1983,
180119)
Point of Departure
3 ppm NOAEL
5.4 ppm NOAEI_HEc
(30 ppm
x6/24
x5/7)
17mg/mJ NOAELHEc
(93 mg/m3
x6/24
x5/7)
Uncertainty
Factors
Total UF = 100
UFA = 10
UFH = 10
Total UF = 300
UFS = 10
UFA = 3
UFH = 10
Total UF = 1000
UFS= 10
UFH = 10
UFD = 10
Notes on
Derivation
NOTE:
CA-REL
was
developed
for6-hours
and for
"severe
adverse
effects"
Adjusted
NOAEL =
30 ppm
(93 mg/m3)
for6hr/d ;
and 5 d/wk
Review
Status
Final
(OEHHA,
2008,
192341)
Final
(OEHHA,
2000,
192222)
Final
(U.S. EPA,
1991,
192218)
September 2009
78
-------
REFERENCES
ACGIH. (2006). Documentation of threshold limit values for chemical substances.
American Conference of Governmental Industrial Hygienists. Cincinnati, OH.
192016
DOE. (2008). Temporary emergency exposure limits for chemicals: methods and
practice. U.S. Department of Energy. Washington, DC. DOE-HDBK-1046-2008.
192182
Hanley Jr TR; Yano BL; Nitschke KD; John JA. (1984). Comparison of the teratogenic
potential of inhaled ethylene glycol monomethyl ether in rats, mice, and rabbits.
Toxicol Appl Pharmacol, 75: 409-422. 180288
Hanley Jr TR; Young JT; John JA; Rao KS. (1984). Ethylene glycol monomethyl ether
(EGME) and propylene glycol monomethyl ether (PGME): inhalation fertility and
teratogenicity studies in rats, mice, and rabbits. Environ Health Perspect, 57: 7-12.
180112
Miller RR; Ayres JA; Young JT; McKenna MJ. (1983). Ethylene glycol monomethyl
ether - subchronic vapor inhalation study with rats and rabbits. Fundam Appl
Toxicol 3: 49-54. 180119
NIOSH. (1996). Methyl cellosolve - IDLH documentation. Retrieved 23-JUN-09, from
http://www.cdc.gov/niosh/idlh/109864.html. 192342
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
Nelson BK; Setzer JV; Brightwell WS; Mathinos PR; Kuczuk MH; Weaver TE; Goad
PT. (1984). Comparative inhalation teratogenicity of four glycol ether solvents
and an amino derivative in rats. Environ Health Perspect, 57: 261-271. 031878
OEHHA. (2000). Chronic toxicity summary - ethylene glycol monomethyl ether. Office
of Environmental Health Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_fmal.pdf#page=25
3.192222
OEHHA. (2008). Acute toxicity summary - ethylene glycol monomethyl ether. Office of
Environmental Health Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD2_fmal.pdf#page=10
7. 192341
OSHA. (2006). Occupational exposure to hexavalent chromium. Fed Regist, 71: 63238-
63245. 192188
Shih TS; Hsieh AT; Chen YH. (2003). Follow-up study of haematological effects in
workers exposed to 2-methoxyethanol. J Occup Environ Med, 60: 130-135.
180246
U.S. EPA. (1991). 2-Methoxyethanol. Retrieved 10-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0525.htm. 192218
September 2009 79
-------
Union Carbide Corporation. (1969). Toxicology studies: methyl cellosolve. New York,
NY: Union Carbide Corporation. 180239
September 2009 80
-------
2.8 Chemical-Specific Reference Values for Ethylene Oxide
(CASRN 75-21-8)
Ethylene oxide (EtO; C2H4O) is a colorless, sweet smelling gas that is highly reactive at
room temperature and pressure. It is rapidly absorbed in the lungs and is irritating to the eyes,
respiratory tract, and skin; exposure to high concentrations may cause severe eye damage
including corneal injury and cataracts. EtO can also cause dermal irritation. EtO is used
commercially as a fumigant, sterilizer, disinfectant, and insecticide; and as an intermediate in the
production of many industrial chemicals (HSDB, 2009, 192343). EtO is listed as carcinogenic in
humans (Group 1) by IARC (IARC, 2008, 192126). Additional details are provided from
multiple other sources (Agency for Toxic Substances and Disease, 1990, 018341; IARC, 2008,
192126: NAC/AEGL, 2008, 192205: OEHHA, 2000, 192224) on the chemical nature of and the
health effects from exposure to ethylene oxide, and are not repeated here.
Available inhalation health effect reference values for EtO are displayed graphically in
Figure 2.8. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.8.
Emergency Response values (AEGLs and ERPGs) were developed for the two most
severe categories (level 2 for irreversible effects or impairment of ability to escape; and level 3
for potentially lethal effects). A level 1 (mild transient effects) AEGL value is not available, as
the lowest concentration causing irritation is above the AEGL-2 levels. As shown in Figure 2.8,
the AEGL-2 and ERPG-2 values are very similar. The ERPG-3 value is higher than the
corresponding 1-hr AEGL-3, however both are derived from the same study (Jacobson et al.,
1956, 061930). The lack of detailed derivation information for the ERPGs precludes a more
critical analysis of the differences between these Emergency Response values. Time scaling was
applied to the AEGL-2 and -3 values using a C" x t = k relationship where n = 1.2, which was
derived from rat lethality data.
Several Occupational reference values are available for ethylene oxide. The NIOSH
IDLH Occupational values are derived by a weight of evidence approach and no particular study
was identified as the basis for the values. The NIOSH and OSHA ceiling values are equivalent,
as are the time weighted average (TWA) OSHA PEL and ACGffl TLV. All of the Occupational
values note the carcinogenic potential for EtO, as well as the potential for effects from dermal
absorption and dermal effects ("skin" designation).
The availability of General Public reference values for ethylene oxide is limited.
Currently, only an intermediate ATSDR MRL and a chronic CA-REL value exist. Both values
use a NOAEL as the point of departure, which is then adjusted for exposures occurring 6 hours
per day, 5 days per week. The chronic CA-REL was based on a subchronic study of neurotoxic
effects in rats (Snellings et al., 1984, 018265), and the intermediate MRL was based on renal
lesions in mice (NTP, 1987, 192179).
Inhalation health effect reference values for EtO are available across all three types of
values (Emergency Response, Occupational and General Public). Coverage is relatively poor,
however, for General Public values and the lowest severity of Emergency Response values. No
acute value for the General Public is currently available, and coupled with the lack of Emergency
Response values for the lowest severity level indicates a weak warning potential for irreversible
effects. The TWA Occupational values are at relatively low concentrations in comparison to the
Emergency Response values, and this is likely due to the concern for the potential for cancer
September 2009 81
-------
from repeated exposures. All of the Occupational values were established prior to the 2008
publication of the latest IARC Monograph on EtO (IARC, 2008, 192126).
September 2009 82
-------
Office of Research and Development
National Center for Environmental Ass
Research Triangle Park, NC
Ethylene Oxide: Comparison of Reference Values
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to
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ACGIH-TLV (TW
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CA-REL (Chronic
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0 OSHA-Ceiling*
15
c
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1
O ACGIH-TLV (TWA)*
o
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_o
S
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15
X CA-REL (Chronic)
1 ฐ
0.1
10 100 1000 10000 100000 1000000
Duration (hours)
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.8. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Ethylene Oxide
September 2009
83
-------
Table 2.8. Details on derivation of the specific inhalation health effect reference values for ethylene oxide.
Reference Value
Type / Name
0)
(/)
C
O
Q.
0)
QL
>,
O
c
0
O)
0)
ฃ
LU
AEGL-3
AEGL-2
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
648
648
360
113
63
144
144
81
25
14
900
(ppm)
360
360
200
63
35
80
80
45
14
7.9
500
Health Effect
Lethality in rats
(Jacobson et al.,
1956,061930)
Neurotoxicity in rats
(Mandella 1997
088809: Snellings et
al., 1982, 018541)
Lethality in rodents
(Jacobson et al.,
1956,061930)
Point of Departure
628 ppm LC01
(4 hrs)
100 ppm NOAEL
(6 hrs)
533 ppm LOAEL
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH = 3
Total UF = 10
UFA-3
UFH = 3
NR
Notes on
Derivation
Time scaling:
Cnxt = k
where
n = 1.2, derived
empirically
Review
Status
Interim
(NAC/AEGL,
2008,
192205)
Final
(AIHA, 2002,
192064)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
84
-------
ERPG-2
1 hr
90
50
Reproductive and
developmental
effects in rats
(Hardinetal., 1983,
061926; Snellings et
al., 1982,018541)
100ppm NOAEL
NR
September 2009
85
-------
Reference Value
Type / Name
Occupational
General Public
NIOSH-
Ceiling*
NIOSH-REL
(TWA)*
NIOSH-
IDLH*
OSHA-PEL
(TWA)*
OSHA-
Ceiling*
ACGIH-TLV
(TWA)*
ATSDR-MRL
(15-365
days)
CA-REL
(Chronic)
Duration
10 min
per day
10 hr
TWA
< 30 min
8hr
TWA
<15 min
8 hr TWA
15 d-
1 yr
Chronic
Reference Value
(mg/mj)
9
0.18
1.4x10J
1.8
9
1.8
0.16
0.03
(ppm)
5
0.1
800
1
5
0.1
0.09
0.018
Health Effect
NR
Acute inhalation
toxicity data in
humans
NR
Reproductive and
hematological effects,
cancer
(Karelova et al.,
1987, 192282)
Renal lesions
(NTP, 1987, 192179)
Impaired neurological
function
(Snellings et al.,
1984.018265)
Point of Departure
NR NR
NR NR
NR NR
NR NR
8.9 ppm NOAEI-ADJ
(50 ppm
x6/24
x5/7)
1 .79 ppm NOAEI_HEc
(10 ppm
x6/24
x5/7)
Uncertainty
Factors
NR
NR
NR
NR
Total UF = 100
UFA = 10
UFH = 10
Total UF = 100
UFS = 3
UFA = 3
UFH = 10
Notes on
Derivation
Adjustments for 6
hr/d; 5 d/wk
Adjustments for 6
hr/d; 5 d/wk; and
RGDR = 1.0
Review
Status
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
192280)
Final
(OSHA,
2006,
1 92276)
Final
(ACGIH,
2001,
192015)
Final
(Agency
for Toxic
Substanc
es and
Disease,
1990,
018341)
Final
(OEHHA,
2000,
1 92224)
September 2009
86
-------
REFERENCES
ACGIH. (2001). Documentation of the threshold limit values for chemical substances. American
Conference of Governmental Industrial Hygienists . Cincinnati, OH. 192015
AIHA. (2002). Ethylene oxide (1994). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene Association.
192064
Agency for Toxic Substances and Disease Registry. (1990). Toxicological profile for ethylene
oxide. 018341
HSDB. (2009). Ethylene oxide. Retrieved 25-JUN-09, from http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/f?./temp/~rtMUV9:1. 192343
Hardin BD; Niemeier RW; Sikov MR; HackettPL. (1983). Reproductive-toxicologic assessment
of the epoxides ethylene oxide, propylene oxide, butylene oxide, and styrene oxide.
Scand J Work Environ Health, 9: 94-102. 061926
IARC. (2008). Ethylene oxide. In 1,3-Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl
Fluoride, Vinyl Chloride and Vinyl Bromide) (pp. 185-309). Lyon, France: International
Agency for Research on Cancer. 192126
Jacobson KH; Hackley EB; Feinsilver L. (1956). The toxicity of inhaled ethylene oxide and
propylene oxide vapors: acute and chronic toxicity of ethylene oxide and acute toxicity of
propylene oxide. Arch Environ Occup Health, 13: 237-244. 061930
Karelova J; Jablonicka A; Vargova M. (1987). Results of cytogenetic testing of workers exposed
to ethylene oxide. J Hyg Epidemiol Microbiol Immunol, 31: 119. 192282
Mandella RC. (1997). An acute inhalation neurotoxicity study of ethylene oxide (498-95A) in
the rat via whole-body exposure. 088809
NAC/AEGL. (2008). Ethylene oxide - interim acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington, DC.
192205
NIOSH. (1996). Ethylene oxide - IDLH documentation. Retrieved 15-JUN-09, from
http://www.cdc.gov/niosh/idlh/7784421 .html. 192280
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National Institute for
Occupational Safety and Health. 192177
NTP. (1987). Toxicology and carcinogenesis studies of ethylene oxide in B6C3F1 mice.
National Toxicology Program. Research Triangle Park, NC. 88-2582. 192179
OEHHA. (2000). Chronic toxicity summary - ethylene oxide. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_fmal.pdf#page=264.
192224
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
September 2009 87
-------
Snellings WM; Weil CS; Maronpot RR. (1984). A subchronic inhalation study on the toxicologic
potential of ethylene oxide inB6C3Fl mice. Toxicol Appl Pharmacol, 76: 510-518.
018265
Snellings WM; Zelenak JP; Weil CS. (1982). Effects on reproduction in Fischer 344 rats exposed
to ethylene oxide by inhalation for one generation. Toxicol Appl Pharmacol, 63: 382-388.
018541
September 2009 88
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2.9 Chemical-Specific Reference Values for Formaldehyde
(CASRN 50-00-0)
Formaldehyde (CH2O) is a colorless flammable gas with a pungent, suffocating odor. It is
ubiquitous in the ambient environment (a constituent of smog), in indoor air (homes that contain
urea-formaldehyde foam insulation, particle board construction, carpeting, etc.), and at industrial
sites (NAC/AEGL, 2008, 192206). Formaldehyde is a constituent of many foods and is a normal
metabolite in the human body. Much more detail can be found on the toxicological effects and
chemical nature of formaldehyde in other sources (AIHA, 1978, 192033; Agency for Toxic
Substances and Disease Registry, 1999, 093087: NAC/AEGL, 2008, 192206: NICNAS, 2006,
192040: NIOSH, 1976, 192344: NIOSH, 1996, 192345: OEHHA, 2008, 1923461 and is not
repeated here. The remainder of the discussion in this document focuses on the development and
use of the available inhalation health effect reference values for formaldehyde.
The primary effect during acute and short term inhalation exposure to formaldehyde is
irritation to the eyes, nose and throat (OEHHA, 2008, 192346). Prolonged low-level exposures
are associated with allergic sensitization, respiratory symptoms (coughing, wheezing and
shortness of breath), changes in respiratory tissues, and decreases in lung function. Long-term,
moderate-level exposures have been found to be carcinogenic in the respiratory tract of
experimental animals.
Figure 2.9 provides a graphical array of the available inhalation health effect reference
values for formaldehyde. Types of reference values (Emergency Response, Occupational and
General Public), levels of severity of effect (e.g., AEGL and ERPG levels 1, 2 and 3), and across
duration categories (acute, short-term, subchronic, and chronic) are all provided in this array.
Additional details on the basis and derivation of the individual reference values is provided in
Table 2.9.
Emergency Response reference values for formaldehyde include both AEGL and ERPG
values. The AEGL values for formaldehyde are largely in agreement with those of the ERPGs,
with the ERPG-3 being somewhat lower than and the ERPG-1 being somewhat higher than the
corresponding one-hour AEGL values. The AEGL program also developed an estimate of the
concentration at which there is a level of distinct odor awareness at 3.6 ppm, although it is also
noted that most individuals will notice but not necessarily be able to identify the distinct, pungent
odor of formaldehyde at the AEGL-1. According to the AEGL SOPs (NRC, 2001, 1920421
unless data provide a reason to do otherwise, low level irritation is assumed to be more
concentration-dependent and therefore there is no time scaling across the 10-minute to 8-hour
duration span for those values - most commonly applied to the AEGL-1. In the case of
formaldehyde, there was no time scaling for the AEGL-1 or for the AEGL-2 due to the endpoint
of eye and nose irritation to which adaptation occurs.
There is quite a large range in the Occupational reference values, with more than an order
of magnitude range between the lowest ceiling value (NIOSH Ceiling) and the highest STEL
(OSHA STEL), and a similar spread between the TWA values. The occupational values from
Australia are also included in this array of values, which are somewhat in the middle of the range
of both the short-term and TWA values. In the discussions supporting the occupational values,
one of the considerations that likely drive these disparities is the weight given to the cancer
potential from repeated long-term exposures to formaldehyde. As often found with other
chemicals, details on the basis and derivation of the occupational values for formaldehyde are
September 2009 89
-------
somewhat lacking and it can be surmised that a weight of evidence approach was used in
establishing the values.
A full set of formaldehyde reference values for the General Public are also available, with
values developed for every duration category. The ATSDR developed formaldehyde MRLs for
all of their duration categories (acute, 1-14 days; intermediate, 15 days to one year; and chronic,
greater than one year). These values do not consider cancer potential and show a fairly shallow
stair step decrease in concentration when going from the acute to chronic values, with the
smallest step down in going from the acute to intermediate values. The CA-RELs also step down
concentrations from short- to long-term durations of exposure, but with the largest decrease
between the one-hour acute and 8-hour value - the chronic CA-REL is the same as the 8-hour
value. An additional general public value is the WHO Air Quality Guideline, which was
developed for a 30 minute exposure. The WHO value is in line with what might be expected in a
progression when going from an eight-hour, to a one-hour CA-REL, to a 30-minute WHO
Guideline. Although copious details were provided on the basis and derivation of the CA-REL
and ATSDR MRL values, only a weight of evidence (WOE) approach could be discerned as the
basis for the WHO value.
IARC (2006) had a finding that "formaldehyde is carcinogenic to humans (Group 1)"
based on "sufficient evidence in humans for the carcinogenicity of formaldehyde" and "sufficient
evidence in experimental animals for the carcinogenicity of formaldehyde."
Overall, the coverage of reference values for formaldehyde was quite good across all
categories (types of value, severity of effect, and duration). This is tempered; however, with the
uneven comparability between the occupational reference values and the acute and short-term
general public values. There was fair concordance between the ATSDR and CA-REL chronic
values. There is a large and deep set of data on formaldehyde that included a substantial amount
of data from human exposures, which lead to the use of relatively low uncertainty factors for
those reference values which reported UFs.
September 2009 90
-------
Office of Rumen and Dmlopmant
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ฐ
.-3
-2
-1
Subchronic
tn
i
^"
^ _ _ _ ^|(. ATSDR-MRL (1-14 d)
"
s
!L (8-hour) A1
Chronic
w
re
0)
6
)OSHA-PEL(TV\
) Australian TWA*
(15-365 d)
)NIOSH-REL(TV
A)*
-A)
^
^ ^
CA-REL (Chroni
=)
ซ AEGL-3
O AEGL-2 >, ,
0 AEGL-1
B ง.
A ERPG-3
E "
A ERPG-2 LU a-
A ERPG-1
0 ACGIH-Ceiling*
O NIOSH-Ceiling*
0 Australian STEL*
O OSHA-STEL*
a.
NIOSH-IDLH*
o
- - - NIOSH-REL (TWA)*
O OSHA-PEL (TWA)*
- O- Australian TWA*
D WHO Air Quality Guideline
X CA-REL (Acute)
X CA-REL (8-hour) 3
X ATSDR-MRL (1-14 d) -5
ai
X ATSDR-MRL (15-365 d) c
X ATSDR-MRL (> 1yr) ฐ
X CA-REL (Chronic)
0.1
10 100 1000
Duration (hours)
10000
100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.9. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Formaldehyde
September 2009
91
-------
Table 2.9. Details on derivation of the specific inhalation health effect reference values for formaldehyde.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
ERPG-2
ERPG-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
1 hr
1 hr
Reference Value
(mg/mj)
123
86
69
43
43
17
17
17
17
17
1.1
1.1
1.1
1.1
1.1
30.7
12
1.2
(ppm)
100
70
56
35
35
14
14
14
14
14
0.9
0.9
0.9
0.9
0.9
25
10
1.0
Health Effect
Lethality
(Nagorny etal., 1979,
1 93928)
Nose and eye
irritation, lacrimation
(Sim and Rattle,
1957,071236)
Eye irritation (Bender
etal., 1983, 180100)
Severe respiratory
irritation, pulmonary
edema, and death
possible for humans
Eye, nasal, and
throat irritation
Detectable
objectionable odor
Point of Departure
350 ppm LC01
(4hr)
13. 8 ppm Threshold
for effects
0.9 ppm NOAEL
> 25 ppm Threshold
(1 hr) for effects
10 ppm Threshold
for effects
1 ppm Threshold
for effects
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH = 3
Total UF = 1
(human data)
Total UF = 1
(human data)
NR
NR
NR
Notes on
Derivation
Time
scaling:
Cn x t = k
where
n = 3 for
shorter and
n = 1 for
longer
durations
Time
scaling not
applied
Time
scaling not
applied
Review
Status
Interim
(NAC/AEGL,
2008,
192206)
Final
(AIHA, 2002,
192056)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
92
-------
Refe
Ty
Occupational
rence Value
pe / Name
ACGIH-
Ceiling*
NIOSH-
Ceiling*
Australian
STEL*
Australian
TWA*
OSHA-PEL
(TWA)*
OSHA-
STEL*
NIOSH-
IDLH*
NIOSH-REL
(TWA)*
Duration
Any
15 min
10 min
8 hr TWA
8 hr TWA
10 min
< 30 min
10 hr
TWA
Reference Value
(mg/mj)
0.37
0.12
0.72
0.36
0.92
2.46
24.6
0.0197
(ppm)
0.3
0.10
0.59
0.29
0.75
2.0
20
0.016
Health Effect
Respiratory and eye
irritation; cancer
See NIOSH REL
(TWA), below
NR
Respiratory and eye
irritation, and cancer
potential
Upper airway
irritation, increased
nasal and lower
airway resistance
chronic pulmonary
obstruction
(Eastman Kodak Co
mpany, 1963,
192350; IARC, 1982,
192124: National
Research, 1981,
026996)
Point of Departure
NR Threshold
for effects
NR NR
NR NR
NR NR
NR NR
0.1 to Threshold
25 ppm for effects
5 to
30 ppm
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(NIOSH,
1976,
192344)
Proposed
(NICNAS,
2006,
192040)
Final
(OSHA,
1992,
192349)
Final
(NIOSH,
1996,
192345)
Final
(NIOSH,
1976,
192344)
September 2009
93
-------
Refe
Ty
General Public
rence Value
pe / Name
WHO Air
Quality
Guideline
CA-REL
(Acute)
CA-REL
(8-hr)
ATSDR-
MRL
(1-14d)
ATSDR-
MRL
(1 5-365 d)
ATSDR-
MRL
(> iyr)
CA-REL
(Chronic)
Duration
30 min
1 hr
8hr
1 -14d
15d-
1 yr
Chronic
Chronic
Reference Value
(mg/mj)
0.1
0.055
9x10"J
0.05
0.037
9.8x10'J
9x10"J
(ppm)
0.081
0.05
7.3x10"J
0.04
0.03
8x10"J
7.3x10"J
Health Effect
Nose and throat
irritation in humans
Mild and moderate
eye irritation in
humans
(Kulleetal., 1987,
023225)
Nasal obstruction and
discomfort, lower
airway discomfort,
eye irritation
(Wilhelmsson and
Holmstrom, 1992,
180138)
Nasal and eye
irritation
(Pazdraketal., 1993,
006631)
Naso-pharyngeal
irritation and nasal
epithelium lesions in
monkeys
(Ruschetal., 1983,
063803)
Eye and respiratory
tract irritation
(Holmstrom et al.,
1989,003564)
Nasal obstruction and
discomfort, lower
airway discomfort,
eye irritation
(Wilhelmsson and
Holmstrom, 1992,
180138)
Point of Departure
0.1 mg/mj WOE
0.44 ppm BMCL05
(Log-probit)
0.09 mg/mj NOAEL
(8hr)
0.4 ppm LOAEL
0.98 ppm NOAEL
0.24 ppm LOAEL
0.09 mg/mj NOAEL
Uncertainty
Factors
NR
Total UF = 10
UFH : 10
TK = 1,
TD = 10
Total UF = 10
UFL = 3
UFH = 3
Total UF = 30
UFA = 3
UFH = 10
Total UF = 30
UFL = 3
UFH = 10
Total UF = 10
UFH : 10
TK = 1,
TD = 10
Notes on
Derivation
Weight of
evidence
approach
Review
Status
Final
(WHO, 2000,
180143)
Final
(OEHHA,
2008,
192346)
Final
(Agency for
Toxic
Substances
and Disease
Registry,
1999,
093087)
Final
(OEHHA,
2008,
192346)
September 2009
94
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (1978). Formaldehyde. Akron, OH: American Industrial Hygiene Association.
192033
AIHA. (2002). Formaldehyde (1988). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192056
Agency for Toxic Substances and Disease Registry (ATSDR). (1999). Toxicological
profile for formaldehyde. 093087
Bender JR; Mullin LS; Grapel GJ; Wilson WE. (1983). Eye irritation response of humans
to formaldehyde. , 44: 463-465. 180100
Eastman Kodak Company. (1963). Personal observations. In Industrial hygiene and
toxicology (pp. 1971). New York, NY: Interscience Publishers Inc. 192350
Holmstrom M; Wilhelmsson B; Hellquist H; Rosen G. (1989). Histological changes in
the nasal mucosa in persons occupationally exposed to formaldehyde alone and in
combination with wood dust. Acta Otolaryngol, 107: 120-129. 003564
IARC. (1982). Some industrial chemicals and dyestuffs. In IARC monographs on the
evaluation of the carcinogenic risk of chemicals to humans (pp. 345-389). Lyon,
France: International Agency for Research on Cancer. 192124
Kulle TJ; Sauder LR; Hebel JR; Green DJ; Chatham MD. (1987). Formaldehyde dose-
response in healthy nonsmokers. J Air Waste Manag Assoc, 37: 919-924. 023225
NAC/AEGL. (2008). Formaldehyde - interim acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192206
NICNAS. (2006). Priority existing chemical assessment report no. 28 formaldehyde.
National Industrial Chemicals Notification and Assessment Scheme. Sydney,
Australia.http://www.nicnas.gov.au/Publications/CAR/PEC/PEC28/PEC_28_Full
_Report_PDF.pdf. 192040
NIOSH. (1976). Criteria for a recommended standard: occupational exposure to
formaldehyde. National Institute for Occupational Safety and Health. Cincinnati,
OH. DHHS (NIOSH) Publication No. 77-126. http://www.cdc.gov/niosh/77-
126.html. 192344
NIOSH. (1996). Formaldehyde - IDLH documentation. Retrieved 16-JUN-09, from
http://www.cdc.gov/niosh/idlh/50000.html. 192345
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
September 2009 95
-------
Nagorny PA; Sudakova ZA; Schablenko SM. (1979). On the general toxic and allergic
action of formaldehyde. , 7: 27-30. 193928
National Research Council. (1981). Health effects of formaldehyde. In Formaldehyde and
other aldehydesWashington, DC: National Academy Press. 026996
OEHHA. (2008). Acute, 8-hour, and chronic referenc exposure levels - formaldehyde.
Office of Environmental Health Hazard Assessment, California EPA.
Sacramento, CA. 192346
OSHA. (1992). Occupational exposure to formaldehyde. Retrieved , from . 192349
Pazdrak K; Gorski P; Krakowiak A; Ruta U. (1993). Changes in nasal lavage fluid due to
formaldehyde inhalation. Int Arch Occup Environ Health, 64: 515-519. 006631
Rusch GM; Clary JJ; Rinehart WE; Bolte HF. (1983). A 26-week inhalation toxicity
study with formaldehyde in the monkey, rat, and hamster. Toxicol Appl
Pharmacol, 68: 329-343. 063803
Sim VM; Pattle RE. (1957). Effect of possible smog irritants on human subjects. JAMA,
165: 1908-1913.071236
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health
Organization Regional Publications. Copenhagen. 91. 180143
Wilhelmsson B; Holmstrom M. (1992). Possible mechanisms of formaldehyde-induced
discomfort in the upper airways. Scand J Work Environ Health, 18: 403-407.
180138
September 2009 96
-------
2.10 Chemical-Specific Reference Values for Soman (Agent GD) and
Cyclosarin (Agent GF) (CASRN 96-64-0 and 329-99-7)
Soman (Agent GD; pinacolyl methylphosphonofluoridate; CAS Registry No. 96-64-0)
and Cyclosarin (Agent GF; O-cyclohexylmethyl-fluorophosphonate; CAS Registry No. 329-99-
7) are organophosphate (OP) nerve agents that have been specifically designed and formulated to
cause death, major injuries, or incapacitation to enemy forces in wartime. The term "nerve"
agent refers to its anti-cholinesterase properties. Nerve agents are particularly effective in a
military sense because of their potency. Detailed descriptions of nerve agent toxicity as well as
the physical nature of this chemical agent can be found in the AEGL Technical Support
Document (NAC/AEGL, 2003,192304), and are not repeated here.
There are only two sources of health effect reference values for the chemical warfare
agents GD and GF: the National Advisory Committee for Acute Exposure Guideline Levels
(2003, 192304) and the US Army (CDC, 2002, 192175). Both organizations determined that
these agents were equally toxic, on a mg/m3 basis, and derived values that were the same for
both agents. The same limited set of data was used for deriving values for GD and GF; however,
the dataset for GB was the most robust of all of the nerve agents for which values were derived,
and the relative potency of the nerve agents Tabun (GA), GD, GF, and VX to Sarin (GB) was
used to derive values for those other nerve agents.
The only Emergency Response reference values available for GD and GF are the AEGLs.
AEGL-3 values for GD and GF were derived based on a calculated lethality at the one percent
level (LCoi) in female rats using observations at 10-, 30-, 60-, 240-, and 360-minutes. Studies
showing miosis (pinpoint pupils) in female rats (Mioduszewski et al., 2002, 192189) and visual
acuity effects in humans (Baker and Sedgewick, 1996, 180099) were the basis for the AEGL-1
and AEGL-2, respectively. For the AEGL-1, a UFA of 1 was used based on the observation that
miosis response to GB vapors is similar across mammalian species.
A Federal Register Notices published by the Centers for Disease Control and Prevention
(CDC, 2002, 192175) documents the Airborne Exposure Levels proposed by the US Army for
application to the agents GA, GB, GD, GF, and VX, for the protection of workers at chemical
weapon decommissioning facilities and the general population living near those facilities. The
CDC determined that due to the fact that GD and GF were "not part of the U.S. stockpile, and
neither transportation nor open-air testing is being considered for these agents" that they would
not adopt values for those agents as part of the program for those applications; however, the U.S.
Army has since used those proposed values in their guidance documents (USACHPPM, 2003,
192131).
The Airborne Exposure Level values for GD and GF include a General Population Limit
(GPL), a Worker Population Limit (WPL), as well as a Short-term Exposure Limit (STEL) and
Immediately Dangerous to Life and Health (IDLH) occupational values. The GPL and WPL
values for GB were based on exposures of 20 minutes per day for 4 days per week and were
adjusted to derive a Lowest Observable Adverse Effect Level Human Equivalent Concentration
(LOAELHEc) for 24 hour and 8 hour time weighted averages (TWAs), respectively. Fewer
details were provided in the derivation of the STEL and IDLH values, and it is assumed that a
weight of evidence approach was used in their derivation.
September 2009 97
-------
The resulting GD and GF values for both the AEGL and the CDC are shown in
Figure 2.10 and Table 2.10. More recent research by the U.S. Army provides additional data that
may lead to further revision of both sets of values (Dabisch et al., 2008, 192038).
September 2009 98
-------
Office el Research and Development
National Center tar Environmental An
Research Triangle Park, NC
Soman (GD) & Cyclosarin (GF): Comparison of Reference Values
1.E+00
1.E-01
1.E-02
O)
6
c
o
O
4-i
0)
O)
1.E-03
1.E-04
1.E-05
1.E-06
ACUTE
AEGL-3
Short Term
Subchronic
AEGL-1
O
o
Chronic
Army
WPL-TWA*
ARMY
GPL-TWA
-AEGL-3
O AEGL-2
-AEGL-1
Army-STEL*
Army-IDLH*
O Army
WPL-TWA*
c
o
Q.
W)
HI
OL
>*
o
c
01
O)
ARMY
GPL-TWA
ll
<1) CO
it
Q.
0.1
10 100 1000
Duration (hours)
10000
100000 1000000
* Indicates an occupational value; expert judgement necessary prior to applying these values to the general public.
Figure 2.10. Comparison of Available Health Effect Reference Values for Inhalation Exposure to
Soman (GD) and Cyclosarin (GF)
September 2009
99
-------
Table 2.10. Details on derivation of the specific inhalation health effect reference values for GD and GF.
Reference Value
Type / Name
Emergency Response2
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value1
(mg/mj)
0.38
0.19
0.13
0.07
0.051
0.044
0.025
0.018
8.5x10"J
6.5x10"J
3.5x10"J
2.0x10'J
1.4x10'J
7.0X10"1
5.0x10'"
(ppm)
0.049
0.025
0.017
9.1 x10"J
6.6x10'J
5.7x10'J
3.3x10'J
2.2x10'J
1.2x10"J
8.5x10""
4.6 x10"4
2.6x10"
1.8x10"
9.1 x10'D
6.5x10'ฐ
Health Effect
Lethality
(Aasetal., 1985,
180091; Anthony et
al.,2002, 192037;
Mioduszewski et
al.. 2000. 192305:
Mioduszewski et
al.. 2001. 192306:
Mioduszewski et
al.,2002, 180121)
Miosis, dyspnea,
photophobia, and
inhibition of RBC-
ChE seen in
humans
(Baker and
Sedgewick, 1996,
180099)
Induction of miosis
in female rat
(Harvey, 1952,
192174; Johns,
1952 192313'
Mioduszewski et
al.,2002, 192189;
van Helden et al.,
2001, 180238)
Point of Departure
11.54mg/mJ |_C01
(female
5.84 mg/mj rats)
4.01 mg/mj
2.09 mg/nf1
1.76 mg/nf1
(6hr)
0.5 mg/mj Sub-
(30 min) clinical
effects
Range of EC50 for
0.01-0.48 miosis
mg/m3 at
10 min,
60 min,
and 240
min
Uncertainty
Factors
Total UF = 30
UFA = 3
UFH = 10
Total UF= 10
IIP - -|
ur/\ I
UFH = 10
Total UF= 10
IIP - -|
ur/\ i
UFH = 10
Notes on
Derivation
Potencies of
GD and GF are
equal to that of
GB for lethality
Potencies of
GD and GF are
approximately
twice that of
GB and GA for
AEGL-2 effects
Potencies of
GD and GF are
approximately
twice the
potency of
agents GB and
GA for AEGL-1
effects
Review Status
Final
(NAC/AEGL,
2003, 192304)
1 Reference values for GD and GF were derived on a mg/ m3 equivalance. The values shown in units of parts per million (ppm) were those reported in the AEGL
Technical Support Document, with the values for GD shown first (top). Values in ppm were not derived for the values used by the Army (CDC, 2002).
2 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
100
-------
Reference Value
Type / Name
(8
C
0
"^
Q.
O
0
O
c
o
1_ "^
-------
REFERENCES
Aas P; Sterri SH; Hjermstad HP; Fonnum F. (1985). A method for generating toxic vapors of
soman: toxicity of soman by inhalation in rats. Toxicol Appl Pharmacol, 80: 437-445.
180091
Anthony J; Haley MV; Manthei J; Way R; Burnett D; Gaviola B; Sommerville D; Crosier R;
Mioduszewski RJ; Jakubowski E; Montgomery J; Thomson S. (2002). Inhalation toxicity
of GF vapor in rats as a function of exposure concentration and duration and its potency
comparison to GB. Presented at 41st Annual Meeting of the Society of Toxicology,
March 21, Nashville, TN. 192037
Baker DJ; SedgewickEM. (1996). Single fibre electromyographic changes in man after
organophosphate exposure. Hum Exp Toxicol, 15: 369-375. 180099
CDC. (2002). Airborne exposure limits for chemical warfare agents GA (tabun), GB (sarin), and
VX. Fed Regist, 67: 894-901. 192175
Dabisch PA; Horsman MS; Taylor JT; Muse WT; Miller DB; Sommerville DR; Mioduszewski
RJ; Thomson S. (2008). Gender difference in the miotic potency of soman vapor in rats.
Cutan Ocul Toxicol, 27: 123-133. 192038
Harvey JC. (1952). Clinical observations on volunteers exposed to concentrations of GB. Army
Chemical Center. Aberdeen Proving Ground, MD. 5030-114. 192174
Johns RJ. (1952). The effect of low concentrations of GB on the human eye. Army Chemical
Center. Aberdeen Proving Grounds, MD. 5030-100. 192313
McKee WE; Woolcott R. (1949). Report on exposures of unprotected men and rabbits to low
concentrations of nerve gas vapor. Military Intelligence Division. Porton Down, United
Kingdom. Porton Technical Paper # 143. 192172
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Anthony J; Durst D;
Sommerville D; Crosier R; Thomson S; Grouse C. (2001). Inhalation toxicity of sarin
vapor in rats as a function of exposure concentration and duration. ECBC Low Level
Operational Toxicology Program. Edgewood, MD. 192306
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S; Sommerville
D; Crosier R. (2000). Estimating the probability of sarin vapor toxicity in rats as a
function of exposure concentration and duration . Presented at International Chemical
Weapons Demilitarization Conference, The Hague, Netherlands. 192305
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S; Sommerville
D; Crosier R. (2002). Interaction of exposure concentration and duration in determining
acute toxic effects of sarin vapor in rats. Toxicol Sci, 66: 176-184. 180121
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S; Sommerville
D; Crosier R; Scotto J; McCaskey D; Crous C; Matson K. (2002). Low-level sarin vapor
exposure in rats: effect of exposure concentration and duration on pupil size. Edgewood
Chemical Biological Center. Aberdeen Proving Ground,
MD.http://www.stormingmedia.us/96/9682/ A968204.html. 192189
September 2009 102
-------
NAC/AEGL. (2003). Nerve agents GA, GB, GD, GF, and VX - final acute exposure guideline
levels (AEGLs). National Advisory Committee for Acute Exposure Guideline Levels.
Washington, DC.http://www.epa.gov/oppt/aegl/pubs/tsd21.pdf. 192304
USACHPPM. (2003). Reference Document (RD) 230 - Chemical Exposure Guidelines for
Deployed Military Personnel. U.S. Army Center for Health Promotion and Preventive
Medicine. Aberdeen Proving Ground, MD. 192131
van Helden HPM; Trap HC; Kuijpers WC; Groen B; Oostdijk JP; Vanwersch RAP; Philippens
IHC; Langenberg JP Benschop JP. (2001). Low level exposure to GB vapor in air:
diagnosis/dosimetry, lowest observable effect level, and performance incapacitation.
Presented at Research and Technology Organisation Meeting Proceedings 75, Estoril,
Portugal. 180238
September 2009 103
-------
2.11 Chemical-Specific Reference Values for Hydrogen Cyanide
(CASRN 74-90-8)
Hydrogen cyanide (HCN) is a colorless, rapidly acting, highly poisonous gas or liquid
that has an odor of bitter almonds. Most HCN is used as an intermediate at the site of production.
Major uses include the manufacture of nylons, plastics, and fumigants (NRC, 2002, 192138).
The acute dose-effect curve in humans is steep (NLM, 2008, 192348). HCN is well absorbed via
the gastrointestinal tract or skin, and rapidly absorbed via the respiratory tract. HCN is rapidly
and ubiquitously distributed throughout the body, with the highest levels typically found in the
liver, lungs, blood, and brain; however, there is no accumulation following chronic or repeated
exposure. Approximately 80% of absorbed HCN is metabolized to thiocyanate in the liver and
excreted in the urine. Additional information on the nature of HCN and detailed summaries of
health effects can be found in other sources (NLM, 2008, 192348: NRC, 2002, 192138:
U.S. EPA, 1994, 192351) and is not repeated here.
Figure 2.11 presents a graphical array of the available inhalation health effect reference
values for HCN. Details are provided in Table 2.11, including the key effects, studies,
adjustments, uncertainty factors (UFs), and other information useful in reconstructing the
derivation of these reference values.
The Emergency Response values (AEGLs and ERPGs) are in close agreement to one
another, although the ERPG levels 2 and 3 are slightly elevated in comparison to the comparable
AEGLs. An AEGL-1 was derived, but the ERPG committee did not believe the available
information allowed for derivation of an ERPG-1. The time scaling performed in deriving the
AEGL-3 and AEGL-2 values utilized the data from the respective key studies to calculate
separate slope factors (value of n) to be applied in the Cn * t formula, as outlined in the AEGL
Standing Operating Procedures (SOPs) (NRC, 2001, 192042). The data in support of the AEGL-
1 values, however, did allow for calculation of a separate duration slope factor, and the default n
value of 3 was applied to the 8 hour data to derive values for shorter durations, also as outlined in
the AEGL SOPs. Additional details used in deriving the AEGLs are provided in the Technical
Support Document for HCN (NRC, 2002, 192138). The details provided in the ERPG
documentation (AIHA, 2002, 192063) indicated that a weight of evidence approach was applied
for both the ERPG-2 and ERPG-3 values, with a route equivalent adjustment from intravenous
injection to inhalation exposure performed for the ERPG-2 (details not provided).
Details on derivation were also lacking for most of the Occupational reference values,
with most of the more detailed documentation (ACGIH, 2007, 192024: NIOSH, 2006, 192177)
indicating that a weight of evidence approach was taken. The OSHA PEL value was based on a
previously available ACGIH TLV (TWA) value that has since been replaced.
Both of the chronic General Public reference values used the same point of departure
from the same study, and performed the same human equivalent concentration (HEC)
adjustments; the differences in the values are due solely to application of different uncertainty
factors. The acute CA-REL was based on a study with observations at 30 minutes, and to adjust
to the one hour target application of the classic Haber's rule (ten Berge et al., 1986, 025664) was
applied using a straight C x t relationship (see discussion on AEGL values, above), which is in
keeping with the recommendations from the NRC in deriving AEGL values (2001, 192042).
Overall, the slate of inhalation reference values for HCN should provide adequate
information for most foreseeable applications. No obvious gaps are evident.
September 2009 104
-------
Office of Research and Development
National Center tar Environmental An
Research Triangle Park, NC
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Hydrogen Cyanide: Comparison of Reference Values
ACUTE
^. S"
O NIOSH-IDLH* 3
0
^^"""""^k ^L 4
O ^^^L
^ A^.j.0
Short Term
to
CQ
0
M
V i^AEGL-3
Oj^ftt'cSIfng* s^
<^^^. OAEGI
^*^^^^.
^\Xy. AEGL
X CA-REL (Acute)
-2
-1
Subchronic
C
tซ
to
0
i^
:
Chronic
to
CO
O
0
h-
)OSHA-PEL (TV
CA-REL ,
(Chronic)
EPA/IRIS RfC.
/A
:
0
W)
O AEGL-2
01
0
or
1 AEGL-1 >>
c
0
A ERPG-3 ^
UJ
A ERPG-2
O ACGIH-Ceiling*
NIOSH-STEL*
* NIOSH-IDLH*
O OSHA-PEL (TWA)*
X CA-REL (Acute) .^
&
3
Q.
X CA-REL (Chronic) -^
m
C
EPA/IRIS RfC $
10 100 1000 10000 100000 1000000
Duration (hours)
Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.11. Presntation of Available Health Effect Reference Values for Inhalation Exposure to Hydrogen Cyanide
September 2009
105
-------
Table 2.11. Details on derivation of the specific inhalation health effect reference values for hydrogen cyanide.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
30
23
17
9.7
7.3
19
11
7.8
3.9
2.8
2.8
2.8
2.2
1.4
1.1
28
(ppm)
27
21
15
8.8
6.6
17
10
7.1
3.5
2.5
2.5
2.5
2
1.3
1
25
Health Effect
Lethality in rats
(DuPont, 1981,
192211)
Slight CMS
depression in
monkeys (Purser et
al., 1984,094953)
Absence of severe
health effects
(El Ghawabi etal.,
1975,064697; Hardy
etal., 1950. 180113)
(Grabois, 1954,
192212)(Maehly and
Swensson, 1970,
193929): (Leeser et
al., 1990, 192352)
Only transient effects
with exposures to 45-
50 ppm
Point of Departure
1 38 ppm LC01
(15 min)
127 ppm
(30 min)
88 ppm
(60 min)
60 ppm NOAEL
(30 min)
1 ppm NOAEL
(8 hour)
NR NR
Uncertainty
Factors
Total UF = 6
1 IF* - 9
UFA t-
UFH ~ 3
Total UF = 6
UFA = 2
UFH - 3
None, as
1 ppm is the
lowest NOAEL
for a chronic
occupational
study
(Leeser et al.,
1990)
NR
Notes on
Derivation
Time scaling:
rn x t - k
where
n = 2.6,
derived from
the key
study.
Time scaling:
x t - k
where
n - 2, derived
from the
effect level
data in key
study.
Time scaling:
x t - k
where
n = 3,
protective for
extrapolating
from an
8 hr exposure
Review
Status
Final
(NRC, 2002,
192138)
Final
(AIHA, 2002,
1 92063)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
106
-------
Refe
"
Occupational
General
Public
rence Value
pe / Name
ERPG-2
ACGIH-
Ceiling*
OSHA-PEL
(TWA)*
NIOSH-
STEL*
NIOSH-IDLH
(<30 min)*
CA-REL
(Acute)
Duration
1 hr
Any
8 hr TWA
10 min
< 30 min
1 hr
Reference Value
(mg/mj)
11
5
11
5
55
0.34
(ppm)
10
4.7
10
4.7
50
0.3
Health Effect
(Flury and Zernik,
1931.059306:
Lehmann, 1903,
192353; Parmenter,
1926, 180125)
No severe effects in
humans with
intravenous sodium
cyanide (0.11 mg/kg )
(Wexleretal., 1947,
1 80224)
Throat irritation,
headache, thyroid
enlargement
(El Ghawabi etal.,
1975,064697;
NIOSH, 1997,
192347; Wolfsie and
Shaffer, 1959,
180140)
NR
Lethal or life-
threatening health
effects
(Flury and Zernik,
1931.059306)
CMS depression/
incapacitation in
monkeys
(Purser, 1984,
064725; Purser etal.,
1984,094953)
Point of Departure
10 ppm NOAEL
(route to
route
equiv-
alent)
NR NR
NR NR
45 - 54 NOAEL
ppm
(30 min- NR
1 hr)
34 mg/mj NOAELAoj
(68 mg/m3
x 30/60
min)
Uncertainty
Factors
NR
NR
NR
NR
NR
Total UF = 100
UFA= 10
UFH = 10
Notes on
Derivation
Based on
previous
ACGIH-TLV
Time scaling
from 30 min
to 1 hr using
straight C x t
Review
Status
Final
(ACGIH,
2007,
1 92024)
Final
(NIOSH,
2006,
192177))
Final
(NIOSH,
1996,
192356)
Final
(OEHHA,
2008,
1 92355)
September 2009
107
-------
Refe
Ty
rence Value
pe / Name
CA-REL
(Chronic)
Chronic RfC
(IRIS)
Duration
Chronic
Chronic
Reference Value
(mg/mj)
9x10"J
3x10"J
(ppm)
8.1 x10"J
2.7x10"J
Health Effect
CMS effects, thyroid
enlargement,
hematological
disorders in humans
(El Ghawabi etal.,
1975,064697)
CMS symptoms and
thyroid effects in
humans
(El Ghawabi etal.,
1975,064697)
Point of Departure
2.5 mg/nf LOAELHEc
(7.1 mg/m3
x 1 0/20
x5/7)
2.5 mg/mj LOAELHEc
(7.1 mg/m3
x 1 0/20
x5/7)
Uncertainty
Factors
Total UF = 300
UFL=10
UFS = 3
UFH = 10
Total UF = 1000
UFH = 10
UFL = 10
UFDB = 3
UFS = 3
Notes on
Derivation
Adjustments
for breathing
rate 1 0 m3
(worker) vs.
20 m3 (avg)
breathing
rate, and
5 day/wk
schedule
Review
Status
Final
(OEHHA,
2000,
1 92354)
Final
(U.S. EPA,
1994,
192351)
September 2009
108
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Hydrogen cyanide (1994). In 2002 Emergency Response Planning
Guidelines (ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial
Hygiene Association. 192063
DuPont. (1981). Inhalation toxicity of common combustion gases. E.I. DuPont de
Nemours. Newark, Delaware. 238-81. 192211
El Ghawabi SH; Gaafar MA; El-Saharti AA; Ahmed SH; Malash KK; Fares R. (1975).
Chronic cyanide exposure: a clinical, radioisotope, and laboratory study. Occup
Environ Med, 32: 215-219. 064697
Flury F; Zernik F. (1931). Schaedliche Gase: Daempfe, Nebel, Rauch- und Staubarten
[Noxious gases, fumes, vapors, and varieties of smoke and dust]. Berlin,
Germany: Verlag von Julius Springer. 059306
Grabois B. (1954). Monthly review 33:33. NY Department of Labor, Division of
Industrial Hygiene. New York. 192212
Hardy JL; Jeffries WM; Wasserman MM; Waddell WR. (1950). Thiocyanate effect
following industrial cyanide exposure - report of two cases. N Engl J Med, 242:
968-972. 180113
Leeser JE; Tomenson JA; Bryson DD. (1990). A cross-sectional study of the health of
cyanide salt production workers. ICI Central Toxicology Laboratory. Cheshire,
UK. OHS/R/2. 192352
Lehmann KB. (1903). About the toxicity of gaseous HCN and hydrogen phosphide with
a demonstration. , 40: 918-919. 192353
Maehly AC; Swensson A. (1970). Cyanide and thiocyanate levels in blood and urine of
workers with low-grade exposure to cyanide . , 27: 195-209. 193929
NIOSH. (1996). Hydrogen cyanide - IDLH documentation. Retrieved 16-JUN-09, from
http://www.cdc.gov/niosh/idlh/74908.html. 192356
NIOSH. (1997). Criteria for a recommended standard - occupational exposure to
hydrogen cyanide and cyanide salts. National Institute for Occupational Safety
and Health. Cincinnati, OH. 192347
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safely and Health. 192177
NLM. (2008). Hydrogen cyanide. Retrieved 16-JUN-09, from
http://toxnet.nlm.nih.gOv/cgi-bin/sis/search/f7./temp/~I6CZ6x: 1. 192348
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
September 2009 109
-------
NRC. (2002). Hydrogen cyanide. In Acute exposure guideline levels for selected airborne
chemicals (pp. 211-259). Washington, DC: National Academies Press. 192138
OEHHA. (2000). Chronic toxicity summary - hydrogen cyanide. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192354
OEHHA. (2008). Acute toxicity summary - hydrogen cyanide. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192355
Parmenter DC. (1926). Observations of mild cyanide poisoning - report of a case. Toxicol
Ind Health, 8: 280-282. 180125
Purser DA. (1984). A bioassay model for testing the incapacitating effects of exposure to
combustion product atmospheres using cynomolgus monkeys. , 2: 20-36. 064725
Purser DA; Grimshaw P; Berrill KR. (1984). Intoxication by cyanide in fires: a study in
monkeys using polyacrylonitrile. Arch Environ Occup Health, 39: 394-400.
094953
U.S. EPA. (1994). Toxicological review of hydrogen cyanide. National Center for
Environmental Assessment. Washington,
DC.http://www.epa.gov/ncea/iris/subst/0060.htm. 192351
Wexler J; Whittenberger JK; Dumko PR. (1947). The effect of cyanide on the electric
cardiogram of man. Am Heart J, 34: 163-173. 180224
Wolfsie JH; Shaffer CB. (1959). Hydrogen cyanide - hazards, toxicology, prevention and
management of poisoning. , 2: 289. 180140
ten Berge WF; Zwart A; Appelman LM. (1986). Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J Hazard Mater,
13:301-309.025664
September 2009 110
-------
2.12 Chemical-Specific Reference Values for Hydrogen Fluoride
(CASRN 7664-39-3)
Hydrogen fluoride (HF) is a colorless, corrosive gas or liquid with a strong,
irritating odor. It is used commercially in the production of herbicides, aluminum,
plastics, fluorescent light bulbs, and pharmaceuticals; as a catalyst in the petroleum
alkylation process; and in the production of fluorocarbons which are used broadly as
refrigerants. The largest sources of human exposure to HF are from aluminum production
plants, phosphate fertilizer plants, and the combustion of fluoride containing materials,
notably coal. Chemical, steel, magnesium, and brick production processes also emit HF.
Hydrogen fluoride is designated a hazardous air pollutant (HAP) under the Clean Air Act
Amendments of 1990. Additional information on the nature of HF and detailed
summaries of health effects can be found in the AEGL TSD (NRC, 2004,192143), the
ATSDR Toxicological Profile (ATSDR, 2003, 192114). the OEHHA REL
documentation (OEHHA, 2003, 192228: OEHHA, 2008, 1922901 and other sources and
is not repeated here.
Hydrogen fluoride has a relatively complete range of inhalation health effect
reference values, which are displayed graphically in Figure 2.12. Details available on the
derivation of these values, including key effects, studies, adjustments, and uncertainty
factors (UFs) are shown in Table 2.12.
Emergency Response AEGL and ERPG values were developed for all three
severity levels (level 1 for mild transient effects; level 2 for irreversible effects or
impairment of ability to escape; and level 3 for potentially lethal effects). ERPG values
were not only derived for one hour durations, as customary, but 10 minute values were
also developed in an addendum (AIHA, 2002, 192090). As shown in Figure 2.12, the one
hour and 10 minute AEGL-3 values are very similar to the corresponding ERPG-3
values, while the ERPG-2 values are slightly lower and the ERPG-1 values are slightly
higher than the corresponding AEGL values. The nature of this difference is difficult to
assess because fewer details are provided for the derivation of the ERPGs than is
provided for the AEGLs. Time-scaling was applied to both the AEGL-2 and AEGL-3
values using a Cnx t = k relationship where n = 2 [derived from empirical data on
lethality, see the AEGL TSD for details (NRC, 2004, 192143)1 for durations up to 1-hr.
The 8-hr AEGL-2 and AEGL-3 values were set equal to the 4-hr values to avoid
inconsistencies with study data.
The NIOSHIDLH Occupational values are derived by a weight of evidence
approach. Observations that 50 ppm may be fatal when inhaled for a period of 30 to 60
minutes (Deichmann and Gerarde, 1969, 009221), and studies with human volunteers
exposed to concentrations as high as 4.7 ppm for 6 hours per day for 10 to 50 days being
tolerated without severe adverse effects (Largent, 1961, 066345) served to bracket the
recommended value of 25 ppm. As displayed in Figure 2.12, all of the time-weighted
average (TWA) Occupational values (the ACGIH TLV, OSHA PEL, and NIOSH REL)
for HF are equivalent. In contrast, the ACGIH and NIOSH ceiling values diverge by a
factor of 3, with the NIOSH value being higher; however, the level of detail provided in
the support documents was not adequate to assess the basis for these differences.
September 2009 111
-------
Two acute General Public reference values are available for HF - an acute CA-
REL and an acute ATSDR MRL. Both organizations use the same study (Lund et al.,
1997, 180115) to derive their reference values with the major differences in derivation of
values relating to the determination of the point of departure (POD) and the application of
UFs. OEHHA determined that the high end of the range of exposures was aNOAEL and
applied a total UF of 10 for inter-individual variability. ATSDR determined that the
midpoint of the same range of exposures was a minimal LOAEL and applied an
additional UF of 3 to account for that. The chronic CA-REL was derived from a
subchronic occupational study that was adjusted to account for exposure occurring 8
hours per day, 5 days per week, which is effectively implying that Haber's rule
(C x t = k) applies in these types of adjustments. An UF of 10 was applied for inter-
individual variability to arrive at a final chronic CA-REL.
In looking across the entire collection of HF reference values, there is a strong
concordance seen within the emergency response and occupational values, especially in
looking at the three TWA occupational values, which all have the same value. The acute
MRL is nearly identical to the chronic CA-REL, despite the difference in duration, while
the acute CA-REL is an order of magnitude higher concentration than the acute MRL.
Differences in the determination of the POD and application of UFs are largely
responsible for these differences in the general public values. It should be noted,
however, that the acute and chronic CA-REL values are consistent with one another in
derivation and are in general keeping with expectations for differences across durations.
September 2009 112
-------
Office of
National Center for Environm
Research Triangle Park, NC
Hydrogen Fluoride: Comparison of Reference Values
0.1
10 100 1000
Duration (hours)
10000
100000 1000000
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^ 1.E+02
3)
ฃ,
O
ง 1.E+01
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o
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J
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ACUTE
to
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O
4
CM
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A *SA ERPG-3
ERPG-2 ฃ ^^N.
Short Term
to
>
CO
9
0
CO
NIOSH-IDLH'O T^ ^AEGL-3
O <>AEGL-2
^ NIOSH-Ceiling*
~ NIOSH-STEL*
ACGIH-Ceiing* C
Q ERPG-1 A ERPG-1
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a aaaaaaaaa aaaa aaaa aaaaaaa aai aai aa aa I
X CA-REL (Acute)
\
^ - - - *AT
Subchronic
W)
re
0
-(
3DR-MRL(1-14d)
/
Chronic
J
L
C
r-
OSHA-PEL Cm
A)*
S ACGIH-TLV("n/VA)"
NIOSH-REL (TWA)*
, CA-REL
1
' (Chronic) X
1 0 AEGL-3
0 AEGL-2
O AEGL-1
A ERPG-3
0)
A ERPG-2 0)
UJ
A ERPG-1
O ACGIH-Ceiling*
O NIOSH-Ceiling*
NIOSH-STEL*
nj
NIOSH-IDLH*
3
O
O ACGIH-TLV (TWA)* g
0 NIOSH-REL (TWA)*
O OSHA-PEL (TWA)*
X CA-REL (Acute) S
0.
[ - X ATSDR-MRL(1-14d) n
i c
I X CA-REL (Chronic) u
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.12. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Hydrogen Fluoride
September 2009
113
-------
Table 2.12. Details on derivation of the specific inhalation health effect reference values for hydrogen fluoride.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
140
51
36
18
18
78
28
20
9.8
9.8
0.8
0.8
0.8
0.8
0.8
41
(ppm)
170
62
44
22
22
95
34
24
12
12
1
1
1
1
1
50
Health Effect
Lethality
(Dalbey, 1996,
192191;Dalbeyet
al., 1998, 180105:
Wohlslagel et al.,
1976.019571)
Pulmonary effects
Blinking, sneezing,
coughing, eye and
nasal irritation in
dogs
(Dalbey, 1996,
192191' Dalbev et
al., 1998, 180105;
Rosenholtz et al.,
1963,019861)
Pulmonary
inflammation,
sensory irritation
(Lundetal., 1997,
1801 15; Lund et
al., 1999, 180265)
Lethality
(Prince, 1989,
080118; Valentine
and Makovec,
Point of Departure
1 ,764 ppm Minimal LOAEL
(10 min)
NOAEL
263 ppm
(1 hour)
950 ppm NOAEL for
(10 min) lethality
243 ppm Threshold for
(1 hour) AEGL-2 effects
3 ppm Sub-threshold
(1 hour)
WOE WOE
Uncertainty
Factors
Total UF = 10
1 IF* - ^
UFA o
UFH = 3
Total UF - 3
UFA=1
UFH- 3
Total UF = 10
UFA = 3
UFH = 3
Total UF = 3
UFH = 3
NR
Notes on
Derivation
Time Scaling:
rn y t - k
where n = 2
to 4 hrs;
8 hr AEGL-3
value equal to
4-h value
Time Scaling:
Cnxt = k
where n = 2
to 4 hrs;
8 hr AEGL-2
value equal to
4-h value
Time scaling
not applied
Weight of
evidence
approach
Review
Status
Interim
(NAC/AEGL,
2004,
192285)
Final
(AIHA, 2002,
192067;
AIHA, 2002,
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
114
-------
Refe
Ty
rence Value
pe / Name
ERPG-2
ERPG-1
Duration
10 min
1 hr
10 min
1 hr
10 min
Reference Value
(mg/mj)
140
16
41
1.6
1.6
(ppm)
170
20
50
2
2
Health Effect
1993, 192192;
Wohlslagel et al.,
1976,019571)
Lethality
(Dalbey, 1996,
192191; Dalbevet
al., 1998, 180105)
Threshold for
non lethal effects for
animals exposed to
260-1300 ppm
(Machle and
Evans, 1940,
180116; Machle et
al.. 1933. 180118)
Respiratory tract
irritation
(Darmer Kl et al.,
1972,010495:
Lewis and Next,
1990, 192287)
Exposure of
humans to 1.4 ppm
was not irritating
and exposure to
2.7-4.7 caused
slight irritation
(Lindberg, 1968,
192288)
Exposure of
humans to 4.6 ppm
for 6 hr caused only
reversible irritation
(Largent, 1961,
066345)
Point of Departure
1700 ppm LC01
(10 min)
20 ppm NOAEL
50 ppm RD50
2 ppm NR
Uncertainty
Factors
NR
NR
NR
NR
NR
Notes on
Derivation
AtotalUF = 10
can be
deduced.
Review
Status
1 92090)
Final
(AIHA, 2002,
192067;
AIHA, 2002,
1 92090)
September 2009
115
-------
Refe
Ty
Occupational
General Public
rence Value
pe / Name
ACGIH-
Ceiling*
ACGIH
TLV-TWA*
NIOSH-
IDLH*
NIOSH-
Ceiling*
NIOSH
REL-TWA*
OSHA-
PEL*
CA-REL
(Acute)
ATSDR-
MRL
(1-14d)
CA-REL
(chronic)
Duration
Any
ShrTWA
30 min
15 min
8hr
8hr
1 hr
1 -14d
Chronic
Reference Value
(mg/mj)
1.6
0.4
25
5
2.5
2.5
0.24
0.016
0.014
(ppm)
2
0.5
30
6
3
3
0.3
0.02
0.017
Health Effect
Lung damage
(Lundetal., 1997,
180115; Lundet
al., 1999, 180265)
Acute inhalation
toxicity data in
humans
Pulmonary effects;
irritation
(NIOSH, 1976,
192167)
NR
Upper respiratory
tract membrane
irritation in humans
(Lundetal., 1997,
180115)
Increased bone
density (skeletal
fluorosis)
(Derryberry et al.,
1963,066269)
Point of Departure
NR NR
NR NR
50 ppm Fatal Threshold
(30 - 60 min) (Deichmann
and Gerarde,
4.7 ppm 1969.009221)
(6h/d, 10 to NOAEL
50 d) (Largent, 1961,
066345)
NR NR
NR NR
NR NR
2.4 mg/mj NOAEL
(1 hr; high
end of range)
0.5 ppm LOAEL
(1 hr; mid-
point of
range)
0.14mg/nfi BMC05-HEc
(0.39 mg/m3 (0.39 mg/m3)
x 10/20
x5/7)
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
Total UF = 10
UFH = 10
Total UF = 30
UFL = 3
UFH = 10
Total UF = 10
UFH = 10
Notes on
Derivation
Minimal LOAEL
Adjustments for
8h/day; 5 d/wk
Review
Status
Final
(ACGIH,
2007,
1 92024)
Final
(NIOSH,
1996,
1 92289)
Final
(NIOSH,
2006,
192177)
Final
(OSHA,
2006,
1 92276)
Final
(OEHHA,
2008,
1 92290)
Final
(ATSDR,
2003,
192114)
Final
(OEHHA,
2003,
1 92228)
September 2009
116
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Hydrogen fluoride (1997). In 2002 Emergency Response Planning
Guidelines (ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial
Hygiene Association. 192067
AIHA. (2002). Hydrogen fluoride: 10-min ERPGs (addendum). In 2002 Emergency
Response Planning Guidelines (ERPG) Complete Set (pp. .). Fairfax, VA:
American Industrial Hygiene Association. 192090
ATSDR. (2003). Toxicologial profile for fluorides, hydrogen fluoride, and fluorine.
Agency for Toxic Substances and Disease Registry. Atlanga, GA. NTIS PB2004-
100002. 192114
Dalbey W. (1996). Evaluation of the toxicity of hydrogen fluoride at short exposure
times. Petroleum Environmental Research Forum Project. Pennington, NJ. 92-09.
192191
Dalbey W; Dunn B; Bannister R; Daughtrey W; Kirwin C; Reitman F; Steiner A; Bruce
J. (1998). Acute effects of 10-minute exposure to hydrogen fluoride in rats and
derivation of a short-term exposure limit for humans. Regul Toxicol Pharmacol,
27: 207-216. 180105
Darmer KI Jr; Haun CC; MacEwen JD. (1972). The acute inhalation toxicology of
chlorine pentafluoride. J Occup Environ Hyg, 33: 661-668. 010495
Deichmann W; Gerarde H. (1969). Toxicology of drugs and chemicals. New York, NY:
Academic Press. 009221
Derryberry OM; Bartholomew MD; Fleming RBL. (1963). Fluoride exposure and worker
health: the health status of workers in a fertilizer manufacturing plant in relation
to fluoride exposure. Arch Environ Occup Health, 6: 503-514. 066269
LargentEJ. (1961). Fluorosis: the health aspects of fluorine compounds. Columbus, OH:
Ohio State University Press. 066345
Lewis R; HextP. (1990). Hydrogen fluoride: assessment of sensory irritation potential in
mice. ICI Central Toxicology Laboratory. United Kingdom. 192287
Lindberg ZY. (1968). The combined effect of hydrogen fluoride and sulfur dioxide on the
body of man and animals. ,11: 32-44. 192288
Lund K; Ekstrand J; Boe J. (1997). Exposure to hydrogen fluoride: an experimental study
in humans of concentrations of fluoride in plasma, symptoms, and lung function.
Occup Environ Med, 54: 32-37. 180115
Lund K; Refsnes M; Sandstrom T; Sostrand P; Schwarze P; Boe J; Kongerud J. (1999).
Increased CD3 positive cells in broncoalveolar lavage fluid after hydrogen
fluoride inhalation. Scand J Work Environ Health, 25: 326-334. 180265
Machle W; Evans EE. (1940). Exposure to fluorine in industry. , 22: 213-217. 180116
September 2009 117
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Machle W; Thamann F; Kitzmiller K; Cholak J. (1933). The effects of inhalation of
hydrogen fluoride. , 16: 129-145. 180118
NAC/AEGL. (2004). Hydrogen fluoride - interim acute exposure guideline levels
(AEGLs). National Advisory Committee for Acute Exposure Guideline Levels.
Washington, DC. 192285
NIOSH. (1976). Criteria for a recommended standard: occupational exposure to hydrogen
fluoride. National Institutes for Occupational Safety and Health. Cincinnati, OH.
DHHS (NIOSH) Publication No. 76-143. http://www.cdc.gov/niosh/76-143.html.
192167
NIOSH. (1996). Hydrogen fluoride - IDLH documentation. Retrieved 1 l-JUN-09, from
http://www.cdc.gov/niosh/idlh/7664393.html. 192289
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
NRC. (2004). Hydrogen fluoride. In Acute exposure guideline levels for selected airborne
chemicals (pp. 123-197). Washington, DC: National Academies Press. 192143
OEHHA. (2003). Chronic toxicity summary - fluorides including hydrogen fluoride.
Office of Environmental Health Hazard Assessment, California EPA.
Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_fmal.pdf#page=27
0. 192228
OEHHA. (2008). Acute toxicity summary - hydrogen fluoride. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192290
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
Prince I. (1989). Pica and geophagia in cross-cultural perspective. , 26: 167-197. 080118
Rosenholtz MJ; Carson TR; Weeks MH; Wilinski F; Ford DF; Oberst FW. (1963). A
toxicopathologic study in animals after brief single exposures to hydrogen
fluoride. J Occup Environ Hyg, 24: 253-261. 019861
Valentine R; Makovec GT. (1993). Effects of exposure duration and relative humidity on
the acute inhalation toxicity of hydrogen fluoride. E.I. du Pont de Nemours and
Co Inc. Newark, DE. 192192
Wohlslagel J; DiPasquale LC; Vernot EH. (1976). Toxicity of solid rocket motor exhaust:
effects of HC1, HF, and alumina on rodents. , 3: 61-69. 019571
September 2009 118
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2.13 Chemical-Specific Reference Values for Hydrogen Sulfide
(CASRN 7783-06-4)
Hydrogen sulfide (H^S) is a flammable, colorless gas that has a sweet taste and a rotten
egg odor (HSDB, 2006,192357). The presence of H2S is detectable at low concentrations, but its
odor may be undetectable at high concentrations. The majority of hydrogen sulfide present in
the environment is produced by natural sources, although several anthropogenic sources exist
as well. It is used in the production of elemental sulfur and sulfuric acid; in the purification of
nickel and manganese; and as a component of inorganic sulfides, used in dyes, pesticides,
polymers, leather, and plastic additives. The largest source of human exposure to H2S is
through the inhalation of polluted ambient air. Additional information on the nature of
hydrogen sulfide and detailed summaries of health effects can be found in a number of sources,
including the AEGL TSD (NAC/AEGL, 2002, 192202). the ATSDR Toxicological Profile
(ATSDR, 2006, 192117). the IRIS Toxicological Review (U.S. EPA, 2003, 192242). the OEHHA
REL documentation (OEHHA, 2008, 192243). and is not repeated here.
Hydrogen sulfide has a rather full range of available inhalation health effect reference
values, as shown in Figure 2.13. Additional details are provided in Table 2.13 on the derivation
of the available reference values, including the basis, point of departure (POD), time scaling, and
uncertainty factors (UFs).
Emergency Response reference values (AEGLs and ERPGs) were developed for all three
severity categories (level 1 for mild transient effects; level 2 for irreversible effects or
impairment of ability to escape; and level 3 for potentially lethal effects). The 1-hr AEGL-2 and
AEGL-3 values are largely in agreement with the corresponding ERPG values, with the ERPG-3
value being slightly higher than the AEGL-3 value and near the same concentration as the
occupational IDLH value. The AEGL-3 and AEGL-2 values were scaled based on the equation
Cn x t = k, where n = 4.4, which was derived from experimental observations in lethality studies.
A higher value of n indicates a predominance of concentration rather than duration of exposure
in the C x t relationship, and is more commonly observed for irritant chemicals. The ERPG-1
and AEGL-1 values occur at much lower concentrations than the other severity level values, with
the ERPG-1 being at the lowest concentration of all of the Emergency Response values for H2S.
Both sets of level-1 values are for low-level, subjective symptoms; the AEGL-1 was based on
reported headaches in exercising asthmatics that were otherwise asymptomatic and the ERPG-1
was based on objectionable odor. The AEGL TSD also includes the estimation of a separate level
of odor awareness (LOA) of 0.01 ppm; the AEGL program bases all of its values on health effect
endpoints (NRC, 2001, 192042), whereas the ERPG program includes objectionable odors as a
criterion for level-1 effects.
The Occupational values typically provide less information on their derivation and are
likely derived by a weight of evidence approach, with no particular study identified as the basis
for the values. The NIOSH IDLH documentation (NIOSH, 1996, 192241) noted the following
evidence in human and occupational studies: 170 to 300 ppm as the maximum concentration
that can be endured for one hour without serious effects (Henderson and Haggard, 1943,
010318): olfactory fatigue noted with exposure to 100 ppm (Poda, 1966, 020850): and in a very
early study (Yant, 1930, 020748) concentrations of 50 to 100 ppm cause mild conjunctivitis and
respiratory irritation after one hour of exposure, 500 to 700 ppm may be dangerous with 30
minutes to one hour of exposure, exposure to 700 to 1,000 ppm results in unconsciousness,
September 2009 119
-------
cessation of respiration, and death, and exposure to 1,000 to 2,000 pm results in
unconsciousness, cessation of respiration, and death in a few minutes.
A large set of General Public reference values are available for H^S, including acute,
intermediate, and chronic values. Acute values include those developed by ATSDR and
California's Office of Environmental Health Hazard Assessment (OEHHA). An intermediate
ATSDR value, covering exposure durations between 15 days and 1 year, and chronic CA-REL
and EPA/IRIS RfC values were also developed for hydrogen sulfide; all three are adjusted using
time scaling to account for exposure occurring 6 hours per day and either 5 or 6 days per week.
The RfC and intermediate MRL reference values cite the same study (Brenneman et al., 2000,
012535) and use an equivalent point of departure. A WHO Air Quality Guideline (WHO, 2000,
180143) value for 24 hours is available, as is a 30-minute value for odor annoyance set at 7
|ig/m3 (not included in figure or table).
Overall, the coverage of reference values for hydrogen sulfide is more heavily weighted
to values available for acute exposures. As noted in a number of the supporting documents for
the reference values, it is likely the chronic effects are due to an accumulation of effects from
repeated short term increases in exposure (NIOSH, 1977, 192166)(CARB. 1984, 192168).
192168)(AIHA, 2002, 192061: ATSDR, 2006, 192117: NIOSH, 1996, 192241: U.S. EPA, 2003,
192242). Regardless, there are inhalation health effect reference values for hydrogen sulfide that
span all durations, including values for effects ranging from odor annoyance to lethality, and
coverage of all three types of reference values (Emergency Response, Occupational and General
Public).
September 2009 120
-------
Office of Research and Development
National Center tar Environmental An
Research Triangle Park, NC
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- 1.E+01
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O
0)
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O)
o
1.E+00
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Hydrogen Sulfide: Comparison of Reference Values
ACUTE
to
c
NIOSH-IDLH* 4
A ERPG-3 ^
_ ^'m..,^^
S~\ ^'^T^t^L.
O A ^^AEGL
SOSHA-CeifinV <> ซ
ACGIH-STEL* V AE
NIOSH-STEL* Q_
>^^^^^\_ .
Short Term
ซ
q
-3
-2
^^^^^ AEG L-1
A. ERPG-1 r] WHO Air Quality Guide
'
X CA-REL (Acute)
I - - - -X ATS
^ATJ
Subchronic
to
(0
I
(
ine
3DR-MRL(1-14d)
Chronic
to
<5
o
o
r-
)ACGIH-TLV (TW
)*
DR-MRL (15-365 d)m
-X i CA-REL i
1
' (Chronic) *
, EPA/IRIS RfC,
1,
1
1
AEGL-3 AEGL-1 a:
>>
A ERPG-3
0
D)
A ERPG-2 J;
E
A ERPG-1 UJ
O OSHA-xSTEl *
O OSHA-Ceiiing*
c
O ACGIH-STEL*
to
a.
HIOSII.-STI-:I.*
8
NIOSH-IDLH*
O ACGIH-TLV (TWA)*
D WHO Air Quality Guideline
X CA-REL (Acute) ^
.0
X ATSDR-MRL(1-14d) rf
"ro
X ATSDR-MRL (15-365 d) Jj
c
X CA-REL (Chronic) fj
D EPA/IRIS RfC
^4
0.1
10 100 1000 10000 100000 1000000
Duration (hours)
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.13. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Hydrogen Sulfide
September 2009
121
-------
Table 2.13. Details on derivation of the specific inhalation health effect reference values for hydrogen sulfide.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value
(mg/mj)
106
85
71
52
44
59
45
39
28
24
1.1
0.84
0.71
0.5
0.46
(ppm)
76
61
51
37.3
31.6
42.3
32.3
28
20.1
17.2
0.75
0.6
0.51
0.36
0.33
Health Effect
Lethality
(MacEwen and Vernot,
1972,041949)
Gross lung pathology,
minor perivascular
edema, increased
protein and LDH in lung
lavage fluid; pulmonary
alveolar marcrophage
viability
(Green etal., 1991,
021 128; Khan etal.,
1991.021080)
Headache in human
asthmatics
(Jappinen et al., 1990,
021082)
Point of Departure
504 ppm
(1h)
Highest
concentration
on causing no
death in rats
200 ppm
NEL
2 ppm
NR
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH = 3
Total UF = 10
i IP ?
UTA o
UFH = 3
Total UF = 1
Notes on
Derivation
Time scaling:
rn y t - k
where
n-4.4
Review
Status
Interim
(NAC/AEGL,
2002,
192202)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
122
-------
Reference Value
Type / Name
0)
c
o
Q.
41%
0)
rv
LL.
c
0)
O)
0)
LU
ERPG-3
ERPG-2
ERPG-1
Duration
1 hr
1 hr
1 hr
Reference Value
(mg/mj)
140
42
0.14
(ppm)
100
30
0.1
Health Effect
Unconsciousness and
decreased blood
pressure in humans
exposed to 230 ppm for
20 min; Conjunctivitis
and respiratory tract
irritation in humans
exposed to 200-300
ppm for 1 hr; LC50 of
712 ppm for 1 hr
exposure for animals
(CUT, 1983. 192169)
No lethality in rats
exposed to 45 ppm for
4 hr; unconsciousness
and cardiac
irregularities in rabbits
exposed to 72 ppm for
1.5 hr (Kosmider et al.,
1967, 061830; Rogers
and Ferin, 1981,
020893)
Distinct objectionable
odor
(Clayton and Clayton
FE, 1982.034134)
Point of Departure
71 2 ppm LC50
45 ppm NR
72 ppm
.03 ppm NR
Uncertainty
Factors
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(AIHA, 2002,
192061)
September 2009
123
-------
Reference Value
Type / Name
Occupational
ACGIH TLV-
TWA*
ACGIH TLV-
STEL*
OSHA
Ceiling*
OSHA-
STEL*
NIOSH
Ceiling*
NIOSH-
STEL*
NIOSH-
IDLH*
Duration
ShrTWA
15 min
Anytime
10 min'1
10 min
15 min
< 30 min
Reference Value
(mg/mj)
14
21
28
70
15
15
140
(ppm)
10
15
20
50
10
10
100
Health Effect
Sudden death, eye
irritation, neurasthenic
symptoms, CMS
damage (Ahlborg,
1951,061803; NIOSH,
1977, 192166)
NR
Acute inhalation toxicity
data in humans
(NIOSH, 1977, 192166)
Acute inhalation toxicity
data in humans (see
discussion)
Point of Departure
NR NR
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(OSHA,
2006,
192291)
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
192241)
210 minutes, once only if no other measured exposure occurs (OSHA, 2006).
September 2009
124
-------
Reference Value
Type / Name
General Public
WHO Air
Quality
Guideline
CA-REL
(Acute)
ATSDR-
MRL
(1-14 d)
ATSDR-
MRL
(15-365 d)
CA-REL
(Chronic)
Chronic RfC
(IRIS)
Duration
24 hr
1 hr
1 -14d
15d-
1 yr
Chronic
Chronic
Reference Value
(mg/mj)
0.15
0.04
0.1
0.02
0.01
2x10"J
(ppm)
0.11
0.03
0.07
0.02
7.2x10'J
1 .4 x 1 0"J
Health Effect
Eye irritation
Headache and nausea
in humans
(California state
department of public,
1969, 192292KCARB.
1984, 192168):
(Amoore, 1985,
192034; Reynolds and
Kamper, 1984. 192170)
Lung effects in humans
(Jappinen et al., 1990,
021082)
Olfactory neuron loss
and basal cell
hyperplasia
(Brenneman et al.,
2000,012535)
Histopathological
inflammatory changes
in nasal mucosa in
mice (CUT, 1983,
192169)
Nasal tract lesions in
rat (Brenneman et al.,
2000,012535)
Point of Departure
15mg/mJ LOAEL
0.03 ppm LOAEL
(Mid
point of
range
for
odor
detect!
on)
0.07 ppm LOAEL
0.46 ppm (10 NOAE
ppm x 6/24 x LHEC
7/7x0.184)
0.85 ppm (30.5 NOAE
ppm x 6/24 x LHEC
5/7x0.16)
0.64 mg/mj NOAE
(13.9mg/m3x LHEC
6/24 x 7/7 x
0.184)
Uncertainty
Factors
Total UF = 100
Total UF = 1
Total UF = 30
UFL = 3
UFH=3
UFDB = 3
Total UF = 30
UFA=3
UFH = 10
Total UF = 100
UFL=1
UFS = 3
UFA = 3
UFH = 10
Total UF = 300
UFA = 3
UFH = 10
UFS= 10
Notes on
Derivation
Odor LOAEL
endpoint
Adjusted for
6 hr/d; 7
d/wk; and
RGDR=0.184
Adjusted for
6 hr/d; 5
d/wk; and
RGDR=0.16
Adjusted for
6 hr/d; 7
d/wk;
RGDR=0.184
Review
Status
Final
(WHO, 2000,
180143)
Final
(OEHHA,
2008,
192243)
Final
(ATSDR,
2006,
192117)
Final
(OEHHA,
2000,
192244)
Final
(U.S. EPA,
2003,
192242)
September 2009
125
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Hydrgon sulfide (1991). In 2002 Emergency Response Planning
Guidelines (ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial
Hygiene Association. 192061
ATSDR. (2006). Toxicologial profile for hydrogen sulfide. Agency for Toxic Substances
and Disease Registry. Atlanta, GA. PB2007-100675. 192117
Ahlborg G. (1951). Hydrogen sulfide poisoning in shale oil industry. Arch Environ
Occup Health, 3: 247-266. 061803
Amoore JE. (1985). The perception of hydrogen sulfide odor in relation to setting an
ambient standard. CA Air Resources Board Contract. Berkeley, CA. ARE
Contract A4-046-33. http://www.arb.ca.gov/research/apr/past/a4-046-33.pdf
192034
Brenneman KA; James RA; Gross EA; Dorman DC. (2000). Olfactory neuron loss in
adult male CD rats following subchronic inhalation exposure to hydrogen sulfide.
Toxicol Pathol, 28: 326-333. 012535
CARB. (1984). Report of the committee regarding the review of the AAQS for hydrogen
sulfide. California Air Resources Board. Sacramento, CA. 192168
CUT. (1983). Ninety day vapor inhalation toxicity study of H2S in Fischer-344 rats.
Chemical Industry Institute of Toxicology. Research Triangle Park, NC. 192169
California state department of public health. (1969). Recommended ambient air quality
standards . California State Department of Public Health. Sacramento, CA.
192292
Clayton GD; Clayton FE eds. (1982). Patty's industrial Hygiene and toxicology Volume
2C, toxicology, with cumulative index for volume 2. 034134
Green FHY; Schurch S; De Sanctis GT; Wallace JA; Cheng S; Prior M. (1991). Effects
of hydrogen sulfide exposure on surface properties of lung surfactant. J Appl
Physiol, 70: 1943-1949. 021128
HSDB. (2006). Hydrogen sulfide. Retrieved 24-JUN-09, from
http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7HSDB. 192357
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Jappinen P; Vilkka V; Marttila O; Haahtela T. (1990). Exposure to hydrogen sulphide
and respiratory function. Occup Environ Med, 47: 824-828. 021082
Khan AA; Yong S; Prior MG; Lillie LE. (1991). Cytotoxic effects of hydrogen sulfide on
pulmonary alveolar macrophages in rats. J Toxicol Environ Health, 33: 57-64.
021080
September 2009 126
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Kosmider S; Rogala E; Pacholek A. (1967). Electrocardiographic and histochemical
studies of the heart muscle in acute experimental hydrogen sulfide poisoning.
Arch Immunol Ther Exp (Warsz), 15: 731-740. 061830
MacEwen JD; Vernot EH. (1972). Toxic hazards research unit annual report: 1972.
041949
NAC/AEGL. (2002). Hydrogen sulfide - interim acute exposure guideline levels
(AEGLs). National Advisory Committee for Acute Exposure Guideline Levels.
Washington, DC. 192202
NIOSH. (1977). Criteria for a recommended standard - occupational exposure to
hydrogen sulfide. National Institute for Occupational Safety and Health.
Cincinnati, OH. DHHS (NIOSH) Publication No. 77-158.
http://www.cdc.gov/Niosh/77-158.html. 192166
NIOSH. (1996). Hydrogen sulfide - IDLH documentation. Retrieved ll-MAY-09, from
http://www.cdc.gov/niosh/idlh/7783064.html. 192241
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safely and Health. 192177
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
OEHHA. (2000). Chronic toxicity summary - hydrogen sulfide. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192244
OEHHA. (2008). Acute toxicity summary - hydrogen sulfide. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192243
OSHA. (2006). Table Z-2 limits for air contaminants. Retrieved , from . 192291
Poda GA. (1966). Hydrogen sulfide can be handled safely. Arch Environ Occup Health,
12: 795-800. 020850
Reynolds RL; Kamper RL. (1984). Review of the state of California ambient air quality
standard for hydrogen sulfide . Lake County Air Quality Management District.
Lakeport, CA. 192170
Rogers RE; Ferin J. (1981). Effect of hydrogen sulfide on bacterial inactivation in the rat
lung. Arch Environ Occup Health, 36: 261-264. 020893
U.S. EPA. (2003). Toxicological review of hydrogen sulfide. National Center for
Environmental Assessment. Washington, DC. EPA/635/R-03/005.
http://www.epa.gov/ncea/iris/toxreviews/0061-tr.pdf. 192242
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health
Organization Regional Publications. Copenhagen. 91. 180143
Yant WP. (1930). Hydrogen sulphide in industry: occurrence, effects, and treatment. Am
J Public Health, 20: 598-608. 020748
September 2009 127
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2.14 Chemical-Specific Reference Values for Lewisite
LEWISITE L-l (CAS Reg. No. 541-25-3)
ClCH=CHAsCl2
LEWISITE L-2 (CAS Reg. No. 40334-69-8)
(C1CH=CH)2 AsCl
LEWISITE L-3 (CAS Reg. No. 40334-70-1)
(ClCH=CH)3As
Lewisite is the name applied to a group of organic arsenical compounds with vesicant
properties. The only purpose for the Lewisite compounds is as chemical weapon agents. Lewiste-
1 (L-l; 2-chlorovinyldichloroarsine) is the main product, with Lewisite-2 [L-2; bis-(2-
chlorovinyl)chloroarsine] and lewisite-3 [L-3; ^ra-(2-19 chlorovinyl)arsine] formed as
byproducts in the production of L-l. L-l can exist as a trans-isomer or a cis-isomer; in aqueous
solutions, the cis isomer undergoes photoconversion to the trans-isomer. Pure Lewisite is a
colorless, odorless oily liquid; however, the synthesized agent is an amber to dark brown liquid
with a geranium-like odor (Munro et al., 1999, 026185). Lewisite causes local corrosive damage
and may cause systemic poisoning after absorption through skin or mucous membranes.
Exposure to Lewisite causes almost immediate irritation and burning sensation of the eyes, skin,
upper respiratory tract, and lungs. Death may result from direct pulmonary damage or circulatory
failure due to fluid loss and arrhythmia. Death that occurs within 24 hours of exposure is likely
due to pulmonary damage (NAC/AEGL, 2007, 192203). A detailed description of Lewisite
toxicity as well as the physical nature of this group of chemical agents can be found in the AEGL
Technical Support Document (NAC/AEGL, 2007, 1922031 with additional details available in
the U.S. National Response Team Quick Reference Guide (NRT, 2008,192160), and are not
repeated here.
There are only two sources of health effect reference values for the chemical warfare
agent Lewisite: the National Advisory Committee for Acute Exposure Guideline Levels
(NAC/AEGL, 2007, 192203) and the Center for Disease Control and Prevention (CDC, 1988,
192173). Both organizations used the same limited set of data for deriving values for Lewisite.
The Emergency Response values for Lewisite are comprised of the AEGLs. AEGL-3
values for Lewisite were derived based on an estimate of the lethality at the one percent level
(LCoi) in dogs using one-third of the LC50 observations at 7.5-, 15-, 30-, 60-, and 240-minutes.
No data was available other than the unclassified report on dogs (Armstrong, 1923, 192132) used
in derivation of the AEGL-3 values, therefore, AEGL-2 values were derived by simply dividing
the AEGL-3 values by 3. No values for AEGL-1 were derived based on the lack of information.
A Federal Register Notice published by the Centers for Disease Control and Prevention
(CDC, 1988, 192173) provided final recommendations for Airborne Exposure Levels proposed
by the US Army for application to Lewisite as well as the agents Tabun (GA), Sarin (GB), VX,
and the Sulfur Mustards (H, HD, HT) for the protection of workers at chemical weapon
decommissioning facilities and the general population living near those facilities.
The Airborne Exposure Level values for Lewisite include a General Population Limit
(GPL), and a Worker Population Limit (WPL). No details were provided in the derivation of
these values and it is assumed that a weight of evidence approach was used in their derivation.
The resulting Lewisite values for both the AEGL and US Army are shown in Figure 2.14
and Table 2.14.
September 2009 128
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Office of Research and Development
National Center tar Environmental An
Research Triangle Park, NC
Lewisite: Comparison of Reference Values
1 E+01
1.E+00
n
~5>
d
o 1-E-ฐ1
0
S
'w
'i
3
1.E-02
IP fit
. c-uo
0
ACUTE
to
3
o
\I
CNI
AEG1
AEG1
O
Short Term
to
>l
m
0
Q
CO
.-3
.-2
CDC-GPL
(TWA)
CDC-WPL
(TWA)*
1 1 10
Subchronic
W)
>^
r~
_ _*
Chronic
to
<5
o
>-
o
h-
I
< AEGL-3 %
c
o
Q.
W)
01
a:
>,
o
c
01
E
0)
O AEGL-2 E
UJ
"TO
c
.0
0 CDC-WPL
(TWA)'
o
o
O
o
Z
3
CDC-GPL ^
(TWA) S
Q)
C
01
C3
100 1000 10000 100000 1000000
Duration (hours)
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.14. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Lewisite
September 2009
129
-------
Table 2.14. Details on derivation of the specific inhalation health effect reference values for lewisite.
Reference Value
Type / Name
Emergency Response2
AEGL-3
AEGL-2
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value1
(mg/mj)
3.9
1.4
0.74
0.21
0.11
0.65
0.23
0.12
0.035
0.018
(ppm)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
Health Effect
Lethality
(Armstrong,
1923, 192132)
Ocular effects
including
blinking and
lacrimation,
sneezing,
excessive
nasal secretion
(Armstrong,
1923. 192132)
Point of Departure
38.7 mg/mj LC01
14.0 mg/mj
7.4 mg/mj
2.1 mg/mj
1.1 mg/mj
1/3 of Estimated
AEGL-3 threshold
for
irreversible
effects
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH -3
Notes on
Derivation
Estimates of LC01
values were
derived by dividing
time-specific LC50
values by 3.
AEGL-3 values for
L-1 adopted as
AEGL-3 values for
mixture of L-1, L-2,
and L-3
1/3 of the AEGL-3
values for Lewisite-
1 ; considered
threshold for the
inability to escape
AEGL-2 values for
L-1 adopted as
AEGL-2 values for
mixture of L-1 , L-2,
and L-3
Review
Status
Final
(NAC/AEGL,
2007,
192203)
1 Values in units of parts per million (ppm) were not provided for this group of agents, but were only reported in units of mg/m3.
2 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
130
-------
Refe
Ty
rc
c
o
Q.
O
O
0
o
5
Q.
2
0)
c
0)
o
rence Value
pe / Name
CDC-WPL
(TWA)*
CDC-GPL
(TWA)
Duration
8 hours
72 Hours
Reference Value1
(mg/mj)
0.003
0.003
(ppm)
NR
NR
Health Effect
Immediate,
severe irritation
to respiratory
system, eyes
and skin
Point of Departure
NR NR
NR NR
Uncertainty
Factors
NR
NR
Notes on
Derivation
Review
Status
Final
(CDC, 1988,
192173)
September 2009
131
-------
REFERENCES
Armstrong GC. (1923). The toxicity of M-l by inhalation for dogs. In The toxicity, pathology,
chemistry, mode of action, penetration, and treatment for M-l and its mixtures with
arsenic trichloride (pp. .). Aberdeen Proving Ground, Maryland: Edgewood Arsenal.
192132
CDC. (1988). Final recommendations for protecting the health and safety against potential
adverse effects of long-term exposure to low doses of agents GA, GB, VX, Mustard
Agent (H, HD, T) and Lewisite (L). Fed Regist, 53: 8504-8507. 192173
Munro NB; Talmage SS; Griffin GD; Waters LC; Watson AP; King JF; Hauschild V. (1999).
The sources, fate, and toxicity of chemical warfare agent degradation products. Environ
Health Perspect, 107: 933-974. 026185
NAC/AEGL. (2007). Lewisite - interim acute exposure guideline levels (AEGLs). National
Advisory Committee for Acute Exposure Guideline Levels. Washington, DC. 192203
NRT. (2008). NRT quick reference guide: lewisite (L). Retrieved 15-JUN-09, from
http://www.nrt. org/Production/NRT/NRTWeb .nsf/All AttachmentsByTitle/A-
1009WMDQRGLewisite/$File/08Lewisite(L)QRG.pdf?OpenElement. 192160
September 2009 132
-------
2.15 Chemical-Specific Reference Values for Elemental Mercury Vapor
(CASRN 7439-97-6)
Elemental mercury vapor (Hgฐ) is a colorless, odorless gas generated from elemental
mercury or inorganic mercury compounds such as mercuric chloride (NAC/AEGL, 2008,
192208). Under ambient conditions, mercury is a silver-white, liquid metal. Metallic mercury is
non-flammable and only slightly volatile (vapor pressure of 0.002 mm). Elemental mercury
vapor is more soluble in plasma, whole blood, and hemoglobin than in distilled water, where it
dissolves only slightly (HSDB, 2005, 192178). Elemental mercury vapor is readily absorbed by
the lung, with up to 80% of inhaled Hgฐ absorbed by the lung, and can readily pass through
exposed skin. The central nervous system is the critical organ for mercury vapor exposure, with
the kidney being more affected by divalent mercury (Hg2+), which is produced by catalases in
red blood cells following exposure to Hgฐ. Acute inhalation exposure to mercury vapor may be
followed by chest pains, dyspnea (shortness of breath), coughing, hemoptysis (bloody sputum),
and sometimes interstitial pneumonitis (inflammation of the connective tissues in the lung)
leading to death. Short term exposures (1-30 days) have given rise to psychotic reactions
characterized by delerium, hallucinations, and suicidal tendencies. Occupational exposure has
resulted in irritation and excitability as the principal feature of a broad ranging functional
disturbance and has long been associated with the development of proteinuria (i.e., excess
protein in urine, indicating effects upon kidney function). More details on the chemical nature
and toxicity from exposure to Hgฐ are available from multiple sources (HSDB, 2005, 192178;
NAC/AEGL, 2008, 192208) and is not repeated here.
As noted in Figure 2.15, the occupational value for ceiling exposures from NIOSH and
for the time-weighted average occupational values (OSHA PEL, ACGffl TLV and NIOSH REL)
are much lower than the emergency response values (AEGL-2 and ERPG-2). This is due in large
part to the repeated exposures expected in the occupational setting and the persistence of
absorbed mercury to remain in the body, and for low-level effects to accumulate with repeated
exposures. In pharmacokinetic terms, the toxicity to Hgฐ is more related to the accumulation of
dose over time (i.e., area under the curve - AUC) than with peak exposures. The NIOSH IDLH
value is essentially equivalent to the 30 minute AEGL-3 value. It should also be noted that the
original documentation for the OSHA PEL cited it as a Ceiling value (OSHA, 1996, 192249) but
OSHA later clarified in a memo that the value was a time-weighted average (OSHA, 1996,
598129).
It is also important to note that neither AEGL-1 nor ERPG-1 was developed due to a lack
of effects at the severity level for Hgฐ or any warning properties (e.g., odor). The lack of AEGL-
1 or ERPG-1 values does not imply that no adverse health effects occur at exposure levels below
the AEGL-2 or ERPG-2, but based on the assumptions applied during their development, no
"irreversible adverse effects or impairment of ability to escape" would be expected to be seen
from a single, rare (i.e., "once-in-a-lifetime") exposure to Hgฐ at lower exposure levels.
The relatively more health protective nature of the California REL (CA-REL) values is
also readily apparent for both the acute and chronic durations. It should also be noted that all of
the chronic reference values use essentially the same data set and have values that are in strong
agreement with one another, with differences related more to derivation methods and application
of uncertainty factors, as shown in Table 2.15.
September 2009 133
-------
t na C n er
h Tr an ซi'arik
Elemental Mercury Vapor: Comparison of Reference Values
Updated: April 2010
1.E+02
1.E+01
E
g
6
c
o
O
O
Q.
(0
1.E-01
1.E-02
1.E-03
(1)
1.E-04
1.E-05
ACUTE
^AEGl
NIOSH-Ceiling*
O
c
X CA-REL (Acute)
XCA-R
Short Term
&
9
0
CO
-3
. . . . .
EL (8-hour)
Subchronic
ฃ
ro
0)
ฃ
r
Chronic
ro
01
0
S OSHA-PEL (TW
A)*
r
s
^NIOSH-REL (TWA)*
) ACGIH-TLV (TWA)*
fj WHO Air Quality Guideline
EPA-IRIS RfC ,
"" ATSDR-MRL(>1yr) "
,
C
, ,
ป '
;A-REL (Chronic
*
:
AEGL-3
o1 ซ>
0 AEGL-2 = c
A ERPG-3 g ซ
LLJ ^
A ERPG-2
O NIOSH-Ceiling*
* N1OSH-IDLH*
O
O ACGIH-TLV (TWA)*
0 NIOSH-REL (TWA)* Q
O OSHA-PEL (TWA)*
D WHO Air Quality Guideline
X CA-REL (Acute) o
3
X CA-REL (8-hour) ฃ
X ATSI)U-MUI.(>1yr)
X CA-REL (Chronic)
D EPA-IRIS RfC
0.1
10 100 1000 10000
Duration (hours)
100000 1000000
Figure 2.15. Comparison of Available Health Effect Reference Values for Inhalation Exposure to
Elemental Mercury Vapor (Hgฐ)
September 2009
134
-------
Table 2.15. Details on derivation of the specific inhalation health effect reference values for elemental mercury vapor.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
16
11
8.9
2.2
2.2
3.1
2.1
1.7
0.67
0.33
4.10E+00
(ppm)
2.0
1.3
1.1
2.7
2.7
0.38
0.26
0.21
0.087
0.040
5.00E-01
Health Effect
No lethality
(Livardjani et al.,
1991,019910)
Fetal toxicity and
developmental
effects in rats
(Morgan et al.,
2002, 192099)
Brain, kidney, and
lung damage
(Asano et al., 2000,
180282; Asheet
al., 1953, 019952;
Bellies etal., 1968,
180283; Etoetal.,
1999, 180285;
Kurisaki et al.,
1999, 192246;
Point of Departure
26.7 mg/mj No deaths;
(1 hour) lung
lesions
27.0 mg/m3 Lethality in
(2 hours) 20/32 rats
4 mg/mj NOAEL for
(2 hr/day, fetal
1 0 day toxicity
exposure)
NR NR
Uncertainty
Factors
Total UF = 3
UFA= 1
1 IF, , - ^
urn o
Total UF = 3
UFA-1
1 1C, - -2
urn o
NR
Notes on
Derivation
Cnxt = k
where
n *3. fnr
shorter and
n = 1 for
longer
durations
(NRC, 2001,
192042). The
8-hour value
was set equal
to the 4-hour
value.
Time scaling
using
rn y t - k
same as in
AEGL-3.
Review
Status
Proposed
(NAC/AEGL,
2008,
1 92208)
Final
(AIHA, 2002,
1 92096)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
135
-------
Ref
Occupational
erence Value
ype / Name
ERPG-2
ACGIH TLV-
TWA*
OSHA-PEL
(TWA)*
NIOSH-
Ceiling*
NIOSH-REL
(TWA)*
NIOSH-IDLH*
Duration
1 hr
8 hr TWA
8 hr TWA
10 min
10 hr
TWA
30 min
Reference Value
(mg/mj)
2.05E+00
2.50E-02
1.00E-01
1.00E-01
5.00E-02
1.00E+01
(ppm)
2.50E-01
3.05E-03
1 .22E-02
1 .22E-02
6.09E-03
1.22E+00
Health Effect
Livardjani et al.,
1991.019910:
Tennant et al.,
1961, 180242)
Lung lesions,
mercury
intoxication (Fraser
etal., 1934,
180287; Kishietal.,
1978,020079;
Livardjani et al.,
1991.019910)
Neurological effects
(Roelsetal., 1985,
180254)
NR
NR
NR
Damage to
kidneys, lungs, and
colon in animals
(Asheetal., 1953,
019952)
Point of Departure
NR NR
50 ug/g biological
creatinine threshold
for effects
NR NR
NR NR
NR NR
28.8 mg/mj NR
(4h)
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
Notes on
Derivation
Value
established in
1971.
Review
Status
Final
(ACGIH,
2007,
1 92024)
Final
(OSHA,
1996,
192249)
(OSHA,
1996,
598129)
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
1 92257)
September 2009
136
-------
Reference Value
Type / Name
O
^^^
.ฃ}
3
Q_
15
*-
c
0)
O
CA-REL
(Acute)
CA-REL (8-hr)
CA-REL
(Chronic)
ATSDR- MRL
Duration
1 hr
8hr
Chronic
Chronic
Reference Value
(mg/mj)
6.00E-04
6.00E-05
3.00E-05
2.00E-04
(ppm)
7.31E-05
7.31 E-06
3.66E-06
2.44E-05
Health Effect
CNS disturbances
in offspring of
exposed mice
(Danielsson et al.,
1993, 180106)
Neurotoxicity and
decreased EEC
activity in humans
(Faweretal., 1983,
019897; Ngim et
al., 1992.019916:
Piikivi, 1989,
019918: Piikivi and
Hanninen, 1989,
061838; Piikivi and
Tolonen, 1989,
019920)
Neurotoxicity and
decreased EEC
activity in humans
(Faweretal., 1983,
019897; Nairn et
al., 1992. 019916:
Piikivi, 1989,
019918: Piikivi and
Hanninen, 1989,
061838; Piikivi and
Tolonen, 1989,
019920)
Increased
Point of Departure
1 .8 mg/mj LOAEL
(1 hr/day,
gestational
days
11-14)
18ug/mJ LOAEI_HEc
(25 ug/m3 (8 hr/d,
x 5/7) 5 d/wk,
13.7-15.6
work years)
9 ug/mj LOAEI_HEc
(25 ug/m3 (8 hr/d,
x 10/20 5 d/wk,
x5/7) 13.7-15.6
work years)
0.0062 LOAEI_HEc
Uncertainty
Factors
Total UF = 3000
UFL = 10
UFA: 30
TK = 3
TD = 10
I LJ I U
UFH: 10
TK = 3
TD = 3
Total UF = 300
UFL=10
UFH: 30
TK = 3
TD - 10
I \i I U
Total UF = 300
UFL=10
UFH: 30
TK = 3
TD = 10
I LJ I U
Total UF = 30
Notes on
Derivation
POD
adjusted to
account for
5 d/wk
exposures.
Factor of 1 0
for UFH TD to
account for
susceptibility of
children.
Adjusted to
account for
5 d/wk
exposures
and
respiratory
rate of
workers over
general
population
(10/20m3).
Factor of 1 0
for UFH TD to
account for
susceptibility
of children.
Adjusted to
Review
Status
Final
(OEHHA,
2008,
1 92259)
Final
(OEHHA,
2008,
1 92259)
Final
September 2009
137
-------
Reference Value
Type / Name
(> 1yr)
WHO Air
Quality
Guideline*
Chronic RfC
(IRIS)
Duration
1 yr
Chronic
Reference Value
(mg/mj)
1.00E-03
3.00E-04
(ppm)
1 .22E-04
3.66E-05
Health Effect
frequency of
tremors
(Faweretal., 1983,
019897)
Renal effects
(WHO, 2000,
180143)
Hand tremor,
memory
disturbance,
autonomic
dysfunction in
humans
(Faweretal., 1983,
019897; Liang et
al., 1993, 192164:
Ngimet al., 1992,
019916)
Point of Departure
mg/mj (8 hr/d,
(0.026 5 d/wk,
mg/m3 13.7-15.6
x 8/24 work years)
x5/7)
1 5-30 LOAEL
ug/m3
0.009 LOAEI_HEc
mg/m3 (8 hr/d,
(0.026 5 d/wk,
mg/m3 13.7-15.6
x 1 0/20 work years)
x5/7)
Uncertainty
Factors
UFL = 3
UFA=1
UFH = 10
NR
Total UF = 30
UFH = 10
UFDB = 3
Notes on
Derivation
account for
5 d/wk and
8 hr/d work
schedule.
Adjusted to
account for
5 d/wk
exposures
and
respiratory
rate of
workers over
general
population
(10/20m3).
Review
Status
(ATSDR,
1999,
192112)
Final
(WHO, 2000,
180143)
Final
(U.S. EPA,
1995,
192216)
September 2009
138
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Mercury vapor . In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192096
ATSDR. (1999). Toxicological profile for mercury. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. NTIS PB/99/142416. 192112
Asano S; Eto K; Kurisaki E; Gungi H; Hiraiwa K; Sato M; Sato H; Hasuike M; Wakasa
H. (2000). Acute inorganic mercury vapor inhalation poisoning. Pathol Int, 50:
169-174. 180282
Ashe WF; Largent EJ; Dutra FR; Hubbard DM; Blackstone M. (1953). Behavior of
mercury in the animal organism following inhalation. Arch Environ Occup
Health, 7: 19-43. 019952
Beliles RP; Clark RS; Yuile CL. (1968). The effects of exposure to mercury vapor on
behavior of rats. Toxicol Appl Pharmacol, 12: 15-21. 180283
Danielsson BR; Fredriksson A; Dahlgren L; Gardlund AT; Olsson L; Dencker L; Archer
T. (1993). Behavioural effects of prenatal metallic mercury inhalation exposure in
rats. Neurotoxicol Teratol, 15: 391-396. 180106
Eto K; Takizawa Y; Akagi H; Haraguchi K; Asano S; Takahata N; Tokunaga H. (1999).
Differential diagnosis between organic and inorganic mercury poisoning in
human cases - the pathological point of view. Toxicol Pathol, 27: 664-671.
180285
Fawer RF; De Ribaupierre Y; Guillemin MP; Berode M; Lob M. (1983). Measurement of
hand tremor induced by industrial exposure to metallic mercury. Occup Environ
Med, 40: 204-208. 019897
Fraser AM; Melville KI; Stehle RL. (1934). Mercury-laden air: the toxic concentration,
the proportion absorbed, and the urinary excretion. , 16: 77-91. 180287
HSDB. (2005). Mercury, elemental - entry on the hazardous substance data bank.
Retrieved 09-JUN-09, from http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/f?./temp/~ZVshAe: 1. 192178
Kishi R; Hashimoto K; Shimizu S; Kobayashi M. (1978). Behavioral changes and
mercury concentrations in tissues of rats exposed to mercury vapor. Toxicol Appl
Pharmacol, 46: 555-566. 020079
Kurisaki E; Sato M; Asano S; Gunji H; Mochizuki M; Odajima H; Wakasa H; Satoh H;
Watanabe C; Hiraiwa K. (1999). Insufficient metallothionein synthesis in the lung
and kidney in human acute inorganic mercury poisoning. Eisei Kagaku, 45: 309-
317. 192246
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Liang YX; Sun RK; Sun Y; Chen ZQ; Li LH. (1993). Psychological effects of low
exposure to mercury vapor: application of a computer-administered
neurobehavioral evaluation system. Environ Res, 60: 320-327. 192164
Livardjani F; Ledig M; Kopp P; Dahlet M; Leroy M; Jaeger A. (1991). Lung and blood
superoxide dismutase activity in mercury vapor exposed rats: effect of N-
acetylcysteine treatment. Toxicology, 66: 289-295. 019910
Morgan DL; Chanda SM; Price HC; Fernando R; Liu J; Brambila E; OConnor RW;
Beliles RP; Barone Jr S. (2002). Disposition of inhaled mercury vapor in pregnant
rats: maternal toxicity and effects on developmental outcome. Toxicol Sci, 66:
261-273. 192099
NAC/AEGL. (2008). Mercury - proposed acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192208
NIOSH. (1996). Mercury (organo) alkyl compounds - IDLH documentation. Retrieved
ll-JUN-09, from http://www.cdc.gov/niosh/idlh/merc-hg.html. 192257
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
Ngim CH; Foo SC; Boey KW; Jeyaratnam J. (1992). Chronic neurobehavioural effects of
elemental mercury in dentists. Occup Environ Med, 49: 782-790. 019916
OEHHA. (2008). Acute and chronic toxicity summary - mercury. Office of
Environmental Health Hazard Assessment, California EPA. Sacramento, CA.
192259
OSHA. (1996). Mercury vapor. Retrieved ll-JUN-09, from
http://www.osha.gov/SLTC/healthguidelines/mercuryvapor/recognition.html.
192249
OSHA (1996). Mercury vapor. Retrieved ll-JUN-09, from
http://www.osha.gov/SLTC/healthguidelines/mercuryvapor/recognition.html.
192249 OSHA (1996). PEL (permissible exposure limit) for inorganic mercury is
a time-weighted average, not a ceiling (Sept 3, 1996), with June 2, 2005
correction. Retrieved 06-APR-10, from
http://www.osha.gov/pls/oshaweb/owadisp. show_document?p_table=INTERPRE
TATIONS&p_id=23866. 598129Piikivi L. (1989). Cardiovascular reflexes and
low long-term exposure to mercury vapour. Int Arch Occup Environ Health, 61:
391-395.019918
Piikivi L; Hanninen H. (1989). Subjective symptoms and psychological performance of
chlorine-alkali workers. Scand J Work Environ Health, 15: 69-74. 061838
Piikivi L; Tolonen U. (1989). EEG findings in chlor-alkali workers subjected to low long
term exposure to mercury vapour. Occup Environ Med, 46: 370-375. 019920
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Roels H; Gennart JP; Lauwerys R; Bucket JP; Malchaire J; Bernard A. (1985).
Surveillance of workers exposed to mercury vapor: validation of a previously
proposed biological threshold limit value for mercury concentration in urine. Am
J Ind Med, 7: 45-71. 180254
Tennant R; Johnston HJ; Wells JB. (1961). Acute bilateral pneumonitis associated with
the inhalation of mercury vapor. Conn Med, 25: 106-109. 180242
U.S. EPA. (1995). Mercury, elemental. Retrieved 10-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0370.htm. 192216
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health
Organization Regional Publications. Copenhagen. 91. 180143
September 2009 141
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2.16 Chemical- Specific Reference Values for Methylene Chloride
(CASRN 75-09-2)
Methylene chloride (MeCl, dichloromethane; CH^Cb) is a colorless liquid with a mild
sweet odor. It is a halogenated hydrocarbon that does not occur naturally in the environment. It
is used as a solvent in paint strippers and removers; as a propellant in aerosols; as an extraction
solvent for food (e.g., decaffeination of coffee); as a process solvent in the manufacture of
drugs, pharmaceuticals, and film coatings; as a metal cleaning and finishing solvent; in
electronics manufacturing; and as an agent in urethane foam blowing. MeCl is a high-
production volume chemical with U.S. production of 229,000 tons in 1988 and total production
in Western Europe ranging from 331,500 tons in 1986 to 254,200 tons in 1991. Due to its rapid
evaporation, the primary route of exposure to MeCl is through the inhalation of contaminated
ambient air, which at low concentrations may cause dizziness, nausea, and a decreased reaction
time, while at higher concentrations may lead to unconsciousness and death. MeCl forms
carbon dioxide as a metabolic byproduct leading to formation of carboxyhemoglobin (COHb).
COHb formation is one of the primary mechanisms for toxicity at high exposure concentrations
to MeCl. IARC determined that MeCl is "possibly carcinogenic to humans (Group 2BJ"
(IARC, 1999, 192122). Additional information on the nature of MeCl and detailed summaries
of health effects can be found in the AEGL TSD (NAC/AEGL, 2008, 192207). the ATSDR
Toxicological Profile (ATSDR, 2000, 192113). the OEHHA REL documentation (OEHHA,
2000, 192225: OEHHA, 2008, 192263), from IARC (1999, 192122), and other sources.
Methylene chloride has a relatively broad range of inhalation health effect
reference values across all types of values (Emergency Response, Occupational, and
General Public), levels of severity and durations. The available reference values are
arrayed graphically in Figure 2.16. Details available on the derivation of these values,
including key effects, critical studies, time scaling and other adjustments, and application
of uncertainty factors (UFs) are shown in Table 2.16.
Emergency Response reference values (AEGLs and ERPGs) were developed for all
three severity categories (level 1 for mild transient effects; level 2 for irreversible effects or
impairment of ability to escape; and level 3 for potentially lethal effects). At all severity levels,
the ERPG values are lower than the corresponding AEGL values, with the largest difference
occurring between the AEGL-3 and ERPG-3. Time scaling was applied to all AEGL values
using a PBPK model, while the basis varied between severity levels and time intervals. The
AEGL-3 reference values for all time intervals were scaled based on the maximum MeCl
concentration in the brain except for the 8-hr value, which was based on COHb formation. The
10- and 30-minute AEGL-2 values were scaled based on the maximum MeCl concentration in
the brain, while the 1-, 4-, and 8-hr values were based on COHb formation. The AEGL-1
reference values for all time intervals were scaled based on maximum MeCl concentration in
the brain, and values for 4- and 8-hours were not derived as the derived values would be at
concentrations greater than the corresponding AEGL-2 values.
Several Occupational reference values for MeCl are available for time-weighted
averages (TWAs) as well as short-term excursions. The NIOSH IDLH value was based on the
results of a study in which exposure to 2,300 ppm of methylene chloride for 1-hr produced no
feeling of dizziness in human subjects (Sax, 1975, 018750). Additional Occupational values
include OSHA STEL and PEL values and an ACGffl TLV TWA reference value. The
September 2009 142
-------
Occupational TWA values - the OSHA PEL and ACGIH TLV - are in close accord with one
another, with the OSHA value being at a two times lower concentration than the ACGIH TLV.
The ACGIH-TLV provides some details on derivation, with a statement that "a safety factor of
four should be adequate to account for interindividual differences in sensitivity and the fact
that a LOAEL rather than a NOAEL was identified in a human study" (2007, 192024).
A wide range of General Public reference values are available for MeCl. ATSDR has
developed MRLs for all of their duration categories (acute, 1-14 days; intermediate, 15 days to
1 year; and chronic, greater than 1 year). The acute (1-14 day) MRL was based on neurological
effects (decreased critical flicker frequency and auditory vigilance performance), whereas both
the intermediate (15 days to 1 year) and chronic (one year or longer) duration MRLs were both
based on effects on the liver. Time scaling was applied to the acute MRL by using a PBPK
model, with uncertainty factors applied for inter-individual variability (UFH =10) and for use
of a LOAEL (UFL = 10) in a human study. Essentially no adjustments were made to the
NOAEL of 25 ppm from a rat study as the basis for the intermediate MRL; the ratio between
blood:gas partition coefficients for rats and humans was set equal to one, and the exposure was
continuous for 14 weeks; only uncertainty factors were applied. Adjustments for exposure
schedule only were made to the chronic rat study used as the basis for the chronic MRL. Acute
and chronic CA-REL reference values, as well as a World Health Organization (WHO) value
are available for methylene chloride.
In looking across the available inhalation health effect reference values for MeCl, a
consistent stair-step decrease in concentration as duration of exposure increases can be seen
across the General Public values. There is strong concordance between the 24-hour WHO value
and the acute ATSRD MRL, and between the chronic MRL and the chronic CA-REL.
It is important to note that the AEGL-1 values stop at one hour. This may be important
if exposures at or near the 1-hour AEGL persist for longer durations, as the steep concentration
by time (C x t) relationship for AEGL-2 levels transect the extrapolation of the AEGL-1 to
longer durations. The AEGL-2 effect for MeCl is based on a clinically significant increase in
the potential to trigger angina (chest pain) in patients with coronary artery disease when blood
COHb levels reach 4% (NAC/AEGL, 2008, 1922071 which is more severe than the slight CNS
effects (light-headedness and difficulty with enunciation) for the AEGL-1.
September 2009 143
-------
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* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.16. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Methylene Chloride
September 2009
144
-------
Table 2.16. Details on derivation of the specific inhalation health effect reference values for methylene chloride.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
ERPG-2
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
1 hr
Reference Value
(mg/mj)
4.2x10"
3x10"
2.4x10"
1.7x10"
7.4x10J
6x10J
4.2x10J
2x10J
350
210
1 x10J
810
710
NR
NR
1 .4 x 1 0"
2.6x10J
(ppm)
12,000
8,500
6,900
4,900
2,100
1.7x10J
1 .2 x 1 0J
580
101
60.5
288
230
204
NR
NR
4x10J
750
Health Effect
CNS effects,
maximum
additional COHb
level of 1 5 % in
humans
(Haskell Laboratory
, 1982, 192293;
NAC/AEGL, 2008,
192294)
Absence of CNS
effects, maximum
additional COHb
level of 4 % in
humans
(NAC/AEGL, 2008,
1 92294; Winneke,
1974, 180142)
Absence of slight
CNS effects
(Stewart et a I.,
1972.029071)
Absence of lethality
or life-threatening
health effects
Dizziness, sedation
effects
(Stewart et a I.,
1972,029071)
Point of Departure
3.01 mM Maximum
in blood target MeCI
level
(PBPK)
0.137
mM in
blood
0.063
mM in
blood
NR NR
NR NR
Uncertainty
Factors
Total UF = 1
UFA - 1
Total UF = 1
UFH - 1
Total UF = 3
UhH - o
NR
NR
Notes on
Derivation
Time scaling based
on maximum MeCI
concentration in
brain (10 min, 30
min, 1 h, and 4 h
values) or COHb
formation (8 h
values) using
PBPK-model
Time scaling based
on maximum MeCI
concentration in
brain using PBPK-
model
Review
Status
Interim
(NAC/AEGL,
2008,
192207)
Final
(AIHA, 2002,
192066)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
145
-------
Refe
11
Occupational
rence Value
pe / Name
ERPG-1
ACGIH TLV-
TWA*
NIOSH-
IDLH*
OSHA-PEL
(TWA)*
OSHA-
STEL*
Duration
1 hr
8 hr TWA
30 min
8 hr TWA
< 15 min
Reference Value
(mg/mj)
1042
174
8x10J
87
434
(ppm)
300
50
2.3x10J
25
125
Health Effect
NR^
CMS Depression in
humans
(Putzetal., 1979,
023137; Winneke,
1974. 180142)
Acute inhalation
toxicity in humans
(Sax, 1975,
018750)
NR
Point of Departure
NR NR
200 ppm LOAEL
2,300 Absence of
ppm effects
(1hr)
NR NR
Uncertainty
Factors
NR
Total UF = 4
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
1 92024)
Final
(NIOSH,
1996,
1 92295)
Final
(OSHA,
2006,
1 92276)
Reference pending
September 2009
146
-------
Reference Value
Type / Name
General Public
WHO Air
Quality
Guideline
CA-REL
(Acute)
ATSDR-MRL
(1-14d)
ATSDR-MRL
(15- 365 d)
ATSDR-MRL
(> iyr)
CA-REL
(Chronic)
Duration
24 hr
1 week
TWA
1 hour
1 -14d
15d-
1 yr
Chronic
Chronic
Reference Value
(mg/mj)
3
0.45
14
2.1
1.04
1.04
0.4
(ppm)
0.86
0.13
4
0.6
0.3
0.3
0.12
Health Effect
Production of
COHb
Impaired
performance on
dual-task and
auditory vigilance
tests
(Putzetal., 1979,
023137)
Neurological effects
in humans
(Reitzetal., 1997,
192184; Winneke,
1974, 180142)
Hepatic effects in
rats
(Haunetal., 1972,
029036)
Liver
histopathology in
female rats
(Nitschke et al.,
1988,029244)
Elevated
carboxyhemoglobin
levels (>2%)
(DiVincenzo and
Kaplan, 1981,
029026)
Point of Departure
NR NR
240 ppm LOAEL
(195 ppm
observed
at 90
min)
60 ppm LOAELADJ
(300 ppm
observed
LOAEL)
25 ppm NOAELHEc
(25 x 1 .0)
8.92 ppm NOAELHEc
(50 ppm
x 6/24 x
5/7 x 1 .0)
14 ppm LOAEL
(40 ppm
x10/20x
5/7)
Uncertainty
Factors
NR
Total UF = 60
UFL = 6
UFA=1
UFH = 10
Total UF= 100
UFL = 10
UFH = 10
Total UF= 100
UFL = 3
UFA = 3
UFH = 10
Total UF = 30
UFA = 3
UFH = 10
Total UF= 100
UFL= 10
UFA= 1
UFH = 10
Notes on
Derivation
1-h concentration
extrapolated from
90 minute duration
using Cnxt = k
where n=2
LOAEL adjusted for
24- hr exposure
scenario using
Reitzetal. (1997,
192184)PBPK
model
Blood:gas partition
coefficient for rat of
19.4 and for human
of 8.94; ratio = 1,
was used
Blood:gas partition
ratio = 1 (See
above); adjusted
for6 hr/day, 5
day/week
Adjusted for 8
hr/day; 5 day/week
Review
Status
Final
(WHO, 2000,
180143)
Final
(OEHHA,
2008,
1 92263)
Final
(ATSDR,
2000,
192113)
Final
(OEHHA,
2000,
1 92225)
September 2009
147
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Methylene chloride (1996). In 2002 Emergency Response Planning
Guidelines (ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial
Hygiene Association. 192066
ATSDR. (2000). Toxicological profile for methylene chloride. Agency for Toxic
Substances and Disease Registry. Atlanta, GA. NTIS PB/2000/108026. 192113
DiVincenzo GD; Kaplan CJ. (1981). Uptake, metabolism, and elimination of methylene
chloride vapor by humans. Toxicol Appl Pharmacol, 59: 130-140. 029026
Haskell Laboratory. (1982). Inhalation approximate lethal concentration of methylene
chloride . Haskell Laboratory. Newark, DE. 88-920009163. 192293
Haun CC; VernotEH; Darmer KI Jr; Diamond SS. (1972). Continuous animal exposure
to low levels of dichloromethane. 029036
IARC. (1999). Dichloromethane. In Re-evaluation of some organic chemicals, hydrazine
and hydrogen peroxide (pp. 251-315). Lyon, France: International Agency for
Research on Cancer. 192122
NAC/AEGL. (2008). Carbon monoxide - final acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192294
NAC/AEGL. (2008). Methylene chloride - interim acute exposure guideline levels
(AEGLs). National Advisory Committee for Acute Exposure Guideline Levels.
Washington, DC. 192207
NIOSH. (1996). Methylene chloride - IDLH documentation. Retrieved ll-JUN-09, from
http://www.cdc.gov/niosh/idlh/75092.html. 192295
Nitschke KD; Burek JD; BellTJ; Kociba RJ; Rampy LW; McKenna MJ. (1988).
Methylene chloride: a 2-year inhalation toxicity and oncogenicity study in rats.
Toxicol Sci, 11: 48-59. 029244
OEHHA. (2000). Chronic toxicity summary - methylene chloride. Office of
Environmental Health Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_final.pdf#page=38
9. 192225
OEHHA. (2008). Acute toxicity summary - methylene chloride. Office of Environmental
Health Hazard Assessment, California EPA. Sacramento, CA. 192263
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
Putz VR; Johnson BL; Setzer JV. (1979). A comparative study of the effects of carbon
monoxide and methylene chloride on human performance. J Environ Pathol
Toxicol Oncol, 2: 97-112. 023137
September 2009 148
-------
Reitz RH; Hays SM; Gargas ML. (1997). Addressing priority data needs for methylene
chloride with physiologically based pharmacokinetic modeling. Halogenated
Solvents Industry Alliance. Washington, DC. 192184
Sax NI. (1975). Dangerous properties of industrial materials. 018750
Stewart RD; Fisher TN; Hosko MJ; Peterson JE; Baretta ED; Dodd HC. (1972).
Experimental human exposure to methylene chloride. Arch Environ Occup
Health, 25: 342-348. 029071
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health
Organization Regional Publications. Copenhagen. 91. 180143
Winneke G. (1974). Behavioral effects of methylene chloride and carbon monoxide as
assessed by sensory and psychomotor performance. In Behavioral toxicology,
Early detection of occupational hazards (pp. 130-144). Washington, D.C.: U.S.
Department of Health, Education, and Welfare. 180142
September 2009 149
-------
2.17 Chemical-Specific Reference Values for Perchloroethylene
(CASRN 127-18-4)
Perchloroethylene (Perc, ethylene tetrachloride, tetrachloroethylene; C2CU) is a
synthetic liquid chemical with a sharp, sweet odor that is detectable at concentrations of 1 ppm
or greater. It is a volatile compound and thus the potential for exposure is greatest through the
inhalation of contaminated air, which can result in dizziness, loss of consciousness, confusion,
nausea, and death. Skin irritation may also occur with repeated exposure. Perchloroethylene is
used primarily as a chemical intermediate; other uses include as a metal cleaner, a degreasing
agent, and a solvent in dry cleaning. IARC found that perchloroethylene "isprobably
carcinogenic to humans (Group 2A)" (IARC, 1995, 192123). Additional information on the
nature of perchloroethylene and detailed summaries of health effects can be found in the AEGL
TSD (NAC/AEGL, 2001, 192200). the ATSDR Toxicological Profile (1997, 192111). the
OEHHAREL documentation (CARB, 1991, 192266: CARB, 1991, 192269: OEHHA, 2008,
192171), as well as other sources and is not repeated here.
Perchloroethylene has a relatively complete set of inhalation health effect reference
values, as shown in Figure 2.17. Additional details are provided in Table 2.17 on the derivation
of the available reference values, including the basis, point of departure (POD), time scaling,
and uncertainty factors (UFs).
Emergency Response reference values (AEGLs and ERPGs) were developed for all three
severity categories (level 1 for mild transient effects; level 2 for irreversible effects or
impairment of ability to escape; and level 3 for potentially lethal effects). The ERPG-3 and
ERPG-1 values are higher than the corresponding 1-hour AEGL values, while the ERPG-2 value
is slightly lower than the AEGL-2. All three AEGL values have time scaling applied following a
Cn x t = k relationship with n = 2. Perchloroethylene AEGL-1 values were based on a human
study in which exposure to 75-80 ppm for 1-4 minutes caused slight eye irritation (Stewart et al.,
1961, 094466), with the 10- and 30-minute values set equal to each other. In the case of the
AEGL-2 value, the 10- and 30-minute values were set equal to the 1-hour value as a human
study showed that exposure to 600 ppm for 10 minutes caused significant health effects
including irritation, dizziness, and numbness (Rowe et al., 1952, 058210). The 10-minute AEGL-
3 value was set equal to the 30-minute AEGL-3 because it was considered inappropriate to scale
from a time period of 4 hours to 10 minutes.
There is a relatively complete set of Occupational reference values available for
perchloroethylene, including values developed by NIOSH, OSHA, ACGIH, and Australia's
National Industrial Chemicals Notification and Assessment Scheme (NICNAS). The NIOSH
IDLH Occupational values are derived by a weight of evidence (WOE) approach and no
particular study was identified as the basis for the values. It has been reported that exposure to
2,000 ppm of perchloroethylene caused slight narcosis in 5 minutes; 9,301,185 ppm caused
irritation of the eyes and throat, and marked dizziness after 2 minutes; 1,000 ppm caused slight
drunkenness, but no narcosis after 95 minutes; 513,690 ppm caused eye, throat, and nose
irritation, dizziness, loss of inhibition, and some incoordination after 10 minutes; 500 ppm for
2 hours caused slight discomfort; 206,356 ppm for 2 hours caused headache, burning of the eyes,
sinus congestion, impaired coordination, and nausea; 206,235 ppm for 20 to 30 minutes caused
eye irritation, sinus congestion, dizziness, and sleepiness; and 106 ppm caused only slight eye
irritation (Negherbon, 1959, 192186: Rowe et al., 1952, 058210). As shown in Figure 2.17, the
September 2009 150
-------
Australian STEL (not labeled) and TWA values are slightly higher than the ACGIH STEL and
TLV values but lower than the OSHA values.
ATSDR and the California OEHHA have published both acute and chronic General
Public reference values for perchloroethylene. Time scaling was applied to the acute CA-REL
value using a Cn x t = k relationship, where n = 2. The acute ATSDR MRL value was adjusted to
extrapolate from intermittent exposure to exposure occurring 4 hours per day, while the chronic
MRL was adjusted to account for exposure occurring 8 hours per day, 5 days per week. Contrary
to most OEHHA-derived values, there is a lack of supporting information on the derivation of
the chronic CA-REL value for perchloroethylene.
There is good coverage across types of inhalation health effect reference values, severity
of effects, and durations for perchloroethylene. All of the General Public reference values are
below the Emergency Response and Occupational values, as would be expected, and the values
decrease in exposure concentration with increasing duration. Cancer is mentioned as a concern
for this compound for all of the Occupational reference values as well as in the chronic CA-REL.
September 2009 151
-------
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National Center tar Environmental An
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100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.17. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Perchloroethylene
September 2009
152
-------
Table 2.17. Details on derivation of the specific inhalation health effect reference values for perchloroethylene.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
ERPG-2
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
1 hr
Reference Value
(mg/mj)
4700
4700
3300
1600
1200
1600
1600
1600
810
550
340
340
240
120
81
6781
1356
(ppm)
690
690
490
240
170
330
330
230
120
81
50
50
35
18
12
1000
200
Health Effect
Lethality
(Friberg et al.,
1953,058329;
NTP, 1986,
192272)
Ataxia
(Goldberg et al.,
1964,058035)
Eye irritation
(Rowe et al.,
1952,058210)
Lethality
(Carpenter, 1937,
058185; Hake
and Stewart,
1977.058147:
Rowe et al.,
1952.058210)
CMS effects
(Rowe et al.,
1952,058210)
Point of Departure
2450 ppm for NOAEL
4 hrs (mice),
2445 ppm for
4 hrs (rats)
11 50 ppm NOAEL
(4 hr/d, 5
d/weekfor2
weeks
106 ppm NR
(1 hr)
1000 ppm Reportedly
well
tolerated in
humans
NR NR
Uncertainty
Factors
Total UF = 10
UFA = 3
UFH - 3
Total UF = 10
UFA = 3
UFH - 3
Total UF = 3
UFH = 3
NR
NR
Notes on
Derivation
Time scaling:
Cn i.
xt - k
where n - 2;
10 min equal to
30-min value
Time scaling:
C xt - k where
n - 2; 10 and 30
min values equal
to 1-hr value
Time scaling:
C xt - k where
n - 2;
10 min equal to
30-min value
Review
Status
Interim
(NAC/AEGL,
2001,
192200)
Final
(AIHA, 2002,
192079)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
153
-------
Refe
Ty
Occupational
rence Value
pe / Name
ERPG-1
ACGIH TLV-
TWA*
ACGIH TLV-
STEL*
OSHA-PEL
(TWA)*
OSHA-
Ceiling*
NIOSH-IDLH
(<30min)*
NIOSH-STEL
(TWA)*
Duration
1 hr
8 hour
TWA
15 min
ShrTWA
Any 5
min
period
< 30 min
15 min
Reference Value
(mg/mj)
678
170
680
680
1360
1020
678
(ppm)
100
25
101
100
200
150
100
Health Effect
Detectable odor
(American
Industrial
Hygiene
Association,
1989, 192018:
Rowe et al.,
1952,058210:
Stewart et al.,
1970,003141)
Headache,
dizziness,
sleepiness,
incoordination
(ATSDR, 1997,
192111: Hake
and Stewart,
1977,058147:
Rowe et al.,
1952,058210:
Stewart et al.,
1970,003141)
Anesthetic-like
effects
(ACGIH, 2007,
192024)
NR
Acute inhalation
toxicity data in
humans
Point of Departure
100 ppm NR
(1 hr)
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
(OSHA,
2006,
1 92276)
Final
(NIOSH,
1996,
192296)
September 2009
154
-------
Refe
Ty
rence Value
pe / Name
Australian
TWA*
Australian
STEL*
Duration
ShrTWA
15 min
Reference Value
(mg/mj)
340
1020
(ppm)
50
150
Health Effect
NR
Point of Departure
NR NR
Uncertainty
Factors
NR
Notes on
Derivation
Review
Status
Final
(NICNAS,
2006,
1 92040)
September 2009
155
-------
Reference Value
Type / Name
General Public
CA-REL
(Acute)
ATSDR-
MRL
(1-14 d)
CA-REL
(Chronic)
ATSDR-
MRL
(> iyr)
Duration
1 hr
1 -14
days
Chronic
Chronic
Reference Value
(mg/mj)
20
1.36
0.035
0.27
(ppm)
2.9
0.2
5 x 1 0"J
0.04
Health Effect
CMS effects,
headache, eye,
nose and throat
irritation
(Stewart et al.,
1970,003141)
Increase in VEP
latencies in
humans
(Altmann et al.,
1992. 180098)
Kidney;
alimentary
system (liver);
Cancer
Increased
reaction time in
humans
(Ferroni et al.,
1992,066305)
Point of Departure
1200mg/mJ LOAELADj
(700 mg/m3
observed)
1 .67 ppm NOAEL
(10 ppm
x 4/24)
NR NR
3.57 ppm LOAEL
(15 ppm
x8/24
x5/7)
Uncertainty
Factors
Total UF = 60
UFL = 6
UFH = 10
Total = 10
UFH=10
NR
Total UF =
100
UFL = 10
UFH= 10
Notes on
Derivation
LOAEL based on
3 hr exposure
extrapolated to
1 hr exposure via
Cn xt = k where n
= 2
Adjusted for
4 hr/d to
extrapolate from
intermittent
exposure
Adjusted for
8 hr/day;
5 d/week
Review
Status
Final
(OEHHA,
2008,
192171)
Final
(ATSDR,
1997,
192111)
Final
(GARB,
1991,
1 92269)
Final
(ATSDR,
1997,
192111)
September 2009
156
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of Governmental
Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Perchloroethylene (1997). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene Association.
192079
ATSDR. (1997). Toxicological profile for tetrachloroethylene. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. NTIS PB/98/101181/AS. 192111
Altmann L; Wiegand H; Bottger A. (1992). Neurobehavioral and neurophysical outcomes of
acute repeated perchloroethylene exposure., 41: 269-279. 180098
American Industrial Hygiene Association (AIHA). (1989). Odor thresholds for chemicals with
established occupational health standards. Fairfax, VA: AIHA. 192018
CARB. (1991). Proposed identification of perchloroethylene as a toxic air contaminant.
California Air Resources Board. Sacramento,
CA.http://www.arb.ca.gov/toxics/id/summary/perchlor.pdf. 192269
CARB. (1991). Technical support document, part B: proposed identification of
perchloroethylene as a toxic air contaminant. California Air Resources Board.
Sacramento, CA.http://www.arb.ca.gov/toxics/id/summary/perchlorethylene_b.pdf.
192266
Carpenter CP. (1937). The chronic toxicity of tetrachlorethylene. , 19: 323-336. 058185
Ferroni C; Selis L; Mutti A; Folli D; Bergamaschi E; Franchini I. (1992). Neurobehavioral and
neuroendocrine effects of occupational exposure to perchloroethylene. Neurotoxicology,
13:243-247.066305
Friberg L; Kylin B; Nystrom A. (1953). Toxicities of trichlorethylene and tetrachloroethylene
and Fujiwara's pyridine-alkali reaction. , 9: 303-312. 058329
Goldberg ME; Johnson HE; Pozzani UC; Smyth HF Jr. (1964). Effect of repeated inhalation of
vapors of industrial solvents on animal behavior: I evaluation of nine solvent vapors on
pole-climb performance in rats. J Occup Environ Hyg, 25: 369-375. 058035
Hake CL; Stewart RD. (1977). Human exposure to tetrachloroethylene: inhalation and skin
contact. Environ Health Perspect, 21: 231-238. 058147
IARC. (1995). Tetrachloroethylene. In Dry cleaning, some chlorinated solvents and other
industrial chemicals (pp. 159-221). Lyon, France: International Agency for Research on
Cancer. 192123
NAC/AEGL. (2001). Tetrachloroethylene - interim acute exposure guideline levies (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington, DC.
192200
September 2009 157
-------
NICNAS. (2006). Priority existing chemical assessment report no. 28 formaldehyde. National
Industrial Chemicals Notification and Assessment Scheme. Sydney,
Australia.http://www.nicnas.gov.au/Publications/CAR/PEC/PEC28/PEC_28_Full_Report
_PDF.pdf. 192040
NIOSH. (1996). Tetrachloroethylene - IDLH documentation. Retrieved ll-JUN-09, from
http://www.cdc.gov/niosh/idlh/127184.html. 192296
NTP. (1986). Toxicology and carcinogenesis studies of tetrachloroethylene (perchloroethylene)
in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program.
Research Triangle Park, NC. 86-2567. 192272
Negherbon WO. (1959). Insecticides, a compendium. In Handbook of toxicology (pp. 737).
Wright Patterson Air Force Base, OH: U.S. Air Force, Air Research and Development
Command. 192186
OEHHA. (2008). Acute toxicity summary - perchloroethylene. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD2_fmal.pdf#page=228.
192171
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
Rowe VK; McCollister DD; Spencer HC; Adams EM; Irish DD. (1952). Vapor toxicity of
tetrachloroethylene for laboratory animals and human subjects. Arch Environ Occup
Health, 5: 566-579. 058210
Stewart RD; Baretta ED; Dodd HC; Torkelson TR. (1970). Experimental human exposure to
tetrachloroethylene. Arch Environ Occup Health, 20: 224-229. 003141
Stewart RD; Gay HH; Erley DS; Hake CL; Schaffer AW. (1961). Human exposure to
tetrachloroethylene vapor. Arch Environ Occup Health, 2: 516-522. 094466
September 2009 158
-------
2.18 Chemical-Specific Reference Values for Phosgene (CASRN 75-44-5)
Phosgene (Agent CG; COCb) is a colorless gas at ambient temperature and pressure,
with an odor reminiscent of newly-mown hay, reportedly detectable at 0.9 ppm (Amoore and
Hautala, 1983, 028918). Phosgene was formerly used as a chemical warfare agent. It is
manufactured from a reaction of carbon monoxide and chlorine gas in the presence of activated
charcoal, and is used in the production of dyestuffs, isocyanates, carbonic acid esters
(polycarbonates), acid chlorides, insecticides, and pharmaceutical chemicals. Manufacture of
phosgene is approximately 1 million tons per year in the United States. Additional details on the
chemical nature of phosgene and its potential for toxic effects are covered more fully elsewhere
(AfflA, 2002, 192095: NRC, 2002, 192139: U.S. EPA, 2005, ). The remainder of this discussion
focuses on the generally available inhalation health effect reference values for phosgene.
Inhalation health effect reference values for phosgene are displayed graphically in
Figure 2.18. Details available on the derivation of these values, including key effects, studies,
adjustments, and uncertainty factors (UFs) are shown in Table 2.18.
Emergency Response values have been developed for AEGLs and ERPGs at severity
levels 2 (irreversible adverse effects or impairment of escape) and 3 (threshold for lethality), but
no level 1 values were derived due to the lack of warning properties (e.g., odor detection) or mild
effect levels at exposures below the AEGL-2 or ERPG-2. The one-hour AEGL values at both
severity levels are in fairly close agreement with the corresponding ERPGs, even though the
documents cite different key studies as the basis for the derived values. The time scaling used in
the AEGLs applied a duration slope factor of one (n = 1 in the Cn x t equation). This is in
keeping with the observations from the seminal work that led to Haber's "rule" (Haber, 1924,
059334) and verified in more recent studies (Zwart et al., 1990, 021153: ten Berge et al., 1986,
025664).
The NIOSH Occupational values are derived by a weight of evidence approach and no
particular study was identified as the basis for the values. A concentration of 5 ppm for 30
minutes was reported to be probably lethal for exposures of 30 minutes (Jacobs, 1967,192298).
Gross et al. (1965, 061915) indicated that exposure to concentrations as low as 0.5 ppm for
2 hours caused definite pathological changes in the lungs of rats; the investigators believed some
abnormalities were present 3 months after rats had been exposed at 2 ppm for 80 minutes. An
IDLH of 2 ppm is used for phosgene to prevent irreversible adverse health effects. It has been
calculated that based on acute toxicity data in humans, the lethal dose for a 30 minute exposure
would be about 17 ppm (Diller, 1978, 061910). It has also been stated that exposure to 25 ppm for
30 to 60 minutes is dangerous and that brief exposure to 50 ppm may be rapidly fatal (Henderson
and Haggard, 1943, 010318). Studies also report that 5 ppm is probably lethal for a 30 minute
exposure (Jacobs, 1967,192298). The occupational time-weighted average (TWA) reference
values - the ACGffl TLV, NIOSH REL, and OSHA PEL - all being identical to one another,
with the ACGIH documentation (2007, 192024) providing the most background on the basis for
the value.
The General Public reference values include both an acute (1-hour) CA-REL and a
chronic EPA/IRIS RfC. The acute CA-REL value is based on a NOAEL for histological changes
in the lung and did not apply any adjustments other than those implied in the uncertainty factors.
The chronic RfC did apply the Regional gas dose ratio (RGDR) used in derivation of an HEC for
gases [details available in the Toxicological Review for Phosgene (U.S. EPA, 2005, 192297)], as
September 2009 159
-------
well as adjustments for the 6 hour per day exposure schedule used with the experimental animals
(rats) in the key studies (Kodavanti et al., 1997, 083623: Belgrade et al., 1995, 180126).
There is fair coverage across types of inhalation health effect reference values, severity of
effects, and durations for phosgene. The greatest gap is for reference values for the general
public in the short-term and subchronic durations.
September 2009 160
-------
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Phosgene: Comparison of Reference Values
ACUTE
to
0
I
A *
^V^ CM
o o^v
NIOSH-Ceiling* ^\_
O AEGL
X CA-REL (Acute)
Short Term
to
eg
9
0
CO
-3
-2
Subchronic
W)
CO
r!
r
i
Chronic
to
1
o
OSHA-PEL (TVW
S ACGIH-TLV(TV\
NIOSH-REL (TW
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0 AEGL-3
O AEGL-2
o
A ERPG-3 a
-------
Table 2.18. Details on derivation of the specific inhalation health effect reference values for phosgene.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
15
6.2
3.1
0.82
0.34
2.5
2.5
1.2
0.33
0.16
4
(ppm)
3.6
1.5
0.75
0.2
0.09
0.6
0.6
0.3
0.08
0.04
1
Health Effect
Lethality
(Zwartetal., 1990,
021153)
Chemical pneumonia
(Gross etal., 1965,
061915)
Pulmonary edema
and lethality
(Dilleretal., 1985,
059296; Rinehart and
Hatch, 1964,061919)
Point of Departure
36 ppm LC01
15 ppm LC0i
2 ppm NR
(90 min)
1 ppm NR
Uncertainty
Factors
Total UF = 10
UFA - 3
UFH-3
Total UF = 10
UFA- 3
UFH = 3
NR
Notes on
Derivation
Time scaling:
Cn A 1
x t - K
where n = 1 .
Haber's Law
(C* X t ~ V\ \A/flซI
originally
derived from
phosgene data
(Haber, 1924,
059334).
Review
Status
Final
(NAC/AEGL,
2002,
192299)
Final
(AIHA, 2002,
192095)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
162
-------
Refe
"
rence Value
pe / Name
ERPG-2
Duration
1 hr
Reference Value
(mg/mj)
0.81
(ppm)
0.2
Health Effect
Pulmonary effects
(Currie etal., 1985,
059289; Frosolono
and Currie, 1985,
059308; Gross etal.,
1965,061915:
Mautone et al., 1985,
059413; Rinehart and
Hatch, 1964,061919)
Point of Departure
0.2 ppm NR
Uncertainty
Factors
NR
Notes on
Derivation
Review
Status
September 2009
163
-------
Reference Value
Type / Name
Occupational
ACGIH TLV-
TWA*
OSHA-PEL
(TWA)*
NIOSH-
Ceiling*
NIOSH-
IDLH*
NIOSH-REL
(TWA)*
Duration
Any
8 hr TWA
15 min
< 30 min
10 hr
TWA
Reference Value
(mg/mj)
0.4
0.4
0.8
8.1
0.4
(ppm)
0.1
0.1
0.2
2
0.1
Health Effect
Pulmonary irritation
(Cameron et al.,
1942, 059386; Diller,
1978,061910:
Henschlerand Laux,
1960,059321;
Underbill, 1920,
059389)
NR
NR
Acute inhalation
toxicity data in
humans
NR
Point of Departure
NR NR
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
Notes on
Derivation
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
1 92300)
Final
(NIOSH,
2006,
192177)
September 2009
164
-------
Reference Value
Type / Name
5
3
0_
15
0)
c
0)
O
CA-REL
(Acute)
Chronic RfC
(IRIS)
Duration
1 hr
8hr
Reference Value
(mg/mj)
4x10'J
3x10'"
(ppm)
1 x10'J
7.4x10'ฐ
Health Effect
Histologic changes in
lungs in rats
(Dilleretal., 1985,
059296)
Increase in lung
displacement volume,
chronic lung damage,
impaired resistance
to bacterial infection
in rats
(Kodavanti et a I.,
1997.083623:
Belgrade etal., 1995,
180126)
Point of Departure
0.1 ppm NOAEL
(1 hr)
LOAEL
(4hr)
0.03 mg/mj BMCL10
(HEC)
(0.73 mg/m
x6/24
x-| 51)
Uncertainty
Factors
Total UF = 100
UFA = 10
UFH = 10
Total UF = 300
UFH = 10
UFA = 3
UFS=3
UFL = 3
Notes on
Derivation
Adjustments for
duration
(6hr/day) and
differences in
animal to
human
respiratory
systems
(RGDR=1.51)
Review
Status
Final
(OEHHA,
2008,
192301)
Final
(U.S. EPA,
2005,
192297)
September 2009
165
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Phosgene (2002). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192095
Amoore JE; Hautala E. (1983). Odor as an aid to chemical safety: odor thresholds
compared with threshold limit values and volatilities for 214 industrial chemicals
in air and water dilution. J Appl Toxicol, 3: 272-290. 028918
Cameron GR; Courtice FC; Foss GL. (1942). Effect of exposing different animals to a
low concentration of phosgene 1:1,000,000 4 mg/m3 for 5 hours (third report).
059386
Currie WD; Pratt PC; Frosolono MF. (1985). Response of pulmonary energy metabolism
to phosgene. Toxicol Ind Health, 1: 17-27. 059289
Diller WF. (1978). Medical phosgene problems and their possible solution. J Occup
Environ Med, 20: 189-193. 061910
Diller WF; Bruch J; Dehnen W. (1985). Pulmonary changes in the rat following low
phosgene exposure. Arch Toxicol, 57: 184-190. 059296
Frosolono MF; Currie WD. (1985). Response of the pulmonary surfactant system to
phosgene. Toxicol Ind Health, 1: 29-35. 059308
Gross P; Rinehart WE; Hatch T. (1965). Chronic pneumonitis caused by phosgene: an
experimental study. Arch Environ Occup Health, 10: 768-775. 061915
Haber F. (1924). Zur Geschichte des Gaskrieges [On the history of the gas war]. 059334
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Henschler D; Laux W. (1960). Zur Spezifitat einer Toleranzsteigerung bei wiederholter
Einatmung von Lungenodem erzeugenden Gasen [On the specificity of a
tolerance increase by repeated inhalation of pulmonary edema-producing gases].
Naunyn Schmiedebergs Arch Pharmacol, 239: 433-441. 059321
Jacobs MB. (1967). The analytical toxicology of industrial inorganic poisons. In The
analytical toxicology of industrial inorganic poisons (pp. 648-649). New York,
NY: Interscience Publishers. 192298
Kodavanti UP; Costa DL; Giri SN; StarcherB; Hatch GE. (1997). Pulmonary structural
and extracellular matrix alterations in Fischer 344 rats following subchronic
phosgene exposure. Toxicol Sci, 37: 54-63. 083623
Mautone AJ; Katz Z; Scarpelli EM. (1985). Acute responses to phosgene inhalation and
selected corrective measures (including surfactant). Toxicol Ind Health, 1: 37-57.
059413
September 2009 166
-------
NAC/AEGL. (2002). Phosgene - final acute exposure guideline levels (AEGLs). National
Advisory Committee for Acute Exposure Guideline Levels. Washington, DC.
192299
NIOSH. (1996). Phosgene - IDLH documentation. Retrieved ll-JUN-09, from
http://www.cdc.gov/niosh/idlh/75445.html. 192300
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safety and Health. 192177
NRC. (2002). Phosgene. In Acute exposure guideline levies for selected airborne
chemicals (pp. 15-70). Washington, DC: National Academies Press. 192139
OEHHA. (2008). Acute toxicity summary - phosgene. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento, CA. 192301
Rinehart WE; Hatch T. (1964). Concentration-time product (CT) as an expression of dose
in sublethal exposures to phosgene. J Occup Environ Hyg, 25: 545-553. 061919
Selgrade MK; Gilmore MI; Yang YG. (1995). Pulmonary host defenses and resistance to
infection following subchronic exposure to phosgene. Inhal Toxicol, 7: 1257-
1268. 180126
U.S. EPA. (2005). Toxicol ogical review of phosgene. National Center for Environmental
Assessment. Washington, DC. EPA/635/R-06/001.
http://www.epa.gov/ncea/iris/toxreviews/0487-tr.pdf. 192297
Underhill FP. (1920). The lethal war gases: physiology and experimental treatment, an
investigation by the section on intermediary metabolism of the medical division
of the Chemical Warfare Service at Yale University under the direction of Frank
P Underhill. 059389
Zwart A; Arts JHE; Klokman-Houweling JM; Schoen ED. (1990). Determination of
concentration-time-mortality relationships to replace LC50 values. Inhal Toxicol,
2: 105-117.021153
ten Berge WF; Zwart A; Appelman LM. (1986). Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J Hazard Mater,
13:301-309.025664
September 2009 167
-------
2.19 Chemical-Specific Reference Values for Phosphine
(CASRN 7803-51-2)
Phosphine (PH3) is a colorless gas used as a fumigant against insects and rodents
in stored grain (NAC/AEGL, 2008, 192209). Paper sachets containing aluminum
phosphide are added to grain and the grain is then sealed. The aluminum phosphide reacts
with moisture in the grain to produce the phosphine gas. Phosphine is also used as a
doping agent to treat silicon crystals in the semiconductor industry and is a byproduct of
metallurgical reactions. Pure phosphine is odorless at concentrations up to 200 ppm.
Additional, chemical-specific details and toxicological summaries are available from
other sources (AfflA, 2002, 192088: NAC/AEGL, 2008, 192209: OEHHA, 2002,
192227: U.S. EPA, 1995, 192217) and are not repeated here.
Inhalation health effect reference values for phosphine are displayed graphically
in Figure 2.19. Details available on the derivation of these values, including key effects,
studies, adjustments, and uncertainty factors (UFs) are shown in Table 2.19.
The Emergency Response reference values (AEGLs and ERPGs) for phosphine
were derived for severity level 2 (irreversible effects or impairment of escape) and level 3
(severe effects with potential lethality), but not for level 1 as the toxicity at lower
concentrations could not be characterized and awareness (e.g., odor detection) occurs at
concentrations above the AEGL-2 and ERPG-2. Chemical-specific data on lethality were
available to allow calculation of the duration slope factor [value of n in the Cn x t formula
(ten Berge et al., 1986, 025664)] of n = 1 which was used in extrapolating from 6-hour
data for both the AEGL-2 and AEGL-3. The 30-minute values were adopted as the 10-
minute values as cited in the AEGL SOPs (NRC, 2001, 192042). where extrapolations
across durations from observations greater than or equal to four hours to shorter durations
is limited to the 30-minute value to avoid extending the extrapolation too far. The AEGL-
3 and ERPG-3 are in close accord with one another; however, the 1-hour AEGL-2 is a
factor of four higher than the corresponding ERPG-2.
Most of the Occupational reference values are based on a single occupational
study (Jones et al., 1964, 095137), with several studies providing additional support
(Henderson and Haggard, 1943, 010318: Misra et al., 1988, 066895). Details on the
derivation for all of the occupational values are sparse, and indications are that a weight
of evidence (WOE) approach was used in arriving at the published values, with the best
documentation provided for the NIOSHIDLH and ACGIH TLV values (ACGffl, 2007,
192024: NIOSH, 1996, 192302). The ACGffl TLV documentation noted that although
the values are protective of gastrointestinal, respiratory and central nervous system
effects, that there is some potential for chronic phosphorus poisoning from phosphine
exposure (ACGIH, 2007, 192024)
The chronic General Public reference values - the Chronic CA-REL and
EPA/IRIS RfC - both used the same key study (Barbosa et al., 1994, 062969) and
performed similar adjustments to arrive at the human equivalent concentration (HEC).
Differences in the calculated values were due to variation in the uncertainty factors
applied and to methodological differences (i.e., the point in the process where unit
conversions and rounding of values were applied). No reference values for less than
September 2009 168
-------
lifetime exposure durations were developed for exposure of the general population to
phosphine.
Overall coverage for the types of exposures anticipated for phosphine is good.
Addition of an acute and other less-than-lifetime general public reference values would
help to complete the collection of available inhalation health effect reference values for
phosphine.
September 2009 169
-------
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h-
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loSHA-PEL (TWA)*
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O OSHA-STEL*
0 ACGIH-STEL*
15
c
NIOSH-IDLH*
O ACGIH-TLV (TWA)*
O NIOSH-REL (TWA)*
O OSHAPRI j
X CA-REL (Chronic)
D tiWMIIItlfC
0.1
10 100 1000
Duration (hours)
CA-REL (Chronic)
10000 100000 1000000
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.19. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Phosphine
September 2009
170
-------
Table 2.19. Details on derivation of the specific inhalation health effect reference values for phosphine.
Reference Value
Type / Name
0)
0
o
(A
0
(ฃ
>,
0
c
0)
s>
0)
E
LU
AEGL-3
AEGL-2
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
10
10
5.1
1.3
0.63
5.6
5.6
2.8
0.71
0.35
7
(ppm)
7.2
7.2
3.6
0.90
0.45
4.0
4.0
2.0
0.50
0.25
5
Health Effect
Lethality
(Newton, 1991,
iQ?rnQi
Red mucoid nasal
discharge seen in rats
from exposure for 6 hr
(Newton et al., 1993,
180123)
4-hr lethal
concentration in
animals between 1 1
and 40 ppm; no lethality
in rats exposed
repeatedly to 5 ppm
(Muller, 1940,
1 93931 KKIigerman et
al., 1994, 180291:
Muthu et al., 1980,
066897; Newton etal.,
1993, 180123: Waritz
and Brown, 1975,
065707)
Point of Departure
18 ppm NR
(6 hrs)
10 ppm NR
(6 hrs)
11 -40 ppm WOE
Uncertainty
Factors
Total UF = 30
UFA = 3
i IF, , - m
Total UF = 30
UFA = 3
UFH-10
NR
Notes on
Derivation
Time Scaling:
Cnxt = k
derived
empirically from
rat lethality
data. 10 min
values adopted
from ^D
minutes as per
SOPs
(NRC 2001
192042)
Weight of
evidence
approach;
details on
derivation not
provided
Review
Status
Final
(NAC/AEG
I PDDR
192209)
Final
(AIHA,
2002,
192088)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
171
-------
Refe
"
C
0
'^
rt
u.
O
0
O
"o
5 n
a.
rence Value
pe / Name
ERPG-2
ACGIH TLV-
TWA*
ACGIH TLV-
STEL*
OSHA-PEL
(TWA)*
NIOSH-REL
(TWA)*
NIOSH-IDLH
(<30 min)*
NIOSH-
STEL*
CA-REL
(Chronic)
Duration
1 hr
ShrTWA
15 min
ShrTWA
10hr
TWA
30 min
15 min
Chronic
Reference Value
(mg/mj)
0.7
0.42
1.4
0.4
0.4
70
1
8x10-"
(ppm)
0.5
0.3
1
0.3
0.3
50
1
6x10'"
Health Effect
Reversible, mild-to-
moderate respiratory
and CNS effects in
humans exposed to 1
ppm for 1-3 hrs
(Misra et al., 1988,
066895)
Respiratory,
gastrointestinal, and
CNS symptoms
(Jones etal., 1964,
095137)
Systemic toxicity
Acute inhalation toxicity
in humans
(Jones etal., 1964,
095137)
Decreased body
weight, increase in
relative organ weights,
increase in micronuclei
in mice
Point of Departure
1 ppm LOAEL
(<2-3 hrs)
2 ppm NOAEL
(10 mins)
NR NR
NR NR
NR NR
NR NR
1 ,000 ppm LCLo
(5 min)
NR NR
0.1 78 ppm NOAELHE
c
(1 ppm
x6/24
x5/7)
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
NR
Total UF = 300
UFS = 3
UFA=10
UFH=10
Notes on
Derivation
Adjustments for
6 hr/day, and
5 day/wk
animal
exposure
Review
Status
Final
(ACGIH,
2007,
192024)
Final
(OSHA,
1989,
192303)
Final
(NIOSH,
2006,
192177)
Final
(NIOSH,
1996,
192302)
Final
(OEHHA,
2002,
192227)
September 2009
172
-------
Reference Value
Type / Name
Chronic RfC
(IRIS)
Duration
Chronic
Reference Value
(mg/mj)
3x10'4
(ppm)
2x10'4
Health Effect
(Barbosa etal., 1994,
062969)
Point of Departure
0.25 mg/mj NOAELHE
c
(1 .4 mg/m
x6/24
x5/7)
Uncertainty
Factors
Total UF = 1000
UFH = 10
UFS=10
UFD=3
UFA = 3
Notes on
Derivation
schedule
Review
Status
Final
(U.S. EPA,
1995,
192217)
September 2009
173
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Phosphine (1999). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192088
Barbosa A; Rosinova E; Dempsey J; Bonin AM. (1994). Determination of genotoxic and
other effects in mice following short term repeated-dose and subchronic
inhalation exposure to phosphine. Environ Mol Mutagen, 24: 81-88. 062969
Henderson Y; Haggard HW. (1943). Noxious gases and the principles of respiration
influencing their action. 010318
Jones AT; Jones RC; Longley EO. (1964). Environmental and clinical aspects of bulk
wheat fumigation with aluminum phosphide. J Occup Environ Hyg, 25: 376-379.
095137
Kligerman AD; Bishop JB; Erexson GL; Price HC; O'Connor RW; Morgan DL; Zeiger
E. (1994). Cytogenetic and germ cell effects of phosphine inhalation by rodents:
II. Subacute exposures to rats and mice. Environ Mol Mutagen, 24: 301-306.
180291
Misra UK; Bhargava SK; Nag D; Kidwai MM; Lai MM. (1988). Occupational phosphine
exposure in Indian workers. Toxicol Lett, 42: 257-263. 066895
Muller W. (1940). Concerning phosphine poisoning (animal trials), part I. acute and
subacute poisoning. , 195: 184-193. 193931
Muthu M; Krishnakumari MK; Muralidhara V; Majumder SK. (1980). A study on the
acute inhalation toxicity of phosphine to albino rats. , 24: 404-410. 066897
NAC/AEGL. (2008). Phosphine and selected metal phosphides - interim acute exposure
guideline levels (AEGLs). National Advisory Committee for Acute Exposure
Guideline Levels. Washington, DC. 192209
NIOSH. (1996). Phosphine - IDLH documentation. Retrieved ll-JUN-09, from
http://www.cdc.gov/niosh/idlh/7803512.html. 192302
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safely and Health. 192177
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
Newton PE. (1991). Acute inhalation exposures of rats to phosphine. Biology Dynamics,
Inc.. East Millstone, NJ. 90-8271. 192039
Newton PE; Schroeder RE; Sullivan JB; Busey WM; Banas DA. (1993). Inhalation
toxicity of phosphine in the rat: acute, subchronic, and developmental. Inhal
Toxicol, 5: 223-239. 180123
September 2009 174
-------
OEHHA. (2002). Chronic toxicity summary - phosphine. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento,
CA.http://www.oehha.ca.gov/air/hot_spots/2008/AppendixD3_fmal.pdf#page=43
7. 192227
OSHA. (1989). Phosphine, H.S. no. 1321. Fed Regist, 54: 2563-2564. 192303
U.S. EPA. (1995). Phosphine. Retrieved 10-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0090.htm. 192217
Waritz RS; Brown RM. (1975). Acute and subacute inhalation toxicities of phosphine,
phenylphosphine and triphenylphosphine. J Occup Environ Hyg, 36: 452-458.
065707
ten Berge WF; Zwart A; Appelman LM. (1986). Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J Hazard Mater,
13:301-309.025664
September 2009 175
-------
2.20. Chemical-Specific Reference Values for Sarin (GB) (CASRN 107-44-8)
Sarin (Agent GB; isopropyl methylphosphonofluoridate) is one of several
organophosphate (OP) nerve agents that have been specifically designed and formulated to cause
death, major injuries, or incapacitation to enemy forces in wartime. The term "nerve" agent
refers to its anti-cholinesterase properties. Nerve agents are particularly effective in a military
sense because of their potency. Detailed descriptions of nerve agent toxicity as well as the
physical nature of this chemical agent can be found in the AEGL Technical Support Document
(NAC/AEGL, 2003, 192304). and is not repeated here.
There are only two sources of health effect reference values for the chemical warfare
agent GB: the National Advisory Committee for Acute Exposure Guideline Levels (2003,
192304) and the Centers for Disease Control and Prevention (CDC, 2003, 192190). Both
organizations used the same limited set of data for deriving values for GB. The dataset for GB
was the most robust of all of the nerve agents, therefore, the relative potency of GB was used to
derive values for the nerve agents Tabun (GA) and Agent VX.
AEGL-3 values for GB were derived based on a calculated lethality at the one percent
level (LCoi) in female rats using observations at 10-, 30-, 60-, 240-, and 360-minutes (see
Table 2.20). Studies showing miosis (pinpoint pupils) in female rats (Mioduszewski et al., 2000,
192305) and visual acuity effects in humans (Baker and Sedgewick, 1996, 180099) were the
basis for the AEGL-1 and AEGL-2, respectively. For the AEGL-1, a UFA of 1 was used based on
the observation that miosis response to GB vapors is similar across mammalian species.
A series of Federal Register Notices published by the Centers for Disease Control and
Prevention (CDC, 1988, 192173: CDC, 2002, 192175: CDC, 2003, 192190: CDC, 2004,
192193) document the Airborne Exposure Levels designed for application to the agents Tabun
(GA), Sarin (GB), VX, Mustard Agent (H, HD, T) and Lewisite (L) for the protection of workers
at chemical weapon decommissioning facilities and the general population living near those
facilities. The first set of recommendations (CDC, 1988, 192173) were applied for over 14 years,
and over the intervening years there was no apparent impact to human health; however, to be
consistent with more recent risk assessment practice a reevaluation using the conventional risk
assessment methods for inhalation exposures developed by the Environmental Protection Agency
(U.S. EPA, 1994, 192307) was conducted and a set of revised values were published in the
Federal Register (CDC, 2003, 192190) for the agents GA, GB and VX.
The Airborne Exposure Level values for GB included a General Population Limit (GPL),
a Worker Population Limit (WPL), as well as a Short-term Exposure Limit (STEL) and
Immediately Dangerous to Life and Health (IDLH) occupational values (CDC, 2003, 192190).
The GPL and WPL values for GB were based on exposures of 20 minutes per day for 4 days per
week and were adjusted to derive a Lowest Observable Adverse Effect Level Human Equivalent
Concentration (LOAELHEc) for 24 hour and 8 hour time weighted averages (TWAs),
respectively. Fewer details were provided regarding the derivation of the STEL and IDLH
values, and it is assumed that a weight of evidence approach was used in their derivation.
The resulting values for both the AEGL and CDC are shown in Figure 2.20 and
Table 2.20. More recent research by the U.S. Army provides additional data that may lead to
further revision of both sets of values (Hulet et al., 2006, 192144).
September 2009 176
-------
(sftl-
\^HlU-S lbn.rdlTri.ngl. Park, NC
Sarin (Agent GB): Comparison of Reference Values
1 E+01
1.E+00
1.E-01
co~*
P
-5 1.E-02
E.
.
<2 1.E-03 -
O
O
C 1.E-04-
n
(0
1.E-05
1.E-06
1C fi7
.c-07 -
0
ACUTE
ซ
1
*^V^
-o q^>^
o
~
O ^AEGL
^^N.
^^^^W
^^>^ AEGL
CDC-STEL*
c
Short Term
ซ
1
O
(O
-3
_2
-1
Subchronic
C
to
re
HI
ri
Chronic
tn
re
-------
Table 2.20. Details on derivation of the specific inhalation health effect reference values for Sarin (GB).
Reference Value
Type / Name
Emergency Response1
Occupatio
nal
AEGL-3
AEGL-2
AEGL-1
CDC-WPL
(TWA)*
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
8 hr TWA
Reference Value
(mg/m3)
0.38
0.19
0.13
0.070
0.051
0.087
0.050
0.035
0.017
0.013
0.0069
0.0040
0.0028
0.0014
0.0010
3x10'D
(ppm)
0.064
0.032
0.022
0.012
0.0087
0.015
0.0085
0.0060
0.0029
0.0022
1.2x10'J
6.8X10"1
4.8X10"1
2.4x10'"
1 .7 x 1 0'"
5.2x10'D
Health Effect
Lethality
(Mioduszewski et
al.,2000, 192305;
Mioduszewski et
al., 2001, 192306:
Mioduszewski et
al., 2002, 180121)
Miosis, dyspnea,
photophobia,
inhibition of RBC-
ChE seen in
humans (Baker and
Sedgewick, 1996,
180099)
Induction of miosis
in female rat
(Mioduszewski et
al., 2002, 192189)
Miosis (McKee and
Woolcott, 1949,
192172)
Point of Departure
1 1 .54 mg/mj LC01
5.84 mg/mj
4.01 mg/mj
2.09 mg/mj
1 .76 mg/mj
(6hr)
0.5 mg/mj Sub-
(30 min) clinical
effects
Range of EC50
0.01-0.48
mg/m3 at
10 min,
60 min,
and 240 min
0.06 mg/mj LOAELHEC
(20 min/d, for
4 days)
Uncertainty
Factors
Total UF = 30
UFA - o
UFH- 10
Total UF = 10
UFA - 1
UFH- 10
Total UF = 10
UFA - 1
UFH- 10
Total UF = 30
UFL = 3
UFS=10
Notes on
Derivation
Discrete
LC01
values
were
derived at
each
duration for
use as
AEGL-3
PODs.
Time
scaling
using
Cnxt
where
n = 2.
Adjusted
for duration
and
breathing
rate,
details not
provided.
Review
Status
Final
(NAC/AEGL,
2003,
1 92304)
Final
(CDC, 2003,
192190)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
178
-------
Reference Value
Type / Name
c
o
IB
c ~~
0) Q.
0 0
Q.
CDC-
IDLH*
CDC-
STEL*
CDC GPL
Duration
30 min
15 min
(up to 4x
per day)
24 hour
Reference Value
(mg/m3)
0.1
1 x 1 0"4
1 x10'D
(ppm)
1.7x10'"
1.7x10'ฐ
1.7x10''
Health Effect
NR
NR
Miosis (McKee and
Woolcott, 1949,
192172)
Point of Departure
NR NR
NR NR
0.06 mg/mj LOAELHEC
(20 min/d,
for 4 d/wk)
Uncertainty
Factors
NR
NR
Total UF = 300
UFL = 3
UFS= 10
UFH= 10
Notes on
Derivation
Adjusted
for duration
and
breathing
rate,
details not
provided.
Review
Status
Final
(CDC, 2003,
192190)
September 2009
179
-------
REFERENCES
Baker DJ; Sedgewick EM. (1996). Single fibre electromyographic changes in man after
organophosphate exposure. Hum Exp Toxicol, 15: 369-375. 180099
CDC. (1988). Final recommendations for protecting the health and safety against
potential adverse effects of long-term exposure to low doses of agents GA, GB,
VX, Mustard Agent (H, HD, T) and Lewisite (L). Fed Regist, 53: 8504-8507.
192173
CDC. (2002). Airborne exposure limits for chemical warfare agents GA (tabun), GB
(sarin), and VX. Fed Regist, 67: 894-901. 192175
CDC. (2003). Final recommendations for protecting human health from potential adverse
effects of exposure to agents GA (tabun), GB (sarin), and VX. Fed Regist, 68:
58348-58351. 192190
CDC. (2004). Interim recommendations for airborne exposure limits for chemical warfare
agents H and HD (sulfur mustard). Fed Regist, 69: 24164-24168. 192193
Hulet SW; Sommerville DR; Crosier RB; Dabisch PA; Miller DB; Benton BJ; Forster JS;
Scotto JA; Jarvis JR; Krauthauser C; Muse WT; Reutter SA; Mioduszewski RJ;
Thomson SA. (2006). Comparison of low-level sarin and cyclosarin vapor
exposure on pupil size of the gottingen minipig: effects of exposure concentration
and duration. Inhal Toxicol, 18: 143-153. 192144
McKee WE; Woolcott R. (1949). Report on exposures of unprotected men and rabbits to
low concentrations of nerve gas vapor. Military Intelligence Division. Porton
Down, United Kingdom. Porton Technical Paper # 143. 192172
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Anthony J; Durst
D; Sommerville D; Crosier R; Thomson S; Grouse C. (2001). Inhalation toxicity
of sarin vapor in rats as a function of exposure concentration and duration. ECBC
Low Level Operational Toxicology Program. Edgewood, MD. 192306
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R. (2000). Estimating the probability of sarin vapor
toxicity in rats as a function of exposure concentration and duration . Presented at
International Chemical Weapons Demilitarization Conference, The Hague,
Netherlands. 192305
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R. (2002). Interaction of exposure concentration and
duration in determining acute toxic effects of sarin vapor in rats. Toxicol Sci, 66:
176-184. 180121
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R; Scotto J; McCaskey D; Crous C; Matson K. (2002).
Low-level sarin vapor exposure in rats: effect of exposure concentration and
duration on pupil size. Edgewood Chemical Biological Center. Aberdeen Proving
Ground, MD.http://www.stormingmedia.us/96/9682/A968204.html. 192189
September 2009 180
-------
NAC/AEGL. (2003). Nerve agents GA, GB, GD, GF, and VX - final acute exposure
guideline levels (AEGLs). National Advisory Committee for Acute Exposure
Guideline Levels. Washington, DC.http://www.epa.gov/oppt/aegl/pubs/tsd21.pdf.
192304
U.S. EPA. (1994). Methods for derivation of inhalation reference concentrations and
application of inhalation dosimetry. Office of Research and Development.
Resarch Triangle Park, NC. EPA/600/8-90/066F.
http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993. 192307
September 2009 181
-------
2.21. Chemical-Specific Reference Values for Styrene (CASRN 100-42-5)
Styrene (CgHg) is a colorless or slightly yellow, viscous liquid (NAC/AEGL, 2008,
192210). Pure Styrene has a pungent, slightly sweetish odor; however, oxidation may lead to the
formation of peroxides, certain aldehydes and ketones giving a sharp, penetrating, disagreeable
odor. When emitted into the air, its half-life is estimated to be about 2 hours, and chemical
transformation products include benzaldehyde and formaldehyde, both of which are odorous air
pollutants. Owing to its volatility, low flash point, and the range of explosive limits in air (lower:
1.1 %, upper: 6.3 % v/v), styrene poses an acute fire and explosion hazard. Due to its tendency to
polymerize at room temperature in the presence of oxygen and to oxidize on exposure to light
and air, styrene is normally stabilized by the addition of tertiary butylcatechol (4-tert-
butylbenzene-l,2-diol) as an inhibitor.
Styrene is predominantly used for the production of polymers (polystyrene, copolymers
of styrene with acrylonitrile and/or butadiene) that are widely used in latex paints and coatings,
synthetic rubbers, polyesters and styrene-alkyd coatings. Styrene is a high production volume
(HPV) chemical with a worldwide production of 17,945 tonnes in 1998. Styrene also occurs in
many agricultural products and foods, however, it is not clear whether styrene is naturally
produced within plants (IARC, 2002, 192043).
Due to its ubiquitous use and a wealth of available health effects data, styrene has a rather
full range of available inhalation health effect reference values, as shown in Figure 2.21.
Additional details are provided in Table 2.21 on the derivation of the available reference values,
including the basis, point of departure (POD), time scaling, etc.
The Emergency Response reference values include both AEGLs and ERPGs. [NOTE:
The AEGL-3 value for 1-hour is equal to 10% of the lower explosive limit (LEL) for styrene,
and the 10-minute and 30-minute AEGL-3 values are greater than 10% of the LEL.] In keeping
with the AEGL SOPs (NRC, 2001, 192042). the 10-minute AEGL-3 is equal to the 30-minute
AEGL-3 due to the 4-hour duration of the POD. Additionally, the 8-hour AEGL-3 was kept
equal to the 4-hour AEGL-3 because toxicokinetic data indicate that there is little increase of
internal dose after four hours of exposure, and the lower 8-hour values derived by the default
approach would generate calculated exposure levels not supported by toxicological data for
humans (NAC/AEGL, 2008, 192210). Using a similar toxicokinetic basis, it was determined that
no increases in internal dose would result from exposures to durations longer than one hour at the
1-hour AEGL-2 concentration, therefore no time scaling was performed for longer durations.
Time scaling was not performed for the AEGL-1 based on observations that irritation did not
increase with increased time at any exposure level. In derivation of the AEGL-2 values, the POD
was noted as a NOAEL in the AEGL TSD, even though the effect was a LOAEL for CNS
depression; the effect was interpreted to not be above a level that could impede the ability to
escape, and therefore less than the AEGL-2 effect level. Similarly, in deriving the ERPG-2 it was
noted that loss of balance in humans resulted from exposure to 200 ppm or more for 1-3 hours -
indicative of a LOAEL for CNS depression but deemed a NOAEL for ERPG-2 effects (AIHA,
2002, 192065). The ERPG-3 and corresponding one-hour AEGL-3 values are quite similar in
exposure concentrations derived, whereas the ERPG-2 and ERPG-1 values are at somewhat
higher concentrations when compared to their corresponding AEGL values.
Occupational values for styrene include time-weighted average (TWA) and ceiling values
developed by ACGIH, NIOSH and OSHA, as well as a NIOSH IDLH value. All the available
September 2009 182
-------
background documentation provided a fairly good discussion of the evidence surrounding the
decision on establishment of the value, but was not explicit in defining a POD and application of
uncertainty factors or other adjustments to a POD. There was half an order of magnitude
difference between the lowest occupational reference values - ACGIH TLV-TWA and STEL -
and the corresponding OSHA values, with the NIOSH values falling between. The reasons for
this variation cannot be easily discerned based on the rather limited information available on the
decisions that went into establishing each of these values.
Styrene reference values for the General Public include one developed for acute duration
from the State of California (1-hour value CA-REL); two values for short-term durations from
ATSDR (acute MRL - 1 to 14 days), and the World Health Organization (WHO; weekly average
Air Quality Guideline); and values for chronic durations developed by California, ATSDR, and
the US EPA. The WHO values are by far set at the lowest exposure concentration when
compared to any other value, regardless of duration. The WHO value was derived from the
lowest end of the range of occupational values showing subclinical effects on color vision (Chia
et al., 1994, 010974: Eguchi et al., 1995, 010998: Fallas et al., 1992, 067341: Gobba and
Cavalleri, 1993, 011026: Gobba et al., 1991, 005830) at 107 mg/m3 and was then adjusted to
approximate continuous exposure from the occupational studies by use of a factor of 4.2 (5/7 x
8/24; assuming a straight C x t time scaling relationship) and application of uncertainty factors
(10 for interindividual variability and 10 for use of a LOAEL instead of a NOAEL). All of the
chronic duration General Public reference values for styrene are within a narrow band of
exposure concentrations, with all either derived from the same study on neurobehavioral effects
(Mutti et al., 1984, 073490) or using a meta-analysis that includes that study plus others for the
same endpoint (Benignus et al., 2005, 180102). As can be seen in Figure 2.21, the resulting
chronic General Public reference values eclipse one another when plotted together.
As noted previously in this discussion, there is a fairly complete coverage of values for
styrene, with a high level of concordance between the chronic reference values developed for the
General Public and amongst the Emergency Response values. The Occupational values,
however, varied quite a bit between the different organizations developing those values.
September 2009 183
-------
National Center tor Environmental Asi
Research Triangle Park, NC
1.E+04
1.E+03
"5)
ฃ
O
c
O
O
o>
s
ฃ
V)
1.E+02
1.E+01
1.E+00
1.E-01
Styrene: Comparison of Reference Values
ACUTE
A A.
^t
ปERPG-3
NW 5
NIOSH IDLlX. M
X*.
Short Term
to
1
o
CO
Ifr + AEGL-3
6AERPG-2
OSHA-Celtfhg*
0 0 0 gAEGL
H<1IOSH-STEL*
A ____, j ^"\
OACGIH-STEL*
2
^ ^ *. *. ^ปAEGL'1
<^^>K) Q-C
X CA-REL (Acute)
>
/
anma
^ - - - *KAT,
ATS
0 WHO A
Subchronic
to
1yr) 5
c
X CA-REL (Chronic) ง
EPA/IRIS RfC
0.1
10 100 1000 10000 100000 1000000
Duration (hours)
Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.21. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Styrene
September 2009
184
-------
Table 2.21. Details on derivation of the specific inhalation health effect reference values for styrene.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
ERPG-3
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
1 hr
Reference Value
(mg/mj)
8090
8090
4700
1450
1450
980
680
550
550
550
85
85
85
85
85
4260
(ppm)
1900'
19002
11002
340
340
230
160
130
130
130
20
20
20
20
20
1000
Health Effect
Lethality in female
rats
(BASF, 1979,
053665)
CMS depression
(Stewart et a I.,
1968,073530)
Slight irritation/
subjective
discomfort, CMS
effects
(Seeber et al.,
2002, 053685)
Eye and nose
irritation and CMS
depression in
humans
(Carpenter et al.,
1944,094758)
Point of Departure
3400 ppm BMDL05
(4 hrs)
376 ppm LOAELJ
(1 hr)
20 ppm NOAEL
(3 hrs)
800 ppm NOAEL for
Lethality
Uncertainty
Factors
Total UF = 10
UFA-3
UFH ~ 3
Total UF = 3
UFH-3
None
NR
Notes on
Derivation
Time scaling:
xt - k
where n=1 2 for
scaling to 30
min and 1 hr;
4-hr value
adopted as 8-hr
value
Time scaling:
xt - k
where n = 3 to
1 hour, then
flat-lined
No time scaling
Review
Status
Interim
(NAC/AEGL,
2008,
192210)
Final
(AIHA, 2002,
1 92065)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
2 The lower explosive limit (LEL) of styrene in air is 1.1 % (11,000 ppm). The AEGL-3 value for 10 minutes, 30 minutes and 1 hour are equal or higher than
1/10 of the LEL. Therefore, safety considerations against hazard of explosion must be taken into account.
3 Although the level cited (376 ppm) was noted as a LOAEL for CNS depression in the study (Stewart et al., 1968), it was cited as a NOAEL for AEGL-2 effects
(NAC/AEGL, 2008).
September 2009
185
-------
Ref
T
Occupational
erence Value
ype / Name
ERPG-2
ERPG-1
ACGIH TLV-
TWA*
ACGIH TLV-
STEL*
NIOSH-
IDLH*
OS HA
Ceiling*
OSHA-PEL
(TWA)*
NIOSH-REL
(TWA)*
NIOSH-
STEL*
Duration
1 hr
1 hr
8 hr TWA
15 min
30 min
< 15 min
(4x/day)
8 hr TWA
10 hr
TWA
15 min
Reference Value
(mg/mj)
1100
213
85
170
3x10J
852
426
213
426
(ppm)
250
50
20
40
700
200
100
50
100
Health Effect
Nose, eye, and
throat irritation,
headache, and
nausea in humans
(Oltramare et al.,
1974,073640)
Mild-to-moderate
odor perception
(Stewart et al.,
1968, 073530; Wolf
etal., 1956,
062279)
NR
(Barale, 1991,
010949; Edling and
Ekberg, 1985,
064271 ;Kohn,
1978,073466)
Signs of neurologic
impairment;
(Stewart et al.,
1968,073530)
NR
NR
NR
NR
Point of Departure
200 ppm NOAEL for
ERPG-2
effects
50 ppm NOAEL for
Irritation
NR NR
NR NR
376 ppm NR
(7hr)
NR NR
NR NR
NR NR
NR NR
Uncertainty
Factors
NR
NR
NR
NR
NR
NR
NR
NR
NR
Notes on
Derivation
Effects also
noted at 200-
700ppm in
occupational
settings
(Benignus et
al., 2005,
180102)
Review
Status
Final
(AIHA, 2002,
1 92065)
Final
(ACGIH,
2007,
192024)
Final
(NIOSH,
1996,
192308)
Final
(OSHA,
2006,
1 92276)
Final
(NIOSH,
2006,
192177)
September 2009
186
-------
Reference Value
Type / Name
General Public
CA-REL
(Acute)
ATSDR-MRL
(Acute)
WHO Air
Quality
Guideline
Chronic RfC
(IRIS)
ATSDR-MRL
(> iyr)
CA-REL
(Chronic)
Duration
1 hr
1 -14d
Weekly
average
Chronic
Chronic
Chronic
Reference Value
(mg/mj)
21
8.5
0.26
1
0.85
0.9
(ppm)
5.1
2
0.06
0.24
0.2
0.2
Health Effect
Eye and throat
irritation in humans
(Stewart et al.,
1968,073530)
Lack of alterations
in tests of simple
reaction time,
choice reaction
time, or attention
(Seeber et al.,
2004. 180249)
Neurological
development
impairments
CMS effects in
humans
(Muttietal., 1984,
073490)
Increases in choice
reaction time and
decrease in color
perception in
humans
(Benignus et al.,
2005, 180102)
Effects to central
nervous system
(Muttietal., 1984,
073490)
Point of Departure
51 ppm NOAEL
20 ppm NOAEL
25.5 mg/mj NOAELADJ
(1 07 mg/m3
^4.2)
34 mg/mj NOAELHEc
(94 mg/m3
x5/7
x 10/20)
20 ppm LOAEL
0.61 ppm BMC05_HEc
(1 .7 ppm
x 10/20
x5/7)
Uncertainty
Factors
Total UF = 10
UFH = 10
Total UF = 10
UFH=10
Total UF = 100
UFH = 10
UFL = 10
Total UF = 30
UFDB = 3
UFH = 3
UFS = 3
Total UF = 100
UFL = 10
UFH = 10
Total UF = 3
UFH=3
Notes on
Derivation
No time scaling
No time scaling
Adjusted from
occupational to
continuous by
factor of 4.2
Adjusted for
5 d/wk; and
10m3/d
(worker) vs. 20
m3/d (avg)
breathing rates
No time scaling
Adjusted
BMC05 for 5
d/wk; and
10m3/d
(worker) vs. 20
m3/d (avg)
breathing rates
Review
Status
Final
(OEHHA,
2008,
192309)
Draft
(ATSDR,
2007,
192120)
Final
(WHO, 2000,
180143)
Final
(U.S. EPA,
1993,
192310)
Draft
(ATSDR,
2007,
192120)
Final
(OEHHA,
2000,
192311)
September 2009
187
-------
REFERENCES
ACGIH. (2007). Documentation of the TLVs and BEIs. American Conference of
Governmental Industrial Hygienists. Cincinnati, OH. 192024
AIHA. (2002). Styrene (1995). In 2002 Emergency Response Planning Guidelines
(ERPG) Complete Set (pp. .). Fairfax, VA: American Industrial Hygiene
Association. 192065
ATSDR. (2007). Draft toxicological profile for styrene. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. 192120
BASF Aktiengesellschaft. (1979). Bericht uber die bestimmung der akuten
inhalationstoxizitat LC50 von styrol als dampf bei 4stundiger exposition an
Sprague-Dawley-ratten. 053665
Barale R. (1991). The genetic toxicology of styrene and styrene oxide. DNA Repair
(Amst), 257: 107-126. 010949
Benignus VA; Geller AM; Boyes WK. (2005). Human neurobehavioral effects of long-
term exposure to styrene: a meta-analysis. Environ Health Perspect, 113: 532-538.
180102
Carpenter CP; Shaffer CB; Weil CS; Smyth HF Jr. (1944). Studies on the inhalation of
l:3-butadiene; with a comparison of its narcotic effect with benzol, toluol, and
styrene, and a note on the elimination of styrene by the human. Arch Environ
Occup Health, 26: 69-78. 094758
Chia S-E; Jeyaratnam J; Ong C-N; Ng T-P; Lee H-S. (1994). Impairment of color vision
among workers exposed to low concentrations of styrene. Am J Ind Med, 26: 481-
488. 010974
Edling C; Ekberg K. (1985). No acute behavioural effects of exposure to styrene: a safe
level of exposure?. Occup Environ Med, 42: 301-304. 064271
Eguchi T; Kishi R; Harabuchi I; Yuasa J; Arata Y; Katakura Y; Miyake H. (1995).
Impaired colour discrimination among workers exposed to styrene: relevance of a
urinary metabolite. Occup Environ Med, 52: 534-538. 010998
Fallas C; Fallas J; Maslard P; Dally S. (1992). Subclinical impairment of colour vision
among workers exposed to styrene. Occup Environ Med, 49: 679-682. 067341
Gobba F; Cavalleri A. (1993). Kinetics of urinary excretion and effects on colour vision
after exposure to styrene. In Sorsa, M; Peltonen, K.; Vainio, H.; Hemminki, K.
(Ed.),Butadiene and styrene: assessment of health hazardsLyon, France:
International Agency for Research on Cancer. 011026
Gobba F; Galassi C; Imbriani M; Ghittori S; Candela S; Cavalleri A. (1991). Acquired
dyschromatopsia among styrene-exposed workers. J Occup Environ Med, 33:
761-765. 005830
IARC. (2002). Styrene. In Some traditional herbal medicines, some mycotoxins,
naphthalene and styrene (pp. 437-522). Lyon, France: International Agency for
Research on Cancer. 192043
September 2009 188
-------
Kohn AN. (1978). Ocular toxicity of styrene. Am J Ophthalmol, 85: 569-570. 073466
Mutti A; Mazzucchi A; Rustichelli P; Frigeri G; Arfmi G; Franchini I. (1984). Exposure-
effect and exposure-response relationships between occupational exposure to
styrene and neuropsychological functions. Am J Ind Med, 5: 275-286. 073490
NAC/AEGL. (2008). Styrene - interim acute exposure guideline levels (AEGLs).
National Advisory Committee for Acute Exposure Guideline Levels. Washington,
DC. 192210
NIOSH. (1996). Styrene - IDLH documentation. Retrieved 1 l-JUN-09, from
http://www.cdc.gov/niosh/idlh/100425.html. 192308
NIOSH. (2006). NIOSH pocket guide to chemical hazards. Cincinnati, OH: National
Institute for Occupational Safely and Health. 192177
NRC. (2001). Standing operating procedures for developing acute exposure guideline
levels (AEGLs) for hazardous chemicals. Washington, DC: National Academies
Press. 192042
OEHHA. (2000). Chronic toxicity summary - styrene. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento, CA. 192311
OEHHA. (2008). Acute toxicity summary - styrene. Office of Environmental Health
Hazard Assessment, California EPA. Sacramento, CA. 192309
OSHA. (2006). Table Z-l limits for air contaminants. Retrieved , from . 192276
Oltramare M; Desbaumes E; Imhoff C; Michiels W. (1974). Toxicologie du styrene
monomere: recherches experimentales et cliniques chez rhomme [Toxicology of
monomeric styrene: experimental and clinical studies on man]. 073640
Seeber A; Blaszkewicz M; Golka K. (2004). Neurobehavioral effects of experimental
exposures to low levels of styrene. Toxicol Lett, 151: 183-192. 180249
Seeber A; Van Thriel C; Haumann K; Kiesswetter E; Blaszkewicz M; Golka K. (2002).
Psychological reactions related to chemosensory irritation. Int Arch Occup
Environ Health, 75: 314-325. 053685
Stewart RD; Dodd HC; Baretta ED; Schaffer AW. (1968). Human exposure to styrene
vapor. Arch Environ Occup Health, 16: 656-662. 073530
U.S. EPA. (1993). Styrene. Retrieved 12-JAN-08, from
http://www.epa.gov/ncea/iris/subst/0104.htm. 192310
WHO. (2000). Air Quality Guidelines for Europe, second edition. World Health
Organization Regional Publications. Copenhagen. 91. 180143
Wolf MA; Rowe VK; McCollister DD; Hollingsworth RL; Oyen F. (1956).
Toxicological studies of certain alkylated benzenes and benzene: experiments on
laboratory animals. Arch Environ Occup Health, 14: 387-398. 062279
September 2009 189
-------
2.22. Chemical- Specific Reference Values for Sulfur Mustard
(CASRN 505-60-2)
Sulfur mustard (Agent HD, mustard gas, bis[2-chloroethyl]sulfide; C^CbS) is
a thick, colorless, and odorless synthetic organic liquid produced for use as a chemical
weapon in World Wars I and II. It is a blister agent that can cause severe eye and skin
irritation, as well as bronchitis and respiratory disease upon inhalation. Sulfur mustard
has been designated as a Group 1 human carcinogen by the IARC (IARC, 1987,
192134). Detailed descriptions of toxicity as well as the physical nature of this chemical
agent can be found in other sources (ATSDR, 2003, 192115: CDC, 2003, 192194:
CDC, 2004, 192193: NRC, 2003, 192141: NRT, 2009, 192158) and are not repeated
here.
Inhalation health effect reference values for sulfur mustard are arrayed
graphically in Figure 2.22. Details available on the derivation of these values, including
key effects, studies, adjustments, and uncertainty factors (UFs) are shown in Table 2.22.
A full set of Emergency Response AEGL values are available for sulfur
mustard. The AEGL values were time scaled via the Cn x t = k formula. The value of n
for the AEGL-3 reference value was set to either 3 for shorter (< 1 hour) and 1 for
longer (> 1 hour) time periods, due to the absence of chemical-specific lethality data
(NRC, 2003, 192141). The value of n = 1 was applied to derivation of the AEGL-1 and
AEGL-2 values, based on analysis of mild ocular irritation (Anderson, 1942, 192035:
Guild et al., 1941, 192161), with both values derived from the same study (Anderson,
1942, 192035). but using different PODs.
The only Occupational reference values developed for sulfur mustard were
designed specifically in relation to airborne exposure limits (AELs) for disposal of
chemical warfare agents (CDC, 2003, 192194: CDC, 2004, 192193). and CDC
admonishes the reader that these values "reflect realistic risk management provisions
associated with chemical demilitarization and do not necessarily apply to other
purposes" These AELs include an 8-hour Worker Protection Limit (WPL), time-
weighted average (TWA); along with a short-term exposure limit (STEL) and an
immediately dangerous to life and health (IDLH) value. Minimal information on the
derivation of these values was provided.
A General Public reference value was also developed by CDC (2003, 192194:
2004, 192193) as AELs for chemical demilitarization, with the same caveat on
applicability to other purposes. The CDC general population limit (CDC-GPL) is a
12-hour TWA value for up to a lifetime chronic exposure (NRT, 2009, 192158). As
with the Occupational AELs, very little detail was provided on the derivation of the
CDC-GPL; no information on key study, POD, duration adjustments and application of
uncertainty factors were provided. ATSDR published sulfur mustard MRLs for both
acute (1-14 days) and intermediate (15 days to 1 year) durations. Duration adjustments
were applied to both the acute and intermediate ATSDR MRL values, with adjustments
in the acute MRL accounting for exposures of 8 hours per day, and in the intermediate
MRL to account for 24 hours per day, 5 days per week exposures. All other details on
derivation were provided in the Sulfur Mustard Toxicological Profile (ATSDR, 2003,
192115), which is summarized in Table 2.22. As can be seen in Figure 2.22 and
September 2009 190
-------
Table 2.22, the CDC GPL and the ATSDR intermediate MRL are both set at 2 x 10"5
mg/m3, indicating good concordance between these two independently-derived
reference values.
Overall, there is fair coverage on inhalation health effect reference values for
sulfur mustard. As noted previously, the AELs were derived by CDC for the purposes
of chemical demilitarization, and may not be applicable for other purposes; therefore, as
with the Occupational values, the AELs should only be used with expert judgment.
September 2009 191
-------
>f Research and Development
il Center for Environmental Aป
Sulfur Mustard (HD): Comparison of Reference Values
1.E+01
1.E+00
"- 1.E-01
"3)
E.
C 1.E-02
O
O
0)
g 1.E-03
1.E-04
0
ACUTE
t/i
*^K>
^\ ฃ
AEG
\^
^^O AEG
''AEGL
O CDOSTEL*
r
1 1 10
Short Term
&
5
o
(O
-3
-2
-1
ATSDR-MRL(1-14d)
* " " " *
ATS
NC
Subchronic
to
TO
0
"""
CDC-WPL (TWA
3R-MRL(1 5-365 d) CDCGPL
*
Chronic
s
"
*
p
(12-hour, TWA)
'
t
O AEGL-3
O AEGL^2
O CDC-STEL*
TO
C
0
CDC-IDLH*
0 CDC-WPL (TWA)*
CDC GPL (12-hour, TWA)
o
3
X ATSDR-MRL(1-14d) g
oi
01
X ATSDR-MRL(1 5-365 d)
100 1000 10000 100000 1000000
Duration (hours)
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.22. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Sulfur Mustard
September 2009
192
-------
Table 2.22. Details on derivation of the specific inhalation health effect reference values for sulfur mustard.
Reference Value
Type / Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value
(mg/mj)
3.9
2.7
2.1
0.53
0.27
0.60
0.20
0.10
0.025
0.013
0.40
0.13
0.067
0.017
8x10'J
(ppm)
0.59
0.41
0.32
0.08
0.04
0.09
0.03
0.02
4x10"J
2x10"J
0.06
0.02
0.01
3x10"J
1 x10"J
Health Effect
Lethality estimate
in mice
(Kumar and, 1998,
1 80292)
Conjunctivitis,
edema,
photophobia, and
eye irritation in
human volunteers
(Anderson, 1942,
192035)
Conjunctival
injection with minor
discomfort in
human volunteers
(Anderson, 1942,
192035)
Point of Departure
21.2 1/2ofthe
mg/m3 1-h LC50
(1 h)
60 mg Threshold
min/m3 for effects
12 mg Threshold
min/m3 for effects
Uncertainty
Factors
Total UF = 10
UFA - 3
UFH = 3
Total UF = 3
UFH - 3
Total UF = 3
UFH - 3
Notes on
Derivation
Time scaling:
Cn A 1
X t - K
where
n = 3 for shorter
and n - 1 for
longer durations
Time scaling:
Cn A 1
X t - K
where
n = 1
Time scaling:
Cn i i.
X t - K
where
n = 1
Review
Status
Final
(NRC,
2003,
192141)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
193
-------
Reference Value
Type / Name
Occupational
General Public
CDC-STEL
CDC-IDLH
CDCWPL
(TWA)*
CDC GPL
(TWA)
ATSDR-
MRL
(Acute)
ATSDR-
MRL
(1 5-365 d)
Duration
15 min
30 min
8 hr TWA
24 hr
TWA,
7d/wk
fora
lifetime
1 -14d
15d-
1 yr
Reference Value
(mg/mj)
3x10'J
0.7
4X10"1
2x10'D
7X10"1
2x10'D
(ppm)
4.6 x10'4
0.11
6.2x10-ฐ
3.1 x10'b
1.1 X10"1
3.1 x10'D
Health Effect
Irritation; ocular
effects
Lethality
Cancer; irritation;
ocular effects
Ocular effects
(Guild etal., 1941,
192161)
Ocular effects in
dogs
(McNamara et al.,
1975, 192163)
Point of Departure
NR NR
NR NR
NR NR
NR NR
0.02 LOAELADj
mg/m3
(0.06
mg/m3 x
8/24)
0.0007 NOAELADj
mg/m3
(0.001
mg/m3 x
5/7)
Uncertainty
Factors
NR
NR
NR
Total UF = 300
Total UF = 30
UFL = 3
UFH = 10
Total UF = 30
UFH = 10
UFA = 3
Notes on
Derivation
Adjusted for
8 hr/day
Adjusted for
24 hr/d; 5 d/week
Review
Status
Final
(CDC,
2003,
192194;
CDC,
2004,
192193)
Final
(ATSDR,
2003,
192115)
September 2009
194
-------
REFERENCES
ATSDR. (2003). Toxicological profile for sulfur mustard. Agency for Toxic Substances and
Disease Registry. Atlanta, GA. PB2004-100006. 192115
Anderson JS. (1942). The effect of mustard gas vapour on eyes under Indian hot weather
conditions. Chemical Defense Research Establishment. India. 241. 192035
CDC. (2003). Proposed airborne exposure limits for chemical warfare agents H, HD, and HT
(sulfur mustard). Fed Regist, 68: 43356-43358. 192194
CDC. (2004). Interim recommendations for airborne exposure limits for chemical warfare agents
H and HD (sulfur mustard). Fed Regist, 69: 24164-24168. 192193
Guild WF; Harrison KP; Fairley A. (1941). The effect of mustard gas vapour on the eyes.
Chemical Board, Physiological Sub-Committee and Panel of Ophthalmic Specialists.
Great Britain. 2297. 192161
IARC. (1987). Mustard gas (sulphur mustard). In IARC Monographs - Overall Evaluations of
Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42 (pp. 259-260).
Lyon, France: International Agency for Research on Cancer. 192134
Kumar O; Vijayaraghavan. (1998). Effect of sulphur mustard inhalation exposure on some
urinary variables in mice. J Appl Toxicol, 18: 257-259. 180292
McNamara BP; Owens EJ; Christensen MK; Vocci FJ; Ford DF; Rozimarek H. (1975).
Toxicological basis for controlling levels of mustard in the environment. Edgewood
Arsenal. Aberdeen Proving Ground, MD. EB-SP-74030 . 192163
NRC. (2003). Sulfur mustard. In Acute exposure guideline levels for selected airborne chemicals
(pp. 301-383). Washington, DC: National Academies Press. 192141
NRT. (2009). NRT quick reference guide: sulfur mustard (H/HD/HT). Retrieved 30-JUN-09,
from http://www.nrt.org/Production/NRT/NRTWeb.nsf/AllAttachmentsByTitle/A-
1044WMDHHDHT(SulfurMustard)QRG/$File/H_HD_HT%20Final%20RevOa_2009.pd
f?OpenElement. 192158
September 2009 195
-------
2.23. Chemical-Specific Reference Values for Tabun (GA) (CASRN 77-81-6)
Tabun (Agent GA; dimethylamidocyanoethylphosphate) is one of several
organophosphate (OP) nerve agents that have been specifically designed and formulated to cause
death, major injuries, or incapacitation to enemy forces in wartime. The term "nerve" agent
refers to its anti-cholinesterase properties. Nerve agents are particularly effective in a military
sense because of their potency. Detailed descriptions of nerve agent toxicity as well as the
physical nature of this chemical agent can be found in the AEGL Techniucal Support Document
(NAC/AEGL, 2003, 192304). and is not repeated here.
There are only two sources of health effect reference values for the chemical warfare
agent GA: the National Advisory Committee for Acute Exposure Guideline Levels
(NAC/AEGL, 2003, 192304) and the Centers for Disease Control and Prevention (CDC, 2003,
192190). Both organizations used the same limited set of data for deriving values for GA;
however, the dataset for Sarin (GB) was the most robust of all of the nerve agents for which
values were derived, and the relative potency of the nerve agents GA and Agent VX to GB was
used to derive values for those other nerve agents.
AEGL-3 values for GA were derived based on the observation that GA appears to
possess one half the toxic potency of GB; the calculated lethality at the one percent level (LCoi)
in female rats using observations at 10-, 30-, 60-, 240-, and 360-minutes for GB was therefore
doubled to derive values for GA, with all other factors remaining the same. The toxic potency of
GA was deemed to be equal to GB for AEGL-1 [miosis - pinpoint pupils - in female rats
(Mioduszewski et al., 2002, 192189)1 and AEGL-2 effects [visual acuity effects in humans
(Baker and Sedgewick, 1996, 180099)1: therefore the AEGL-1 and AEGL-2 values derived for
GB were adopted as AEGL values for GA, with all other factors and conditions likewise
adopted.
A series of Federal Register Notices published by the Centers for Disease Control and
Prevention (CDC, 1988, 192173: CDC, 2002, 192175: CDC, 2003, 192190: CDC, 2004,
192193) document the Airborne Exposure Levels designed for application to the agents Tabun
(GA), Sarin (GB), VX, Mustard Agent (H, HD, T) and Lewisite (L) for the protection of workers
at chemical weapon decommissioning facilities and the general population living near those
facilities. The first set of recommendations (CDC, 1988, 192173) were applied for over 14 years,
and over the intervening years there was no apparent impact to human health; however, to
maintain to be consistent with more recent risk assessment practice a reevaluation using the
conventional risk assessment methods for inhalation exposures developed by the Environmental
Protection Agency (U.S. EPA, 1994, 192307) was conducted and a set of revised values were
published in the Federal Register (CDC, 2003, 192190) for the agents GA, GB and VX.
The Airborne Exposure Level values for GA were determined to be equal to those
derived for GB, and included a General Population Limit (GPL), a Worker Population Limit
(WPL), as well as a Short-term Exposure Limit (STEL) and Immediately Dangerous to Life and
Health (IDLH) occupational values (CDC, 2003, 192190). The GPL and WPL values for GB
(and hence GA) were based on exposures of 20 minutes per day for 4 days per week and were
adjusted to derive a Lowest Observable Adverse Effect Level Human Equivalent Concentration
(LOAELnEc) for 24 hour and 8 hour time weighted averages (TWAs), respectively. Fewer
details were provided in the derivation of the STEL and IDLH values, and it is assumed that a
weight of evidence approach was used in their derivation.
September 2009 196
-------
The resulting values for both the AEGL and CDC are shown in Figure 2.23 and
Table 2.23, with the details on derivation for GA being identical to those developed for GB.
More recent research by the U.S. Army provides additional data that may lead to further revision
of both sets of values (Hulet et al., 2006, 192144).
September 2009 197
-------
Offico of baoareh and Donlopmant
National Cantor for Envlranmontal An
Rssaarch Triangle Park, NC
Tabun (GA): Comparison of Reference Values
0.1
1.E+00
1.E-01
1.E-02
co~*
"oi
.ง. 1.E-03
U
c
o
ฐ 1.E-04
+j
C
0)
O)
1.E-05
1.E-06
i P.n7
ACUTE
%.,
- ^ 0 CDC-IDLH^**^ AEG
o
o
^ OAEG
^s.
^^wv AEG
- 0 CDC-STEL*
[
Short Term
I
-3
-1
Subchronic
(A
(5
r-
Chronic
V)
1
s
. CDC
' WPL-TWA*
CDC-GPL
AEGL-3 a
to
0
Q.
to
0)
O AEGL-2 ^
u
E
HI
1 AEGL-1 UJ
O CDC-STEL*
* CDC-IDLH*
O CDC WPL-TWA*
ll
D CDC-GPL | I
0 0
Q.
10 100 1000 10000 100000 1000000
Duration (hours)
Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 2.23. Comparison of Available Health Effect Reference Values for Inhalation Exposure to Tabun (GA)
September 2009
198
-------
Table 2.23. Details on derivation of the specific inhalation health effect reference values for Tabun (GA).
Refe
Ty
Emergency Response1
rence Value
pe / Name
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value
(mg/mj)
7.60E-01
3.80E-01
2.60E-01
1.40E-01
1.00E-01
8.70E-02
5.00E-02
3.50E-02
1 70E-02
1 .30E-02
6.90E-03
4.00E-03
2.80E-03
1 .40E-03
1 .OOE-03
(ppm)
1.15E-01
5.73E-02
3.92E-02
2.11E-02
1.51E-02
1.31E-02
7.54E-03
5.28E-03
2.56E-03
1.96E-03
1.04E-03
6.03E-04
4.22E-04
2.11E-04
1.51E-04
Health Effect
Lethality
(Mioduszewski et
al., 2000, 192305:
Mioduszewski et
al., 2001, 192306:
Mioduszewski et
a I., 2002, 180121)
Miosis, dyspnea,
photophobia,
inhibition of RBC-
ChE seen in
humans (Baker and
Sedgewick, 1996,
180099)
Induction of miosis
in female rat
(Harvey, 1952,
192174: Johns,
1952, 192313:
Mioduszewski et
al., 2002, 192189:
van Helden et al.,
2001, 180238)
Point of Departure
11. 54 mg/nf |_C01
5.84mg/mJ (femalb
rats')
4.01 mg/nf1
2.09 mg/nf1
1.76 mg/nf1
(6hr)
0.5 mg/mj Sub-
(30 min) clinical
effects
Range of EC50
0.01-0.48
mg/m3 at
10 min,
60 min,
and 240
min
Uncertainty
Factors
Total UF = 30
UFA - 3
UFH-10
Total UF = 10
UFA- 1
UFH = 10
Total UF = 10
UFA- 1
UFH = 10
Notes on
Derivation
Potency of GA
is
approximately
1/2 that of GB
for lethality.
Potency of GA
is equal to that
of GB for
AEGL-2 effects
Potency of GA
is equal to that
of GB for
AEGL-1
effects, EC50
for miosis in
rats
Review
Status
Final
(NAC/AEGL,
2003,
192304)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
199
-------
Refe
Ty
_
(3
o
(0
Q.
O
o
C
re
<1) JO
S =
0 o
Q.
rence Value
pe / Name
CDC-WPL
(TWA)*
CDC-IDLH*
CDC-STEL*
CDC GPL
Duration
8 hr TWA
30 min
15 min
(up to 4x
per day)
24 hour
Reference Value
(mg/mj)
3x10"D
0.1
1 x10'4
1 x10'D
(ppm)
5.2x10"b
1.7x10"^
1.7x10'D
1.7x10"'
Health Effect
Miosis (McKee and
Woolcott, 1949,
192172)
NR
NR
Miosis (McKee and
Woolcott, 1949,
192172)
Point of Departure
0.06 mg/mj LOAELHEC
(20 min/d,
for 4 days)
NR NR
NR NR
0.06 mg/mj LOAELHEC
(20 min/d,
for 4 d/wk)
Uncertainty
Factors
Total UF = 30
UFL = 3
UFS= 10
NR
NR
Total UF = 300
UFL = 3
UFS=10
UF|H 10
Notes on
Derivation
Adjusted for
duration and
breathing rate,
details not
provided.
Adjusted for
duration and
breathing rate,
details not
provided.
Review
Status
Final
(CDC, 2003,
192190)
September 2009
200
-------
REFERENCES
Baker DJ; Sedgewick EM. (1996). Single fibre electromyographic changes in man after
organophosphate exposure. Hum Exp Toxicol, 15: 369-375. 180099
CDC. (1988). Final recommendations for protecting the health and safety against
potential adverse effects of long-term exposure to low doses of agents GA, GB,
VX, Mustard Agent (H, HD, T) and Lewisite (L). Fed Regist, 53: 8504-8507.
192173
CDC. (2002). Airborne exposure limits for chemical warfare agents GA (tabun), GB
(sarin), and VX. Fed Regist, 67: 894-901. 192175
CDC. (2003). Final recommendations for protecting human health from potential adverse
effects of exposure to agents GA (tabun), GB (sarin), and VX. Fed Regist, 68:
58348-58351. 192190
CDC. (2004). Interim recommendations for airborne exposure limits for chemical warfare
agents H and HD (sulfur mustard). Fed Regist, 69: 24164-24168. 192193
Harvey JC. (1952). Clinical observations on volunteers exposed to concentrations of GB.
Army Chemical Center. Aberdeen Proving Ground, MD. 5030-114. 192174
Hulet SW; Sommerville DR; Crosier RB; Dabisch PA; Miller DB; Benton BJ; Forster JS;
Scotto JA; Jarvis JR; Krauthauser C; Muse WT; Reutter SA; Mioduszewski RJ;
Thomson SA. (2006). Comparison of low-level sarin and cyclosarin vapor
exposure on pupil size of the gottingen minipig: effects of exposure concentration
and duration. Inhal Toxicol, 18: 143-153. 192144
Johns RJ. (1952). The effect of low concentrations of GB on the human eye. Army
Chemical Center. Aberdeen Proving Grounds, MD. 5030-100. 192313
McKee WE; Woolcott R. (1949). Report on exposures of unprotected men and rabbits to
low concentrations of nerve gas vapor. Military Intelligence Division. Porton
Down, United Kingdom. Porton Technical Paper # 143. 192172
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Anthony J; Durst
D; Sommerville D; Crosier R; Thomson S; Grouse C. (2001). Inhalation toxicity
of sarin vapor in rats as a function of exposure concentration and duration. ECBC
Low Level Operational Toxicology Program. Edgewood, MD. 192306
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R. (2000). Estimating the probability of sarin vapor
toxicity in rats as a function of exposure concentration and duration . Presented at
International Chemical Weapons Demilitarization Conference, The Hague,
Netherlands. 192305
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R. (2002). Interaction of exposure concentration and
duration in determining acute toxic effects of sarin vapor in rats. Toxicol Sci, 66:
176-184. 180121
September 2009 201
-------
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R; Scotto J; McCaskey D; Crous C; Matson K. (2002).
Low-level sarin vapor exposure in rats: effect of exposure concentration and
duration on pupil size. Edgewood Chemical Biological Center. Aberdeen Proving
Ground, MD.http://www.stormingmedia.us/96/9682/A968204.html. 192189
NAC/AEGL. (2003). Nerve agents GA, GB, GD, GF, and VX - final acute exposure
guideline levels (AEGLs). National Advisory Committee for Acute Exposure
Guideline Levels. Washington, DC.http://www.epa.gov/oppt/aegl/pubs/tsd21.pdf
192304
U.S. EPA. (1994). Methods for derivation of inhalation reference concentrations and
application of inhalation dosimetry. Office of Research and Development.
Resarch Triangle Park, NC. EPA/600/8-90/066F.
http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993. 192307
van Helden HPM; Trap HC; Kuijpers WC; Groen B; Oostdijk JP; Vanwersch RAP;
Philippens IHC; Langenberg JP Benschop JP. (2001). Low level exposure to GB
vapor in air: diagnosis/dosimetry, lowest observable effect level, and performance
incapacitation. Presented at Research and Technology Organisation Meeting
Proceedings 75, Estoril, Portugal. 180238
September 2009 202
-------
2.24. Chemical-Specific Reference Values for Agent VX (CASRN 50782-69-9)
Agent VX (S-(diisopropyl aminoethyl) methyl phosphonothiolate, O-ethyl ester)) is one
of several organophosphate (OP) nerve agents have been specifically designed and formulated to
cause death, major injuries, or incapacitation to enemy forces in wartime. The term "nerve"
agent refers to its anti-cholinesterase properties. Nerve agents are particularly effective in a
military sense because of their potency. Detailed descriptions of nerve agent toxicity as well as
the physical nature of this chemical agent can be found in the AEGL Technical Support
Document (NAC/AEGL, 2003, 192304). and are not repeated here.
Agent VX is a persistent compound, deliberately formulated for low volatility; it is
designed to contaminate surfaces and remain unchanged for long periods of time. VX can also be
absorbed percutaneously, although all of the reference values described below are based on
vapors. Since VX has a low vapor pressure, monitoring for VX presence in air is not likely to be
an effective determinant in designating an area free of contamination; surface sampling should
be the critical method for determining levels of contamination or presence of this compound.
There are only two sources of health effect reference values for the chemical warfare
agent VX: the National Advisory Committee for Acute Exposure Guideline Levels (NRC, 2003,
192140) and the Centers for Disease Control and Prevention (CDC, 2003, 192190). Both
organizations used the same limited set of data and relied on deriving values for VX based on the
relative potency to sarin (GB).
The only Emergency Response values for VX are the AEGLs (NRC, 2003, 192140). Two
studies (Grob and Harvey, 1958, 180110: Sidell and Groff, 1974, 180129)indicated that VX was
four times more potent than sarin (GB), and this evidence was used as the basis to estimate the
potency of VX (Mioduszewski et al., 2002, 180121). The adjusted value was used as the point of
departure (POD) for deriving AEGL-3 values for VX. Similarly, a factor of four was used to
account for the relative toxicity in deriving values based on sarin studies showing miosis (pupil
dilation) (Mioduszewski et al., 2002, 192189) and visual acuity effects (Baker and Sedgewick,
1996, 180099) for the AEGL-1 and AEGL-2, respectively.
A series of Federal Register Notices published by the Centers for Disease Control and
Prevention (CDC, 1988, 192173: CDC, 2002, 192175: CDC, 2003, 192190: CDC, 2004,
192193) document the Airborne Exposure Levels designed for application to the agents Tabun
(GA), Sarin (GB), VX, Mustard Agent (H, HD, T) and Lewisite (L) for the protection of workers
at chemical weapon decommissioning facilities and the general population living near those
facilities The first set of recommendations (CDC, 1988, 192173) were applied for over 14 years,
and over the intervening years there was no apparent impact to human health; however, to be
consistent with more recent risk assessment practice a reevaluation using the conventional risk
assessment methods for inhalation exposures developed by the Environmental Protection Agency
(U.S. EPA, 1994, 192307) and used by other agencies was conducted and a set of revised values
were published in the Federal Register (CDC, 2003, 192190) for the agents GA, GB and VX.
The approach to developing the CDC Airborne Exposure Levels for VX was quite similar
to the approach taken in the development of the AEGL values (NRC, 2003, 192140) in that the
relative potency of sarin to VX was used as the basis for applying the more robust database for
sarin. In deriving values for VX, an assumption of a 12 fold increase in toxic potency of VX over
GB was applied, along with application of a modifying factor of 3 for the sparse VX data set;
there was no explanation provided on why a factor of 12 instead of 4 (as in the AEGL
September 2009 203
-------
derivation). Values were derived for a General Population Limit (GPL), a Worker Population
Limit (WPL), as well as a Short-term Exposure Limit (STEL) and Immediately Dangerous to
Life and Health (IDLH) occupational values. Adjustments were made, however, to the GPL
value to accommodate the detection limit for monitoring. The resulting values for both the
AEGL and CDC are shown in Figure 2.24 and Table 2.24. More recent research by the U.S.
Army provides additional data that may lead to further revision of both sets of values (Benton et
al., 2005, 192358: Benton et al., 2006, 192360).
September 2009 204
-------
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC
Agent VX: Comparison of Reference Values
1.E-01
1.E-02 --
-------
Table 2.24. Details on derivation of the specific inhalation health effect reference values for agent VX.
Reference Value Type
/ Name
Emergency Response1
AEGL-3
AEGL-2
AEGL-1
Duration
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
10 min
30 min
1 hr
4hr
8hr
Reference Value
(mg/mj)
2.90E-02
1.50E-02
1.00E-02
5.20E-03
3.80E-03
7.20E-03
4.20E-03
2.90E-03
1.50E-03
1.00E-03
5.70E-04
3.30E-04
1.70E-04
1.00E-04
7.10E-05
(ppm)
2.65E-03
1.37E-03
9.14E-04
4.75E-04
3.47E-04
6.58E-04
3.84E-04
2.65E-04
1.37E-04
9.14E-05
5.21 E-05
3.02E-05
1.55E-05
9.14E-06
6.49E-06
Health Effect
Lethality in rats
(Mioduszewski et
al., 2002,
180121)
Miosis, dyspnea,
photophobia,
inhibition of RBC-
ChE seen in
humans
(Baker and
Sedgewick, 1996,
180099)
Induction of
miosis by sarin in
female rat
(Mioduszewski et
al., 2002,
192189)
Point of Departure
1 .46 mg/mj LC0i
(6 hour)
0.125mg/mJ LOAEL
(30 min) for sub-
clinical
effects
0.017mg/mJ EC50
(10 min)
0.005 mg/mj
(1 hour)
0.003 mg/mj
(4 hour)
Uncertainty
Factors
Total UF = 100
UFA = 3
i ic -in
Urn - 1U
MF "~ 3 (sparse
VX dataset)
Total UF = 30
UFA=1
i ic -in
Urn - 1U
MF ~ 3 (sparse
VX dataset)
Total UF = 30
1 IF. - 1
UTA I
UFH = 10
MF = 3 (sparse
VX dataset)
Notes on
Derivation
Potency of
agent VX is
approximately
4 times that of
agent GB
(sarin) for
AEGL-3 effects
(Grab &
Harvey, 1958;
Sidell & Groff,
1974)and
relative potency
was used
throughout;
AEGL values
are estimates
for VX vapor
exposures only.
Review
Status
Final
(NRC, 2003,
192140)
1 Emergency Response reference values are developed using an assumption of a rare, "once-in-a-lifetime" exposure scenario, which is a key consideration when
comparing these reference values to any Occupational or General Public reference values.
September 2009
206
-------
Reference Value Type
/ Name
Occupational
General
Population
CDC WPL
TWA*
CDC-STEL*
CDC-IDLH
(<30min)*
CDC GPL
Duration
8 hr TWA
<15 min,
once/day
30 min
24 hour
Reference Value
(mg/mj)
1 .OOE-06
1.00E-05
3.00E-03
6.00E-07
(ppm)
9.14E-08
9.14E-07
2.74E-04
5.48E-08
Health Effect
Miosis (McKee
and Woolcott,
1949, 192172)
Point of Departure
0.06 mg/mj LOAEL
(20-min/day, (Sarin)
4 days/week)
Uncertainty
Factors
Total UF = 100
UFL=3
UFH = 10
MF = 3
NR
Total UF = 1000
UFL=3
UFH = 10
UFS= 10
MF = 3
Notes on
Derivation
Assumes VX is
1 2x potency of
sarin (GB).
Adjustements
for duration,
breathing rates,
and detection
limits.
Review
Status
Final
(CDC, 2003,
192190)
September 2009
207
-------
REFERENCES
Baker DJ; Sedgewick EM. (1996). Single fibre electromyographic changes in man after
organophosphate exposure. Hum Exp Toxicol, 15: 369-375. 180099
Benton BJ; McGuire JM; Sommerville DR; Dabisch PA; Jakubowski EM; Matson KL;
Mioduszewski RJ; Thomson SA; Grouse CL. (2006). Effects of whole-body VX
vapor exposure on lethality in rats. Inhal Toxicol, 18: 1091-1099. 192360
Benton BJ; Sommerville DR; Scotto J; Burnett DC; Gaviola BI; Crosier RB; Jakubowski
EM; Whalley CE; Anthony JS; Hulet SW; Dabisch PA; Reutter SA; Forster JS;
Mioduszewski RJ; Thomson SA; Matson KL; Grouse CL; Miller DB; Evans RA;
McGuire JM; Jarvis JR. (2005). Low-level effects of VX vapor exposure on pupil
size and cholinesterase levels in rats. U.S. Army ECBC. Edgewood, MD. TR-428
DTIC#ADA432945. 192358
CDC. (1988). Final recommendations for protecting the health and safety against
potential adverse effects of long-term exposure to low doses of agents GA, GB,
VX, Mustard Agent (H, FID, T) and Lewisite (L). Fed Regist, 53: 8504-8507.
192173
CDC. (2002). Airborne exposure limits for chemical warfare agents GA (tabun), GB
(sarin), and VX. Fed Regist, 67: 894-901. 192175
CDC. (2003). Final recommendations for protecting human health from potential adverse
effects of exposure to agents GA (tabun), GB (sarin), and VX. Fed Regist, 68:
58348-58351. 192190
CDC. (2004). Interim recommendations for airborne exposure limits for chemical warfare
agents H and HD (sulfur mustard). Fed Regist, 69: 24164-24168. 192193
Grob D; Harvey JC. (1958). Effects in man of the anticholinesterase compound sarin. J
Clin Invest, 37: 350-368. 180110
McKee WE; Woolcott R. (1949). Report on exposures of unprotected men and rabbits to
low concentrations of nerve gas vapor. Military Intelligence Division. Porton
Down, United Kingdom. Porton Technical Paper # 143. 192172
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R. (2002). Interaction of exposure concentration and
duration in determining acute toxic effects of sarin vapor in rats. Toxicol Sci, 66:
176-184. 180121
Mioduszewski RJ; Manthei J; Way R; Burnett D; Gaviola B; Muse W; Thomson S;
Sommerville D; Crosier R; Scotto J; McCaskey D; Crous C; Matson K. (2002).
Low-level sarin vapor exposure in rats: effect of exposure concentration and
duration on pupil size. Edgewood Chemical Biological Center. Aberdeen Proving
Ground, MD.http://www.stormingmedia.us/96/9682/A968204.html. 192189
NAC/AEGL. (2003). Nerve agents GA, GB, GD, GF, and VX - final acute exposure
guideline levels (AEGLs). National Advisory Committee for Acute Exposure
Guideline Levels. Washington, DC.http://www.epa.gov/oppt/aegl/pubs/tsd21.pdf
192304
September 2009 208
-------
NRC. (2003). Nerve agents GA, GB, GD, GF, and VX. In Acute exposure guideline
levels for selected airborne chemicals (pp. 15-300). Washington, DC: National
Academies Press. 192140
Sidell FR; Groff WA. (1974). The reactivability of cholinesterase inhibited by VX and
sarin in man. Toxicol Appl Pharmacol, 27: 241-252. 180129
U.S. EPA. (1994). Methods for derivation of inhalation reference concentrations and
application of inhalation dosimetry. Office of Research and Development.
Resarch Triangle Park, NC. EPA/600/8-90/066F.
http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=71993. 192307
September 2009 209
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APPENDIX A:
SUMMARY OF THE CLIENT WORKSHOP FOR REFERENCE
VALUE ARRAYS
Workshop Summary
George Woodall, NCEA-RTP
This document provides a summary of a workshop that gathered a number of client
programs together to discuss the development of reference value arrays. This workshop
was conducted as a combination telephone and web-based conference, with voice
communication conducted via a telephone conference line and visual presentations
presented via the EPA Science Portal Web Conferencing capabilities.
Background
The U.S. EPA's National Center for Environmental Assessment (NCEA) has undertaken
a project to standardize the development of graphical arrays that compare inhalation
health effect reference values (e.g., RfCs, AEGLs) across durations, populations (e.g.,
general public vs. healthy workers), and intended use (e.g., general public vs. emergency
response vs. repeated occupational vs. occupational ceiling values). A number of program
offices within the Agency, as well as other Federal and State agencies, have an interest in
having these types of arrays available. The eventual users of these arrays and
accompanying documentation includes risk assessment professionals, decision makers
(risk managers), and the general public. Accompanying explanatory text will need to be
provided with all arrays to provide an adequate foundation for understanding the arrays,
to enable an appropriate comparison of the displayed reference values, and to clearly
indicate that the various reference values are not "one-size-fits-all." Tables will also be
provided that include the numerical values, along with the details on derivation of the
values (i.e., critical study[ies], point of departure [POD], uncertainty factors [UF],
duration extrapolations, etc). The intent is to have finished, reviewed arrays available to
the public via the NCEA internet site.
Examples of these comparative arrays, accompanying tables, and the plans for this
project were discussed at the web-based workshop of representatives from client
organizations. The agenda is shown below.
Workshop Agenda
Introductions
Goals for the Workshop
Background and Context on Array Development
Review of Existing Arrays and Summaries
Supporting Information
o Context for comparing the available health effect reference values
o Data to include in accompanying tables
o Other elements to include?
September 2009 A- 1
-------
Programmatic Needs and Applications
o How can these arrays best support clients?
o What elements are most useful? What might be a distraction?
o What are some of the potential issues? Can they be addressed?
o Do arrays need to be tailored for different client needs?
Decisions on Elements and Format of Arrays
o Add Point of departure for each value?
o Include Cancer risk values? How best to do so?
Conclusions and Next Steps
o Current Project Schedule
o Is there a desire for continued Client Input?
o Which chemicals should be considered for the next phase?
Phase 1 of the Project Plan
Perform an inventory of existing arrays (January 26, 2009)
1. Currently 23 arrays are in various stages of completion, utilizing varying
formats
Determine priority list of chemicals for which arrays should be developed (January
31,2009)
1. Cross reference lists from OAQPS, NHSRC, DHS and others.
2. Develop draft list
3. Review with client Offices/Agencies in web-based workshop (see below)
Review existing arrays for completeness (QC) and accuracy (QA), and comparing
formats to determine most appropriate for final template to be used with all arrays
(February 27, 2009)
1. Review within NCEA
2. Review with client Program Offices and Agencies in a web-based workshop
(may delay finish date, depending on ability to schedule)
3. Determine final template(s)
Work to revise and finalize currently available arrays to conform to final template(s),
with priority given to arrays for the general public (April 30, 2009)
Develop additional general public arrays to meet APM (May 30, 2009)
Perform quality control checks and peer review of all chemical-specific array
products prior to posting
Example Arrays and Supporting Materials
The arrays themselves are the focal point for a broader discussion of the available
inhalation health effect reference values for a specific chemical. The most fully
developed package of array, introductory discussion, and supporting tables and text is
provided in the summary for mercury (Appendix B).
In addition to the more complete example using mercury, two representations of the
arrays developed for the chemical phosgene are shown below to illustrate how the
representation of the arrays have changed over time. Figure A-l shows one of the earliest
examples of array development for the chemical phosgene. Note that only the acute
reference values are represented here, the x-axis is not formatted logarithmically, and the
September 2009 A- 2
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long-term or chronic values are merely segregated to be longer than 24-hours. In
Figure A-2 more of the available reference values are displayed (including provisional
values), along with formatting that allows a more inclusive set of values across all
durations via the use of logarithmic scaling on the x-axis (denoted in hours).
Supporting Information
One of the basic requirements in providing the information represented in the arrays
credibly, is to include a foundational discussion of the nature, appropriate application,
and limitations for each type of reference value. This includes information that is taken
from a previously published paper42 where these issues were discussed, with explanatory
text and a table such as shown in Table 1-1.
In addition to the introductory information, more detailed information regarding the
specific reference values such as the study used as the basis for the derived reference
value, the uncertainty factors applied to the study NOAEL/LOAEL or other indicator of
toxic effect (e.g. BMDL), adjustments such as calculation of a human equivalent
concentration from an animal study, and extrapolations across durations. [NOTE:
Examples of the tables providing such information are shown in the tables included with
the individual, chemical-specific summaries in Section 2 of this document.]
Phosgene (CG)
Health Reference Value Array
l.\JC.-r\Jฃ. =
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-A-AEGL-3
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ERPG-3
D ERPG-2
D ERPG-1
O MRL
X CA-REL
IDLH*
O STEL*
O PEL / TLV / WPL *
O RfCorGPL
8 12 16 20 24
Exposure Duration (Hours)
Long-term/
Chronic
Figure A-l. First generation array example for phosgene.
42 Woodall, GM (2005) Acute health reference values: Overview, perspective, and current forecast of
needs. Journal of Toxicology and Environmental Health, Part A, 68:901-926
September 2009
A-3
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Phosgene
Inhalation Health Effect Reference Value Array
1 -Day 30-Days 7-Years 70-Years
A nc*no
1.0E+01 !
1.0E+00 =
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ERPG-3
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X CA-REL
IDLH *
O STEL *
O PEL/TLV/WPL*
MRL(1-14d)
- - MRL (14-364 d)
^ RfCorGPL
O Draft PAL-1
O Draft PAL-2
Draft PAL-3
0 1 10 100 1,000 10,000 100,000 1,000,000
Exposure Duration (Hours)
I * Indicates an occupational value; expert judgement necessary prior to applvinq these values to the general public. I
Figure A-2. Later version of the comparative array of inhalation health effect
reference values for phosgene.
September 2009
A-4
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Regarding the supporting information, a number of questions were posed for the
participants to consider and respond to following the meeting. Those questions are listed
below.
Is there an adequate foundation for understanding the arrays?
Do the arrays enable an appropriate comparison of reference values?
Is it clear that the Reference Values are not "one-size-fits-all?"
Programmatic Needs and Applications
An additional set of questions were posed to the participants regarding the needs for
and application of the arrays by their respective programs. Those questions along with
some of the discussion are provided below.
How can these arrays best support Program Offices and other clients?
What elements are most useful? What might be a distraction?
Do arrays need to be tailored for different client needs?
o Provisional values (PALs, and PPRTVs) are developed for a select Program
Office Need. Should they be included in "Public View" versions of arrays?
o Should there be "For Official Use Only" versions of the arrays?
In development of the final draft, selected participants were asked to respond to the
following questions:
What is your need for the graphical arrays?
What are you going to be using the graphical data arrays for?
The responses are quoted below:
Office of Air Quality Planning and Standards - "1. We need the graphical data arrays
to improve risk communication (with both our own risk managers and the public) in
our assessments of hazardous air pollutants emitted from industrial sources. 2. That's
what we're going to be using them for.
National Homeland Security Research Center - "I see their value in emergency
response or remedial actions - therefore, less for current use (for me) and more for
potential future use. Graphical representations such as the data arrays are excellent
tools when trying to communicate confusing sets of numbers to non-toxicologists. If
I were still a Regional Toxicologist, I would use them for risk communication with
community groups. If I had them during the hurricane Katrina response, they would
have been useful when selecting action levels. I have used them during table-top
exercises when acting either in the Environmental Unit or as a Subject Matter Expert
for selecting action levels and communicating the reason for my selection to the
Incident Command."
Decisions on Elements, Format and Appearance of Arrays
The latest versions of the arrays have attempted to use standard shapes to denote
related types of values.
Diamonds and Triangles for emergency response values
Circles for Occupational values
Squares for General Public values
Standard colors have also been used to denote severity as well as different systems of
reference values (e.g., to differentiate among several occupational values).
September 2009 A- 5
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Red for defining lethality threshold values
Gold for Irreversible/Serious effects
Blue for Reversible/Mild effects
Green for values deemed without any adverse effects
There was general agreement on using standards that are the same across arrays, so
that as these are used, they become familiar (e.g., the lack of a type of value would stand
out). The IDLH values are colored red; the other occupational values are shown in shades
ranging from gold to orange to yellow. Since the only occupational values that have a
readily understandable severity rating on them are the IDLH values, it was planned to
keep the shapes all circles for the occupational values and have the different color
shadings consistent for each type of occupational value (i.e., OSHA, NIOSH, ACGIH,
etc). On a related note, there was discussion of using hatching patterns or other ways to
distinguish between values for those who may be unable to distinguish colors or when
printing to a black and white printer.
A separate set of issues discussed the format for posting on the web. A set of
questions were provided to the participants in the workshop for consideration and
response after the meeting.
How best should the arrays and accompanying text be presented?
Is the Mercury Summary a good Template?
The introductory material and accompanying tables need to be linked (somehow)
with the arrays; are there any suggestions on accomplishing that goal?
The level of peer review (ranging from none to e.g., NAS review) would also be very
useful to include in the supporting tables. Not mentioned in the meeting, but used in some
applications, would be the level of confidence in the value and/or database. This is used
in the IRIS values where ratings of high, medium or low are provided. It should be noted,
however, that numerical values of total UFs and confidence levels are typically inversely
related.
Discussion also touched upon whether a standard range of concentrations be used
across all arrays or to have the range reflect the range of concentrations for the specific
chemical. The advantage of the former is that it would make it easier to do cross-
chemical comparisons of toxicity. The counter argument is that all values would not be
spread out for easy comparisons within a chemical array. There was general agreement
that arrays should have both a standard y-axis for cross-chemical comparisons, and a
more focused array for comparing values for a single chemical (i.e., both types of arrays
would be developed). One related suggestion was to use a Map and Map Inset approach
on the web site.
Labeling and shading of array legends to highlight the types of values (e.g.,
emergency response vs. occupational vs. protective) was also mentioned as an
enhancement to the arrays.
Conclusions and Next Steps
A request was made that the participants access the Environmental Science Connector
Project Page
(http://oaspub.epa.gov/portal/page/portal/ESConnector/CNTR ESC/ESCHOME/MYWO
September 2009 A- 6
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RKBENCH?escSelectedProjectId=24396) to help address some of the questions raised in
the workshop.
Mention was made of having a "protected" PDF version of the summaries such that
the array could not be copied and pasted by itself. The suggestion was also made to create
links to the source/supporting documents and doing "map insets" on the standardized
arrays to expand the details out for better within-chemical comparisons of values.
Also,the addition of cancer unit risks for inhalation and cancer slope factors for the oral
route at varying exposure levels will also be investigated, as will some of the
recommendations for more interactive arrays that would allow popups, dropdowns, etc.
with detailed information for specific reference values by clicking on the appropriate
portions of the arrays.
An update on progress is expected to be posted using the ESC Project page for the
client programs to be able to keep abreast of developments. Reciprocally, the project
team is hopeful that the representatives from the programs will provide useful input to the
project using that resource.
List of Workshop Participants
William Ashman, Battelle, Contractor to Department of Homeland Security
Deborah McKean, US EPA, National Homeland Security Research Center
Michele Burgess, US EPA, Office of Solid Waste and Emergency Response
Sarah Mazur, US EPA, Office of Science Policy
Deborah Burgin, ATSDR
Jayne Michaud, US EPA, Office of Solid Waste and Emergency Response
Ernest Falke, US EPA, Office of Pollution Prevention and Toxic Substances
Stan Durkee, US EPA, Office of Science Policy
John Lipscomb, US EPA, National Center for Environmental Assessment
John Vandenberg, US EPA, National Center for Environmental Assessment
Debra Walsh, US EPA, National Center for Environmental Assessment
Jess Rowland, US EPA, Office of Pollution Prevention and Toxic Substances
Schatzi Fitz-James, US EPA, Office Emergency Management
Roy Smith, US EPA, Office of Air Quality Planning and Standards
September 2009 A- 7
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APPENDIX B: PROCEDURES FOR DEVELOPING ARRAYS OF
HEALTH EFFECT REFERENCE VALUES
September 2009
Standardized procedures were used to identify source materials, extract and
process relevant information, incorporate the information into Reference Value Arrays,
and document the results. This set of procedures is anticipated to evolve as the process
for developing these arrays becomes more automated and database-oriented.
Additionally, it is anticipated that changes to format and customized options for
variations on the reference value arrays will need to be accommodated based on client
input.
This version begins with use of the best available electronic source for this
information at this time (the Air Toxics Health Effects Database or ATHED) and a
Microsoft Excel template for manipulating the data and rendering a graphical array of the
values. It is anticipated that ATHED will eventually be linked into or become a part of
the Health and Environmental Research Online (HERO) database, a data management
resource being developed by NCEA-RTP. It would be through HERO that a more
automated mechanism for the development and updating of reference value arrays would
be created.
The remainder of this document describes the process used to develop reference
value arrays and the supporting summary document. This process includes the use of
ATHED, original technical support documents and other reference materials describing
the derivation and use of the various reference values included in the arrays, a template
for developing two variations of the arrays developed in MS-Excel, and a template of
the summary document developed in MS-Word. The process is described below as the
steps taken in the process of developing the data arrays and supporting documentation.
Stepl: Query ATHED
ATHED is a database developed in MS-Access and the 2009 version was used
in this process (ATHED2009.mdb); however, the database is not at present available on-
line. A separate Access file (Link2ATHED2009.mdb) was developed that links to the
data tables in ATHED for the various purposes of querying and performing QC on the
database without cluttering up the original database. A series of queries were developed
within that linked database to standardize the units for the various values, and to create a
cross-tabulation that is most useful for creating an array using the Excel template. All
queries are provided in SQL format in Appendix A to this procedures document.
The first in the series of queries (RefValue-Std) performed the following: (1)
developed an ordering for exposure durations with acute, followed by subchronic, then
chronic; (2) standardized the "origin" field from ATHED; (3) converted the IDLH/10
back to IDLH values; (4) reported the values in original units and converted from ppm to
mg/m3 and vice versa; and (5) converted all durations into hours, including an assumption
of 613,200 hours (70 years) and 61,320 hours (7 years) as the upper limits for chronic and
subchronic values, respectively.
September 2009 B- 1
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The next query (RefValue-Std_Crosstab) took the output from the first query and
put into a cross-tabulation more amenable to use in Excel. This array also formatted
several fields (e.g., duration hours) to make them consistent and more well ordered. The
query also limited the selection of reference values to only be those for the inhalation
route, and for chemicals limited to the 24 identified for the current work effort. The
results from this query were copied into the Excel template as the initial basis for array
development.
Step 2: Verification of ATHED Data
As the data were taken from the ATHED output, they were verified by
comparison to the most updated versions of the source materials from the originating
organization responsible for each of the reference values. If there was a discrepancy, it
was noted in the spreadsheet by a yellow highlight and text in red font. This was done to
help facilitate QC of ATHED and support the upcoming update to that database.
Step 3: Development of the Reference Value Arrays
Once the data were verified and the values input into the "Plot Data" tab in the
Excel file, a draft of the array using a standard y-axis for concentrations of exposure
ranging from 10"7 to 105 mg/m3 was developed. This array, labeled the "Comparison
Array," was then manipulated to include labels for certain reference values and to adjust
the labeling of the legend to match the reference value to its appropriate type (i.e.,
Emergency Response, Occupational, or General Public).
The more critical array for the development of summary documents is found in
the tab labeled "Chemical-specific Array." In this array the range of concentrations is
limited to display only the range applicable to the specific chemical and to more clearly
enable the user to distinguish between reference values in close proximity to one another
on the array.
Hiding rows in the spreadsheet labeled Plot Data where a type of reference value
is not available removes the label from legend in both of the arrays. Additionally,
changes in the labels may be performed to reflect chemical-specific values not generally
found for most chemicals. For example, many of the chemical warfare agents have IDLH
and/or TWA values developed by the Army instead of one of the occupational health
agencies/organizations.
Once all of the appropriate labels have been hidden or revised, work may be
needed to add, format, or move the labels included in the array proper to avoid
overlapping text and other issues that make the labels unreadable or otherwise unclear.
Additionally, formatted, semi-transparent colored boxes with labels have been added to
the legend to segregate the emergency response, occupational, and general public values
from one another and to help identify which are in each category. The boundaries of these
colored boxes need to be manipulated based on the changes made to the Plot Data
spreadsheet.
Step 4: Export the Final Array
Once all of the manipulations of the array have been finalized and all the
formatting changes have been performed, the array area is highlighted and pasted into a
formatted PowerPoint file (ChemicalSpecificArrays.ppt) where additional formatting
September 2009 B- 2
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changes are performed and final branding labels are added. The most reliable way to
paste the array into the PowerPoint file is by using the pull-down "Edit" menu item,
selecting "Paste Special" and choosing to paste as an "Enhanced Metafile." Adjustments
are made to ensure that the array fits into the slide by dragging the top left and top right
corners to the edges of the slide. At this point, selecting "select all" from the pull-down
"Edit" menu item will select all elements on the slide. A right click on the mouse brings
up an options menu, and "Save as picture" should be selected to save the final array as an
enhanced metafile. The final array for that chemical is now available for inclusion into
the summary document.
Step 5: Develop the Summary Document
This step actually consists of several sub-steps and can be done in parallel with
the development of the graphical array. The introductory section of the summary
document is generally the same for each array and briefly describes the differences
between the categories of reference values (emergency response, occupational, and
general public), the durations for which each type of value is derived, and some
discussion of the populations and purposes for which the various reference values were
derived. Included in this introductory material is Table 1-1, which provides some of these
details in an organized fashion.
Summary tables are provided as a direct companion to the individual, chemical-
specific graphical arrays with many of the details that are important for a thorough
comparison between the reference values but are not easily included in a graphical
format. These details include the numerical concentration in both mg/m3 and ppm, the
duration for each value, the critical endpoint on which the value was based, identification
of the study(ies) from which the point of departure was taken, the uncertainty factors
used, and any other details relevant to derivation of the final reference value (e.g., use of
adjustments or extrapolations, such as for duration).
A final discussion section is provided to help lead the reader through a
comparison of the available reference values for the specific chemical, and to point out
any particular variation in the derivation of the values from usual procedures. As much as
possible, an objective tone is maintained and judgment on the merits of the use of one
value over another is avoided, with the exception that caution is urged to use the derived
values within the context for which they developed.
September 2009 B- 3
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APPENDIX C: QUERIES OF ATHED
RefValue-Std
SELECT tblBenchmarks.Benchmark_ID, tblBenchmarks.CAS_No,
tblChemical_Info.Chemical_Name, tblChemical_Info. Sortable_Name,
tblChemical_Info.Molecular_Weight, tblBenchmarks.Exposure_Route,
IIf([exposure_Type]="acute",l,IIf([exposure_Type]="subchronic",2,IIf([exposure_Type]="chron
ic",3,Null))) AS ExpTypeOrder, tblBenchmarks.Exposure_Type,
IIf(InStr([Data_Source],"AEGL")>0,"NAC/AEGL",IIf(InStr([Data_Source],"ERPG")>0,"AIHA/
ERPG",IIf(InStr([Data_Source],"ATSDR")>0,"ATSDR",IIf(InStr([Data_Source],"CAL")>0,"C
AL",[Data_Source])))) AS RefValOrigin, RefValueType.RefValueType,
IIf([tblBenchmarks].[Benchmark_Type]="ID/10","IDLH",IIf([tblBenchmarks].[Benchmark_Typ
e]="STEL",Trim([Data_Source]) & "-STEL",[tblBenchmarks].[Benchmark_Type])) AS
Benchmark_Type,
IIf(tblBenchmarks.Benchmark_Type="ID/l 0",tblBenchmarks.Benchmark_Value* 10,tblBenchm
arks.Benchmark_Value) AS Benchmark_Value, tblBenchmarks.Benchmark_Units,
IIf(UCase([Benchmark_Units])="PPM",[Benchmark_Value],IIf([Exposure_Route]="inhalation",
Ilf([B enchmark_Units]=" mg/cu
m",(24.45*[Benchmark_Value])/[Molecular_Weight],IIf([Benchmark_Units]="ug/cu
m",((24.45*[Benchmark_Value])/[Molecular_Weight])/1000,Null))))ASStd_ppm,
IIf(UCase([Benchmark_Units])="mg/cu
m",[Benchmark_Value],IIf([Exposure_Route]="inhalation",IIf(UCase([Benchmark_Units])="PP
M",([Benchmark_Value]*[Molecular_Weight])/24.45,IIf([Benchmark_Units]="ug/cu
m",[Benchmark_Value]/1000,Null)))) AS [Std_mg/m3],
Val(IIf([Exposure_Type]="chronic",613200,IIf([Exposure_Type]="subchronic",61320,IIf([Expo
sure_Type]="acute",IIf([AvgTime] Is Not
Null,IIf([AvgTime_Units]="min",Round([AvgTime]/60,2),[AvgTime]), 1))))) AS [Duration-hrs],
tblBenchmarks.AvgTime, tblBenchmarks.AvgTime_Units, tblBenchmarks.Benchmark_Date,
tblBenchmarks.Benchmark_Confidence, tblBenchmarks.Cancer, tblBenchmarks.Cancer_sites,
tblBenchmarks.Weight_of_Evidence, tblBenchmarks.HEC, tblBenchmarks.UF_cumulative,
tblBenchmarks.UF_interspecies, tblBenchmarks.UF_intraspecies, tblBenchmarks.UF LOAEL,
tblBenchmarks.UF_subchronic, tblBenchmarks.UF_database, tblBenchmarks.UF_other,
tblBenchmarks.Modifying_F actor
FROM [APM-125] LEFT JOIN (RefValueType RIGHT JOIN (tblBenchmarks LEFT JOIN
tblChemicalJnfo ON tblBenchmarks.CAS_No = tblChemical_Info.CAS_No) ON
RefValueType.Type_ID = tblBenchmarks.Benchmark_Type) ON [APM-125].CAS_No =
tblBenchmarks.CAS_No
WHERE (((tblBenchmarks.CAS_No)<>""))
ORDER BY tblChemical_Info.Sortable_Name, tblBenchmarks.Exposure_Route,
IIf([exposure_Type]="acute",l,IIf([exposure_Type]="subchronic",2,IIf([exposure_Type]="chron
ic",3,Null))), RefValueType.RefValueType,
IIf([tblBenchmarks].[Benchmark_Type]='TD/10",'TDLH",IIf([tblBenchmarks].[Benchmark_Typ
e]="STEL",Trim([Data_Source])&"-STEL",[tblBenchmarks].[Benchmark_Type]));
September 2009 C- 1
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RefValue-Std Crosstab
TRANSFORM Avg([RefValue-Std].[Std_mg/m3]) AS [AvgOfStd_mg/m3]
SELECT [RefValue-Std].CAS_No, [RefValue-Std].Chemical_Name, [RefValue-
Std].ExpTypeOrder, [RefValue-Std].RefValueType, [RefValue-Std].Exposure_Route,
[RefValue-Std].Exposure_Type, [RefValue-Std].RefValOrigin, [RefValue-
Std]. B enchmark_Ty pe
FROM [RefValue-Std] INNER JOIN [APM-125] ON [RefValue-Std].CAS_No = [APM-
125].CAS_No
WHERE ((([RefValue-Std].Exposure_Route)="inhalation"))
GROUP BY [RefValue-Std].CAS_No, [RefValue-Std].Chemical_Name, [RefValue-
Std].ExpTypeOrder, [RefValue-Std].RefValueType, [RefValue-Std].Exposure_Route,
[RefValue-Std].Exposure_Type, [RefValue-Std].RefValOrigin, [RefValue-
Std]^ enchmark_Ty pe
ORDER BY [RefValue-Std].CAS_No, [RefValue-Std].ExpTypeOrder, [RefValue-
Std].RefValueType, [RefValue-Std].Benchmark_Type
PIVOT Format([Duration-hrs],"000000.00");
September 2009 C- 2
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