5

Nitric Acid1

Acute Exposure Guideline Levels

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 (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) 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, nonsensory

________________________________

1This document was prepared by the AEGL Development Team composed of Carol Wood (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Chemical Managers Loren Koller and George Woodall (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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5 Nitric Acid1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished 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, nonsensory 1 This document was prepared by the AEGL Development Team composed of Carol Wood (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Chemical Managers Loren Koller and George Woodall (National Advisory Committee [NAC] on Acute Ex- posure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environ- mental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifi- cally valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 139

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140 Acute Exposure Guideline Levels 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 sus- ceptible 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 sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory 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 concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Nitric acid is a highly corrosive, strongly oxidizing acid. Nitric acid may exist in the air as a gas, vapor, mist, fume, or aerosol. Nitric acid mist will prob- ably be scrubbed in the mouth or nasal passages, gas and vapor in the upper res- piratory tract, and fume and aerosol in the alveolar region of the lungs. Toxicity after inhalation exposure to nitric acid is similar in humans and animals. Nitric acid fumes may cause immediate irritation of the respiratory tract, pain, and dyspnea, followed by a period of recovery that may last several weeks. A re- lapse may occur resulting in death caused by bronchopneumonia and pulmonary fibrosis. At nonlethal concentrations, allergic or asthmatic individuals appear to be sensitive to acidic atmospheres (NIOSH 1976a; ACGIH 1991). Both human and animal data were used to derive AEGL values. The point of departure for AEGL-1 values was selected on the basis of a study in which five healthy volunteers were exposed to nitric acid at 1.6 ppm for 10 min and had no changes in pulmonary function (vital capacity, respiratory resistance, and forced expiratory volume [FEV1]) (Sackner and Ford 1981). That was the high- est no-effect level available in humans. An uncertainty factor of 10 was applied to account for variability in the general population and possibly greater sensitivi- ty of asthmatics to effects of a direct-acting irritant on pulmonary function. The 10-min AEGL value of 0.16 ppm was adopted for all the other AEGL durations, because the point of departure was a no-effect level for pulmonary irritation and

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Nitric Acid 141 such irritation is generally concentration dependent but not time dependent. AEGL-1 values are higher than the odor threshold for nitric acid, which pro- vides a warning about exposure before an individual could experience notable discomfort. AEGL-2 and AEGL-3 values were based on a well-conducted, lethality study in rats (DuPont 1987). Groups of five male and five female Crl:CD®BR rats were exposed nose-only to nitric acid aerosol at 260-3,100 ppm for 1 h, and were observed for 14 days. Rats exposed at 470 ppm exhibited transient body weight loss 1-2 days post-exposure. At the next higher concentration, partially closed eyes (a possible sign of severe ocular irritation), which could definitely impair escape, and lung noise were reported. Thus, 470 ppm was used as the point of departure for deriving AEGL-2 values, because it is a no-effect level for impaired ability to escape. Time scaling to the 10- and 30-min and 4- and 8-h AEGL durations was performed using the equation Cn × t = k (ten Berge et al. 1986). Because an empirical value for n could not be derived from the data, scal- ing was performed using default values of n = 3 for extrapolating to shorter du- rations and n = 1 for extrapolation to longer durations. A total uncertainty factor of 10 was applied: a factor of 3 to account for interspecies differences and an- other factor of 3 for intraspecies variability. Larger uncertainty factors were con- sidered unnecessary because the mechanism of action for a direct ocular irritant and for a corrosive acid in the lung is not expected to differ greatly between spe- cies or among individuals. In addition, a modifying factor of 2 was applied be- cause clinical observations were not well described, and AEGL-2 and AEGL-3 values overlap, suggesting a very steep concentration-response relationship. AEGL-3 values were based on an LC01 (lethal concentration, 50% lethali- ty) of 919 ppm, calculated by log-probit analysis of lethality data in rats (DuPont 1987). Time scaling was performed as was done for the AEGL-2 values, and the same uncertainty factors were applied. AEGL values for nitric acid are presented in Table 5-1. If nitrogen dioxide is of concern, AEGL values for that chemical are available (see NRC 2012). 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, which gives the liquid a yellow color. Con- centrated nitric acid containing dissolved nitrogen dioxide is termed fuming nitric acid, which evolves suffocating, poisonous fumes of nitrogen dioxide and nitrogen tetroxide (O’Neil et al. 2006). White fuming nitric acid contains 0.5% dissolved nitrogen dixoide while red fuming nitric acid contains 14% dissolved nitrogen dioxide (ACGIH 1991). Inhalation of nitric acid involves exposure to nitric acid as well as nitrogen oxides, such a nitrogen dioxide and nitric oxide. Fuming nitric acid reacts with wood or metals and emits fumes of nitrogen dioxide, which form equimolar amounts of nitrous and nitric acid when in contact with steam (NIOSH 1976a;

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142 Acute Exposure Guideline Levels O’Neil et al. 2006). Nitrogen oxide reacts quantitatively with oxygen in air to form nitrogen dioxide, which then reacts with water to form nitric acid. Most reports of human occupational exposure are limited to measurements of nitrogen oxides (NIOSH 1976a). If other oxides of nitrogen are of concern, NRC (2012) should be consulted for relevant AEGL values for nitrogen dioxide, nitric oxide, and nitrogen tetroxide. Production of nitric acid atmospheres for inhalation exposure experiments potentially results in a variety of physical states (gas, fume, and vapor) depend- ing on the production method used. For each study described in this chapter, the physical state and atmosphere-generation methods are presented as described by the study authors. Nitric acid is used to dissolve noble metals, for etching and cleaning met- als, to make nitrates and nitro compounds found in explosives, and, primarily, to make ammonium nitrate fertilizer (ACGIH 1991). Nitric acid contributes to acid deposition (or acid rain). It is a large contributor to acid deposition in the west- ern United States compared with the eastern states (NARSTO 2004). Selected chemical and physical properties of nitric acid are presented in Table 5-2. TABLE 5-1 AEGL Values for Nitric Acid End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm No-effect level (nondisabling) (0.41 (0.41 (0.41 (0.41 (0.41 for notable mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) discomfort in humans (changes in pulmonary function: vital capacity, respiratory resistance, and FEV1) (Sackner and Ford 1981). AEGL-2 43 ppm 30 ppm 24 ppm 6.0 ppm 3.0 ppm No-effect level (disabling) (110 (77 (62 (15 (7.7 for inability to mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) escape; eye closure in rats exposed at 470 ppm for 1 h (DuPont 1987). AEGL-3 170 ppm 120 ppm 92 ppm 23 ppm 11 ppm No-effect level (lethal) (440 (310 (240 (59 (28 for lethality mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (estimated LC01, 919 ppm) in rats (DuPont 1987). Abbreviations: FEV1, forced expiratory volume; LC01, lethal concentration, 50% lethali- ty).

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Nitric Acid 143 TABLE 5-2 Chemical and Physical Data for Nitric Acid Parameter Value Reference Common name Nitric acid Synonyms Aqua fortis, azotic acid O’Neil et al. 2006 CAS registry no. 7697-37-2 Chemical formula HNO3 O’Neil et al. 2006 Molecular weight 63.01 O’Neil et al. 2006 Physical state Colorless liquid; fumes O’Neil et al. 2006 in moist air Melting point -41.59°C O’Neil et al. 2006 Boiling point 83°C HSDB 2012 Density/specific gravity 1.51269 O’Neil et al. 2006 Vapor density (air = 1) 2-3 (estimated) HSDB 2012 Solubility in water Freely soluble EPA 1993 Vapor pressure 47.9 mm Hg at 20°C ACGIH 1991 Flammability Noncombustible HSDB 2012 pH (0.5% in saline) 1.6 Coalson and Collins 1985 Conversion factors in air 1 mg/m3 = 0.388 ppm EPA 1993 1 ppm = 2.58 mg/m3 2. HUMAN TOXICITY DATA Nitric acid may exist in the following airborne forms: gas, vapor, mist, fume, and aerosol. Nitric acid mist will probably be scrubbed in the mouth or nasal passages, gas and vapor in the upper respiratory tract, and fume and aero- sol in the alveolar region of the lungs. For each study description below, the physical state and atmosphere-generation methods are presented as described by the study authors. 2.1. Acute Lethality Hall and Cooper (1905) described 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. Therefore, firemen were exposed to a mixture of nitric acid fumes and reaction products (e.g., nitrogen monoxide), which may have contrib- uted to clinical outcomes observed. Of the 20 individuals exposed to the fumes, dyspnea was present in 100%, cough in 93%, pain in the sides, stomach, lungs,

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144 Acute Exposure Guideline Levels 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 gen- erally 3 weeks after exposure and persisted an average of 15.5 days. Four indi- viduals died, two on the second day after exposure and two several weeks later after relapse. The two who died after relapse appeared to be recovering as well as the other survivors, however, both were exposed to cold air and almost im- mediately relapsed. Autopsy revealed hemorrhagic edema and coagulation ne- crosis. Exposure concentrations were not measured but the investigators con- cluded that the severity of the initial exposure was the most important factor in determining recovery or 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 explo- sion of a tank containing approximately 1,736 L of 68% nitric acid. Escape from the building took 10-15 min. No respiratory problems were apparent during medical examination immediately after exposure; however, increasing respirato- ry difficulties developed 4-6 h later. On admission to the hospital, all subjects were cyanotic and had frothy fluid escaping from the nose and mouth. All died within 21 h after the accident. Pathologic evaluation of the lungs revealed degranulated and necrotic neutrophils within the alveolar capillaries. Concentra- tions 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. Exposure was very likely to ni- trogen monoxide (a reaction product of nitric acid with silver and other metals) or a mixture of the monoxide and nitric acid. The first symptoms of respiratory distress occurred 30 min later; approximately 1 h later he entered a hospital emergency room with dyspnea, expiratory stridor, peripheral cyanosis, and gen- eral paleness. Chest X-ray showed pulmonary edema. The patient stabilized for 3 days after intense treatment and lung function improved. However, the patient died from refractory respiratory failure on the fourth day, and pulmonary edema was observed at autopsy (Bur et al. 1997). Other lethal exposure scenarios have been summarized by others (see NIOSH 1976a; ACGIH 1991). 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. Relapse may occur, with death caused by bronchopneumonia or pulmonary fibrosis. Nitric acid concentrations were not provided in the primary reports. 2.2. Nonlethal Toxicity Nitric acid is described as having a characteristic choking odor (O’Neil et al. 2006). Low and high odor thresholds were reported as 0.29 and 0.97 ppm, respectively (EPA 1993).

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Nitric Acid 145 2.2.1. Case Reports A 42-year old man with no history of respiratory disease was exposed for 3 h 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 pul- monary edema; he was treated with oxygen and high doses of corticosteroids. After 3 months his chest X-ray was clear and lung function tests were normal (Myint and Lee 1983). 2.2.2. Epidemiologic Studies 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 asth- matics 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 itself was not specifically associated with any respiratory symptom analyzed. Nitric acid concentrations ranged from 0.06 to 13.54 μg/m3 (0.15 to 34.93 ppb) during the study period. Health effects from exposure to acidic air pollution in children (8-12 years old) were monitored in 24 communities in the United States and Canada (Dock- ery et al. 1996; Raizenne et al. 1996). Air quality and meteorology were meas- ured for 1 year in each community and parents completed a respiratory health questionnaire. At the end of the 1-year monitoring period, children were admin- istered pulmonary function tests consisting of forced vital capacity (FVC) and forced expiratory volume (FEV) measurements. Cconcentrations 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 signifi- cantly higher risk of asthma (odds ratio = 2.00; 95% confidence interval[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 concentrations of both acid and nitrogen dioxide in boys, whereas regression analysis showed that acid vapor was significantly associated with lower FVC, FEV1, peak expiratory flow rate, and maximal midexpiratory flow in girls. When the data were further analyzed by month (Millstein et al. 2004), wheezing during the spring and sum- mer months was not associated with either nitric acid or nitrogen dioxide. How- ever, in asthmatics, the monthly prevalence of asthma medication use was asso-

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146 Acute Exposure Guideline Levels ciated with monthly concentrations of ozone, nitric acid, and acetic acid (Mill- stein et al. 2004). 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. Concentra- tions of total oxidation products, expressed as nitrous acid concentration, were determined analytically by either oxidation of hydrogen peroxide or by reduc- tion using potassium iodide. Although the generated atmospheres were likely a mixture of nitrogen oxides, exposure concentrations were expressed as total ni- tric acid content and are reported in ppm as was done by NIOSH (1976b). One researcher exposed himself to nitric acid at 62 ppm (160 mg/m3) for 1 h and reported irritation of the larynx, thirst, and an objectionable odor. He was then exposed at 74-101 ppm (190-260 mg/m3) for 1 h and then at 23-43 ppm (60-110 mg/m3) for another hour. Immediate severe irritation with cough and an increase in pulse and respiratory rates were reported after 40 min. He was able to tolerate exposure at 158 ppm (408 mg/m3) but for only 10 min, 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. On the basis of their results and comparing them with other work, the investigators 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 h (Diem 1907). Symptoms included irritation of the nasal mu- cosa, 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 min, all symptoms except nasal secretion abated somewhat and a slight frontal headache developed. Some of these symptoms persisted for about 1 h post-exposure. In a second experiment, the researcher could tolerate 85 ppm (219 mg/m3) for only 2-3 min. In these experiments, concentrations of nitric acid were produced by warming the acid and samples of the chamber air were measured by simple titra- tion with the indicator Congo red. 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 nine allergic adolescents (12-18 years old) was exposed to ni- tric acid gas and their pulmonary function was assessed. All subjects had exer- cise-induced bronchospasm defined as a greater than 15% drop in FEV1 after 6 min of exercise at 85% maximum oxygen consumption. Five individuals also had allergic asthma. Individuals were exposed to nitric acid at 0.05 ppm (0.129

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Nitric Acid 147 mg/m3) through a rubber mouthpiece with nose clips for 40 min (30 min at rest, 10 min of moderate exercise on a treadmill). Each individual served as his or her own control with post-exposure pulmonary function values compared with base- line. After exposure to nitric acid, FEV1 decreased by 4% and respiratory re- sistance 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, short- ness of breath, or wheezing. On a separate testing day when subjects were ex- posed to only air, FEV1 decreased by 2% and respiratory resistance increased by 7% (Koenig et al. 1989). No changes in pulmonary function (vital capacity, respiratory resistance, and FEV1) occurred in five healthy volunteers exposed at rest to nitric acid fumes at 1.6 ppm (4.13 mg/m3) for 10 min (Sackner and Ford 1981). No changes in pul- monary function, lavage constituents, or bronchial biopsy specimens were found in 10 healthy, athletic subjects exposed to nitric acid gas at 0.194 ppm (0.5 mg/m3) for 4 h during moderate exercise (Aris et al. 1993). 2.3. Developmental and Reproductive Toxicity No information regarding the developmental or reproductive toxicity of nitric acid in humans was found. 2.4. Genotoxicity No information regarding the genotoxicity of nitric acid in humans was found. 2.5. Carcinogenicity No information regarding the carcinogenicity of nitric acid in humans was found. 2.6. Summary Studies and case reports of exposure to nitric acid fumes and reaction products (e.g., nitrogen monoxide) are not directly relevant to nitric acid mists and vapor. However, the course of toxicity following inhalation exposures to atmospheres resulting from spills of nitric acid is consistent among the case re- ports. Nitric acid fumes may cause immediate irritation of the respiratory tract, pain, and dyspnea, followed by a period of recovery that may last several weeks. Relapse may occur, with death caused by bronchopneumonia or pulmonary fi- brosis. Allergic or asthmatic individuals are the most sensitive populations when considering nonlethal concentrations of nitric acid.

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148 Acute Exposure Guideline Levels 3. ANIMAL TOXICITY DATA Production of nitric acid atmospheres for inhalation exposure experiments potentially results in a variety of physical states (gas, fume, and vapor) depend- ing on the production method used. For each study description below, the physi- cal state and atmosphere generation methods are presented as described by the investigators. 3.1. Acute Lethality 3.1.1. Cats Lehmann and Hasegawa (1913) conducted a series of experiments using cats exposed to nitric acid gases produced as described in Section 2.2.3. In gen- eral, as concentration or duration of exposure to nitric acid increased, death re- sulted from severe pulmonary edema. At concentrations less than about 388 ppm (1,000 mg/m3), examination of the concentration and time relationship indicated that Ct products greater than about 900 ppm-h resulted in death whereas Ct products up to 760 ppm-h resulted in only a slight increase in respiration for several hours after exposure. Further, exposure at 287 ppm (740 mg/m3) for 1.83 h (Ct = 526 ppm-h) caused no effects, whereas exposure at either 341 ppm (880 mg/m3) for 3.83 h (Ct = 1,309 ppm-h) or 217 ppm (560 mg/m3) for 4.25 h (Ct = 922 ppm-h) resulted in death. In contrast, at concentrations of 388 ppm (1,000 mg/m3) or greater, severe clinical signs or death occurred at a Ct product as low as 277 ppm-h. 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 because only one animal was test- ed at each concentration and time combination. 3.1.2. Rats Groups of five male and five female Crl:CD®BR rats were exposed nose- only for to nitric acid aerosol at 260-3,100 ppm for 1 h, followed by a 14-day observation period (DuPont 1987). Atmospheres were generated with a nebuliz- er and airborne test material was dispersed with a baffle. Although an aerosol was generated, concentrations were reported in the study as ppm instead of mg/m3. Aerosol content was assumed to be 100% at the three highest concentra- tions and ranged from 15-73% at the five lower concentrations as measured on a gravimetric filter sample. Except for the 2,500 and 2,700 ppm concentrations, all exposures contained 70% or more respirable particles, with a mass median aero- dynamic diameter (MMAD) of 4.0 μm or less. The 2,500- and 2,700-ppm con- centrations contained 59 and 61% respirable particles and had mass median aer- odynamic diameters of 6.5 and 6.6 μm, respectively. Despite generation of the small particle size resulting in a high percentage of respirable particles, it is un-

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Nitric Acid 149 clear why the concentrations were reported in ppm rather than 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 1,300 ppm or higher, lung noise and gasping at 1,600 ppm or higher, and extended weight loss up to 12 days post-exposure at 1,500 ppm or higher for males and 1,600 ppm or higher for females. Mortality results are presented in Table 5-3. The 1-h LC50 for males and females combined was 2,500 ppm. Although males died at lower concentrations than females, no apparent differences in clinical responses or LC50 values were observed between males and females (DuPont 1987). Gray et al. (1954) compared the toxicities of nitrogen dioxide, red fuming nitric acid (RFNA) (containing 8-17% nitrogen dioxide), and white fuming ni- tric acid (WFNA) (containing 0.1-0.4% nitrogen dioxide) by inhalation in rats. Outcomes related to exposure to RFNA and nitrogen dioxide are reported here to provide a complete description of the study; however, the chemicals are not directly relevant to nitric acid fumes. Although graphs of the dose-response curves were presented in the paper, the authors did not include the data from which those curves were plotted. Exposure concentrations for RFNA and WFNA were measured and reported as nitrogen dioxide. Thirty-minute LC50 values were reported to be 174 ppm (449 mg/m3) for nitrogen dioxide, 138 ppm (356 mg/m3) for RFNA as nitrogen dioxide, and 244 ppm (630 mg/m3) for WFNA as nitrogen dioxide. Deaths were from pulmonary edema. The dose- response curves for nitrogen dioxide and RFNA for 30-min exposures were par- allel statistically, indicating a possible similar mode of action for the two gases. But the curves were somewhat different at lower concentrations for an exposure duration of 240 min. For WFNA, the investigators reported that deaths were not as “predictable” as with the other gases. The approximate LC50 indicates that WFNA is much less toxic (has a higher LC50) than either RFNA or nitrogen di- oxide. Therefore, the investigators concluded that the main toxic component of these oxides of nitrogen is nitrogen dioxide. However, NIOSH (1976a) calculat- ed LC50s for RFNA and WFNA of 310 ppm (800 mg/m3) and 334 ppm (862 mg/m3), respectively, on the basis of total nitric acid concentration. The calcula- tions were based on molecular weights and the percentage of nitrogen dioxide in RFNA and WFNA. These estimates suggest the possibility that both nitric acid vapor and nitrogen dioxide contribute to the toxicity. 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 per week, dogs were anesthetized and a catheter placed in the mainstem bronchus; nitric acid at 1% was delivered as a course spray via a nebulizer with approximately 5 mL to the

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Nitric Acid 165 Swedish Work Environment Authority. 2005. P. 44 in Occupational Exposure Limit Val- ue and Measures against Air Contaminants. AFS 2005:17 [online]. Available: http://www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed Jan. 30, 2013]. 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. Haz- ard. Mater. 13(3):301-309. Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solu- tions. Toxicol. Appl. Pharmacol. 42(2):417-423.

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166 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR NITRIC ACID Derivation of AEGL-1 Values Key study: 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 results in normals exposed to nitric acid fumes. Am. Rev. Resp. Dis. 123(4Pt 2):151. Toxicity end point: No changes in pulmonary function (vital capacity, respiratory resistance, and FEV1) were reported in five healthy volunteers exposed to nitric acid vapor at 1.6 ppm (4.13 mg/m3) for 10 min at rest. Time scaling: Values were set equal across all AEGL durations because the point of departure is a no-effect level for irritation. Uncertainty factors: 10 for intraspecies variability; to account for variability in response in the general population and possible greater sensitivity of asthmatics to effects of a direct-acting irritant on pulmonary function. Modifying factors: None Calculations: 10-min AEGL-1: 1.6 ppm ÷ 10 = 0.16 ppm 30-min AEGL-1: Set equal to 10-min AEGL value of 0.16 ppm 1-h AEGL-1: Set equal to 10-min AEGL value of 0.16 ppm 4-h AEGL-1: Set equal to 10-min AEGL value of 0.16 ppm 8-h AEGL-1: Set equal to 10-min AEGL value of 0.16 ppm

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Nitric Acid 167 Derivation of AEGL-2 Values Key study: DuPont. 1987. One-hour Inhalation Median Lethal Concentration (LC50) Study with Nitric Acid. Report No 451-87. Haskell Laboratory, DuPont, Newark, DE. 26 pp. Toxicity end points: Exposure to nitric acid at 470 ppm for 1 h resulted in transient body weight loss 1-2 days post-exposure and was a no-effect level for eye closure and impairment of escape. Time scaling: Cn × t = k (default of n = 3 for extrapolating to the 10- and 30-min durations; default of n = 1 for extrapolating to the 4- and 8-h durations (470 ppm ÷ 20)3 × 1 h = 12,977.875 ppm-h (470 ppm ÷ 20)1 × 1 h = 23.5 ppm-h Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Total uncertainty factor of 10 Modifying factor: 2, because clinical observations were not well described, and AEGL-2 and AEGL-3 values overlap suggesting a very steep concentration-response relationship. Calculations: 10-min AEGL-2: C = (12,977.875 ppm-h ÷ 0.167 h)1/3 C = 43 ppm 30-min AEGL-2: C = (12,977.875 ppm-h ÷ 0.5 h)1/3 C = 30 ppm 1-h AEGL-2: 470 ppm ÷ 20 = 24 ppm 4-h AEGL-2: C = (23.5 ppm-h ÷ 4 h)1 C = 6.0 ppm 8-h AEGL-2: C = (23.5 ppm-h ÷ 8 h)1 C = 3.0 ppm

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168 Acute Exposure Guideline Levels Derivation of AEGL-3 Levels Key study: DuPont. 1987. One-hour Inhalation Median Lethal Concentration (LC50) Study with Nitric Acid. Report No 451-87. Haskell Laboratory, DuPont, Newark, DE. 26 pp. Toxicity end point: LC01 of 919 ppm was calculated by log-probit analysis of mortality data in rats. Time scaling: Cn × t = k (default of n = 3 for extrapolating to the 10- and 30-min durations; default of n = 1 for extrapolating to the 4- and 8-h durations (919 ppm ÷ 10)3 × 1 h = 776,151.559 ppm-h (919 ppm ÷ 10)1 × 1 h = 91.9 ppm-h Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Total uncertainty factor of 10 Modifying factor: None Calculations: 10-min AEGL-3: C = (776,151.559 ppm-h ÷ 0.167 h)1/3 C = 170 ppm 30-min AEGL-3: C = (776,151.559 ppm-h ÷ 0.5 h)1/3 C = 120 ppm 1-h AEGL-3: C = 919 ppm ÷ 10 = 92 ppm 4-h AEGL-3: C = (91.9 ppm-h ÷ 4 h)1 C = 23 ppm 8-h AEGL-3: C = (91.9 ppm-h ÷ 8 h)1 C = 11 ppm

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Nitric Acid 169 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR NITRIC ACID Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) Reference: 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 results in normals exposed to nitric acid fumes. Am. Rev. Resp. Dis. 123(4Pt 2):151. Test species/Strain/Number: Humans, sex not specified, 10 Exposure route/Concentrations/Durations: Inhalation, 1.6 ppm for 10 min Effects: No effects End point/Concentration/Rationale: No-effect level for changes in pulmonary function (vital capacity, respiratory resistance, and FEV1); highest no-effect level available in humans. Uncertainty factors/Rationale: Total uncertainty factor: 10 Intraspecies: 10, to account for variability in response in the general population and possibly greater sensitivity of asthmatics to effects of a direct-acting irritant on pulmonary function. Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: Not performed; values were set equal across all AEGL durations because the point of departure is a no-effect level for irritation. Data adequacy: Although no dose-response data was included in the study, the values are based on human data. The point of departure is the highest no-observed- adverse-effect level in humans. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 43 ppm 30 ppm 24 ppm 6.0 ppm 3.0 ppm (110 mg/m3) (77 mg/m3) (62 mg/m3) (15 mg/m3) (7.7 mg/m3) Reference: DuPont. 1987. One-hour Inhalation Median Lethal Concentration (LC50) Study with Nitric Acid. Report No 451-87. Haskell Laboratory, DuPont, Newark, DE. 26 pp. (Continued)

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170 Acute Exposure Guideline Levels AEGL-2 VALUES Continued Test species/Strain/Sex/Number: Rat, Crl:CD®BR, 5 males and 5 females per group Exposure route/Concentrations/Durations: Inhalation, 270-3,100 ppm for 1 h Effects: Concentration (ppm) Effects 260 and 470 Body weight loss for 1-2 days ≥1,300 Partially closed eyes ≥1,600 Lung noise and gasping ≥1,500 Extended weight loss up to 12 days post-exposure in males ≥1,600 Extended weight loss up to 12 days post-exposure in females 3,100 100% lethality End point/Concentration/Rationale: No-effect level for impaired ability to escape (eye closure) was 470 ppm for 1 h. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the mechanism of toxicity (direct reaction of nitric acid with ocular or pulmonary tissue) is not expected to vary between humans and animals. Intraspecies: 3, because the mechanism of action of a corrosive acid in the eye or lung is not expected to differ greatly among individuals. Modifying factor: 2, because clinical observations were not well described, and AEGL-2 and AEGL-3 values overlap suggesting a very steep concentration-response relationship. Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; n = 3 for extrapolating to the 10- and 30-min durations, and n = 1 for extrapolating to the 4- and 8-h duration Comments: Nitrogen dioxide content monitored during exposures; none measured. AEGL -3 VALUES 10 min 30 min 1h 4h 8h 170 ppm 120 ppm 92 ppm 23 ppm 11 ppm (440 mg/m3) (310 mg/m3) (240 mg/m3) (59 mg/m3) (28 mg/m3) Reference: DuPont. 1987. One-hour Inhalation Median Lethal Concentration (LC50) Study with Nitric Acid. Report No 451-87. Haskell Laboratory, DuPont, Newark, DE. 26 pp. Test species/Strain/Sex/Number: Rat, Crl:CD®BR, 5 males and 5 females per group Exposure rRoute/Concentrations/Durations: Inhalation, 270-3,100 ppm for 1 h Effects:

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Nitric Acid 171 Concentration (ppm) Effects 260 and 470 Body weight loss for 1-2 days; no death 1,300 1/10 died 1,500 1/10 died 1,600 2/10 died 2,500 3/10 died 2,700 3/10 died 3,100 10/10 died End point/Concentration/Rationale: LC01 of 919 ppm estimated by log-probit analysis of mortality data. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because the mechanism of toxicity (direct reaction of nitric acid with ocular or pulmonary tissue) is not expected to vary between humans and animals. Intraspecies: 3, because the mechanism of action of a corrosive acid in the eye or lung is not expected to differ greatly among individuals. Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k; n = 3 for extrapolating to the 10- and 30-min durations, and n = 1 for extrapolating to the 4- and 8-h durations Comments: Nitrogen dioxide content monitored during exposures; none measured.

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172 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR NITRIC ACID FIGURE C-1 Category plot of toxicity data and AEGL values for nitric acid. TABLE C-1 Data Used in Category Plot for Nitric Acid No. of Source Species Sex Exposures ppm Minutes Category Comments NAC/AEGL-1 0.16 10 AEGL NAC/AEGL-1 0.16 30 AEGL NAC/AEGL-1 0.16 60 AEGL NAC/AEGL-1 0.16 240 AEGL NAC/AEGL-1 0.16 480 AEGL NAC/AEGL-2 43 10 AEGL NAC/AEGL-2 30 30 AEGL NAC/AEGL-2 24 60 AEGL NAC/AEGL-2 6 240 AEGL (Continued)

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Nitric Acid 173 TABLE C-1 Continued No. of Source Species Sex Exposures ppm Minutes Category Comments NAC/AEGL-2 3 480 AEGL NAC/AEGL-3 170 10 AEGL NAC/AEGL-3 120 30 AEGL NAC/AEGL-3 92 60 AEGL NAC/AEGL-3 23 240 AEGL NAC/AEGL-3 11 480 AEGL Koenig et al. 1989 Human 1 0.05 40 0 Sackner and Human 1 1.6 10 0 Ford 1981 Aris et al. 1993 Human 1 0.194 240 0 DuPont 1987 Rat Both 1 260 60 1 Transient weight loss Rat Both 1 470 60 2 Transient weight loss Rat Both 1 1,300 60 SL Mortality (1/10); partially closed eyes Rat Both 1 1,500 60 SL Mortality (1/10); weight loss Rat Both 1 1,600 60 SL Mortality (2/10); lung noise, gasping Rat Both 1 2,500 60 SL Mortality (3/10) Rat Both 1 2,700 60 SL Mortality (3/10) Rat Both 1 3,100 60 3 Mortality (10/10) For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality.

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174 Acute Exposure Guideline Levels APPENDIX D DERIVATION OF LC01 VALUE FOR NITRIC ACID Filename: ten Berge Spreadsheet Data for Log Probit Model Date: 01 March 2012 Time: 16:01:18 Sequence No. Concentration (ppm) Minutes Exposed Responded 1 260 60 10 0 2 470 60 10 0 3 1300 60 10 1 4 1500 60 10 1 5 1600 60 10 2 6 2500 60 10 3 7 2700 60 10 3 8 3100 60 10 10 Observations 1 through 8 considered! Sequence No. Concentration (ppm) Minutes Exposed Responded 1 260 60 10 0 2 470 60 10 0 3 1300 60 10 1 4 1500 60 10 1 5 1600 60 10 2 6 2500 60 10 3 7 2700 60 10 3 8 3100 60 10 10 Used Probit Equation Y = B0 + B1*X1 X1 = ppm, ln-transformed Chi-Square = 9.29 Degrees of freedom = 6 Probability Model = 1.58E-01 Ln(Likelihood) = -11.92 B 0 = -1.2890E+01 Student t = -2.7813 B 1 = 2.2809E+00 Student t = 3.7913 Variance B 0 0 = 2.1479E+01 Covariance B 0 1 = -2.7859E+00 Variance B 1 1 = 3.6193E-01

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Nitric Acid 175 Estimation of ppm at response of 1% Point estimate ppm = 9.192E+02 for response of 1% Lower limit (95% CL) ppm = 3.509E+02 for response of 1% Upper limit (95% CL) ppm = 1.273E+03 for response of 1%