[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]


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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.

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SUMMARY: The National Advisory Committee for Acute Exposure Guideline 
Levels for Hazardous Substances (NAC/AEGL Committee) is developing 
AEGLs on an ongoing basis to provide Federal, State, and local agencies 
with information on short-term exposures to hazardous chemicals. This 
notice provides AEGL values and Executive Summaries for 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