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

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: June 23, 2000 (Volume 65, Number 122)]
[Notices]
[Page 39263-39277]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23jn00-131]

[[Page 39263]]

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Part V

Environmental Protection Agency

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

[[Page 39264]]

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ENVIRONMENTAL PROTECTION AGENCY

[OPPTS-00293; FRL-6591-2]

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 14 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 14 chemicals.

DATES: Comments, identified by the docket control number OPPTS-00293,
must be received by EPA on or before July 24, 2000.

ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I. of the ``SUPPLEMENTARY INFORMATION.'' To ensure
proper receipt by EPA, it is imperative that you identify docket
control number OPPTS-00293 in the subject line on the first page of
your response.

FOR FURTHER INFORMATION CONTACT: For general information contact:
Barbara Cunningham, Director, Office of Program Management and
Evaluation, Office of Pollution Prevention and Toxics (7401),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (202) 554-1404; e-mail address:
TSCA-Hotline@epa.gov.
For technical information contact: Paul S. Tobin, Designated
Federal Officer (DFO), Office of Prevention, Pesticides and Toxic
Substances (7406), 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (202) 260-1736; e-mail address: tobin.paul@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

This action is directed to the general public to provide an
opportunity for review and comment on ``Proposed'' AEGL values and
their supporting scientific rationale. This action may be of particular
interest to anyone who may be affected if the AEGL values are adopted
by government agencies for emergency planning, prevention, or response
programs, such as EPA's Risk Management Program under the Clean Air Act
(CAA) 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
technical person listed under ``FOR FURTHER INFORMATION CONTACT.''

B. How Can I Get Additional Information, Including Copies of this
Document or Other Related Documents?

1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number OPPTS-00293. The official
record consists of the documents specifically referenced in this
action, any public comments received during an applicable comment
period, and other information related to this action, including any
information claimed as Confidential Business Information (CBI). This
official record includes the documents that are physically located in
the docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period, is available
for inspection in the TSCA Nonconfidential Information Center, North
East Mall Rm. B-607, Waterside Mall, 401 M St., SW., Washington, DC.
The Center is open from noon to 4 p.m., Monday through Friday,
excluding legal holidays. The telephone number of the Center is (202)
260-7099.
3. Fax-on-Demand. You may request to receive a faxed copy of the
document(s) by using a faxphone to call (202) 401-0527 and select the
item number 4800 for an index of the items available by fax-on-demand
in this category, or select the item number for the document related to
the chemical(s) identified in this document as listed in the chemical
table in Unit III. You may also follow the automated menu.

C. How and to Whom Do I Submit Comments?

You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number OPPTS-00293 in the subject line on
the first page of your response.
1. By mail. Submit your comments to: OPPT Document Control Office
(7407), Office of Pollution Prevention and Toxics (OPPT), Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
For express delivery, use the address in Unit I.C.2.
2. In person or by courier. Deliver your comments to: OPPT Document
Control Office (DCO) in East Tower Rm. G-099, Waterside Mall, 401 M
St., SW., Washington, DC. The DCO is open from 8 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays. The telephone number for the
DCO is (202) 260-7093.
3. Electronically. You may submit your comments electronically by
e-mail to: ``oppt.ncic@epa.gov,'' or mail your computer disk to the
address identified above. Do not submit any information electronically
that you consider to be CBI. Electronic comments must be submitted as
an ASCII file avoiding the use of special characters and any form of
encryption. Comments and data will also be accepted on standard disks
in WordPerfect 6.1/8.0 or ASCII file format. All comments in electronic
form must be identified by docket control numbers OPPTS-00293.
Electronic comments may also be filed online at many Federal Depository
Libraries.

D. How Should I Handle CBI that I Want to Submit to the Agency?

Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any

[[Page 39265]]

information claimed as CBI, a copy of the comment that does not contain
the information claimed as CBI must be submitted for inclusion in the
public version of the official record. Information not marked
confidential will be included in the public version of the official
record without official notice. If you have any questions about CBI or
the procedures for claiming CBI, please consult the technical person
listed under ``FOR FURTHER INFORMATION CONTACT.''

E. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data that you
used that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Offer alternative ways to improve the proposed notice.
7. Make sure to submit your comments by the deadline in this
document.
8. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.

II. Background

A. Introduction

EPA's Office of Prevention, Pesticides and Toxic Substances (OPPTS)
provided notice in the Federal Register of October 31, 1995 (60 FR
55376) (FRL-4987-3) of the establishment of the NAC/AEGL Committee with
the stated charter objective as ``the efficient and effective
development of Acute Exposure Guideline Levels (AEGLs) and the
preparation of supplementary qualitative information on the hazardous
substances for federal, state, and local agencies and organizations in
the private sector concerned with [chemical] emergency planning,
prevention, and response.'' The NAC/AEGL Committee is a discretionary
Federal advisory committee formed with the intent to develop AEGLs for
chemicals through the combined efforts of stakeholder members from both
the public and private sectors in a cost-effective approach that avoids
duplication of efforts and provides uniform values, while employing the
most scientifically sound methods available. An initial priority list
of 85 chemicals for AEGL development was published in the Federal
Register of May 21, 1997 (62 FR 27734) (FRL-5718-9). This list is
intended for expansion and modification as priorities of the
stakeholder member organizations are further developed. While the
development of AEGLs for chemicals are currently not statutorily based,
at lease one rulemaking references their planned adoption. The CAA and
Amendments Section 112(r) Risk Management Program states, ``EPA
recognizes potential limitations associated with the Emergency Response
Planning Guidelines and Level of Concern and is working with other
agencies to develop AEGLs. When these values have been developed and
peer-reviewed, EPA intends to adopt them, through rulemaking, as the
toxic endpoint for substances under this rule (see 61 FR 31685).'' It
is believed that other Federal and State agencies and private
organizations will also adopt AEGLs for chemical emergency programs in
the future.

B. Characterization of the AEGLs

The AEGLs represent threshold exposure limits for the general
public and are applicable to emergency exposure periods ranging from 10
mins. to 8 hrs. AEGL-2 and AEGL-3 levels, and AEGL-1 levels as
appropriate, will be developed for each of five exposure periods (10
and 30 mins., 1 hr., 4 hrs., and 8 hrs.) 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
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 effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels
that could produce mild and progressively increasing odor, taste, and
sensory irritation, or certain non-symptomatic, non-sensory effects.
With increasing airborne concentrations above each AEGL level, there is
a progressive increase in the likelihood of occurrence and the severity
of effects described for each corresponding AEGL level. Although the
AEGL values represent threshold levels for the general public,
including sensitive subpopulations, it is recognized that certain
individuals, subject to unique or idiosyncratic responses, could
experience the effects described at concentrations below the
corresponding AEGL level.

C. Development of the AEGLs

The NAC/AEGL Committee develops the AEGL values on a chemical-by-
chemical basis. Relevant data and information are gathered from all
known sources including published scientific literature, State and
Federal agency publications, private industry, public databases 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 concensus . Once the NAC/AEGL
Committee reaches a concensus, 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 document the NAC/AEGL Committee is publishing proposed AEGL
values and the accompanying scientific rationale for their development
for 14 hazardous substances. These values represent the third set of
exposure levels proposed and published by the NAC/AEGL

[[Page 39266]]

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) and for 10 chemicals in the
Federal Register of March 15, 2000 (65 FR 14186-14196) (FRL-6492-4) in
order to provide an opportunity for public review and comment. In
developing the proposed AEGL values, the NAC/AEGL Committee has
followed the methodology guidance Guidelines for Developing Community
Emergency Exposure Levels for Hazardous Substances, published by the
National Research Council of the National Academy of Sciences (NSC/NAS)
in 1993. The term Community Emergency Exposure Levels (CEELs) 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
concensus for the establishment of interim AEGL values. Although the
interim AEGL values will be available to Federal, State, and local
agencies and to organizations in the private sector as biological
reference values, it is intended to have them reviewed by a
subcommittee of the NAS. The NAS subcommittee will serve as a peer
review of the interim AEGLs and as the final arbitor 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. Fax-On-Demand Item Number for Chemicals Listed in this
Document

On behalf of the NAC/AEGL Committee, EPA is providing an
opportunity for public comment on the AEGLs for the 14 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 ?????.

------------------------------------------------------------------------
Fax-On-Demand Item
CAS No. Chemical name No.
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75-78-5 Dimethyldichlorosil 4867
ane
75-79-6 Methyltrichlorosila 4868
ne
91-08-7 and 584-84-9 2,4- and 2,6- 4873
Toluene
diisocyanate
107-11-9 Allylamine 4876
107-15-3 Ethylenediamine 4878
108-91-8 Cyclohexylamine 4883
123-73-9 (4170-30-3) trans- 4903
Crotonaldehyde
(cis/trans
Crotonaldehyde
mixture)
624-83-9 Methyl isocyanate 4898
7647-01-0 Hydrogen chloride 4907
7803-51-2 Phosphine 4923
13463-39-3 Nickel carbonyl 4929
13463-40-6 Iron pentacarbonyl 4930
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IV. Executive Summaries

The following are executive summaries from the chemical specific
Technical Support Documents (which may be obtained as described in Unit
I.B.1 and III.) that support the NAC/AEGL Committee's development of
AEGL values for each chemical substance. This information provides the
following information: A general description of each chemical,
including its properties and principle uses; a summary of the rationale
supporting the AEGL-1, 2, and 3 concentration levels; a summary table
of the AEGL values; and a listing of key references that were used to
develop the AEGL values. More extensive toxicological information and
additional references for each chemical may be found in the complete
Technical Support Documents. Risk managers may be interested to review
the complete Technical Support Document for a chemical when deciding
issues related to use of the AEGL values within various programs.

A. Dimethyldichlorosilane

1. Description. Dimethyldichlorosilane is an alkyl-substituted
silicon tetrahydride existing as a clear liquid with a sharp acrid odor
that is similar to hydrogen chloride (HCl) (HSDB, 1996).
Dimethyldichlorosilane is used as a high-purity derivation reagent for
gas chromatography (HSDB, 1996) and as an intermediate in the
production of silicones that are used as lubricating fluids, resins,
and plastic copolymers (Bisesi, 1994). It reacts vigorously with water
and decomposes to form HCl and other hydrolysis products (AIHA, 1996).
Complete hydrolysis of one mole of dimethyldichlorosilane would yield a
maximum of two moles of HCl. Hydrogen chloride is a known respiratory
irritant. Data on dimethyldichlorosilane are limited to LC50
studies in rats.
In the absence of appropriate chemical-specific data for
dimethyldichlorosilane, a modification of the AEGL-1 values for HCl was
utilized to derive AEGL-1 values for dimethyldichlorosilane. The use of
HCl as a surrogate for dimethyldichlorosilane was deemed appropriate
since it is believed that it is the hydrolysis product, HCl, that is
responsible for the adverse effect. The HCl AEGL-1 values were based on
a no-adverse-effect-level (NOAEL) in exercising asthmatics (Stevens et
al., 1992). Since two moles of HCl are produced for every mole of
dimethyldichlorosilane hydrolyzed, a modifying factor of 2 was applied
to the HCl AEGL-1 values to approximate AEGL-1 values for
dimethyldichlorosilane. The AEGL-1 values were held constant for all
specified exposure periods since mild irritant effects represent
threshold effects and generally do not vary over time.
The AEGL-2 was based on corneal opacity, and grey spots on the
lungs of rats exposed to 1,309 ppm dimethyldichlorosilane for 1 hr.
(Dow

[[Page 39267]]

Corning, 1997a). This level was considered to be the threshold for
impairment of escape and the onset of serious long-term effects. An
uncertainty factor of 10 was applied to account for interspecies
variability since data for dimethyldichlorosilane were available for
only one species and an uncertainty factor of 3 was applied to account
for sensitive human subpopulations since the irritant effects observed
are not likely to vary greatly among individuals. A modifying factor of
3 was applied to account for the sparse database for effects as defined
by AEGL-2. Thus, the total uncertainty/modifying factor is 100. 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). Much of the acute toxicity of dimethyldichlorosilane
appears to be due to HCl and the value of n reported for HCl is 1 (Ten
Berge et al., 1986). Therefore, the exponent n = 1 was used for scaling
of the AEGL values for dimethyldichlorosilane across time.
The AEGL-3 was based on the calculated LC01 of 1,590 ppm
in rats exposed to dimethyldichlorosilane for 1 hr. (Dow Corning,
1997a). An uncertainty factor of 10 was applied to account for
interspecies variability since data for dimethyldichlorosilane were
available for only one species and an uncertainty factor of 3 was
applied to account for sensitive human subpopulations since the
irritant effects observed are not likely to vary greatly among
individuals. Thus, the total uncertainty factor is 30. The
concentration-exposure time relation-ship 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). Much of the acute toxicity of dimethyldichlorosilane
appears to be due to HCl, the dimethyldichlorosilane hydrolysis
product, and the value of n for HCl is 1 (Ten Berge et al., 1986).
Therefore, the exponent n = 1 was used for scaling of the AEGL values
for dimethyldichlorosilane across time.
The calculated values are listed in the table below.

Summary of Proposed AEGL Values For Dimethyldichlorosilane [ppm (mg/m³)]
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Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
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AEGL-1 (Nondisabling) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) 0.90 (4.8) Modification of HCl
AEGL-1 values
(USEPA, 1997)
AEGL-2 (Disabling) 78 (410) 26 (140) 13 (69) 3.3 (17) 1.6 (8.5) Corneal opacity,
gray spots on
lungs in rats (Dow
Corning, 1997a)
AEGL-3 (Lethality) 320 (1700) 110 (560) 53 (280) 13 (69) 6.6 (35) 1 hr. LC01 in rats
(Dow Corning,
1997a)
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2. References--i. AIHA (American Industrial Hygiene Association).
1996. Emergency Response Planning Guidelines. Dimethyldichlorosilane.
AIHA, Fairfax, VA.
ii. Bisesi, M.S. 1994. Organic Silicon Esters. Patty's Industrial
Hygiene and Toxicology. Fourth Ed. Vol. II, Part D. G.D. Clayton and
F.E. Clayton, Eds. pp. 3096-3101.
iii. Dow Corning. 1997a. An acute whole body inhalation toxicity
study of dimethyldichlorosilane in Fischer 344 rats. Report No. 1997-
I0000-43381. Study No. 8487. Dow Corning Corporation. Health and
Environmental Sciences. Midland, MI.
iv. HSDB (Hazardous Substances Data Bank). 1996.
Dimethyldichlorosilane. Retrieved online 7-22-96.
v. Stevens, B., Koenig, J.Q., Rebolledo, V., Hanley, Q.S., and
Covert, D.S. 1992. Respiratory effects from the inhalation of hydrogen
chloride in young adult asthmatics. Journal of Occupational Medicine.
34:923-929.
vi. Ten Berge, W.F., Zwart, A., and Appleman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapours and gases. Journal of Hazardous Materials.
13:301-309.
vii. USEPA (United States Environmental Protection Agency). 1997.
Acute exposure guideline levels (AEGLs) for hydrogen chloride (NAC/PRO
Draft 3:7/97).

B. Methyltrichlorosilane

1. Description. Methyltrichlorosilane is an alkyl-substituted
silicon tetrahydride existing as a clear liquid with a sharp acrid odor
that is similar to HCl (HSDB, 1997). Methyltrichlorosilane is used as
an intermediate in the production of silicones that are used as
lubricating fluids, resins, and plastic copolymers (Bisesi, 1994). It
reacts vigorously with water and may decompose to form three moles of
HCl for every mole of methyltrichlorosilane (AIHA, 1996). Hydrogen
chloride is a known respiratory irritant. Data on methyltrichlorosilane
are limited to 1-hr. and 4-hr. LC50 studies in rats.
In the absence of relevant chemical-specific data for
methyltrichlorosilane, AEGL a modification of the AEGL-1 values for HCl
was utilized to derive AEGL-1 values for methyltrichlorosilane. The use
of HCl as a surrogate for methyltrichlorosilane was deemed appropriate
since it is believed that it is the hydrolysis product, HCl, that is
responsible for the adverse effect. The HCl AEGL-1 values were based on
a NOAEL in exercising asthmatics (Stevens et al., 1992). Since three
moles of HCl are produced for every mole of methyltrichlorosilane
hydrolyzed, a modifying factor of 3 was applied to the HCl AEGL-1
values to approximate AEGL-1 values for methyltrichlorosilane. The
AEGL-1 values were held constant for all specified exposure periods
since mild irritant effects represent threshold effects and generally
do not vary over time.
The AEGL-2 was based on ocular opacity, clear fluid around the
eyes, nose, and mouth, nasal staining, and hunched posture observed in
rats exposed to 622 ppm methyltrichlorosilane for 1 hr. (Dow Corning,
1997a). This level was considered to be the threshold for impairment of
escape and the onset of serious long-term effects. An uncertainty
factor of 10 was applied to these data to account for interspecies
variability since data for methyltrichlorosilane were available for
only one species and an uncertainty factor of 3 was applied to account
for sensitive human subpopulations since the irritant effects observed
are not likely to vary greatly among individuals. A modifying factor of
3 was applied to account for the sparse database for effects as defined
by AEGL-2. Thus, the total uncertainty/modifying factor is 100. 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). Much of the acute toxicity of methyltrichlorosilane appears
to be due to HCl and the value

[[Page 39268]]

of n reported for HCl is 1 (Ten Berge et al., 1986). Therefore, the
exponent n = 1 was used for scaling of the AEGL values for
methyltrichlorosilane across time.
The AEGL-3 was based on the calculated LC01 of 844 ppm
in rats exposed to methyltrichlorosilane for 1 hr. (Dow Corning,
1997a). An uncertainty factor of 10 was applied to account for
interspecies variability since data were available for only one species
and an uncertainty factor of 3 was applied to account for sensitive
human subpopulations since the irritant effects observed are not likely
to vary greatly among individuals. Thus, the total uncertainty/
modifying factor is 30. 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). Much of the acute toxicity of
methyltrichlorosilane appears to be due to HCl and the value of n
reported for HCl is 1 (Ten Berge et al., 1986). Therefore, the exponent
n = 1 was used for scaling of the AEGL values for methyltrichlorosilane
across time.
The calculated values are listed in the following table.

Proposed AEGL Values for Methyltrichlorosilane [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) 0.60 (3.7) Modification of HCl
AEGL-1 values
(USEPA, 1997)
AEGL-2 (Disabling) 37 (230) 12 (73) 6.2 (38) 1.6 (9.8) 0.78 (4.8) Ocular opacity,
irritation and
hunched posture in
rats (Dow Corning,
1997a)
AEGL-3 (Lethality) 170 (1000) 56 (340) 28 (170) 7.0 (43) 3.5 (21) 1 hr. LC01 in rats
(Dow Corning,
1997a)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. AIHA. 1996. Emergency Response Planning
Guidelines. Methyltrichlorosilane. AIHA, Fairfax, VA,
ii. Bisesi, M.S. 1994. Organic Silicon Esters. Patty's Industrial
Hygiene and Toxicology. Fourth Ed. Vol II, Part D. G.D. Clayton and
F.E. Clayton, Eds. pp. 3096-3101.
iii. Dow Corning. 1997a. An acute whole body inhalation toxicity
study of methyltrichlorosilane in Fischer 344 rats. Report No. 1997-
I0000-43537. Study No. 8602. Dow Corning Corporation. Health and
Environmental Sciences. Midland, MI.
iv. HSDB. 1997. Methyltrichlorosilane. Retrieved online 10-10-97.
v. Stevens, B., Koenig, J.Q., Rebolledo, V., Hanley, Q.S., Covert,
D.S. 1992. Respiratory effects from the inhalation of hydrogen chloride
in young adult asthmatics. Journal of Occupational Medicine. 34:923-
929.
vi. Ten Berge, W.F. et al. 1986. Concentration-time mortality
response relationship of irritant and systemically acting vapours and
gases. Journal of Hazardous Materials. 13:301-309.
vii. USEPA. 1997. Acute exposure guideline levels (AEGLs) for
hydrogen chloride (NAC/PRO Draft 3:7/97).

C. and D. 2,4- and 2,6-Toluene Diisocyanate (TDI)

1. Description. Toluene diisocyanate (TDI) is among a group of
chemicals, the isocyanates, that are highly reactive compounds
containing an -NCO group. Toluene diisocyanate exists as both the 2,4-
and 2,6- isomers which are available commercially usually in ratios of
65:35 or 80:20 (Karol, 1986; WHO, 1987). Toluene diisocyanate is used
extensively in the manufacture of polyurethane foam products as well as
paints, varnishes, elastomers, and coatings (WHO, 1987).
Toxicological effects from inhaled TDI consist of irritation and
sensitization of the respiratory tract. Sensitization may occur from
either repeated exposure over a relatively long period of time (i.e.,
years), or, it may consist of an induction phase precipitated by a
relatively high concentration followed by a challenge phase in which
sensitized individuals react to a low concentration of TDI. Because
repeated exposures are required for sensitization, only irritation
effects were considered in establishing AEGL values.
Human data were available for derivation of AEGL-1 and -2.
Asthmatics were exposed to 0.01 ppm (0.071 mg/m³) TDI for 1
hr., then after a rest of 45 mins., to 0.02 ppm (0.142 mg/
m³) TDI for 1 hr. Controls were exposed to 0.02 ppm (0.142
mg/m³) TDI for 2 hrs. (Baur, 1985). Although no
statistically significant differences in lung function parameters were
observed among asthmatics during or after exposure, non-pathological
bronchial obstruction was indicated in several individuals. In the
control group, there was a significant increase in airway resistance
immediately and 30 mins. after the beginning of exposure but none of
the subjects developed bronchial obstruction. Both groups reported
symptoms of eye and throat irritation, cough, chest tightness,
rhinitis, dyspnea, and/or headache but time to onset of symptoms was
not given. There was also no indication whether the effects were worse
in asthmatics with 0.01 or 0.02 ppm. Therefore, the concentration of
0.02 ppm (0.142 mg/m³) was chosen as the basis for the 10-
mins., 30-mins., and 1-hr. AEGL-1 values and the concentration of 0.01
ppm (0.071 mg/m³) was chosen as the 4- and 8-hr. AEGL-1
values. Extrapolations were not performed.
Derivation of AEGL-2 was based on human data. Exposure of
volunteers to 0.5 ppm (3.56 mg/m³) for 30 mins. resulted in
severe eye and throat irritation and lacrimation (Henschler et al.,
1962). A higher-exposure concentration was intolerable. Extrapolations
were made using the equation Cⁿ x t = k, where n ranges from
0.8 to 3.5 (Ten Berge et al., 1986). In the absence of an empirically
derived, chemical-specific exponent, to obtain conservative and
protective AEGL-2 values, scaling was performed using n = 3 for
extrapolating to the 10-min. time point and n = 1 for the 1- and 4-hr.
time points. The 4-hr. value is also proposed for the 8-hr. value since
extrapolation to 8 hrs. resulted in a concentration similar to that
shown to be tolerated for >7 hrs. with only mild effects. An
uncertainty factor of 3 was applied to account for sensitive
individuals because the mechanism of action of an irritant gas is not
expected to differ among individuals.
No human data were available for derivation of AEGL-3 values.
Reports of human fatalities occurred under unusual circumstances and
exposure concentrations were not measured. Deaths were attributed to
chemical pneumonitis. Therefore, animal data were used to derive AEGL-3
values. Based on LC50 values, the mouse is the most
sensitive species to the effects of TDI. The 4-hr. mouse
LC50 of 9.7 ppm (69.1 mg/m³) (Duncan et al.,
1962) was divided by 3 to estimate a threshold of lethality. This
estimated 4-hr. lethality threshold was used to extrapolate to the 30-
min. and 1- and 8-hr. AEGL-3 time

[[Page 39269]]

points. Values were scaled using the equation Cⁿ x t = k,
where n ranges from 0.8 to 3.5 (Ten Berge et al., 1986). In the absence
of an empirically derived, chemical-specific exponent, to obtain
conservative and protective AEGL-2 values, scaling was performed using
n = 3 for extrapolating to the 30-min. and 1-hr. time points and n = 1
for the 8-hr. time point. A total uncertainty factor of 10 was applied
which includes 3 to account for sensitive individuals and 3 for
interspecies extrapolation (the mechanism of action of an irritant gas
is not expected to vary greatly between or among species). The 10-min.
values were not extrapolated from 4 hrs. because the NAC/AEGL Committee
determined that extrapolating from greater than or equal to 4 hrs. to
10 mins. is associated with unacceptably large inherent uncertainty,
and the 30-min. values were adopted for 10 min. to be protective of
human health. Therefore, the 10-min. AEGL-3 value was flatlined from
the 30-min. value. The NAC/AEGL Committee recognizes that individuals
pre-sensitized to TDI may exist in the general population, but that
this rate of sensitization cannot be predicted. If the rate of
sensitization to TDI in the general population were quantifiable, the
NAC/AEGL Committee might have considered lower values for AEGL-3. At
the proposed AEGL-3 levels, there may be individuals who have a strong
reaction to TDI and these individuals may not be protected.

Summary of Proposed AEGL Values for 2,4-/2,6-Toluene Diisocyanate [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.020 (0.14) 0.020 (0.14) 0.020 (0.14) 0.010 (0.07) 0.010 (0.07) Chest tightness,
eye and throat
irritation (Baur,
1985)
AEGL-2 (Disabling) 0.24 (1.71) 0.17 (1.21) 0.083 (0.59) 0.021 (0.15) 0.021 (0.15) Severe eye and
throat irritation,
lacrimation
(Henschler et al.,
1962)
AEGL-3 (Lethal) 0.65 (4.6) 0.65 (4.6) 0.51 (3.6) 0.32 (2.3) 0.16 (0.93) 4-hrs. LC50 in the
mouse (Duncan et
al., 1962)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Baur, X. 1985. Isocyanate hypersensitivity. Final
Report to the International Isocyanate Institute. III File No. 10349;
III Project: E-AB-19.
ii. Duncan, B., Scheel, L.D., Fairchild, E.J., Killens, R., and
Graham, S. 1962. Toluene diisocyanate inhalation toxicity: Pathology
and mortality. American Industry Hygiene Association Journal. 23:447-
456.
iii. Henschler, D., Assman, W., and Meyer, K. O. 1962. On the
Toxicology of Toluenediisocyanate [in German]. Archivs fur Toxikologie
19:364-387.
iv. Karol, M.H. 1986. Respiratory effects of inhaled isocyanates.
CRC Critical Reviews in Toxicology. Vol. 16. CRC Press.
v. 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.
vi. WHO (World Health Organization). 1987. Toluene diisocyanates.
Environmental Health Criteria 75. WHO, Geneva. pp.72.

E. Allylamine

1. Description. Allylamine is a colorless or yellowish volatile
liquid with a very sharp ammonia-like odor that is irritating to mucous
membranes. It is highly flammable and moderately reactive with
oxidizing materials. Industrially, it is used in the vulcanization of
rubber and in the synthesis of pharmaceuticals. In addition to being a
severe respiratory, eye, and skin irritant, allylamine is a
cardiovascular toxin when administered at high doses orally, by
injection or by inhalation. Allylamine cardiotoxicity is proposed to be
related to its metabolism to acrolein and hydrogen peroxide. Allylamine
acute inhalation toxicity has been studied in rats and mice; the
response in human volunteers briefly exposed to irritating levels has
been reported.
AEGL-1 values were based on an occupational study in which exposure
to 0.2 ppm allylamine for 3-4 hrs. a day was not associated with worker
detection or complaints, but exposure to higher but undefined
concentrations caused mucous membrane irritation (Shell Oil Co., 1992).
The same AEGL-1 value is proposed for 10 mins. to 8 hrs. (i.e., ``flat-
line'') because 0.2 ppm is expected to produce no or mild irritation,
which does not generally vary greatly with time. No uncertainty factors
were applied because 0.2 ppm was a no-effect-level (NOEL) for mucous
membrane irritation in humans exposed repeatedly.
The AEGL-2 was based on a rat study in which exposure to 60 ppm for
14 hrs. caused heart lesions including scattered myofibril fragments
with loss of striation, perivascular edema, and cellular infiltration
(Guzman et al., 1961). Extrapolation to 30, 60, 240, and 480 mins. was
performed using the equation Cⁿ x t = k, where n = 1.71
(calculated from a linear regression of rat cardiotoxicity data of
Guzman et al., 1961). The 10-min. value was not extrapolated from 16
hrs. because the NAC has determined that extrapolating from 4 hrs. to
10 mins. is associated with unacceptably large inherent uncertainty,
and the 30-min. value was adopted for 10 mins. to be protective of
human health. An interspecies uncertainty factor of 10 was applied to
account for the lack of acute toxicity studies and toxicokinetic and
metabolism data from other species. An intraspecies uncertainty factor
of 10 was applied because significant intraspecies variation occurred
in the rat cardiotoxic responses in the key study, and there were no
data to determine the human variability of allylamine-induced
cardiotoxicity.
The AEGL-3 values were derived from a rat inhalation
LC50 study where exposure was for 1, 4, or 8 hrs. (Hine et
al., 1960). The threshold for lethality, as represented by
LC01 values calculated using probit analysis, was the AEGL-3
toxicity endpoint. The 1, 4, and 8-hr. AEGL-3 values were based on
their respective LC01 values, and the 10- and 30-min. AEGL-3
values were extrapolated from the 1-hr. LC01 using the
equation Cⁿ x t = k, where n = 0.8458 (calculated from a
linear regression of the Hine et al., 1960 data). An uncertainty factor
of 30 was applied: 10 to account for interspecies variability (to
account for the lack of acute toxicity studies and toxicokinetic and
metabolism data from other species) and 3 for human variability
(lethality, as an endpoint associated with severe pulmonary edema, is
not likely to vary greatly among humans). Similar AEGL-3 values were
obtained from other rat studies that used fewer animals and exposure
concentrations.

[[Page 39270]]

Summary of Proposed AEGL Values for Allylamine [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) 0.2 (0.47) NOAEL for human
mucous membrane
irritation (Shell
Oil Co., 1992)
AEGL-2 4.2 (9.8) 4.2 (9.8) 2.8 (6.5) 1.2 (2.8) 0.83 (1.9) Heart lesions in
rats (Guzman et
al., 1961)
AEGL-3 140 (330) 40 (94) 18 (42) 3.5 (8.1) 2.3 (5.4) Lethality threshold
in rats (Hine et
al., 1960)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Guzman, R.J., Loquvam, G.S., Kodama, J.K., and
Hine, C.H. 1961. Myocarditis produced by allylamines. Archives of
Environmental Health. 2:62-73.
ii. Hine, C.H., Kodama, J.K., Guzman, R.J., and Loquvam, G.S. 1960.
The toxicity of allylamines. Archives of Environmental Health. 1:343-
352.
iii. Shell Oil Co. 1992. Initial submission: Letter submitting
enclosed information on exposure of workers to mono-allylamine, di-
allylamine, and tri-allylamine. EPA/OTS Doc. #88-920002051.
iv. Ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
13:302-309.

F. Ethylenediamine (EDA)

1. Description. Ethylenediamine (EDA) is a basic, hygroscopic,
flammable liquid that is an eye, mucous membrane, and respiratory
irritant and a known respiratory and skin sensitizer. Occupational
inhalation exposure has resulted in an asthmatic response including
rhinitis, coughing, wheezing, shortness of breath, and bronchospasm.
EDA is used to stabilize rubber latex, as an inhibitor in antifreeze
solutions, and in the preparation of dyes, insecticides, and
fungicides.
The values developed for AEGL-2 and AEGL-3 level were based on
studies in which toxicity endpoints occurred that were within the scope
of the definition for that level. However, persons previously
sensitized to EDA may experience more severe effects, the extent of
which cannot be predicted from the available information. No data were
available to determine the concentration-time relationship for EDA
toxic effects. The concentration-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-2 and
AEGL-3 values, scaling across time was performed using n = 3 to
extrapolate to exposure times 8 hrs., except for the 10-min. values.
The NAC determined that extrapolating from 4 hrs. to 10 mins. is
associated with unacceptably large inherent uncertainty, and the 30-
min. values were adopted for 10 mins. to be protective of human health.
AEGL-1 values were not recommended due to insufficient data.
AEGL-2 values were based on a study in which rats and guinea pigs
(6/group) exposed for 8 hrs. to 484 ppm EDA (1,000 ppm
nominal) had bronchiolar edema of unspecified severity and ``light
cloudy swelling of the kidney'' but none died (Carpenter et al., 1948).
An uncertainty factor of 100 was used: 10 for intraspecies variability
(mechanism of toxicity and variability of the toxic response among
humans is uncertain) and 10 for interspecies variability (key study
tested only one EDA concentration and reported few experimental
details, not providing a clear picture of species variability). The
derived AEGL-2 values are supported by a study in which rats (15/sex)
exposed to 132 ppm 7 hours/day for 30 days had a slight increase in the
incidence (i.e., 1/26 vs. 0/27 for controls) of unspecified ``major''
histopathological lesions (Pozzani and Carpenter, 1954).
The AEGL-3 values were derived from a range-finding test in which
0/6 rats died from exposure for 8 hrs. to 1,000 ppm (2,000
ppm nominal) but 6/6 died from 8-hr. exposure to 2,000 ppm
(4,000 ppm nominal) (Smyth et al., 1951). Toxic effects (other than
death) were not described; 1,000 ppm was considered to be the estimated
lethality threshold. An uncertainty factor of 100 was applied: 10 for
intraspecies variability (cause of death was not defined in key study
and variability of the toxic response among humans cannot be predicted)
and 10 for interspecies extrapolation (only one EDA concentration was
tested, the cause of death was not defined in the key study, and there
were no data from other species). The AEGL-3 values are supported by a
study in which rats (15/sex) exposed to 225 ppm 7 hours/day for 30 days
had fractional mortality (first two deaths were on exposure day 4), and
most rats had cloudy swelling of the liver and kidney convoluted
tubules (Pozzani and Carpenter, 1954).

Summary of AEGL Values For Ethylenediamine [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 min. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 Not recommended Not recommended Not recommended Not recommended Not recommended Not recommended
AEGL-2 12 (30) 12 (30) 9.7 (24) 6.1 (19) 4.8 (13) Bronchiolar edema,
kidney swelling
(Carpenter et
al., 1948)
AEGL-3 25 (62) 25 (62) 20 (49) 13 (31) 10 (26) Lethality
threshold; no
stated toxic
effects (Smyth et
al., 1951)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Carpenter, C.P., Smyth, Jr., H.F., and Shaffer,
C.B. 1948. The acute toxicity of ethylene imine to small animals.
Journal of Industrial Hygiene and Toxicology. 30:2-6.
ii. Pozzani, U.C. and Carpenter, C.P. 1954. Response of rats to
repeated inhalation of ethylenediamine vapors. AMA Archives of
Industrial Hygiene and Occupational Medicine. 9:223-226.
iii. Smyth, H.F., C.P. Carpenter, and C.S. Weil. 1951. Range-
finding toxicity data: List IV. AMA Archives of Industrial Hygiene and
Occupational Medicine. 4:119-122.

[[Page 39271]]

iv. Ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
13:302-309.

G. Cylohexylamine

1. Description. Cyclohexylamine is a respiratory, eye, and skin
irritant, as well as a strong base (pKa = 10.7) with a
fishy, amine odor that has only recently been found naturally. It is
used primarily for boiler water treatment (corrosion inhibition) as
well as organic synthesis of rubber and agricultural chemicals.
Occupational exposures to cyclohexylamine caused headache, nausea,
dizziness, vomiting, eye, nose and throat irritation, and rapid and
irregular heartbeats in some individuals. Acute exposure in animals
resulted in extreme mucous membrane irritation, gasping, CNS effects
(tremors, clonic muscular spasms), lung hemorrhage, opaque corneas,
vascular lesions, and hemolysis.
No data were available to determine the concentration-time
relationship for cyclohexylamine toxicity. The concentration-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-2 and AEGL-3 values, scaling across time was performed
using n = 3 to extrapolate to shorter exposure times and n = 1 to
extrapolate to longer exposure times for 30 min. through 8-hr. values
(scaling was not performed for AEGL-1 derivation). The 10-min. values
were not extrapolated from 4 hrs. because the NAC determined that
extrapolating from 4 hrs. to 10 mins. is associated with unacceptably
large inherent uncertainty, and the 30-min. values were adopted for 10
mins. to be protective of human health.
AEGL-1, AEGL-2, and AEGL-3 values were derived from a study in
which Sprague-Dawley rats (5/sex/dose) were exposed for 4 hrs. to 54.2
ppm or 567 ppm cyclohexylamine vapor, or to a vapor/aerosol combination
containing 542 ppm vapor and 612 mg/m³ aerosol (Bio/
dynamics, Inc., 1990). At 54.2 ppm, rats had labored breathing,
partially closed eyes, and red nasal discharge; rats exposed to the two
higher doses additionally had rales, gasping, dried red facial
material, tremors, weight loss, irreversible ocular lesions, and two
rats exposed to the aerosol-containing atmosphere died. AEGL-1 values
were obtained by dividing the lowest-observed-adverse-effect-level
(LOAEL) of 54.2 ppm by 3 to estimate a NOAEL, which may be associated
with mild or no respiratory and ocular irritation. An uncertainty
factor of 10 was applied: 3 to account for sensitive humans and 3 for
interspecies variability, because mild sensory irritation from a
surface-contact, basic irritant gas is not likely to vary greatly among
humans or animals. The same AEGL value was adopted for 10 mins., 30
mins., 1, 4, and 8 hrs.; flat-lining across time was considered
appropriate since mild irritant effects generally do not vary greatly
over time.
AEGL-2 values were based on exposure for 4 hrs. to 54.2 ppm, at
which concentration the rats had moderate respiratory effects and
ocular irritation, and which was a NOAEL for irreversible ocular
lesions. An uncertainty factor of 10 was used: 3 for interspecies
variability and 3 for intraspecies variability (moderate respiratory
and ocular irritation from a surface-contact, basic irritant gas is not
likely to vary greatly among humans or animals).
The AEGL-3 values were based on exposure for 4 hrs. to 567 ppm,
which caused severe respiratory effects and irreversible ocular lesions
and was regarded as an estimate of the lethality threshold because 2/10
animals died at the next higher concentration tested. An uncertainty
factor of 30 was applied: 3 to account for intraspecies variability
(lethality response resulting from a basic irritant gas is not likely
to vary greatly among humans) and 10 for extrapolation from animals to
humans (significant variation was seen among species for the exposure
causing lethality, and the data were insufficient to determine that
rats were the most sensitive species).

Summary of Proposed AEGL Values for Cyclohexylamine [ppm(mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) 1.8 (7.3) NOAEL for
respiratory and
ocular irritation;
may cause mild or
no sensory
irritation (Bio/
dynamics, Inc.,
1990)
AEGL-2 11 (44) 11 (44) 8.6 (35) 5.4 (22) 2.7 (11) Moderate
respiratory
effects, ocular
irritation; NOAEL
for irreversible
ocular lesions
(Bio/dynamics,
Inc., 1990).
AEGL-3 38 (150) 38 (150) 30 (120) 19 (77) 9.4 (38) Lethality
threshold, severe
respiratory
effects, and
irreversible
ocular lesions
(Bio/dynamics,
Inc., 1990).
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Bio/dynamics, Inc. 1990. An acute inhalation
toxicity study of C-1388 in the rat. Final Report. Project No. 89-8214.
December 4, 1990.
ii. Ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
13:302-309.

H. and I. Cis- and Trans-Crotonaldehyde

1. Description. Crotonaldehyde is a colorless, flammable liquid and
an extreme eye, skin, and respiratory irritant. It causes a burning
sensation in the nasal and upper respiratory tract, lacrimation,
coughing, bronchoconstriction, pulmonary edema, and deep lung damage.
Crotonaldehyde is used primarily for the manufacture of sorbic acid and
other organic chemicals. It is found in tobacco smoke and is a
combustion product of diesel engines and wood, but also occurs
naturally in meat, fish, and many fruits and vegetables.
Crotonaldehyde can exist as either the cis or the trans isomer;
commercial crotonaldehyde is a mixture of the two isomers consisting of
>95% trans isomer. Because virtually no physical or chemical data or in
vivo exposure studies were located for the cis or trans isomers
individually (information was for the commercial mixture), and because
OSHA, NIOSH, and the ACGIH have adopted the same occupational exposure
limits for both isomers, the AEGL values prepared in this report will
apply to both trans-crotonaldehyde (123-73-9) and to the cis/trans
mixture (4170-30-3), which contains predominantly the trans isomer.
AEGL-1 values were derived from a Health Hazard Evaluation
conducted by NIOSH where workers exposed to about

[[Page 39272]]

0.56 ppm crotonaldehyde for >8 hrs. reported occasional minor eye
irritation (Fannick, 1982). Exponential scaling across time was not
performed because results from another study suggested that the
concentration-time relationship determined from the rat LC50
study of Rinehart (1967) was not appropriate for predicting human
sensory irritation (i.e., irritation was much greater for shorter
exposure durations than for longer exposure durations yielding
comparable concentration x time (Ct) values. An uncertainty factor of 3
was applied to account for sensitive humans; a greater uncertainty
factor is not needed because the endpoint of mild eye irritation is not
expected to vary greatly among humans.
AEGL-2 values were based on a study in which rats exposed to 8,000
ppm-min crotonaldehyde had about a 20-40% reduction in pulmonary
function (manifested as a decrease in carbon monoxide and ether uptake
rates compared to pre-exposure values). The animals had proliferative
lesions of the respiratory bronchioles but there was little or no
evidence of alveolar edema (Rinehart, 1967). The individual
experimental concentrations and exposure times were not given, but
exposure was stated to be for 5-240 mins. AEGL-2 values were calculated
by dividing 8,000 ppm-min by 10, 30, 60, 240, or 480 mins.
(concentration and time appeared to be equally important for toxicity).
An uncertainty factor of 30 was used: 3 to account for sensitive humans
(crotonaldehyde acts primarily as a surface-contact irritant and the
irritation response is not expected to vary greatly among humans) and
10 for extrapolation from animals to humans (based on the lack of
actual concentration and time data, and the stated variability in the
animal responses, and the absence of supporting animal or human
studies).
The AEGL-3 was based on a LC50 study in which Wistar
rats were exposed to crotonaldehyde vapor for 5 mins. to 4 hrs.
(Rinehart, 1967). The 10-min., 30-min., 1-hr., and 4-hr. AEGLs were
obtained using the respective LC01 values (268, 138, and 26
ppm, respectively; calculated by probit analysis from mortality data).
The 8-hr. AEGLs were derived from the 4-hr. LC01; scaling
across time was performed using the exponential relationship
Cⁿ x t = k , where n = 1.2 was derived by Ten Berge et al.
(1986) from this study LC50 data. During exposure, all
animals gasped and had a lowered breathing rate; those exposed to
>1,000 ppm had an excitatory stage. Rats lost up to 25% of their body
weight by 1-3 days post-exposure, after which time they began to
recover their weight. Most rats died by 4 days after exposure and had
clear or slightly blood-tinged nasal exudate; all animals that died
within 1 day also had terminal convulsions. An uncertainty factor of 10
was applied: 3 to account for extrapolation of rats to humans, and 3 to
account for sensitive humans. Similar or higher AEGL-3 values were
obtained from LC50 studies in rats, mice, and guinea pigs.

Summary of Proposed AEGL Values For Crotonaldehyde [ppm(mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) 0.19 (0.53) Human mild eye
irritation
(Fannick, 1982)
AEGL-2 (Disabling) 27 (76) 8.9 (25) 4.4 (13) 1.1 (3.2) 0.56 (1.6) Rat impaired
pulmonary
function,
bronchiole lesions
(Rinehart, 1967)
AEGL-3 (Lethal) 44 (130) 27 (76) 14 (40) 2.6 (7.4) 1.5 (4.2) Rat lethality
threshold using
LC1 values
(Rinehart, 1967).
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Fannick, N. 1982. Sandoz Colors and Chemicals,
East Hanover, New Jersey (Health Hazard Evaluation Report, No. HETA-81-
102-1244), Cincinnati, OH. United States National Institute for
Occupational Safety and Health, Hazard Evaluations and Technical
Assistance Branch.
ii. Rinehart, W. 1967. The effect on rats of single exposures to
crotonaldehyde vapor. American Industrial Hygiene Association Journal.
28:561-566.
iii. Ten Berge, W.F., Zwart, A., and Appelman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapors and gases. Journal of Hazardous Materials.
13:302-309.

J. Methyl Isocyanate (MIC)

1. Description. Methyl isocyanate (MIC) is one of the most reactive
of all isocyanates and is rapidly degraded in aqueous medium (Varma and
Guest, 1993). Because of its reactivity, MIC is used as an intermediate
in the synthesis of N-methylcarbamate and N -methylurea insecticides
and herbicides (Hartung, 1994). During the night of December 2/3, 1984,
an estimated 30 tons of MIC was released from a chemical plant in
Bhopal, India, resulting in one of the worst industrial accidents in
history (Karlsson et al., 1985).
Signs of severe irritation to the respiratory tract were reported
for victims of the Bhopal disaster and autopsies revealed the cause of
death to be pulmonary edema (Weill, 1988). Long-term pulmonary and
ocular effects have been documented in survivors. The spontaneous
abortion rate (Arbuckle and Sever, 1998) and the infant death rate
(Varma, 1987) among women who were pregnant at the time of the release
were significantly increased in the months following the disaster.
Numerous animal studies corroborate the epidemiological findings in
humans. A compilation of case reports in industrial workers
consistently noted skin and respiratory irritation in MIC exposed
workers but no definitive case of sensitization (Ketcham, 1973). The
mechanism of action for the pulmonary, skin, and eye effects is
irritation, but the mechanism of action for the systemic effects is
unknown.
AEGL-1 values were not derived. Although human and animal data were
available for irritation levels, the irritation threshold for MIC may
be above the level of concern for systemic effects such as embryo and
fetal lethality.
Systemic and developmental toxicity data from rats and mice were
used for derivation of AEGL-2. An increase in cardiac arrhythmias
occurred in rats 4 months after a 2-hr. exposure to 3 ppm (Tepper et
al., 1987). Pregnant Swiss-Webster mice were exposed to analytically
monitored concentrations of 0, 2, 6, 9, and 15 ppm MIC for 3 hrs. on
gestation day 8 (Varma, 1987). Placental weights and fetal body weights
were significantly reduced at all concentrations. Exposures to
concentrations of 9 and 15 ppm resulted in deaths of two dams in each
group, a significant increase in complete litter resorption among
surviving dams, and fetuses with significant reductions in the lengths
of the mandible and long bones. The concentration of 2 ppm for 3 hrs.
was an experimentally derived

[[Page 39273]]

lowest-observed effect level for decreased fetal body weights. Values
scaled for the derivation of the 10- and 30-min., and 1-, 4-, and 8-hr.
time points were calculated from the equation Cⁿ x t = k,
where n = 1. The value of n was empirically derived from regression
analysis of lethality data for rats. Identical AEGL-2 values are
derived based on the exposures of 3 ppm for 2 hrs. and 2 ppm for 3 hrs.
The experimental concentrations were reduced by a factor of 3 to
estimate a threshold for effects on cardiac arrhythmias or fetal body
weights. A total uncertainty factor of 30 was applied including 3 for
interspecies variation because similar developmental toxicity results
have been obtained in both rats and mice and 10 for intraspecies
variation since the mechanism of action for systemic effects is
unknown.
The neonatal survival study with mice by Schwetz et al. (1987) was
used for derivation of AEGL-3 values. Pregnant mice were exposed to 0,
1, or 3 ppm for 6 hours/day on gestation days 14-17. Dams were allowed
to litter for evaluation of neonatal survival. A concentration-related
increase in the number of dead fetuses at birth was observed in both
exposure groups and an increase in pup mortality during lactation was
observed in the 3 ppm group. No differences in pup body weights
occurred during lactation between the treated and control groups. The
6-hr. exposure to 1 ppm was used to derive AEGL-3 values and is
considered a NOEL for pup survival during lactation. Values scaled for
the derivation of the 10- and 30-min., and 1-, 4-, and 8-hr. time
points were calculated from the equation Cⁿ x t = k, where n
= 1. The value of n was empirically derived from regression analysis of
lethality data for rats. A total uncertainty factor of 30 was applied
including 3 for interspecies variation because similar developmental
toxicity results have been obtained in both rats and mice and 10 for
intraspecies variation since the mechanism of action for systemic
effects is unknown. However, because n was derived from exposures
ranging from 7.5 to 240 mins., it is felt that extrapolation from 6
hrs. to the 10-min. AEGL-3 value is valid.
The proposed values for the three AEGL classifications for the five
time periods are listed in the table below.

Summary of Proposed AEGL Values for Methyl Isocyanate [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) NA NA NA NA NA NA
AEGL-2 (Disabling) 0.40 (0.94) 0.13 (0.32) 0.067 (0.16) 0.017 (0.034) 0.0083 (0.019) Decreased fetal
body weights
(Varma, 1987);
cardiac
arrhythmias
(Tepper et al.,
1987)
AEGL-3 (Lethal) 1.2 (2.8) 0.40 (0.95) 0.20 (0.47) 0.050 (0.12) 0.025 (0.059) Decreased pup
survival during
lactation (Schwetz
et al., 1987)
--------------------------------------------------------------------------------------------------------------------------------------------------------
NA: Not assigned, since AEGL-1 effects would occur at concentration levels higher than AEGL-2 levels.

2. References--i. Arbuckle, T.E. and Sever, L.E. . 1998. Pesticide
exposures and fetal death: a review of the epidemiologic literature.
Critical Reviews in Toxicology . 28:229-270.
ii. Hartung, R. 1994. Cyanides and Nitriles. Patty's Industrial
Hygiene and Toxicology . 4th Ed. G.D. Clayton and F.E. Clayton, Eds.
New York: John Wiley & Sons, Inc. pp. 3161-3172.
iii. Karlsson, E., Karlsson, N., Lindberg, G., Lindgren, B., and
Winter S. 1985. The Bhopal catastrophe--consequences of a liquefied gas
discharge. National Defense Research Institute, Sweden. NTIS ISSN 0347-
2124.
iv. Ketcham, N.H. 1973. Methyl isocyanate (MIC) survey of
experience concerning human sensitization. Union Carbide Corporation.
EPA/OTS; Doc #86- 910000666D.
v. Schwetz, B.A., Adkins, Jr., B., Harris, M., Moorman, M., and
Sloane, R. 1987. Methyl isocyanate: reproductive and developmental
toxicology studies in Swiss mice. Environmental Health Perspectives.
72:149-152.
vi. Tepper, J.S., Wiester, M.J., Costa, D.L., Watkinson, W.P., and
Weber, M.F. 1987. Cardiopulmonary effects in awake rats four and six
months after exposure to methyl isocyanate. Environmental Health
Perspectives 72:95-103.
vii. Varma, D.R. 1987. Epidemiological and experimental studies on
the effects of methyl isocyanate on the course of pregnancy.
Environmental Health Perspectives. 72:153-157.
viii. Varma, D.R. and Guest, I.. 1993. The Bhopal accident and
methyl isocyanate toxicity. Journal of Toxicology and Environmental
Health. 40:513-529.
ix. Weill, H. 1988. Disaster at Bhopal: the accident, early
findings and respiratory health outlook in those injured. Physiology.
23:587-590.

K. Hydrogen Chloride (HCl)

1. Description. Hydrogen chloride (HCl) is a colorless gas with a
pungent suffocating odor. It is used in the manufacture of organic and
inorganic chemicals, oil well acidizing, steel pickling, food
processing, and processing of minerals and metals. A large amount of
HCl is released from solid rocket fuel exhaust. It is an upper
respiratory irritant at relatively low concentrations and may cause
damage to the lower respiratory tract at higher concentrations.
Hydrogen chloride is very soluble in water, and the aqueous solution is
highly corrosive.
The AEGL-1 values are based on a 45 min. NOAEL in exercising adult
asthmatics (Stevens et al., 1992). No uncertainty factors were applied
for inter- or intraspecies variability since the study population
consisted of sensitive humans. Additionally, the same value was applied
across the 10- and 30-min., and 1-, 4-, and 8-hr. exposure time points
since mild irritancy is a threshold effect and generally does not vary
greatly over time. Thus, prolonged exposure will not result in an
enhanced effect.
The AEGL-2 for the 30-min., 1-, 4-, and 8-hr. time points was based
on severe nasal or pulmonary histopathology in rats exposed to 1,300
ppm HCl for 30 mins. (Stavert et al.,1991). An uncertainty factor of 3
was applied for interspecies variability because the test species
(rodents) is 2-3 times more sensitive to the effects of HCl than
primates. An uncertainty factor of 3 was applied for intraspecies
extrapolation since the mechanism of action is direct irritation and
the subsequent effect or response is not expected to vary greatly among
individuals. An additional modifying factor of 3 was applied to account
for the sparse database of effects defined by AEGL-2 and since the
effects observed at the concentration used to derive AEGL-2 values were
somewhat severe. Thus, the total uncertainty and

[[Page 39274]]

modifying factor adjustment is 30-fold. It was then time-scaled to the,
and 1-, 4-, and 8-hr. AEGL exposure periods using the Cⁿ x t
= k relationship, where n = 1 based on regression analysis of combined
rat and mouse LC50 data (1 min. to 100 min1.) as reported by
Ten Berge et al., 1986. The 10-min. AEGL-2 value was derived by
dividing the mouse RD50 of 309 ppm by a factor of 3 to
obtain a concentration causing irritation (Barrow et al., 1977). One-
third of the mouse RD50 for HCl corresponds to an
approximate decrease in respiratory rate of 30%, and decreases in the
range of 20 to 50% correspond to moderate irritation (ASTM, 1991).
The AEGL-3 was based on an estimated NOEL for death of one-third of
a 1-hr. LC50 reported for rats (Vernot et al., 1977;
Wohlslagel et al., 1976). An uncertainty factor of 3 was applied for
interspecies variability because the test species (rodents) is 2-3
times more sensitive to the effects of HCl than primates. An
uncertainty factor of 3 was applied for intraspecies extrapolation
since the mechanism of action is direct irritation and the subsequent
effect or response is not expected to vary greatly among individuals.
Thus, the total uncertainty factor is 10. It was then time-scaled to
the specified 10- and 30-min., and 1-, 4-, and 8-hr. AEGL exposure
periods using the Cⁿ x t = k relationship, where n = 1 based
on regression analysis of combined rat and mouse LC50 data
(1 min. to 100 mins.) as reported by Ten Berge et al., 1986.
The calculated values are listed in the table below.

Summary of Proposed AEGL Values For Hydrogen Chloride [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) 1.8 (2.7) NOAEL in exercising
human asthmatics
(Stevens et al.,
1992)
AEGL-2 (Disabling) 100 (160) 43 (65) 22 (33) 5.4 (8.1) 2.7 (4.1) Mouse RD50
(Barrowet al,
1977);
Histopathology in
rats (Stavert et
al., 1991)
AEGL-3 (Lethality) 620 (940) 210 (310) 100 (160) 26 (39) 13 (19) Estimated NOEL for
death from 1-hr.
rat LC50
(Wohlslagel et
al., 1976; Vernot
et al., 1977)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. ASTM. (American Society for Testing and
Materials). 1991. Standard Test Method for estimating sensory irritancy
of airborne chemicals. Method E981, Volume 11.04, p. 610-619. ASTM
Philadelphia, PA.
ii. Barrow, C.S., Alarie, Y., Warrick, M., and Stock, M.F. 1977.
Comparison of the sensory irritation response in mice to chlorine and
hydrogen chloride. Archives of Environmental Health. 32:68-76.
iii. Stavert , D.M., Archuleta, D.C., Behr, M.J., and Lehnert, B.E.
1991. Relative acute toxicities of hydrogen fluoride, hydrogen
chloride, and hydrogen bromide in nose- and pseudo-mouth-breathing
rats. Fundamental and Applied Toxicology. 16:636-655.
iv. Stevens, B., Koenig, J.Q., Rebolledo, V., Hanley, Q.S., and
Covert, D.S. 1992. Respiratory effects from the inhalation of hydrogen
chloride in young adult asthmatics. Journal of Occupational Medicine.
34: 923-929.
v. Ten Berge, W.F., Zwart, A., and Appleman, L.M. 1986.
Concentration-time mortality response relationship of irritant and
systemically acting vapours and gases. Journal of Hazardous Materials.
13:301-309.
vi. 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.
vii. Wohlslagel, J., DiPasquale, L..C., and Vernot, E.H. 1976.
Toxicity of solid rocket motor exhaust: effects of HCl, HF, and alumina
on rodents. Journal of Combustion Toxicology. 3:61-70.

L. Phosphine

1. Description. Phosphine is a colorless gas used as a fumigant
against insects and rodents in stored grain. The pesticide is usually
applied as a metal phosphide and reacts with moisture to liberate
phosphine gas. Phosphine is also used in the semiconductor industry.
Information concerning human exposure to phosphine is of limited use in
derivation of AEGL values since exposure durations and concentrations
are not precisely reported. Appropriate animal data are more abundant;
however, data consistent with the definition of AEGL-1 values are not
available. Therefore, due to insufficient data, AEGL-1 values were not
derived.
The AEGL-2 was based on a NOEL for renal, cardiac, and liver
histopathology in mice exposed to 5 ppm phosphine 6 hours/day for 4
days (Morgan et al, 1995). Values were derived assuming a single 6 hr.
exposure. An uncertainty factor of 3 was applied to account for
interspecies variability since lethality data from rats, mice, rabbits,
and guinea pigs suggest little species variability. An uncertainty
factor of 10 was applied to account for intraspecies variability since
the human data suggest that children may be more sensitive than adults
when exposed to presumably similar phosphine concentrations (total UF =
30). The concentration-exposure time relationship for many irritant and
systemically-acting vapors and gases may be described by Cⁿ
x t = k, where the exponent, n, ranges from 0.8 to 3.5 (Ten Berge ,
1986). To obtain conservative and protective AEGL values for the 30-
min., 1-, 4-, and 8-hr. time points 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. The 30-min AEGL-2 value was also adopted as the 10-min.
value due to the fact that reliable data are limited to durations 4
hrs., and it is considered inappropriate to extrapolate back to 10-
mins.
The AEGL-3 was based on a NOEL for lethality (18 ppm phosphine) in
Sprague Dawley rats exposed to phosphine for 6 hrs. (Newton, 1991). An
uncertainty factor of 3 was applied to account for interspecies
variability since lethality data from rats, mice, rabbits, and guinea
pigs suggest little species variability. An uncertainty factor of 10
was applied to account for intraspecies variability since the human
data suggest that children may be more sensitive than adults when
exposed to presumably similar phosphine concentrations (total UF = 30).
The concentration-exposure time relationship for many irritant and
systemically-acting vapors and gases may be described by Cⁿ
x t = k, where the exponent, n, ranges from 0.8 to 3.5 (Ten Berge ,
1986). To obtain conservative and protective AEGL values for the 30-
min., 1-, 4-, and 8-hr.

[[Page 39275]]

time points 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. The 30-min
AEGL-3 value was also adopted as the 10-min. value due to the fact that
reliable data are limited to durations 4 hrs., and it is considered
inappropriate to extrapolate back to 10-mins.
The calculated values are listed in the table below.

Summary of Proposed AEGL Values For Phosphine [ppm(mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) Appropriate data
not available
AEGL-2 (Disabling) 0.38 (0.54) 0.38 (0.54) 0.30 (0.42) 0.19 (0.27) 0.13 (0.18) NOEL for
histopathology in
mice exposed to 5
ppm phosphine 6
hours/day for 4
days. Values were
calculated
assuming a single
6 hr exposure
(Morgan et al.,
1995)
AEGL-3 (Lethality) 1.4 (1.9) 1.4 (1.9) 1.1 (1.6) 0.69 (0.97) 0.45 (0.63) NOEL for lethality
in rats exposed to
18 ppm phosphine
for 6 hrs.
(Newton, 1991)
--------------------------------------------------------------------------------------------------------------------------------------------------------

2. References--i. Newton, P.E. 1991. Acute Inhalation exposures of
rats to phosphine. Bio/Dynamics, Inc. East Millstone, NJ. Project No.
90-8271.
ii. Morgan, D.L., Moorman, M.P., Elwell, M.R., Wilson, R.E., Ward,
S.M., Thompson, M.B., O'Connor, R.W., and Price, H.C. 1995. Inhalation
toxicity of phosphine for Fischer 344 rats and B6C3F1 mice. Inhalation
Toxicology. 7: 225-238.
iii. 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.

M. Nickel Carbonyl

1. Description. Nickel carbonyl, formed by the reaction of carbon
monoxide with metallic nickel, is used in nickel refining, in the
synthesis of acrylic and methacrylic esters, and for other organic
synthesis. In air, nickel carbonyl rapidly decomposes to nickel and
carbon monoxide with a 50% decomposition at room temperature and total
decomposition at 150-200 deg.C.
Human data are limited to case reports, primarily of nickel
workers, that affirm the extreme toxicity of the compound. However,
definitive exposure terms are lacking in these reports. Significant
signs and symptoms of toxicity are known to occur in the absence of
recognizable odor. Human case studies have shown that a latency period
of 10 occurs between initial signs of toxicity and subsequent serious
effects that may progress to death. The primary target of nickel
carbonyl-induced acute toxicity appears to be the lungs, although
extrapulmonary involvement has also been reported. The specific
mechanism of toxicity is unclear but appears to involve damage to
pulmonary tissue.
Animal data are limited to lethality and developmental toxicity.
Lethality values (LC50) are available for rats, mice, cats,
and rabbits. Thirty-minute LC50 values for these species
range from 33.6 to 266 ppm. These lethality data indicate notable
species variability in the lethal response to inhaled nickel carbonyl;
smaller species are generally more sensitive. Developmental toxicity
has been demonstrated in rats and hamsters following single 30-min.
(11.2-42 ppm, rats) or 15-min. (8.4 ppm, hamsters) exposures of dams
during gestation.
Limited data in rats have provided equivocal evidence of pulmonary
carcinogenicity following acute or long-term exposure to nickel
carbonyl. Studies of respiratory tract cancer in nickel workers suggest
that nickel dusts and nickel sulfides may be more relevant than nickel
carbonyl. Data are unavailable for a quantitative assessment of the
carcinogenic potential of nickel carbonyl in humans or animals.
Exposure-response data over multiple time periods are unavailable
for nickel carbonyl and, empirical derivation of a scaling factor (n)
was not possible. 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.
In the absence of an empirically derived exponent (n), and to obtain
conservative and protective AEGL values, 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.
Neither human nor animal data are available for deriving AEGL-1
values. Both human and animal data affirm the extreme toxicity of
nickel carbonyl, and human exposures indicate that signs and symptoms
of toxicity may occur in the absence of detection. Therefore, AEGL-1
values are not recommended.
With the exception of teratogenicity and fetotoxicity data in rats
and hamsters, neither human nor animal data are available that identify
effects consistent with AEGL-2. The developmental effects are notable
(ocular malformations, fetotoxicity, and neonate lethality) and the
exposures producing these effects approach those known to cause
lethality in animal species. The AEGL-2 values were based upon
significantly increased incidences of malformations in the offspring of
Syrian hamsters which had been exposed to 8.4 ppm nickel carbonyl for
15 mins. per day on gestation days 4 or 5 (Sunderman et al., 1980). As
previously noted, time scaling was accomplished by the use of linear
C¹ x t = k) extrapolation for 30-min., 1-hr. and 4-hr. AEGL-
2 time points and exponential extrapolation C ³ x t = k) for
the 10-min. AEGL-2 values. A total uncertainty factor adjustment of 100
(10 for interspecies variability and 10 for intraspecies variability)
was applied. The interspecies uncertainty factor adjustment is
justified by the absence of human data and only limited data in animal
species with which to assess species variability in the toxic responses
to nickel carbonyl. The uncertainty factor for individual variability
accounted for lack of data with which to identify sensitive
subpopulations or to determine individual variability in the toxic
responses to nickel carbonyl.
AEGL-3 values were derived based upon an estimated lethality
threshold in mice (3.17 ppm) exposed to nickel carbonyl for 30 mins.
(Kincaid et al., 1953). Lethality data were available for several
species (rats, mice, rabbits, and cats). A total uncertainty adjustment
of 10 was applied (each uncertainty factor of 3 is the approximate
logarithmic mean of 10 which is 3.16; hence, 3.16 x 3.16 = 10).
Analysis of the available data indicated that the mouse was the most
sensitive species and larger species tended to be somewhat less
sensitive. Therefore the uncertainty factor adjustment for interspecies
variability

[[Page 39276]]

was limited to 3. An additional factor of 3 was applied to account for
uncertainties regarding individual variability in the lethal response
due to direct contact pulmonary damage by nickel carbonyl.
There are limited, equivocal data showing the development of
pulmonary tumors in rats exposed chronically to nickel carbonyl and
equivocal data suggestive of a tumorigenic response following a single
massive exposure of rats to nickel carbonyl. However, a quantitative
cancer assessment was not feasible.

Summary of Proposed Aegl Values For Nickel Carbonyl [ppm mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) NR NR NR NR NR Not recommended
AEGL-2 (Disabling) 0.096 (0.66) .042 (0.29) 0.021 (0.14) 0.0053 (0.037) NA Developmental
toxicity in
hamsters;
gestational
exposure (15
mins., 8.4 ppm)
AEGL-3 (Lethal) 0.46 (3.2) 0.32 (2.2) 0.16 (1.1) 0.040 (0.27) NA Estimated lethality
threshold (LC01 of
3.17 ppm); mouse
lethality data
(Kincaid et al.,
1953)
--------------------------------------------------------------------------------------------------------------------------------------------------------
NR: Not recommended. Numeric values for AEGL-1 are not recommended because:
1. The lack of available data,
2. An inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or
3. The derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.
NA: Not appropriate. AEGL values for 8 hrs. were not developed due to the rapid decomposition of nickel carbonyl under ambient atmospheric conditions.

2. References--i. Kincaid, J.F., Strong, J.S., and Sunderman, F.W.
1953. Nickel poisoning. Experimental study of the effects of acute and
subacute exposure to nickel carbonyl. Archives of Industrial Hygiene
and Occupational Medicine. 8:48-60.
ii. Sunderman, F.W., Jr., Shen, S.K., Reid, M.C., and Alpist, P.R.
1980. Teratogenicity and embryotoxicity of nickel carbonyl in Syrian
hamsters. Teratogenicity Carcinogenicity Mutagenicity. 1:223-233.

N. Iron Pentacarbonyl

1. Description. Iron pentacarbonyl is one of several iron
carbonyls. It is formed by the interaction of carbon monoxide with
finely divided iron. Iron pentacarbonyl is used in the manufacture of
powdered iron cores for electronic components, as a catalyst and
reagent in organic reactions, and as an anti-knock agent in gasoline.
Iron pentacarbonyl is pyrophoric in air (-15 deg.C flashpoint), burning
to ferric oxide.
Quantitative toxicity data and odor detection data for humans are
unavailable. Qualitative descriptions of the signs and symptoms of iron
pentacarbonyl exposure include giddiness and headache, and occasionally
dyspnea and vomiting. With the exception of dyspnea, these signs and
symptoms are alleviated upon removal from exposure but fever, cyanosis,
and coughing may occur at 12 to 36 hrs. after exposure. This
information could not be validated and additional details were
unavailable.
Animal data are limited to lethality findings in rats, mice, and
rabbits. Based upon the limited data available, the rat appears to be
the most sensitive species as determined by the 30-min. LC50
of 118 ppm and a 4-hr LC50 of 10 ppm relative to the 30-
min. LC50 of 285 ppm for the mouse. A steep exposure-
response relationship is suggested by data showing 50% lethality in
rats following only two 6-hr exposures to 3 ppm. For mice, a 1.35-fold
increase in the LC50 results in near 100% mortality for the
same exposure duration, suggesting a steep exposure-response
relationship for this species as well. Similarly, a 2.8-fold increase
in exposure concentration (86-244 ppm) results in a mortality rate in
rats of 4/12 to 11/12. No reproductive/developmental toxicity,
genotoxicity, or carcinogenicity data are available for iron
pentacarbonyl.
Although exposure-response data for the same toxicity endpoint over
multiple time periods were limited to several LC50 values,
these data suggested a near-linear relationship. Therefore, the value
of n was set at unity for the exponential temporal scaling equation,
Cⁿ x t=k AEGL values were developed for 10 mins., 30 mins.,
1 hr., and 4 hrs. only. AEGL values were not developed for the 8-hr.
time point due to the rapid decomposition of iron pentacarbonyl under
ambient atmospheric conditions.
Data consistent with AEGL-1 effects were limited to labored
breathing and signs of irritation in rats exposed to 5.2 ppm for 4 hrs.
and no observable effects in rats exposed for 6 hours/day to 1 ppm for
28 days. However, analysis of the overall data set for iron
pentacarbonyl indicated a very steep exposure-response curve with
little margin between exposures producing no observable effects and
those resulting in lethality. Therefore, it was the consensus of the
NAC/AEGL Committee on AEGLs to recommend no AEGL-1 values.
Limited data in rats revealed that there is only a small margin
between exposures causing little or no toxicity and those causing more
severe effects and death. No effect was observed following exposure of
rats to 1 ppm, 6 hours/day for up to 28 days while a single exposure to
2.91 ppm for 6 hours/day caused notable signs of toxicity with a 10%
mortality. The occurrence of deaths in laboratory species several days
following cessation of exposure is also a factor to consider in the
derivation of AEGL-2 values showed. In the absence of exposure-response
data for serious and/or possibly irreversible effects, AEGL-2 value
were developed by a three-fold reduction in the AEGL-3 values. This 3-
fold reduction was justified by the apparently steep exposure-response
relationship in rats where there appears to be about a three-fold
difference between exposures that produce no lethality and those
resulting in 50-100% lethality. The AEGL-2 values also reflect the
application of uncertainty factors of 10 for interspecies variability
and 3 for intraspecies variability as described for the development of
AEGL-3 values.
Animal data consistent with AEGL-3 were limited to 30-min.
LC50 values for rats (118 ppm) and mice (285 ppm), a 45.5-
min. LClo value for rabbits (250 ppm), and 4-hr.
LC50 in rats (10 ppm). In addition to a 4-hr.
LC50 value for rats, Biodynamics (1988) also provided 4-hr.
LC16 estimate of 6.99 ppm and an estimated lethality
threshold (4 hrs) of 5.2 ppm for male and female rats. Data from a
study by BASF (1995), however,

[[Page 39277]]

showed that a single 6-hr exposure to 2.91 ppm resulted in 10% (1 of 10
rats) mortality and that a second exposure resulted in 50% mortality.
Remaining rats, however, survived an additional 26 6-hr. exposures. A
total uncertainty factor of 30 was applied. An uncertainty factor of 10
was applied to account for interspecies variability and justified due
to the absence of definitive quantitative lethality data in humans and
the uncertainties regarding the mechanism of iron pentacarbonyl-induced
lethality. An additional factor of 3 was applied to account for
uncertainties regarding individual variability in the toxic response to
iron pentacarbonyl. The adjustment for this area of uncertainty was
limited to 3 because the available data did not indicate a high level
of variability among test species and because the mechanism of action
for the observed toxic responses appears to be a port-of-entry effect
mediated by contact irritation and destruction of pulmonary epithelium.
The AEGL values for iron pentacarbonyl are presented in the table
below.
Neither quantitative nor qualitative data are available regarding
the potential carcinogenicity of iron pentacarbonyl by any route of
exposure. Therefore, a quantitative assessment of potential risk is not
possible. Genotoxicity tests in several strains of Salmonella
typhimurium were negative.

Summary of Proposed AEGL Values For Iron Pentacarbonyl [ppm (mg/m³)]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Endpoint
Classification 10 mins. 30 mins. 1 hr. 4 hrs. 8 hrs. (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) NR NR NR NR NR Not recommended;
insufficient data
AEGL-2 (Disabling) 1.2 (9.6) 0.40 (3.2) 0.19 (1.5) 0.050 (0.40) NA Based upon a three-
fold reduction in
the AEGL-3 values
AEGL-3 (Lethal) 3.5 (28) 1.2 (9.6) 0.58 (4.6) 0.15 (1.2) NA Estimated lethality
threshold in rats
(6-hr. exposure to
2.91 ppm) (BASF,
1995). n = 1; UF =
30 (10 for
interspecies
variability, 3 for
individual
variability)
--------------------------------------------------------------------------------------------------------------------------------------------------------
NR: Not recommended. Numeric values for AEGL-1 are not recommended because:
1. The lack of available data,
2. An inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or
3. The derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.
NA: Not appropriate; AEGL values for 8 hr. were not developed due to the rapid decomposition of iron pentacarbonyl under ambient atmospheric conditions.

2. References --i. BASF (Badische Anilin & Soda Fabrik). 1995.
Study on the inhalation toxicity of eisenpentacarbonyl as a vapor in
rats--28 day test. BASF Department of Toxicology. Environmental
Protection Agency/Office of Toxic Substances, Document #89-950000244.
ii. Biodynamics. 1988. An acute inhalation toxicity study of iron
pentacarbonyl in the rat. Final Report. Environmental Protection
Agency/Office of Toxic Substances, Document #88-920001300.

V. 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 2000.
The NAC/AEGL Committee will review and consider all public comments
received on this notice, with revisions to the ``Proposed'' AEGL values
as appropriate. The resulting AEGL values will be established as
``Interim'' AEGLs and will be forwarded to the NRC/NAS, for review and
comment. The ``Final'' AEGLs will be published under the auspices of
the NRC/NAS following concurrence on the values and the scientific
rationale used in their development.

List of Subjects

Environmental protection, Hazardous substances.

Dated: June 16, 2000.
Susan H. Wayland,
Acting Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 00-15916 Filed 6-22-00; 8:45 am]
BILLING CODE 6560-50-F

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

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