[Federal Register Volume 66, Number 85 (Wednesday, May 2, 2001)]
[Notices]
[Pages 21940-21964]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-11001]
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ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-00312; FRL-6776-3]
National Advisory Committee for Acute Exposure Guideline Levels
(AEGLs) for Hazardous Substances; Proposed AEGL Values
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: The National Advisory Committee for Acute Exposure Guideline
Levels for Hazardous Substances (NAC/AEGL Committee) is developing
AEGLs on an ongoing basis to provide Federal, State, and local agencies
with information on short-term exposures to hazardous chemicals. This
notice provides AEGL values and Executive Summaries for 18 chemicals
for public review and comment. Comments are welcome on both the AEGL
values in this notice and the Technical Support Documents placed in the
public version of the official docket for these 18 chemicals.
DATES: Comments, identified by the docket control number OPPTS-00312,
must be received by EPA on or before June 1, 2001.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I. of the SUPPLEMENTARY INFORMATION. To ensure proper
receipt by EPA, it is imperative that you identify docket control
number OPPTS-00312 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: For general information contact:
Barbara Cunningham, Acting Director, Environmental Assistance Division
(7401), Office of Pollution Prevention and Toxics, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (202) 554-1404; e-mail address: [email protected].
For technical information contact: Paul S. Tobin, Designated
Federal Officer (DFO), Office of Prevention, Pesticides and Toxic
Substances (7406), 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (202) 260-1736; e-mail address: [email protected].
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the general public to provide an
opportunity for review and comment on ``Proposed'' AEGL values and
their supporting scientific rationale. This action may be of particular
interest to anyone who may be affected if the AEGL values are adopted
by government agencies for emergency planning, prevention, or response
programs, such as EPA's Risk Management Program under the Clean Air Act
and Amendments Section 112r. It is possible that other Federal agencies
besides EPA, as well as State and local agencies and private
organizations, may adopt the AEGL values for their programs. As such,
the Agency has not attempted to describe all the specific entities that
may be affected by this action. If you have any questions regarding the
applicability of this action to a particular entity, consult the DFO
listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document or Other Related Documents?
1. Electronically . You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations,'' ``Proposed Rules and Regulations,'' and then look up the
entry for this document under the ``Federal Register--Environmental
Documents.'' You can also go directly to the Federal Register listings
at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number OPPTS-00312. The official
record consists of the documents specifically referenced in this
action, any public comments received during an applicable comment
period, and other information related to this action, including any
information claimed as Confidential Business Information (CBI). This
official record includes the documents that are physically located in
the docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period, is available
for inspection in the TSCA Nonconfidential Information Center, North
East Mall Rm. B-607, Waterside Mall, 401 M St., SW., Washington, DC.
The Center is open from noon to 4 p.m., Monday through Friday,
excluding legal holidays. The telephone number of the Center is (202)
260-7099.
3. Fax-on-Demand. You may request to receive a faxed copy of the
document(s) by using a faxphone to call (202) 401-0527 and select the
item number 4800 for an index of the items available by fax-on-demand
in this category, or select the item number for the document related to
the chemical(s) identified in this document as listed in the chemical
table in Unit III. You may also follow the automated menu.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number OPPTS-00312 in the subject line on
the first page of your response.
1. By mail. Submit your comments to: Document Control Office
(7407), Office of Pollution Prevention and Toxics (OPPT), Environmental
Protection Agency, 1200 Pennsylvania Ave., NW, Washington, DC 20460.
(Note: for express delivery, please see ``In person or by courier'' in
Unit I.C.2.).
2. In person or by courier. Deliver your comments to: OPPT Document
Control Office (DCO) in East Tower Rm. G-099, Waterside Mall, 401 M
St., SW., Washington, DC. The DCO is open from 8 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
DCO is (202) 260-7093.
3. Electronically. You may submit your comments electronically by
e-mail to: [email protected], or mail your computer disk to the address
identified above. Do not submit any information electronically that you
consider to be CBI. Electronic comments must be submitted as an ASCII
file avoiding the
[[Page 21941]]
use of special characters and any form of encryption. Comments and data
will also be accepted on standard disks in WordPerfect 6.1/8.1 or ASCII
file format. All comments in electronic form must be identified by
docket control numbers OPPTS-00312. Electronic comments may also be
filed online at many Federal Depository Libraries.
D. How Should I Handle CBI that I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without official notice.
If you have any questions about CBI or the procedures for claiming CBI,
please consult the DFO listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data that you
used that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Offer alternative ways to improve the notice.
7. Make sure to submit your comments by the deadline in this
document.
8. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. Background
A. Introduction
EPA's Office of Prevention, Pesticides and Toxic Substances (OPPTS)
provided notice on October 31, 1995 (60 FR 55376) (FRL-4987-3) of the
establishment of the NAC/AEGL Committee with the stated charter
objective as ``the efficient and effective development of Acute
Exposure Guideline Levels (AEGLs) and the preparation of supplementary
qualitative information on the hazardous substances for federal, state,
and local agencies and organizations in the private sector concerned
with [chemical] emergency planning, prevention, and response.'' The
NAC/AEGL Committee is a discretionary Federal advisory committee formed
with the intent to develop AEGLs for chemicals through the combined
efforts of stakeholder members from both the public and private sectors
in a cost-effective approach that avoids duplication of efforts and
provides uniform values, while employing the most scientifically sound
methods available. An initial priority list of 85 chemicals for AEGL
development was published in the Federal Register of May 21, 1997 (62
FR 27734) (FRL-5718-9). This list is intended for expansion and
modification as priorities of the stakeholder member organizations are
further developed. While the development of AEGLs for chemicals are
currently not statutorily based, at lease one rulemaking references
their planned adoption. The Clean Air Act and Amendments Section 112(r)
Risk Management Program states, ``EPA recognizes potential limitations
associated with the Emergency Response Planning Guidelines and Level of
Concern and is working with other agencies to develop AEGLs. When these
values have been developed and peer reviewed, EPA intends to adopt
them, through rulemaking, as the toxic endpoint for substances under
this rule (see 61 FR 31685).'' It is believed that other Federal and
State agencies and private organizations will also adopt AEGLs for
chemical emergency programs in the future.
B. Characterization of the AEGLs
The AEGLs represent threshold exposure limits for the general
public and are applicable to emergency exposure periods ranging from 10
minutes to 8 hours. AEGL-2 and AEGL-3 levels, and AEGL-1 levels as
appropriate, will be developed for each of five exposure periods (10
and 30 minutes, 1 hour, 4 hours, and 8 hours) and will be distinguished
by varying degrees of severity of toxic effects. It is believed that
the recommended exposure levels are applicable to the general
population including infants and children, and other individuals who
may be sensitive and susceptible. The AEGLs have been defined as
follows:
AEGL-1 is the airborne concentration (expressed as parts per
million (ppm) or milligram/meter cubed (mg/m\3\)) of a substance above
which it is predicted that the general population, including
susceptible individuals, could experience notable discomfort,
irritation, or certain asymptomatic, non-sensory effects. However, the
effects are not disabling and are transient and reversible upon
cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m\3\)
of a substance above which it is predicted that the general population,
including susceptible individuals, could experience irreversible or
other serious, long-lasting adverse health effects, or an impaired
ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m\3\)
of a substance above which it is predicted that the general population,
including susceptible individuals, could experience life-threatening
health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels
that could produce mild and progressively increasing odor, taste, and
sensory irritation, or certain non-symptomatic, non-sensory effects.
With increasing airborne concentrations above each AEGL level, there is
a progressive increase in the likelihood of occurrence and the severity
of effects described for each corresponding AEGL level. Although the
AEGL values represent threshold levels for the general public,
including sensitive subpopulations, it is recognized that certain
individuals, subject to unique or idiosyncratic responses, could
experience the effects described at concentrations below the
corresponding AEGL level.
C. Development of the AEGLs
The NAC/AEGL Committee develops the AEGL values on a chemical-by-
chemical basis. Relevant data and information are gathered from all
known sources including published scientific literature, State and
Federal agency publications, private industry, public data bases, and
individual experts in both the public and private sectors. All key data
and information are summarized for the Committee in draft form by Oak
Ridge National Laboratories together with ``draft'' AEGL values
prepared in conjunction with NAC/AEGL Committee members. Both
[[Page 21942]]
the ``draft'' AEGLs and ``draft'' technical support documents are
reviewed and revised as necessary by the NAC/AEGL Committee members
prior to formal committee meetings. Following deliberations on the AEGL
values and the relevant data and information for each chemical, the
NAC/AEGL Committee attempts to reach a consensus. Once the NAC/AEGL
Committee reaches a consensus, the values are considered ``Proposed''
AEGLs. The Proposed AEGL values and the accompanying scientific
rationale for their development are the subject of this notice.
In this notice the NAC/AEGL Committee publishes proposed AEGL
values and the accompanying scientific rationale for their development
for 18 hazardous substances. These values represent the fourth set of
exposure levels proposed and published by the NAC/AEGL Committee EPA
published the first ``Proposed'' AEGLs for 12 chemicals from the
initial priority list in the Federal Register of October 30, 1997 (62
FR 58840-58851) (FRL-5737-3); for 10 chemicals in the Federal Register
of March 15, 2000 (65 FR 14186-14196) (FRL-6492-4); for 14 chemicals in
the Federal Register of June 23, 2000 (65 FR 39263-39277) (FRL-6591-2);
and for 7 chemicals in the Federal Register of December 13, 2000 (65 FR
77866-77874) (FRL-6752-5) in order to provide an opportunity for public
review and comment. In developing the proposed AEGL values, the NAC/
AEGL Committee has followed the methodology guidance ``Guidelines for
Developing Community Emergency Exposure Levels for Hazardous
Substances,'' published by the National Research Council of the
National Academy of Sciences (NAS) in 1993. The term Community
Emergency Exposure Levels (CELLS) is synonymous with AEGLs in every
way. The NAC/AEGL Committee has adopted the term Acute Exposure
Guideline Levels to better connote the broad application of the values
to the population defined by the NAS and addressed by the NAC/AEGL
Committee. The NAC/AEGL Committee invites public comment on the
proposed AEGL values and the scientific rationale used as the basis for
their development.
Following public review and comment, the NAC/AEGL Committee will
reconvene to consider relevant comments, data, and information that may
have an impact on the NAC/AEGL Committee's position and will again seek
consensus for the establishment of Interim AEGL values. Although the
Interim AEGL values will be available to Federal, State, and local
agencies and to organizations in the private sector as biological
reference values, it is intended to have them reviewed by a
subcommittee of the NAS. The NAS subcommittee will serve as a peer
review of the Interim AEGLs and as the final arbiter in the resolution
of issues regarding the AEGL values, and the data and basic methodology
used for setting AEGLs. Following concurrence, ``Final'' AEGL values
will be published under the auspices of the NAS.
III. List of Chemicals
On behalf of the NAC/AEGL Committee, EPA is providing an
opportunity for public comment on the AEGLs for the 18 chemicals
identified in the following table. This table also provides the fax-on-
demand item number for the chemical specific documents, which may be
obtained as described in Unit I.B.3.
A. Fax-On-Demand Table
Table 1.--Fax-On-Demand Numbers
------------------------------------------------------------------------
Fax-on-demand item
CAS No. Chemical name no.
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67-56-1 Methanol 4938
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77-81-6, Nerve Agents GA, 4940
107-44-8,....................... GB, GD, GF
96-64-0,........................
329-99-7........................
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79-10-7 Acrylic acid 4941
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107-18-6 Allyl alcohol 4879
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107-30-2 Chloromethyl 4880
methyl ether
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108-88-3 Toluene 4882
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108-95-2 Phenol 4943
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110-00-9 Furan 4885
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127-18-4 Tetrachloroethylen 4889
e
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509-14-8 Tetranitromethane 4894
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594-42-3 Perchloromethyl 4897
mercaptan
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630-08-0 Carbon monoxide 4944
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10294-34-5 Boron trichloride 4928
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19287-45-7 Diborane 4931
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50782-69-9 Nerve Agent VX 4945
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[[Page 21943]]
B. Executive Summaries
The following are executive summaries from the chemical specific
Technical Support Documents (which may be obtained as described in Unit
I.B.) that support the NAC/AEGL Committee's development of AEGL values
for each chemical substance. This information provides the following
information: A general description of each chemical, including its
properties and principle uses; a summary of the rationale supporting
the AEGL-1, -2, and -3 concentration levels; a summary table of the
AEGL values; and a listing of key references that were used to develop
the AEGL values. More extensive toxicological information and
additional references for each chemical may be found in the complete
Technical Support Documents. Risk managers may be interested to review
the complete Technical Support Document for a chemical when deciding
issues related to use of the AEGL values within various programs.
1. Methanol--i. Description. Methanol is a clear, colorless,
volatile flammable liquid with a pungent odor. It is used in industrial
production as a solvent and raw material for the production of many
important organic compounds.
The acute and short-term toxicity of methanol varies greatly
between different species: Due to pharmacokinetic differences, at
higher exposure concentrations rodents develop higher blood methanol
concentrations than humans and monkeys. Primate, but not rodent
species, show accumulation of the metabolite formate. At lower
concentrations methanol causes symptoms characteristic of effects on
the visual system, such as blurred vision, and the central nervous
system (CNS), such as nausea, dizziness, and headaches, as well as
slight eye and nose irritation. At high concentrations, the
accumulation of the toxic metabolite formic acid may lead to blindness
and death by metabolic acidosis. In rodents methanol causes
developmental toxic effects and fetal death.
The AEGL-1 was based on a pharmacokinetic study in which human
volunteers were exposed to 800 ppm methanol for 8 hours (Batterman et
al., 1998), because no other experimental human study was available
that used an exposure concentration above a level of 200 ppm, which was
used in other studies and which was considered below the AEGL-1
threshold. In this pharmacokinetic study no statement was made on the
presence or absence of any signs or symptoms of the methanol exposure;
in a personal communication, the second author, Dr. Franzblau, stated
that none of the subjects reported symptoms. A factor of 3 was applied
for intraspecies variation because the exposure level in the Batterman
et al. (1998) study was considered below the effect threshold and thus
the effect level was less severe than defined for the AEGL-1 level.
However, interindividual variability with regard to slight neurotoxic
effects (e.g., headache) is likely to exist (although it cannot be
quantified exactly from the existing experimental and epidemiological
studies) and, thus, it cannot be ruled out that a fraction of the
general population might experience slight effects under the exposure
conditions of the experimental study of Batterman et al. (1998), which
used healthy individuals. Because exposure repsonse data were
unavailable for all of the AGEL-specific exposure durations, temporal
extrapolation was used in the development of AEGL values for the
specific AEGL-time periods. The concentration exposure-time
relationship for many systematically acting vapors and gases may be
described by C\n\ x t = k, where C = concentration, t = time, k is a
constant, and the exponent n ranges from 0.8 to 3.5. In this case, the
value was scaled to appropriate exposure periods according to the dose-
response regression equation C\n\ x t = k, using the default of n = 3
for shorter exposure periods, due to the lack of suitable experimental
data for deriving the concentration exponent.
The AEGL-2 values were based on developmental toxic effects in
mice. After a single exposure to different concentration-time
combinations on gestational day 7, the most sensitive endpoint was
cervical rib induction, which occurred at concentration-time products
greater than or equal to 15,000 ppm x h, but not at concentration-
time products below 15,000 ppm x h (i.e., no effects were observed
after exposure to 2,000 ppm x 5 h, 2,000 ppm x 7 h and 5,000 ppm
x 2 h; authors expressed data only as C x t values) (Rogers et al.
1995, abstract; Rogers, 1999, personal communication). These results
are supported by a repeated exposure teratogenicity study (Rogers et
al., 1993), in which a significant increase in cervical vertebrae was
observed at 2,000 ppm or higher, and by a single 7-hour exposure study
at 10,000 ppm (Rogers et al., 1997). For the no-observed-effect level
(NOEL) of 2,000 ppm for 7 hours (Rogers et al. 1995, abstract; Rogers,
1999, personal communication), the corresponding end-of-exposure blood
concentration was measured as 487 mg/Liter (l) (Rogers et al., 1993). A
total uncertainty factor (UF) of 10 was applied. A factor of 1 was
applied for interspecies variability because a sensitive species was
used for derivation of AEGL-2 values and because toxicokinetic
differences between species were accounted for by using a
pharmacokinetic model for calculating exposure concentrations. A factor
of 10 was used for intraspecies variability because no information on
developmental toxic effects of methanol on humans is available and
because also for other chemicals the variability in susceptibility of
humans for developmental toxic effects is not well characterized. The
total UF was applied to the blood methanol concentration resulting in a
concentration of 48.7 mg/l. For this blood methanol concentration,
inhalation exposure concentrations for appropriate time periods were
calculated so that a blood methanol concentration of 48.7 mg/l would be
reached at the end of the time period. For these calculations, a
pharmacokinetic model based on the model from Perkins et al. (1995) was
used. The calculated exposure concentrations were set as AEGL-2 values.
For 10 minutes, a concentration of 11,000 ppm was calculated using the
pharmacokinetic model. Since this value was considered too close to the
10-minute AEGL-3 value of 15,000 ppm, the 10-minute AEGL-2 was set at
the 30-minute value.
The AEGL-3 values were based on acute lethal effects on humans
after oral methanol uptake (Naraqi et al., 1979; Erlanson et al., 1965;
Bennett et al., 1955; Gonda et al., 1978). For lethal cases without
relevant concommitant ethanol exposure, the peak blood methanol
concentration was calculated from the measured concentration and the
time between intoxication and measurement using Michaelis-Menten
kinetics. The lowest calculated peak blood concentration was 1,109 mg/l
from the study by Naraqi et al. (1979). Due to the very steep dose-
response curve for lethality in monkeys (Gilger and Potts, 1955), a
factor of 2 was applied to derive a peak blood concentration of 555 mg/
l as the NOEL for lethality. An factor of 3 was applied for
intraspecies variability, because of the very steep dose response-
relationship for lethality after oral exposure seen in rhesus monkeys
(Gilger and Potts, 1955) and because a factor of 10 would have resulted
in blood methanol concentrations of about 70 mg/l which would be far
below a level of 130-200 mg/l, at which ethanol therapy is recommended
(ATSDR, 1993; Becker, 1983; Meyer et al., 2000) (these
[[Page 21944]]
values refer to concentrations measured after hospital admission, which
are usually considerably lower than peak concentrations). For the
resulting blood methanol concentration of 185 mg/l, inhalation exposure
concentrations for appropriate time periods were calculated so that a
blood methanol concentration of 185 mg/l would be reached at the end of
the time period. For calculations, a pharmacokinetic model based on the
model from Perkins et al. (1995) was used. These exposure
concentrations were set as AEGL-3 values. The 10-minute AEGL-3 was set
at the 30-minute value because at the concentration of 44,000 ppm
calculated by the model additional immediate toxic effects could not be
excluded and because the calculated value is close to the lower
explosive limit in air.
The calculated values are listed in Table 2 below:
Table 2.--Summary Table of Proposed AEGL Values for Methanol\a\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 670 ppm 670 ppm 530 ppm 340 ppm 270 ppm Pharmacokinetic
(Nondisabling)................. (880 mg/m\3\)..... (880 mg/m\3\)..... (690 mg/m\3\)..... (450 mg/m\3\)..... (350 mg/m\3\)..... study (Batterman
et al., 1998);
according to a
personal
communication,
none of the
subjects reported
symptoms
(Franzblau, 1999;
2000)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 4,000 ppm 4,000 ppm 2,100 ppm 720 ppm 510 ppm No developmental
(Disabling).................... (5,200 mg/m\3\)... (5,200 mg/m\3\)... (2,800 mg/m\3\)... (940 mg/m\3\)..... (670 mg/m\3\)..... toxic effects in
mice Rogers et al.
(1993; 1995,
abstract; 1997);
Rogers (1999,
personal
communication)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 15,000 ppm 15,000 ppm 7,900 ppm 2,500 ppm 1,600 ppm Lethality in humans
(Lethal)....................... (20,000 mg/m\3\).. (20,000 mg/m\3\).. (10,000 mg/m\3\).. (3,300 mg/m\3\)... (2,100 mg/m\3\)... after oral
exposure (Naraqi
et al., 1979;
Erlanson et al.,
1965; Bennett et
al., 1955; Gonda
et al., 1978;
Meyer et al.,
2000)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Cutaneous absorption may occur; direct skin contact with the liquid should be avoided.
ii. References.
a. ATSDR (Agency for Toxic Substances and Disease Registry). 1993.
Methanol toxicity. American Family Physician. Vol. 47:163-171.
b. Batterman, S.A., Franzblau, A., D'Arcy, J.B., Sargent, NE.,
Gross, K.B., and Schreck, R.M. 1998. Breath, urine, and blood
measurements as biological exposure indices of short-term inhalation
exposure to methanol. International Archives of Occupational and
Environmental Health. Vol. 71:325-335.
c. Becker, C.E. 1983. Methanol poisoning. Journal of Emergency
Medicine. Vol. 1:51-58.
d. Bennett, I., Cary, F.H., Mitchell, G.L., and Cooper, M.N. 1953.
Acute methyl alcohol poisoning: a review based on experiences in an
outbreak of 323 cases. Medicine. Vol. 32:431-463.
e. Erlanson, P., Fritz, H., Hagstam, K. E., Liljenberg, B.,
Tryding, N., and Voigt, G. 1965. Severe methanol intoxication. Acta
Medica Scandinavica. Vol. 177:393-408.
f. Franzblau, A. 1999. Dr. Alfred Franzblau, University of Michigan
School of Public Health, Ann Arbor, MI. Personal communication. E-mail
dated June 14, 1999.
g. Franzblau, A. 2000. Dr. Alfred Franzblau, University of Michigan
School of Public Health, Ann Arbor, MI. Personal communication. E-mail
dated October 3, 2000.
h. Gilger, A.P. and Potts, A.M. 1955. Studies on the visual
toxicity of methanol. V. The role of acidosis in experimental methanol
poisonings. American Journal of Ophthalmology. Vol. 39:63-86.
i. Gonda, A., Gault, H., Churchill, D., and Hollomby, D. 1978.
Hemodialysis for methanol intoxication. The American Journal of
Medicine. Vol. 64:749-758.
j. Meyer, R.J., Beard, M.E.J., Ardagh, M.W., and Henderson, S.
2000. Methanol poisoning. New Zealand Medical Journal. Vol. 113:11-13.
k. Naraqi, S., Dethlefs, R.F., Slobodniuk, R.A., and Sairere, J.S.
1979. An outbreak of acute methyl alcohol intoxication. Australia and
New Zealand Journal of Medicine. Vol. 9:65-68.
l. Perkins, R.A., Ward, K.W., and Pollack, G.M. 1995. A
pharmacokinetic model of inhaled methanol in humans and comparison to
methanol disposition in mice and rats. Environmental Health
Perspectives. Vol. 103:726-733.
m. Rogers, J.M., Mole, M.L., Chernoff, N., Barbee, B.D., Turner,
C.I., Logsdon, T.R., and Kavlock, R.J. 1993. The developmental toxicity
of inhaled methanol in the CD-1 mouse, with quantitative dose-response
modeling for estimation of benchmark doses. Teratology. Vol. 47:175-
188.
n. Rogers, J.M., Barbee, B.D., and M.L. Mole. 1995. Exposure
concentration and time (C x T) relationships in the developmental
toxicity of methanol in mice. Toxicologist. Vol. 15:164 (abstract).
o. Rogers. J.M. and Mole, M.L. 1997. Critical periods of
sensitivity to the developmental toxicity of inhaled methanol in the
CD-1 mouse. Teratology. Vol. 55:364-372.
p. Rogers, J.M. 1999. USEPA. National Health and Environmental
Effects Research Laboratory, Research Triangle Park, NC. Personal
communication. Letter dated May 27, 1999.
2-5. Nerve Agents GA, GB, GD, GF--i. Description. The G-series
agents [GA (tabun), GB (sarin), GD (soman), and GF] are all toxic ester
derivatives of phosphonic acid containing either a cyanide or fluoride
substituent group, and are commonly termed ``nerve'' agents as a
consequence of their anticholinesterase properties. These compounds
were developed as chemical warfare agents, and one was used by chemical
terrorists in the 1995 incident of nerve agent exposure that took place
in the Tokyo subway system. The chemical names of these 4 agents are as
follows: Agent GA, dimethylamidocyanophosphate; Agent GB, isopropyl
methyl phosphonofluoridate; Agent GD, pinacolyl
methylphosphonofluoridate; and Agent GF, O-cyclohexylmethyl-
fluorophosphonate.
The G-agents are all viscous liquids of varying volatility (vapor
density relative to air between 4.86 and 6.33) with faint odors
(``faintly fruity,'' or ``spicy,'' ``odor of camphor''). Toxic effects
may occur at
[[Page 21945]]
concentrations below those of odor detection.
The vapor pressures and acute toxicity of the G-series agents are
sufficiently high for the vapors to be rapidly lethal. Within the G-
series, GB is considered largely a vapor hazard, while GD is considered
mainly a vapor hazard. GA represents a smaller vapor hazard and is
expected to present a relevant contact hazard. The vapor pressure of
agent GF is intermediate between that of agents GA and GD.
Exposure to acutely toxic concentrations of G-agents can result in
excessive bronchial, salivary, ocular, and intestinal secretion,
sweating, miosis, bronchospasm, intestinal hypermotility, bradycardia,
muscle fasciculations, twitching, weakness, paralysis, loss of
consciousness, convulsions, depression of the central respiratory
drive, and death. Minimal effects observed at low vapor concentrations
include miosis (pinpointing of the pupils of the eye, with subsequent
decrease in pupil area), tightness of the chest, rhinorrhea, and
dyspnea.
The results of agent GB vapor exposure studies conducted with human
volunteers indicate that the threshold for miosis and other minimal
toxic effects falls in the range of 0.05 to 0.5 mg/m\3\ for 10-30
minute exposures. These findings are based on the results of low-
concentration nerve agent exposures to informed volunteers who were
under clinical supervision during the periods of exposure as well as
for post-exposure periods of several months. Inconsistencies between
the studies in identifying the toxicity threshold may be due to
differences in individual sensitivities or breathing rates of the test
subjects, or to differences in experimental protocols or analytical
methods.
There is at present no evidence to indicate that asymptomatic
exposures to any of the G-agents result in chronic neurological
disorders. A major concern associated with symptomatic exposures to
anticholinesterase compounds such as the G agents is the possibility of
chronic neurological effects. In general, the available epidemiological
data indicate that most clinical signs of toxicity resolve within hours
to days; severe miosis may require several months after exposure for
resolution. However, several studies have shown that subclinical signs
may persist for longer periods. Following the chemical terrorist
attacks with nerve agent GB that occurred in Japan in 1994 and 1995,
clinical signs of agent toxicity were no longer apparent in the
surviving victims 3 months after the exposures had occurred. However,
several studies conducted on a small number of asymptomatic individuals
6-8 months after the attack revealed subclinical signs of
neurophysiological deficits as measured by event-related and visual
evoked potentials, psychomotor performance, and increases in postural
sway.
Small but measurable changes in single fibre electromyography
(SFEMG) of the forearm were detectable between 4 and 15 months
following exposure to a concentration of agent GB that produced minimal
clinical signs and symptoms in fully informed human subjects who were
under clinical supervision in compliance with Helsinki accords (Baker
and Sedgwick, 1996). The SFEMG effects were not clinically significant
and were not detectable after 15-30 months. In a separate study of
workers who had been occupationally exposed to agent GB (sarin),
altered electroencephalograms (EEGs) were recorded 1 year or more after
the last exposure had occurred. Spectral analysis of the EEGs indicated
significant increases in brain beta activity (12-30 Hz) in the exposed
group when compared to non-exposed controls, and sleep EEGs revealed
significantly increased rapid eye movement in the exposed workers;
these observations were not clinically significant. Increases in beta
activity were also observed in rhesus monkeys 1 year after being dosed
with 5 g GB/killogram (kg). Slight, but non-significant
increases in beta activity, without deleterious effects on cognitive
performance, were reported for marmosets injected with 3.0 g
GB/kg and tested 15 months later. The significance of subclinical
neurological effects for the long-term health of exposed individuals
has not been determined.
Animal data from vapor and oral exposure studies for agent GB
suggest that agent GB does not induce reproductive or developmental
effects in mammals. Oral exposure studies of agents GB and GD in lab
animals, as well as injection exposure studies of agent GA, likewise
suggest the lack of reproductive or development effects for these
agents. Agent GB was not found to be genotoxic in a series of microbial
and mammalian assays, but agent GA was reported to be weakly mutagenic.
There is no evidence that agents GB and GA are carcinogenic.
The data base for toxicological effects in humans is more complete
for agent GB than for any of the other G-agents. Furthermore, agent GB
is the only G-agent for which sufficient human data are available to
directly derive AEGL-1 and AEGL-2 values, and the only G-agent for
which sufficient laboratory animal data are available for deriving an
AEGL-3 value for all five AEGL time periods. The AEGL-1 values for
agent GB were derived from a study on human volunteers in which minimal
and reversible effects occurred as a consequence of a 20-minute
exposure to a GB vapor concentration of 0.05 mg/m\3\ (Harvey, 1952;
Johns, 1952).
The AEGL-2 values for agent GB were derived from a study in which
miosis, dyspnea, photophobia, inhibition of red blood cell
cholinesterase (RBC-ChE), and changes in SFEMG were observed in human
volunteers following a 30-minute exposure to 0.5 mg/m\3\ (Baker and
Sedgwick, 1996). The SFEMG changes noted in the study were not
clinically significant, and were not detectable after 15-30 months.
Baker and Sedgwick considered SFEMG changes to be a possible early
indicator or precursor of the nondepolarising neuromuscular block found
associated with Intermediate Syndrome paralysis in severe
organophosphorous insecticide poisoning cases. The study concluded that
these electromyographic changes were persistent (>15 months), but that
they were reversible and subclinical. While not considered debilitating
or permanent effects in themselves, SFEMG changes are here considered
an early indicator of exposures that could potentially result in more
significant effects. Selection of this effect as a protective
definition of an AEGL-2 level is considered appropriate given the steep
dose-response toxicity curve of nerve agents. This concept of added
precaution for steep dose-response is consistent with emergency
planning guidance for nerve agents previously developed by the National
Center for Environmental Health of the Centers for Disease Control and
Protection.
Animals exposed to low concentrations of the G agents exhibit the
same signs of toxicity as humans, including miosis, salivation,
rhinorrhea, dyspnea, and muscle fasciculations. Studies on dogs and
rats indicate that exposures to 0.001 mg GB/m\3\ for up to 6 hours per
day are unlikely to produce any signs of toxicity.
Because exposure-response data were unavailable for all of the
AEGL-specific exposure durations, temporal extrapolation was used in
the development of AEGL values for the AEGL-specific time periods. The
concentration-exposure time relationship for many systemically acting
vapors and gases may be described by C\n\ x t = k, where the exponent
n ranges from 0.8 to 3.5.
[[Page 21946]]
Ongoing but unpublished analyses of rat exposure data as performed by
Mioduszewski and his colleagues is indicating that the n value for
agent GB likely varies with exposure duration (t) (Mioduszewski et al.,
2000a, b). Future analyses may provide separate n values for different
duration periods of concern, and will be used when available. Current
analyses are based on a log-log linear regression of the lethality of
GB to female Sprague-Dawley rats (Mioduszewski et al., 2000a, b), which
yields an n value of 1.93 with a r\2\ of 0.9948. This value indicates a
good agreement between the data points. Given that all mammalian
toxicity endpoints observed in the data set for all nerve agents
represent different points on the response continuum for
anticholinesterase exposure, and that the mechanism of mammalian
toxicity (cholinesterase inhibition) is the same for all nerve agents,
the experimentally derived n = 2 from the Mioduszewski et al. (2000a,
b) rat lethality data set is used as the scaling function for the AEGL-
1 and AEGL-2 derivations rather than a default value. An n of 1.16 was
calculated for comparison using other data (human volunteer) and other
endpoints (e.g., GB-induced miosis in humans; see Appendix B). However,
due to a poor r\2\ (0.6704) and other uncertainties associated with
some of the exposure measurements in these earlier studies, Mioduszewki
et al., data were determined to be the best source of an estimate for
n. An n value of 2 was also used to derive the 8-hour AEGL-3 value for
GB from the experimental rat lethality data set in which animals were
exposed to GB vapor for a maximal period of 6 hours (Mioduszewski et
al., 2000a, b).
The fact that AEGL-1 and AEGL-2 analyses for agent GB are based on
data from human volunteers (Harvey, 1952; Johns 1952; Baker and
Sedgwick, 1996) precludes the use of an interspecies UF. To accommodate
known variation in human cholinesterase activity that may make some
individuals susceptible to the effects of cholinesterase inhibitors
such as nerve agents, a factor of 10 was applied for intraspecies
variability (protection of susceptible populations). A modifying factor
is not applicable. Thus, the total UF for estimating AEGL-1 and AEGL-2
values for agent GB is 10.
In comparison to agent GB, the data sets characterizing toxicity of
agents GA, GD, and GF are less complete. Nevertheless, the literature
clearly indicates that inhibition of cholinesterase activity is a
common mechanism of toxicity shared by all these nerve agents. Thus, it
was possible to develop AEGL estimates for agents GA, GD, and GF by a
comparative method of relative potency analysis from the more complete
data set for agent GB. This approach has been previously applied in the
estimation of nerve agent exposure limits, most recently by
Mioduszewski et al (1998).
The AEGL-1 and AEGL-2 values for agents GA, GD, and GF were derived
from the AEGL-1 and AEGL-2 values for GB using a relative potency
approach, based on the potency of the agents to induce LOAEL effects of
miosis, rhinorrhea, and SFEMG; and agent concentration in units of mg/
m\3\. Agents GA and GB were considered to have an equivalent potency
for causing miosis. Agents GD and GF are each considered approximately
twice as potent as agents GB or GA for these endpoints, and equipotent
to each other for AEGL-1 and AEGL-2 effects. Thus, the AEGL-1 and AEGL-
2 concentration values for agents GD and GF are equal to 0.5 times
those values derived for agents GA and GB.
AEGL-3 values for agent GB were derived from recent inhalation
studies in which the lethality of GB to female Sprague-Dawley rats was
evaluated for the time periods of 10, 30, 60, 90, 240, and 360 minutes
(Mioduszewski et al., 2000a, b). Both experimental LC01 and
LC50 values were evaluated. The use of a rat data set
resulted in selection of an interspecies UF of 3; the full default
value of 10 was not considered appropriate since the mechanism of
toxicity in mammals is cholinesterase inhibition. The full default
value of 10 for intraspecies uncertainty was considered necessary to
protect susceptible populations. Since a modifying factor is not
applicable, the total UF for AEGL-3 determination for agent GB is equal
to 30.
The AEGL-3 values for agent GA were derived from the AEGL-3 values
for GB using a relative potency approach based on lethality of the
agents; the potency of agent GA was considered to be only 1/2 that of
agent GB for this endpoint. Thus, the AEGL-3 concentration values for
agent GA are equal to 2.0 times the AEGL-3 values for agent GB.
The lethal potencies of agents GD and GF are considered equivalent,
and equipotent to that of agent GB. Thus, the AEGL-3 concentration
values for agent GB, GD, and GF are equivalent. A secondary and short-
term GD inhalation study of rat lethality for exposure times
30 minutes (Aas et al., 1985) lends support to the
assumption of lethal equipotency for agents GB and GD. Since the
principal mode of action (cholinesterase inhibition) for the G-agents
is identical, an n = 2 was used for deriving AEGL-3 values from the
data of Aas and his colleagues. Due to the sparse data set for this
agent, the full default values for interspecies (10) and intraspecies
(10) uncertainty were applied. Since a modifying factor is not
applicable, a total UF of 100 was used in deriving 10-minute AEGL-3
(0.27 mg/m\3\) and 30-minsute AEGL-3 (0.15 mg/m\3\) estimates for agent
GD from Aas et al. (1985).
The calculated values are listed in Table 3 below:
Table 3.--Summary of Proposed AEGL Values for Nerve Agents\a\ GA, GB, GD, and GF [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Agent Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
GA AEGL-1 0.0010 ppm 0.00060 ppm 0.00042 ppm 0.00021 ppm 0.00015 ppm Based on
(Non-disabling). (0.0069 mg/m\3\) (0.0040 mg/m\3\) (0.0028 mg/ (0.0014 mg/ (0.0010 mg/ relative
m\3\). m\3\). m\3\). potency from
GB\b\
--------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.013 ppm 0.0075 ppm 0.0053 ppm 0.0026 ppm 0.0020 ppm Based on
(Disabling)..... (0.087 mg/m\3\). (0.050 mg/m\3\). (0.035 mg/m\3\) (0.017 mg/m\3\) (0.013 mg/m\3\) relative
potency from
GB\b\
--------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.11 ppm 0.057 ppm 0.039 ppm 0.021 ppm 0.015 ppm Based on
(Lethal)........ (0.76 mg/m\3\).. (0.38 mg/m\3\).. (0.26 mg/m\3\). (0.14 mg/m\3\). (0.10 mg/m\3\). relative
potency from
GB\c\
[[Page 21947]]
--------------------------------------------------------------------------------------------------------------------------------------------------------
GB AEGL-1 0.0012 ppm 0.00068 ppm 0.00048 ppm 0.00024 ppm 0.00017 ppm Headache, eye
(Non-disabling). (0.0069 mg/m\3\) (0.0040 mg/m\3\) (0.0028 mg/ (0.0014 mg/ (0.0010 mg/ pain,
m\3\). m\3\). m\3\). rhinorrhea,
tightness in
chest, cramps,
nausea,
malaise, miosis
in human
volunteers
exposed to 0.05
mg/m\3\ for 20
minutes
(Harvey, 1952;
Johns, 1952)
--------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.015 ppm 0.0085 ppm 0.0060 ppm 0.0029 ppm 0.0022 ppm Miosis, dyspnea,
(Disabling)..... (0.087 mg/m\3\). (0.050 mg/m\3\). (0.035 mg/m\3\) (0.017 mg/m\3\) (0.013 mg/m\3\) RBC-ChE
inhibition,
SFEMG changes
in human
volunteers
exposed to 0.5
mg/m\3\ for 30
minutes (Baker
and Sedgwick,
1996)
--------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.064 ppm 0.032 ppm 0.022 ppm 0.012 ppm 0.0087 ppm Based on
(Lethal)........ (0.38 mg/m\3\).. (0.19 mg/m\3\).. (0.13 mg/m\3\). (0.070 mg/m\3\) (0.051 mg/m\3\) experimental
Sprague-Dawley
rat lethality
data (LC01 and
LC50); whole-
body dynamic
exposure to
concentrations
between 2-56 mg/
m\3\ for 3, 10,
30, 60, 90,
240, and 360
minutes
(Mioduszewski
et al.,
2000a,b)
--------------------------------------------------------------------------------------------------------------------------------------------------------
GD AEGL-1 0.00046 ppm 0.00026 ppm 0.00018 ppm 0.000091 ppm 0.000065 ppm Based on
(Non-disabling). (0.0035 mg/m\3\) (0.0020 mg/m\3\) (0.0014 mg/ (0.00070 mg/ (0.00050 mg/ relative
m\3\). m\3\). m\3\). potency from
GB\d\
--------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.0057 ppm 0.0033 ppm 0.0022 ppm 0.0012 ppm 0.00085 ppm Based on
(Disabling)..... (0.044 mg/m\3\). (0.025 mg/m\3\). (0.018 mg/m\3\) (0.0085 mg/ (0.0065 mg/ relative
m\3\). m\3\). potency from
GB\d\
--------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.049 ppm 0.025 ppm 0.017 ppm 0.0091 ppm 0.0066 ppm Based on
(Lethal)........ (0.38 mg/m\3\).. (0.19 mg/m\3\).. (0.13 mg/m\3\). (0.070 mg/m\3\) (0.051 mg/m\3\) relative
potency from
GB. Supported
by Wistar rat
LC50; dynamic
chamber
exposures at 21
mg/m\3\ for 3
time periods of
<30 minutes
duration (Aas
et al.,
1985)\e\
--------------------------------------------------------------------------------------------------------------------------------------------------------
GF AEGL-1 0.00049 ppm 0.00028 ppm 0.00020 ppm 0.00010 ppm 0.000070 ppm Based on
(Non-disabling). (0.0035 mg/m\3\) (0.0020 mg/m\3\) (0.0014 mg/ (0.00070 mg/ (0.00050 mg/ relative
m\3\). m\3\). m\3\). potency from
GB\d\
--------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.0062 ppm 0.0035 ppm 0.0024 ppm 0.0013 ppm 0.00091 ppm Based on
(Disabling)..... (0.044 mg/m\3\). (0.025 mg/m\3\). (0.018 mg/m\3\) (0.0085 mg/ (0.0065 mg/ relative
m\3\). m\3\). potency from
GB\d\
--------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.053 ppm 0.027 ppm 0.018 ppm 0.0098 ppm 0.0071 ppm Based on
(Lethal)........ (0.38 mg/m\3\).. (0.19 mg/m\3\).. (0.13 mg/m\3\). (0.070 mg/m\3\) (0.051 mg/m\3\) relative
potency from
GB\e\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Percutaneous absorption of G-agent vapor is known to be an effective route of exposure; nevertheless, percutaneous vapor concentrations needed to
produce similar adverse effects are greater than inhalation vapor concentrations by several orders of magnitude. Thus, the AEGL values presented are
considered protective for both routes of exposure.
\b\ Based on relative potency equal to that of agent GB (see section 4.3 and Mioduszewski et al., 1998)
\c\ Agent GA is considered approximately 1/2 as potent as GB in causing lethality; thus, AEGL-3 values for GA are estimated by multiplying each time-
specific AEGL-3 value for agent GB by a factor of 2 (see section 4.3 and Mioduszewski et al., 1998)
\d\ Agents GD and GF are considered approximately twice as potent as agents GA and GB for causing miosis, and equipotent to each other. Thus, AEGL-1
and AEGL-2 values are estimated by multiplying each time-specific AEGL-1 or AEGL-2 value for agent GB by a factor of 0.5 (see section 4.3 and
Mioduszewski et al., 1998)
\e\ Based on a relative potency for lethality of GD = GF = GB and lethality data of Aas et al. (1985) (which provides a 10-minute AEGL-3 estimate of
0.27 mg/m\3\and a 30-minute AEGL-3 value of 0.15 mg/m\3\) (see section 4.3 and Appendix A)
ii. References.
a. Aas, P., Sterri, S.H., Hjermstad, H.P., and Fonnum, F. 1985. A
method for generating toxic vapors of soman: toxicity of soman by
inhalation in rats. Toxicology and Applied Pharmacology. Vol. 80:437-
445.
b. Baker, D.J. and Sedgwick, E.M. 1996. Single fibre
electromyographic changes in man after organophosphate exposure. Human
and Experimental Toxicology. Vol. 15:369-375.
c. Harvey, J.C. 1952. Clinical observations on volunteers exposed
to concentrations of GB. Medical Laboratories Research Report No. 114,
[[Page 21948]]
Publication Control No. 5030-114 (CMLRE-ML-52), MLCR 114. Army Chemical
Center, Aberdeen Proving Ground, MD.
d. Johns, R.J. 1952. The effect of low concentrations of GB on the
human eye. Research Report No. 100, Publication Control No. 5030-100
(CMLRE-ML-52). Chemical Corps Medical Laboratories, Army Chemical
Center, Aberdeen Proving Ground, MD.
e. Mioduszewski, R.J., Reutter, S.H., Thomson, S.A., Miller, L.L.,
and Olajos, E.J. 1998. Evaluation of airborne exposure limits for G-
agents: occupational and general population exposure criteria. ERDEC-
TR-489. U.S. Department of the Army, Edgewood Research, Development and
Engineering Center, U.S. Army Chemical and Biological Defense Command,
Aberdeen Proving Ground, MD.
f. Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola,
B., Muse, W., Crosier, R., and Sommerville, D. 2000a. Estimating the
probability of sarin vapor toxicity in rats as a function of exposure
concentration and duration. Presented at the 39th Annual Meeting of the
Society of Toxicology, March, 2000, Philadelphia, PA. Toxicologist.
Vol. 54(1):18 (#84).
g. Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola,
B. Muse, W., Thomson, S., Sommerville, D., and Crosier, R. 2000b.
Estimating the probability of sarin vapor toxicity in rats as a
function of exposure concentration and duration. Proceedings of the
International Chemical Weapons Demilitarization Conference (CWD-2000),
The Hague, NL. May 21-24, 2000.
6. Acrylic acid--i. Description. Acrylic acid is a clear,
colorless, corrosive liquid with a pungent odor. The primary use of
acrylic acid, accounting for about two third of its use, is in the
production of acrylic esters and resins, which are used primarily in
coatings, paint, plastics, and adhesives. Acrylic acid is also used in
oil treatment chemicals, detergent intermediates, and water treatment
chemicals.
Except for reports on odor threshold and a personal communication
about irritative effects in humans no studies reporting effects in
humans are available. Irritative effects of acrylic acid in animals
have been described in studies using repeated 6-hour exposures of
rabbits, rats, and mice. Consistently, histopathological alterations of
the nasal mucosa was a more sensitive toxicological endpoint than the
appearance of clinical signs of irritation: The lowest concentrations
leading to clinical signs of irritation (concentrations without effect
given in brackets) were 129 (77) ppm in rabbits (blepharospasm,
perinasal and perioral wetness), 218 (114) ppm in rats (eyelid closure,
discharge from eyes), and 223 (72) ppm in mice (scratching at the
nose). Repeated exposure for 1-2 weeks led to histopatholgical changes
of the nasal mucosa at the lowest concentrations tested, which were 34
ppm for rabbits, 74 ppm for rats and 25 ppm for mice. In mice, effects
were found after exposure to 5 ppm for 22 hours/day, but not 6 hours/
day, for 2 weeks. A number of studies described lethal effects in rats.
In a study in which rats were exposed to acrylic acid aerosol (Hagan
and Emmons, 1988), LC50 values of 5,670; 3,804; and 2,553
ppm for 30 minutes, 1 hour, and 2 hours, respectively, were reported.
Studies evaluating the acute toxicity of acrylic acid vapors used very
small numbers of animals or were not reported in detail and gave
somewhat varying results. In summary, the available studies do not
indicate a large difference in the toxicity of acrylic acid vapor and
aerosol. No developmental toxic effects of acrylic acid were found in
several inhalation studies. Acrylic acid may have a weak clastogenic
effect in vitro. No carcinogenic effects were found after application
of acrylic acid in the drinking water, while after subcutaneous and
topical application tumors were found (probably attributable to local
irritative effects).
AEGL-1 values were based on the odor recognition threshold of 1 ppm
determined by Hellman and Small (1974). Since this odor threshold was
determined in a trained odor panel, it was assumed that the olfaction
of the general population is less good. For this reason, the reported
recognition threshold and not the detection threshold was chosen for
derivation of AEGL-1 values. This concentration of acrylic acid is
supposed to have warning properties since most people should perceive
the odor of acrylic acid at this concentration. Since the odor
threshold is considered to depend primarily on exposure concentration
and not much on exposure time, a flat line was used for time scaling.
An UF of 1 was applied for intraspecies variability because this factor
was considered adequate for an odor threshold. The derived values are
supported by irritative effects in humans: In a personal communication,
Renshaw (1991) reported that eye irritation was noted after exposure to
concentrations of 5-23 ppm for 15-30 minutes and that slight eye
irritation was experienced after exposure to 0.3-1.6 ppm for 30 minutes
to 2.5 hours. Since occurrence of slight eye irritation can be
tolerated at the AEGL-1 level these data support AEGL-1 values in the
latter concentration range.
The AEGL-2 was based on blepharospasm in rabbits observed during
the first and subsequent exposures in a teratogenicity study using
repeated exposures (Neeper-Bradley et al., 1997). Blepharospasm was
considered a sign of impaired ability to escape. The highest
concentration not leading to this effect was 77 ppm (the LOEL was 129
ppm). A total UF of 3 was used. An interspecies factor of 1 was applied
because the rabbit was considered a species especially sensitive for
blepharospasm/eyelid closure. An intraspecies factor of 3 was used
because it was assumed that only toxicodynamic, but not toxicokinetic
differences contribute to variability of this local effect. No
information was available on the exposure concentration dependence of
the time to onset of blepharospasm. Since the increase of this effect
with time was assumed to be small and observations from 6-hour exposure
periods were available, use of a flat line to derive values for
appropriate exposure periods was considered an appropriate approach.The
AEGL-3 was based on a mortality study in rats using single exposures
against acrylic acid aerosol for 30 minutes, 1 hour, or 2 hours (Hagan
and Emmons, 1988). Using Probit analysis, maximum likelihood estimates
for LC01 values were calculated for appropriate exposure
periods between 10 minutes and 8 hours. These values were similar to
the lower 95% confidence limit of LC05 values calculated by
Probit analysis. The same values were obtained when time scaling was
done according to the dose-response regression equation C\n\ x t = k,
using an n of 1.7, that was derived by Probit analysis from the data of
the AEGL-3 key study (Hagan and Emmons, 1988) or by linear regression
of log (LC50)-log (time) data. A total UF of 10 was used. An
interspecies factor of 3 was applied because the interspecies
variability was assumed to be small due to the facts that acrylic acid
is a contact-site, direct-acting toxicant, the mechanism of action is
unlikely to differ between species and the influence of metabolism,
detoxification, and elimination on lethal effects after inhalation is
estimated to be small. An intraspecies factor of 3 was applied because
a small interindividual variability can be assumed since acrylic acid
is a contact-site, direct-acting toxicant not requiring metabolic
conversion.
The calculated values are listed in Table 4 below:
[[Page 21949]]
Table 4.--Summary Table of Proposed AEGL Values for Acrylic Acid
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm 1.0 ppm Odor detection
(Nondisabling)................. (3.0 mg/m\3\)..... (3.0 mg/m\3\)..... (3.0 mg/m\3\).... (3.0 mg/m\3\).... (3.0 mg/m\3\).... threshold in humans
(Hellman and Small,
1974)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 26 ppm 26 ppm 26 ppm 26 ppm 26 ppm Blepharospasm in
(Disabling).................... (78 mg/m\3\)...... (78 mg/m\3\)...... (78 mg/m\3\)..... (78 mg/m\3\)..... (78 mg/m\3\)..... rabbits (Neeper-
Bradley et al., 1997)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 470 ppm 250 ppm 170 ppm 77 ppm 51 ppm Lethality in rats
(Lethal)....................... (1,400 mg/m\3\)... (750 mg/m\3\)..... (510 mg/m\3\).... (231 mg/m\3\).... (153 mg/m\3\).... (Hagan and Emmons,
1988)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. Hellman, T.M. and Small, F.H. 1974. Characterization of the odor
properties of 101 petrochemicals using sensory methods. Journal of the
Air Pollution Control Association. Vol. 24:979-982.
b. Hagan, J.V. and Emmons, H.F. 1988. Acrylic acid--acute
inhalation toxicity study in rats. Unpublished Report No. 87R-106. Rohm
and Haas Co., Spring House, PA.
c. Neeper-Bradley, T.L., Fowler, E.H., Pritts, I.M., and Tyler,
T.R. 1997. Developmental toxicity study of inhaled acrylic acid in New
Zealand White rabbits. Food and Chemical Toxicology. Vol. 35:869-880.
d. Renshaw, F.M. and Renshaw, F.M. 1988. Rohm and Haas Co. Personal
communication cited in Emergency Response Planning Guidelines, Acrylic
acid. AIHA (American Industrial Hygiene Association), Akron, OH.
7. Allyl alcohol--i. Description. Allyl alcohol is a colorless
liquid that is a potent sensory irritant. Toxic effects following
inhalation exposures to allyl alcohol vapor include lacrimation,
pulmonary edema and congestion, and inflammation, hemorrhage, and
degeneration of the liver and kidney. Human data were limited to
voluntary exposures for short durations and general statements about
the signs of toxicity following accidental exposures to unknown
concentrations of allyl alcohol for unspecified amounts of time in the
workplace. Animal data were limited to studies in which lethality was
the only endpoint of interest, subchronic exposures, or single-exposure
experiments in which the model was questionable.
The AEGL-1 value was based on the mean odor detection threshold
concentration of 1.8 ppm (AIHA, 1989). Odor is considered a threshold
effect; therefore the values were not scaled across time, but rather
the threshold value is applied to all times.
The AEGL-2 values were based on a subchronic exposure study in
which rats were repeatedly exposed to 40 ppm for 7 hours/day (Dunlap et
al., 1958). Irritation was noted to occur during the first few
exposures. An UF of 3 was applied for species to species extrapolation
because there did not appear to be much variation between species: A
NOEL for lethality was the same for 3 different species (mice, rats,
and rabbits). An UF of 3 was also applied for intraspecies
extrapolation. Although the traditional approach for UF in a case such
as this would argue for an uncertainty factor of 10 because of the lack
of data addressing interindividual variability, this would result in a
composite uncertainty factor of 30. An UF of 30 would drive the AEGL-2
values (8 hour AEGL-2 of 1.2 ppm) to a level that would be inconsistent
with available data: Dunlap, et al. (1958) reported that rats exposed
for 7 hours/day, 5 days/week for 60 exposures to 1, 2, or 5 ppm had no
observable adverse effects, while rats exposed to 20 ppm only exhibited
decreased body-weight gain, and Torkelson et al. (1959) reported that
no adverse effects were noted when rats, guinea pigs, rabbits, and dogs
were exposed to 2 ppm for 7 hours/day, 5 days/week for 28 exposures,
while exposure of rats, guinea pigs, and rabbits exposed to 7 ppm for 7
hours/day, 5 days/week for 134 exposures exhibited only reversible
liver and kidney damage. Therefore, a total UF of 10 was applied to the
AEGL-2 value.
The experimentally derived exposure value was then scaled to AEGL
time frames using the concentration-time relationship given by the
equation C\n\ x t = k, where the exponent n generally ranges from 1
to 3.5 (ten Berge, 1986). The value of n was not empirically derived
due to the unreliability and inconsistencies of the data; therefore,
the default value of n = 1 was used for extrapolating from shorter to
longer exposure periods and a value of n = 3 was used to extrapolate
from longer to shorter exposure periods. The 10-minute value was set
equal to the 30-minute value because it was considered too precarious
to extrapolate from the exposure duration of 7 hours to 10 minutes.
The AEGL-3 values were based upon a NOEL for lethality in mice,
rats, and rabbits of 200 ppm for 1 hour (Union Carbide, 1951). An UF of
3 was applied for species to species extrapolation because there did
not appear to be much variation across species for lethality. A NOEL
for lethality was the same for 3 different species (mice, rats, and
rabbits), and this endpoint was used for the AEGL-3 derivation.
Additionally, the use of a NOEL for lethality is inherently
conservative. An UF of 3 was also applied for intraspecies
extrapolation. As discussed in the AEGL-2 derivation unit, applying the
traditional UF of 10 to account for the lack of data addressing
interindividual variability would result in a composite UF of 30, which
would drive the AEGL-3 values to a level that would be inconsistent
with available data (1 hour AEGL-3 of 6.7 ppm; see AEGL-2 derivation in
this unit). Therefore, a total UF of 10 was applied to the AEGL-3
value.
The experimentally derived exposure value was then scaled to AEGL
time frames using the concentration-time relationship given by the
equation
C\n\ x t = k, where the exponent n generally ranges from 1 to 3.5
(ten Berge, 1986). Again, the value of n was not empirically derived
due to the unreliability and inconsistencies of the data; therefore a
default value of n should be used in the temporal scaling of AEGL
values across time. If one applies the default value of n = 1 for
extrapolating from shorter to longer exposure periods and a value of n
= 3 to extrapolate from longer to shorter exposure periods, one obtains
the following values: 10 minutes: 36 ppm; 30 minute: 25 ppm; 1 hour: 20
ppm; 4 hours: 5.0 ppm; 8 hours: 2.5 ppm. Going with a default value
results in AEGL values that are inconsistent with the available data.
The AEGL-2 data do not support the hypothesis that n = 1 for
extrapolation to 4 or 8 hours: When using an n = 1 (which assumes a
``worse case'' scenario) to extrapolate from 1 hour to 4 or 8 hours,
one obtains a 4-hour AEGL-3 value of 5.0 ppm, which
[[Page 21950]]
is almost identical to the 4-hour AEGL-2 value of 4.8 ppm, and an 8-
hour AEGL-3 value of 2.5 ppm, which is lower than the 8-hour AEGL-2
value of 3.5 ppm. The AEGL-2 values help to serve as a baseline: They
are based on a multiple exposure scenario in which rats exposed for 40
ppm for 7 hours/days exhibited reversible signs of irritation. It is
unreasonable to have AEGL-3 values below the AEGL-2 values. Therefore,
in the absence of any further data, an n of 2 was selected as a
reasonable compromise between the possible values for n as reported by
ten Berge (1986): It is between the most conservative n = 1 (which
results in unreasonable values) and an n = 3, a least conservative
value. AEGL-3 values are therefore derived using an n = 3 for
extrapolation to 10 and 30 minutes and an n = 2 for extrapolation to 4
or 8 hours.
The calculated values are listed in Table 5 below:
Table 5.--Summary of Proposed AEGL Values for Allyl Alcohol [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 1.8 1.8 1.8 1.8 1.8 Mean odor detection
(Nondisabling)................. (4.4)............. (4.4)............. (4.4)............ (4.4)............ (4.4)............ threshold (AIHA,
1989)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 9.6 9.6 7.7 4.8 3.5 Irritation in rats at
(Disabling).................... (23).............. (23).............. (19)............. (12)............. (8.5)............ 40 ppm for 7 hours
(Dunlap et al., 1958)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 36 25 20 10 7.1 NOEL for lethality in
(Lethality).................... (87).............. (61).............. (48)............. (24)............. (17)............. mice, rats, and
rabbits exposed to
200 ppm for 1 hour
(Union Carbide, 1951)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. AIHA. 1989. Odor thresholds for chemicals with established
occupational health standards. AIHA, Fairfax, VA.
b. Dunlap, M.K., Kodama, J.K., Wellington, J.S., Anderson, H.H.,
and Hine, C.H. 1958. The toxicity of allyl alcohol. American Medical
Association Archives of Industrial Health. Vol. 18:303-311.
c. ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases.
Journal of Hazardous Materials. Vol. 13:301-309.
d. Torkelson, T.R., Wolf, M.A., Oyen, F., and Rowe, V.K. 1959a.
Vapor toxicity of allyl alcohol as determined on laboratory animals.
American Industrial Hygiene Association Journal. Vol. 20:217-229.
e. Union Carbide and Carbon Corporation. 1951. Initial submission:
letter from DuPont Chemical to USEPA regarding a letter about toxicity
studies with allyl alcohol with cover letter dated October 15, 1992.
Doc. #88-920009857. Union Carbide and Carbon Corp., New York, NY.
8. Chloromethyl methyl ether--i. Description. Chloromethyl methyl
ether (CMME) is a man-made chemical that is highly flammable and a
severe respiratory, eye, nose, and skin irritant. Technical grade CMME
contains 1-8% bis-chloromethyl ether (BCME) as a contaminant. Since
humans are only exposed to technical grade CMME (a great deal of effort
is needed to remove ``all'' BCME from CMME), and the human and animal
inhalation exposure data all involved technical grade CMME, the AEGL
values derived in this document will address the toxicity and
carcinogenicity of technical grade CMME.
Acute exposure to technical grade CMME can lead to delayed fatal
pulmonary edema in humans and animals, whereas chronic occupational
exposure is linked with small-cell lung carcinoma. The carcinoma has a
distinct histology from that of cigarette smoking-associated lung
cancer and has a shorter latency period. BCME is a much more potent
carcinogen than CMME, and is widely believed to account for most or all
of the carcinogenicity of technical grade CMME. The EPA places
technical grade CMME (and BCME) in classification A (``human
carcinogen'') based on sufficient human carcinogenicity data. Technical
grade CMME acute inhalation toxicity has been studied in rats, mice,
and hamsters. Numerous epidemiological studies describe occupational
exposure to technical grade CMME, although CMME concentrations were
almost never measured.
No data were available to determine the concentration-time
relationship for CMME toxic effects. The concentration-time
relationship for many irritant and systemically acting vapors and gases
may be described by C\n\ x t = k, where the exponent n ranges from
0.8 to 3.5 (ten Berge et al., 1986). To obtain protective AEGL-2 and
AEGL-3 values for 30-480 minutes, n = 3 and n = 1 were used to
extrapolate to durations shorter and longer, respectively, than the
exposure duration in the key study (AEGL-1 values were not derived).
The 10-minute values were not extrapolated because the NAC determined
that extrapolating from 4 hours to 10 minutes is associated
with unacceptably large inherent uncertainty, and the 30-minute values
were adopted for 10 minutes to be protective of human health.
AEGL-1 values were not recommended because there were no inhalation
studies that had endpoints consistent with the definition of AEGL-1.
AEGL-2 values for technical grade CMME were based on a study in
which rats were exposed 30 times (probably for 6 hours/day, 5 days/
week) to 1 ppm technical grade CMME vapor (Drew et al., 1975). Two rats
died (exposure days 16 and 22) but their cause of death was not stated.
Some of the rats were allowed to live for their lifetime; they had
minimal mucosal effects and several had lung hyperplasia or squamous
metaplasia, but no tumors were reported. The AEGL-2 values were based
on a single 6-hour exposure, which is expected to cause a similar or
lower incidence of hyperplasia and/or metaplasia than 30 exposures. An
UF of 10 was used: 3 to account for sensitive humans (response to an
irritant gas hydrolyzed in situ is not likely to vary greatly among
humans) and 3 for interspecies extrapolation (little interspecies
variability was seen; the key study was repeat-exposure). A modifying
factor of 3 was applied to account for potential differences in BCME
content of technical grade CMME. The resulting AEGL values were
supported by a lifetime CMME rat and hamster study (Laskin et al.,
1975) and a 6-month BCME rat and mouse study (Leong et al., 1975,
1981).
CMME AEGL-2 values were also calculated using a BCME inhalation
cancer slope factor with extrapolation to 1/2 to 8 hours, and based on
10-\4\, 10-\5\, and
[[Page 21951]]
10-\6\ excess cancer risk levels (BCME was assumed to
represent 8% of CMME and to account for all CMME carcinogenicity). CMME
AEGL-2 values based on the noncarcinogenicity endpoints were lower than
those calculated for 10-\4\ excess cancer risk but were
similar to or greater than those calculated for 10-\5\ or
10-\6\ excess cancer risk. AEGL-2 values based on the
noncarcinogenic endpoints were considered to be more appropriate
because only multiple exposures to CMME were shown to result in tumor
formation, and AEGL values are applicable to rare events or single,
once-in-a-lifetime exposures of small populations in limited geographic
areas.
AEGL-3 values were derived from a rat inhalation LC50
study where exposure was for 7 hours (Drew et al., 1975). The threshold
for lethality, as represented by the LC01 (14.8 ppm)
calculated using probit analysis, was the AEGL-3 toxicity endpoint.
Animals that died, and to a lesser degree, animals surviving to 14
days, had increased relative lung weights, congestion, edema,
hemorrhage, and acute necrotizing bronchitis. An UF of 10 was used: 3
for sensitive humans (response to an irritant gas hydrolyzed in situ is
not likely to vary greatly among humans) and 3 for interspecies
extrapolation (little interspecies variability was seen, as expected
for an irritant gas hydrolyzed in situ). An additional modifying factor
of 3 was applied to account for potential differences in BCME content
of technical grade CMME. Comparable AEGL-3 values were obtained with
CMME in a hamster LC50 study and in a BCME single-exposure
rat study (Drew et al., 1975).
The calculated values are listed in Table 6 below:
Table 6.--Summary of Proposed AEGL Values for Chloromethyl Methyl Ether (CMME) [ppm(mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Level 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 Not Recommended (No studies available consistent with AEGL-1 definition)
(Nondisabling).................
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.076 0.076 0.061 0.038 0.025 Tracheal or bronchial
(Disabling).................... (0.25)............ (0.25)............ (0.20)........... (0.13)........... (0.082).......... squamous metaplasia;
regenerative lung
hyperplasia (Drew et
al., 1975).
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 1.2 1.2 0.94 0.59 0.43 Lethality threshold
(Lethal)....................... (3.9)............. (3.9)............. (3.1)............ (2.0)............ (1.4)............ for rats (Drew et
al., 1975).
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. Drew, R.T., Laskin, S., Kuschner, M., and Nelson, N. 1975.
Inhalation carcinogenicity of alpha halo ethers. I. The acute
inhalation toxicity of chloromethyl methyl ether and
bis(chloromethyl)ether. Archives of Environmental Health. Vol. 30:61-
69.
b. Laskin, S., Drew, R.T., and Cappiello, V., et al., 1975.
Inhalation carcinogenicity of alpha halo ethers. II. Chronic inhalation
studies with chloromethyl methyl ether. Archives of Environmental
Health. Vol. 30:70-72.
c. Leong, B.K.J., Kociba, R.J., Jersey, G.C., and Gehring, P.J.
1975. Effects from repeated inhalation of parts per billion of
bis(chloromethyl)ether in rats. Toxicology and Applied Pharmacology.
Vol. 33:175.
d. Leong, B.K.J., Kociba, R.J., and Jersey, G.C. 1981. A lifetime
study of rats and mice exposed to vapors of bis(chloromethyl)ether.
Toxicology and Applied Pharmacology. Vol. 58:269-281.
e. ten Berge, W. F., Zwart, A., and Appelman, L. M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
Vol. 13:302-309.
9. Toluene--i. Description. Toluene is a ubiquitous substance that
is widely used as a raw material in the chemical manufacturing
industry, as an additive in gasoline to increase the octane level, and
as a solvent in lacquers, paint thinners, glue, and other compounds.
The odor threshold for toluene ranges from 0.16 to 37 ppm for detection
and 1.9 to 69 ppm for recognition; the odor is not unpleasant. Toluene
is readily absorbed from the respiratory tract and distributed
throughout the body, accumulating in tissues with high lipid content.
Toluene is a CNS depressant and, at high concentrations, is irritating
to the eyes. Other toxic effects observed in humans include renal
toxicity, cardiac arrhythmias, blood dyscrasias, hepatomegaly, and
developmental abnormalities. A considerable amount of human and animal
data were available for derivation of AEGLs.
Mouse lethality data were used for the regression analyses of the
concentration-exposure durations. Regression analysis of the
relationship between time and concentration (C\n\ x t = k), based on
four studies with the mouse, the most sensitive species, showed that n
= 2. This relationship was used for all AEGL levels because the primary
mechanism of action of toluene is CNS depression, which at high
concentrations results in death.
The AEGL-1 was based on observations of mild sensory irritation and
headache in humans at a concentration of 100 ppm for up to 6 hours in
an atmosphere controlled setting (Andersen et al., 1983; Rahill et al.,
1996; Dick et al., 1984; Baelum et al., 1985; 1990). An UF of 3 was
chosen to protect sensitive individuals because the mechanism of action
for irritation is not expected to vary greatly among individuals and no
effects on ventilatory parameters were found at much higher
concentrations. Extrapolation was made to the relevant AEGL time points
using the relationship C\n\ x t = k where n = 2, based on the mouse
lethality data. The endpoint and values are supported by the multiple
studies with human subjects, some of which reported no effects at the
100 ppm concentration.
The AEGL-2 was based on more serious effects in humans at
concentrations of 200 ppm for 8 hours including
incoordination, dizziness, decreased reaction time, mental confusion,
muscular weakness, and nausea (Wilson, 1943; von Oettingen et al.,
1942). These effects were considered to represent the threshold for
impaired ability to escape. An UF of 3 was applied to account for
sensitive individuals because the threshold for CNS impairment does not
vary greatly among individuals. Extrapolation was made to the 10-
minute, 30-minute, 1-hour and 4-hour time points using the equation
C\n\ x t = k where n = 2 (based on mouse lethality data). The above
values are supported by the behavioral effects observed in monkeys
after a 50-minute exposure to 2,000 ppm toluene (Taylor and Evans,
1985). At this concentration-duration, these animals exhibited
significantly decreased
[[Page 21952]]
reaction time and decreased accuracy on matching to sample tasks.
Dividing the 2,000 ppm concentration by intra- and interspecies UF of 3
each (for a total of 10) results in values similar to those based on
the human data.
The AEGL-3 values were derived from the exposure concentrations
equal to one third of the mouse 1-hour LC50 reported by
Moser and Balster (1985). The 1-hour mouse LC50 of 19,018
ppm was divided by 3 to estimate the threshold for lethality. A total
UF of 10 was applied which includes 3 to account for sensitive
individuals and 3 for interspecies extrapolation (the mechanism of
action for severe CNS depression does not vary greatly among
individuals or among species). The estimated 1-hour threshold for
lethality of 6,339 ppm was extrapolated to the 10-minute, 30-minute, 4-
hour, and 8-hour AEGL-3 time points using the relationship C\n\ x t =
k where n = 2 (calculated from the mouse lethality data). These values
are supported by the accidental exposure of two men to an estimated
concentration of >1,842 ppm toluene for an average duration of 2.5
hours which resulted in severe but reversible CNS depression
(Meulenbelt et al., 1990). Scaling of this exposure to the 10-minute,
30-minute, 1-, 4-, and 8-hour time points yields slightly higher values
(2,400; 1,400; 970; 490; and 340 ppm, respectively) than those based on
the threshold for lethality in the mouse. The proposed values are
considered adequately protective since the mouse is more sensitive than
humans to the CNS effects of toluene.
The calculated values are listed in Table 7 below:
Table 7.--Summary of Proposed AEGL Values for Toluene [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 260 120 82 41 29 Eye irritation,
(Nondisabling)................. (980)............. (450)............. (300)............ (150)............ (112)............ headache in humans
(Andersen et al.,
1983)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 600 270 190 94 67 Incoordination, mental
(Disabling).................... (2,260)........... (1,020)........... (710)............ (340)............ (260)............ confusion, neuro-
behavioral deficits
in humans (Wilson,
1943; von Oettingen
et al., 1942)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 1,600 900 630 320 220 Lethality, \1/3\ of
(Lethal)....................... (6,000)........... (3,380)........... (2,360).......... (1,200).......... (830)............ the mouse 1-hour LC50
(Moser and Balster,
1985)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. Andersen, I., Lundqvist, G.R., Molhave, L., Pedersen, O.F.,
Proctor, D.F., Vaeth, M., and Wyon, D.P. 1983. Human response to
controlled levels of toluene in six-hour exposures. Scandinavian
Journal of Work and Environmental Health. Vol. 9:405-418.
b. Wilson, R.H. 1943. Toluene poisoning. Journal of American
Medical Association. Vol. 123:1106-1108.
c. von Oettingen, W.F., Neal, P.A., and Donahue, D.D., et al. 1942.
The toxicity and potential dangers of toluene with special reference to
its maximal permissible concentration. U.S. Public Health Service
Publication Health Bulletin No. 279:50.
d. Moser, V.C. and Balster, R.L. 1985. Acute motor and lethal
effects of inhaled toluene, 1,1,1-trichloroethane, halothane, and
ethanol in mice: Effects of exposure duration. Toxicology and Applied
Pharmacology. Vol. 77:285-291.
10. Phenol--i. Description. Phenol is a colorless to pink,
hygroscopic solid with a characteristic, sweet, tarry odor. Pure phenol
consists of white to clear acicular crystals. In the molten state, it
is a clear, colorless liquid with a low viscosity.
Cases of lethal poisoning of humans by phenol have been reported in
the literature after oral uptake or skin contact. Only few studies
reporting effects on humans after inhalation of phenol are available:
One study reported slight effects on liver and blood parameters
(increased serum transaminase activity, increased hemoglobin
concentration, increased numbers of white blood cells) after repeated
occupational exposure to a mean time-weighted average concentration of
5.4 ppm phenol (Shamy et al., 1994). Piotrowski (1971) did not report
on effects in a toxicokinetic study, in which subjects were exposed to
6.5 ppm for 8 hours. Likewise, Ogata et al. (1974) in a toxicokinetic
field study did not mention any effects on workers exposed to mean
workshift concentrations of 4.95 ppm. In persons exposed to >1 mg/l
phenol in contaminated drinking water for several weeks following an
accidental spill of phenol, gastrointestinal symptoms (diarrhea,
nausea, burning pain and sores in the mouth) and skin rashes occurred
(Baker et al., 1978). A geometric mean odor detection threshold of
0.060 ppm (range of all critiqued odor thresholds 0.0045-1 ppm) has
been reported (AIHA, 1989).
No studies reporting LC50 values for phenol in animals
are available. Oral LD50 values were reported as 420 mg/kg
for rabbits, 400-650 mg/kg for rats and 282-427 mg/kg for mice. In
rats, exposure to a phenol aerosol concentration of 900 mg/m3 resulted
in ocular and nasal irritation and slight incoordination after 4 hours
and tremors and prostration in 1 of 6 animals after 8 hours
(Flickinger, 1976). After 4 hours exposure to 211 and 156 ppm, a
decrease of the number of white blood cells, but no signs of toxicity
were reported (Brondeau et al., 1990). After exposure of rats to 0.5,
5, and 25 ppm for 6 hours/day, 5 days/week for 2 weeks no clinical,
hematological or histopathological effects were found (CMA, 1998;
Hoffmann et al., 1999). Continuous exposure to 5 ppm phenol for 90 days
caused no hematological or histological effects in rhesus monkeys, rats
and mice. A concentration of 166 ppm (for 5 minutes) resulted in a 50%
decrease of respiration (RD50) in mice. No teratogenic
effects were found in rats and mice. An oral carcinogenicity study in
rats and mice, using exposure through drinking water, found an
increased tumor incidence in male rats of the low exposure group, but
not in male rats of the high exposure group or in female rats and mice.
Phenol has tumor promoting activity when applied dermally and can cause
clastogenic and possibly very weak mutagenic effects.
The AEGL-1 was based on a repeated inhalation exposure study in
rats (CMA, 1998; Hoffmann et al., 1999), which found no clinical,
hematological or histopathological effects after exposure to 25 ppm
phenol (highest concentration used) for 6 hours/day, 5 days/week for 2
weeks. A total UF of 10 was used. An UF of 3 was applied for
interspecies variability because a multiple exposure study was used for
the derivation of AEGL. A factor of 3 was applied for intraspecies
variability because the study reported no effects and thus was below
the AEGL-1 effect
[[Page 21953]]
level and because available human data do not point at a large
interindividual variability. The other exposure duration-specific
values were derived by time scaling according to the dose-response
regression equation C\n\ x t = k, using the default of n = 3 for
shorter exposure periods and n = 1 for longer exposure periods, due to
the lack of suitable experimental data for deriving the concentration
exponent. Continuation of the time scaling to the 10-minute period is
supported by the reported RD50 value of 166 ppm for an
exposure period of 5 minutes in mice (De Ceaurriz et al., 1981): The
resulting 10-minute AEGL-1 is 20-fold below the RD50 value
in mice.
The AEGL-2 was based on a repeated inhalation exposure study in
rats (CMA, 1998; Hoffmann et al., 1999), which found no clinical,
hematological or histopathological effects after exposure to 25 ppm
phenol (highest concentration used) for 6 hours/day, 5 days/week for 2
weeks, and on a single exposure study in rats, in which exposure to 900
mg/m\3\ phenol aerosol (equivalent to 234 ppm) led to ocular and nasal
irritation, muscle spasms and slight loss of coordination within 4
hours of exposure and to tremors and prostration in 1 of 6 animals at
the end of the 8-hour exposure period (Flickinger, 1976). A total UF of
3 was used for the study of CMA (1998), because the exposure
concentration used was a no-observed-adverse-effect level (NOAEL) in a
repeated exposure study and because use of a higher UF would resulted
in the same concentrations set as AEGL-1. This factor was formally
split up into an interspecies factor of 1 and an intraspecies factor of
3. A total UF of 30 was used for the Flickinger (1976) study. This
factor was formally split up into an interspecies factor of 3 and an
intraspecies factor of 10. The other exposure duration-specific values
were derived by time scaling according to the dose-response regression
equation C\n\ x t = k, using the default of n = 3 for shorter
exposure periods, due to the lack of suitable experimental data for
deriving the concentration exponent. For the 10-minute AEGL-2 the 30-
minute value was applied because the derivation of AEGL values was
based on a long experimental exposure period and no supporting studies
using short exposure periods were available for characterizing the
concentration-time-response relationship. Calculations were done on the
basis of both studies and resulted in very similar concentrations.
Since slightly lower values were obtained on basis of the CMA (1998)
study, these values were set as AEGL-2 values.
The AEGL-3 was based on an inhalation study in rats, in which
exposure to a phenol aerosol concentration of 900 mg/m\3\ phenol
(equivalent to 234 ppm phenol vapor) for 8 hours resulted in tremors,
incoordination and prostration in 1 of 6 animals, but not in death
(Flickinger, 1976). This study is supported by the study of Brondeau et
al. (1990), which did report only slight effects after exposure of rats
to 211 ppm phenol vapor for 4 hours. The comparison of the dose
equivalent to the derived AEGL-3 values with human oral lethality data
supports use of a total UF of 10. An additional argument for not
choosing a total UF higher than 10 is that a factor of 30 would have
resulted in corresponding body doses in the dose range described by
Baker et al. (1978) for an incident of drinking water contamination. In
this study mainly mild gastrointestinal (local) effects, but no
systemic/severe effects, were observed upon repeated oral exposure. The
total UF of 10 was formally split up into an interspecies factor of 3
and an intraspecies factor of 3. The other exposure duration-specific
values were derived by time scaling according to the dose-response
regression equation C\n\ x t = k, using the default of n = 3 for
shorter exposure periods, due to the lack of suitable experimental data
for deriving the concentration exponent. For the 10-minute AEGL-3 the
30-minute value was applied because the derivation of AEGL values was
based on a long experimental exposure period and no supporting studies
using short exposure periods were available for characterizing the
concentration-time-response relationship.
The calculated values are listed in Table 8 below:
Table 8.--Summary Table of Proposed AEGL Values for Phenol \a\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 8.3 ppm 5.7 ppm 4.5 ppm 2.9 ppm 1.9 ppm No effects in rats
(Nondisabling)................. (32 mg/m\3\)...... (22 mg/m\3\)...... (17 mg/m\3\)..... (11 mg/m\3\)..... (7.3 mg/m\3\).... (CMA, 1998; Hoffmann
et al., 1999)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 19 ppm 19 ppm 15 ppm 9.5 ppm 6.3 ppm No effects in rats
(Disabling).................... (73 mg/m\3\)...... (73 mg/m\3\)...... (58 mg/m\3\)..... (36 mg/m\3\)..... (24 mg/m\3\)..... (CMA, 1998; Hoffmann
et al., 1999);
irritation, loss of
coordination,
tremors, and
prostration in rats
(Flickinger, 1976)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 59 ppm 59 ppm 47 ppm 29 ppm 23 ppm No lethality in rats
(Lethal)....................... (230 mg/m\3\)..... (230 mg/m\3\)..... (180 mg/m\3\).... (110 mg/m\3\).... (88 mg/m\3\)..... (Flickinger, 1976)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Rapid dermal penetration occurs from phenol vapor, molten phenol and phenol solutions; skin contact with molten phenol or concentrated phenol
solutions should be avoided; fatal intoxications have been observed when a small part of the body surface was involved.
ii. References.
a. Baker, E.L., Landrigan, P.J., Bertozzi, P.E., Field, P.H.,
Basteyns, B.J., and Skinner, H.G. 1978. Phenol poisoning due to
contaminated drinking water. Archives of Environmental Health. Vol.
33:89-94.
b. Brondeau, M.T., Bonnet, P., Guenier, J.P., Simon, P., and De
Ceaurriz, J. 1990. Adrenal-dependent leucopenia after short-term
exposure to various airborne irritants in rats. Journal of Applied
Toxicology. Vol. 10:83-86.
c. CMA (Chemical Manufacturers Association). 1998. Two-week (ten
day) inhalation toxicity and two-week recovery study of phenol vapor in
the rat. Huntingdon Life Scienes Study No. 96-6107, CMA Reference No.
PHL-4.0-Inhal-HLS. CMA, Phenol Panel, Arlington, VA 22209.
d. De Ceaurriz, J.C., Micillino, J.C., Bonnet, P., and Guinier,
J.P. 1981. Sensory irritation caused by various industrial airborne
chemicals. Toxicology Letters. Vol. 9:137-143.
e. Flickinger, C.W. 1976. The benzenediols: catechol, resorcinol
and hydroquinone--a review of the industrial toxicology and current
industrial exposure limits. American Industrial Hygiene Association
Journal. Vol. 37:596-606.
f. Hoffmann, G.M., Dunn, B.J., Morris, C.R., Butala, J.H., Dimond,
S.S., Gingell,
[[Page 21954]]
R., and Waechter, Jr., J.M. 1999. Two-week (ten-day) inhalation
toxicity and two-week recovery study of phenol vapor in the rat. The
Toxicologist. Vol. 48:115 (abstract).
g. Ogata, M., Yamasaki, Y., and Kawai, T. 1986. Significance of
urinary phenyl sulfate and phenyl glucuronide as indices of exposure to
phenol. International Archives of Occupational and Environmental
Health. Vol. 58:197-202.
h. Piotrowski, J.K. 1971. Evaluation of exposure to phenol:
absorption of phenol vapour in the lungs and through the skin and
excretion of phenol in urine. British Journal of Industrial Medicine.
Vol. 28:172-178.
i. Shamy, M.Y., el Gazzar, R.M., el Sa,yed, M.A., and Attia, A.M.
1994. Study of some biochemical changes among workers occupationally
exposed to phenol, alone or in combination with other organic solvents.
Industrial Health. Vol. 32:207-214.
11. Furan--i. Description. Furan is a colorless, highly flammable
liquid with a strong, ethereal odor. It is used primarily as an
industrial intermediate. Because of its relatively high vapor pressure,
furan is predicted to exist almost entirely in the vapor phase in the
atmosphere.
No toxicity data regarding human exposures to furan were available.
Animal toxicity data were limited, with much of the literature focused
on metabolism and disposition. Metabolism studies indicate that furan
is bioactivated to a reactive metabolite, cis-2-butene-1,4-dial, by
cytochrome P450 2E1. Quantitative toxicology data for effects following
inhalation exposure to furan were limited to one study.
An AEGL-1 was not derived for furan. No human or animal data
relevant to the derivation of an AEGL-1 for furan were available in the
searched literature.
The AEGL-2 derivation is based on the threshold for adverse effects
in male and female rats at a concentration of 1,014 ppm for 1 hour
(Terrill et al., 1989). Although the severity of the reported clinical
signs (respiratory distress, increased secretory response) was not
reported, this lowest-exposure concentration group did not exhibit a
decrease in body weights like the rats exposed to 2,851 ppm or 4,049
ppm.
The AEGL-3 derivation is based upon the highest NOEL for mortality
in male and female rats of 2,851 ppm for 1 hour (Terrill et al., 1989).
Rats exposed to 1,014; 2,851; or 4,049 ppm exhibited clinical signs
including respiratory distress and increased secretory response:
however, the degree of the signs at each concentration was not
provided. Death occurred in the highest exposure group.
An UF of 10 was applied for species to species extrapolation
because quantitative toxicology data were available in only one
species, rats. Despite the predicted lower absorbed dose and liver dose
of the reactive metabolite in humans compared to rodents (following a
simulated exposure to 10 ppm for 4 hours, the predicted absorbed dose
of furan (mg/kg) in humans, and consequently the liver dose of the
reactive metabolite cis-2-butene-1,4-dial, was 10-fold less than in
mice and 3.5-fold lower than in rats (Kedderis and Held, 1996), the
differences between humans and rodents in sensitivity to the reactive
metabolite are not known, and the liver was the only organ
investigated. An UF of 3 was applied for sensitive individuals
(intraspecies) because interindividual variations in the activating
enzyme are not predicted to be a factor in bioactivation (Kedderis and
Held, 1996). A modifying factor of 3 was applied because only one data
set addressing furan toxicity following inhalation exposure was
available: This study was not repeated, and there was no information on
furan toxicity in other species or on reproductive/developmental
toxicity. Therefore, a total uncertainty factor/modifying factor of 100
was applied to the AEGL-2 and -3 values.
The experimentally derived exposure values were scaled to AEGL time
frames using the concentration-time relationship given by the equation
C\n\ x t = k, where the exponent n generally ranges from 1 to 3.5
(ten Berge, 1986). The value of n was not empirically derived because
of insufficient data; therefore, the default value of n = 1 was used
for extrapolating from shorter to longer exposure periods and a value
of n = 3 was used to extrapolate from longer to shorter exposure
periods.
The calculated values are listed in Table 9 below:
Table 9.--Summary of Proposed AEGL Values for Furan [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 Insufficient Data ID ID ID ID ID were available to
(Nondisabling)................. (ID)\a\ derive an AEGL-1
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 18 (50) 13 (39) 10 (28) 2.5 (7.0) 1.3 (3.6) 1,014 ppm for 1 hour:
(Disabling).................... Threshold for adverse
effects in rats
(clinical signs:
Severity of
respiratory distress,
increased secretory
response not
reported; no decrease
in body weights)
(Terrill et al.,
1989)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 52 (140) 46 (100) 29 (81) 7.1 (20) 3.6 (10) 2,851 ppm for 1 hour:
(Lethality).................... Threshold for
lethality in rats
(Terrill et al.,
1989)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects
ii. References.
a. ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases.
Journal of Hazardous Materials. Vol. 13:301-309.
b. Terrill, J.B., Van Horn, W.E., Robinson, D., and Thomas, D.L.
1989. Acute inhalation toxicity of furan, 2 methylfuran, furfuryl
alcohol, and furfural in the rat. American Industrial Hygiene
Association Journal. Vol. 50:A359-A361.
12. Tetrachloroethylene--i. Description. Tetrachloroethylene (PCE),
also commonly known as perchloroethylene or Perc, is a colorless,
nonflammable liquid. It has an ethereal odor, with a reported odor
threshold ranging from 2-71 ppm. PCE is commonly used as a dry-cleaning
solvent and as a degreaser, and is also used as a chemical intermediate
and as a veterinary antithelmintic.
Following exposure to PCE, humans primarily experience CNS effects
and irritation, with some cases of reversible
[[Page 21955]]
liver effects reported. CNS effects also predominate in animals,
although liver effects are noted in mice, and nephrotoxicity is
observed in rats. However, the hepatotoxicity and nephrotoxicity is
commonly associated with repeated or chronic exposures.
The AEGL-1 derivation is based on the exposure of six volunteers to
106 ppm for 1 hour (Rowe et al., 1952). At this level, an apparent non-
objectionable odor and eye irritation were noted, and one subject
experienced a light fullness in the head An interspecies UF was not
applicable. An intraspecies UF of 3 is applied because the Minimum
Alveolar Concentration (MAC; the concentration that produces lack of
movement in 50% of persons exposed) for volatile anesthetics does not
vary by more than a factor of 2-3-fold. The AEGL-1 values are
consistent with values that would be obtained using a study addressing
minor central nervous effects (changes in visual evoked potentials and
visual contrast sensitivity, significant performance deficits for
vigilance and eye-hand coordination) following exposure to 50 ppm for 4
hours (Altmann et al., 1990; 1992). If one bases on AEGL-1 on these
exposure parameters and uses the same UFs and value of n, one obtains
almost identical values.
The AEGL-2 value is based upon the no-effect level for ataxia in
rats following exposure to 1,150 ppm PCE for 4 hours/day, 5 days/week
for 2 weeks (4 hour time period was used for the derivation) (Goldberg
et al., 1964). Exposure to the next higher concentration of 2,450 ppm
resulted in reversible ataxia. An interspecies UF of 3 is applied based
on the similarity of effects manifested in rodents compared to humans
produced by agents that are CNS depressants. Additionally, a no-effect
level for lethality is identical for rats and mice and the 4-hour and
6-hour LC50 values in mice compared to rats vary by less
than 1.5-fold. An intraspecies UF of 3 is applied because the MAC for
volatile anesthetics does not vary by more than a factor of 2-3-fold.
The AEGL-2 values are supported by the Carpenter (1937) inhalation
study in which volunteers exposed to 475 ppm for 2 hours, 10 minutes
reported salivation, slight eye irritation, tightness in the frontal
sinuses, increased hand perspiration, and increased nasal irritation.
These effects are milder than those defined by AEGL-2. An AEGL
derivation based on the exposure parameters, a total UF of 3 (3 to
account for intraspecies variability; an interspecies UF not needed
because the derivation is based on human data), and an n of 2 results
in identical AEGL-2 values.
The AEGL-3 derivation is based on a no-effect-level for lethality
in mice of 2,450 ppm for 4 hours and in rats of 2,445 ppm for 4 hours
(Friberg et al., 1953; NTP, 1986). An interspecies UF of 3 is applied
because a no-effect level for lethality is identical for rats and mice
and the 4-hour and 6-hour LC50 values in mice compared to
rats vary by less than 1.5-fold. The interspecies UF of 3 is further
supported by the similarity of effects manifested in rodents compared
to humans produced by agents that are CNS depressants. An intraspecies
UF of 3 is applied because the MAC for volatile anesthetics should not
vary by more than a factor of 2-3-fold. The AEGL-3 values are supported
by a human study in which the effects noted were milder than those
defined by the AEGL-3 definition (humans exposed to 934 ppm for 95 min
experienced tightness of the frontal sinuses, increased hand
perspiration, nostril irritation, congestion of eustachian tubes,
lassitude, slight mental fogginess, stinging eyes, exhilaration, and/or
the tip of nose and lips anesthetized; Carpenter, 1937), and an animal
study in which rats exposed to 2,300 ppm for 4 hours/day, 5 days/week
for 2 weeks exhibited overt ataxia only following the first 4 hour
exposure (Goldberg et al., 1964). Although the Carpenter study (1937)
was not used because the effects were below that of the definition of
AEGL-3 type endpoints, the study does support the use of a total UF of
10 for the Friberg et al. (1953) and NTP (1986) studies as being
protective of human health.
The experimentally derived exposure values were then scaled to AEGL
time frames using the equation C\n\ x t = k, where the exponent n
generally ranges from 1 to 3.5 (ten Berge, 1986). The value of n used
for PCE was the calculated and published value of n = 2 based upon the
Rowe et al. (1952) rat mortality data for PCE (ten Berge, 1986). The
10-minute AEGL-1, -2, and -3 values were set equal to the 30-minute
values. The 10-minute AEGL-1 value was set equal to the 30-minute value
of 50 ppm because human data indicated that exposure to 75-80 ppm for
1-4 minutes resulted in slight eye irritation (Stewart et al., 1961).
The 10-minute AEGL-2 value was set equal to the 30-minute value of 330
ppm because it was considered too precarious to extrapolate from the
exposure duration of 4 hours to 10 minutes, and because a human study
demonstrated an exposure to 600 ppm for 10 minutes caused significant
effects (eye and nose irritation, dizziness, tightness, and numbing
about the mouth, some loss of inhibitions, and motor coordination
required great effort; Rowe et al., 1952). The 10-minute AEGL-3 was set
equal to the 30-minute value of 690 ppm because it was considered too
precarious to extrapolate from the exposure duration of 4 hours to 10
minutes.
The calculated values are listed in Table 10 below:
Table 10.--Summary of Proposed AEGL Values for Tetrachloroethylene [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 50 50 35 18 12 Mild eye irritation in
(Nondisabling)................. (340)............. (340)............. (240)............ (120)............ (81)............. six subjects exposed
to 106 ppm for 1 hour
(Rowe et al., 1952)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 330 330 230 120 81 No-effect level for
(Disabling).................... (2,200)........... (2,200)........... (1,600).......... (810)............ (550)............ ataxia in rats
following exposure to
1,150 ppm PCE for 4
hours/day, 5 days/
week for 2 weeks (4
hour time period used
for the derivation)
(Goldberg et al.,
1964).
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 690 690 490 240 170 No-effect-level for
(Lethal)....................... (4,700)........... (4,700)........... (3,300).......... (1,600).......... (1,200).......... lethality in mice of
2,450 ppm for 4 hours
and in rats of 2,445
ppm for 4 hours
(Friberg et al.,
1953; NTP, 1986)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 21956]]
ii. References.
a. Altmann, L., Bottger, A., and Wiegand, H. 1990.
Neurophysiological and psychophysical measurements reveal effects of
acute low-level organic solvent exposure in humans. Archives of
Occupational and Environmental Health. Vol. 62:493-499.
b. Altmann, L., Wiegand, H., Bottger, A., Elstermeier, F., and
Winneke, G. 1992. Neurobehavioral and neurophysiological outcomes of
acute repeated perchloroethylene exposure. Applied Psychology:
International Review. Vol. 41:269-279
c. Carpenter, C.P. 1937. The chronic toxicity of
tetrachloroethylene. Journal of Industrial Hygiene and Toxicology. Vol.
19:323-336.
d. Friberg, L., Kylin, B., and Nystrom, A. 1953. Toxicities of
trichloroethylene and tetrachloroethylene and Fujiwara's pyrindine-
alkali reaction. Acta Pharmacologica et Toxicologica. Vol. 9:303-312.
e. Goldberg, M.E., Johnson, H.E., Pozzani, U.C., and Smyth, H.F.
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. American Journal of Industrial Hygiene. Vol.
25:369-375.
f. NTP (National Toxicology Program). 1986. Toxicology and
Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) (CAS
No. 127-18-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP
TR 311, NIH Publication No. 86-2567, U.S. Department of Health and
Human Services, Research Triangle Park, NC.
g. Rowe, V.K., McCollister, D.D., Spencer, H.C., Adams, E.M., and
Irish, D.D. 1952. Vapor toxicity of tetrachloroethylene for laboratory
animals and human subjects. American Medical Association Archives of
Industrial Hygiene and Occupational Medicine. Vol. 5:566-579.
h. Stewart, R.D., Gay, H.H., Erley, D.S., Hake, C.L., and Schaffer,
A.W. 1961. Human exposure to tetrachloroethylene vapor. Archives of
Environmental Health. Vol. 2:40-46.
i. ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases.
Journal of Hazardous Materials. Vol. 13:301-309.
13. Tetranitromethane--i. Description. Tetranitromethane (TNM) is a
highly explosive chemical that is used as an oxidizer in rocket
propellants, to increase the cetane of diesel fuels, and as a reagent
to detect double bonds in organic molecules (Budavari et al., 1996;
ACGIH, 1996). TNM is also formed as an impurity during the manufacture
of trinitrotoluene (TNT). In humans, impure TNM has caused irritation
of the eyes, nose, throat, dizziness, chest pain, dyspnea,
methemoglobinemia, and cyanosis (Budavari et al., 1996). TNM causes a
variety of lung lesions and induced lung tumors in both rats and mice
(NTP, 1990).
No data were available to determine the concentration-time
relationship for TNM concentration-time relationship for many irritant
and systemically acting vapors and gases may be described by C\n\ x t
= k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al.,
1986). To obtain protective AEGL values, scaling across time was
performed using n = 3 to extrapolate to <6 hours (exposure duration in
key study) and n = 1 to extrapolate to >6 hours. The 10-minute values
were not extrapolated from 6 hours because the NAC determined that
extrapolating from 4 hours to 10 minutes is associated with
unacceptably large inherent uncertainty, and the 30-minute values were
adopted for 10 minutes to be protective of human health.
AEGL-1, AEGL-2, and AEGL-3 values were derived from an NTP (1990)
study in which rats and mice were exposed to 2, 5, 10, 25, or 50 (mice
only) ppm TNM for 2 weeks (6 hours/day, 5 days/week). At 2 ppm, no
effects were specifically noted in either species. A single 6-hour
exposure to 2 ppm was used for AEGL-1 derivation. An UF of 10 was
applied: 3 to account for sensitive humans (response to an irritant gas
is not likely to vary greatly among humans) and 3 for interspecies
extrapolation (toxicity of TNM did not vary greatly between two
species; the key study was repeat-exposure).
Exposure to 5 ppm TNM resulted in lowered body weight gains and
reddened lungs in mice (rats may have been lethargic), and one 6-hour
exposure is the basis for the derived AEGL-2 values. An UF of 10 was
used: 3 to account for sensitive humans (response to an irritant gas is
not likely to vary greatly among humans) and 3 for interspecies
extrapolation (most sensitive species was used; the key study was
repeat-exposure). The resulting AEGL-2 values were similar to those
derived using a TNM inhalation cancer slope factor (derived from a 103-
week NTP, 1990 carcinogenicity study) and based on a 10-\4\
excess cancer risk level. Use of the noncarcinogenicity endpoints was
considered to be more appropriate because it appears that the
tumorigenic response to inhaled TNM is a function of prolonged nasal
and lung tissue irritation resulting from repeated exposures and not
the result of a single-low exposure.
Rats and mice exposed to 10 ppm in the NTP (1990) 2-week study were
lethargic, lost weight, and the mice had reddened lungs, polypnea, and
ataxia, whereas rats exposed to 25 ppm all died on the first day, and
most mice exposed to 25 ppm died on day 3 or 4. Therefore, 10 ppm is
considered to approximate the lethality threshold for both species, and
is supported by an LC50 study in which the NOEL for
lethality for a 4-hour exposure was 10 and 17 ppm for rats and mice,
respectively (Kinkead et al., 1977a; 1977b). AEGL-3 values were
developed using one 6-hour exposure and an UF of 10: 3 to account for
sensitive humans (response to an irritant gas is not likely to vary
greatly among humans) and 3 for interspecies extrapolation (toxicity of
TNM did not vary greatly between two species; the key study was repeat-
exposure).
The calculated values are listed in Table 11 below:
Table 11.--Summary of Proposed AEGL Values for Tetranitromethane (TNM) [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 0.46 0.46 0.36 0.23 0.15 No effects in rats or
(Nondisabling)................. (3.7)............. (3.7)............. (2.9)............ (1.8)............ (1.2)............ mice (NTP, 1990).
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 1.1 1.1 0.91 0.57 0.38 Lower weight gain and
(Disabling).................... (9.1)............. (9.1)............. (7.3)............ (4.6)............ (3.5)............ reddened lungs in
mice (NTP, 1990).
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 2.3 2.3 1.8 1.1 0.75 Lethality threshold
(Lethal)....................... (28).............. (28).............. (15)............. (9.2)............ (6.0)............ for rats and mice
(NTP, 1990).
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 21957]]
ii. References.
a. NTP. 1990. Toxicology and carcinogenesis studies of
tetranitromethane in F344/N rats and B6C3F1 mice. TR #386, U.S.
Department of Health and Human Services, Public Health Service,
National Institutes of Health, Research Triangle Park, NC.
ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986. Concentration-
time mortality response relationship of irritant and systemically
acting vapors and gases. Journal of Hazardous Materials. Vol. 13:302-
309.
14. Perchloromethyl mercaptan--i. Description. Perchloromethyl
mercaptan is an oily, yellow liquid with an unbearable, acrid odor.
Although it was used as a chemical warfare gas by the French in the
battle of the Champagne in 1915, its wartime use was abandoned shortly
thereafter because of its strong warning odor, decomposition in the
presence of iron and steel, and because the vapors could easily be
removed by charcoal (Prentiss, 1937). Today, perchloromethyl mercaptan
is used as an intermediate in the synthesis of dyes and fungicides
(Captan, Folpet).
Data addressing human and animal toxicity following exposure to
perchloromethyl mercaptan vapors were very limited. Human data were
generally limited to case reports describing exposures to an
unquantifiable amount of perchloromethyl mercaptan, secondary sources,
and/or sources in which the experimental details were not provided.
Animal data addressing the lethal and nonlethal effects of
perchloromethyl mercaptan were primarily limited to rats.
Exposure to perchloromethyl mercaptan for 6 hours/day, 5 days/week
for 2 weeks at a concentration of 0.02 ppm did not result in any
measurable changes in rats, while exposure to 0.13 ppm resulted only in
mild nasal epithelial changes in rats (Knapp et al., 1987). Likewise,
no clear treatment related changes were observed in rats exposed to
0.014 or 0.079 ppm perchloromethyl mercaptan for 6 hours/day, 5 days/
week, for a total of 70 to 72 exposure days (Knapp and Thomassen,
1987). Based on these data, a NOAEL of 0.079 ppm in rats exposed for 6
hours/day, 5 days/week, for a total of 70 to 72 exposure days was used
for the derivation of an AEGL-1 (Knapp and Thomassen, 1987). An
interspecies factor of 3 was applied because although little is known
about differences in perchloromethyl mercaptan toxicity between
species, the AEGL-1 is based on a NOAEL from a subchronic study and is
therefore inherently conservative. An intraspecies UF of 3 was applied
to protect for sensitive individuals because the mechanism of action of
perchloromethyl mercaptan is likely to be that of an irritant.
A subchronic study in which rats were exposed to 0.58 ppm for 6
hours/day, 5 days/week for 70 days was chosen for the AEGL-2 derivation
(Knapp and Thomassen, 1987). Rats exposed to 0.58 ppm for 70 days
exhibited only minimal effects: Lung weights were increased, and the
only treatment-related pulmonary lesion was mild to minimal focal
subacute interstitial pneumonia in 28% of males and 6% of females. An
interspecies factor of 10 was applied because little is known about
differences in perchloromethyl mercaptan toxicity between species. An
intraspecies UF of 3 was applied to protect for sensitive individuals
because the mechanism of action of perchloromethyl mercaptan is likely
to be that of an irritant.
The no-effect level for lethality of 9 ppm for 1 hour in male and
female rats was chosen for use in the AEGL-3 derivation (Stauffer
Chemical Company, 1971). An interspecies factor of 10 was applied
because little is known about differences in perchloromethyl mercaptan
toxicity between species. An intraspecies UF of 3 was applied to
protect for sensitive individuals because the mechanism of action of
perchloromethyl mercaptan is likely to be that of an irritant.
The experimentally derived exposure values were scaled to AEGL time
frames using the concentration-time relationship given by the equation
C\n\ x t = k, where the exponent n generally ranges from 1 to 3.5
(ten Berge, 1986). The value of n was not empirically derived because
of insufficient data; therefore, the default value of n = 1 was used
for extrapolating from shorter to longer exposure periods and a value
of n = 3 was used to extrapolate from longer to shorter exposure
periods. The 10-minute values for the AEGL-1 and AEGL-2 levels were
flat-lined from the 30-minute values because it was considered too
precarious to extrapolate from an exposure duration of 6 hours to an
exposure duration of 10 minutes.
The calculated values are listed in Table 12 below:
Table 12.--Summary of Proposed AEGL Values for Perchloromethyl Mercaptan [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 0.018 0.018 0.014 0.0090 0.0060 NOAEL of 0.079 ppm for
(Nondisabling)................. (0.14)............ (0.14)............ (0.11)........... (0.068).......... (0.046).......... 6 hours/day, 5 days/
week for 70-72
exposure days (Knapp
and Thomassen, 1987)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.044 0.044 0.035 0.022 0.015 Treatment-related mild
(Disabling).................... (0.33)............ (0.33)............ (0.27)........... (0.17)........... (0.11)........... to minimal focal
subacute interstitial
pneumonia and
slightly increased
lung weights in rats
exposed to 0.58 ppm
for 6 hours/day, 5
days/week for 70 days
(Knapp and Thomassen,
1987)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.54 0.38 0.30 0.075 0.038 No-effect level for
(Lethality).................... (4.1)............. (2.9)............. (2.3)............ (0.57)........... (0.29)........... lethality in rats (9
ppm for 1 hour)
(Stauffer Chemical
Co., 1971)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. Knapp, H.F. and Thomassen, R.W. 1987. Subchronic inhalation
study with perchloromethyl mercaptan (PMM) in rats. Stauffer Chemical
Company. Report No. T-11848. Submitted by Zeneca, Inc., EPA/OTS; Doc.
#86-960000548. pp. 436.
b. Stauffer Chemical Co. 1971. Initial submission: acute inhalation
test with perchloromethyl mercaptan in rats with cover letter dated
August 28, 1992. Report No. T-1683. Submitted by ICI Americas Inc.,
EPA/OTS, Doc #88-920006928. pp. 7.
c. ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically
[[Page 21958]]
acting vapours and gases. Journal of Hazardous Materials. Vol. 13:301-
309.
15. Carbon monoxide--i. Description. Carbon monoxide (CO) is a
tasteless, non-irritating, odorless and colorless gaseous substance.
The main source of CO production is the combustion of fuels.
Environmental exposure to CO can occur while traveling in motor
vehicles (9-25 and up to 35 ppm), working, visiting urban locations
with heavily traveled roads (up to 50 ppm), or cooking and heating with
domestic gas, kerosene, coal or wood (up to 30 ppm) as well as in fires
and by environmental tobacco smoke. Endogenous CO formation during
normal metabolism leads to a background carboxyhemoglobin concentration
([COHb]) of about 0.5-0.8%. Smokers are exposed to considerable CO
concentrations leading to a [COHb] of about 3-8%.
CO binds to hemoglobin forming [COHb] and thereby renders the
hemoglobin molecule less able to bind oxygen. Due to this mechanism,
the oxygen transport by the blood and the release of bound oxygen in
the tissues are decreased. Tissue damage results from local hypoxia.
Organs with a high oxygen requirement, such as the heart and the brain,
are especially sensitive for this effect.
CO is a tasteless, non-irritating, odorless and colorless toxic gas
which can cause lethal poisonings with very few and late occurring
warning signs. Until very severe symptoms occur none or only
nonspecific symptoms are noted. For this reason, AEGL-1 values were not
recommended.
The AEGL-2 was based on cardiovascular effects in patients with
coronary artery disease, which constitute the most susceptible
subpopulation. For the derivation of AEGL-2 values a level of 4% [COHb]
was chosen. At this exposure level, patients with coronary artery
disease may experience a reduced time until onset of angina (chest
pain) during physical exertion (Allred et al., 1989; 1991). In the
available studies, the CO exposure alone (i.e., with subjects at rest)
did not cause angina, while exercise alone did so. However, it should
be noted that all studies used patients with stable exertional angina,
who did not experience angina while at rest. Thus, it cannot be ruled
out that in more susceptible individuals (a part of the patients with
unstable angina pectoris might belong to this group) CO exposure alone
could increase angina symptoms. The changes in the electrocardiogram
(ST-segment depression of 1 mm or greater) associated with angina
symptoms were fully reversible. An exposure level of 4% [COHb] is
unlikely to cause a significant increase in the frequency of exercise-
induced arrhythmias. Ventricular arrhythmias have been observed at
[COHb] of 5.3%, but not at 3.7% (Sheps et al., 1990; 1991), while in
another study no effect of CO exposure on ventricular arrhythmia was
found at 3 and 5% [COHb] (Dahms et al., 1993). An exposure level of 4%
[COHb] was considered protective of acute neurotoxic effects in
children, such as syncopes, headache, nausea, dizziness, and dyspnea
(Crocker and Walker, 1985), and long-lasting neurotoxic effects
(defects in the cognitive development and behavioral alterations) in
children (Klees et al., 1985). A mathematical model (Coburn et al.,
1965; Peterson and Stewart, 1975) was used to calculate exposure
concentrations in air resulting in a [COHb] of 4% at the end of
exposure periods of 10 and 30 minutes and 1, 4, and 8 hours. A total UF
of 1 was used. An intraspecies UF of 1 was considered adequate because
the values are based on observations in the most susceptible human
subpopulation (patients with coronary artery disease).
The AEGL-3 was based on observations in humans. Several case
reports indicate that in patients with coronary artery disease, CO
exposure can contribute to myocardial infarction (which was considered
an AEGL-3 endpoint). In the published cases of myocardial infarction,
the following [COHb] were measured after transport to the hospital:
52.2% (Marius-Nunez, 1990), 30%, 22.8% (Atkins and Baker, 1985), 21%
(Ebisuno et al., 1986), 15.6% (Grace and Platt, 1981). Case reports on
stillbirths after CO poisoning of pregnant women reported measured
maternal [COHb] of about 22-25% or higher (Caravati et al., 1988; Koren
et al., 1991). Since in all case studies COHb levels were determined
after admission to hospital, the [COHb] at the end of the exposure were
probably higher than the measured concentrations. These anecdotal case
reports were not considered an adequate basis for the derivation of
AEGL-3 values because of uncertainties in the end-of-exposure [COHb]
and the insufficient characterization of the exposure conditions (with
repeated and/or prolonged exposures in several cases). Therefore, the
experimental studies of Chiodi et al. (1941) and Haldane (1895), that
reported no severe or life-threatening symptoms in healthy subjects
exposed to a [COHb] of about 40-56%, were used as the basis for
derivation of AEGL-3 values. A mathematical model (Coburn et al., 1965;
Peterson and Stewart, 1975) was used to calculate exposure
concentrations in air resulting in a [COHb] of 40% at the end of
exposure periods of 10 and 30 minutes and 1, 4, and 8 hours. A total UF
of 3 was used. An intraspecies UF of 3 was applied to the calculated CO
concentrations in air because a factor of 10 would have resulted in
exposure concentrations sometimes found in homes and the environment
and because the derived values (corresponding to a [COHb] of about 15%)
are supported by information on effects, such as myocardial infarction
and stillbirths, reported in more susceptible subpopulations.
The calculated values are listed in Table 13 below:
Table 13.--Summary Table of Proposed AEGL Values for Carbon Monoxide
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 NR\a\ NR NR NR NR
(Nondisabling).................
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 420 ppm 150 ppm 83 ppm 33 ppm 27 ppm Cardiac effects in
(Disabling).................... (480 mg/m\3\)..... (170 mg/m\3\)..... (95 mg/m\3\)..... (38 mg/m\3\)..... (31 mg/m\3\)..... humans with coronary
artery disease
(Allred et al., 1989;
1991)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 1700 ppm 600 ppm 330 ppm 150 ppm 130 ppm No severe or life-
(Lethal)....................... (1,900 mg/m\3\)... (690 mg/m\3\)..... (380 mg/m\3\).... (170 mg/m\3\).... (150 mg/m\3\).... threatening effects
in humans (Chiodi et
al., 1941; Haldane,
1895)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Not recommended since CO is a non-irritating orderless gas which can cause lethal poisonings with very few late occurring warning signs.
[[Page 21959]]
ii. References.
a. Allred, E.N., Bleecker, E.R., Chaitman, B.R., Dahms, T.E.,
Gottlieb, S.O., Hackney, J.D., Pagano, M., Selvester, R.H., Walden,
S.M., and Warren, J. 1989. Short-term effects of carbon monoxide
exposure on the exercise performance of subjects with coronary artery
disease. New England Journal of Medicine. Vol. 321:1426-1432.
b. Allred, E.N., Bleecker, E.R., Chaitman, B.R., Dahms, T.E.,
Gottlieb, S.O., Hackney, J.D., Pagano, M., Selvester, R.H., Walden,
S.M., and Warren, J. 1991. Effects of carbon monoxide on myocardial
ischemia. Environmental Health Perspectives. Vol. 91:89-132.
c. Atkins, E.H. and Baker, E.L. 1985. Exacerbation of coronary
artery disease by occupational carbon monoxide exposure: A report of
two fatalities and a review of the literature. American Journal of
Industrial Medicine. Vol. 7:73-79.
d. Caravati, E.M., Adams, C.J., Joyce, S.M., and Schafer, N.C.
1988. Fetal toxicity associated with maternal carbon monoxide
poisoning. Annals of Emergency Medicine. Vol. 17:714-717.
e. Chiodi, H., Dill, D.B., Consolazio, F., and Horvath, S.M. 1941.
Respiratory and circulatory responses to acute carbon monoxide
poisoning. American Journal of Physiology. Vol. 134:683-693.
f. Coburn, R.F., Forster, R.E., and Kane, P.B. 1965. Considerations
of the physiological variables that determine the blood
carboxyhemoglobin concentration in man. Journal of Clinical
Investigation. Vol. 44:1899-1910.
g. Crocker, P.J. and Walker, J.S. 1985. Pediatric carbon monoxide
toxicity. The Journal of Emergency Medicine. Vol. 3:443-448.
h. Dahms, T.E., Younis, L.T., Wiens, R.D., Zarnegar, S., Byers,
S.L., and Chaitman, B.R. 1993. Effects of carbon monoxide exposure in
patients with documented cardiac arrhythmias. Journal of the American
College of Cardiology. Vol. 21:442-450.
i. Ebisuno, S., Yasuno, M., Yamada, Y., Nishino, Y., Hori, M.,
Inoue, M., and Kamada, T. 1972. Myocardial infarction after acute
carbon monoxide poisoning: case report. Angiology. Vol. 37:621-624.
j. Grace, T.W. and Platt, F.W. 1981. Subacute carbon monoxide
poisoning. Journal of the American Medical Association. Vol. 246:1698-
1700.
k. Haldane, J. 1895. The action of carbonic acid on man. Journal of
Physiology. Vol. 18:430-462.
l. Klees, M., Heremans, M., and Dougan, S. 1985. Psychological
sequelae to carbon monoxide intoxication in the child. The Science of
the Total Environment. Vol. 44:165-176.
m. Koren, G., Sharav, R., Pastuszak, A., Garrettson, L.K., Hill,
K., Samson, I., Rorem, M., King, A., and Dolgin, J.E. 1991. A
multicenter, prospective study of fetal outcome following accidental
carbon monoxide poisoning in pregnancy. Reproductive Toxicology. Vol.
5:397-403.
n. Marius-Nunez, A.L. 1990. Myocardial infarction with normal
coronary arteries after acute exposure to carbon monoxide. Chest. Vol.
97:491-494.
o. Peterson, J.E. and Stewart, R.D. 1975. Predicting the
carboxyhemoglobin levels resulting from carbon monoxide exposures.
Journal of Applied Physiology. Vol. 39:633-638.
p. Sheps, D.S., Herbst, M.C., Hinderliter, A.L., Adams, K.F.,
Ekelund, L.G., O'Neill, J.J., Goldstein, G.M., Bromberg, P.A., Dalton,
J.L., Ballenger, M.N., Davis, S.M., and Koch, G.G. 1990. Production of
arrhythmias by elevated carboxyhemoglobin in patients with coronary
artery disease. Annals of Internal Medicine. Vol. 113:343-351.
q. Sheps, D.S., Herbst, M.C., Hinderliter, A.L., Adams, K.F.,
Ekelund, L.G., O'Neill, J.J., Goldstein, G.M., Bromberg, P.A.,
Ballenger, M., Davis, S.M., and Koch, G. 1991. Effects of 4 Percent and
6 Percent Carboxyhemoglobin on Arrhythmia Production in Patients with
Coronary Artery Disease. Research Report No. 41. Health Effects
Institute, Cambridge, MA.
16. Boron trichloride--i. Description. Boron trichloride is a
colorless gas at room temperature that fumes in moist air, or a
colorless fuming liquid at low temperatures. It hydrolyzes in water and
moist air to produce heat, hydrochloric acid, and boric acid at
ordinary temperatures. No data were available regarding human exposures
to boron trichloride, and animal inhalation toxicity data were limited
to two studies. Vernot et al. (1977) reported 1-hour LC50
values of 2,541 ppm for male rats and 4,418 ppm for female rats. The
other available study by Stokinger and Spiegl (1953) served only as a
pilot study, and provided preliminary data on the toxicity of boron
trichloride vapor following inhalation exposure in rats, mice, and
guinea pigs.
No data relevant to the AEGL-1 defined endpoints were available.
Based on the knowledge that one mole of boron trichloride theoretically
hydrolyzes to form 3 moles of hydrogen chloride in moist air, the AEGL-
1 values were derived by a \1/3\ reduction of the accepted hydrogen
chloride (HCl) values and are recommended as guidance levels\a\. The
hydrogen chloride AEGL-1 was based on a 45 minute NOAEL in exercising
adult asthmatics (Stevens et al., 1992). No UFs were applied for inter-
or intraspecies variability since the study population consisted of
sensitive humans. Additionally, the same value was applied across the
10- and 30-minute, and 1-, 4-, and 8-hour exposure time points since
mild irritantcy is a threshold effect and generally does not vary
greatly over time. Thus, prolonged exposure will not result in an
enhanced effect.
No data relevant to the AEGL-2 defined endpoints were available.
Based on the knowledge that one mole of boron trichloride theoretically
hydrolyzes to form 3 moles of hydrogen chloride in moist air, the AEGL-
2 values were derived by a \1/3\ reduction of the accepted HCl values
and are recommended as guidance levels\a\. The hydrogen chloride AEGL-2
for the 30- minute, 1-, 4-, and 8-hour time points was based on severe
nasal or pulmonary histopathology in rats exposed to 1,300 ppm hydrogen
chloride for 30 minutes (Stavert et al.,1991). An UF of 3 was applied
for interspecies variability because the test species (rodents) is more
sensitive to the effects of hydrogen chloride than primates and because
direct irritation is not expected to vary greatly between species. An
UF of 3 was applied for intraspecies extrapolation since the mechanism
of action is direct irritation and the subsequent effect or response is
not expected to vary greatly among individuals. An additional modifying
factor of 3 was applied to account for the sparse database of effects
defined by AEGL-2 and since the effects observed at the concentration
used to derive AEGL-2 values were somewhat severe. Thus, the total
uncertainty and modifying factor adjustment is 30-fold. It was then
time-scaled to the 1-, 4-, and 8-hour AEGL exposure periods using the
C\n\ x t = k relationship, where n = 1 based on regression analysis
of combined rat and mouse LC50 data (1 minute to 100
minutes) as reported by ten Berge et al., 1986. The 10-minute AEGL-2
value was derived by dividing the mouse RD50 of 309 ppm by a
factor of 3 to obtain a concentration causing irritation (Barrow et
al., 1977). One-third of the mouse RD50 for hydrogen
chloride corresponds to an approximate decrease in respiratory rate of
30%, and decreases in the range of 20 to 50% correspond to moderate
irritation (ASTM, 1991).
The AEGL-3 was based on \1/3\ of the 1-hour boron trichloride
LC50 of 2,541 ppm in male rats (Vernot et al., 1977). An UF
of 3 was applied for intraspecies variability and an additional UF of
10
[[Page 21960]]
was applied for interspecies extrapolation to account for a poor data
base (total UF = 30). No boron trichloride data were available from
which to derive an n value for the scaling of the derived AEGL-3 value
across time. Because boron trichloride hydrolyzes in moist air to form
hydrogen chloride, the value of n = 1 for hydrogen chloride as
calculated by ten Berge (1986) was used for the scaling to the 10- and
30-minute, 1-, 4-, and 8-hour exposures using the relationship C\n\ x
t = k. The derived AEGL-3 values were consistent with the application
of the Stokinger and Spiegl (1953) data where exposure to 50 ppm for 2
x 7 hours in rats, mice, and guinea pigs did not result in mortality
when clean cages were substituted every 2 hours of the exposure (to
reduce contact with the hydrolysis products formed in the cage).
It is recommended that in the event of a boron trichloride release,
the concentrations of both boron trichloride and HCl should be
monitored. It is conceivable that boron trichloride concentrations
could be within the acceptable AEGL range, while the hydrolysis product
HCl could exceed permissible AEGL levels. Another likely situation is
that the concentration of each will fall below the AEGL criteria but
the combination of the two will produce an overall HCl exposure
exceeding a given AEGL criteria and thus produce more toxicity than
expected by the designated AEGL level.
The calculated values are listed in Table 14 below:
Table 14.--Summary of Proposed AEGL Values for Boron Trichloride [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 0.6 (2.9) 0.6 (2.9) 0.6 (2.9) 0.6 (2.9) 0.6 (2.9) Recommended as
(Nondisabling)................. guidance levels: \1/
3\ the NAC-approved
HCl values [NOAEL of
HCl in exercising
human asthmatics
(Stevens et al.,
1992)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 34 (160) 14 (67) 7.3 (35) 1.8 (8.6) 0.90 (4.3) Recommended as
(Disabling).................... guidance levels: \1/
3\ the NAC-approved
HCl values [Mouse
RD50 (Barrow et al.,
1977); Histopathology
in rats (Stavert et
al., 1991)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 170 (810) 57 (270) 28 (130) 7.1 (34) 3.5 (17) \1/3\ the 1-hour boron
(Lethal)....................... trichloride LC50
value of 2,541 ppm in
male rats (Vernot et
al., 1977)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References.
a. ASTM. (American Society for Testing and Materials). 1991.
Standard Test Method for estimating sensory irritancy of airborne
chemicals. Method E981, Vol. 11.04, pp. 610-619. Philadelphia, PA.
b. Barrow, C.S., Alarie, Y., Warrick, M., and Stock, M.F. 1977.
Comparison of the sensory irritation response in mice to chlorine and
hydrogen chloride. Archives of Environmental Health. Vol. 32:68-76.
c. Tavert , D.M., Archuleta, D.C., Behr, M.J., and Lehnert, B.E.
1991. Relative acute toxicities of hydrogen fluoride, hydrogen
chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing
rats. Fundamental and Applied Toxicology. Vol. 16:636-655.
d. Stevens, B., Koenig, J.Q., Rebolledo, V., Hanley, Q.S., and
Covert, D.S. 1992. Respiratory effects from the inhalation of hydrogen
chloride in young adult asthmatics. Journal of Occupational Medicine.
Vol. 34:923-929.
e. Stokinger, H.E. and Spiegl, C.J. 1953. Pharmacology and
Toxicology of Uranium Compounds. Vol. IV. McGraw-Hill, New York, NY.
f. ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases.
Journal of Hazardous Materials. Vol. 13:301-309.
g. USEPA (Environmental Protection Agency). 2000. Acute exposure
guideline levels (AEGLs) for hydrogen chloride (NAC/Proposed Draft 1:
5/2000).
h. Vernot, E.H., MacEwen, J.D., Haun, C.C., and Kinkead, E.R. 1977.
Acute toxicity and skin corrosion data for some organic and inorganic
compounds and aqueous solutions. Toxicology and Applied Pharmacology.
Vol. 42:417-423.
17. Diborane--i. Description. Diborane a highly unstable gas, and
is combustible upon exposure to moist air or high heat. It rapidly
hydrolyzes in water to produce boric acid, hydrogen, and heat. Because
of its strong reducing character, it has many industrial uses such as a
rubber vulcanizer, a catalyst for olefin polymerization, an
intermediate in the production of other boron hydrides, and as a doping
gas in the semiconductor industry. Diborane was also investigated in
the 1950's as a potential rocket fuel.
Data on acute exposures of humans to diborane were limited to case
reports of accidental work-related exposures. Signs and symptoms of
exposure included chest tightness, shortness of breath and dyspnea,
wheezing, nonproductive cough, and precordial pain. Workers exposed to
diborane generally experienced a complete recovery of symptoms within a
short period following exposure. No quantitative information was given
regarding the exposure terms of these individuals, and the data were
therefore unsuitable for derivation of AEGLs. No reports of death were
found in the literature.
Data on lethal and sublethal effects of diborane were available for
several animal species, including dogs, rats, mice, hamsters, rabbits,
and guinea pigs. Fifteen-minute LC50 values in rats ranged
from 159-182 ppm, and 4-hour LC50 values ranged from 40-80
ppm in rats and 29-31.5 ppm in mice. Animals exposed to lethal and
sublethal concentrations developed pulmonary hemorrhages, congestion,
and edema, and death was related to these severe pulmonary changes.
Recent studies in rats and mice have also uncovered the development of
multi-focal and/or diffuse inflammatory epithelial degeneration in the
bronchioles following exposure to diborane. These pulmonary changes
produced by exposure to sublethal concentrations were completely
reversible in rats by two weeks after an acute exposure, and were being
repaired in the mouse by 2 weeks post-exposure. The signs of toxicity
and repair of pulmonary lesions following acute exposure to sublethal
concentrations in animals were similar
[[Page 21961]]
to the human case reports. It is likely that the mechanism of toxicity
is due to direct interaction of diborane with cellular components,
especially since diborane is such a potent reducer. There appears to be
a similar mechanism of toxicity between species because the cause of
death from diborane exposure has always been from pulmonary damage,
including edema, hemorrhage, and congestion. Mice appeared to be the
more sensitive species, and the mice data were therefore used for the
derivations of AEGLs.
An AEGL-1 value was not derived because it was not appropriate. The
AEGL-2 value is below the odor threshold of diborane and no other data
pertaining to endpoints relevant to AEGL-1 definition were available.
The AEGL-2 values were based on a LOAEL (lowest-observed-adverse-
effect level) for pulmonary changes in male ICR mice following acute
inhalation exposure to diborane. No effects were observed in mice
exposed to 5 ppm for 1 hour, while exposure to 5 ppm for 2 hours
resulted in 4/10 mice developing multi-focal and/or diffuse
inflammatory epithelial degeneration in the bronchioles (Nomiyama et
al., 1995). There were no other treatment related changes, such as
changes in behavior or appearance, body or organ weight, or in
hematological or clinical chemistry indices.
The AEGL-3 values were based on the estimate a 4-hour
LC01 of 9.2 ppm obtained by probit analysis of data from a
4-hour LC50 study in male ICR mice (Uemura et al., 1995).
A total UF of 10 was applied to the AEGL-2 and AEGL-3 values. An
interspecies UF of 3 was applied because the most sensitive species,
the mouse, was used, and the endpoint of toxicity, histological changes
in the lungs, was the most sensitive endpoint. Further support of a
value of 3 is that signs of toxicity and repair of pulmonary lesions
following acute exposure to sublethal concentrations in animals were
similar to the human case reports. It is likely that the mechanism of
toxicity is due to direct interaction of diborane with cellular
components, especially since diborane is such a potent reducer. There
appears to be a similar mechanism of toxicity between species because
the cause of death from diborane exposure has always been from
pulmonary damage, including edema, hemorrhage, and congestion. An
intraspecies factor of 3 was applied because the mechanism of action is
not expected to differ greatly among individuals. The lung remained the
target organ at all concentrations of exposure, and the biological
response remained the same, becoming more severe with increasing
concentration until death occurred from anoxia as a consequence of
severe pulmonary changes.
The derived AEGL values were scaled to 10-minute, 30-minute, 1-
hour, 4-hour, and 8-hour exposures using C\n\ x t = k. To calculate n
for diborane, a regression plot of the effective concentration
(EC50) values was derived from the studies by Nomiyama et
al. (1995) and Uemura et al. (1995) investigating 1-, 2-, and 4-hour
exposures to 1, 5, or 15 ppm diborane, with multi-focal and/or diffuse
inflammatory epithelial degeneration in the bronchioles as the endpoint
of toxicity. From the regression analysis, the derived value of n = 1
was used in the temporal scaling of all the AEGL values (C\1\ x t =
k; Haber's Law). For the AEGL-3, the 30-minute value was flat-lined for
the 10-minute value because it was considered too precarious to
extrapolate from the exposure duration of 4 hours to 10 minutes.
Although it is considered appropriate to extrapolate from a 2-hour
exposure to a 10-minute exposure duration in the AEGL-2 derivation, the
10-minute value of 6.0 ppm would approach that of the 10-minute AEGL-3
value of 7.3 ppm. Therefore, the 30-minute AEGL-2 value was flat-lined
for the 10-minute value.
The calculated values are listed in Table 15 below:
Table 15.--Summary of Proposed AEGL Values for Diborane [ppm (mg/m\3\)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 Not recommended NR NR NR NR Not recommended
(Nondisabling)................. (NR)\a\ because proposed AEGL-
2 value is below the
odor threshold, and
no other data
pertaining to
endpoints relevant to
the AEGL-1 definition
were available
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 6.0 (6.6) 2.0 (2.2) 1.0 (1.1) 0.25 (0.28) 0.13 (0.14) LOAEL for pulmonary
(Disabling).................... changes in male ICR
mice; 5 ppm for 2
hour (Nomiyama et
al., 1995)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 7.3 (8.0) 7.3 (8.0) 3.7 (4.1) 0.92 (1.0) 0.46 (0.51) 4-hour LC01 of 9.2 ppm
(Lethality).................... estimated from a 4-
hour LC50 in male ICR
mice (Uemura et al.,
1995)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.
ii. References.
a. Nomiyama, T., Omae, K., Uemura, T., Nakashima, H., Takebayashi,
T., Ishizuka, C., Yamazaki, K., and Sakurai, H. 1995. No-observed-
effect level of diborane on the respiratory organs of male mice in
acute and subacute inhalation experiments. Journal of Occupational
Health. Vol. 37:157-160.
b. Uemura, T., Omae, K., Nakashima, H., Sakurai, H., Yamazaki, K.,
Shibata, T., Mori, K., Kudo, M., Kanoh, H., and Tati, M. 1995. Acute
and subacute inhalation toxicity of diborane in male ICR mice. Archives
of Toxicology. Vol. 69:397-404.
18. Nerve Agent VX--i. Description. Nerve agent VX [O-ethyl-S-
(isopropylaminoethyl) methyl phosphonothiolate] is a toxic ester
derivative of phosphonic acid containing a sulfur substituent group,
and is commonly termed a ``nerve'' agent as a consequence of its
anticholinesterase properties. Agent VX was developed as a chemical
warfare agent, and shares many of the same properties as the G-series
nerve agents (GA, GB, GD, and GF).
Agent VX is a amber-colored liquid with a molecular weight of
267.38; it has a vapor density of 9.2 (air = 1) and a liquid density of
1.006 gram/milliter (g/ml) at 20 deg. C; its water solubility is 3 g
per 100 g at 25 deg. C and 7.5 g per 100 g at 15 deg. C. Agent VX was
deliberately formulated to possess a low volatility (10.5 mg/m\3\ at
25 deg. C), and is approximately 2,000 times less volatile
[[Page 21962]]
than nerve agent GB (DA, 1990). As a consequence, agent VX is a
persistent, ``terrain denial'' military compound with the potential to
off-gas toxic concentrations for days following surface application.
Toxic effects may occur at concentrations below those of odor
detection.
Exposure to acutely toxic concentrations of agent VX can result in
excessive bronchial, salivary, ocular, and intestinal secretion,
sweating, miosis, bronchospasm, intestinal hypermotility, bradycardia,
muscle fasciculations, twitching, weakness, paralysis, loss of
consciousness, convulsions, depression of the central respiratory
drive, and death (Dunn and Sidell, 1989). Minimal effects observed at
low vapor concentrations include miosis (pinpointing of the pupils of
the eye, with subsequent decrease in pupil area), tightness of the
chest, rhinorrhea, and dyspnea.
There is at present no evidence to indicate that asymptomatic
exposures to agent VX result in chronic neurological disorders.
However, a major concern associated with symptomatic exposures to
anticholinesterase compounds such as agent VX is the possibility of
chronic neurological effects. No human data exist for evaluating the
potential of agent VX for inducing chronic neurological effects
following acute symptomatic exposures.
Animal studies have shown that exposures to agent VX have not
caused reproductive or developmental effects. Agent VX was not found to
be genotoxic in a series of microbial and mammalian assays, and there
is no evidence indicating that VX is carcinogenic.
Animals exposed to acutely toxic concentrations of agent VX exhibit
the same signs of toxicity as humans, including miosis, salivation, and
tremors. In a short-term inhalation toxicity study, no signs of
toxicity, except miosis, were observed in rats, mice, guinea pigs, or
rabbits exposed to VX vapor concentrations of 0.0002 mg/m\3\ or less (6
hours/day, 5 days/week, for 2 weeks) (Crook et al., 1983).
Insufficient data are available from which to derive AEGL values
for VX from human or animal inhalation toxicity studies. The few
studies available are historical, and are considered nonverifiable due
to flawed study design, poor sampling techniques, or suspect
contamination of sampling and detection apparatus. Nevertheless,
available literature clearly indicates that inhibition of
cholinesterase activity is a common mechanism of toxicity shared by the
G-series nerve agents and nerve agent VX. Thus, it was possible to
develop AEGL estimates for agent VX by a comparative method of relative
potency analysis from the more complete data set for nerve agent GB.
This approach has been previously applied in the estimation of nerve
agent exposure limits, most recently by Reutter et al. (2000).
Available literature indicates that Agent VX is considered
approximately 12 times more potent than agent GB (Callaway and
Dirnhuber, 1971).
All mammalian toxicity endpoints observed in the data set for nerve
agent VX as well as the G-series agents represent different points on
the response continuum for anticholinesterase effects. Further, the
mechanism of mammalian toxicity (cholinesterase inhibition) is the same
for all nerve agents. As a consequence, the experimentally derived n =
2 from the Mioduszewski et al. (2000a, b) rat lethality data set for
agent GB is here used as the scaling function for the agent VX AEGL-1,
AEGL-2, and AEGL-3 derivations rather than a default value.
Under comparable conditions of exposure, the current analysis finds
that agent VX has a potency to cause miosis and other transient effects
approximately 12 times greater than that of agent GB. The AEGL-1 values
for agent GB were derived from a study of human subjects in which
minimal effects occurred following a 20-minute exposure to a GB vapor
concentration of 0.05 mg/m\3\ (Harvey, 1952; Johns, 1952). These
findings are based on the results of low-concentration nerve agent
exposures to informed volunteers who were under clinical supervision
during the periods of exposure as well as for post-exposure periods of
several months.
The AEGL-2 values for agent GB were derived from a study of human
subjects in which miosis, dyspnea, photophobia, inhibition of red blood
cell cholinesterase (RBC-ChE) to approximately 60% of individual
baseline, and small but measurable changes in SFEMG of the forearm
occurred following a 30-minute exposure to 0.5 mg GB/m\3\ (Baker and
Sedgwick, 1996). This recent study was performed under Helsinki accords
and clinical supervision, and was conducted with the cooperation of
fully informed human subjects.
The fact that AEGL-1 and AEGL-2 analyses for agent VX are based on
data from human volunteers (Harvey, 1952; Johns 1952; Baker and
Sedgwick, 1996; GB vapor exposure to clinically supervised human
volunteers) precludes the use of an interspecies UF. To accommodate
known variation in human cholinesterase activity that may make some
individuals more susceptible to the effects of cholinesterase
inhibitors such as nerve agents, a factor of 10 was applied for
intraspecies variability (protection of susceptible populations). With
application of a modifying factor of 3 for the incomplete VX data set,
the total UF for estimating AEGL-1 and AEGL-2 values for agent VX is
30.
The SFEMG effects noted in the study chosen for estimation of AEGL-
2 values were not clinically significant, and were not detectable after
15-30 months. Baker and Sedgwick (1996) considered SFEMG changes to be
a possible early indicator or precursor of the nondepolarising
neuromuscular block found associated with Intermediate Syndrome
paralysis in severe organophosphorous insecticide poisoning cases. The
Baker and Sedgwick (1996) study concluded that these electromyographic
changes were persistent (>15 months), but that they were reversible and
subclinical. While not considered debilitating or permanent effects in
themselves, SFEMG changes are here considered an early indicator of
exposures that could potentially result in more significant effects.
Selection of this effect as a protective definition of an AEGL-2 level
is considered appropriate given the steep dose-response toxicity curve
of nerve agents.
Insufficient data are available to directly derive an AEGL-3 for
agent VX. The AEGL-3 values for agent VX were indirectly derived from
the AEGL-3 values for GB using a relative potency approach in which
agent VX is considered 12 times more potent than agent GB for
lethality. As a result, AEGL-3 values for agent VX were derived from
recent inhalation studies in which the lethality of GB to female
Sprague-Dawley rats was evaluated for the time periods of 10, 30, 60,
90, 240, and 360 minutes (Mioduszewski et al., 2000a, b). Both
experimental LC01 and LC50 values were evaluated.
The use of a rat data set resulted in selection of an interspecies UF
of 3; the full default value of 10 was not considered appropriate for
the interspecies UF since the mechanism of toxicity in both laboratory
rodents and humans is cholinesterase inhibition. To accommodate known
variation in human cholinesterase activity, the full default value of
10 for intraspecies uncertainty was considered necessary to protect
susceptible populations. With the additional application of a modifying
factor of 3 for the incomplete VX data set, the total UF for AEGL-3
determination for agent VX is equal to 100.
[[Page 21963]]
The NAC noted that an earlier report by the National Research
Council (NRC) (NRC, 1997) included an evaluation of the same VX
toxicity data base, and had recommended at that time that additional
research was needed to more fully characterize the toxicity of VX
vapor. The NAC further notes that such studies could be limited and
should specifically focus on obtaining data that would reduce
uncertainties regarding the relative potency between agents GB and VX,
or the potency of agent VX, for critical effects such as miosis,
rhinorrhea, and lethality. To acknowledge the significant gaps in the
data base for this nerve agent, the NAC considers the proposed AEGL
values to be temporary in nature and subject to re-evaluation in 3
years.
The calculated values are listed in Table 16 below:
Table 16.--Summary of Proposed Temporary AEGL Values\a\ for Agent VX [ppm (mg/m\3\)]\b\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 10-Minutes 30-Minutes 1-Hour 4-Hours 8-Hours Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 0.000018 ppm 0.000010 ppm 0.0000073 ppm 0.0000037 ppm 0.0000026 ppm Derived by relative
(Non-disabling)................ (0.00020 mg/m\3\). (0.00011 mg/m\3\). (0.000080 mg/ (0.000040 mg/ (0.000028 mg/ potency from study of
m\3\). m\3\). m\3\). multiple minimal
effects in human
volunteers exposed to
0.05 mg/m\3\ GB vapor
for 20 minutes;
headache, eye pain,
rhinorrhea, tightness
in chest, cramps,
nausea, malaise,
miosis (Harvey, 1952;
Johns, 1952)\c\
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 0.00022 ppm 0.00013 ppm 0.000090 ppm 0.000045 ppm 0.000032 ppm Derived by relative
(Disabling).................... (0.0024 mg/m\3\).. (0.0014 mg/m\3\).. (0.00098 mg/m\3\) (0.00049 mg/m\3\) (0.00035 mg/m\3\) potency from study of
GB vapor exposure to
exercising human
volunteers exposed to
0.5 mg/m\3\ for 30
minutes; miosis,
dyspnea, inhibition
of RBC-ChE changes in
SFEMG (Baker and
Sedgwick, 1996)\d\
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 0.00088 ppm 0.00045 ppm 0.00030 ppm 0.00016 ppm 0.00012 ppm Derived by relative
(Lethal)....................... (0.0096 mg/m\3\).. (0.0049 mg/m\3\).. (0.0033 mg/m\3\). (0.0017 mg/m\3\). (0.0013 mg/m\3\). potency from
experimental Sprague-
Dawley rat lethality
data (LC01 and LC50);
whole-body dynamic
exposure to GB vapor
concentrations
between 2-56 mg/m\3\
for 3, 10, 30, 60,
90, 240, and 360
minutes (Mioduszewski
et al., 2000a, b)\e\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Percutaneous absorption of VX vapor is known to be an effective route of exposure; nevertheless, percutaneous vapor concentrations needed to
produce similar adverse effects are greater than inhalation vapor concentrations by an approximate factor of 10. Thus, the AEGL values presented in
this table are considered protective for both routes of exposure.
\b\ Agent VX is considered approximately 12 times more potent than agent GB. (see section 4.3, and Callaway and Dirnhuber, 1971).
\c\ Derived from multiple minimal effects noted in human volunteers exposed to agent GB vapor at 0.05 mg-min/m\3\ for 20 minutes (Harvey, 1952; Johns,
1952). VX concentration to achieve same endpoint estimated by relative potency comparison presented in footnote ``b'' in this table.
\d\ Derived from transient effects noted in exercising human volunteers exposed to agent GB vapor at 0.5 mg-min/m\3\ for 30 minutes (Baker and
Sedgwick, 1996). VX concentration to achieve same endpoint estimated by relative potency comparison presented in footnote ``b'' in this table.
\e\ Derived from LC01 values for female Sprague-Dawley rats exposed to GB vapor in dynamic exposure chamber (Mioduszewski et al., 2000a, b). VX
concentrations to achieve same endpoint estimated by relative potency comparison presented in footnote ``b'' in this table.
ii. References.
a. Baker, D.J. and Sedgwick, E.M. 1996. Single fibre
electromyographic changes in man after organophosphate exposure. Human
and Experimental Toxicology. Vol. 15:369-375.
b. Callaway, S. and Dirnhuber, P. 1971. Estimation of the
concentration of nerve agent vapour required to produce measured
degrees of miosis in rabbit and human eyes. Technical Paper No. 64
Chemical Defence Establishment, Porton Down, Salisbury, Wilts., UK
c. Crook, J.W., Hott, P., and Owens, E.J., et al. 1983. The effects
of subacute exposures of the mouse, rat, guinea pig, and rabbit, to
low-level VX concentrations. U.S. Army Armament Research and
Development Command, Chemical Systems Laboratory, Technical Report
ARCSL-TR-82038, Aberdeen Proving Ground, MD.
d. DA (U.S. Department of the Army). 1990. Potential military
chemical/biological agents and compounds. Field Manual FM 3-9 (NAVFAC
P-467, AFR 355-7), Headquarters, Department of the Army, Department of
the Navy, Department of the Air Force, Washington, DC (December 12,
1990).
e. Dunn, M.A. and Sidell, F.R. 1989. Progress in the medical
defense against nerve agents. Journal of the American Medical
Association. Vol. 262:649-652.
f. Harvey, J.C. 1952. Clinical observations on volunteers exposed
to concentrations of GB. Medical Laboratories Research Report No. 114,
Publication Control No. 5030-114 (CMLRE-ML-52), MLCR 114. Army Chemical
Center, Aberdeen Proving Ground, MD.
g. Johns, R.J. 1952. The effect of low concentrations of GB on the
human eye. Research Report No. 100, Publication Control No. 5030-100
(CMLRE-ML-52). Chemical Corps Medical Laboratories, Army Chemical
Center, Aberdeen Proving Ground, MD.
h. Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola,
B., Muse, W., Crosier, R., and Sommerville, D. 2000a. Estimating the
probability of sarin vapor toxicity in rats as a function of exposure
concentration and duration. Presented at the 39th Annual Meeting of the
Society of Toxicology, March, 2000. Philadelphia, PA. Toxicologist.
Vol. 54(1):18 (#84).
i. Mioduszewski, R.J., Manthei, J., Way, R., Burnett, D., Gaviola,
B. Muse, W., Thomson, S., Sommerville, D., and Crosier, R. 2000b.
Estimating the probability of sarin vapor toxicity in rats as a
function of exposure concentration and duration. Proceedings of the
International Chemical Weapons Demilitarization Conference (CWD-2000).
The Hague, NL (May 21-24, 2000).
j. NRC. 1997. Review of the acute human-toxicity estimates for
selected chemical warfare agents. Committee on Toxicology, Subcommittee
on Toxicity Values for Selected Nerve Agents and Vesicant Agents.
National Academy Press, Washington, DC.
[[Page 21964]]
k. Reutter, S.A., Mioduszewski, R.J., and Thomson, S.A. 2000.
Evaluation of airborne exposure limits for VX: worker and general
population exposure criteria. ECBC-TR-074. Edgewood Chemical Biological
Center, U.S. Army Soldier and Biological Chemical Command, Aberdeen
Proving Ground, MD.
IV. Next Steps
The NAC/AEGL Committee plans to publish ``Proposed'' AEGL values
for five-exposure periods for other chemicals on the priority list of
85 in groups of approximately 10 to 20 chemicals in future Federal
Register notices during the calendar year 2001.
The NAC/AEGL Committee will review and consider all public comments
received on this notice, with revisions to the ``Proposed'' AEGL values
as appropriate. The resulting AEGL values will be established as
``Interim'' AEGLs and will be forwarded to the NRC/NAS, for review and
comment. The ``Final'' AEGLs will be published under the auspices of
the NRC/NAS following concurrence on the values and the scientific
rationale used in their development.
List of Subjects
Environmental protection, Hazardous substances.
Dated: April 23, 2001.
Stephen L. Johnson,
Acting Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 01-11001 Filed 5-1-01; 8:45 am]
BILLING CODE 6560-50-S