[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.
------------------------------------------------------------------------
67-56-1                           Methanol            4938
------------------------------------------------------------------------
77-81-6,                          Nerve Agents GA,    4940
107-44-8,.......................   GB, GD, GF
96-64-0,........................
329-99-7........................
------------------------------------------------------------------------
79-10-7                           Acrylic acid        4941
------------------------------------------------------------------------
107-18-6                          Allyl alcohol       4879
------------------------------------------------------------------------
107-30-2                          Chloromethyl        4880
                                   methyl ether
------------------------------------------------------------------------
108-88-3                          Toluene             4882
------------------------------------------------------------------------
108-95-2                          Phenol              4943
------------------------------------------------------------------------
110-00-9                          Furan               4885
------------------------------------------------------------------------
127-18-4                          Tetrachloroethylen  4889
                                   e
------------------------------------------------------------------------
509-14-8                          Tetranitromethane   4894
------------------------------------------------------------------------
594-42-3                          Perchloromethyl     4897
                                   mercaptan
------------------------------------------------------------------------
630-08-0                          Carbon monoxide     4944
------------------------------------------------------------------------
10294-34-5                        Boron trichloride   4928
------------------------------------------------------------------------
19287-45-7                        Diborane            4931
------------------------------------------------------------------------
50782-69-9                        Nerve Agent VX      4945
------------------------------------------------------------------------



[[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