[Federal Register Volume 62, Number 210 (Thursday, October 30, 1997)]
[Notices]
[Pages 58840-58851]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-28642]
[[Page 58839]]
_______________________________________________________________________
Part IV
Environmental Protection Agency
_______________________________________________________________________
National Advisory Committee for Acute Exposure Guideline Levels for
Hazardous Substances; Notices
Federal Register / Vol. 62, No. 210 / Thursday, October 30, 1997 /
Notices
[[Page 58840]]
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ENVIRONMENTAL PROTECTION AGENCY
[OPPTS-00218; FRL-5737-3]
National Advisory Committee for Acute Exposure Guideline Levels
for Hazardous Substances
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
Acute Exposure Guideline Levels (AEGLs) on an on going basis to assist
Federal and State agencies and private sector organizations with their
needs for short-term hazardous chemical exposure information (one time
only exposures during chemical emergency situations). The NAC/AEGL
Committee has completed work on ``Proposed AEGLs'' for 12 chemicals.
The purpose of today's notice is to solicit comments on proposed values
and the accompanying scientific rationale for their development. More
specifically, this notice solicits comments on the proposed AEGL
values, the methodologies used to determine no-observed-adverse-effect-
levels (NOAELs) or lowest-observed-adverse-effect-levels (LOAELs) for
specific effects, the uncertainty factors selected for intraspecies and
interspecies extrapolation, the uncertainity factors used to
accommodate for sensitive or susceptible individuals in the human
population, the use of modifying factors and the values applied, and
other aspects related to the development of the AEGL values.
DATES: Submit written comments on or before December 1, 1997.
ADDRESSES: Submit three copies of written comments on the Proposed
AEGLs, identified by docket control number (OPPTS-00218; FRL- 5737-3)
to: Environmental Protection Agency, Office of Pollution Prevention and
Toxics (OPPT), Document Control Office (7407), Rm. G-009, 401 M St.,
SW., Washington, DC 20460.
Comments and data may also be submitted electronically to:
[email protected]. Follow the instructions under Unit V. of
this document. No Confidential Business Information (CBI) should be
submitted through e-mail.
All comments which contain information claimed as CBI must be
clearly marked as such. Three sanitized copies of any comments
containing information claimed as CBI must also be submitted and will
be placed in the public record for this notice. Persons submitting
information on any portion of which they believe is entitled to
treatment as CBI by EPA must assert a business confidentiality claim in
accordance with 40 CFR 2.203(b) for each such portion. This claim must
be made at the time that the information is submitted to EPA. If a
submitter does not assert a confidentiality claim at the time of
submission, EPA will consider this as a waiver of any confidentiality
claim and the information may be made available to the public by EPA
without further notice to the submitter.
FOR FURTHER INFORMATION CONTACT: Susan B. Hazen, Director,
Environmental Assistance Division (7408), Rm. ET-543B, Office of
Pollution Prevention and Toxics, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460; telephone: (202) 554-1404; TDD: (202)
554-0551; e-mail: TSCA-H[email protected].
SUPPLEMENTARY INFORMATION:
Electronic Availability
Internet
Electronic copies of this notice and various support documents are
available from the EPA Home Page at the Federal Register--Environmental
Documents entry for this document under ``Laws and Regulations''
(http://www.epa.gov/fedrgstr/).
Fax-On-Demand
Using a faxphone call (202) 401-0527 and select item 3800 for an
index of items in this category. For a more specific item number, see
the table in Unit IV. of this document.
I. Introduction
EPA's Office of Prevention, Pesticides and Toxic Substances (OPPTS)
provided notice on October 31, 1995 (60 FR 55376 (FRL-4987-3)) of the
establishment of the NAC/AEGL Committee with the objective stated in
the charter 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
using 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 May 21, 1997 (62 FR 27734 (FRL-5718-9)). This
list is intended to be expanded and also may be modified as priorities
of the stakeholder member organizations are further developed.
While the development of AEGLs for chemicals is not statutorily
based; at least one EPA rulemaking references their planned adoption.
In the final Clean Air Act and Amendment section 112 Risk Management
rulemaking (June 20, 1996, 61 FR 31685, (FRL-5516-5)), ``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 toxicity
reference for substances under this rule.'' Federal and State agencies
and private organizations may also adopt AEGLs for chemical emergency
programs in the future.
The NAC/AEGL Committee meets four times per year and plans to
develop AEGL values for 30-40 chemicals per year during the next 8 to
10 years. Since its first meeting on June 19-21, 1996, the NAC/AEGL
Committee has completed work on ``Proposed AEGLs'' for 12 chemicals.
The basic approach and guidance used to derive AEGLs has been the
National Academy of Sciences (NAS) publication, ``Guidelines for
Developing Community Emergency Exposure Levels for Hazardous
Substances'' (National Academy Press, Washington, DC, 1993; copies are
available in the Docket). The NAC/AEGL Committee meetings have been
public and numerous public comments and presentations have been made.
At this time, the NAC/AEGL Committee is providing further opportunity
for public input through this notice. Comments are welcome on both the
AEGL values and their related Technical Support Documents (filed in the
public Docket).
The NAC/AEGL Committee will review comments received and revise the
Proposed AEGLs as deemed appropriate. The resulting values will be
established as ``Interim AEGLs'' and will be available for use in
various public and private sector programs on human health effects
related to short-term exposures to hazardous chemicals. It is planned
that Interim AEGLs will be forwarded to the National Research Council,
National Academy of Sciences (NRC/NAS) for further review,
collaboration with the NAC/AEGL Committee, and possible revision of the
[[Page 58841]]
AEGL values and the methodologies used to derive them. It is
anticipated that ``Final AEGLs'' will be published under the auspices
of the NAS following concurrence on the values and the scientific
rationale used for their development. Until Final AEGLs are published
by the NAS, the Interim AEGLs are intended for use as needed by
individuals or organizations in both the public and private sectors.
II. Characterization of the AEGLs
The AEGLs represent short-term threshold or ceiling exposure values
intended for the protection of the general public, including
susceptible or sensitive individuals, but not hypersusceptible or
hypersensitive individuals. The AEGLs represent biological reference
values for this defined human population and consist of three
biological endpoints for each of four different exposure periods of 30
minutes (mins), l hour (hr), 4 hours (hrs), and 8 hrs. In certain
instances, AEGL values have been and will be developed for additional
exposure periods of 5 or 10 mins. The biological endpoints include
AEGL-1, AEGL-2, and AEGL-3 and are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per
millions (ppm) or milligrams (mg)/meters (m)3) of a
substance at or above which it is predicted that the general
population, including ``susceptible'' but excluding
``hypersusceptible'' individuals, could experience notable discomfort.
Airborne concentrations below AEGL-1 represent exposure levels that
could produce mild odor, taste, or other sensory irritations.
AEGL-2 is the airborne concentration (expressed as ppm or mg/
m3) of a substance at or above which it is predicted that
the general population, including ``susceptible'' but excluding
``hypersusceptible'' individuals, could experience irreversible or
other serious, long-lasting effects or impaired ability to escape.
Airborne concentrations below the AEGL-2 but at or above AEGL-1
represent exposure levels that may cause notable discomfort.
AEGL-3 is the airborne concentration (expressed as ppm or mg/
m3) of a substance at or above which it is predicted that
the general population, including ``susceptible'' but excluding
``hypersusceptible'' individuals, could experience life-threatening
effects or death. Airborne concentrations below AEGL-3 but at or above
AEGL-2 represent exposure levels that may cause irreversible or other
serious, long-lasting effects or impaired ability to escape.
III. Development of the AEGLs
The NAC/AEGL Committee develops the AEGL values on a chemical-by-
chemical basis. Relevant data and information are gathered from all
known sources including published scientific literature, State and
Federal agency publications, private industry, public data bases, and
individual experts in both the public and private sectors. All key data
and information are summarized for the NAC/AEGL Committee in draft form
by Oak Ridge National Laboratories and ``Draft AEGL'' values are
prepared in conjunction with designated 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
Draft AEGL values and the relevant data and information for each
chemical presented at the meeting, the NAC/AEGL Committee attempts to
reach a consensus on acceptable values. Once the NAC/AEGL Committee
reaches a consensus, the values are considered ``Proposed AEGLs.'' The
Proposed AEGL values and the accompanying scientific rationale for
their development are the subject of this notice.
In this notice the NAC/AEGL Committee publishes Proposed AEGL
values and the accompanying scientific rationale for their development
for 12 hazardous substances. These values represent the first exposure
levels proposed and published by the NAC/AEGL Committee. In developing
the proposed AEGL values, the NAC/AEGL Committee has followed the
methodology guidance ``Guidelines for Developing Community Emergency
Exposure Levels for Hazardous Substances,'' published by the National
Research Council of the National Academy of Sciences (NAS) in 1993
(copies of this guidance document are available for review in the
Docket). The term Community Emergency Exposure Levels (CEELs) used by
the NAS is synonymous with AEGLs in every way. The NAC/AEGL Committee
has adopted the term Acute Exposure Guideline Levels or AEGLs to better
connote the broad application of the values to the population defined
by the NAS in its guidance document and addressed by the NAC/AEGL
Committee in its development of the AEGLs. 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 proposed values and will
again seek consensus for the establishment of ``Interim AEGL'' values.
Although the Interim AEGL values will be available to Federal, State,
and local agencies and to organizations in the private sector as
biological reference values, it is intended to have them reviewed by a
subcommittee of the NAS. It has been planned to have the NAS
subcommittee participate in the peer review of the Interim AEGLs and in
the resolution of issues regarding the AEGL values and the data and
basic methodology used for setting AEGLs. It is anticipated that
``Final AEGL'' values will be published under the auspices of the NAS.
IV. List of Twelve Chemicals With Proposed AEGL Values
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Fax-On-Demand item
CAS No. Chemical name no.
------------------------------------------------------------------------
57-14-7......................... 1,1-Dimethylhydraz 3852
ine
60-34-4......................... Methylhydrazine 3853
62-53-3......................... Aniline 3854
75-21-8......................... Ethylene oxide 3861
302-01-2........................ Hydrazine 3891
540-59-0........................ 1,2-Dichloroethene 3895
540-73-8........................ 1,2-Dimethylhydraz 3852
ine
7697-37-2....................... Nitric acid 3912
7782-41-4....................... Fluorine 3915
7782-50-5....................... Chlorine 3916
7784-42-1....................... Arsine 3921
7803-51-2....................... Phosphine 3923
------------------------------------------------------------------------
Chemicals With Proposed AEGLs (Alphabetical Order)
Aniline
Aniline is an aromatic amine used chiefly in the chemical industry
in the manufacture of dyes, dye intermediates, rubber accelerators,
antioxidants, drugs, photographic chemicals, isocyanates, herbicides,
and fungicides. The primary effect of an acute exposure to aniline is
on the hemoglobin of the red blood cell, resulting in the formation of
methemoglobin. The effect may occur following inhalation, ingestion, or
cutaneous absorption. In addition to methemoglobinemia, chronic
exposures or exposures to high concentrations may produce signs and
symptoms of headache, paresthesia, tremor, pain,
[[Page 58842]]
narcosis/coma, cardiac arrhythmia, and possibly death.
All AEGL values are based on a study in which rats were exposed to
concentrations of 0, 10, 30, 50, 100, or 150 ppm for 8 hrs (Kim and
Carlson, 1986). The only reported effect was formation of
methemoglobin. At a constant concentration (100 ppm), the formation of
methemoglobin over time was basically linear, reaching an asymptote at
8 hrs.
The AEGL-1 was based on a concentration of 100 ppm for 8 hrs which
resulted in elevation of methemoglobin from a control value of 1.1%
(range, 0.4-2.1%) to 22%. This level of methemoglobin results in
clinical cyanosis but no hypoxic symptoms. Additional studies on oral
ingestion showed that humans are much more sensitive than rats to
aniline exposure as indicated by formation of methemoglobin. Thus, an
uncertainty factor of 10 was used for interspecies extrapolation.
Several sources also indicate that newborns are more sensitive to
methemoglobin-forming chemicals than adults; thus, an intraspecies
uncertainty factor of 10 was applied. The data were scaled across time
using C1 x t = k (the relationship between concentration of
aniline and methemoglobin formation at a fixed time [8 hrs] is linear
as is the relationship between time and severity of effect when
concentration is held constant; in addition, data from several
lethality [LC50] studies show that the relationship between
C and t is linear).
The AEGL-2 was based on the same study with rats in which a
concentration of 150 ppm for 8 hrs resulted in elevation of
methemoglobin from a control value of 1.1% to 41%. This level of
methemoglobin is associated with fatigue, lethargy, exertional dyspnea,
and headache in humans and was considered the threshold for disabling
effects. The 150 ppm concentration was divided by a combined
uncertainty factor of 100 and scaled across time using the same reasons
and relationships as for the AEGL-1 above. Because of the small data
base and the lack of recent, reliable human inhalation studies,
uncertainty factors of 10 were applied for each of the interspecies and
intraspecies variabilities.
Data on concentrations of aniline inducing methemoglobin levels at
the threshold for lethality were not available. Based on the fact that
the relationship between concentration of aniline and methemoglobin
formation is linear, the dose-response curve from the study on which
the AEGL-1 and AEGL-2 were based was extrapolated to a concentration
resulting in >70% formation of methemoglobin, the threshold for
lethality. The concentration of 250 ppm for 8 hrs was chosen as the
threshold for lethality. The AEGL-3 was based on dividing the 250 ppm
value by a combined uncertainty factor of 100 and scaled across time
using the same reasons and relationships as for the AEGL-1 above. The
uncertainty factors of 10 for each of the interspecies and intraspecies
variabilities are supported by the small data base of information and
the lack of recent, reliable human inhalation studies.
Studies with repeated exposures at approximately the same
concentrations in the rat resulted in additional effects on the blood
and spleen, but concentrations up to 87 ppm, 6 hrs/day, 5 days/week,
for 2 weeks were not disabling or life-threatening. The calculated
values are listed in the table below. Because aniline is absorbed
through the skin, a skin notation was added to the summary table.
Summary Table of Proposed AEGL Values for Aniline a
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 16 ppm (61 mg/m3) 8.0 ppm (30 mg/m3) 2.0 ppm (7.6 mg/m3) 1.0 ppm (3.8 mg/m3) 22% methemoglobin--
cyanosis (Kim and
Carlson, 1986)
AEGL-2 24 ppm (91 mg/m3) 12 ppm (46 mg/m3) 3.0 ppm (11 mg/m3) 1.5 ppm (5.7 mg/m3) 41% methemoglobin--
lethargy (Kim and
Carlson, 1986)
AEGL-3 40 ppm (152 mg/m3) 20 ppm (76 mg/m3) 5.0 ppm (19 mg/m3) 2.5 ppm (9.5 mg/m3) >70% methemoglobin--
lethality
(extrapolated from
data of Kim and
Carlson, 1986)
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aCutaneous absorption may occur; direct skin contact with the vapor or liquid should be avoided.
References
1. Kim, Y.C. and G.P. Carlson. 1986. The effect of an unusual
workshift on chemical toxicity. Part II. Studies on the exposure of
rats to aniline. Fundamental and Applied Toxicology 7:144-152.
Arsine
Arsine is an extremely toxic, colorless gas used in the
semiconductor industry. Exposure to arsine may also result from mining
and manufacturing processes involving arsenicals, and from paints and
herbicides containing arsenicals.
Arsine is a potent hemolytic agent, ultimately causing death via
renal failure. Numerous human case reports are available documenting
the extreme toxicity of arsine exposure but these reports lack
definitive quantitative exposure data.
Exposure-response data from animal studies were used to derive AEGL
values for arsine. AEGL values derived with animal data were more
conservative than AEGLs estimated from limited anecdotal human data.
The greater conservatism afforded by the animal data may be justified
by the incomplete and often equivocal data for human exposures, the
documented extreme toxicity of arsine, and the known latency involved
in arsine-induced lethality. The AEGL values for the various exposure
periods of concern (0.5, 1, 4, and 8 hrs) were scaled from the
experimental exposure duration using exponential scaling (C2
x t = k), where n = 2 represented an estimate of the concentration-time
relationship. 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 1 to 3.5 (ten
Berge et al 1986). The mid-point value of 2 was used as the exponent n
for scaling the AEGL values for arsine across time, because no exposure
versus time data were available.
Based upon the available data, derivation of AEGL-1 values was
considered to be inappropriate. The available human and animal data
affirm that there is little margin between exposures that result in
little or no signs of toxicity and those that result in lethality. The
mechanism of arsine toxicity (induction of hemolysis that may rapidly
result in renal failure and death), and the fact that toxicity in
animals and humans has been demonstrated at concentrations at or below
the odor threshold also support
[[Page 58843]]
such a conclusion by the NAC/AEGL Committee.
The AEGL-2 values were based upon exposure levels that did not
result in significant alterations in hematologic parameters in mice
exposed to arsine for 1 hr (Peterson and Bhattacharyya, 1985). AEGL-2
derivations based upon several data sets were similar, thereby
providing validation to the proposed AEGLs. Derivation of AEGLs based
upon limited data for humans resulted in values indicative of
potentially hazardous exposures. Uncertainty factor application
included a factor of 10 for interspecies variability because of
uncertainties regarding species-specific sensitivity to arsine-induced
hemolysis. Uncertainty regarding intraspecies variability was limited
to 3 because the hemolytic response to arsine is not expected to vary
greatly among individuals.
The AEGL-3 values were based upon data assessing the lethality in
mice exposed to arsine for 1 hr (Peterson and Bhattacharyya, 1985). A
total uncertainty factor application of 30 was applied as for AEGL-2
values and for the same reasons. Derivation of AEGL-3 values using
limited data in monkeys affirmed the values derived based upon the
mouse data. AEGL-3 values derived from limited human exposure data
resulted in levels considered potentially hazardous.
The three AEGL exposure levels reflect the narrow range between
exposures resulting in minor effects and those producing lethality. A
conservative approach in the development of AEGLs for arsine was
justified by the known steep dose-response curve, the induction of
hemolysis by arsine at extremely low concentrations, and the potential
of hemolysis to progress to life-threatening renal failure.
Summary of Proposed AEGL Values for Arsine
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Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. NAa................... NAa................... NAa.................. NAa.................. Inappropriate based
upon steep dose-
response
relationship,
mechanism of
toxicity, and
because toxicity
occurs at or below
the odor threshold
AEGL-2............................. 0.24 ppm (0.8 mg/m3).. 0.17 ppm (0.5 mg/m3).. 0.08 ppm (0.3 mg/m3). 0.06 ppm (0.3 mg/m3). Absence of
significant
hematological
alterations in mice
consistent with the
known continum of
arsine toxicity
(Peterson and
Bhattacharyya, 1985)
AEGL-3............................. 0.7 ppm (2.2 mg/m3)... 0.5 ppm (1.6 mg/m3)... 0.25 ppm (0.8 mg/m3). 0.18 ppm (0.6 mg/m3). Estimated threshold
for nonlethality in
mice (Peterson and
Bhattacharyya, 1985)
--------------------------------------------------------------------------------------------------------------------------------------------------------
a NA Not appropriate
References
1. Peterson, D.P. and Bhattacharyya, M.H. 1985. Hematological
responses to arsine exposure: quantitation of exposure response in
mice. Fundamental and Applied Toxicology 5:499-505.
Chlorine
Chlorine is a greenish-yellow, highly reactive halogen gas with a
pungent, suffocating odor. Like other halogens, chlorine does not occur
in the elemental state in nature; it rapidly combines with both
inorganic and organic substances. Chlorine is used in the manufacture
of a wide variety of chemicals, as a bleaching agent in industry and
household products, and as a biocide in water and waste treatment
plants.
Chlorine is an irritant to the eyes and respiratory tract; reaction
with moist surfaces produces hydrochloric and hypochlorous acids. Its
irritant properties have been studied in human volunteers and its acute
inhalation toxicity has been studied in several laboratory animal
species. The data from the human and laboratory animal studies were
sufficient for development of three AEGLs for four time periods (i.e.,
30 mins and 1, 4, and 8 hrs). Probit and regression analyses of the
animal exposure time-concentration-mortality data determined that the
relationship between concentration and time is approximately
C2 x t = k.
The AEGL-1 was based on the observation that exposure to human
volunteers, including a sensitive individual, of 0.5 ppm for 4 hrs
produced no sensory irritation but did result in transient changes in
some pulmonary function parameters for the sensitive individual (Rotman
et al., 1983). Because both sexes were tested and all subjects were
undergoing light exercise, making them more vulnerable to sensory
irritation, and because a sensitive individual was included in the
test, no uncertainty factor to account for differences in human
sensitivity was applied. The 0.5 ppm exposure for 4 hrs was scaled to
the other time periods using the relationship C2 x t = k.
The scaling factor n = 2 was based on probit and regression analyses of
animal lethality data.
The AEGL-2 values were derived based on the same study (Rotman et
al., 1983) in which healthy human subjects experienced transient
changes in pulmonary function measurements and a sensitive individual
experienced an asthmatic attack (shortness of breath and wheezing) at a
concentration of 1 ppm for 4 hrs. The sensitive individual remained in
the exposure chamber for the full 4 hrs. Because both sexes were tested
and all subjects were undergoing light exercise, making them more
vulnerable to sensory irritation, and because a sensitive individual
was included in the test, no uncertainty factor to account for
differences in human sensitivity was applied. The 4-hr 1 ppm
concentration was scaled to the other time periods using the
C2 x t = k relationship. The scaling factor or exponent of n
= 2 is based on probit and regression analyses of animal lethality
data.
In the absence of human data, the AEGL-3 values were based on
animal lethality data. Because the mouse was shown to be more sensitive
than other mammals to irritant gases including chlorine and does not
provide an appropriate basis for quantitatively predicting mortality in
humans, a value below that resulting in no deaths in the rat, 213 and
322 ppm in two studies (MacEwen and Vernot, 1972; Zwart and Woutersen,
1988) and above that resulting in no deaths in the mouse (150 ppm) for
exposure periods of 1 hr was chosen. Mice exposed to chlorine
experienced delayed deaths attributable to bronchopneumonia. The AEGL-3
values were derived from a 1-hr concentration of 200 ppm. This value
was divided by a combined uncertainty factor of 10. An uncertainty
factor of 3
[[Page 58844]]
was used to extrapolate from rats to humans, since interspecies values
for the same endpoint differed by a factor of approximately 2 within
each of several studies. An uncertainty factor of 3 was used to account
for differences in human sensitivity, since the toxic effect is due to
a chemical reaction with biological tissue of the respiratory tract
which is unlikely to be different among individuals. The AEGL-3 values
were scaled to the other exposure periods based on the C2 x
t = k relationship. The scaling factor or exponent of n = 2 is based on
probit and regression analyses of animal lethality data.
Based on the large data base and the extensive, well-conducted
studies, confidence in the AEGL values is high. The calculated values
are listed in the table below.
Summary of Proposed AEGL Values for Chlorine
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 1.4 ppm (4.1 mg/m3)... 1.0 ppm (2.9 mg/m3)... 0.5 ppm (1.5 mg/m3).. 0.5 ppm (1.5 mg/m3).. Pulmonary function--
human (Rotman et
al., 1983)
AEGL-2 2.8 ppm (8.1 mg/m3)... 2.0 ppm (5.8 mg/m3)... 1.0 ppm (2.9 mg/m3).. 0.7 ppm (2.0 mg/m3).. Asthmatic attack--
human (Rotman et
al., 1983)
AEGL-3 28 ppm (81 mg/m3)..... 20 ppm (58 mg/m3)..... 10 ppm (29 mg/m3).... 7.1 ppm (21 mg/m3)... Lethality--rat
(MacEwen and Vernot,
1972; Zwart and
Woutersen, 1988)
--------------------------------------------------------------------------------------------------------------------------------------------------------
References
1. MacEwen, J.D. and E.H. Vernot. 1972. Toxic Hazards Research
Unit Annual Technical Report: 1972. AMRL-TR-72-62, Aerospace Medical
Research Laboratory, Wright-Patterson Air Force Base, OH; National
Technical Information Service, Springfield, VA.
2. Rotman, H.H., M.J. Fliegelman, T. Moore, R.G. Smith, D.M.
Anglen, C.J. Kowalski, and J.G. Weg. 1983. Effects of low
concentration of chlorine on pulmonary function in humans. Journal
of Applied Physiology 54:1120-1124.
3. Zwart, A. and R.A. Woutersen. 1988. Acute inhalation toxicity
of chlorine in rats and mice: time-concentration-mortality
relationships and effects on respiration. Journal of Hazardous
Material 19:195-208.
1,2-Dichloroethene
1,2-dichloroethene is a flammable, colorless liquid existing in
both cis- and trans- forms and as a mixture of these two isomers. It
has been used as an intermediate in the production of chlorinated
solvents and as a low-temperature extraction solvent for decaffeinated
coffee, dyes, perfumes, lacquers, and thermoplastics. The compound is a
narcotic. Data on narcosis in humans, cats, rats, and mice, and
systemic effects in cats, rats, and mice were available for development
of AEGLs. The data were considered adequate for derivation of the three
AEGL classifications for four time periods.
The AEGL-1 was based on a human exposure concentration of 1,100 ppm
trans-1,2-dichloroethene for 5 mins (Lehmann and Schmidt-Kehl 1936).
Although this is a no-effect-level for narcotic effects it represents a
concentration that is above the odor threshold. Because of the mode of
action and similarity in response to this chemical as an irritant, this
value was divided by an uncertainty factor of 3 to protect sensitive
individuals and by a modifying factor of 2 to account for the probable
difference in toxicity between the cis- and trans- isomers. It was then
scaled to the 30-min, 1-, 4-, and 8-hr exposures using the
cn x t = k relationship, where n = 2. 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 1 to 3.5 (ten Berge et al 1986). Because no
exposure versus time data were available, the mid-point value of 2 was
used as the exponent n for scaling the AEGL values for dichloroethene
across time.
The AEGL-2 was based on slight dizziness in humans exposed to 3300
ppm trans-1,2-dichloroethene for 5 mins (Lehmann and Schmidt-Kehl
1936). Because of the mode of action and similarity in response to this
chemical, this value was divided by an uncertainty factor of 3 to
protect sensitive individuals and by a modifying factor of 2 to account
for the probable difference in toxicity between the cis- and trans-
isomers. It was then scaled up to the 30-minute (min), 1-, 4-, and 8-hr
exposure periods using the cn x t = k relationship, where
the mid-point of the exponential range n = 2 was used.
The AEGL-3 was based on fibrous swelling and hyperemia of cardiac
muscle with little striation in rats exposed to 3000 ppm trans-1,2-
dichloroethene for 8 hrs. Because the lethality data are limited and
quite variable across species for the data that do exist this value was
divided by an uncertainty factor of 10 to account for interspecies
variation. An additional uncertainty factor of 3 was applied to protect
sensitive individuals and a modifying factor of 2 was also applied to
account for the probable difference in toxicity between the cis- and
trans- isomers. The 8-hr AEGL value was then scaled to the 30-min, 1-,
and 4-hr exposures using the cn x t = k relationship, where
the midpoint of the experimental range n = 2 was used. The calculated
values are listed in the table below.
Summary of Proposed AEGL Values for 1,2-Dichloroethene
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) 19 ppm (75 mg/m3) 13 ppm (53 mg/m3) 6.6 ppm (26 mg/m3) 4.7 ppm (19 mg/m3) No effect in humans
(Lehmann and Schmidt-
Kehl, 1936)
AEGL-2 (Disabling) 56 ppm (224 mg/m3) 40 ppm (160 mg/m3) 20 ppm (80 mg/m3) 14 ppm (56 mg/m3) Slight dizziness in
humans (Lehmann and
Schmidt-Kehl, 1936)
[[Page 58845]]
AEGL-3 (Lethality) 200 ppm (800 mg/m3) 141 ppm (564 mg/m3) 71 ppm (284 mg/m3) 50 ppm (200 mg/m3) Fibrous swelling and
hyperemia of cardiac
muscle with poorly
maintained striation
in rats (Freundt et
al., 1977)
--------------------------------------------------------------------------------------------------------------------------------------------------------
References
1. Freundt, K.J., Liebalt, G.P., and Lieberwirth, E. 1977.
Toxicity studies on trans-1,2-dichloroethylene. Toxicology 7:141-
153.
2. Lehmann, K.B. and Schmidt-Kehl, L. 1936. The thirteen most
important chlorinated aliphatic hydrocarbons from the standpoint of
industrial hygiene. Archive Fur Hygiene 116:9-268.
3. 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.
1,1- and 1,2-Dimethylhydrazine
Dimethylhydrazine occurs as a symmetrical (1,2-dimethylhydrazine)
and asymmetrical (1,1-dimethylhydrazine) isomer. Both compounds are
clear, colorless liquids. Asymmetrical dimethylhydrazine (1,1-
dimethylhydrazine) is a component of jet and rocket fuels and is also
used as an absorbent for acid gas, as a plant growth control agent, and
in chemical synthesis. Although it has been evaluated as a high-energy
rocket fuel, commercial use of the symmetrical isomer (1,2-
dimethylhydrazine) is limited to small quantities and it is usually
considered to be a research chemical. Because data are limited for 1,2-
dimethylhydrazine (symmetrical dimethylhydrazine), the AEGL values are
based upon 1,1-dimethylhydrazine (asymmetrical). Limited data suggest
that1,1-dimethylhydrazine may be somewhat more toxic than 1,2-
dimethylhydrazine.
Data on acute exposures of humans to both isomers of
dimethylhydrazine are limited to case reports of accidental exposures.
Signs and symptoms of exposure include respiratory irritation,
pulmonary edema, nausea, vomiting, and neurological effects. However,
definitive exposure data (concentration and duration) were unavailable
for these exposures.
Toxicity data of varying degrees of completeness are available for
several laboratory species, including, rhesus monkeys, dogs, rats,
mice, and hamsters (Weeks et al., 1963). Most of the animal studies
were conducted using 1,1-dimethylhydrazine, although limited data
suggest that 1,2-dimethylhydrazine exerts similar toxic effects. Minor
nonlethal effects such as respiratory tract irritation appear to occur
at cumulative exposures of <100 (ppm)(hrs). At cumulative exposures at
or only slightly greater than 100 (ppm)(hrs), more notable effects have
been reported, including, muscle fasciculation, behavioral changes,
tremors, and convulsions. At only slightly higher exposure levels,
lethality has been demonstrated. The available data suggest that there
is very little margin between exposure levels resulting in no
significant toxicity and those causing substantial lethality
(LC50 900-2,000 ppm hrs).
Developmental toxicity of dimethylhydrazines has been demonstrated
in rats following parenteral administration of maternally toxic doses.
Both isomers of dimethylhydrazine have been shown to be carcinogenic in
rodents following oral exposure and 6-month inhalation to 1,1-
dimethylhydrazine resulted in an increased tumor response in mice,
although these findings are compromised by the contaminant
dimethylnitrosamine. Inhalation slope factors are currently
unavailable. It was the consensus of the NAC/AEGL Committee that AEGL-1
values for dimethylhydrazine are inappropriate. This conclusion was
based upon the onset of toxic effects at or below the odor threshold,
and a concentration-response relationship for dimethylhydrazine that
indicated little margin between exposures producing no toxic response
and those resulting in significant toxicity.
Behavioral changes and muscle fasciculations in dogs exposed for 15
mins to 360 ppm 1,1-dimethylhydrazine (Weeks et al., 1963) served as
the basis for deriving AEGL-2 values. Following temporal scaling
(C1 x t = k) to AEGL-specific exposure durations, the values
were adjusted by an uncertainty factor of 30. An uncertainty factor of
3 for interspecies variability was applied because the toxic response
to dimethylhydrazine was similar across the species tested. An
uncertainty factor of 10 for intraspecies variability was applied
because of the uncertainties regarding the mechanism of action of
dimethylhydrazine toxicity and its impact on susceptible individuals.
The AEGL-3 was derived from the 1-hr LC50 (981 ppm) for
1,1-dimethylhydrazine in dogs (Weeks et al., 1963). Because of the
steep slope of the dose-response curve of 1,1-dimethyl hydrazine, a
modifying factor of 3 was applied to the 1-hr LC50 of 981
ppm. Hence, the modified lethality threshold used to determine the
AEGL-3 was 327 ppm. The downward adjustment of the LC50
using a modification factor of 3 was considered a conservative approach
and, in part, justified the total uncertainty factor of 30 (3 for
interspecies variability and 10 for intraspecies variability). An
uncertainty factor of 3 for interspecies variability was applied
because the toxic response to dimethylhydrazine was similar across the
species tested. An uncertainty factor of 10 for intraspecies
variability was applied because of the uncertainties regarding the
mechanism of action of dimethylhydrazine toxicity and its potential
impact on susceptible individuals. Temporal scaling as previously
described was applied to obtain exposure values for AEGL-specific
exposure periods.
An estimation of AEGLs based upon carcinogenic potential resulting
from a one time, short term exposure was conducted and the assessment
revealed that AEGLs derived from carcinogenic toxicity for a
10-4 carcinogenic risk exceeded AEGL-3 values based on non
cancer endpoints. The relationship of the various AEGL values reflects
the exposure-response relationship shown by available animal data.
[[Page 58846]]
Summary of Proposed AEGL Values for 1,1- and 1,2-Dimethylhydrazines
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. NAb................... NAb................... NAb.................. NAb.................. Inappropriate because
notable toxicity may
occur at
concentrations below
the odor threshold;
concentration-
response
relationships
suggest little
margin between
exposures causing
minor effects and
those resulting in
serious toxicity.a
AEGL-2............................. 6 ppm (14.7 mg/m3) 3 ppm (7.4 mg/m3) 0.8 ppm (2 mg/m3) 0.4 ppm (1 mg/m3) Behavioral changes
and muscle
fasciculations in
dogs exposed to 360
ppm for 15 mins
(Weeks et al., 1963)
AEGL-3............................. 22 ppm (54 mg/m3) 11 ppm (27 mg/m3) 3 ppm (7.4 mg/m3) 1.5 ppm (3.7 mg/m3).. Lethality threshold
of 327 ppm for 1-hr
estimated from 1-hr
LC50 in dogs (Weeks
et al., 1963)
--------------------------------------------------------------------------------------------------------------------------------------------------------
aRefer to AEGL-1 for hydrazine if hydrazine is also present.
bNA Not appropriate
References
1. Weeks, M.H., Maxey, G.C., Sicks, and Greene, E.A. 1963. Vapor
toxicity of UDMH in rats and dogs from short exposures. American
Industrial Hygiene Association Journal 24:137-143.
Ethylene Oxide
Ethylene oxide is a highly flammable gas produced in very large
quantities in the United States (5.3-6.3 billion pounds). It is very
reactive with nucleophiles, such as water, alcohols, halides, amines,
and sulfhydryl compounds. Ethylene oxide is used as an intermediate in
the production of ethylene glycol and nonionic surfactants; a small
amount is used as a fumigant for sterilizing foods and heat-sensitive
medical equipment. The odor detection level for ethylene oxide is 260
ppm (468 mg/m3) to 700 ppm (1,260 mg/m3).
The database of toxicity to ethylene oxide vapor in humans and
experimental animals is very extensive including data on all aspects of
toxicity except lethality in humans. Pharmacokinetics data show that
ethylene oxide is readily absorbed from the respiratory tract of both
humans and animals. It alkylates proteins and DNA, and it is
metabolized by hydrolysis and glutathione conjugation.
In humans, inhaled ethylene oxide vapor affects the eyes,
respiratory tract, central and peripheral nervous systems,
gastrointestinal tract (probably secondary effects to nervous system
toxicity), hematopoietic system, and possibly the reproductive system,
and fetus. Acute exposure to ethylene oxide at the odor detection level
(260 ppm) causes eye and upper respiratory tract irritation
and signs and symptoms of effects on the central and peripheral nervous
system. Acute exposure to a calculated concentration of 500 ppm for 2
to 3 minutes caused hematologic effects and more severe effects on the
central nervous system than those noted at the odor detection level.
Effects observed after acute exposure are reversible, including severe
nervous system effects. Peripheral nervous damage is exacerbated by
repeated exposures. Human studies have provided suggestive evidence of
reproductive toxicity, some evidence of an association between exposure
to ethylene oxide and genetic damage to somatic cells and limited
evidence of carcinogenicity.
Acute lethality studies in experimental animals showed that mice
are the most sensitive species (4-hrs LC50 = 660-835 ppm)
(Jacobson et al., 1956), followed by the dog (4-hrs LC50 =
960 ppm) (Jacobson et al., 1956) and rat (4-hrs LC50 = 1537-
1972 ppm; 1-hr LC50 = 4439-5748 ppm) (Jacobson et al.,
1956). Immediate deaths were due to respiratory failure and delayed
deaths were due to secondary respiratory infections. Experimental
animals exposed to lethal and nonlethal concentrations of ethylene
oxide showed evidence of eye and respiratory irritation and effects on
the central and peripheral nervous system (Embree et al., 1977).
Additional studies in animals exposed to ethylene oxide for various
durations up to 6 hrs/day provided evidence of reproductive toxicity at
50 ppm, developmental toxicity at 50 ppm, genetic
toxicity in germ cells at 75 ppm, and carcinogenicity at 100
ppm.
Data were available for deriving AEGL-2 and -3 values. Values for
AEGL-1 were not derived because the odor threshold and concentrations
causing mild sensory irritation would be above the AEGL-2 levels.
The AEGL-2 values were based on a rat study showing central nervous
system depression, diarrhea, and eye and respiratory tract irritation
after exposure to 1,000 ppm of ethylene oxide for 4 hrs (Embree et al.,
1977); genetic toxicity (dominant lethality) was also seen at this
concentration in this same study. An uncertainty factor of 10 was
applied for intraspecies variability, because of the steep slope of the
dose response relationship from severe irritation and central nervous
system depression to the lethality threshold. An uncertainty factor of
3 was applied for interspecies sensitivity, because modes of action are
likely to be similar between rodents and humans and systemic uptake of
ethylene oxide is similar across species. The time-scaling approach
used ten Berge's equation in which Cn t = k, and n = 1.2
based on analysis of rat lethality data.
AEGL-3 values were derived from lethality data in the rat. An
LC01 value (628 ppm), which is considered an approximation
of the lethality threshold, was estimated from data in a 4-hr acute
inhalation study with rats reported by Jacobson et al. (1956). An
uncertainty factor of 10 for intraspecies sensitivity was applied to
the LC01 estimated value and this was followed by scaling to
the different AEGL exposure periods based on ten Berge's equation
(Cn t = k, where n = 1.2 was used based on reported
lethality data for 1- and 4-hr exposures). An interspecies uncertainty
factor of 3 was applied because systemic uptake, distribution, and
modes of action are likely to be similar between rodents and humans.
There are differences in metabolism kinetics, but they are unlikely to
affect responses to high acute exposures. Assessment of carcinogenicity
data (lung adenomas/carcinomas in female mouse) (NTP, 1987) showed that
extrapolating the total cumulative exposure over a 2-year period to
single exposures and estimating a 10-4 risk resulted in
AEGL-3 values of 2,764, 1,382, 346, and 173 ppm for 0.5-, 1-, 4-, and
8-hr exposures. These values exceed those derived from lethality data.
[[Page 58847]]
AEGL values derived for ethylene oxide are summarized below:
Summary of Proposed AEGL Values for Ethylene Oxide
--------------------------------------------------------------------------------------------------------------------------------------------------------
Exposure Periods
Classification ---------------------------------------------------------------------------------------------- Endpoint (Reference)
30-minute 1-hour 4-hour 8-hour
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. No values derived No values derived No values derived No values derived
AEGL-2............................. 190 ppm (342 mg/m3) 110 ppm (198 mg/m3) 33 ppm (59 mg/m3) 19 ppm (34 mg/m3) Central nervous
system effects
Embree et al., 1977
AEGL-3............................. 360 ppm (648 mg/m3) 200 ppm (360 mg/m3) 63 ppm (113 mg/m3) 35 ppm (63 mg/m3) Lethality threshold
Jacobson et al.,
1956
--------------------------------------------------------------------------------------------------------------------------------------------------------
References
1. Embree, J.W., Lyon, J.P., and Hine, C.H. 1977. The mutagenic
potential of ethylene oxide using the dominant-lethal assay in rats.
Toxicology and Applied Pharmacology 40:261-267.
2. Jacobson, K.H., Hackley, E.B., and Feinsliver, L. 1956. The
toxicity of inhaled ethylene oxide and propylene oxide vapors.
Archive for Industrial Health 13:237-244.
Fluorine
Fluorine is a reactive, highly irritant gas used in the nuclear
energy industry, as an oxidizer of liquid rocket fuels, and in the
manufacture of various fluorides and fluorocarbons. Fluorine is a
severe irritant to the eyes, mucous membranes, lungs, and skin; the
eyes and the respiratory tract are the target organ/tissues of an acute
exposure. Data on irritant effects in humans and lethal and sublethal
effects in five species of mammals (dog, rat, mouse, guinea pig, and
rabbit) were available for development of AEGLs (Keplinger and Suissa,
1968). Regression analyses of the concentration-exposure durations (for
the fixed endpoint of mortality) for all of the animal species reported
determined that the relationship between concentration and time is
Cn x t = k, where n = approximately 2 (actual value for n
for the most sensitive species, the mouse = 1.77). The data were
considered adequate for derivation of the three AEGL classifications
for four time periods.
The AEGL-1 was based on the observation that human volunteers could
tolerate exposure to 10 ppm for 15 mins without irritant effects
(Keplinger and Suissa, 1968). An uncertainty factor of 3 was applied to
this NOAEL value to protect sensitive individuals, since fluorine
reacts corrosively with the tissues of the respiratory tract and
effects are not likely to differ greatly among individuals, including
sensitive individuals. The value was then scaled to the 30-min and 1-,
4-, and 8-hr exposure durations using the C1.77 x t = k
concentration-exposure duration relationship. It was the consensus of
the NAC/AEGL Committee that at mildly irritating concentrations there
is a tolerance to irritating gases. Therefore, the calculated 30-min
and 1-hr values of 2.3 and 1.5 ppm, respectively, were rounded to 2 ppm
and the calculated 4- and 8-hr values of 0.7 and 0.5 ppm, respectively,
were rounded to 1 ppm.
The AEGL-2 was based on an animal study in which mild lung
congestion was observed in mice at 67 ppm for 30 mins and 30 ppm for 60
mins (Keplinger and Suissa, 1968). Although concentrations causing
irritant effects for each species for the same time periods suggested
similar species sensitivity, the mouse data, because of slightly lower
values, were chosen as the basis for developing the AEGL-2 and AEGL-3.
Because the action of irritant and corrosive gases is directly on the
tissues, with no pharmacokinetic component involved in the toxicity,
there is likely to be little difference among species in response to
fluorine exposure. Because similar sensitivity was observed among all
species in the key study, no uncertainty factor for interspecies
variability was applied. The values were divided by an intraspecies
uncertainty factor of 3 to protect sensitive individuals, since effects
are not likely to differ greatly among individuals. The values also
were adjusted by a modifying factor of 2, based on a limited data base.
AEGL-2 values for the other exposure periods were scaled based on the
C1.77 x t = k relationship.
The AEGL-3 values were derived from exposure concentrations equal
to one half of the LC50 values reported (Keplinger and
Suissa, 1968). The experimental \1/2\ LC50 concentrations
tested resulted in no deaths in any species for up to 45 days post
exposure, but did produce severe lung congestion in the mouse
(Keplinger and Suissa, 1968). For the mouse, the 60-min value was 75
ppm. Because of the similar species sensitivity in the key study, no
uncertainty factor for interspecies variability was applied. The values
were divided by an uncertainty factor of 3 to protect sensitive
individuals and by a modifying factor of 2, based on a limited data
base. AEGL-3 values for the other exposure times were calculated based
on the C1.77 x t = k relationship.
The calculated values are listed in the table below.
Summary of Proposed AEGL Values for Fluorinea
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. 2ppm (3.1 mg/m3) 2 ppm (3.1 mg/m3) 1 ppm (1.6 mg/m3) 1 ppm (1.6 mg/m3) No irritant effect-
humans (Keplinger
and Suissa, 1968)
AEGL-2b............................ 11 ppm (17 mg/m3)..... 5.0 ppm (7.8 mg/m3)... 2.3 ppm (3.6 mg/m3).. 1.5 ppm (2.3 mg/m3).. Mild lung congestion--
mice (Keplinger and
Suissa, 1968)
AEGL-3............................. 19 ppm (29 mg/m3)..... 13 ppm (20 mg/m3)..... 5.7 ppm (8.8 mg/m3).. 3.9 ppm (6.0 mg/m3).. Severe lung
congestion--mice
(Keplinger and
Suissa, 1968)
--------------------------------------------------------------------------------------------------------------------------------------------------------
a AEGL-1 values were rounded off because of tolerance to low concentrations of irritant gases. AEGL-2 and AEGL-3 values were rounded to two significant
figures.
b30-min and 1-hr AEGL-2 values are based on separate data points.
[[Page 58848]]
References
1. Keplinger, M.L. and L.W. Suissa. 1968. Toxicity of fluorine
short-term inhalation. American Industrial Hygiene Association
Journal 29:10-18.
Hydrazine
Hydrazine is a highly reactive reducing agent used in various
chemical manufacturing processes. Hydrazine is used by the military as
a missile and rocket propellant, and in power sources.
Human data on the toxicity of hydrazine following acute inhalation
exposure are limited to anecdotal accounts that lack definitive
exposure data. The utility of this information is compromised by
concurrent exposure to other chemicals and involvement of simultaneous
multiple exposure routes.
Studies have shown that the toxicity of methylated derivatives of
hydrazine is qualitatively similar to that of hydrazine except in dogs
wherein methylhydrazine has been observed to cause intravascular
hemolysis. Based upon limited acute toxicity data, methylhydrazine and
symmetrical dimethylhydrazine appear to be somewhat more toxic in rats
and mice than is hydrazine while asymmetrical hydrazine appears to be
slightly less toxic.
Data from animal studies indicate that hydrazine may be metabolized
to acetylhydrazine, diacetylhydrazine, ammonia, and urea, and may form
hydrazones with pyruvate and 2-oxoglutarate. The biotransformation of
hydrazine is mediated, at least in part, by hepatic monooxygenases. The
role of metabolism and absorption/excretion kinetics is uncertain
regarding immediate port-of-entry toxic effects from acute inhalation
exposures. The highly reactive nature of hydrazine per se is a
plausible determinant of acute port-of-entry toxic effects.
AEGLs were based upon data sets defining toxicity endpoints that
were specific for the AEGL level. Values for the specific exposure
durations were derived based upon exponential scaling (Cn x
t = k, where n = 2) from the experimental exposure period. This method
was more appropriate for concentration-dependent effects than linear
(Haber's Law) scaling. 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 1 to 3.5
(ten Berge et al 1986). Because no exposure versus time data were
available, the mid-point value of 2 was used as the exponent n for
scaling the AEGL values for hydrazine across time.
AEGL-1 values were based upon a study by House (1964) in which male
monkeys exhibited skin flushing and eye irritation after a 24-hr
continuous exposure to 0.4 ppm hydrazine. A total uncertainty factor of
10 was applied to derive the AEGL-1 values.1 An uncertainty
factor of 3 was applied for interspecies variability because the
contact irritation response to the highly reactive hydrazine is not
likely to vary greatly among species, and because a nonhuman primate
was the test species. An uncertainty factor of 3 was applied for
intraspecies variability because the contact irritation from the highly
reactive hydrazine is not expected to vary greatly among individuals.
The 24-hr experimental value was scaled to 8 hrs using Cn x
t = k, where n = 2 as described above. Because hydrazine is extremely
reactive and the effects are considered to be concentration dependent
rather than time dependent, the 0.1 ppm AEGL-1 value derived for the 8-
hr duration was also applied to the 30-min, 1-hr, and 4-hr durations.
---------------------------------------------------------------------------
1 Each uncertainty factor of 3 is actually the geometric mean of
10 which is 3.16, hence 3.16 x 3.16 = 10.
---------------------------------------------------------------------------
The AEGL-2 was derived based upon data from a study by Latendresse
et al. (1995) in which rats exposed to hydrazine (750 ppm) for 1 hr
exhibited nasal lesions. Following a dosimetric adjustment based upon
regional gas dose (U.S. EPA 1994), the values were scaled to AEGL-
specific durations as for AEGL-1 and a total uncertainty factor of 30
applied. An uncertainty factor of 10 for interspecies variability was
applied to account for a deficiency in data pertaining to species
variability and also variability in the data that are available. An
uncertainty factor of 3 was applied for intraspecies variability
because the toxic response to hydrazine is not likely to vary
considerably among individuals of the same species, including
susceptible individuals.
The AEGL-3 values were derived based upon a rat inhalation study
(HRC, 1993) that provided data to estimate a lethality threshold
(LC01 = 337 ppm). Temporal scaling was again applied using
the exponential expression C2 x t = k. Dosimetric conversion
using a regional gas dose methodology (U.S. EPA 1994) was applied and
resulting exposure values adjusted by a total uncertainty factor of 30.
An uncertainty factor of 10 for interspecies variability was applied to
account for a deficiency in data pertaining to species variability and
also variability in the data that are available. An uncertainty factor
of 3 was applied for intraspecies variability because the toxic
response to hydrazine is not likely to vary considerably among
individuals of the same species.
An estimation of AEGLs based upon carcinogenic potential resulting
from a one-time, short term exposure was conducted using the inhalation
cancer slope factor for hydrazine. The assessment revealed that AEGLs
derived from noncarcinogenic toxicity endpoints were lower values and
so the AEGL-3 values were based on the noncarcinogenic endpoint.
The proposed AEGLs, their respective toxicity endpoints and
references are summarized below.
Summary of Proposed AEGL Values for Hydrazine
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. 0.1 ppm (0.1 mg/m3)... 0.1 ppm (0.1 mg/m3)... 0.1 ppm (0.1 mg/m3).. 0.1 ppm (0.1 mg/m3).. Eye and facial
irritation inmonkeys
(House, 1964)a
AEGL-2............................. 8 ppm (10 mg/m3)...... 6 ppm (8 mg/m3)....... 3 ppm (4 mg/m3)...... 2 ppm (3 mg/m3)...... Nasal lesions
(Latendresse et al.,
1995)
AEGL-3............................. 47 ppm (61 mg/m3)..... 33 ppm (43 mg/m3)..... 17 ppm (22 mg/m3).... 12 ppm (16 mg/m3).... Lethality in rats
(HRC, 1993)
--------------------------------------------------------------------------------------------------------------------------------------------------------
a Because the contact irritation response to the extremely reactive hydrazine is concentration dependent rather than time-dependent, the AEGL-1 is the
same of all time periods.
[[Page 58849]]
References
1. House, W.B. 1964. Tolerance criteria for continuous exposure
inhalation exposure to toxic materials. Part III. Effects on animals
of 90-day exposure to hydrazine, unsymmetrical dimethylhydrazine
(UMDH), decaborane, and nitrogen dioxide. ASD-TR-61-519 (iii).
Wright-Patterson AFB, OH. 84 pp.
2. HRC (Huntington Research Centre, Ltd.). 1993. Hydrazine 64%
aqueous solution: acute inhalation toxicity in rats 1-hr exposure.
Huntington Research Centre, Cambridge, England. CMA 8/930523.
3. Latendresse, J.R., Marit, G.B., Vernot, E.H., Haun, C.C., and
Flemming, C.D. 1995. Oncogenic potential of hydrazine in the nose of
rats and hamsters after 1 or 10 1-hr exposures. Fundamental and
Applied Toxicology 27:33-48.
4. 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.
5. U.S. EPA 1994. EPA/600/8-90/066F, Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation
Dosimetry.
Methylhydrazine
Methylhydrazine is a clear, colorless liquid used extensively in
military applications as a missile and rocket propellant, in chemical
power sources, and as a solvent and chemical intermediate. Upon contact
with strong oxidizers (e.g., hydrogen peroxide, nitrogen tetroxide,
chlorine, and fluorine) spontaneous ignition may occur.
Human volunteers exposed to 90 ppm methylhydrazine for 10 mins
reported minor irritation as the only effect of exposure (MacEwen et
al., 1970).
Toxicity data are available for multiple laboratory species
including, rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice,
and hamsters. Nonlethal toxic effects include irritation of the
respiratory tract, hemolytic responses, and some evidence of renal and
hepatic toxicity. Lethal exposures are usually preceded by convulsions.
Lethal toxicity varies somewhat among species. One-hour LC50
values of 162, 82, 96, 244, 122, and 991 ppm have been determined for
rhesus monkeys, squirrel monkeys, beagle dogs, rats, mice, and
hamsters, respectively. Concentration-time relationships appear to
follow Haber's Law although there appears to be a critical threshold
for lethality with little margin between exposures causing only minor,
reversible effects, and those resulting in lethality.
In a 1-year inhalation bioassay using dogs, rats, mice, and
hamsters, methylhydrazine concentrations of 2 ppm and 5 ppm, there was
no evidence of treatment-related carcinogenicity in dogs or rats even
after a 1-year post exposure observation period. However, mice exposed
to 2 ppm for the same duration exhibited an increased incidence of lung
tumors, nasal adenomas, nasal polyps, nasal osteomas, hemangioma, and
liver adenomas and carcinomas. In hamsters exposed to 2 or 5 ppm, there
was an increase in nasal polyps and nasal adenomas (5 ppm only),
interstitial fibrosis of the kidney, and benign adrenal adenomas.
It was the consensus of the NAC/AEGL Committee that the setting of
AEGL-1 values for methylhydrazine would be inappropriate. This
conclusion was based on the occurrence of toxic effects at or below the
odor threshold, and a concentration-response relationship for
methylhydrazine that indicated little margin between exposures
producing no toxic response and those resulting in significant
toxicity.
The AEGL-2 values were derived by applying a modifying factor of 3
to each of the AEGL-3 values. This estimate of a threshold for
irreversible effects was justified because of the absence of exposure-
response data related to irreversible or other serious, long-lasting
effects and the steep dose-response relationship indicated by the data
that was available on methylhydrazine. For AEGL-3, lethality data (1-hr
LC50 of 82 ppm) for squirrel monkeys (Haun et al., 1970) was
adjusted using a modifying factor of 3 to estimate a lethality
threshold (27 ppm). The lethality data for the species tested indicated
a linear relationship between concentration and time. Therefore,
temporal scaling to obtain time-specific AEGL values was described as
C1 x t = k where the exponent n = 1. The derived exposure
values were adjusted by a total uncertainty factor of 10. An
uncertainty factor of 3 was applied for interspecies variability
because a sensitive nonhuman primate was used to estimate the lethality
threshold, and an uncertainty factor of 3 was used for intraspecies
variability due to the steep exposure-response
relationship.2
---------------------------------------------------------------------------
2Each uncertainty factor of 3 is the geometric mean of 10 which
is 3.16; hence, 3.16. x 3.16 = 10.
---------------------------------------------------------------------------
The AEGL values reflect the steep exposure-response relationship
exhibited by the toxicity data. Additional information regarding the
mechanism(s) of action and metabolism of methylhydrazine may provide
insight into understanding and defining the threshold between nonlethal
and lethal exposures.
An estimation of AEGLs based upon carcinogenic potential resulting
from a one-time, short-term exposure was conducted and the assessment
revealed that AEGLs derived from carcinogenic toxicity for a
10-4 carcinogenic risk exceeded AEGL-3 values based on non
cancer endpoints.
Summary of Proposed AEGL Values for Methylhydrazine
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. NA.................... NA.................... NA................... NA................... Inappropriate because
notable toxicity may
occur at
concentrations below
the odor threshold;
concentration-
response
relationships
suggest little
margin between
exposures causing
minor effects and
those resulting in
serious toxicity.a
AEGL-2............................. 2 ppm (3.8 mg/m3) 1 ppm (1.9 mg/m3) 0.2 ppm (0.4 mg/m3) 0.1 ppm (0.2 mg/m3) Three-fold reduction
in AEGL-3.
AEGL-3............................. 6 ppm (11.3 mg/m3) 3 ppm (5.6 mg/m3) 0.7 ppm (1.1 mg/m3) 0.3 ppm (0.6 mg/m3) 1-hr LC50 of 82 ppm
reduced 3-fold to
estimate a lethality
threshold; UF-10
--------------------------------------------------------------------------------------------------------------------------------------------------------
a Refer to AEGL-1 for hydrazine if hydrazine is also present.
[[Page 58850]]
References
1. Haun, C.C., MacEwen, J.D., Vernot, E.H., and Egan, G.F. 1970.
Acute inhalation toxicity of monomethylhydrazine vapor. American
Industrial Hygiene Association Journal 31:667-677.
2. MacEwen, J.D., Theodore, J., and Vernot, E.H. 1970. Human
exposure to EEL concentrations of monomethylhydrazine. Proceedings.
First Annual Conference on Environmental Toxicology. AMRL-TR-70-102,
Aerospace Medical Research Laboratory, Wright-Patterson Air Force
Base, OH.
Nitric Acid
Nitric acid is a highly corrosive, strongly oxidizing acid. The
course of toxicity following inhalation exposure to nitric acid is
consistent between humans and animals. Nitric acid fumes may cause
immediate irritation of the respiratory tract, pain, and dyspnea which
are followed by a period of recovery that may last several weeks. After
this time, a relapse may occur with death caused by bronchopneumonia
and/or pulmonary fibrosis. For exposure to nonlethal concentrations,
allergic or asthmatic individuals appear to be a sensitive
subpopulation.
For derivation of the AEGL values, both human and animal data were
utilized. For AEGL-1, humans exposed to 1.6 ppm (4.13 mg/m3)
for 10 mins showed no changes in pulmonary function (Sackner and Ford,
1981). An uncertainty factor of 3 was applied to account for sensitive
populations, since the mechanism of action of an irritant gas is not
expected to vary greatly among individuals. Scaling to the 30-min, 1-,
4-, and 8-hr exposure periods was not performed because this was a no
effect level and irritation is generally concentration dependent but
not time dependent. The derived AEGL-1 value is above the odor
threshold which provides a warning of exposure before an individual
would experience notable discomfort.
AEGL-2 values were derived from data on human studies (Diem, 1907).
Individuals exposed to 12 ppm (31 mg/m3) nitric acid for 1
hour experienced respiratory irritation, pressure in the chest, slight
stabbing pains in the trachea and larynx, coughing, marked secretion
from the nose and salivary glands, burning of the eyes and lacrimation,
and burning and itching of facial skin. An uncertainty factor of 3 was
applied to the 1-hr exposure level reported in this study and scaling
of the value to 30 mins, 4 hrs, and 8 hrs was accomplished as described
below.
Very little data were available for determining AEGL-3 levels.
Human case reports of severe injury or death did not contain exposure
concentrations and in most animal studies, nitric acid was administered
by intratracheal instillation. Extrapolation from a mortality versus
concentration curve in the published literature indicated that the
LC0 was approximately one-third the LC50 value of
138 ppm (356 mg/m3) for the rat. This concentration was
reported as nitrogen dioxide (NO2) instead of total nitric
acid. From the estimated LC0 an uncertainty factor of 3 was
applied to account for sensitive individuals. Due to the steepness of
the dose-response curve for nitric acid, application of additional
uncertainty factors would lower the AEGL-3 values below the values
derived for AEGL-2 which were based on human data and, since the
mechanism of action appears to be the same in both humans and animals
with the production of both pulmonary edema and bronchiolitis
obliterans, additional uncertainty factors were not used.
The concentration-exposure time relationship is described by the
equation cn t = k. Although insufficient data on nitric acid
were available to calculate the exponent n, structure-activity
relationships indicated that nitric acid and NO2 have
parallel dose-response curves for a 30-min exposure. Therefore, for
extrapolation to the various time points for the AEGL-2 and -3 levels,
a previously published n of 3.5 derived from NO2 data was
used.
The calculated values for the three AEGL classifications for the
four time periods are listed in the table below.
Summary Table of Proposed AEGL Values for Nitric Acid
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1............................. 0.5 ppm (1.3mg/m3).... 0.5 ppm (1.3mg/m3).... 0.5 ppm (1.3mg/m3)... 0.5 ppm (1.3mg/m3)... No observed effect
level (NOEL) for
changes in pulmonary
function in humans
(Sackner and Ford,
1981); UF=3
AEGL-2............................. 5 ppm (13mg/m3) 4 ppm (10mg/m3) 3 ppm (8mg/m3) 2 ppm (5mg/m3) Irritation with
cough; burning of
eyes and skin;
lacrimationand
salivation (Diem,
1907); UF=3
AEGL-3............................. 15 ppm (39mg/m3) 13 ppm (34mg/m3) 8 ppm (21mg/m3) 7 ppm (18mg/m3) LC0 estimated from a
30-min LC50 in the
rat (Gray et al.,
1954); UF=3
--------------------------------------------------------------------------------------------------------------------------------------------------------
References
1. Diem, L.1907. [Experimentelle Untersuchungen uber die
Einatmung von Saltpetersaure-Dampfen].Thesis, D-8700, Wurzburg. (as
cited in Henschler, 1991).
2. Gray, E.Le B., Patton, F.M., Goldberg, S.B., and Kaplan,
E.1954. Toxicity of the oxides of nitrogen. Part II. Acute
inhalation toxicity of nitrogen dioxide, red fuming nitric acid, and
white fuming nitric acid. Archive for Industrial Hygiene and
Occupational Medicine 10:418-422.
3. Henschler, D.1991. Occupational Toxicants Critical Data
Evaluation for MAK Values and Classification of Carcinogens, Vol. 3.
VCH Publishers, New York (USA) and Weinheim (FRG).
4. Sackner, M.A. and Ford, D. 1981. Effects of breathing nitrate
aerosols in high concentrations for 10 mins on pulmonary function of
normal and asthmatic adults, and preliminary results in normals
exposed to nitric acid fumes. American Review of Respiratory
Diseases 123:151.
Phosphine
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 duration and concentration 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 and pulmonary pathology in
Fischer 344 rats exposed to 3.1 ppm phosphine 6 hrs/day, 5 days/week
for 13 weeks (Newton et al, 1993). Scaling to the 30-min, 1-, 4-, and
8-hr exposures was accomplished using the cn x t = k
relationship, where n = 2. The
[[Page 58851]]
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 1 to 3.5 (ten Berge et al
1986). For scaling the AEGL values for phosphine across time, the mid-
point value of 2 was used as the exponent n because no exposure versus
time data were available. An uncertainty factor of 3 was used for
interspecies extrapolation since the rat is the most sensitive species.
An uncertainity factor of 10 was used for intraspecies extrapolation
since the data indicate that children are more sensitive than adults
when exposed to phosphine.
The AEGL-3 was based on a NOEL for lethality (18 ppm phosphine) in
Sprague Dawley rats exposed to phosphine for 6 hrs. Scaling to the 30-
min, 1-, 4-, and 8-hr exposures was accomplished using the
cn x t = k relationship, where n = 2. An uncertainty factor
of 3 was used for interspecies extrapolation since the rat is the most
sensitive species and an uncertainity factor of 10 was used for
intraspecies extrapolation since data indicate that children are more
sensitive than adults when exposed to phosphine.
The calculated values are listed in the table below.
Summary Table of Proposed AEGL Values Phosphine
--------------------------------------------------------------------------------------------------------------------------------------------------------
Classification 30-minute 1-hour 4-hour 8-hour Endpoint (Reference)
--------------------------------------------------------------------------------------------------------------------------------------------------------
AEGL-1 (Nondisabling) .................... .................... ................... ................... Appropriate data not
available
AEGL-2 (Disabling)................. 0.36 ppm (0.52 mg/m3). 0.25 ppm (0.35 mg/m3). 0.13 ppm (0.18mg/m3). 0.09 ppm (0.13 mg/m3) NOEL for renal and
pulmonary pathology
in rats exposed to
3.1 ppm phosphine, 6
hr/day, 5 days/week
for 13 weeks (Newton
et al., 1993)
AEGL-3 (Lethality)................. 2.1 ppm (2.9 mg/m3)... 1.5 ppm (2.1 mg/m3)... 0.74 ppm (1.0 mg/m3). 0.52 ppm (0.73 mg/m3) NOEL for lethality in
rats exposed to 18
ppm phosphine for 6
hr.(Newton, 1991)
--------------------------------------------------------------------------------------------------------------------------------------------------------
References
1. Newton, P.E. 1991. Acute Inhalation exposures of rats to
phosphine. Biology Dynamics, Inc. East Millstone, NJ. Project No.
90-8271.
2. Newton, P.E., Schroeder, R.E., Sullivan, J.B., Busey, W.M.,
and Banas, D.A. 1993. Inhalation toxicity of phosphine in the rat:
acute, subchronic, and developmental. Inhalation Toxicology 5:223-
239.
V. Public Record and Electronic Submission
The official record for this notice, as well as the public version,
has been established for this notice under docket control number
(OPPTS-00218; FRL-5737-3) (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 12 noon to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located in the TSCA Nonconfidential
Information Center, Rm. NE-B607, 401 M St., SW., Washington, DC.
Electronic comments can be sent directly to EPA at:
[email protected]
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 disks in WordPerfect in 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (OPPTS-00218; FRL-5737-3).
Electronic comments on this notice may be filed online at many Federal
Depository Libraries.
All comments which contain information claimed as CBI must be
clearly marked as such. Three sanitized copies of any comments
containing information claimed as CBI must also be submitted and will
be placed in the public record for this notice. Persons submitting
information on any portion of which they believe is entitled to
treatment as CBI by EPA must assert a business confidentiality claim in
accordance with 40 CFR 2.203(b) for each such portion. This claim must
be made at the time that the information is submitted to EPA. If a
submitter does not assert a confidentiality claim at the time of
submission, EPA will consider this as a waiver of any confidentiality
claim and the information may be made available to the public by EPA
without further notice to the submitter.
List of Subjects
Environmental protection, Hazardous substances.
Dated: October 20, 1997.
Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 97-28642 Filed 10-29-97; 8:45 am]
BILLING CODE 6560-50-F