[Federal Register: March 15, 2000 (Volume 65, Number 51)]
[Notices]
[Page 14185-14197]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr15mr00-155]

[[Page 14185]]

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Part VIII

Environmental Protection Agency

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National Advisory Committee for Acute Exposure Guideline Levels (AEGLs)
for Hazardous Substances, Proposed AEGL Values; Notice

[[Page 14186]]

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ENVIRONMENTAL PROTECTION AGENCY

[OPPTS-00289; FRL-6492-4]

National Advisory Committee for Acute Exposure Guideline Levels
(AEGLs) for Hazardous Substances; Proposed AEGL Values

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice and request for comments.

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SUMMARY: The National Advisory Committee for Acute Exposure Guideline
Levels for Hazardous Substances (NAC/AEGL Committee) is developing AEGL
values on an ongoing basis to provide Federal, State, and local
agencies with information on short-term exposures to hazardous
chemicals. This notice provides ``Proposed'' AEGL values and Executive
Summaries for 10 chemicals for public review and comment. Comments are
welcome on both the ``Proposed'' AEGL values in this notice and the
Technical Support Documents placed in the public version of the
official record in the TSCA Docket for these 10 chemicals.

DATES: Comments, identified by the docket control number OPPTS-00289,
must be received by EPA on or before April 14, 2000.

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-00289 in the subject line on the first page of
your response.

FOR FURTHER INFORMATION CONTACT: For general information contact:
Joseph S. Carra, Deputy Director, Office of Pollution Prevention and
Toxics (7401), Environmental Protection Agency, Ariel Rios Bldg., 1200
Pennsylvania Ave., NW., Washington, DC 20460; telephone numbers: (202)
554-1404 and TDD: (202) 554-055; e-mail address: TSCA-Hotline@epa.gov.
For technical information contact: Paul S. Tobin, Designated
Federal Officer (DFO), Office of Pollution Prevention and Toxics
(7406), Environmental Protection Agency, Ariel Rios Bldg., 1200
Pennsylvania Ave., NW., Washington, DC 20460; telephone number: (202)
260-1736; e-mail address: tobin.paul@epa.gov.

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'' 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-00289. 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. Using a faxphone call (202) 401-0527 and select
item 4800 for an index of items in this category. For a more specific
item number, see the table in Unit III.

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-00289 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, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW.,
Washington, DC 20460.
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: ``oppt.ncic@epa.gov,'' 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 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 number OPPTS-00289.
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

[[Page 14187]]

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 prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the technical person identified 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 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 proposed rule or
collection activity.
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

Since its first meeting on June 19-21, 1996, the NAC/AEGL Committee
has been evaluating scientific data and developing ``Proposed'' AEGLs
for 76 of the first 85 priority chemicals initially scheduled for
development of AEGL values. This first list of 85 chemicals was
published in the Federal Register of May 21, 1997 (62 FR 27733-27734)
(FRL-5718-9). EPA published the first ``Proposed'' AEGL values for 12
chemicals from the initial priority list in the Federal Register of
October 30, 1997 (62 FR 58839-58851) (FRL-5737-3) in order to provide
an opportunity for public review and comment. That Federal Register
notice also provides the AEGL Program's history and development
process. Since then, the NAC/AEGL Committee continues to develop AEGL
values for other chemicals from the initial priority list and continues
to establish greater consistency in the procedures and methodologies
used in their development. Additionally, the NAC/AEGL Committee has
expanded the number of exposure periods to include AEGL values for 10
minute exposure periods to cover a wider range of potential exposures
to hazarous chemicals. The NAC/AEGL Committee plans to publish
``Proposed'' AEGL values for 10 minute exposure periods for other
chemicals on the priority list of 85 in groups of approximately 10 to
20 chemicals in future Federal Register notices.
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'' AEGL values and will be forwarded to the National
Research Council, National Academy of Sciences (NRC/NAS), for review
and comment. The ``Final'' AEGL values will be published under the
auspices of the NRC/NAS following concurrence on the values and the
scientific rationale used in their development.

III. 10 Chemicals for Public Notice and Comment

A. Fax-On-Demand Table

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CAS No. Chemical name Fax-On-Demand item no.
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71-55-6 1,1,1-Trichloroethane 4937
74-90-8 Hydrogen cyanide 4858
156-59-2 Cis-1,2-Dichloroethylene 4895
156-60-5 Trans-1,2-Dichloroethylene 4895
505-60-2 Agent HD (sulfur mustard) 4936
811-97-2 HFC-134a (1,1,1,2-tetrafluoroethane) 4899
1717-00-6 HCFC-141b (1,1-dichloro-1-fluoroethane) 4902
7664-39-3 Hydrogen fluoride 4909
7783-06-4 Hydrogen sulfide 4917
106602-80-6 Otto Fuel II (main component propylene 4935
glycol dinitrate; CAS No. 6423-43-4)
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B. Executive Summaries

1. Cis-1,2-Dichloroethylene and 2. Trans-1,2-Dichloroethylene--i.
Description. 1,2-Dichloroethylene is a flammable, colorless liquid
existing in both cis- and trans-forms and as a mixture of these two
isomers. It has been used as an intermediate in the production of
chlorinated solvents and as a low-temperature extraction solvent for
decaffeinated coffee, dyes, perfumes, lacquers, and thermoplastics. The
compound is a narcotic. Data on narcosis in humans, cats, rats, and
mice, and systemic effects in cats, rats, and mice were available for
development of AEGLs. The data were considered adequate for derivation
of the three AEGL classifications.
The AEGL-1 was based on a human exposure concentration of 825 parts
per million (ppm) trans-1,2-dichloroethene for 5 minutes (Lehmann and
Schmidt-Kehl 1936). This concentration is a no-effect-level for eye
irritation. Because the mechanism of irritation is not expected to
differ greatly among individuals (including sensitive individuals),
this value was divided by an uncertainty factor (UF) of 3 to protect
sensitive individuals. This UF of 3 was applied for AEGL-1 values for
both the cis- and trans-isomers. Since animal data suggest that the
cis-isomer is approximately twice as toxic as the trans-isomer, a
modifying factor of 2 was applied in the derivation of the cis-isomer
values only. The same value was applied across the 10- and 30-minute
and 1-, 4-, and 8-hour exposure time points since mild irritantancy is
a threshold effect and generally does not vary greatly over time. Thus,
prolonged exposure will not result in an enhanced effect.
The AEGL-2 for the 4- and 8-hour time points was based on narcosis
observed in pregnant rats exposed to 6,000 ppm of the trans-isomer for
6 hours (Hurtt et al., 1993). Uncertainty factors of 3 each (total UF =
10) were applied for both inter- and intraspecies differences because
the endpoint,

[[Page 14188]]

narcosis, is unlikely to vary greatly among individuals or species.
This total UF of 10 was applied for AEGL-2 values for both the cis- and
trans-isomers. The concentration-exposure time relationship for many
irritant and systemically acting vapors and gases may be described by
Cⁿ x t = k, where the exponent, n, ranges from 0.8 to 3.5
(ten Berge et al., 1986). To obtain protective AEGL values in the
absence of an empirically derived chemical-specific scaling exponent, a
conservative approach to temporal scaling was performed using n = 3
when extrapolating to shorter time points and n = 1 when extrapolating
to longer time points using the Cⁿ x t = k equation. The
AEGL-2 for the 10- and 30-minute and 1-hour time points was set as a
ceiling based on a plateau for anesthetic effects in humans (Lehman and
Schmidt-Kehl, 1936). Since data suggest that the cis-isomer is
approximately twice as toxic as the trans-isomer, a modifying factor of
2 was applied in the derivation of the cis-isomer values only.
The AEGL-3 for the 4- and 8-hour time points was based on a 4-hour
no-effect-level for death in rats of 12,300 ppm trans-1,2-
dichloroethene (Kelly, 1999). Uncertainty factors of 3 each (total UF =
10) were applied for both inter- and intraspecies differences. Rat and
mouse lethality data indicate little species variability with regard to
death. This total UF of 10 was applied for AEGL-3 values for both the
cis- and trans-isomers. The concentration-exposure time relationship
for many irritant and systemically acting vapors and gases may be
described by Cⁿ x t = k, where the exponent, n, ranges from
0.8 to 3.5 (ten Berge et al., 1986). To obtain protective AEGL values
in the absence of an empirically derived chemical-specific scaling
exponent, a conservative approach to temporal scaling was performed
using n = 3 when extrapolating to shorter time points and n = 1 when
extrapolating to longer time points using the Cⁿ x t = k
equation. The AEGL-3 for the 10- and 30-minute and 1-hour time points
was set as a ceiling based on a plateau for intracranial pressure,
nausea, and severe dizziness in humans (Lehman and Schmidt-Kehl, 1936).
Since data suggest that the cis-isomer is approximately twice as toxic
as the trans-isomer, a modifying factor of 2 was applied in the
derivation of the cis-isomer values only.
The calculated values are listed in the tables below.

Summary of Proposed AEGL Values for Trans-1,2-Dichloroethene [ppm (mg/m³ (milligram/meter³)]
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Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
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AEGL-1 (Nondisabling) 280 (1,109) 280 (1,109] 280 (1,109) 280 (1,109) 280 (1,109) Ocular irritation
in humans (Lehman
and Schmidt-Kehl,
1936)
AEGL-2 (Disabling) 1,000 (3,960) 1,000 (3,960) 1,000 (3,960) 690 (2,724) 450 (1,782) Narcosis in rats: 4-
and 8-hour (Hurtt
et al., 1993);
Anesthetic effects
in humans (Lehman
and Schmidt-Kehl,
1936)
AEG L-3 (Lethality) 1,700 (6,732) 1,700 (6,732) 1,700 (6,732) 1,200 (4,752) 620 (2,455) No-effect-level
for death in rats:
4- and 8-hour
(Kelly, 1999);
Nausea,
intracranial
pressure, and
dizziness in
humans (Lehman and
Schmidt-Kehl,
1936)
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Summary of Proposed AEGL Values for Cis-1,2-Dichloroethene [ppm (mg/m³)]
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Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
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AEGL-1 (Nondisabling) 140 (554) 140 (554) 140 (554) 140 (554) 140 (554) Ocular irritation
in humans (Lehman
and Schmidt-Kehl,
1936)
AEGL-2 (Disabling) 500 (1,980) 500 (1,980) 500 (1,980) 340 (1,346) 230 (911) Narcosis in rats:
4- and 8-hour
(Hurtt et al.,
1993); Anesthetic
effects in humans
(Lehman and
Schmidt-Kehl,
1936)
AEGL-3 (Lethality) 850 (3,366) 850 (3,366) 850 (3,366) 620 (2,455) 310 (1,228) No-effect-level
for death in rats:
4- and 8-hour
(Kelly, 1999);
Nausea,
intracranial
pressure, and
dizziness in
humans (Lehman and
Schmidt-Kehl,
1936)
--------------------------------------------------------------------------------------------------------------------------------------------------------

ii. References.
Hurtt, M.E., Valentine, R., and Alvarez, L. 1993. Developmental
toxicity of inhaled trans-1,2-dichloroethylene in the rat. Fundamental
and Applied Toxicology. 20:225-230.
Kelly, D. P. 1999. Trans-1,2-dichloroethylene and cis-1,2-
dichloroethylene: Inhalation median lethal concentration
(LC50) study in rats. E.I. du Pont de Nemours and Company,
Haskell Laboratory for Toxicology and Industrial Medicine, Newark, DE.
Laboratory Project ID: DuPont-2806.
Lehman, K.B. and Schmidt-Kehl, L. 1936. The thirteen most important
chlorinated aliphatic hydrocarbons from the standpoint of industrial
hygiene. Archiv Fuer Hygiene und Bakteriologie. 116:9-268.
ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986. Concentration-
time mortality response relationship of irritant and systemically
acting vapours and gases. Journal of Hazardous Materials. 13:301-309.
3. Agent HD (sulfur mustard)--i. Description. Sulfur mustard (Agent
HD) is an alkylating chemical vesicant developed as a warfare agent
that affects any epithelial surface it contacts. The active component
is bis(2-chloroethyl)sulfide (CAS No. 505-60-2). Although the chemical
is a liquid at ordinary ambient temperatures, its volatility results in
rapid generation of vapors with a garlic-like odor. Due to its low
aqueous solubility, it is persistent in the environment. Odor
thresholds of 1 mg-min/m³ (milligram-minute/meter) and 0.6
mg/m³ have been reported.
Exposure to sulfur mustard vapor may result in irritation and
damage to the eyes, respiratory tract, and skin. The toxic effects of
sulfur mustard are temperature and humidity dependent; for a given
exposure, the effects may be greater with increasing temperature and
humidity. An exposure-dependent latency period of hours to days is
documented for the toxic effects of sulfur mustard and is relevant for
all routes of exposure but may be less for

[[Page 14189]]

ocular and upper respiratory tract effects than for dermal and systemic
responses. Both human and animal data indicate that the eyes are the
most sensitive organ/tissue although deaths resulting from sulfur
mustard exposure are likely the result of respiratory tract
involvement. Because the toxic effects of sulfur mustard (at least for
short-time periods) appear to be a linear function of exposure duration
and exposure concentration, most of the available exposure-response
data are expressed as cumulative exposures (Ct).
Minor ocular irritation (conjunctival injection in the absence of
irritation) is reported to occur in humans following exposures to 12-30
mg-min/m³ and more severe effects at 60-75 mg-min/
m³ (conjunctivitis, irritation, photophobia) and 100 mg-min/
m³ (severe ocular irritation). Exposure estimates for human
lethality range from 900-1,500 mg-min/m³.
Animal lethality following acute exposure to sulfur mustard occurs
at cumulative exposures ranging from approximately 600-1,500 mg-min/
m³. Nonlethal effects were similar to those observed in
humans and included effects on the eyes, respiratory tract, and skin.
Long-term exposure of dogs, rats, and guinea pigs to concentrations of
0.03 mg/m³ produced only minor signs of ocular and
respiratory tract irritation. 1-hour exposure of mice to concentrations
up to 16.9 mg/m³ resulted in notable but not serious effects
on respiratory parameters and acute exposures of rabbits (20 minutes to
12 hours) to concentrations ranging from 58-389 mg/m³ (Ct
2,300 mg-min/m³) resulted in severe respiratory
tract damage.
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 irritant and
systemically acting vapors and gases may be described by Cⁿ
x t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge, 1986).
Analysis of available data regarding AEGL-1 type effects reported by
Reed (1918), Reed et al. (1918), Guild et al. (1941), and Anderson
(1942) indicate that, for exposure periods up to several hours, the
concentration-exposure time relationship is a near-linear function
(i.e., Haber's Law where n = 1 for Cⁿ x t = k) as shown by n
values of 1.11 and 0.96 for various data sets analyzed that were
consistent with AEGL-1 effects. Therefore, an empirically derived,
chemical-specific estimate of n = 1 was used for derivation of most of
the AEGL values rather than a default value based upon the ten Berge
(1986) analysis. Due to uncertainty regarding linear extrapolation to a
time duration notably shorter than that for which empirically derived
lethality data were available, the 10-minute AEGL-3 values utilized
exponential time scaling where n was 3.
The AEGL-1 values were based upon data from Anderson (1942) who
found that an exposure concentration-time product of 12 mg-min/
m³ represented a threshold for ocular effects (conjunctival
injection and minor discomfort with no functional decrement) in human
volunteers acutely exposed to sulfur mustard. An UF adjustment was
limited to a factor of 3 for protection of sensitive individuals. This
adjustment was considered appropriate for acute exposures to chemicals
whose mechanism of action primarily involves surface contact irritation
of ocular and/or respiratory tract tissue rather than systemic activity
that involves absorption and distribution of the parent chemical or a
biotransformation product to a target tissue. Anderson (1942) noted
that there was little variability in the ocular responses among the
subjects in his study, thereby providing additional justification for
the intraspecies UF of 3.
The AEGL-2 values for sulfur mustard were also developed using the
data from Anderson (1942). Anderson reported that a Ct value of
approximately 60 mg-min/m³ represented the lowest
concentration-time product for which ocular effects could be
characterized as military casualties. The 60 mg-min/m³
exposure was used as the basis for developing the AEGL-2 values because
it represented an acute exposure causing an effect severe enough to
impair escape and, although not irreversible, would certainly result in
potential for additional injury. Anderson (1942) characterized the 60
mg-min/m³ Ct as representing the lower margin of the
concentration-effect zone that would result in ineffective military
performance (necessary to complete a mission), and that may require
treatment for up to 1 week. The ocular irritation and damage were also
considered appropriate as a threshold estimate for AEGL-2 effects
because the eyes are generally considered the most sensitive indicator
of sulfur mustard exposure and would likely occur in the absence of
vesication effects and severe pulmonary effects. The fact that the
AEGL-2 is based upon human data precludes the use of an interspecies
UF. A factor of 3 was applied for intraspecies variability (protection
of sensitive populations). This factor was limited to three under the
assumption that the primary mechanism of action of sulfur mustard
involves a direct effect on the ocular surface and that this response
will not vary greatly among individuals. Anderson also noted little
variability in the ocular responses among the subjects in his study. A
modifying factor of 3 was applied to accommodate potential onset of
long-term ocular or respiratory effects. This was justified by the fact
that there was no long-term follow-up reported by Anderson with which
to confirm or deny the development of permanent ocular or respiratory
tract damage. The total uncertainty/modifying factor adjustment was 10
[The total adjustment is 10 because the factors of 3 each represent a
logarithmic mean (3.16) of 10, therefore 3.16 x 3.16 = 10].
For development of the AEGL-3, a 1-hour exposure of mice to 21.2
mg/m³ was used as an estimated lethality threshold (Kumar
and Vijayaraghavan, 1998). This value is also near the lower bound of
the 95% confidence interval for the 1-hour mouse LC50 of
42.5 mg/m³ reported by Vijayaraghavan (1997). An UF for
intraspecies variability of 3 was used because the lethality resulting
from acute inhalation exposure to sulfur mustard appears to be a
function of pulmonary damage resulting from direct contact of the agent
with epithelial surfaces and would not likely exhibit an order-of-
magnitude variability among individuals. An UF of 3 was also applied to
account for possible interspecies variability in the lethal response to
sulfur mustard. The resulting total UF adjustment was 10. The modifying
factor of 3 utilized for AEGL-2 development to account for
uncertainties regarding the latency and persistence of the irritant
effects of low-level exposure to sulfur mustard was not applied for
AEGL-3 because lethality of the mice was assessed at 14 days post
exposure in a study by Vijayaraghavan (1997). Application of any
additional UFs or modifying factors was not warranted because the
proposed AEGL-3 values are equivalent to exposures in humans that are
known to produce only ocular and respiratory tract irritation.
The AEGL values for sulfur mustard are based upon noncancer
endpoints. Sulfur mustard is genotoxic and has induced carcinogenic
responses in humans following single high exposures and following
multiple exposures that were sufficient to produce adverse effects.
Carcinogenic responses, however, are not known to occur with
asymptomatic exposures. Limitations on the currently available data do
not allow for a definitive quantitative cancer risk

[[Page 14190]]

assessment, especially for an acute, once-in-a-lifetime, exposure.
The AEGL-1 and AEGL-2 values are based upon human exposure data and
are considered to be defensible estimates for exposures representing
thresholds for the respective AEGL effect levels. The ocular irritation
upon which the AEGL-1 and AEGL-2 values are based is the most sensitive
response to sulfur mustard vapor. The AEGL-3 values provide Ct products
(approximately 60-130 mg-min/m³) that are known to cause
only moderate to severe ocular irritation and possible respiratory
tract irritation in human subjects but not life- threatening health
effects or death. Although, the overall database for acute inhalation
exposure to sulfur mustard is not extensive, the AEGL values appear to
be supported by the available data and in some cases, similar values
obtained using somewhat differing approaches.

Summary of Proposed AEGL Values for Sulfur Mustard [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.06 (0.40) 0.02 (0.13) 0.01 (0.067) 0.003 (0.017) 0.001 (0.008) Conjunctival
injection and
minor discomfort
with no functional
decrement in human
volunteers
(Anderson, 1942)
AEGL-2 (Disabling) 0.09 (0.60) 0.03 (0.20) 0.02 (0.10) 0.004 (0.025) 0.002 (0.013) Well marked,
generalized
conjunctivitis,
edema,
photophobia, and
eye irritation in
human volunteers
(Anderson, 1942)
AEGL-3 (Lethality) 0.91 (6.1) 0.63 (4.2) 0.32 (2.1) 0.08 (0.53) 0.04 (0.27) Lethality estimate
in mice (Kumar and
Vijayaraghavan,
1998)
--------------------------------------------------------------------------------------------------------------------------------------------------------

ii. References.
Anderson, J.S. 1942. The effect of mustard gas vapour on eyes under
Indian hot weather conditions. CDRE Report No. 241. Chemical Defense
Research Establishment (India).
Guild, W.J., Harrison, K.P., Fairly, A., and Childs, A.E. 1941. The
effect of mustard gas vapour on the eyes. Porton Report No. 2297,
Serial No. 12. November 8, 1941.
Kumar, O. and Vjayaraghavan, R. 1998. Effect of sulphur mustard
inhalation exposure on some urinary variables in mice. Journal of
Applied Toxicology. 18:257-259.
Reed, C.I. 1918. The minimum concentration of mustard gas effective
for man. Preliminary Report. Report 318. War Department, Medical
Division, Chemical Warfare Section, Pharmacological Research Section,
American University Experiment Station. October 26, 1918.
Reed, C.I., Hopkins, E.F., and Weyand, C.F. 1918. The minimum
concentration of mustard gas effective for man. Final Report. Report
329. War Department, Medical Division, Chemical Warfare Section,
Pharmacological Research Section, American University Experiment
Station. December 2, 1918.
ten Berge, W.F. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases.
Journal of Hazardous Materials. 13:301-309.
Vijayaraghavan, R. 1997. Modifications of breathing pattern induced
by inhaled sulphur mustard in mice. Archives of Toxicology. 71:157-164.
4. HCFC-141b (1,1-dichloro-1-fluoroethane) or
hydrochlorofluorocarbon-141b--i. Description. 1,1-Dichloro-1-
fluoroethane has been developed as a replacement for fully halogenated
chlorofluorocarbons as its residence time in the atmosphere is shorter
and its ozone depleting potential is lower than that of presently used
chlorofluorocarbons. HCFC-141b may be used in the production of rigid
polyurethane and polyisocyanurate or phenolic insulation foams for
residential and commercial buildings. It may also be used as a solvent
in electronic and other precision cleaning applications.
HCFC-141b is of low inhalation toxicity. Its effects have been
studied with human subjects and several animal species including the
monkey, dog, rat, mouse, and rabbit. In addition, studies addressing
repeated and chronic exposures, genotoxicity, carcinogenicity,
neurotoxicity, and cardiac sensitization were also available. At high
concentrations, halogenated hydrocarbons may produce cardiac
arrhythmias; this sensitive endpoint was considered in development of
AEGL values.
Adequate data were available for development of the three AEGL
classifications. Inadequate data were available for determination of
the relationship between concentration and exposure duration for a
fixed effect. However, based on the rapidity with which blood
concentrations in humans approached equilibrium, the similarity in
lethality values in rats exposed for 4 or 6 hours, and the fact that
the cardiac sensitization effect is based on a concentration threshold
rather than exposure duration, all AEGL values were flat-lined across
time. The fact that some experimental exposure durations in both human
and animal studies were generally long, 4 to 6 hours, lends confidence
to flat-lining the values for the shorter exposure durations.
The AEGL-1 value was based on the observation that exercising human
subjects could tolerate exposure to concentrations of 500 or 1,000 ppm
for 4 hours with no effects on lung functions, respiratory symptoms,
irritation of the eyes, or cardiac symptoms (Utell et al., 1997).
Results of exposures of two subjects for an additional 2 hours to the
500 ppm concentration and one of the subjects to the 1,000 ppm
concentration for an additional 2 hours did not indicate a clear effect
on neurobehavioral parameters. Because the 4- or 6-hour 1,000 ppm
concentration is a no-observed-effect-level (NOEL), there were no
indications of response differences among tested subjects, and animal
studies indicate that adverse effects occur only at considerably higher
concentrations, the value was not adjusted by an UF to protect
sensitive individuals. Because blood concentrations of HCFC-141b
rapidly approached equilibrium and did not greatly increase after 55
minutes of exposure, the value of 1,000 ppm was used for all time
periods.
The AEGL-2 value was based on the lowest concentration that caused
cardiac sensitization in dogs exposed to HCFC-141b for 10 minutes
(Mullin, 1977). This value of 5,200 ppm is far below the lowest
concentrations that caused death from cardiac fibrillation (10,000 ppm
in this study and 20,000 ppm in a similar study [Hardy et al., 1989a]).
Because the cardiac sensitization test is supersensitive as the
response to epinephrine is optimized (the epinephrine dose is greater
than the physiological level in stressed animals by up to a factor of
10), a single

[[Page 14191]]

intraspecies UF of 3 was applied to protect sensitive individuals.
Cardiac sensitization is concentration dependent; duration of exposure
did not influence the concentration at which this effect occurred.
Using the reasoning that the concentration is the determining factor in
cardiac sensitization and exposure duration is of lesser importance,
the resulting value of 1,700 ppm is proposed for all time periods.
The AEGL-3 values were based on the concentration of 9,000 ppm, the
highest value that resulted in mild to marked cardiac responses but did
not cause death in a cardiac sensitization study with the dog (Hardy et
al., 1989a). Because the cardiac sensitization test is supersensitive
as the response to epinephrine is optimized, a single intraspecies UF
of 3 was applied to protect sensitive individuals. Using the reasoning
that the concentration is the determining factor in cardiac
sensitization and exposure duration is of lesser importance, the
resulting value of 3,000 ppm is proposed for all time periods.
Based on the extensive database involving both human and animal
exposures and use of the most sensitive endpoint in the studies,
confidence in the AEGL values is high. Values are summarized in the
table below.

Summary Table of Proposed AEGL Values for HCFC-141^b (1,1-Dichloro-1-fluoroethane) [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 1,000 (4,850) 1,000 (4,850) 1,000 (4,850) 1,000 (4,850) 1,000 (4,850) No effect-humans
(Utell et al.,
1997)
AEGL-2 (Disabling) 1,700 (8,245) 1,700 (8,245) 1,700 (8,245) 1,700 (8,245) 1,700 (8,245) Threshold for
cardiac
arrhythmia--dog\1\
(Mullin, 1977)
AEGL-3 (Lethality) 3,000 (14,550) 3,000 (14,550) 3,000 (14,550) 3,000 (14,550) 3,000 (14,550) Threshold for
severe cardiac
response--dog\1\
(Hardy et al.,
1989a)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Response to challenge dose of epinephrine (cardiac sensitization test).

ii. References.
Hardy, J.C., Sharman, I.J., and Chanter, D.O. 1989a. Assessment of
cardiac sensitization potential in dogs and monkeys. Comparison of I-
141b and F11. PWT 86/89437, Huntingdon Research Centre Ltd.,
Huntingdon, Cambridgeshire, England.
Mullin, L.S. 1977. Cardiac sensitisation. Haskell Laboratory Report
957-77, E.I. du Pont de Nemours and Co., Newark, DE.
Utell, M.J., Anders, M.W., and Morrow, P.E. 1997. Clinical
inhalation studies with HCFC-141b. Final Report: December 4, 1997. MA-
RR-97-2406, Departments of Medicine, Environmental Medicine, and
Pharmacology and Physiology, University of Rochester Medical Center,
Rochester, NY.
5. HFC-134a (1,1,1,2-tetrafluoroethane) or hydrofluorocarbon-134a--
i. Description. 1,1,1,2-Tetrafluoroethane has been developed as a
replacement for fully halogenated chlorofluorocarbons because its
residence time in the atmosphere is shorter and its ozone depleting
potential is insignificant. HFC-134a may be used in refrigeration and
air conditioning systems, as a blowing agent for polyurethane foams,
and as a propellant for medical aerosols. Yearly production is
estimated at 175,000 tons.
HFC-134a has a very low acute inhalation toxicity. Its acute
inhalation effects have been studied with human subjects and several
animal species including the monkey, dog, rat, and mouse. In addition,
studies addressing repeated and chronic exposures, genotoxicity,
carcinogenicity, neurotoxicity, and cardiac sensitization were also
available. At high concentrations, halogenated hydrocarbons may produce
cardiac arrhythmias; this sensitive endpoint was considered in
development of AEGL values.
Adequate data were available for development of the three AEGL
classifications. Inadequate data were available for determination of
the relationship between concentration and time for a fixed effect.
Based on the observations that:
a. Blood concentrations in humans rapidly approach equilibrium with
negligible metabolism and tissue uptake.
b. The endpoint of cardiac sensitization is a blood concentration-
related threshold phenomenon, derived values for each AEGL
classification were flat-lined across time.
The AEGL-1 concentration was based on a 1-hour no-effect
concentration of 8,000 ppm in human subjects (Emmen and Hoogendijk,
1998). This concentration was without effects on lung functions,
respiratory parameters, the eyes (irritation), or the heart (cardiac
symptoms). Because this concentration is considerably below that
causing any effect in animal studies, no intraspecies UF was applied.
Based on the fact that blood concentrations in this study appeared to
be approaching equilibrium following 55 minutes of exposure and effects
are determined by blood concentrations, the value of 8,000 ppm was used
across all time periods.
The AEGL-2 concentration was based on the no-effect concentration
of 40,000 ppm for cardiac sensitization in dogs (Hardy et al., 1991).
Because the cardiac sensitization test is supersensitive as the
response to epinephrine is optimized (the epinephrine dose is greater
than the physiological level in stressed animals by up to a factor of
10), a single intraspecies UF of 3 was applied to protect sensitive
individuals. Cardiac sensitization is concentration dependent; duration
of exposure does not influence the concentration at which this effect
occurs. Using the reasoning that the concentration is the determining
factor in cardiac sensitization and exposure duration is of lesser
importance, the resulting value of 13,000 ppm is proposed for all time
periods.
The AEGL-3 concentration was based on the concentration of 80,000
which caused marked cardiac effects but no deaths in dogs (Hardy et
al., 1991). Because the cardiac sensitization test is supersensitive as
the response to epinephrine is optimized (the epinephrine dose is
greater than the physiological level in stressed animals by up to a
factor of 10), a single intraspecies UF of 3 was applied to protect
sensitive individuals. Cardiac sensitization is concentration
dependent; duration of exposure does not influence the concentration at
which this effect occurs. Using the reasoning that the concentration is
the determining factor in cardiac sensitization and exposure duration
is of lesser importance, the resulting value of 27,000 ppm is proposed
for all time periods.
Based on the extensive database involving both human and animal

[[Page 14192]]

exposures and use of the most sensitive endpoint in the studies,
confidence in the AEGL values is high. Values are summarized in the
table below.

Summary Table of Proposed AEGL Values for HFC-134^a (1,1,1,2-Tetrafluoroethane) [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 8,000 (34,000) 8,000 (34,000) 8,000 (34,000) 8,000 (34,000) 8,000 (34,000) No effects--humans
(Emmen and
Hoogendijk, 1998)
AEGL-2 (Disabling) 13,000 (55,250) 13,000 (55,250) 13,000 (55,250) 13,000 (55,250) 13,000 (55,250) No effect, cardiac
sensitization--dog
s (Hardy et al.,
1991)
AEGL-3 (Lethality) 27,000 (114,750) 27,000 (114,750) 27,000 (114,750) 27,000 (114,750) 27,000 (114,750) Marked effect,
cardiac
sensitization--dog
s (Hardy et al.,
1991)
--------------------------------------------------------------------------------------------------------------------------------------------------------

ii. References.
Emmen, H.H. and Hoogendijk, E.M.G. 1998. Report on an ascending
dose safety study comparing HFA-134a with CFC-12 and air, administered
by whole-body exposure to healthy volunteers. MA-250B-82-306, TNO
Report V98.754, The Netherlands Organization Nutrition and Food
Research Institute, Zeist, The Netherlands.
Hardy, C.J., Sharman, I.J., and Clark, G.C. 1991. Assessment of
cardiac sensitisation potential in dogs: Comparison of HFA 134a and
A12. Report No. CTL/C/2521. Huntingdon Research Centre, Huntingdon,
Cambridgeshire, U.K.
6. Hydrogen cyanide (HCN)--i. Description. Hydrogen cyanide is a
colorless, rapidly acting, highly poisonous gas or liquid having an
odor of bitter almonds. Most HCN is used as an intermediate at the site
of production. Major uses include the manufacture of nylons, plastics,
and fumigants; it is also used in electroplating and mining. Exposures
to HCN may occur in industrial situations as well as from cigarette
smoke, combustion products, and naturally occurring cyanide compounds
in foods.
HCN is a systemic poison; toxicity is due to inhibition of
cytochrome oxidase which prevents cellular utilization of oxygen. Lack
of oxygen supply to the brain results in loss of consciousness,
respiratory arrest, and, ultimately, death. Stimulation of the
chemoreceptors of the carotid and aortic bodies produces a brief period
of hyperpnea; cardiac irregularities may also occur. These mechanisms
of action are the same for all species.
Inhalation studies resulting in sublethal effects such as
incapacitation and changes in respiratory and cardiac parameters were
described for the monkey, rat, and mouse; lethality studies were
available for the rat, mouse, and rabbit. Exposure durations ranged
from a few seconds to 24 hours. Regression analyses of the exposure
duration-concentration relationships for both incapacitation and
lethality for the monkey determined that the relationship is
C² x t = k and that the relationship for lethality (based on
rat data) is C^2.6 x t = k. Although human exposures have
occurred, no reliable data on exposure concentrations were available.
The AEGL-1 was not determined because serious effects may occur at
concentrations below those causing irritation or notable discomfort. In
addition, the onset of serious effects is very rapid.
The AEGL-2 was based on a concentration of 60 ppm for 30 minutes
which resulted in a slight depressive effect on the central nervous
system of monkeys as evidenced by changes in electroencephalograms;
there was no physiological response (Purser, 1984; Purser et al.,
1984). The mechanism of action of HCN is the same for all mammalian
species, but the rapidity of the toxic effect may be related to
relative respiration rates as well as pharmacokinetic considerations.
The monkey is an appropriate model for extrapolation to humans as the
respiratory systems of monkeys and humans are similar. Because the
monkey is an appropriate model and the mechanism of action of HCN is
the same for all species, an interspecies UF of 2 was applied. Humans
may differ in their sensitivity to HCN but no data regarding specific
differences were located in the available literature. Therefore, an
intraspecies UF of 3 was applied. The 30-minute concentration of 60 ppm
was divided by a combined interspecies and intraspecies UF of 6 and
scaled across time for the AEGL specified exposure periods using the
relationship C² x t = k. The safety of the 10- and 30-minute
values are supported by monitoring studies in which concentrations of
10-15 ppm produced central nervous system effects in some workers.
The rat provided the only data set for calculation of
LC01 values for different time periods (E.I. du Pont de
Nemours and Company, 1981). The LC01 values were considered
the threshold for lethality and were used as the basis for deriving
AEGL-3 values. The mouse, rat, and rabbit were equally sensitive to the
lethal effects of HCN as determined by similar LC50 values
for the same time periods. In an earlier study, times to death for
several animal species showed that mice and rats may be slightly more
sensitive to HCN than monkeys (and presumably humans). The differences
in sensitivity were attributed, at least partially, to the more rapid
respiratory rate of the rodent species. Because LC50 values
for several species were within a factor of 1.5 of each other, an
interspecies UF of 2 was applied. Humans may differ in their
sensitivity to HCN but no data regarding specific differences were
located in the available literature. Therefore, an intraspecies UF of 3
was applied to protect sensitive individuals. The 15- and 30-minute and
1-hour LC01 values, 138, 127, and 88 ppm, respectively, were
divided by a total UF of 6. The 15-minute value was time scaled to 10
minutes to derive the 10-minute AEGL-3, the 30-minute LC01
was used for the 30-minute AEGL-3 value, and the 60-minute
LC01 was used to calculate the 1-, 4-, and 8-hour AEGL-3
concentrations. For the AEGL-3 values, scaling across time utilized the
lethal concentration-exposure duration relationship for the rat,
C^2.6 x t = k.
The proposed values appear in the table below.

[[Page 14193]]

Summary of Proposed AEGL Values for Hydrogen Cyanide [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) NA\1\ NA NA NA NA Serious effects
may occur below
detectable
concentrations or
concentrations
causing discomfort
AEGL-2 (Disabling) 17 (19) 10 (11) 7.1 (7.8) 3.5 (3.9) 2.5 (2.8) Slight central
nervous system
depression--monkey
(Purser, 1984)
AEGL-3 (Lethality) 27 (30) 21 (23) 15 (17) 8.6 (9.7) 6.6 (7.3) Lethality (LC01)--
rat (E.I. du Pont
de Nemours, 1981)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Not appropriate.

ii. References.
E.I. du Pont de Nemours and Company. 1981. Inhalation Toxicity of
Common Combustion Gases. Haskell Laboratory Report No. 238-81. Haskell
Laboratory, Newark, DE.
Purser, D.A. 1984. A bioassay model for testing the incapacitating
effects of exposure to combustion product atmospheres using cynomolgus
monkeys. Journal of Fire Sciences. 2:20-36.
Purser, D.A., Grimshaw, P., and Berrill, K.R. 1984. Intoxication by
cyanide in fires: A study in monkeys using polyacrylonitrile. Archives
of Environmental Health. 39:394-400.
7. Hydrogen fluoride (HF)--i. Description. Hydrogen fluoride is a
colorless, highly irritating and corrosive gas. Reaction with water is
rapid, producing heat and hydrofluoric acid. Hydrogen fluoride is used
in the manufacture of artificial cryolite; in the production of
aluminum, fluorocarbons, and uranium hexafluoride; as a catalyst in
alkylation processes in petroleum refining; in the manufacture of
fluoride salts; and in stainless steel pickling operations. It is also
used to etch glass and as a cleaner in metal finishing processes.
Hydrogen fluoride is a severe irritant to the eyes, skin, and nasal
passages; high concentrations may penetrate to the lungs resulting in
edema and hemorrhage. Data on irritant effects in humans and lethal and
sublethal effects in six species of mammals (monkey, dog, rat, mouse,
guinea pig, and rabbit) were available for development of AEGLs. The
data were considered adequate for derivation of the three AEGL
classifications for five exposure periods. Regression analyses of the
reported concentration-exposure durations for lethality for the animal
species determined that the relationship between concentration and time
is C² x t = k.
The AEGL-1 values were based on the observation that human
volunteers could tolerate exposure to a concentration of 2 ppm for 6
hours with only mild irritation of the eyes, skin, and upper
respiratory tract (Largent, 1960, 1961). This concentration was
adjusted by an UF of 3 to protect sensitive individuals and scaled to
the 30-minute and 1-, 4-, and 8-hour exposure durations using
C² x t = k. The factor of 3 was selected because hydrogen
fluoride reacts chemically with the tissues of the respiratory tract;
the adverse effects are unlikely to differ among individuals. The
resulting derived values, 2.3, 1.6, 0.82, and 0.58 ppm, were rounded to
the nearest whole integers of 2.0, 2.0, 1.0, and 1.0, respectively, by
the NAC/AEGL Committee. Because irritant properties would not change
greatly between the 10-minute and 30-minute time frames, the 10-minute
AEGL-1 was set at the same value of 2.0 ppm as the 30-minute AEGL-1.
The 10-minute AEGL-2 value was based on an absence of serious
pulmonary or other adverse effects in rats during direct delivery of HF
to the trachea for an exposure period of 10 minutes (Dalbey, 1996;
Dalbey et al., 1998). This reported concentration-exposure value of 950
ppm for 10 minutes was adjusted by a combined UF of 10: 3 for
interspecies variation since the rat was not the most sensitive species
in other studies (but direct delivery to the trachea is a sensitive
model) and an intraspecies UF of 3 since HF reacts chemically and
indiscriminately with the tissues of the respiratory tract and adverse
effects are unlikely to differ among individuals.
The 30-minute and the 1-, 4- and 8-hour AEGL-2 values were based on
a study in which dogs exposed to 243 ppm for 1 hour showed signs of
more than mild irritation, including blinking, sneezing, and coughing
(Rosenholtz et al., 1963). The 1-hour value of 243 ppm was adjusted by
a total UF of 10: 3 for intraspecies variation since the dog is a
sensitive species for sensory irritation and 3 for intraspecies
variation since HF reacts chemically and indiscriminately with the
tissues of the respiratory tract and effects are unlikely to differ
among individuals. The values were scaled across time using
C² x t = k where the value of n = 2 was derived from
concentration: Exposure duration relationships based on lethality.
The 10-minute AEGL-3 value was based on the reported 10-minute
lethal threshold in orally cannulated rats of 1,764 ppm (Dalbey, 1996;
Dalbey et al., 1998). This value was rounded down to 1,700 ppm and
adjusted by UFs of 3 for interspecies differences (LC50
values differ by a factor of approximately 2-4 between the mouse and
rat) and 3 for intraspecies differences since HF reacts chemically and
indiscriminately with tissues of the respiratory tract and effects are
unlikely to differ among individuals. The total adjustment for UFs for
the 10-minute AEGL-3 value was 10.
The 30-minute and the 1-, 4-, and 8-hour AEGL-3 values were derived
from a reported 1-hour exposure resulting in no deaths in mice
(Wohlslagel et al., 1976). The data indicated that the value of 263 ppm
was the threshold for lethality. A comparison of LC50 values
among species in several studies determined that the mouse was the most
sensitive species in lethality studies. The 1-hour value of 263 ppm was
adjusted by an interspecies UF of 1 since the mouse was the most
sensitive species and intraspecies UF of 3 since HF reacts chemically
and indiscriminately with tissues of the respiratory tract and effects
are unlikely to differ among individuals. A modifying factor of 2 was
applied to account for the steepness of the lethal dose-response curve
and the value was scaled to the other AEGL-specified exposure periods
using a value of n = 2.
Based on the extensive database involving both human and animal
exposures (six species of mammals) for various exposure durations,
confidence in the AEGL values is high. Values are summarized in the
table below.

[[Page 14194]]

Summary of Proposed AEGL Values for Hydrogen Fluoride (HF) [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 2 (1.6) 2 (1.6) 2 (1.6) 1 (0.8) 1 (0.8) Irritation in
humans (Largent,
1960; 1961)
AEGL-2 (Disabling) 95 (78) 34 (28) 24 (20) 12 (9.8) 8.6 (7.0) NOAEL for lung
effects in
cannulated rats
(Dalbey, 1996;
Dalbey et al.,
1998);\1\ sensory
irritation in dogs
(Rosenholtz et
al., 1963)\2\
AEGL-3 (Lethality) 170 (139) 62 (51) 44 (36) 22 (18) 15 (12) Lethality
threshold in
cannulated rats
(Dalbey, 1996;
Dalbey et al.,
1998);\3\
Lethality threshold
in mice
(Wohlslagel et
al., 1976)\4\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ 10-minute AEGL-2 value.
\2\ 30-minute and 1-, 4-, and 8-hour AEGL-2 values.
\3\ 10-minute AEGL-3 value.
\4\ 30-minute and 1-, 4-, and 8-hour AEGL-3 values.

ii. References.
Dalbey, W. 1996. Evaluation of the toxicity of hydrogen fluoride at
short exposure times. Petroleum Environmental Research Forum Project
92-09, performed at Stonybrook Laboratories Inc., Pennington, NJ.
Dalbey, W., Dunn, B., Bannister, R., Daughtrey, W., Kirwin, C.,
Reitman, F., Steiner, A., and Bruce, J. 1998. Acute effects of 10-
minute exposure to hydrogen fluoride in rats and derivation of a short-
term exposure limit for humans. Regulatory Toxicology and Pharmacology.
27:207-216.
Largent, E.J. 1960. The metabolism of fluorides in man. American
Medical Association Archives of Industrial Health. 21:318-323.
Largent, E.J. 1961. Fluorosis: The Health Aspects of Fluorine
Compounds. Ohio State University Press, Columbus, OH.
Rosenholtz, M.J., Carson, T.R., Weeks, M.H., Wilinski, F., Ford,
D.F., and Oberst, F.W. 1963. A toxicopathologic study in animals after
brief single exposures to hydrogen fluoride. American Industrial
Hygiene Association Journal. 24:253-261.
Wohlslagel, J., DiPasquale, L.C., and Vernot, E.H. 1976. Toxicity
of solid rocket motor exhaust: Effects of HCl, HF, and alumina on
rodents. Journal of Combustion Toxicology. 3:61-69.
8. Hydrogen sulfide (H2S)--i. Description. The AEGL-1
was based on persistent odors, eye and throat irritation, headache, and
nausea in six workers exposed to a mean concentration of 0.09 ppm
H2S for approximately 5 hours in a monitoring van downwind
from an oil refinery (TNRCC, 1998). An UF of 3 was applied to account
for intraspecies variability since minor irritation is not likely to
vary greatly between individuals. The value was flat-lined across the
10- and 30-minute and 1-, 4-, and 8-hour exposure time points. The
flat-lining approach was considered appropriate since mild irritant
effects generally do not vary greatly over time.
The AEGL-2 was based on focal areas of perivascular edema and an
increase in protein and lactic acid dehydrogenase (LDH) in
bronchioalveolar lavage fluid in rats exposed to 200 ppm hydrogen
sulfide for 4 hours (Green et al., 1991; Khan et al., 1991). An UF of 3
was used to extrapolate from animals to humans since rat and mouse data
suggest little interspecies variability. An UF of 3 was also applied to
account for sensitive individuals since data suggest little strain
variability of hydrogen sulfide toxicity among rats (total UF = 10).
The 4-hour experimental value was then scaled to the 10- and 30-minutes
and 1- and 8-hour time points, using C^4.36 x t = k. The
exponent of 4.36 was derived from rat lethality data ranging from 10-
minutes to 6-hour exposure duration.
The AEGL-3 was based on a 1-hour no-effect-level for death in rats
(504 ppm) (MacEwen and Vernot, 1972). An UF of 3 was used to
extrapolate from animals to humans since rat and mouse data suggest
little interspecies variability. An UF of 3 was also applied to account
for sensitive individuals since data suggest little strain variability
of hydrogen sulfide toxicity among rats (total UF = 10). The value was
then scaled to the 10- and 30-minutes and 1-, 4-, and 8-hour time
points, using C^4.36 x t = k. The exponent of 4.36 was
derived from rat lethality data ranging from 10 minutes to 6 hours
exposure duration.
The calculated values are listed in the table below.

Summary of Proposed AEGL Values for Hydrogen Sulfide [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.03 (0.04) 0.03 (0.04) 0.03 (0.04) 0.03 (0.04) 0.03 (0.04) Persistent odor,
eye, and throat
irritation,
headache, nausea
(TNRCC, 1998)
AEGL-2 (Disabling) 42 (59) 32 (45) 28 (39) 20 (28) 17 (24) Perivascular
edema, increased
protein, and LDH
in lavage fluid in
rats (Green et
al., 1991; Khan et
al., 1991)
AEGL-3 (Lethality) 76 (106) 60 (85) 50 (71) 37 (52) 31 (44) 1 hour no-effect-
level for death in
rats (MacEwen and
Vernot, 1972)
--------------------------------------------------------------------------------------------------------------------------------------------------------

ii. References.
Green, F. H. Y., Schurch, S., and DeSanctis, G. T., et al. 1991.
Effects of hydrogen sulfide exposure on surface properties of lung
surfactant. Journal of Applied Physiology. 70:1943-1949.
Khan, A. A., Yong, S., and Prior, M. G., et al. 1991. Cytotoxic
effects of hydrogen sulfide on pulmonary alveolar macrophages in rats.
Journal of Toxicology and Environmental Health. 33:57-64.
MacEwen, J. D. and Vernot, E. H. 1972. Toxic Hazards Research Unit
Annual Report. Aerospace Medical Research Laboratory, Air Force Systems
Command, Wright-Patterson Air Force Base, Ohio. Report No. ARML-TR-72-
62. pp. 66-69.

[[Page 14195]]

TNRCC (Texas Natural Resources Conservation Commission). 1998. Memo
from Tim Doty to JoAnn Wiersma. Corpus Christi Mobile Laboratory Trip,
January 31-February 6, 1998; Real-Time Gas Chromatography and Composite
Sampling, Sulfur Dioxide, Hydrogen Sulfide, and Impinger Sampling.
April 20, 1998.
9. Otto Fuel II (main component propylene glycol dinitrate; CAS No.
6423-43-4)--i. Description. Otto Fuel II, a liquid propellant used
exclusively by the U.S. Navy in torpedoes and other weapon systems, is
a mixture of three synthetic compounds: 1,2-Propylene glycol dinitrate
(PGDN), which is a nitrate ester explosive, dibutyl sebacate (a
desensitizer), and 2-nitrodiphenylamine (a stabilizer). The primary
component and the one responsible for the toxicity of Otto Fuel II is
PGDN, a volatile liquid with a disagreeable odor. Because PGDN is the
primary and most toxic component of Otto Fuel II and because only PGDN
is relatively volatile compared with the other components, AEGLs have
been derived in terms of PGDN with the notation that the values are
appropriate for Otto Fuel II.
PGDN is a systemic toxicant with effects on the cardiovascular and
central nervous systems. Its vasodilatory action results in headaches
during human exposures. Symptoms of dizziness, loss of balance, nasal
congestion, eye irritation, palpitations, and chest pains have also
been reported. Methemoglobinemia has been reported at the high
concentrations used in studies with animals.
Few data were available that met the definitions of AEGL endpoints.
One inhalation study with 20 human subjects described effects of
headaches and slight loss of balance at exposure concentrations of 0.1
to 1.5 ppm for exposure durations up to 8 hours (Stewart et al., 1974).
Acute exposure of monkeys to concentrations of 70-100 ppm for 6 hours
resulted in severe signs of toxicity including convulsions but no
deaths (Jones et al., 1972). In the same study, exposure of rats to a
higher concentration (#199 ppm for 4 hours) resulted in no toxic signs.
Examination of the relationship between exposure duration and
concentration for both mild and severe headaches in humans over periods
of time of 1 to 8 hours determined that the relationship is
C¹ x t = k.
The AEGL-1 values were based on concentrations of 0.5 ppm and 0.1
ppm which were the thresholds for mild headaches at exposure durations
of 1 and 6 hours, respectively (Stewart et al., 1974). This effect can
be considered the threshold for mild discomfort (only one subject was
affected at each exposure) which falls within the definition of an
AEGL-1. The 0.5 ppm concentration was used to derive the 30-minutes and
1-hour AEGL-1 values and the 0.1 ppm concentration was used for the 4-
and 8-hour values. Because the time and concentration values were based
on the most sensitive subject, these concentrations were adjusted by an
UF of 3 to account for additional differences in human sensitivity and
scaled to the appropriate time periods using the C¹ x t = k
relationship. An UF of 3 was considered sufficient as no susceptible
populations were identified (the headache effect is the same as that
experienced by heart patients medicated with nitroglycerin for angina
and these concentrations are far below those inducing methemoglobinemia
in infants); the vasodilatory effects of PGDN, responsible for the
headaches, are not expected to vary greatly among individuals. The 10-
minute AEGL-1 value was made equal to the 30-minute value.
The AEGL-2 values were based on a concentration of 0.5 ppm which
caused severe headaches accompanied by dizziness in one subject and
slight loss of equilibrium in two subjects in one of several sensitive
equilibrium tests after 6 hours of exposure (Stewart et al., 1974).
This concentration-exposure duration was considered the threshold for
impaired inability to escape as defined by the AEGL-2. The 0.5 ppm
concentration was adjusted by an intraspecies UF of 3 to protect
sensitive individuals and scaled across time using the C¹ x
t = k relationship as for the AEGL-1 in Unit III.B.9.
The AEGL-3 values were based on the exposure of squirrel monkeys to
concentrations of 70-100 ppm for 6 hours which resulted in vomiting,
pallor, cold extremities, semiconscousness, and clonic convulsions;
these signs disappeared upon removal from the exposure chamber (Jones
et al., 1972). The lower concentration, 70 ppm, was adjusted by a total
UF of 10. An interspecies UF of 3 was chosen because both the monkey
and human subjects showed changes in electrical activity of the brain
at similar PGDN concentrations, the threshold for central nervous
system depressants does not vary widely among mammalian species, and
the monkey is an appropriate model for extrapolation to humans. An
intraspecies UF of 3 was chosen because the threshold for central
nervous system depression also does not vary greatly among individuals.
Because the endpoint for the AEGL-3 values is different than the
endpoint for the AEGLs-1 and -2 and no data on the relationship between
concentration and exposure duration is available for the endpoint of
central nervous system depression, the more conservative values of n =
3 and n = 1 were used to scale from 6 hours to the shorter- and longer-
time periods, respectively.
The proposed values appear in the table below.

Summary of Proposed AEGL Values for Otto Fuel II [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1\a\ (Nondisabling) 0.33 (2.3) 0.33 (2.3) 0.17 (1.1) 0.05 (0.34) 0.03 (0.17) Mild headaches in
humans (Stewart et
al., 1974)
AEGL-2 (Disabling) 6.0 (43) 2.0 (14) 1.0 (6.8) 0.25 (1.7) 0.13 (0.8) Severe headaches
and slight
imbalance in
humans (Stewart et
al., 1974)
AEGL-3 (Lethality) 23 (165) 16 (114) 13 (93) 8.0 (57) 5.3 (38) Convulsions in
monkeys (Jones et
al., 1972)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ The distinctive odor of PGDN will be noticeable to most individuals at the 0.33 and 0.17 ppm concentrations.

ii. References.
Jones, R.A., Strickland, J.A., and Siegel, J. 1972. Toxicity of
propylene glycol 1,2-dinitrate in experimental animals. Toxicology and
Applied Pharmacology. 22:128-137.
Stewart, R.D., Peterson, J.E., Newton, P.E., Hake, C.L., Hosko,
M.J., Lebrun, A. J., and Lawton, G.M. 1974. Experimental human exposure
to propylene glycol dinitrate. Toxicology and Applied Pharmacology.
30:377-395.
10. 1,1,1-Trichloroethane--i. Description. 1,1,1-Trichloroethane is
a colorless, nonflammable liquid used primarily as an industrial metal
degreasing agent. It is also used as a solvent for adhesives, inks, and
coatings

[[Page 14196]]

and as an aerosol propellant (Nolan et al., 1984). Solvent vapor is
readily absorbed from the respiratory tract and distributed throughout
the body, accumulating in tissues with high lipid content. In both
humans and animals, the primary response to acute inhalation exposures
involve effects on the central nervous system (CNS). This chemical is
arrhythmogenic and there is some evidence that it produces transient
hepatotoxicity (Mcleod et al., 1987; Stahl et al., 1969; Hodgson et
al., 1989). It has little effect on other organs and does not seem to
be a developmental toxin although reliable epidemiological data for
humans are unavailable. 1,1,1-Trichloroethane does not seem to have
carcinogenic activity based on the available animal studies. A
considerable amount of human and animal data are available for
derivation of AEGLs. Rat ataxia and lethality data were used for the
regression analyses of the concentration-exposure durations. The
relationship between time and concentration was Cⁿ x t = k,
where n = 3.3 or 3.
The AEGL-1 was based on consistent complaints of eye irritation and
slight dizziness experienced by humans in an atmosphere controlled
setting with exposures of 450 ppm for two 4-hour sessions separated by
a 1.5-hour interval (Salvini et al., 1971). Stewart et al., 1969,
exposed human subjects to time-weighted average (TWA) concentration of
500 ppm for 7 hour repeatedly for 5 days, the only consistent complaint
was mild sleepiness and failure of the Romberg test by two of the
subjects which had trouble with this test initially. Torkelson et al.
(1958) reported a NOAEL for the Romberg test in humans after exposure
to a TWA of 506 ppm for 7.5 hour. For derivation of the AEGL-1, the
observations of Salvini et al. (1971) were used as the starting point
for the threshold of eye irritation and very subtle CNS effects in
humans at a concentration of 450 ppm for 4 hour. An UF of 2 was chosen
based on the observation that the severity of the eye irritation did
not increase with time and the threshold for mild CNS effects does not
vary by more than two-three fold which should be protective of
sensitive individuals. The resulting figure of 230 ppm was used at all
time points based on the information reported by Salvini et al. (1971)
indicating that this exposure represented a threshold for these effects
and the severity did not increase with duration of exposure.
The AEGL-2 was based on more serious CNS effects which might impede
escape. Mullin and Krivanek (1982) calculated EC50 values
for ataxia in rats at 30-minute and 1-, 2-, and 4-hour exposures to be
6,740; 6,000; 4,240; and 3,780 ppm. These values were used as the basis
for AEGL-2 derivation using an UF of 10 and extrapolations were made to
the 10-minute and 8-hour time points using the equation Cⁿ x
t = k, where n = 3.3 based on the data presented by Mullin and Krivanek
(1982). An UF of 10 was applied which includes a factor of 3 to account
for sensitive individuals and a factor of 3 for interspecies
extrapolation. These UFs were based on the two-three fold variation of
minimum alveolar concentration for anesthesia (MAC) values among humans
and the similarities in toxicity, metabolism, and excretion of 1,1,1-
trichloroethane in rats compared to humans. The resulting
concentrations are similar to the concentration exposure durations
applied in experimental human studies which resulting in effects that
could impede escape, i.e., CNS intoxication.
The AEGL-3 values were derived from a lethality concentration-
effect curve in the rat for a 6-hour exposure duration (Bonnet et al.,
1980). The LC0 was conservatively estimated from this curve
as a concentration of about 7,000 ppm for a 6-hour exposure duration.
An extrapolation was made to the 30-minute and 1-, 4-, and 8-hour time
points using the equation Cⁿ x t = k, where n = 3 based on
the rat lethality data. An UF of 10 was applied. An intraspecies factor
of 3 was used to account for sensitive individuals based on the two-
three fold variation of MAC values observed among humans and an
interspecies factor of 3 was used because of the similarities in
toxicity, metabolism, and excretion of 1,1,1-trichloroethane in rats
compared to humans. The resulting concentrations were multiplied by a
modifying factor of 3 in order to achieve a reasonable concentration at
which humans might experience life-threatening toxic effects. This
factor is justified by the existence of a higher blood: Air partition
coefficient for rats compared to humans. This principle determines the
relative blood concentration for a vapor and because it is higher for
rats, a higher blood concentration is achieved.
The proposed values appear in the table below.

Summary of Proposed AEGL Values for 1,1,1-Trichloroethane [ppm (mg/m³ )]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-min. 30-min. 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 230 (1,252) 230 (1,252) 230 (1,252) 230 (1,252) 230 (1,252) Eye irritation and
slight dizziness
in humans observed
(Salvini et al.,
1971)
AEGL-2 (Disabling) 930 (5,064) 670 (3,650) 600 (3,270) 380 (2,070) 310 (1,688) EC50 for ataxia in
rats (Mullin and
Krivanek, 1982)
AEGL-3 (Lethality) 4,800\1\ (26,135) 4,800 (26,135) 3,800 (20,690) 2,400 (13,067) 1,900 (10,345) LC0 extrapolated
(Bonnet et al.,
1980)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\The 30-minute value was used as the 10-minute value so as not to exceed the threshold for cardiac sensitization observed in dogs (Reinhardt et al.,
1973).

ii. References.
Bonnet, P., Francin, J.M., Gradiski, D., Raoult, G., and Zissu, D.
1980. Determination of the median lethal concentration of principle
chlorinated aliphatic hydrocarbons in the rat Archives des Maladies
Professionelles. 41:317-321.
Mullin, L.S. and Krivanek, N.D. 1982. Comparison of unconditioned
avoidance tests in rats exposed by inhalation to carbon monoxide,
1,1,1-trichloroethane, and toluene or ethanol. Neurotoxicology. 1:126-
137.
Reinhardt, C.F., Mullin, L.S., and Maxfield, M.E. 1973.
Epinephrine-induced cardiac arrhythmia potential of some common
industrial solvents. Journal of Occupational Medicine. 15(12):953-955.
Salvini, M. S. and Binaschi, M. Riva. 1971. Evaluation of the
psychophysiological functions in humans exposed to the threshold limit
value of 1,1,1-trichloroethane. British Journal of Industrial Medicine.
28(3):286-292.

List of Subjects

Environmental protection, Hazardous substances.

[[Page 14197]]

Dated: March 8, 2000.
Susan H. Wayland,
Deputy Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 00-6397 Filed 3-14-00; 8:45 am]
BILLING CODE 6560-50-F