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Twenty-first Interim Report of the Committee on
Acute Exposure Guideline Levels: Part B
BACKGROUND
In 1991, the U.S. Environmental Protection Agency (EPA) and the Agency for Toxic
Substances and Disease Registry (ATSDR) asked the National Research Council (NRC) to provide
technical guidance for establishing community emergency exposure levels for extremely hazardous
substances (EHSs) pursuant to the Superfund Amendments and Reauthorization Act of 1986. In response
to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels
for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute
Exposure Guideline Levels for Hazardous Substances was published in 2001; it provided updated
procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute
Exposure Guideline Levels for Hazardous Substances for assessing acute adverse health effects. The
NRC’s previous name for acute exposure levels—community emergency exposure levels—was replaced
by the term acute exposure guideline levels (AEGLs) to reflect the broad application of these values to
planning, response, and prevention in the community, the workplace, transportation, the military, and the
remediation of Superfund sites.
NAC was established to identify, review, and interpret relevant toxicologic and other scientific
data and to develop AEGLs for high-priority, acutely toxic chemicals. AEGLs developed by NAC have a
broad array of potential applications for federal, state, and local governments and for the private sector.
AEGLs are needed for emergency-response planning for potential releases of EHSs, from accidents or
terrorist activities.
AEGLs represent threshold exposure limits for the general public and are applicable to
emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). AEGL-2 and AEGL-3, and
AEGL-1 values as appropriate will be developed for each of five exposure periods (10 and 30 min and
1 h, 4 h, and 8 h) 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 susceptible. The three AEGLs have been defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million [standard pressure] or
milligrams per cubic meter [ppm or 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 nonsensory effects. However, the effects are not disabling and are transient and reversible
upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which
it is predicted that the general population, including susceptible individuals, could experience irreversible
or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which
it is predicted that the general population, including susceptible individuals, could experience life-
threatening health effects or death.
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THE CHARGE TO THE COMMITTEE
The NRC convened the Committee on Acute Exposure Guideline Levels to review the AEGL
documents approved by NAC. The committee members were selected for their expertise in toxicology;
medicine, including pharmacology and pathology; industrial hygiene; biostatistics; and risk assessment.
The charge to the committee is to (1) review the proposed AEGLs for scientific validity,
completeness, internal consistency, and conformance to the NRC (1993) guidelines report; (2) review
research recommendations and—when appropriate—identify additional priorities for research to fill
data gaps; and (3) review periodically the recommended standard procedures for developing AEGLs.
This interim report presents the committee’s conclusions and recommendations for improving
the following AEGL technical support documents (TSDs): aliphatic nitriles (acetonitrile, isobutyronitrile,
propionitrile, chloroacetonitrile, and malononitrile), benzonitrile, and methacrylonitrile. These documents
were reviewed by the committee at a meeting on May 2-4, 2012.
ALIPHATIC NITRILES
The committee reviewed the AEGL TSD on five aliphatic nitriles (acetonitrile, isobutyronitrile,
propionitrile, chloroacetonitrile, and malononitrile) that was presented by Julie Klotzbach of SRC, Inc.
Table 1 presents a summary of the proposed AEGL values for the aliphatic nitriles and their basis. The
committee agreed that its previous comments (NRC 2011a) on the TSD have been adequately addressed,
and that the document can be finalized for publication after a few clarifications and editorial changes are
made.
General Comments
A statement of caution should be given for the cumulative effects of concomitant exposure to
multiple aliphatic nitriles that share a common mechanism of toxicity through their biotransformation
to cyanide.
For each of the aliphatic nitriles with extant standards and guidelines, more substantive
discussion should be added about the basis for the differences between the AEGL values and other
relevant guidelines. Simply presenting the other values without discussion is not sufficiently informative.
See section on Comments Relevant to All AEGL TSDs in Part A of this report (NRC 2012) for guidance.
Acetonitrile
AEGL Specific Comments
The context for selecting the point-of-departure for AEGL-3 values should include the following
data:
Maternal deaths were observed after exposure to acetonitrile at 400 and 1,200 ppm in the
NTP (1994) study
Deaths of male rats exposed at 800 and 1,600 ppm and female rats at 1,600 ppm in the NTP
(1996) study; the deaths that occurred during week 1 of the 13-week segment of the study are especially
pertinent.
Because the number of days of exposure preceding death of these adult rats was not reported, the
rationale for selecting a higher point-of-departure can be strengthened by emphasizing embryonic and
fetal end points that could occur after a single exposure. Moreover, a no-effect level of 1,200 ppm for
fetal effects in the NTP (1994) study also lends support for the 6-h point-of-departure of 1,500 ppm
from the Saillenfait et al. (1993) study.
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TABLE 1 Summary of Proposed AEGL Values for Five Aliphatic Nitriles Reviewed by the Committee
End Point,
Classification 10 min 30 min 1h 4h 8h Derivation Factors
Acetonitrile
AEGL-1 13 ppm 13 ppm 13 ppm 13 ppm Not Slight chest tightness and
(22 mg/m3) (22 mg/m3) (22 mg/m3) (22 mg/m3)
(nondisabling) recommended cooling sensation in lung
(1 of 3 human volunteers
at 40 ppm); MF = 3
AEGL-2 80 ppm 80 ppm 50 ppm 21 ppm 14 ppm One third of AEGL-3 values
(130 mg/m3) (130 mg/m3) (84 mg/m3) (35 mg/m3) (24 mg/m3)
(disabling)
AEGL-3 240 ppm 240 ppm 150 ppm 64 ppm 42 ppm No-effect level for maternal
(400 mg/m3) (400 mg/m3) (250 mg/m3) (110 mg/m3) (71 mg/m3)
(lethality) and fetal lethality in rats
(1,500 ppm, 6 h); UF = 30;
n = 1.6 for time scaling
Isobutyronitrile
AEGL-1 Not Not Not Not Not Insufficient data
(nondisabling) recommended recommended recommended recommended recommended
AEGL-2 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 0.83 ppm One third of AEGL-3 values
(7.1 mg/m3) (7.1 mg/m3) (5.7 mg/m3) (3.7 mg/m3) (2.3 mg/m3)
(disabling)
AEGL-3 7.6 ppm 7.6 ppm 6.1 ppm 3.8 ppm 2.5 ppm No-effect level for maternal
(22 mg/m3) (22 mg/m3) (17 mg/m3) (11 mg/m3) (7.1 mg/m3)
(lethal) lethality (100 ppm, 6 h);
UF = 30; default time
scaling
Propionitrile
AEGL-1 Not Not Not Not Not Insufficient data
(nondisabling) recommended recommended recommended recommended recommended
AEGL-2 3.7 ppm 3.7 ppm 3.0 ppm 1.9 ppm 1.3 ppm One third of AEGL-3 values
(8.3 mg/m3) (8.3 mg/m3) (6.8 mg/m3) (4.3 mg/m3) (2.9 mg/m3)
(disabling)
AEGL-3 11 ppm 11 ppm 9.1 ppm 5.7 ppm 3.8 ppm No-effect level for maternal
(25 mg/m3) (25 mg/m3) (20 mg/m3) (13 mg/m3) (8.6 mg/m3)
(lethal) and fetal mortality (50 ppm,
6 h); UF = 30); default time
scaling
Chloroacetonitrile
AEGL-1 Not Not Not Not Not Insufficient data
(nondisabling) recommended recommended recommended recommended recommended
AEGL-2 8.0 ppm 8.0 ppm 5.0 ppm 2.1 ppm 1.4 ppm Derived by analogy to
(25 mg/m3) (25 mg/m3) (15 mg/m3) (6.5 mg/m3)
(disabling) (4.3 AEGL-2 values for
mg/m3) acetonitrile
AEGL-3 24 ppm 24 ppm 15 ppm 6.4 ppm 4.2 ppm Derived by analogy to
(74 mg/m3) (74 mg/m3) (46 mg/m3) (20 mg/m3) (13 mg/m3)
(lethal) AEGL-3 values for
acetonitrile
Malononitrile
AEGL-1 Not Not Not Not Not Insufficient data
(nondisabling) recommended recommended recommended recommended recommended
AEGL-2 1.2 ppm 1.2 ppm 0.77 ppm 0.32 ppm 0.22 ppm Derived by analogy to
(3.3 mg/m3) (3.3 mg/m3) (2.1 mg/m3) (0.87 mg/m3) (0.59 mg/m3)
(disabling) AEGL-2 values for
acetonitrile
AEGL-3 3.7 ppm 3.7 ppm 2.3 ppm 0.98 ppm 0.65 ppm Derived by analogy to
(10 mg/m3) (10 mg/m3) (6.2 mg/m3) (2.7 mg/m3) (1.7 mg/m3)
(lethal) AEGL-3 values acetonitrile
Accordingly, emphasis on fetal death should be reflected in the summary table on page II-35,
Appendix II-B, where detailed data were given for maternal death but not fetal resorption/nonsurviving
implants.
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Editorial Comments
The spelling errors of “Saillenfait” should be corrected throughout the TSD.
Page II-20, Table II-3: data from the Saillenfait et al. (1993) and NTP (1994, 1996) studies
should be added. For the NTP (1996) study, the time-to-death for male and female rats should be
specified, if possible.
Page II-26, Table II-9: the IDLH (immediately dangerous to life and health) value of 840 should
expressed as mg/m3 not ppm.
Appendix II-B, page II-35: In the “Effects” row of the table, the data on resorptions and
nonsurviving implants at 1,800 ppm were for rats not hamsters.
Appendix II-C: Data from the Saillenfait et al. (1993) and NTP (1994) studies should be added
to the category plot and data list.
Add the citation of van Raaij et al. (2003) regarding the window of vulnerability for fetal effects
in the section on acetonitrile, as well as in the reference section.
Isobutyronitrile
In several places, the lowest exposure concentration for maternal death in the Saillenfait et al.
(1993) study was reported to be 150 ppm (for example, see page III-12, line 28 and 35; page III-13,
line 15). The correct concentrations used in this study were 200 and 300 ppm.
Page III-25, Appendix III-C: For the sake of consistency, the data from the Saillenfait et al.
(1993) study should be reported as nominal concentration of 200 and 300 ppm rather than analytic
concentrations of 208 and 308 ppm. The distinction has already been made in the study description on
page III-11.
Page III-15: The AIHA (2002) citation was not mentioned in the text.
Propionitrile
Appendix IV-C, page IV-25: The data from the study by Saillenfait et al. (1993) should be
added to the category plot and database.
Chloroacetonitrile
Page V-22: The dose units for chloroacetonitrile administered to rats in the Younger Labs (1976)
study should be in mg/kg not in ppm.
Page V-23: The citation for Hashimoto (1984) should be Tanii and Hashimoto (1984).
Malononitrile
The committee had no specific comments on malononitrile.
BENZONITRILE
The committee reviewed the AEGL TSD on benzonitrile that was presented by Heather Carlson-
Lynch of SRC, Inc. Table 2 presents a summary of the proposed AEGL values for benzonitrile and their
basis.
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The committee agreed that its previous comments (NRC 2011b) on the TSD have been
adequately addressed, but recommended one substantive change to the AEGL values. Specifically, the
uncertainty factor for interspecies differences should be 10 instead of 3. The TSD currently cites small
differences in the toxicity of benzonitrile in rats and mice in the study by Agaev (1977) to support a factor
of 3. However, the study lacks adequate detail about the methods, and differences between two rodent
species give no indication of differences between rodents and humans. Thus, an uncertainty factor of 3
cannot be justified. After the AEGL values for benzonitrile are recalculated and the supporting text
revised, the committee agreed that the TSD can be finalized.
METHACRYLONITRILE
The committee reviewed a presentation of proposed AEGL values for methacrylonitrile by
Heather Carlson-Lynch of SRC, Inc. Revisions to the originally proposed AEGL-2 and AEGL-3 values
were required because of a transcription error in the data of the key study, and revisions to the AEGL-1
values were proposed after further consideration of the warning properties of the chemical. The proposed
AEGL values and options considered are presented in Table 3. The committee agreed that after the TSD
is revised to incorporate the proposed changes, it can be finalized for publication.
TABLE 2 Summary of Proposed AEGL Values for Benzonitrile Reviewed by the Committee
End Point,
Classification 10 min 30 min 1h 4h 8h Derivation Factors
AEGL-1 Not Not Not Not Not Insufficient data
(nondisabling) recommended recommended recommended recommended recommended
AEGL-2 33 ppm 24 ppm 19 ppm 7.3 ppm 3.7 ppm No effect level for
(140 mg/m3) (100 mg/m3) (80 mg/m3) (31 mg/m3) (16 mg/m3)
(disabling) impairment of escape
(one-third of AEGL-3)
AEGL-3 100 ppm 71 ppm 56 ppm 22 ppm 11 ppm No effect level for
(420 mg/m3) (300 mg/m3) (240 mg/m3) (93 mg/m3) (46 mg/m3)
(lethal) lethality (estimated
lethal threshold in mice,
445 ppm, 2 h); UF = 10
(3 × 3)
TABLE 3 Summary of Proposed AEGL Values for Methacrylonitrile Reviewed by the Committee
End Point,
Classification 10 min 30 min 1h 4h 8h Derivation Factors
AEGL-1 Not Not Not Not Not Poor odor warning
(nondisabling) recommended recommended recommended recommended recommended properties
AEGL-2 To be To be To be To be To be One-third of
(disabling) determined determined determined determined determined AEGL-3 values
AEGL-3 7.3 ppm 7.3 ppm 5.8 ppm 3.6 ppm 1.8 ppm One-third of the 4-h
(lethal): LC50 of 109 ppm in
Option 1 rats; UF = 30; default
time scaling
AEGL-3 3.9 ppm 3.9 ppm 3.1 ppm 2.0 ppm 0.99 ppm 4-h nonlethal
(lethal): concentration of
Option 2a 19.7 ppm in mice and
rabbits; UF = 10;
default time scaling
a
Option supported by the committee.
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AEGL Specific Comments
SRC proposed not establishing AEGL-1 values because it is not clear that methacrylonitrile has
adequate warning properties. The committee supports this proposal. As part of the rationale for not using
the human data in the study by Pozzani et al. (1968), which was a basis for proposing AEGL-1 values in
the past, the TSD should note that the focus of the study was sensory effects and it was not designed to
detect systemic effects. The study also reported that the test subjects showed olfactory fatigue after a few
minutes of exposure to methacrylonitrile at 2 ppm, which supports that the chemical has poor odor
warning properties.
SRC discovered that the point-of-departure for calculating AEGL-3 values for
methacrylonitrile had to be revised because of an error in reporting that no deaths occurred in rats
exposed to methyacrylonitrile at 176 ppm in the study by Pozzani et al. (1968). One male rat died at
that concentration. A reevaluation of the toxicity database led to the following observations. For a 4-h
exposure, the margin between the LC50 (lethal concentration, 50% lethality) and the no-effect level for
lethality is narrow in mice (36 ppm vs 19.7 ppm) and rabbits (37 ppm vs 19.7 ppm). The same pattern is
demonstrated in other test species, albeit at slightly higher concentrations. For example, there were no
deaths of dogs at 40 ppm for 7 h, but 100% death at 52.5 ppm. One dog vomited at 20 ppm. Although rats
appear to be less sensitive, the wide range of 4-h LC50 values (378-700 ppm) is alarming when
considering the narrow margin for lethality observed in other test species.
SRC presented two options for recalculating the AEGL-3 values (see Table 3). The committee
judged that Option 2 was the better approach for deriving AEGL-3 values, because the overall database
supported a point-of-departure of 19.7 ppm and it is preferable to use an empirical no-effect level rather
than estimating a no-effect level by adjusting an LC50 value (as was done in Option 1). The committee
supports SRC’s proposal to derive AEGL-2 values by calculating one-third of the AEGL-3 values,
because of the lack of data to support a point-of-departure for AEGL-2 end points.
Editorial Comments
Page 13, Table 5, and page 18, Table 6: Tables should be corrected to indicate that one rat died
within 3 h after exposure to methacrylonitrile at 176 ppm.
Page 16, lines 17-19: The description of fetal body-weight reduction appears to be in error,
because it refers to acrylonitrile not methacrylonitrile. The Saillenfait et al. (1993) study reported
lower fetal body weight occurred only at 100 ppm and was accompanied by lower maternal weight gain.
Page 18, Table 6: (1) The table should indicate that there were no deaths in dogs (not 100%
mortality) after exposure to methacrylonitrile at 40 ppm for 7 h; (2) the entry in the “Effects” column
for rats exposed at 110 ppm should indicate that the 17% mortality was on day 1, and that mortality was
33% (2 of 6 rats) in males; and (3) the entry in the “Effects” column for rats exposed at 109.3 ppm
should indicate that the 28% mortality was on day 1, and that mortality was 58% (7 of 12 rats) in males.
Appendix C: The text should be corrected to indicate that the death of one rat was observed at
176 ppm.
REFERENCES
Agaev, F.B. 1977. Experimental basis of the maximum allowable concentration of benzonitrile in the air of the
workplace [in Russian]. Gig. Tr. Prof. Zabol. 6:34-37.
NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for
Hazardous Substances. Washington, DC: National Academy Press.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline
Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
NRC (National Research Council). 2011a. Nineteenth Interim Report of the Committee on Acute Exposure
Guideline Levels: Part B. Washington, DC: The National Academies Press.
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NRC (National Research Council). 2011b. Nineteenth Interim Report of the Committee on Acute Exposure
Guideline Levels: Part A. Washington, DC: The National Academies Press.
NRC (National Research Council). 2012. Twenty-first Interim Report of the Committee on Acute Exposure
Guideline Levels: Part A. Washington, DC: The National Academies Press.
NTP (National Toxicology Program). 1994. Inhalation Developmental Toxicity Studies: Acetonitrile in Rats. Final
Report. NTP Report No. TER91039, NTIS No. DE94008272. National Institute of Environmental Health
Sciences, U.S. Department of Health and Human Services, Research Triangle Park, NC.
NTP (National Toxicology Program). 1996. NTP Technical Report on the Toxicology and Carcinogenesis Studies
of Acetonitrile (CAS No. 75-05-8) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP Technical
Report Series No. 447. National Institute for Environmental Health Sciences, U.S. Department of Health
and Human Services, Research Triangle Park, NC [online]. Available: http://ntp.niehs.nih.gov/ntp/htdocs/
LT_rpts/tr447.pdf [accessed June 25, 2012].
Pozzani, U.C., E.R. Kinkead, and J.M. King. 1968. The mammalian toxicity of methacrylonitrile. Am. Ind. Hyg.
Assoc. J. 29(3):202-210.
Saillenfait, A.M., P. Bonnet, J.P. Gurnier, and J. de Ceaurriz. 1993. Relative developmental toxicities of inhaled
aliphatic mononitriles in rats. Fundam. Appl. Toxicol. 20:365-375.
van Raaij, M.T.M., P.A.H. Janssen, and A.H. Piersma. 2003. The Relevance of Developmental Toxicity
Endpoints for Acute Limit Setting. RIVM Report 601900004/2003. RIVM (National Institute for
Public Health and the Environment), Bilthoven, The Netherlands [online]. Available:
http://www.epa.gov/oppt/aegl/pubs/meetings/mtg35b.pdf [accessed July 6, 2012].
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