[Federal Register Volume 67, Number 32 (Friday, February 15, 2002)]
[Notices]
[Pages 7164-7176]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-3774]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-00330; FRL-6815-8]
National Advisory Committee for Acute Exposure Guideline Levels
(AEGLs) for Hazardous Substances; Proposed AEGL Values
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
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 eight 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 eight chemicals.
DATES: Comments, identified by docket control number OPPTS-00330, must
be received on or before March 18, 2002.
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-00330 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
(7408M), 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 Pollution Prevention and Toxics
(7406M), Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (202) 564-8557; 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,'' ``Regulations and Proposed Rules,'' 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-00330. 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 for the Center is (202)
260-7099.
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-00330 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.
2. In person or by courier. Deliver your comments to: OPPT Document
Control Office (DCO) in EPA East
[[Page 7165]]
Building Rm. 6428, 1201 Constitution Ave., NW., 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) 564-8930.
3. Electronically. You may submit your comments electronically by
e-mail to: [email protected], or mail or deliver your computer disk to
the appropriate address identified in this unit. 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 6.1/8.0 or ASCII file format.
All comments in electronic form must be identified by docket control
number OPPTS-00330. Electronic comments may also be filed online at
many Federal Depository Libraries.
D. How Should I Handle CBI Information 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 prior 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?
We invite you to provide your views on the various options we
propose, new approaches we have not considered, the potential impacts
of the various options (including possible unintended consequences),
and any data or information that you would like the Agency to consider
during the development of the final action. 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 notice or collection
activity.
7. Make sure to submit your comments by the deadline in this
notice.
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 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, State and local 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-1, AEGL-2, and AEGL-3 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 milligrams/meter cubed (mg/m3) 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/
m3) 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/
m3) 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
[[Page 7166]]
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 NAC/AEGL Committee in draft form
by Oak Ridge National Laboratories together with ``draft'' AEGL values
prepared in conjunction with NAC/AEGL Committee members. Both the
``draft'' AEGLs and ``draft'' technical support documents are reviewed
and revised as necessary by the NAC/AEGL Committee members prior to
formal NAC/AEGL 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 eight hazardous substances. These values represent the sixth 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 (65FR 14186-14196) (FRL-6492-4); for 14 chemicals in
the Federal Register of June 23, 2000 (65 FR 39263-39277) (FRL-6492-4);
for 7 chemicals in the Federal Register of December 13, 2000 (65 FR
77866-77874) (FRL-6752-5); and for 18 chemicals in the Federal Register
of May 2, 2001 (66 FR 21940-21964) (FRL-6776-3) 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 entitled ``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 AEGL values 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 eight 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.
A. Fax-On-Demand Table
Table 1.--Fax-On-Demand Number
------------------------------------------------------------------------
Fax-On-Demand Item
CAS No. Chemical name No.
------------------------------------------------------------------------
56-23-5 Carbon 4851
tetrachloride
------------------------------------------------------------------------
75-56-9 Propylene oxide 4864
------------------------------------------------------------------------
7637-07-2 Boron trifluoride- 4892
dimethyl ether
------------------------------------------------------------------------
7782-50-5 Chlorine 4916
------------------------------------------------------------------------
7783-81-5 Uranium 4919
hexafluoride
------------------------------------------------------------------------
10049-04-4 Chlorine dioxide 4926
------------------------------------------------------------------------
163702-07-6 Methyl 4933
nonafluorobutyl
ether (HFE-7100
component)
------------------------------------------------------------------------
163702-08-7 Methyl 4934
nonafluoroisobutyl
ether (HFE-7100
component)
------------------------------------------------------------------------
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. and III.) that support the NAC/AEGL Committee's development of
AEGL values for each chemical substance. This information provides the
following: 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
[[Page 7167]]
to use of the AEGL values within various programs.
1. Carbon tetrachloride--i. Description. Carbon tetrachloride (CAS
No. 56-23-5) is a colorless, nonflammable, heavy liquid only slightly
soluble in water that is used as a laboratory and industrial solvent,
an intermediate in the synthesis of trichlorofluoromethane and
dichlorodifluoromethane, and was formerly used as a dry-cleaning agent,
grain fumigant, anthelmintic, and fire suppressant.
Numerous case reports were available regarding acute inhalation
exposure of humans to carbon tetrachloride although most lacked
definitive-exposure terms. These reports, however, affirmed the
hepatotoxic and renal toxicity of carbon tetrachloride as well as a
delayed response for serious and fatal effects. Additionally, data from
controlled exposures of humans to carbon tetrachloride were also
available.
Animal toxicity data for inhaled carbon tetrachloride indicate
hepatotoxic and renal effects, as well as anesthetic-like effects, as
primary endpoints. The most sensitive endpoint for evaluating the
toxicity of carbon tetrachloride in animals appears to be measurement
of serum enzyme activities that reflect hepatic damage. Several studies
provided lethality data for various concentrations and exposure
durations but data regarding nonlethal effects were limited or
available only from long-term exposure studies.
Studies in animals have shown the metabolism and disposition of
carbon tetrachloride to be complex and varied among species. Although
the precise mechanism of toxicity is equivocal, the biotransformation
of carbon tetrachloride by the monooxygenase enzymes (specifically
CYP2E1) to reactive intermediates is critical for expression of
toxicity. It is this activation process that is critical in modifying
the toxic response to carbon tetrachloride.
The AEGL-1 values were based upon a controlled exposure of human
subjects to 158 ppm for 30 minutes (Davis, 1934). The exposure resulted
in a feeling of nervousness and slight nausea. Development of AEGL
values for the various exposure periods was based upon the exponential
function, Cn x t = k (ten Berge et al., 1986), where n = 2.5
as determined by the lethal response of rats to various exposures of
carbon tetrachloride. The AEGL-1 values were adjusted by an uncertainty
factor of 10 to account for the protection of sensitive individuals
(such as users of alcohol) who, due to metabolism and disposition
factors, are known to be more susceptible to the toxic effects of
carbon tetrachloride.
The AEGL-2 was also based upon human data from controlled exposure
experiments in which subjects experienced headache, nausea, and
vomiting following 15-minute exposure to 1,191 ppm carbon tetrachloride
(Davis, 1934). It is believed that these effects may impair escape. The
AEGL-2 values were derived with temporal scaling based upon the
exponential function where n = 2.5. The AEGL values were further
adjusted by the application of an uncertainty factor of 10 to account
for individuals who may be more susceptible to the toxic effects of
carbon tetrachloride due to variability in metabolism and disposition
of the chemical.
The AEGL-3 was based upon an estimated lethality threshold (1-hour
LC01 of 5,135.5 ppm) using data from multiple studies on
laboratory rats (Adams et al., 1952; Dow Chemical, 1986). Temporal
scaling using the exponential function where n = 2.5 was derived from
lethality data and used to develop values for AEGL-specific exposure
durations. An uncertainty factor of 10 was again applied to account for
individuals who may be more susceptible to the toxic effects of carbon
tetrachloride (e.g., P-450 induction by ethanol consumption and overall
variability in metabolism and disposition of the chemical). Because
animal data were used, an uncertainty factor of 3 was applied to
account for possible variability in metabolism and the toxic response
among species, bringing the total uncertainty factor adjustment to 30.
Application of additional uncertainty factors did not appear to be
warranted because animal data showed that long-term exposures to carbon
tetrachloride above the AEGL-3 values did not result in notable toxic
effects.
Although a carcinogenic response following oral exposure of
laboratory species has been demonstrated, quantitative data for
inhalation exposures were unavailable. However, a unit risk of 1.5E-5
per g (gram)/m3 has been established based upon
route-to-route extrapolation from carcinogenicity data for oral
exposures in various laboratory species. An estimation of AEGLs based
upon carcinogenic potential was conducted but the assessment revealed
that AEGLs derived from noncarcinogenic toxicity endpoints were more
applicable for human health protection relative to adverse effects
following acute inhalation exposures.
The AEGL values developed for carbon tetrachloride did not
incorporate the possibility of dermal exposure. If the potential for
dermal absorption exists, the AEGL values may not be appropriate.
Additionally, for AEGL-2 and AEGL-3 exposures, the possibility exists
for long-term hepatotoxic effects possibly requiring the need for
antioxidant therapy.
The calculated values are listed in Table 2 below:
Table 2.--Summary of Proposed AEGL Values for Carbon Tetrachloride [ppm (mg/m3)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minutes 30-minutes 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 25 (157) 16 (101) 12 (75) 6.9 (43) 5.2 (33) Nervousness and
slight nausea in
human subjects
exposed for 30
minutes to 158 ppm
(Davis, 1934)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 140 (881) 90 (566) 68 (428) 39 (245) 30 (189) Nausea, vomiting,
headache in human
subjects exposed
to 1,191 ppm for
15 minutes (Davis,
1934)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethal) 350 (2,202) 230 (1,447) 170 (1,069) 99 (623) 75 (472) Lethality in rats;
estimated LC01
(Adams et al.,
1952; Dow
Chemical, 1986)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. Adams, E.M.; Spencer, H.C.; Rowe, V.K.;
McCollister, D.D.; and Irish, D.D. 1952. Vapor toxicity of carbon
tetrachloride determined by experiments on laboratory animals. Archives
of Industrial Hygiene and Occupational Medicine. 6:50-66.
[[Page 7168]]
b. Davis, P. A. 1934. Carbon tetrachloride as an industrial hazard.
Journal of the American Medical Association. 103:962-966.
c. Dow Chemical. 1986. Comparison of the result of exposure of rats
and cavies to the vapors of carbon tetrachloride and
bromochloromethane. Dated: 7/11/60. EPA-OTS 86-870002363.
d. 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.
2. Propylene oxide--i. Description. Propylene oxide (CAS No. 75-56-
9) is an extremely flammable, highly volatile, colorless liquid. The
odor of propylene oxide has been described as sweet and alcoholic in
nature, and has reported odor thresholds ranging from 10 ppm to 200
ppm. The primary industrial uses of propylene oxide include its use in
the production of polyurethane foams and resins, propylene glycol,
functional fluids (such as hydraulic fluids, heat transfer fluids, and
lubricants), and propylene oxide-based surfactants. It is also used as
a food fumigant, soil sterilizer, and acid scavenger.
Data addressing inhalation toxicity of propylene oxide in humans
were limited to one case report, general environmental work surveys,
and molecular biomonitoring studies. Studies addressing lethal and
nonlethal inhalation toxicity of propylene oxide were available in
monkeys, dogs, rats, mice, and guinea pigs. General signs of toxicity
following acute exposure to propylene oxide vapor included nasal
discharge, lacrimation, salivation, gasping, lethargy/hypoactivity,
weakness, and incoordination. Repeated exposures resulted in similar
but generally reversible signs of toxicity.
Propylene oxide is a direct alkylating agent that will covalently
bind to DNA and proteins. Consequently, it has tested positive in a
number of in vitro tests, but has produced equivocal results in in vivo
test systems. Data addressing the potential carcinogenicity of
propylene oxide in animals is considered adequate for establishing
propylene oxide as a carcinogen in experimental animals.
The proposed AEGL-1 values for propylene oxide were based on an
environmental health survey in which 8-hour time weighted averages
(TWA) were determined from a 3-day sampling period during which no
worker complaints were noted (Chemical Manufacturers Association (CMA),
1998). The highest 8-hour TWA value of 31.8 ppm was chosen for the
derivation. An interspecies uncertainty factor was not needed, since
the data were from human exposures. An intraspecies uncertainty factor
of 3 was applied because the toxic effects (no complaints noted) were
less severe than those defined for the AEGL-1 tier. Therefore, a total
uncertainty factor of 3 was applied. These values are supported by
mouse data from the National Toxicology Program (NTP) (1985) study.
Mice were the most sensitive species tested, and dyspnea was the most
sensitive endpoint of toxicity following exposure to propylene oxide.
Dyspnea was observed in mice exposed for 4 hours to 387 ppm propylene
oxide vapor, the lowest concentration tested, but not in mice exposed
to 98.5 ppm propylene oxide vapor or less for 6 hours/day, 5 days/week
for 2 weeks (NTP, 1985). Therefore, an AEGL-1 can be derived using the
exposure concentration of 98.5 ppm for 6 hours (a no-observed-effect
level (NOEL) for dyspnea). Following application of a total uncertainty
factor of 3 (interspecies uncertainty factor of 1 because mice were the
most sensitive laboratory species tested, and available data indicate
that mice are equally or slightly more sensitive than humans; an
intraspecies uncertainty factor of 3 because the toxic effect (NOEL for
dyspnea) was less severe than that defined for the AEGL-1 tier), one
obtains AEGL-1 values approximately two-fold greater than those
generated using the human data.
The proposed AEGL-2 values are based on the average of AEGL-2
values derived using four propylene oxide exposure concentrations
measured in the breathing zone of three workers (380 ppm for 177
minutes, 525 ppm for 121 minutes, 392 ppm for 135 minutes, and 460 ppm
for 116 minutes) (CMA, 1998). The industrial hygienist noted that ``the
odor was quite strong during the sampling; however, the irritation was
not intolerable.'' The exact nature of the irritation, other than the
strong odor, was not provided, but occasional eye irritation was noted
in the report as the reason for the monitoring program. When deriving
AEGL-2 values, an interspecies uncertainty factor was not applicable.
An intraspecies uncertainty factor of 3 was applied because the toxic
effects (occasional eye irritation; strong odor) were less severe than
those defined for the AEGL-2 tier. Therefore, a total uncertainty
factor of 3 was applied. The AEGL-2 values are supported by the data
from the NTP study in which mice exposed to 387 ppm for 4 hours
exhibited dyspnea. Although a NOEL was not established for dyspnea at
this concentration, no other effects were noted. In addition, when
compared to other studies investigating propylene oxide toxicity in
mice, the NTP study reported toxic effects occurring at much lower
concentrations than those observed in other studies. Following
application of a total uncertainty factor of 3 (interspecies
uncertainty factor of 1 because mice were the most sensitive laboratory
species tested, and available data indicate that mice are equally or
slightly more sensitive than humans; an intraspecies uncertainty factor
of 3 because the toxic effect was less severe than that defined for the
AEGL-2 tier), one obtains AEGL-2 values approximately 1.4-fold greater
than those generated using the human data.
The highest nonlethal concentration in humans was chosen for the
AEGL-3 derivation (CMA, 1998). A worker exposed to 1,520 ppm propylene
oxide for 171 minutes did not experience mortality; in fact, exposure
to this concentration did not cause the worker to cease working. The
notation was made by the industrial hygienist that ``the odor was quite
strong during the sampling; however, the irritation was not
intolerable.'' In deriving AEGL-3 levels, an interspecies uncertainty
factor is not needed. An intraspecies uncertainty factor of 3 was
applied because the toxic effects (strong odor) were less severe than
those defined for the AEGL-3 tier. A modifying factor of 2 was applied
to account for the sparse data set (one sample measurement from one
worker; old survey from 1968). That these values should be protective
of human health is supported by the mouse data. The highest nonlethal
concentration in mice was 859 ppm for 4 hours (NTP, 1985). Following
application of a total uncertainty factor of 3 (an interspecies
uncertainty factor of 1 because mice were the most sensitive laboratory
species tested, and available data indicate that mice are equally or
slightly more sensitive than humans; an intraspecies uncertainty factor
of 3 because the mechanism of toxicity is not expected to differ
greatly between individuals), one obtains AEGL-3 values approximately
1.4-fold greater than those generated using the human data.
The experimentally derived exposure values were then scaled to AEGL
time frames using the concentration-time relationship given by the
equation Cn x t = k, where c = concentration, t = time, k is
a constant, and n generally ranges from 1 to 3.5 (ten Berge, 1986).
Data appropriate for the derivation of n were extremely limited.
Because of the lack of data for empirical derivation of n for propylene
oxide, and based on the
[[Page 7169]]
similar mechanism of action of propylene oxide as compared to ethylene
oxide, the derived value of n for ethylene oxide will be used in the
scaling of propylene oxide AEGL values across time. The value of n =
1.2 for ethylene oxide was derived empirically from 1- and 4-hour
LC50 values for rats. An n value of approximately 1 is
further supported by propylene oxide guinea pig data that also suggest
a linear relationship. The 10-minute AEGL-1 value was set equal to the
30-minute AEGL value because the NAC considers it inappropriate to
extrapolate from the exposure duration of 8 hours to 10 minutes.
A carcinogenic risk assessment of propylene oxide resulted in
values that exceed the values based on acute toxicity. Therefore, they
are not proposed for AEGL-3. Additionally, while long-term inhalation
exposure studies have demonstrated that propylene oxide is carcinogenic
in mice and rats, no tumors were observed when 12-week-old male
Sprague-Dawley rats were exposed to 433 or 864 ppm propylene oxide for
30 days or 1,724 ppm for 8 days (exposures were for 6 hours/day, 5
days/week) and allowed to die naturally (Sellakumar et al., 1987). This
shorter-term exposure suggests a lack of carcinogenic effect following
acute exposures.
The calculated values are listed in Table 3 below:
Table 3.--Summary of Proposed AEGL Values for Propylene Oxide [ppm (mg/m3)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minutes 30-minutes 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 110 (260) 110 (260) 60 (140) 19 (45) 11 (26) 8-hour TWA of 31.8
ppm resulted in no
worker complaints
(CMA, 1998)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 1,300 (3,100) 510 (1,200) 290 (690) 91 (220) 51 (120) Humans: Strong odor
and irritation
noted in
monitoring study;
average of AEGL-2
values using 4
exposure
concentrations and
durations: 380 ppm
for 177 minutes,
525 ppm for 121
minutes, 392 ppm
for 135 minutes,
460 ppm for 116
minutes (CMA,
1998)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethal) 2,700 (6,400) 1,100 (2,600) 610 (1,400) 190 (450) 110 (260) Humans: Highest
recorded nonlethal
concentration of
1,520 ppm for 171
minutes (CMA,
1998)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. CMA. 1998. Chemical Manufacturers Association to
National Advisory Committee, (NAC)/AEGLs, Human Experience with
Propylene Oxide. Dated: October 16, 1998.
b. NTP. 1985. Toxicology and Carcinogenesis Studies of Propylene
Oxide (CAS No. 75-56-9) in F344/N Rats and B6C3F1 Mice
(Inhalation Studies). NTP TR 267, National Institutes of Health (NIH)
Publication No. 85-2527, U.S. Department of Health and Human Services,
Research Triangle Park, NC.
c. Sellakumar, A.R.; Snyder, C.A.; and Albert, R.E. 1987.
Inhalation carcinogenesis of various alkylating agents. Journal of the
National Cancer Institute. 79:285-289.
d. 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.
3. Boron trifluoride-dimethyl ether--i. Description. Boron
trifluoride-dimethyl ether (CAS No. 7637-07-2) is one of several
different complexes that can be formed with boron trifluoride. The
complexes are generally formed for ease of handling boron trifluoride.
The ether complexes consist of a 1:1 molar ratio of boron trifluoride
and the dimethyl or diethyl ether and can dissociate under the proper
temperature and pressure conditions. A single study was found that
addressed the toxicity of boron trifluoride-dimethyl ether, but it
reported only nominal concentrations. Because the complex can
dissociate to form boron trifluoride, the AEGL derivations are based
upon this one chemical species alone.
Boron trifluoride is a colorless gas with an odor that has been
described both as pungent and suffocating or as pleasant. Although the
gas is stable in dry air, it immediately forms a dense white mist or
cloud when exposed to moist air. It has been reported that upon
exposure to even low levels of moisture in the air, boron trifluoride
reacts to form the dihydrate, BF3 2H2O. It has been
demonstrated that boron trifluoride dihydrate is strongly corrosive to
the eyes and skin of rabbits. Boron trifluoride is an excellent
catalyst, and has fire retardant and antioxidant properties, nuclear
applications, and insecticidal properties.
No definitive data were available addressing the toxicity of boron
trifluoride in humans. A statement was made in one study that a worker
could detect the odor of boron trifluoride at a concentration of 1.5
ppm (4.1 mg/m3) (Torkelson et al., 1961). Acute toxicity
data were available in dogs, rats, mice, and guinea pigs, but exposure
concentrations were generally expressed only in terms of nominal
concentrations. Studies which actually measured the exposure
concentrations and compared them to nominal concentrations found actual
concentrations ranged from 25-56% of nominal (Rusch et al., 1986;
Torkelson et al., 1961). Studies identifying endpoints other than those
of mortality were limited. No data were available to evaluate the
potential for boron trifluoride to cause developmental/reproductive
toxicity or carcinogenicity in animals. Boron trifluoride was not
mutagenic to several strains of Salmonella typhimurium.
The AEGL-1 derivation is based upon lacrimation noted in some rats
starting at week 2 of exposure to 6 mg/m3 boron trifluoride
for 6 hours/day, 5 days/week for 13 weeks (exposures were to liquid
aerosols of boron trifluoride dihydrate; concentrations reported are
based on boron trifluoride) (Rusch et al., 1986; Hoffman and Rusch,
1982). This essentially represents a no-effect level for irritation for
an acute exposure. Lacrimation was also reported in some rats exposed
to 2 mg/m3 for 6 hours/day, 5 days/week for 13 weeks, but
the observation did not occur until week 10, which is even less
relevant to an acute exposure scenario. A total uncertainty factor of
10 was applied. Because the AEGL-1 is based upon essentially a no-
effect level for an acute exposure
[[Page 7170]]
scenario, an interspecies uncertainty factor of 3 was applied. An
intraspecies uncertainty factor of 3 was applied based upon the
following reasoning. At higher exposure levels boron trifluoride is an
irritant, while at lower levels of exposure it is a renal toxicant. In
both cases, the dose response curve is very steep. An example of the
steepness of the dose-response curve is seen in the Rusch et al. (1986)
study, in which all animals died from renal toxicity as a result of
five, 6-hour exposures at 180 mg/m3, while none even showed
signs of renal effects following 10 exposures at 66mg/m3.
Also, none of the animals that died from the exposures at 180 mg/
m3 showed signs of pulmonary irritation even though this
exposure was only 16th of the LC50 and was for a longer
daily duration of 6 hours compared to 4 hours. For these reasons, it
was judged that an intra-species uncertainty factor of 3 would protect
even the sensitive members of the exposed population. The derived value
was set equal to all AEGL time points because the endpoint is a no-
effect level for an irritant.
The key study chosen for derivation of the AEGL-2 is the Rusch et
al. (1986) study in which five male and five female rats were exposed
to 180 mg/m3 of boron trifluoride for 6 hours/day for 5 days
(exposures were to liquid aerosols of boron trifluoride dihydrate;
concentrations reported are based on boron trifluoride). Although all
rats died from renal toxicity at the end of 5 days of exposure, the
only signs observed after 1 day of exposure were those of irritation.
It is possible that there may have been some renal toxicity as a
consequence of the first day of exposure. The AEGL-2 value was
developed by dividing the 180 mg/m3 exposure level by 2 as a
modifying factor since no pathology was conducted after the first
exposure; therefore, renal effects could not be characterized or
quantified. The resulting value of 90 mg/m3 is divided by a
total uncertainty factor of 10:3 for intraspecies and 3 for
interspecies. This provides a starting value of 9 mg/m3 for
a 6-hour exposure. An interspecies uncertainty factor of 3 was used
because no effects were seen in rats exposed to 66 mg/m3 for
6 hours/day for 10 days (Rusch et al., 1986); 1 dog exposed to boron
trifluoride at 1,380-2,760 mg/m3 for 2 hours exhibited only
breathing sounds and on necropsy visible signs of irritation to the
respiratory tract (DuPont Company, 1948); another group of 2 rats,
exposed to 2,760 mg/m3 for 1 hour exhibited similar necropsy
signs (DuPont Company, 1948); and while 1/10 mice died when exposed to
2,100 mg/m3 for 5.5 hours, none died or even lost body
weight when exposed to 350 mg/m3 for 5.5 hours (Stokinger
and Spiegl, 1953). An intraspecies uncertainty factor of 3 was chosen
based on the same reasoning provided for the AEGL-1: The dose-response
curve was steep for boron trifluoride's actions as both an irritant and
renal toxicant. The AEGL-2 starting value of 9 mg/m3 is in
between the 6 hours/day, 5 days/week, 13-week exposure to 17 mg/
m3, which resulted in irritation in rats and renal toxicity
in 2/40 rats (one of the rats died of renal toxicity at week 12), and
the 6 hours/day, 5 days/week, 13-week exposure to 6 mg/m3
which resulted only in minimal irritation (lacrimation starting at week
2) (Rusch et al., 1986; Hoffman and Rusch, 1982).
The AEGL-3 derivation is based upon a 4-hour LC01 value
of 736 mg/m3 calculated using rat mortality data from Rusch
et al. (1986) (exposures were to liquid aerosols of boron trifluoride
dihydrate; concentrations reported are based on boron trifluoride).
Although other LC50 values were available (1-hour
LC50S of 1,000 and 1,100 mg/m3 in rats
[Vernot et al, 1977]; 2-hour LC50 of 3,460 mg/m3
in mice [Kasparova and Kirii, 1972], and 4-hour LC50 of 109
mg/m3 in guinea pigs [Stokinger and Spiegl, 1953]), the
Rusch et al. (1986) rat study was chosen for the AEGL-3 derivation
because it was the best characterized study and the actual exposure
concentrations of boron trifluoride were measured. An interspecies
uncertainty factor of 10 was applied because the LC50 values
indicated variability among species in their sensitivity to boron
trifluoride. An intraspecies uncertainty factor of 3 was chosen based
on the same reasoning provided for the AEGL-1 and AEGL-2: The dose-
response curve was steep for boron trifluoride's actions as both an
irritant and renal toxicant.
Experimentally derived exposure values are scaled to AEGL time
frames using the concentration-time relationship given by the equation
Cn x t = k, where C = concentration, t = time, k is a
constant, and n generally ranges from 1 to 3.5 (ten Berge, 1986). The
value of n could not be empirically derived due to the inadequate 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 for the AEGL-2 and
AEGL-3. The 10-minute value was set equal to the 30-minute value for
the AEGL-2 and AEGL-3 because it is not considered appropriate to
extrapolate from a 6-hour or 4-hour exposure duration, respectively, to
a 10-minute exposure duration.
The calculated values are listed in Table 4 below:
AEGL values are given in terms of mg/m3 because
exposures were to liquid aerosols of boron trifluoride dihydrate and
boron trifluoride gas becomes an aerosol upon contact with moisture in
the air.
Table 4.--Summary of Proposed AEGL Values for Boron Trifluoride (mg/m3)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minute 30-minute 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.60 mg/m3 0.60 mg/m3 0.60 mg/m3 0.60 mg/m3 0.60 mg/m3 Value representing
a no-effect level
for irritancy
following an acute
exposure;
exposures were to
6 mg/m3 for 6 hour/
day, 5 day/week,
for 13 week (Rusch
et al., 1986;
Hoffman and Rusch,
1982a)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 21 mg/m3 21 mg/m3 16 mg/m3 10 mg/m3 6.8 mg/m3 Signs of irritation
and renal toxicity
(resulting in
death) following
exposure to 180 mg/
m3 for 6 hour/day
for 5 days (Rusch
et al., 1986;
Hoffman and Rusch,
1982b)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 7171]]
AEGL-3 (Lethal) 49 mg/m3 49 mg/m3 39 mg/m3 25 mg/m3 12 mg/m3 Calculated 4-hour
LC01 in male and
female rats of 736
mg/m3; based upon
analytical
concentrations
(Rusch et al.,
1986; Hoffman,
1981)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. DuPont Company. 1948. Toxicity of boron
trifluoride (BF3). Unpublished Haskell Laboratory Report No.
13-48. April 15, 1948. E.I. duPont de Nemours & Co., Newark, DE 19714.
b. Hoffman, G.M. and Rusch, G.M. 1982a. A 13-week inhalation
toxicity study of boron trifluoride dihydrate in the rat. Unpublished
Report No. MA-40-80-7. September 28, 1983. Allied Corporation,
Department of Toxicology, Morristown, NJ 07960.
c. Kasparov, A.A. and Kirii, V.G. 1972. Toxicity of boron
trifluoride. Farmakologiya i Toksikologia. (Moscow) 35:372. (in
Russian; English abstract).
d. Rusch, G.M.; Hoffman, G.M.; McConnell, R.F.; and Rinehart, W.E.
1986. Inhalation toxicity studies with boron trifluoride. Toxicology
and Applied Pharmacology. 83:69-78.
e. Stokinger, H.E. and Spiegl, C.J. 1953. Part A. Inhalation-
toxicity studies of boron halide and certain fluorinated hydrocarbons.
Voegtlin, C. and Hodge, H.C. (eds). Pharmacology and Toxicology of
Uranium Compounds. New York: McGraw-Hill Book Co., Inc. pp. 2291-2311.
f. 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.
g. Torkelson, T.R., Sadek, S.E., and Rowe, V.K. 1961. The toxicity
of boron trifluoride when inhaled by laboratory animals. American
Industrial Hygiene Association Journal. 22: 263-270.
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.
42:417-423.
4. Chlorine--i. Description. Chlorine (CAS No. 7782-50-5) is a
greenish-yellow, highly reactive halogen gas with a pungent,
suffocating odor. The vapor is heavier than air and will form a cloud
in the vicinity of a spill. Like other halogens, chlorine does not
occur in the elemental state in nature; it rapidly combines with both
inorganic and organic substances. Chlorine is used in the manufacture
of a wide variety of chemicals, as a bleaching agent in industry and
household products, and as a biocide in water and waste treatment
plants.
Chlorine is an irritant to the eyes and respiratory tract; reaction
with moist surfaces produces hydrochloric and hypochlorous acids. Its
irritant properties have been studied in human volunteers and its acute
inhalation toxicity has been studied in several laboratory animal
species. The data from the human and laboratory animal studies were
sufficient for development of three AEGLs for 5-time periods (i.e., 10
and 30 minutes and 1, 4, and 8 hours). Regression analysis of human
data on nuisance irritation responses (itching or burning of the eyes,
nose, or throat) for exposure durations of 30-120 minutes and during
exposures to 0-2 ppm of chlorine determined that the relationship
between concentration and time is approximately C2 x t = k
(ten Berge and Vis van Heemst, 1983).
The AEGL-1 was based on the observation that exposure of adult
human volunteers, including an atopic individual with allergic
rhinitis, to 0.5 ppm for 4 hours produced no sensory irritation but did
result in transient changes in some pulmonary function parameters for
the atopic individual (Rotman et al., 1983). Because both sexes were
tested, subjects were undergoing light exercise during exposures on a
treadmill or step test that increased the heart rate to 100 beats/
minute, making them more vulnerable to sensory irritation, and an
exercising susceptible individual did not exhibit adverse effects, no
uncertainty factor to account for differences in human sensitivity was
applied. The intraspecies uncertainty factor of 1 is supported by
another study in which a concentration of 0.4 ppm for 1 hour was a no-
effect concentration for changes in pulmonary function parameters in
individuals with airway hyperreactivity/asthma (D'Alessandro et al.,
1996). Chlorine is a highly irritating and corrosive gas that reacts
directly with the tissues of the respiratory tract with no
pharmacokinetic component involved in toxicity; therefore, effects are
not expected to vary greatly among other susceptible populations.
Because the 0.5 ppm concentration appeared to be a threshold
concentration for more severe effects in susceptible individuals,
regardless of the exposure duration, the 0.5 ppm concentration was
applied across all AEGL-1 exposure durations. The 0.5 ppm concentration
was considered appropriate for the 8-hour AEGL-1 because effects were
not increased in the susceptible individual following a second 4-hour
exposure on the same day.
The AEGL-2 values were based on the same study in which healthy
human subjects experienced some sensory irritation and transient
changes in pulmonary function measurements and a susceptible individual
experienced an asthmatic-like attack (shortness of breath and wheezing)
at a concentration of 1 ppm after 4 hours of exposure (Rotman et al.,
1983). The susceptible individual remained in the exposure chamber for
the full 4 hours before the symptoms occurred. Because both sexes were
tested, subjects were undergoing light exercise during the exposures,
making them more vulnerable to sensory irritation, and an exercising
susceptible individual exhibited effects consistent with the definition
of the AEGL-2, no uncertainty factor to account for differences in
human sensitivity was applied. The intraspecies uncertainty factor of 1
is supported by another study in which a concentration of 1.0 ppm for 1
hour resulted in significant changes in pulmonary function parameters
for all five tested individuals who had a history of airway
hyperreactivity/asthma; two of the five subjects experienced undefined
respiratory symptoms following exposure (D'Alessandro et al., 1996).
Chlorine is a highly irritating and corrosive gas that reacts directly
with the tissues of the respiratory tract with no pharmacokinetic
component involved in toxicity; therefore, effects are not expected to
vary greatly among other susceptible populations. Time-scaling was
considered appropriate for the AEGL-2 as the AEGL-2 is defined as the
threshold for irreversible effects which in the case of irritants
generally involves tissue damage. Although the endpoint used in this
case, wheezing and a significant increase in airways resistance, may be
below the AEGL-2
[[Page 7172]]
definition, it is assumed that some biomarkers of tissue irritation
would be present in the airways and lungs. The 4-hour 1 ppm
concentration was scaled to the other time periods using the
C2 x t = k relationship. The scaling factor was based on
regression analyses of concentrations and exposure durations that
attained nuisance levels of irritation in human subjects. The 10-minute
value was set equal to the 30-minute value in order to not exceed the
highest exposure of 4.0 ppm in controlled human studies.
In the absence of human data, the AEGL-3 values were based on
animal lethality data. The mouse was not chosen as an appropriate model
for lethality because mice often showed delayed deaths which several
authors attributed to bronchopneumonia. Because the mouse was shown to
be more sensitive than other mammals (dog and rat) to irritant gases
including chlorine and does not provide an appropriate basis for
quantitatively predicting mortality in humans, a value below that
resulting in no deaths in the rat (213 and 322 ppm in two studies) and
above that resulting in no deaths in the mouse (150 ppm) for a period
of 1 hour was chosen (MacEwen and Vernot, 1972; Zwart and Woutersen,
1988). The AEGL-3 values were derived from a 1-hour concentration of
200 ppm. This value was divided by a total uncertainty factor of 10:3
to extrapolate from rats to humans (interspecies values for the same
endpoint differed by a factor of approximately 2 within each of several
studies), and by an uncertainty factor of 3 to account for differences
in human sensitivity. The susceptibility of asthmatics relative to
healthy subjects when considering lethality is unknown, but the data
from two studies with human subjects showed that doubling a no-effect
concentration for irritation and bronchial constriction resulted in
potentially serious effects in the asthmatics but not in the normal
individuals. Time-scaling was considered appropriate for the AEGL-3
because tissue damage is involved (data in animal studies clearly
indicate that time-scaling is appropriate when lung damage is
involved). The AEGL-3 values for the other exposure times were
calculated based on the C2 x t = k relationship which was
derived based on the endpoint of irritation from a study with humans.
The calculated values are listed in Table 5 below:
Table 5.--Summary of Proposed AEGL Values for Chlorine [ppm (mg/m3)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minute 30-minute 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1\a\ (Nondisabling) 0.50 (1.5) 0.50 (1.5) 0.50 (1.5) 0.50 (1.5) 0.50\b\ (1.5) No to slight
changes in
pulmonary function
parameters in
humans (Rotman et
al., 1983;
D'Alessandro et
al., 1996)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 2.8 (8.1) 2.8 (8.1) 2.0 (5.8) 1.0 (2.9) 0.70 (2.0) Asthmatic-like
attack in human
subjects (Rotman
et al., 1983;
D'Alessandro et
al., 1996)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethal) 50 (145) 28 (81) 20 (58) 10 (29) 7.1 (21) Lethality--rat
(MacEwen and
Vernot, 1972;
Zwart and
Woutersen, 1988)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ The distinctive, pungent odor of chlorine will be noticeable to most individuals at these concentrations.
\b\ Because effects were not increased following an interrupted 8-hour exposure of anatopic individual to 0.5 ppm, the 8-hour AEGL-1 was set equal to
0.5 ppm.
ii. References. a. D'Alessandro, A.; Kuschner, W.; Wong, H.;
Boushey, H.A.; and Blanc, P.D. 1996. Exaggerated responses to chlorine
inhalation among persons with nonspecific airway hyperreactivity.
Chest. 109:331-337.
b. MacEwen, J.D. and Vernot, E.H. 1972. Toxic Hazards Research Unit
Annual Technical Report. 1972. AMRL-TR-72-62, Aerospace Medical
Research Laboratory, Wright-Patterson Air Force Base, OH. National
Technical Information Service, Springfield, VA.
c. Rotman, H.H.; Fliegelman, M.J.; Moore, T.; Smith, R.G.; Anglen,
D.M.; Kowalski, C.J.; and Weg, J.G. 1983. Effects of low concentration
of chlorine on pulmonary function in humans. Journal of Applied
Physiology. 54:1120-1124.
d. ten Berge, W.F. and Vis van Heemst, M. 1983. Validity and
accuracy of a commonly used toxicity-assessment model in risk analysis.
IChemE Symposium Series No. 80:17-21.
e. Zwart, A. and Woutersen, R.A. 1988. Acute inhalation toxicity of
chlorine in rats and mice: time-concentration-mortality relationships
and effects on respiration. Journal of Hazardous Materials. 19:195-208.
5. Uranium hexafluoride--i. Description. Uranium hexafluoride (CAS
No. 7783-81-5) is a volatile solid. It is one of the most highly
soluble industrial uranium compounds and, when airborne, hydrolyzes
rapidly on contact with moisture to form hydrofluoric acid (HF) and
uranyl fluoride (UO2F2) as follows:
UF6 +
2H2OUO2F2 + 4HF
Thus, an inhalation exposure to uranium hexafluoride is actually an
inhalation exposure to a mixture of both fluorides. Pulmonary
irritation, corrosion, or edema may occur from the hydrofluoric acid
component and/or renal injury may be observed from the uranium
component. As concentration is decreased and duration is increased, the
effects of hydrogen fluoride are reduced, and the effects of the
uranium component may be increased (Spiegel, 1949).
In the absence of relevant chemical-specific data for derivation of
AEGL-1 values for uranium hexafluoride, a modification of the AEGL-1
values for hydrogen fluoride was used to derive AEGL-1 values for
uranium hexafluoride. The use of hydrogen fluoride as a surrogate for
uranium hexafluoride was deemed appropriate since it is likely that it
is the hydrolysis product, HF, that is responsible for adverse effects.
The hydrogen fluoride AEGL-1 values were based on the threshold for
pulmonary inflammation in healthy human adults (Lund et al., 1999).
Since a maximum of four moles of hydrogen fluoride are produced for
every mole of uranium hexafluoride hydrolyzed, a stoichiometric
adjustment factor of 4 was applied to the hydrogen fluoride AEGL-1
values to approximate AEGL-1 values for uranium hexafluoride. AEGL-1
values were derived only for the 10-minute, 30-minute, and 1-hour time
points since it is likely that renal toxicity may be more relevant at
the longer time points and no data exist for renal toxicity consistent
with the definition of AEGL-1.
[[Page 7173]]
The AEGL-2 was based on renal pathology in dogs exposed to 192 mg/
m3 UF6 for 30 minutes (Morrow et al., 1982). An
uncertainty factor of 3 was used to extrapolate from animals to humans,
and an uncertainty factor of 3 was also applied to account for
sensitive individuals (total uncertainty factor = 10). This total
uncertainty factor is considered sufficient since the observed renal
pathology is generally considered reversible and thus this effect may
be below the definition of AEGL-2. Furthermore, the use of a larger
total uncertainty factor would yield AEGL-2 values below or approaching
the AEGL-1 values. 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 conservative and protective AEGL
values in the absence of an empirically derived chemical-specific
scaling exponent, 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. (Although
a chemical-specific exponent of 0.66 was derived from rat lethality
data in which the endpoint was pulmonary edema, the default values were
utilized for time-scaling AEGL-2 values since the endpoints for AEGL-2
(renal toxicity) and death (pulmonary edema) involve different
mechanisms of action).
The AEGL-3 was based on an estimated 1-hour threshold for death in
rats (13 LC50 of 365 mg/m3) (Leach et
al, 1984). This approach is considered appropriate due to the steepness
of the concentration-response curve for lethality in rats after
exposure to UF6. An uncertainty factor of 3 was used to
extrapolate from animals to humans; the interspecies uncertainty factor
of 3 is considered sufficient since the cause of death (pulmonary
edema) is due to the hydrogen fluoride hydrolysis product, and
lethality studies of hydrogen fluoride suggest that the rat was
approximately 3-times less sensitive than the most sensitive (hyper-
susceptible) species (mouse) (EPA, 2001). An uncertainty factor of 3
was also applied to account for sensitive individuals since death is
due to severe tissue damage resulting in pulmonary edema from the HF
hydrolysis product (total uncertainty factor = 10). Furthermore, the
total uncertainty factor of 10 is considered sufficient in light of the
steep concentration-response curve. The value was then scaled to the
10-minute, 30-minute, 4-hour, and 8-hour time points, using
C0.66 x t = k. The exponent of 0.66 was derived from rat
lethality data ranging from 2 minutes to 1 hour exposure duration in
the key study.
The calculated values are listed in Table 6 below:
Table 6.--Summary of Proposed AEGL Values for Uranium Hexafluoride (mg/m3)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minute 30-minute 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 3.6 mg/m3 3.6 mg/m3 3.6 mg/m3 NR NR Modification of
hydrogen fluoride
AEGL-1 values
(EPA, 2001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 28 mg/m3 19 mg/m3 9.6 mg/m3 2.4 mg/m3 1.2 mg/m3 Renal tubular
pathology in dogs
(Morrow et al.,
1982)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethality) 550 mg/m3 100 mg/m3 36 mg/m3 4.4 mg/m3 1.6 mg/m3 Estimated 1-hour
NOEL for death in
the rat (Leach et
al., 1984)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. Leach, L.J.; Gelein, R.M.; Panner, B.J.; Yulie,
C.L.; Cox, C. C.; Balys, M.M.; and Rolchigo, P.M. 1984. Acute Toxicity
of the Hydrolysis Products of Uranium Hexafluoride (UF6)
when Inhaled by the Rat and Guinea Pig. Final Report. (K/SUB/81-9039/
3). University of Rochester Medical Center, Rochester, NY.
b. Lund, K.; Refsnes, M.; Sandstrom, T.; Sostrand, P.; Schwarze,
P.; Boe, J.; and Kongerud, J. 1999. Increased CD3 positive cells in
bronchoalveolar lavage fluid after hydrogen fluoride inhalation.
Scandinavian Journal of Work, Environment, and Health. 25:326-334.
c. Morrow, P.; Gelein, R.; Beiter, H.; Scott, J.; Picano, J.; and
Yulie, C. 1982. Inhalation and intravenous studies of UF6
and UO2F2 in dogs. Health Physics. 43:859-873.
d. Spiegel, C.J. 1949. Uranium Hexafluoride. Pharmacology and
Toxicology of Uranium Compounds. New York: McGraw-Hill Book Company,
Inc. pp. 532-548
e. 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.
f. EPA. 2001. Acute exposure guideline levels for hydrogen
fluoride. (Interim Draft 2:7/2001).
6. Chlorine dioxide--i. Description. Chlorine dioxide (CAS No.
10049-04-4) is a yellow to reddish-yellow gas at room temperature. It
has an unpleasant odor, similar to the odor of chlorine and reminiscent
of nitric acid. It is a respiratory irritant. Pure chlorine dioxide is
stable in the dark and unstable in light. Chlorine dioxide dissociates
in water into chlorite and chloride, and to a lesser extent into
chlorate. The major use of chloride dioxide is that of a drinking water
disinfectant. Other uses include the bleaching of textiles, paper pulp,
flour, cellulose, leather, fats, oils, and beeswax; taste and odor
control of water; an oxidizing agent; and the manufacture of chlorite
salts. The acute inhalation data base for chlorine dioxide is quite
sparse for both human and animal exposures.
The AEGL-1 was based on slight salivation, slight lacrimation, and
slight red-ocular discharge in rats exposed to 3 ppm chlorine dioxide
for 6 hours (DuPont, 1955). A total combined uncertainty factor of 10
was applied to account for interspecies and intraspecies variability,
and a modifying factor of two was applied to account for the sparse
data base and the resulting uncertainty about the most sensitive
species. Thus, the total uncertainty/modifying factor is 20. Chlorine
dioxide is a highly reactive chemical. The clinical signs of minor
irritation are likely caused by a direct chemical effect on external
tissue. This minor irritation is not likely to vary greatly among
species or among individuals. The AEGL-1 value was held constant across
all time points since minor irritation is not likely to be time
dependent.
The AEGL-2 was based on lacrimation, salivation, dyspnea, weakness,
and pallor in rats exposed to
[[Page 7174]]
12 ppm chlorine dioxide for 6 hours (DuPont, 1955). A total combined
uncertainty factor of 10 was applied to account for interspecies and
intraspecies variability, and a modifying factor of 2 was applied to
account for the sparse data base and the resulting uncertainty about
the most sensitive species. Thus, the total uncertainty/modifying
factor is 20. This total adjustment factor of 20 is reasonable since
the derived 4 hour AEGL-2 value is 0.69 ppm yet rats repeatedly exposed
to 3 ppm chlorine dioxide (Dupont, 1955), 6 hours/day for 10 days
showed only minor irritation (slight salivation, slight lacrimation,
and slight red-ocular discharge on the first day of the study). Even
allowing for differences in response between species and individuals,
this comparison indicates that the derived AEGL-2 values are reasonable
and the threshold for disabling susceptible humans should be above this
level. The use of a higher combined uncertainty factor/modifying factor
of 200 would give a 4 hour AEGL value of 0.069 ppm yet when rats were
exposed to 0.1 ppm of chlorine dioxide for 5 hours/day for 10 weeks, no
clinical signs were observed during treatment and at necropsy (Dalhamn,
1957). This comparison shows that a combined uncertainty/modifying
factor of 200 is excessively large. 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 conservative
and protective AEGL values in the absence of an empirically derived
chemical-specific scaling exponent, temporal scaling was performed
using n = 3 when extrapolating to shorter time points (30-minutes, 1-
hour, and 4-hours) and n = 1 (8-hours) when extrapolating to longer
time points using the Cn x t = k equation. The 30-minute
AEGL-2 value was also adopted as the 10-minute AEGL-2 value due to the
added uncertainty of extrapolating from a 6-hour time point to 10-
minutes.
The AEGL-3 was based on a study showing no deaths in rats exposed
to 26 ppm chlorine dioxide for 6 hours (DuPont, 1955). A total combined
uncertainty factor of 10 was applied to account for interspecies and
intraspecies variability, and a modifying factor of 2 was applied to
account for the sparse data base and the resulting uncertainty about
the most sensitive species. Thus, the total uncertainty/modifying
factor is 20. The total factor of 20 is considered adequate. Using a
larger combined uncertainty/modifying factor of 200 would give a 4 hour
AEGL-3 value of 0.15 ppm. The value of 0.15 ppm is too low, because
rats exposed to 0.1 ppm of chlorine dioxide for 5 hours/day for 10
weeks showed no clinical signs during treatment or at necropsy
(Dalhamn, 1957). This comparison shows that a combined uncertainty/
modifying factor of 200 is excessively large. 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
conservative and protective AEGL values in the absence of an
empirically derived chemical-specific scaling exponent, temporal
scaling was performed using n = 3 when extrapolating to shorter time
points (30-minutes, 1-hour, and 4-hours) and n = 1 (8-hours) when
extrapolating to longer time points using the Cn x t = k
equation. The 30-minute AEGL-3 value was also adopted as the 10-minute
AEGL-3 value due to the added uncertainty of extrapolating from a 6-
hour time point to 10-minutes.
The calculated values are listed in Table 7 below:
Table 7.--Summary of Proposed AEGL Values for Chlorine Dioxide [ppm (mg/m3)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minute 30-minute 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) 0.15 (0.41) Slight salivation,
slight
lacrimation, and
slight red-ocular
discharge in rats
exposed to 3 ppm
for 6 hours
(DuPont, 1955)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-2 (Disabling) 1.4 (3.9) 1.4 (3.9) 1.1 (3.0) 0.69 (1.9) 0.45 (1.2) Lacrimation,
salivation,
dyspnea,
weakness, and
pallor in rats
exposed to 12 ppm
for 6 hours
(DuPont, 1955)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethal) 3.0 (8.3) 3.0 (8.3) 2.4 (6.6) 1.5 (4.1) 0.98 (2.7) No lethality in
rats exposed to
26 ppm for 6 hour
(DuPont, 1955)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. Dalhamn, T. 1957. Chlorine Dioxide: Toxicity in
animal experiments and industrial risks. Archives of Industrial Health.
15:101-107.
b. DuPont. 1955. Summary of Toxicological Evaluations of Chlorine
Dioxide. Haskell Laboratory for Toxicology and Industrial Medicine.
Haskell Lab Report No. 80-55. E.I. du Pont de Nemours and Company, Inc.
Wilmington, DE.
c. ten Berge, W.F.; Zwart, A.; and Appleman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
13:301-310.
7. and 8. Methyl nonafluorobutyl ether and Methyl
nonafluoroisobutyl ether--i. Description. HFE-7100 is a mixture of
methyl nonafluorobutyl (CAS No. 163702-07-6) and methyl
nonafluoroisobutyl (CAS No. 163702-08-7) ethers in ratios of 30-50 and
50-70%, respectively. This mixture has been developed as a replacement
for presently used chlorofluorocarbons and other ozone-depleting
chemicals. It is used in industrial situations as a cleaning agent,
lubricant carrier, drying agent, specialty solvent, and heat-transfer
medium. It is a volatile liquid with a slight ethereal odor. No
information on production was located.
Except for a single monitoring study conducted by 3M Company and
reported by AIHA (1999) in which exposures were noted to be below 50
ppm, no information on human exposures was located. Animal data using
the rat as the model addressed anesthetic properties, toxicity,
neurotoxicity, and genotoxicity. A study with the beagle addressed
cardiac
[[Page 7175]]
sensitization. HFE-7100 is practically nontoxic; it does not have
anesthetic properties and is not a cardiac sensitizer. No information
useful for time-scaling across the AEGL exposure durations was
available.
The AEGL-1 value is based on a subchronic study with the rat
(Coombs et al., 1996b). In this study, rats were exposed to
concentrations up to 15,159 ppm for 6 hours/day, 5 days/week for 13
weeks. This concentration was not neurotoxic. Only reversible organ
weight increases were observed and these were attributed to the
repeated nature of the exposure. Because the concentration was
basically a NOAEL, the exposures were repeated, and uptake is greater
in the rodent than in primates, based on the higher respiratory rate
and cardiac output of rodents compared with primates, an interspecies
uncertainty factor of 1 was applied. Studies addressing neurotoxicity
and cardiac sensitization and studies with pregnant rats failed to
identify significant toxicological endpoints. Therefore, an
intraspecies uncertainty factor of 3 was applied. Because human data
are very limited and because some of the key studies used limited
numbers of animals, a modifying factor of 2 was applied. The resultant
value is 2,500 ppm. Time-scaling may not be relevant for anesthetics
and halogenated hydrocarbons as blood concentrations of these chemicals
rapidly reach equilibrium and do not greatly increase as exposure
duration is increased. The presence of the perfluoro group of HFE-7100
limits its solubility in biological fluids. Furthermore, the repeated
nature of the exposures of the key study support the use of the same
value across all time points. Therefore, the 2,500 ppm concentration is
applicable for all AEGL-1 time points.
The AEGL-2 value is based on a 10-minute cardiac sensitization test
with beagles (Kenny et al., 1996) and is supported by a 4-week repeat
exposure study with the rat (Coombs et al., 1996a). Six male beagles
exposed to 48,900 ppm for 10 minutes and challenged with an adrenaline
dose of 1-12 g/kilogram (kg) (individualized for each dog) did
not show cardiac sensitization. However, all of the beagles exhibited
signs of restlessness, agitation, tremors, and muscle rigidity. These
signs were described following the second challenge, but may have been
present pre-challenge. All beagles recovered fully and were used for
subsequent studies. The cardiac sensitization test is very conservative
as the levels of adrenaline administered represent an approximate 10-
fold excess over blood concentrations that would be achieved
endogenously in dogs or humans, even in highly stressful situations.
Because this is a conservative endpoint (the dogs exhibited clinical
signs but fully recovered), the test addresses the stress that might be
experienced in an escape situation, and the dog heart is considered an
appropriate model for the human heart, an interspecies uncertainty
factor of 1 was applied. Heart patients would not be at extra risk
because HFE-7100 is not a cardiac sensitizer and studies with pregnant
rats failed to identify significant toxicological endpoints. Therefore,
an intraspecies uncertainty factor of 3 was applied to protect
potentially susceptible individuals. Because human data are very
limited and because some of the key studies used limited numbers of
animals, a modifying factor of 2 was applied. The resulting value is
8,200 ppm. Time-scaling may not be relevant for anesthetics and
halogenated hydrocarbons as blood concentrations of these chemicals
rapidly reach equilibrium and do not greatly increase as exposure
duration is increased. Furthermore the presence of the perfluoro group
of HFE-7100 limits its solubility in biological fluids. Therefore, the
8,200 ppm concentration is applicable for all AEGL-2 time points. The
values are supported by a study in which rats were exposed to
concentrations up to 30,000 ppm for 6 hours/day, 5 days/week for 4
weeks. These rats exhibited reversible liver hypertrophy which is
attributable to the repeated nature of the exposures (Coombs et al.,
1996a). The repeated nature of this study supports using a single value
across the AEGL-2 time points.
The AEGL-3 value is based on the same cardiac sensitization study
with beagles (Kenny et al., 1996) and is supported by an acute
inhalation study with the rat (3M Company, 1995). Prior to the second
challenge dose of adrenaline during a cardiac sensitization test, one
of two dogs exposed to 89,300 ppm for 10 minutes exhibited severe
clinical signs including restlessness, cold extremities, limb rigidity,
head and whole-body tremors, head shaking, arched back, agitation, and
salivation. The second dog survived the second challenge dose of
adrenaline but exhibited similar adverse clinical signs. The cardiac
sensitization test is very conservative as the levels of adrenaline
administered represent an approximate 10-fold excess over blood
concentrations that would be achieved endogenously in dogs or humans,
even in highly stressful situations. Because this is a conservative
endpoint (the dogs exhibited clinical signs but fully recovered), the
test addresses the stress that might be experienced in an escape
situation, and the dog heart is considered an appropriate model for the
human heart, an interspecies uncertainty factor of 1 was applied. Heart
patients would not be at extra risk because HFE-7100 is not a cardiac
sensitizer and studies with pregnant rats failed to identify
significant toxicological endpoints. Therefore, an intraspecies
uncertainty factor of 3 was applied to protect potentially susceptible
individuals. Because human data are very limited and because some of
the key studies used limited numbers of animals, a modifying factor of
2 was applied. Time-scaling may not be relevant for anesthetics and
halogenated hydrocarbons as blood concentrations of these chemicals
rapidly reach equilibrium and do not greatly increase as exposure
duration is increased. Therefore, the resulting 15,000 ppm
concentration is applicable for all AEGL-3 time points. The 89,300 ppm
concentration may be a conservative estimate of the threshold for
lethality as rats survived a 4-hour exposure to 100,000 ppm (3M
Company, 1995).
The calculated values are listed in Table 8 below:
Table 8.--Summary of Proposed AEGL Values for HFE-7100 [ppm (mg/m3]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10-minute 30-minute 1-hour 4-hour 8-hour (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 2,500 (25,550) 2,500 (25,550) 2,500 (25,550) 2,500 (25,550) 2,500 (25,550) Reversible organ
weight changes,
repeated
exposures, rat
(Coombs et al.,
1996b)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 7176]]
AEGL-2 (Disabling) 8,200 (84,000) 8,200 (84,000) 8,200 (84,000) 8,200 (84,000) 8,200 (84,000) Clinical signs,
cardiac
sensitization
test, dog (Kenny
et al., 1996)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-3 (Lethal) 15,000 (150,000) 15,000 (150,000) 15,000 (150,000) 15,000 (150,000) 15,000 (150,000) Severe clinical
signs, cardiac
sensitization
test, dog (Kenney
et al., 1996)
--------------------------------------------------------------------------------------------------------------------------------------------------------
ii. References. a. 3M Company. 1995. Acute inhalation toxicity for
HFE-7100 in the rat. Memo, 3M Company, Toxicology Services. 3M Center,
St. Paul, MN.
b. AIHA. 1999. Workplace Environmental Exposure Levels: HFE-7100.
American Industrial Hygiene Association, Fairfax, VA.
c. Coombs, D.W.; Shepherd, C.K.; Bannerman, M.; Hardy, C.J.; Crook,
D.; Hall, M.; Hughes, E.W.; and Gopinath, C. 1996a. T-6334: 28-Day
repeat dose inhalation toxicity study in rats. MIN 181/952688.
Huntingdon Life Sciences, Huntingdon, Cambridgeshire, England.
d. Coombs, D.W.; Shepherd, C.K.; Bannerman, M.; Hardy, C.J.; Crook,
D.; Hall, M.; and Healey, G.F. 1996b. T-6334: 13-Week repeat dose
inhalation toxicity study in rats. MIN 196/961181. Huntingdon Life
Sciences, Huntingdon, Cambridgeshire, England.
e. Kenny, T.J.; Shepherd, C.K.; Bannerman, M.; Hardy, C.J.; and
Gilkison, I.S. 1996. T-6334: Assessment of cardiac sensitization
potential in dogs. MIN 182/953117. Huntingdon Life Sciences, Limited.
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 2002.
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 National Research
Council, National Academy of Sciences (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, Acute exposure guideline levels,
Hazardous substances.
Dated: February 1, 2002.
Susan B. Hazen,
Acting Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 02-3774 Filed 2-14-02; 8:45 am]
BILLING CODE 6560-50-S