Interim 2: 12/2008
ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs)
FOR
NITRIC ACID
(CAS Reg. No. 7697-37-2)
For
NAS/COT Subcommittee for AEGLs
December 2008
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PREFACE
Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of
1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous
Substances (NAC/AEGL Committee) has been established to identify, review and interpret
relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic
chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to
emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1,
AEGL-2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1
hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects.
The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million 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, non-sensory effects. However, the effects are not disabling and are
transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
which it is predicted that the general population, including susceptible individuals, could
experience irreversible or other serious, long-lasting adverse health effects or an impaired ability
to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above
which it is predicted that the general population, including susceptible individuals, could
experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce
mild and progressively increasing but transient and nondisabling odor, taste, and sensory
irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations
above each AEGL, there is a progressive increase in the likelihood of occurrence and the
severity of effects described for each corresponding AEGL. Although the AEGL values
represent threshold levels for the general public, including susceptible subpopulations, such as
infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized
that individuals, subject to unique or idiosyncratic responses, could experience the effects
described at concentrations below the corresponding AEGL.
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TABLE OF CONTENTS
PREFACE 2
LIST OF TABLES 5
SUMMARY 6
1. INTRODUCTION 8
2. HUMAN TOXICITY DATA 9
2.1 Acute Lethality 9
2.2 Nonlethal Toxicity 10
2.2.1 Case Reports 10
2.2.2 Epidemiologic Studies 10
2.2.3 Experimental Studies 11
2.3 Developmental/Reproductive Toxicity 12
2.4 Genotoxicity 13
2.5 Carcinogenicity 13
2.6 Summary 13
3. ANIMAL TOXICITY DATA 13
3.1 Acute Lethality 13
3.1.1 Cats 13
3.1.2 Rats 14
3.2 Nonlethal Toxicity 15
3.2.1 Dogs 15
3.2.2 Rats 16
3.2.3 Hamsters 16
3.2.4 Sheep 16
3.3 Developmental/Reproductive Toxicity 17
3.4 Genotoxicity 17
3.5 Carcinogenicity 17
3.6 Summary 17
4. SPECIAL CONSIDERATIONS 17
4.1 Metabolism and Disposition 17
4.2 Mechanism of Toxicity 18
4.3 Structure-Activity Relationships 18
4.4 Other Relevant Information 19
4.4.1 Species Variability 19
4.4.2 Susceptible Populations 19
4.4.3 Concentration-Exposure Duration Relationship 20
5. DATA ANALYSIS FOR AEGL-1 20
5.1 Summary of Human Data Relevant to AEGL-1 20
5.2 Summary of Animal Data Relevant to AEGL-1 20
5.3 Derivation of AEGL-1 21
6. DATA ANALYSIS FOR AEGL-2 21
6.1 Summary of Human Data Relevant to AEGL-2 21
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6.2 Summary of Animal Data Relevant to AEGL-2 21
6.3 Derivation of AEGL-2 22
7. DATA ANALYSIS FOR AEGL-3 22
7.1 Summary of Human Data Relevant to AEGL-3 22
7.2 Summary of Animal Data Relevant to AEGL-3 23
7.3 Derivation of AEGL-3 23
8. SUMMARY OF AEGLS 23
8.1 AEGL Values and Toxicity Endpoints 23
8.2 Comparison with Other Standards and Guidelines 24
8.3 Data Adequacy and Research Needs 26
9. REFERENCES 27
APPENDIX A: Derivation of AEGL Values 31
APPENDIX B: Derivation Summary for AEGL Values 34
Appendix C: Time-scaling category plot 37
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LIST OF TABLES
TABLE S 1. Summary of AEGL Values (ppm [mg/m3]) 7
TABLE 1. PHYSICOCHEMICAL DATA FOR NITRIC ACID 9
TABLE 2. Lethality in rats exposed nose-only to nitric acid for 1 hour 14
TABLE 3. AEGL-1 Values for Nitric Acid (ppm [mg/m3]) 21
TABLE 4. AEGL-2 Values for Nitric Acid (ppm [mg/m3]) 22
TABLE 5. AEGL-3 Values for Nitric Acid (ppm [mg/m3]) 23
TABLE 6. Summary of AEGL Values (ppm [mg/m3]) 24
TABLE 7. Extant Standards and Guidelines for Nitric Acid 25
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SUMMARY
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 sensitive to acidic atmospheres
(ACGIH 1991; NIOSH 1976a).
For derivation of the AEGL values, both human and animal data were utilized. For AEGL-1
a concentration of 0.53 ppm was adopted for all time points. The point of departure was based
on the study of Sackner and Ford (1981) in which five healthy volunteers exposed to 1.6 ppm for
10 minutes showed no changes in pulmonary function. This is the highest NOAEL available in
humans. An uncertainty factor of 3 was applied to account for sensitive populations because the
mechanism of action of a direct acting irritant is not expected to differ greatly among
individuals. Extrapolation to the 30-minute, 1-, 4-, and 8-hour time points was not performed
because this was based on 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 could experience notable discomfort.
AEGL-2 and -3 values were based on a lethality study in rats (Du Pont 1987). This was a
well conducted study in which mortality ratios at each concentration were given. Groups of 5
Crl:CD BR rats/sex were exposed nose-only for 1 hour to 260-3100 ppm of nitric acid aerosol
followed by a 14-day observation period. Exposure of rats to 470 ppm for 1 hour, which resulted
in transient body weight loss 1-2 days post-exposure, was used to derive AEGL-2 values. The
point of departure is a NOAEL for AEGL-2 effects and would not be escape impairing; higher
concentrations resulted in more severe clinical signs including partially closed eyes and lung
noise. Extrapolations to the 10- and 30-minute, and 4-, and 8-hour time periods were done
following the equation Cn x t = k (ten Berge et al., 1986). In the absence of an empirically
derived, chemical-specific exponent, scaling was performed using n = 3 for extrapolating to the
10- and 30-minute time points and n = 1 for the 4- and 8-hour time points. A total uncertainty
factor of 10 was used including a 3 for interspecies extrapolation and 3 for intraspecies
extrapolation. Use of greater uncertainty factors was not considered to be necessary because the
mechanism of action of a corrosive acid in the lung is not expected to differ greatly between
species or among individuals. In addition, a modifying factor of 2 was applied because clinical
observations were not well described, a concentration-response could not be determined for
nonlethal effects, and clear evidence of AEGL-2 effects did not occur in the study.
AEGL-3 was based on an estimated LCoi calculated by a log-probit analysis from the
lethality study in rats (Du Pont 1987). The resulting LCoi of 919 ppm was used to derive AEGL-
3 values. Values were scaled using the equation Cn x t = k where n ranges from 0.8 to 3.5 (ten
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Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling
was performed using n = 3 for extrapolating to the 10- and 30-minute time points and n = 1 for
the 4- and 8-hour time points. A total uncertainty factor of 10 was used including a 3 for
interspecies extrapolation and 3 for intraspecies extrapolation. Use of greater uncertainty factors
was not considered to be necessary because the mechanism of action of a corrosive acid in the
lung is not expected to differ greatly between species or among individuals.
The calculated values for the three AEGL classifications for the five time periods are listed
in the table below. Note that if NC>2 is of concern the technical support document on AEGLs for
NC>2 should be consulted.
TABLE S 1. Summary of AEGL Values (ppm [mg/m3])
Classificatio
n
AEGL-1
AEGL-2
AEGL-3
10-
minute
0.53 [1.4]
43 [111]
170 [439]
30-
minute
0.53 [1.4]
30 [77]
120 [310]
1-hour
0.53
[1.4]
24 [62]
92 [237]
4-hour
0.53
[1.4]
6.0
[15]
23 [59]
8-hour
0.53
[1.4]
3.0 [8]
11 [28]
Endpoint (Reference)
NOAEL for changes in pulmonary
function in humans (Sackner and
Ford 1981)
transient weight loss in rats 1-2 days
after a 1-hour exposure to 470 ppm
(Du Pont 1987)
estimated LCM from lethality data in
rats (Du Pont 1987)
References
ACGIH. 1991. American Conference of Governmental Industrial Hygienists, Inc. Nitric Acid.
In: Documentation of the Threshold Limit Values and Biological Exposure Indicies, 6th ed.,
ACGIH, Cincinnati, OH, pp. 1088-1089.
Du Pont Co. 1987. One-hour inhalation median lethal concentration (LC50) study with nitric
acid. Haskell Laboratory Report No 451-87. Newark, Delaware. 26pp.
NIOSH. 1976a. National Institute for Occupational Safety and Health. NIOSH criteria for a
recommended standard.... occupational exposure to nitric acid. U.S. Department of Health,
Education, and Welfare, Washington, D.C., HEW publication No. (NIOSH) 76-141, 78pp.
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response
relationship of irritant and systemically acting vapours and gases. J. Hazard. Mat. 13:301-
309.
Sackner, M.A. and D. Ford. 1981. Effects of breathing nitrate aerosols in high concentrations
for 10 minutes on pulmonary function of normal and asthmatic adults, and preliminary
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NITRIC ACID Interim 2: 12/2008
results in normals exposed to nitric acid fumes. Am. Rev. Resp. Dis. 123:151.
1. INTRODUCTION
Nitric acid is a corrosive, inorganic acid. Commercial formulations of the compound contain
approximately 56-68% nitric acid. Exposure to light causes the formation of nitrogen dioxide
(NO2) which gives the liquid a yellow color. Concentrated nitric acid containing dissolved NO2
is termed fuming nitric acid which evolves suffocating, poisonous fumes of nitrogen dioxide and
nitrogen tetroxide (Budavari et al. 1996). White fuming nitric acid contains 0.5% dissolved NO2
while red fuming nitric acid contains 14% dissolved NO2 (ACGIH 1991).
Inhalation exposures to nitric acid involves exposure to nitric acid as well as nitrogen oxides
such a nitrogen dioxide (NO2) and nitric oxide (NO). Fuming nitric acid reacts with wood or
metals and emits fumes of NO2 which form equimolar amounts of nitrous and nitric acid when in
contact with steam (Budavari et al. 1996; NIOSH 1976a). NO reacts quantitatively with oxygen
in air to form NO2 which then reacts with water to form nitric acid. Most reports of human
occupational exposure are limited to measurements of nitrogen oxides (NIOSH 1976a). Note
that if other oxides of nitrogen are of concern the technical support document on AEGLs for NO2
should be consulted.
Production of nitric acid atmospheres for inhalation exposure experiments potentially results
in a variety of physical states (i.e., gas, fume, vapor) depending on the production method used.
For each study description in this technical support document, the physical state and atmosphere
generation methods are given as described by the study authors.
Nitric acid is used to dissolve noble metals, for etching and cleaning metals, to make nitrates
and nitro compounds found in explosives, and, primarily, to make ammonium nitrate fertilizer
(ACGIH 1991). The chemical contributes to acid deposition (or acid rain). Nitric acid is a large
contributor to acid deposition in the in the western United States compared to the eastern states
(NARSTO 2004). Selected physicochemical properties of nitric acid are listed in Table 1.
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TABLE 1. PHYSICOCHEMICAL DATA FOR NITRIC ACID
Parameter
Common name
Synonyms
CAS registry no.
Chemical formula
Molecular weight
Physical state
Vapor pressure
Vapor density (air = 1 )
Specific gravity
Melting/boiling
Solubility in water
Conversion factors in air
Flammability
pH (0.5% in saline)
Value
nitric acid
Aquafortis
7697-37-2
HNO3
63.2
colorless liquid; fumes in moist air
47.9mmHgat20°C
2-3 (estimated)
1.50269
-41.59°C/83°C
freely soluble
1 mg/m3 = 0.388 ppm
1 ppm = 2.58 mg/m3
noncombustible
1.6
Reference
Budavari et al., 1996
Budavarietal., 1996
Budavari etal., 1996
Budavarietal., 1996
ACGIH, 1991
HSDB, 1996
Budavarietal., 1996
Budavari et al., 1996; HSDB, 1996
U.S. EPA, 1993a
U.S. EPA, 1993a
U.S. EPA, 1993a
Coalson and Collins, 1985
2. HUMAN TOXICITY DATA
Production of nitric acid atmospheres for inhalation exposure experiments potentially
results in a variety of physical states (i.e., gas, fume, vapor) depending on the production method
used. For each study description below, the physical state and atmosphere generation methods
are given as described by the study authors.
2.1 Acute Lethality
Hall and Cooper (1905) described the case reports of firemen exposed to nitric acid fumes.
Approximately 10 gallons of a 38% nitric acid solution were spilled and came in contact with
zinc. Sawdust used to absorb the spill rapidly oxidized and burst into flame. Of the 20
individuals exposed to the fumes, dyspnea was present in 100%, cough in 93%, pain in the sides,
stomach, lungs, throat, loins, and head was present in 87%, dizziness and nausea in 73%, and
vomiting in 53%. Relapse of these symptoms occurred in 33% of the cases generally 3 weeks
after exposure and persisting an average of 15.5 days. Four individuals died, two on the second
day following exposure and two several weeks later from relapse. The two who died during
relapse appeared to be recovering as well as the other survivors, however, both were exposed to
cold air and almost immediately entered relapse. Autopsy revealed hemorrhagic edema and
coagulation necrosis. Exposure concentrations were not measured but the authors concluded that
the "severity of the initial exposure" was the most important factor in determining recovery or
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death (Hall and Cooper 1905).
Three men died of rapidly progressive pulmonary edema after inhalation of fumes from an
explosion of nitric acid (Hajela et al. 1990). The men entered the area with the heaviest
concentration of fumes and dust following an explosion of a tank containing approximately
1736 L of 68% nitric acid. Escape from the building took 10-15 minutes. No respiratory
problems were apparent upon medical examination immediately following exposure, however,
increasing respiratory difficulties developed 4-6 hours later. On admission to the hospital, all
were cyanotic with frothy fluid escaping from the nose and mouth. All died within 21 hours
after the accident. Pathological evaluation of the lungs revealed degranulated and necrotic
neutrophils within the alveolar capillaries. The concentrations of nitric acid or its oxides were
not determined at the site of the accident.
A man cleaned a copper chandelier with a 60% nitric acid solution by placing the chemical
and chandelier in a bowl. The first symptoms of respiratory distress occurred 30 minutes later;
approximately 1 hour later he entered a hospital emergency room with dyspnea, exspiratory
stridor, peripheral cyanosis, and general paleness. Chest x-ray showed pulmonary edema. With
intense treatment the patient stabilized for 3 days and lung function improved. However, on the
fourth day the patient died from refractory respiratory failure and pulmonary edema was
observed at autopsy (Bur et al. 1997).
Other lethal exposure scenarios have been summarized (ACGIH 1991; NIOSH 1976a).
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.
Unfortunately exposure concentrations were not given in the primary reports.
2.2 Nonlethal Toxicity
Nitric acid is described as having a characteristic choking odor (Budavari et al. 1996). Low
and high odor thresholds in air were listed as 0.29 and 0.97 ppm, respectively (U.S. EPA 1993a).
2.2.1 Case Reports
A 42-year old male with no history of respiratory disease was exposed for 3 hours to fumes
from a leaking nitric acid drum (air concentrations not measured). Twelve hours post exposure
he presented with dry cough and acute dyspnea and was admitted to a hospital. Chest X-rays
showed opacities compatible with pulmonary edema; he was treated with oxygen and high doses
of corticosteroids. After 3 months the chest X-ray was clear and lung function tests were normal
(Myint and Lee 1983).
2.2.2 Epidemiologic Studies
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Ostro et al. (1991) correlated acidic aerosols and other air pollutants with respiratory
symptoms in asthmatics in Denver, Colorado. Daily concentrations of several pollutants,
including nitric acid were measured while a panel of asthmatics recorded respiratory symptoms,
frequency of medication use, and related information. Airborne acidity, as measured by H+,
significantly correlated with such symptoms as cough and shortness of breath, however, nitric
acid per se was not specifically associated with any respiratory symptom analyzed. The nitric
acid concentrations ranged from 0.06 to 13.54 ug/m3 (0.15 to 34.93 ppb) during the study period.
The health effects of exposure to acidic air pollution among children aged 8 to 12 years were
monitored in 24 communities in the United States and Canada (Dockery et al. 1996; Raizenne et
al. 1996). Air quality and meteorology were measured for 1 year in each community and parents
completed a respiratory health questionnaire. At the end of the 1-year monitoring, the children
were administered pulmonary function tests consisting of forced vital capacity (FVC) and forced
expiratory volume (FEV) measurements. The concentration of nitric acid ranged from 0.3 to 2.1
ppb and nitrous acid ranged from 0.1 to 1.4 ppb; these were combined as gaseous acids.
Gaseous acids were associated with a significantly higher risk of asthma (odds ratio = 2.00; 95%
CI, 1.14-3.53) and showed a positive correlation with higher reporting of attacks of wheezing,
persistent wheeze, and any asthmatic symptoms (Dockery et al. 1996). However, no changes in
FVC or FEV were associated with gaseous acid concentrations in the communities (Raizenne et
al., 1996).
In a more recent study, children from 12 communities in California were assessed for
respiratory disease prevalence and pulmonary function (Peters et al., 1999a,b). Wheeze
prevalence was positively correlated with levels of both acid and NC>2 in boys, whereas
regression analysis showed that acid vapor was significantly associated with lower FVC, FEVi,
peak expiratory flow rate, and maximal midexpiratory flow in girls.
2.2.3 Experimental Studies
An experimental self-exposure was reported by Lehmann and Hasegawa (1913). Nitrogen
oxide gas was produced by reaction of copper with nitric acid; the gas produced was collected
over water and mixed with fresh air. Concentrations of total oxidation products, expressed as
nitrous acid concentration, were determined analytically by either oxidation of hydrogen
peroxide or by reduction using potassium iodide. Although the generated atmospheres were
likely a mixture of nitrogen oxides, the exposure concentrations were expressed as total nitric
acid content and are listed here in ppm as reported by NIOSH (1976b). One of these researchers
exposed himself to 62 ppm (160 mg/m3) for 1 hour and reported irritation of the larynx, thirst,
and an objectionable odor. He was then exposed to 74-101 ppm (190-260 mg/m3) for 1 hour
followed by 23-43 ppm (60-110 mg/m3) for another hour and experienced immediate severe
irritation with cough and an increase in pulse and respiratory rates after 40 minutes. He was able
to tolerate exposure to 158 ppm (408 mg/m3) but for only 10 minutes due to coughing, severe
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burning in the nose and throat, lacrimation and heavy mucous secretion from the nose, a feeling
of suffocation, headache, dizziness, and vomiting. Based on their results of human exposures
and by comparing this to other work, the authors estimated that the concentration causing no
significant adverse effects would be below 50 ppm (130 mg/m3).
In contrast to the above report, another researcher exposed himself and another individual to
nitric acid fumes at a concentration of 11.6-12.4 ppm (30-32 mg/m3) for 1 hour (Diem 1907).
Symptoms included irritation of the nasal mucosa, 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. After 20 minutes, all symptoms
except nasal secretion abated somewhat and a slight frontal headache developed. Some of these
symptoms persisted for about 1 hour postexposure. For a second experiment, the author could
tolerate 85 ppm (219 mg/m3) for only 2-3 minutes. In these experiments, the exposure
concentrations were produced by warming the acid and samples of the chamber air were
measured for concentration by simple titration with the indicator Congo red. The differences in
the methods used by Lehmann and Hasegawa (1913) and Diem (1907) for the production of
nitric acid fumes as well as the detection methods probably account for the differences in effect
levels.
A group of 9 allergic adolescents ranging in age from 12-18 years old, was exposed to nitric
acid gas and pulmonary function was assessed. All subjects had exercise-induced bronchospasm
defined as a >15% drop in FEVi after 6 minutes of exercise at 85% maximum oxygen
consumption. Five individuals also had allergic asthma. Individuals were exposed through a
rubber mouthpiece with nose clips to 0.05 ppm (0.129 mg/m3) nitric acid for 40 minutes (30
minutes at rest plus 10 minutes of moderate exercise on a treadmill). Each individual served as
his or her own control with post exposure pulmonary function values compared to baseline.
After exposure to nitric acid, as compared to preexposure, FEVi decreased by 4% and
respiratory resistance increased by 23%. A post exposure survey taken later that day or the
following day did not indicate any correlation between exposure and symptoms of respiratory
distress such as cough, pain or burning of the chest, fatigue, shortness of breath, or wheezing.
On a separate testing day when the subjects were exposed to air only, FEVi decreased by 2% and
respiratory resistance increased by 7% (Koenig et al. 1989).
No changes in pulmonary function occurred in five healthy volunteers exposed at rest for 10
minutes to 1.6 ppm (4.13 mg/m3) nitric acid fumes (Sackner and Ford 1981). No changes in
pulmonary function, lavage constituents, and bronchial biopsy specimens were found in 10
healthy, athletic subjects exposed to 0.194 ppm (0.5 mg/m3) nitric acid gas for 4 hours during
moderate exercise (Aris et al. 1993).
2.3 Developmental/Reproductive Toxicity
No information was found regarding the developmental or reproductive toxicity of nitric acid
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in humans.
2.4 Genotoxicity
No information was found regarding the genotoxicity of nitric acid in humans.
2.5 Carcinogenicity
No information was found regarding the carcinogenicity of nitric acid in humans.
2.6 Summary
The course of toxicity following inhalation exposure to nitric acid is consistent among the
case reports. 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 are the most sensitive
population.
3. ANIMAL TOXICITY DATA
Production of nitric acid atmospheres for inhalation exposure experiments potentially results
in a variety of physical states (i.e., gas, fume, vapor) depending on the production method used.
For each study description below, the physical state and atmosphere generation methods are
given as described by the study authors.
3.1 Acute Lethality
3.1.1 Cats
Lehmann and Hasegawa (1913) conducted a series of experiments using cats exposed to
gases of nitric acid which were produced as described in section 2.2.3. In general, as
concentration and/or duration of exposure increased, death resulted from severe pulmonary
edema. For concentrations less than -388 ppm (1000 mg/m3), examination of the data as
concentration x time revealed that Ct products greater than -900 ppm-hr resulted in death while
a Ct up to 760 ppm-hr resulted in only a slight increase in respiration for several hours after
exposure. Further, exposure to 287 ppm (740 mg/m3) for 1.83 hours (Ct = 526 ppm-hr) caused
no effects whereas exposure to either 341 ppm (880 mg/m3) for 3.83 hours (Ct = 1309 ppm-hr) or
217 ppm (560 mg/m3) for 4.25 hours (Ct = 922 ppm-hr) resulted in death. In contrast for
concentrations of 388 ppm (1000 mg/m3) or greater, severe clinical signs or death occurred at a
Ct product as low as 277 ppm-hr. The response probably depended on whether either the
concentration of the acid, or the duration of exposure, was great enough to induce corrosive
effects leading to edema. The data are limited in that only one animal was used at each
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concentration and time combination.
3.1.2 Rats
Groups of 5 Crl:CD°BR rats/sex were exposed nose-only for 1 hour to 260-3100 ppm of
nitric acid aerosol followed by a 14-day observation period (Du Pont Co. 1987). The
atmospheres were generated with a nebulizer and the airborne test material was dispersed with a
baffle. Although an aerosol was generated the concentrations were reported in the study as ppm
instead of mg/m3. Aerosol content was assumed to be 100% at the three highest concentrations
and ranged from 15-73% in the five lower concentrations as measured on a gravimetric filter
sample. Except for the 2500 and 2700 ppm concentrations, all exposures contained >70%
respirable particles with a mass median aerodynamic diameter (MMAD) of <4.0 um. The 2500
and 2700 ppm concentrations contained 59 and 61% respirable particles and had a MMAD of 6.5
and 6.6 um, respectively. Despite generation of the small particle size resulting in a high
percentage of respirable particles, it is not clear why the concentrations were reported in ppm
instead of mg/m3. Nitrogen dioxide was not detected in the exposure atmospheres.
Clinical signs included clear nasal discharge at "some" concentrations, body weight loss for
1-2 days at 260 and 470 ppm, partially closed eyes at > 1300 ppm, lung noise and gasping at
> 1600 ppm, and extended weight loss up to 12 days post-exposure at > 1500 ppm for males and
> 1600 ppm for females. Mortality results are shown in Table 2. The 1-hour LCso for males and
females combined was 2500 ppm. Although males died at lower concentrations than females, no
apparent differences in clinical responses or LCso values were observed between males and
females (Du Pont 1987).
TABLE 2. Lethality in rats exposed nose-only to nitric acid for 1 hour
Concentration (ppm)
260
470
1300
1500
1600
2500
2700
3100
Mortality
Males
0/5
0/5
1/5
1/5
2/5
2/5
2/5
5/5
Females
0/5
0/5
0/5
0/5
0/5
1/5
1/5
5/5
Data from Du Pont Co. 1987.
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Gray et al. (1954) compared the toxicities of nitrogen dioxide, red fuming nitric acid (RFNA,
containing 8-17% nitrogen dioxide), and white fuming nitric acid (WFNA, containing 0.1-0.4%
nitrogen dioxide) by inhalation in rats. Although graphs of the dose-response curves were
presented in the paper, unfortunately, the authors did not include the actual data from which
those curves were plotted. Exposure concentrations for RFNA and WFNA in this paper were
measured and reported as NC>2. Thirty-minute LCso values for nitrogen dioxide and RFNA were
reported as 174 ppm (449 mg/m3) and 138 ppm as NC>2 (356 mg/m3), respectively, while that for
WFNA was 244 ppm as NC>2 (630 mg/m3). Deaths were due to pulmonary edema. The dose-
response curves for nitrogen dioxide and RFNA for 30-minute exposures were statistically
parallel indicating a possible similar mode of action for the two gases. But, at lower
concentrations for 240 minutes the curves differed somewhat. With exposures to WFNA, the
authors stated that deaths were not as "predictable" as with the other gases. The approximate
LCso indicates that WFNA is much less toxic (i.e., higher LCso) than either RFNA or nitrogen
dioxide. Therefore, the authors concluded that the main toxic component of these oxides of
nitrogen is nitrogen dioxide. However, NIOSH (1976a) calculated the LCsoS for RFNA and
WFNA in terms of total concentration, based on molecular weights and the percentage of NC>2 in
each, and determined them to be 310 ppm (800 mg/m3) and 334 ppm (862 mg/m3), respectively.
This suggests the possibility that both nitric acid vapor and nitrogen dioxide contribute to the
toxi city.
3.2 Nonlethal Toxicity
3.2.1 Dogs
Mongrel dogs were used as a model of bronchial injury induced by nitric acid (Peters and
Hyatt 1986; Fujita et al. 1988). One day/week, dogs were anesthetized and a catheter placed in
the mainstem bronchus; 1% nitric acid was delivered as a course spray via a nebulizer with
approximately 5 mL to the left lung and 8 mL to the right lung. For an additional 2
exposures/week, dogs were intubated and spontaneously breathed 1% nitric acid as a mist for 2
hours. This exposure regime was continued for 4 weeks and the animals killed either
immediately or after a 5 month recovery period. Within one week after exposure began, treated
animals developed intermittent cough and produced clear mucoid sputum. After four weeks of
exposure, there was a decrease in total lung capacity and vital capacity with evidence of
obstruction as measured by a decrease in forced expiratory volume and expiratory flow.
Increased flow resistance was observed after 14 days and continued to increase throughout the
exposure period. Airway obstruction persisted for 5 months postexposure with significant
reductions in maximal expiratory flows. At necropsy immediately after cessation of treatment,
the lungs from nitric acid exposed dogs were edematous with areas of focal hemorrhage. The
lungs appeared normal after 5 months of recovery. Histologically, there was chronic airway
inflammation, slight epithelial changes, slight peribronchiolar fibrosis, and an increase in smooth
muscle that persisted to 5 months postexposure. The severity of the pathological lesions directly
correlated with decreases in pulmonary function (Peters and Hyatt 1986; Fujita et al. 1988).
However, it is not possible to determine from this protocol which method of exposure was the
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most damaging to the airways.
Bronchiolitis obliterans was produced in dogs by instillation of 1% nitric acid into the
airways. Two instillations of three 5-mL alliquots were given approximately 2 weeks apart and
pulmonary function tests performed two weeks later. Nitric acid treated dogs had mild cough
with slight hemoptysis immediately following each treatment; several pulmonary function tests
indicated increased peripheral airway resistance; and, at necropsy, acute and chronic
inflammation of the small airways were observed (Mink et al. 1984).
3.2.2 Rats
Rats were given a single dose of 0.15 mL of 1% nitric acid by intratracheal instillation. At 1
day after administration, focal lung damage consisted of bronchiolar inflammation with
inflammatory cell infiltration. Absorption rates from the lung were significantly (p < 0.05)
increased for both lipid-soluble and lipid-insoluble drugs (Gardiner and Schanker 1976).
To study the long-term effects of exposure to nitric acid, rats (approximately
10/concentration) were exposed nose-only to 0, 5.1, 7.0, 13, or 19 ppm for 6 hours/day on
alternate days for a total of six exposures. The animals were then held for 22 months. Mortality
was not affected in any group and no adverse effects were noted (Ballou et al. 1978).
3.2.3 Hamsters
Lung injury was induced in Syrian golden hamsters by a single tracheal instillation of 0.5%
nitric acid in 0.5 mL saline/100 g body weight (Coalson and Collins 1985). "Several" animals
(exact number not given) died before day 3 posttreatment and showed severe hemorrhagic
pulmonary edema. Airway changes in the remaining hamsters included acute bronchitis, acute
bronchiolitis, obliterative bronchiolitis, bronchiolectasia, and bronchiectasis. These pathological
changes were accompanied by decreased lung volumes, decreased internal surface areas,
increased lung weights, and increased elastin content. The airway dilatation and morphometric
and biochemical endpoints persisted through day 60 posttreatment (the last day examined).
In a similar experiment, hamsters were exposed via an intratracheal instillation of 0.5 mL of
0. IN nitric acid. Up to 17 weeks postexposure, histological lesions in the lung included
secretory cell metaplasia, interstitial fibrosis, bronchiolectasis, and diffuse extension of
hyperplastic bronchiolar epithelium into adjacent alveoli (Christensen et al. 1988).
3.2.4 Sheep
The effects of nitric acid vapor on carbachol reactivity in normal and allergic sheep were
investigated (Abraham et al. 1982). Allergic sheep are those with a history of reacting with
bronchospasm to inhalation challenge withAscaris suum antigen; the induced airway response is
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similar to that which occurs in humans with allergic airway disease. Measurements of lung
resistance were taken initially, following 20 breaths of 2.5% carbachol (to induce
bronchoconstriction), and following 4 hours of exposure to 1.6 ppm (4.13 mg/m3) nitric acid
vapor. Immediately after nitric acid exposure, the animals were given a second bronchial
challenge with aerosolized carbachol. Nitric acid exposure alone did not result in
bronchoconstriction in either normal or allergic sheep as measured by specific lung resistance.
However, airway hyperreactivity to carbachol after nitric acid exposure, occurred in the allergic
sheep. Pulmonary flow resistance from carbachol challenge prior to and postexposure to nitric
acid, increased by 68% and 78%, respectively in normal sheep and 82% and 120% (p < 0.05),
respectively in allergic sheep (Abraham et al. 1982).
3.3 Developmental/Reproductive Toxicity
No information was found regarding the developmental or reproductive toxicity of nitric acid
in animals.
3.4 Genotoxicity
Nitric acid, up to 0.008%, was negative for mutagenicity in Escherichia coll (Demerec et al.
1951).
3.5 Carcinogenicity
No information was found regarding the carcinogenicity of nitric acid in animals. Lung
damage in rats, induced by intratracheal instillation of 0.25 mL 1% nitric acid, did not enhance
the rate of lung cancer caused by 3-methylcholanthrene (Blenkinsopp 1968).
3.6 Summary
Because of the corrosive nature of nitric acid, the chemical has been used to produce changes
in the lung in animal models of obstructive lung disease (Peters and Hyatt 1986; Fujita et al.
1988; Coalson and Collins 1985). Experiments in sheep (Abraham et al. 1982) have emphasized
the sensitivity of allergic individuals to acidic atmospheres.
4. SPECIAL CONSIDERATIONS
4.1 Metabolism and Disposition
No information was found regarding the pharmacokinetics of nitric acid. Because of its high
water solubility and reactivity, nitric acid would be expected to undergo significant removal in
the upper respiratory tract. However in a model system, Chen and Schlesinger (1996) showed
that particulates can act as vectors for adsorbed/absorbed nitric acid transport to the lower
respiratory tract.
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4.2 Mechanism of Toxicity
Nitric acid is a highly corrosive, strongly oxidizing acid (Budavari et al. 1996). Contact with
the liquid causes burns on the skin and corneal opacity (NIOSH 1976a). A 4-hour occluded
patch test induced skin corrosion in rabbits at 8%, but not 6% (Vernot et al. 1977). The
respiratory irritation attributed to nitric acid exposure is almost certainly due to the corrosive
properties of the chemical. Because of its high water solubility and reactivity, nitric acid would
be expected to undergo significant removal in the upper respiratory tract. However, some
experiments indicate that bronchial responsiveness can be altered. In a model system, Chen and
Schlesinger (1996) showed that particulates can act as vectors for adsorbed/absorbed nitric acid
transport to the lower respiratory tract. Reaction with endogenous ammonia and water may also
produce particulates which can act as vectors.
4.3 Structure-Activity Relationships
Inhalation exposures to nitric acid fumes involve exposure to nitric acid as well as nitrogen
oxides such a nitrogen dioxide (NC^) and nitric oxide (NO). Fuming nitric acid reacts with
wood or metals and emits fumes of NC>2 which form equimolar amounts of nitrous and nitric acid
when in contact with steam (Budavari et al. 1996; NIOSH 1976a). In the presence of light, nitric
acid undergoes an oxidation-reduction reaction to produce nitrogen dioxide, water, and oxygen.
NO reacts quantitatively with oxygen in air to form NO2 which then reacts with water to form
nitric acid. Most reports of human occupational exposure are limited to measurements of
nitrogen oxides (NIOSH 1976a). In animal experiments, Lehmann and Hasagawa (1913)
showed that up to a concentration of about 272 ppm (700 mg/m3), the toxic response was the
same whether the gas mixture contained nitric acid alone or a mixture of nitrous and nitric acid.
As discussed in Section 3.1.2, Gray et al. (1954) compared the toxicities of NO2, red fuming
nitric acid (RFNA), and white fuming nitric acid (WFNA) in male rats. The dose-response
curves for nitrogen dioxide and RFNA for 30-minute exposures were statistically parallel
indicating a similar mode of action for the two gases. For both gases, deaths were due to
pulmonary edema. The thirty-minute LCso values for nitrogen dioxide and RFNA were 174 ppm
(449 mg/m3) and 138 ppm as NO2 (356 mg/m3), respectively. With exposures to WFNA, the
authors stated that deaths were not as "predictable" as with the other gases. The approximate
LC50 (244 ppm as NO2 [630 mg/m3]) indicates that WFNA is less toxic than either RFNA or
nitrogen dioxide. Therefore, the authors concluded that the main toxic component of these
oxides of nitrogen is nitrogen dioxide and that RFNA is approximately 25% more toxic than NO2
because of the contribution by the acid component. However, NIOSH (1976a) calculated the
LCsoS for RFNA and WFNA in terms of total nitric acid concentration and determined them to
be 310 ppm (800 mg/m3) and 334 ppm (862 mg/m3), respectively. The calculations were based
on molecular weights and the percentage of NO2 in RFNA and WFNA. Because these values are
very similar, this suggests the possibility of a synergistic effect between nitric acid vapor and
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nitrogen dioxide since RFNA has a higher nitrogen dioxide content by weight than WFNA.
The supposition that nitric acid and NO2 interact to cause enhanced toxicity is also
supported, in part, by the inhalation experiments of Goldstein et al. (1977) in Rhesus monkeys.
Approximately 50-60% of the inhaled NO2 was retained by the animals and distributed
throughout the lungs. Radioactivity was retained in the lungs during the 21-minute post
exposure period with extrapulmonary distribution (per cent not quantified) via the bloodstream.
The authors speculate that the reaction of inhaled NO2 with water vapor in the lungs and with
liquid water in the mucous results in the formation of nitric acid and accounts for the long
retention time in the lung.
It is apparent from the above discussion that the toxic action of nitric acid can not be
considered without taking into account the effects of NO2. However, nitric acid fumes will
contain NO2 upon contact with water so that reports of experimental or accidental exposures to
nitric acid fumes will account for the toxicity contributed by NO2. NIOSH (1976b) summarized
the effects of NO2 in humans as initial irritation with mild dyspnea during exposure followed by
delayed onset of pulmonary edema after several hours of apparent recovery. A similar toxic
response, including interstitial fibrosis, has been shown in five species of animals following
acute inhalation exposure to NO2 (Hine et al. 1970). This course of toxicity is identical to that
described for nitric acid albeit the concentrations eliciting similar responses are very different for
the two chemicals. For example, deaths of rats from a one hour exposure were first observed at
75 ppm NO2 (Hine et al. 1970) and at 1300 ppm nitric acid (Du Pont Co. 1987). Also, based on
the LCso values discussed for the rat, it would appear that NO2 is more toxic than nitric acid.
Therefore, it seems that data from inhalation studies with NO2 might be an overly conservative
approach used for establishing the AEGL levels for nitric acid. If NO2 is of concern the
technical support document on AEGLs for NO2 should be consulted.
4.4 Other Relevant Information
4.4.1 Species Variability
There are no apparent species differences in the toxic response to acute inhalation exposure
to nitric acid. 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
(ACGIH 1991; NIOSH 1976a). Because the response is similar between humans and animals,
dogs (Peters and Hyatt 1986; Fujita et al. 1988) and hamsters (Coalson and Collins 1985) have
been used as models of obstructive airway disease and experiments in sheep (Abraham et al.
1982) have emphasized the sensitivity of allergic individuals.
4.4.2 Susceptible Populations
Epidemiologic studies indicate that asthmatics may be more sensitive to acidic atmospheres
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(Ostro et al. 1991; Dockery et al. 1996). Data from one of these studies indicates that children
with a history of allergy or asthma may be a sensitive subpopulation. In 24 communities in the
United States and Canada, the concentration of nitric acid ranged from 0.3 to 2.1 ppb and of that
nitrous acid ranged from 0.1 to 1.4 ppb; these were combined as gaseous acids. Among children
aged 8-12 years, these gaseous acids (but not nitric acid alone) were associated with a
significantly higher risk of asthma (odds ratio = 2.00; 95% CI, 1.14-3.53) and showed a positive
correlation with higher reporting of attacks of wheezing, persistent wheeze, and any asthmatic
symptoms (Dockery et al. 1996). However, no effects were seen in an experimental study in
which allergic adolescents were exposed specifically to nitric acid (Koenig et al. 1989).
Abraham et al. (1982) showed that airway hyperreactivity to carbachol occurred in allergic
sheep following a 4-hour exposure to 1.6 ppm (4.13 mg/m3) nitric acid. Specific airway
resistance prior to and postexposure to nitric acid, increased by 68% and 78%, respectively in
normal sheep and 82% and 120% (p < 0.05), respectively in allergic sheep. These data confirm
that allergic individuals are potentially a sensitive subpopulation.
4.4.3 Concentration-Exposure Duration Relationship
Little data were available to analyze the concentration-exposure duration relationship. The
most reliable study found (Du Pont 1987) used only one duration over a large range of
concentrations. However, from these lethality data in the rat it appears that 100% mortality is
reached abruptly indicating a steep concentration-response.
5. DATA ANALYSIS FOR AEGL-1
AEGL-1 is the airborne concentration (expressed as parts per million 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, non-sensory effects. However, the effects are not disabling and are transient and
reversible upon cessation of exposure.
5.1 Summary of Human Data Relevant to AEGL-1
A no-observed adverse effect level (NOAEL) of 1.6 ppm (4.13 mg/m3) was reported for
changes in pulmonary function in five healthy volunteers exposed to nitric acid vapor at rest for
10 minutes (Sackner and Ford 1981). This is the highest NOAEL available in humans. An
experimental self-exposure to 62 ppm (160 mg/m3) for 1 hour resulted in irritation of the larynx,
thirst, and an objectionable odor (Lehmann and Hasegawa 1913).
5.2 Summary of Animal Data Relevant to AEGL-1
Most animal experimental studies were either at a lethal concentration or administered nitric
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acid by intratracheal instillation which is not comparable to inhalation exposure.
5.3 Derivation of AEGL-1
The highest NOAEL in humans of 1.6 ppm (4.13 mg/m3) for 10 minutes was used to derive
AEGL-1 values. An uncertainty factor of 3 was applied to account for sensitive populations
because the mechanism of action of a direct acting irritant is not expected to differ greatly among
individuals. Extrapolations were not performed because this was based on a no effect level and
because irritation is generally concentration dependent but not time dependent. AEGL-1 values
are presented in Table 3.
TABLE 3. AEGL-1 Values for Nitric Acid (ppm [mg/m3])
AEGL level
AEGL-1
10-min
0.53 [1.4]
30-min
0.53 [1.4]
1-hr
0.53 [1.4]
4-hr
0.53 [1.4]
8-hr
0.53 [1.4]
6. DATA ANALYSIS FOR AEGL-2
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.
6.1 Summary of Human Data Relevant to AEGL-2
Human data relevant to AEGL-2 were not found. Experimental studies in which results
consistent with AEGL-2 endpoints were described did not expose individuals to pure nitric acid,
but generated an atmosphere containing a mixture of nitrogen oxides (Lehmann and Hasegawa
1913; Diem 1907).
6.2 Summary of Animal Data Relevant to AEGL-2
The most relevant animal data to AEGL-2 were those from Du Pont (1987). This was a well
conducted study which controlled for potential nitrogen dioxide contamination. Groups of 5
Crl:CD BR rats/sex were exposed nose-only for 1 hour to 260-3100 ppm of nitric acid aerosol
followed by a 14-day observation period. Clinical signs included clear nasal discharge at "some"
concentrations, body weight loss for 1-2 days at 260 and 470 ppm, partially closed eyes at > 1300
ppm, lung noise and gasping at > 1600 ppm, and extended weight loss up to 12 days post-
exposure at > 1500 ppm for males and > 1600 ppm for females.
No long-term effects of exposure to nitric acid were observed in rats following six exposures
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on alternate days to up to 19 ppm for 6 hours/day (Ballou et al. 1978).
6.3 Derivation of AEGL-2
Exposure of rats to 470 ppm for 1 hour, which resulted in transient body weight loss 1-2 days
post-exposure (Du Pont 1987), was used to derive AEGL-2 values. The point of departure is a
NOAEL for AEGL-2 endpoints and would not be escape-impairing. The next higher
experimental concentration used in the study resulted in partially closed eyes which could
definitely impair escape. Extrapolations to the 10- and 30-minute, and 4-, and 8-hour time
periods were done following the equation Cn x t = k (ten Berge et al., 1986). In the absence of
an empirically derived, chemical-specific exponent, scaling was performed using n = 3 for
extrapolating to the 10- and 30-minute time points and n = 1 for the 4- and 8-hour time points. A
total uncertainty factor of 10 was used including a 3 for interspecies extrapolation and 3 for
intraspecies extrapolation. Use of greater uncertainty factors was not considered to be necessary
because the mechanism of action of a corrosive acid in the lung is not expected to differ greatly
between species or among individuals. In addition, a modifying factor of 2 was applied because
clinical observations were not well described, a concentration-response could not be determined
for nonlethal effects, and clear evidence of AEGL-2 effects did not occur in the study. The
values for AEGL-2 are given in Table 4.
TABLE 4. AEGL-2 Values for Nitric Acid (ppm [mg/m3])
AEGL level
AEGL-2
10-min
43 [111]
30-min
30 [77]
1-hr
24 [62]
4-hr
6.0 [15]
8-hr
3.0 [8]
7. DATA ANALYSIS FOR AEGL-3
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.
7.1 Summary of Human Data Relevant to AEGL-3
Limited human data useful for derivation of AEGL-3 are available. Case reports of lethal
exposures from accidents do not contain exposure concentration information. An experimental
self-exposure was reported by Lehmann and Hasegawa (1913). One of these researchers
exposed himself to 74-101 ppm (190-260 mg/m3) for 1 hour followed by 23-43 ppm (60-110
mg/m3) for another hour and experienced immediate severe irritation with cough and an increase
in pulse and respiratory rates after 40 minutes. Because the severe symptoms were immediate, it
could be assumed that the average concentration of 88 ppm during the first hour of exposure
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would be close to intolerable but not lethal. He was able to tolerate exposure to 158 ppm (408
mg/m3) but for only 10 minutes due to coughing, severe burning in the nose and throat,
lacrimation and heavy mucous secretion from the nose, a feeling of suffocation, headache,
dizziness, and vomiting.
7.2 Summary of Animal Data Relevant to AEGL-3
Animal data relevant to derivation of AEGL-3 are limited to the LCso study by Du Pont
(1987). This was a well conducted study which controlled for potential nitrogen dioxide
contamination. Groups of 5 Crl:CD BR rats/sex were exposed nose-only for 1 hour to 260-3100
ppm of nitric acid aerosol followed by a 14-day observation period. Clinical signs included clear
nasal discharge at "some" concentrations, body weight loss for 1-2 days at 260 and 470 ppm,
partially closed eyes at > 1300 ppm, lung noise and gasping at > 1600 ppm, and extended weight
loss up to 12 days post-exposure at > 1500 ppm for males and > 1600 ppm for females. The 1-
hour LCso for males and females combined was 2500 ppm.
7.3 Derivation of AEGL-3
A 1-hour LCso in rats was calculated by Du Pont (1987). This was a well conducted study in
which mortality ratios at each concentration were given. From these data, an LCoi was
calculated by a log-probit analysis. The resulting LCoi of 919 ppm was used to derive AEGL-3
values. Values were scaled using the equation Cn x t = k where n ranges from 0.8 to 3.5 (ten
Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling
was performed using n = 3 for extrapolating to the 10- and 30-minute time points and n = 1 for
the 4- and 8-hour time points. A total uncertainty factor of 10 was used including a 3 for
interspecies extrapolation and 3 for intraspecies extrapolation. Use of greater uncertainty factors
was not considered to be necessary because the mechanism of action of a corrosive acid in the
lung is not expected to differ greatly between species or among individuals. The values for
AEGL-3 are given in Table 5.
TABLE 5. AEGL-3 Values for Nitric Acid (ppm [mg/m3])
AEGL level
AEGL-3
10-min
170 [439]
30-min
120 [3 10]
1-hr
92 [237]
4-hr
23 [59]
8-hr
1 1 [28]
8. SUMMARY OF AEGLS
8.1 AEGL Values and Toxicity Endpoints
The derived AEGL values for various levels of effects and durations of exposure are
summarized in Table 6. AEGL-1 was based on a no effect level in humans. AEGL-2 was based
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on a concentration which produced transient weight loss in rats. The basis for AEGL-3 was an
estimated LCoi from the reported 1-hour LCso in the rat. Note that if NC>2 is of concern the
technical support document on AEGLs for NC>2 should be consulted.
TABLE 6. Summary of AEGL Values (ppm [mg/m3])
AEGL Level
AEGL-1
AEGL-2
AEGL-3
10-minute
0.53 [1.4]
43 [111]
170 [439]
30-minute
0.53 [1.4]
30 [77]
120 [3 10]
1-hour
0.53 [1.4]
24 [62]
92 [237]
4-hour
0.53 [1.4]
6.0 [15]
23 [59]
8 -hour
0.53 [1.4]
3.0 [8]
1 1 [28]
8.2 Comparison with Other Standards and Guidelines
Standards and guidance levels for workplace and community exposures are listed in Table 7.
Some of these standards and guidance levels have been developed on the basis of nitrogen
dioxide or comparison to other acids in the workplace. An occupational TWA of 2 ppm and a
STEL of 4 ppm have been adopted by several groups (ACGIH 2003, NIOSH 1996, OSHA
1999). ACGIH (2003) set the TWA as intermediate between that for hydrogen chloride and
sulfuric acid and considers both the TWA and STEL as sufficiently low to prevent ocular and
upper respiratory tract irritation. International standards are also 2 ppm for a workday and 2-5
ppm for short-term limits (German Research Association 2002, National MAC List 2000,
Swedish National Board of Occupational Safety and Health 1996). The MAK value in Germany
is based on the results of the study by Diem (1907). The immediate danger to life and health
(IDLH) of 25 ppm (NIOSH, 1996) is based on acute toxicity data in humans (conversion of
lethal oral dose to inhalation equivalent) and animals (secondary source).
ERPG levels were developed specifically for white fuming nitric acid (AIHA, 2001) and are
based on toxicity data in animals with nitric acid or nitrogen dioxide and dose-response estimates
in humans exposed to nitrogen dioxide.
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TABLE 7. Extant Standards and Guidelines for Nitric Acid
Guideline
AEGL-1
AEGL-2
AEGL-3
ERPG-1 (AIHA)a
ERPG-2 (AIHA)
ERPG-3 (AIHA)
PEL-TWA
(OSHA)b
IDLH (NIOSH)C
REL-TWA
(NIOSH)d
REL-STEL
(NIOSH)e
TLV-TWA
(ACGIH)f
TLV-STEL
(ACGIH)g
MAK
(Germany)11
MAK Peak Limit
(Germany)1
MAC
(The Netherlands)"
OEL-LLV
(Sweden)k
OEL-STV
(Sweden)1
Exposure Duration
10 minute
0.53 ppm
43 ppm
170 ppm
30 minute
0.53 ppm
30 ppm
120 ppm
25 ppm
4 ppm
4 ppm
2 ppm
5 ppm
1 hour
0.53 ppm
24 ppm
92 ppm
1 ppm
6 ppm
78 ppm
4 hour
0.53 ppm
6.0 ppm
23 ppm
8 hour
0.53 ppm
3.0 ppm
11 ppm
2 ppm
2 ppm
2 ppm
2 ppm
2 ppm
2 ppm
"ERPG (Emergency Response Planning Guidelines, American Industrial Hygiene Association (AIHA 2002)
The EPJ'G-l is the maximum airborne concentration below which it is believed nearly all individuals could be
exposed for up to one hour without experiencing other than mild, transient adverse health effects or without
perceiving a clearly defined objectionable odor.
The EPJ)G-2 is the maximum airborne concentration below which it is believed nearly all individuals could be
exposed for up to one hour without experiencing or developing irreversible or other serious health effects or
symptoms that could impair an individual's ability to take protection action.
The EPJ'G-S is the maximum airborne concentration below which it is believed nearly all individuals could be
exposed for up to one hour without experiencing or developing life-threatening health effects.
bOSHA PEL-TWA (Occupational Safety and Health Administration, Permissible Exposure Limits - Time
Weighted Average) (OSHA 1999) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no
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more than 10 hours/day, 40 hours/week.
CIDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health)
(NIOSH 1996) represents the maximum concentration from which one could escape within 30 minutes without
any escape-impairing symptoms, or any irreversible health effects.
dNIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits -
Time Weighted Average) (NIOSH 2003) is defined analogous to the ACGIH-TLV-TWA.
'NIOSH REL-STEL (Recommended Exposure Limits - Short Term Exposure Limit) (NIOSH 2003) is defined
analogous to the ACGffl TLV-STEL.
fACGIH TLV-TWA (American Conference of Governmental Industrial Hygienists, Threshold Limit Value -
Time Weighted Average) (ACGIH 2003) is the time-weighted average concentration for a normal 8-hour
workday and a 40-hour workweek, to which nearly all workers may be repeatedly exposed, day after day,
without adverse effect.
gACGIH TLV-STEL (Threshold Limit Value - Short Term Exposure Limit) (ACGIH 2003) is defined as a 15-
minute TWA exposure which should not be exceeded at any time during the workday even if the 8-hour TWA is
within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 minutes
and should not occur more than 4 times per day. There should be at least 60 minutes between successive
exposures in this range.
hMAK (Maximale Arbeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche
Forschungsgemeinschaft [German Research Association] 2002) is defined analogous to the ACGIH-TLV-TWA.
'MAK Spitzenbegrenzung (Peak Limit [Category 1,1]) (German Research Association 2002) constitutes the
maximum average concentration to which workers can be exposed for a period up to 15 minutes with no more
than 4 exposure periods per work shift and a minimum of 1 hour between excursions.
JMAC (Maximaal Aanvaaarde Concentratie [Maximal Accepted Concentration]) (National MAC List 2000) is
defined analogous to the ACGIH-TLV-TWA.
kOEL-LLV (Occupational Exposure Limits - Level Limit Value) (Swedish National Board of Occupational
Safety and Health, 1996) is an occupational exposure limit value for exposure during one working day.
'OEL-STV (Occupational Exposure Limits - Short-term Value) (Swedish National Board of Occupational Safety
and Health, 1996) is a recommended value consistin of a time-weighted average for exposure during a reference
period of 15 minutes.
8.3 Data Adequacy and Research Needs
Limited inhalation data were available for determining the AEGL levels. Only one well-
conducted study in rats was available. Most animal data administered nitric acid by intratracheal
instillation which does not necessarily mimic inhalation exposures. Data from human case
reports lacked exposure concentrations and durations.
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9. REFERENCES
Abraham, W.M., C.S. Kim, M.M. King, W. Oliver, and L. Yerger. 1982. Effects of nitric acid on carbachol
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Du Pont Co. 1987. One-hour inhalation median lethal concentration (LC50) study with nitric acid. Haskell
Laboratory Report No 451-87. Newark, Delaware. 26pp.
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Goldstein, E., N.F. Peek, N.J. Parks, H.H. Hines, E.P. Steffey, and B. Tarkington. 1977. Fate and distribution of
inhaled nitrogen dioxide in Rhesus monkeys. Am. Rev. Resp. Dis. 115:403-412.
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inhalation toxicity of nitrogen dioxide, red fuming nitric acid, and white fuming nitric acid. Arch. Ind. Hyg.
Occup. Med. 10:418-422.
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nitric acid fume inhalation in three pulp-mill workers. Chest 97:487-489.
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Hine, C.H., F.H. Meyers, and R.W. Wright. 1970. Pulmonary changes in animals exposed to nitrogen dioxide,
effects of acute exposures. Toxicol. Appl. Pharmacol. 16:201-213.
HSDB. 1996. Hazardous Substances Data Bank. TOXNET Online Information Retrieval System, National Library
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Mink, S.N., J. J. Coalson, L. Whitley, H. Greville, and C. Jadue. 1984. Pulmonary function tests in the detection of
small airway obstruction in a canine model of bronchiolitis obliterans. Am. J. Respir. Dis. 130:1125-1133.
Myint, S.S. and S.K. Lee. 1983. Pulmonary effects of acute exposure to nitrous fumes-a case report. Singapore
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NARSTO. 2004. Paniculate Matter Assessment for Policy Makers: A NARSTO Assessment. McMurry, M.
Shepherd, and J. Vickery, eds. Cambridge, UK: Cambridge University Press.
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NIOSH. 1976a. National Institute for Occupational Safety and Health. NIOSH criteria for a recommended
standard.... occupational exposure to nitric acid. U.S. Department of Health, Education, and Welfare,
Washington, D.C., HEW publication No. (NIOSH) 76-141, 78pp.
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Health, Education, and Welfare, Washington, D.C., HEW publication No. (NIOSH) 76-149, 195pp.
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(§1910.1000), p. 14.
Ostro, B.D., MJ. Lipsett, M.B. Wiener, and J.C. Seiner. 1991. Asthmatic responses to airborne acid aerosols. Am.
J. Public Health 81:694-702.
Peters, S.G. and R.E. Hyatt. 1986. A canine model of bronchial injury induced by nitric acid. Lung mechanics and
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Peters, J.M., Avol, E., Navidi, W., London, S.J., Gauderman, W.J., Lurmann, F., Linn, W.S., Margolis, H.,
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ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of
irritant and systemically acting vapours and gases. J. Hazard. Mat. 13:301-309.
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of Pollution Prevention and Toxics, U.S. EPA, Washington, D.C. 17pp.
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organic and inorganic compounds and aqueous solutions. Toxic. Appl. Pharmacol. 42:417-423.
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APPENDIX A: Derivation of AEGL Values
DERIVATION OF AEGL-1 VALUES
Key study: Sackner and Ford, 1981
Toxicity endpoint: No changes in pulmonary function were reported in five healthy
volunteers exposed to 1.6 ppm (4.13 mg/m3) nitric acid vapor at rest for 10
minutes.
Time scaling: Not applied
Uncertainty factors: 3 for intraspecies variability
Modifying factors: None
Calculations: None; 0.53 ppm value applied across AEGL-1 exposure durations
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DERIVATION OF AEGL-2 VALUES
Key study: Du Pont 1987
Toxicity endpoints: Exposure to 470 ppm for 1 hour resulted in transient body weight loss 1-2
days post-exposure.
Scaling: C" x t = k (ten Berge et al., 1986)
n = 3 for extrapolating to the 10- and 30-minute timepoints
n = 1 for extrapolating to the 4- and 8-hour timepoints
Uncertainty factors: Total 10: 3 for interspecies variability and 3 for intraspecies variability
Modifying factor: 2 because clinical observations were not well described, a concentration-
response could not be determined for nonlethal effects, and clear evidence of
AEGL-2 effects did not occur in the study
Calculations: 10- and 30-min timepoints: (C/uncertainty and modifying factors)3 x t = k
(470 ppm/20)3 x 1 hr = 12977.875 ppm3-hr
4- and 8-hr timpoints: (C/uncertainty and modifying factors)1 x t = k
(470 ppm/20)1 x 1 hr = 23.5 ppm-hr
10-minute AEGL-2: C = (12977.875 ppm-hour/0.167 hours)173
C = 43 ppm
30-minute AEGL-2: C = (12977.875 ppm-hour/0.5 hour)173
C = 30 ppm
1 -hour AEGL-2: C = (470 ppm/20) = 24 ppm
4-hour AEGL-2: C = (23.5 ppm-hour/4 hours)1
C = 6.0 ppm
8-hour AEGL-2: C = (23.5 ppm-hour/8 hours)1
C =3.0 ppm
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DERIVATION OF AEGL-3 LEVELS
Key study: Du Pont 1987
Toxicity endpoint: An LCoi of 919 ppm was calculated by a log-probit analysis of mortality
data in the rat.
Scaling: C" x t = k (ten Berge et al., 1986)
n = 3 for extrapolating to the 10- and 30-minute timepoints
n = 1 for extrapolating to the 4- and 8-hour timepoints
Uncertainty factors: Total 10: 3 for interspecies variability and 3 for intraspecies variability
Modifying factor: None
Calculations: 10- and 30-min timepoints: (C/uncertainty factors)3 x t = k
(919ppm/10)3x Ihr = 776151.559 ppm3-hr
4- and 8-hr timpoints: (C/uncertainty factors)1 x t = k
(919ppm/10)1 x 1 hr = 91.9ppm-hr
10-minute AEGL-3: C = (776151.559 ppm-hour/0.167 hours)173
C= 170 ppm
30-minute AEGL-3: C = (776151.559 ppm-hour/0.5 hour)173
C = 120 ppm
1-hour AEGL-3: C = (919 ppm/10) = 92 ppm
4-hour AEGL-3: C = (91.9 ppm-hour/4 hours)1
C = 23 ppm
8-hour AEGL-3: C = (91.9 ppm-hour/8 hours)1
C = 11 ppm
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APPENDIX B: Derivation Summary for AEGL Values
for Nitric Acid
(CAS No. 7697-37-2)
10 minutes
0.53 ppm
30 minutes
0.53 ppm
1 hour
0.53 ppm
4 hours
0.53 ppm
8 hours
0.53 ppm
AEGL-1 VALUES FOR NITRIC ACID
Reference: Sackner, M.A. and Ford, D. 1981. Effects of breathing nitrate aerosols in high
concentrations for 10 minutes on pulmonary function of normal and asthmatic
adults, and preliminary results in normals exposed to nitric acid fumes. Am. Rev.
Resp. Pis. 123:151.
Test Species/Strain/Number: Human subjects, sex not given, healthy, 10
Exposure Route/Concentrations/Durations: Inhalation: 1.6 ppm for 10 minutes
Effects: no effects
Endpoint/Concentration/Rationale: NOAEL for changes in pulmonary function (vital
capacity, respiratory resistance, and FEVi); this is the
highest NOAEL available in humans
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applicable; human data used
Intraspecies: 3 - The mechanism of action, irritation, is not expected to differ greatly
among individuals because nitric acid is a direct acting irritant.
Modifying Factor: None
Animal to Human Dosimetric Adjustment: Not applicable; human data used
Time Scaling: Extrapolation to time points was not conducted.
Data Quality and Support for the AEGL Values: Although no dose-response data was
included in the study, the values are based on human data. The point of departure is the
highest NOAEL available in humans.
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10 minutes
43 ppm
30 minutes
30 ppm
1 hour
24 ppm
4 hours
6.0 ppm
8 hours
3.0 ppm
AEGL-2 VALUES FOR NITRIC ACID
Reference: Du Pont Co. 1987. One-hour inhalation median lethal concentration (LCso) study
with nitric acid. Haskell Laboratory Report No 451-87. Newark, Delaware. 26pp.
Test Species/Strain/Sex/Number: rat/Crl:CD"BR/males and females/5 per sex per
concentration
Exposure Route/Concentrations/Durations: inhalation/270-3100 ppm/1 hour
Effects: 260 and 470 ppm: body weight loss for 1-2 days
> 1300 ppm: partially closed eyes
> 1600 ppm: lung noise and gasping
> 1500 ppm: extended weight loss up to 12 days post-exposure in males
> 1600 ppm: extended weight loss up to 12 days post-exposure in females
3100 ppm: 100% lethality
Endpoint/Concentrati on/Rationale:
470 ppm for 1 hour; the point of departure is a NOAEL
for AEGL-2 endpoints and would not be escape
impairing.
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3 - The mechanism of toxicity, the direct reaction of nitric acid with
biological tissue is not expected to vary between humans and animals.
Intraspecies: 3 - The mechanism of action of a corrosive acid in the lung is not expected
to differ greatly among individuals.
Modifying Factor: 2 - Clinical observations were not well described, a concentration-response
could not be determined for nonlethal effects, and clear evidence of
AEGL-2 effects did not occur in the study
Animal to Human Dosimetric Adjustment: not applicable
Time Scaling: Cn x t = k
n = 3 for extrapolating to the 10- and 30-minute timepoints
n = 1 for extrapolating to the 4- and 8-hour timepoints
Comments: Nitrogen dioxide content monitored during exposures; none measured.
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10 minutes
170 ppm
30 minutes
120 ppm
1 hour
92 ppm
4 hours
23 ppm
8 hours
11 ppm
AEGL-3 VALUES FOR NITRIC ACID
Reference: Du Pont Co. 1987. One-hour inhalation median lethal concentration (LCso) study
with nitric acid. Haskell Laboratory Report No 451-87. Newark, Delaware. 26pp.
Test Species/Strain/Sex/Number: rat/Crl:CD"BR/males and females/5 per sex per
concentration
Exposure Route/Concentrations/Durations: inhalation/270-3100 ppm/1 hour
Effects: 260 and 470 ppm: body weight loss for 1-2 days; no death
1300 ppm: 1/10 died
1500 ppm: 1/10 died
1600 ppm: 2/10 died
2500 ppm: 3/10 died
2700 ppm: 3/10 died
3100 ppm: 100% lethality
Endpoint/C oncentrati on/Rati onal e:
LCoi of 919 ppm estimated by log-probit analysis of
mortality data
Uncertainty Factors/Rationale:
Total uncertainty factor: 10
Interspecies: 3- The mechanism of toxicity, the direct reaction of nitric acid with
biological tissue is not expected to vary between humans and animals.
Intraspecies: 3 - The mechanism of action of a corrosive acid in the lung is not expected
to differ greatly among individuals.
Modifying Factor: None
Animal to Human Dosimetric Adjustment: not applicable
Time Scaling: Cn x t = k
n = 3 for extrapolating to the 10- and 30-minute timepoints
n = 1 for extrapolating to the 4- and 8-hour timepoints
Comments: Nitrogen dioxide content monitored during exposures; none measured.
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Appendix C: Time-scaling category plot
for Nitric Acid
Chemical Toxicity - TSD All Data
Nitric Acid
10000.0
1000.0
100.0
Q. 10.0
1.0
0.1
0.0
n
Human - No Effect
Human - Discomfort
Human - Disabling
Animal-No Effect
Animal - Discomfort
Animal - Disabling
Animal - Some Lethality
Animal - Lethal
0 60 120 180 240 300 360 420 480
Minutes
No effect = No effect or mild discomfort
Discomfort = Notable transient discomfort/irritation consistent with AEGL-1 level effects
Disabling = Irreversible/long lasting effects or an impaired ability to escape
Some lethality = Some, but not all, exposed animals died
Lethal = All exposed animals died
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