Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 14 (2013)

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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 

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 

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; 

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). 

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, 

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). 

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- 

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 

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. 

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- 

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 

150 Acute Exposure Guideline Levels left lung and 8 mL to the right lung. For an additional two exposures per week, dogs were intubated and spontaneously breathed nitric acid mist at 1% for 2 h. This exposure regime was continued for 4 weeks and the dogs were killed either immediately or after a 5-month recovery period. Dogs developed intermittent cough and produced clear mucoid sputum within one week after treatment be- gan. After 4 weeks, animals exhibited a decrease in total lung capacity and vital capacity with evidence of obstruction, as measured by a decrease in forced ex- piratory 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 post-exposure with significant reductions in maximal expiratory flows. Necropy performed on dogs killed immediately after exposure revealed edematous lungs with areas of focal hemorrhage. Lungs ap- peared normal in dogs after 5 months of recovery. Histologically, chronic air- way inflammation, slight epithelial changes, slight peribronchiolar fibrosis, and an increase in smooth muscle that persisted for 5 months post-exposure were found. Severity of the pathologic 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 most damaging to the airways. Bronchiolitis obliterans was produced in dogs after instillation of nitric ac- id at 1% into the airways. Two instillations of three 5-mL aliquots were given approximately 2 weeks apart and pulmonary function tests performed 2 weeks later. Treated dogs had mild cough with slight hemoptysis immediately after each treatment. Several pulmonary function tests indicated increased peripheral airway resistance, and acute and chronic inflammation of the small airways were observed at necropsy (Mink et al. 1984). TABLE 5-3 Mortality in Rats Exposed Nose-Only to Nitric Acid for 1 Hour Mortality Concentration (ppm) Males Females 260 0/5 0/5 470 0/5 0/5 1,300 1/5 0/5 1,500 1/5 0/5 1,600 2/5 0/5 2,500 2/5 1/5 2,700 2/5 1/5 3,100 5/5 5/5 Source: DuPont 1987. 

Nitric Acid 151 3.2.2. Rats Rats were treated once with 0.15 mL of nitric acid at 1% by intratracheal instillation. Focal lung damage found 1 day after administration 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 (about 10 per group) were exposed nose-only to nitric acid at 0, 5.1, 7.0, 13, or 19 ppm for 6 h/day on alternate days for a total of six exposures. Rats 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 nitric acid at 0.5% (0.5 mL saline/100 g body weight) (Coalson and Collins 1985). Several animals (number not specified) died before day 3 post-treatment and had severe hemorrhagic pulmonary edema. Airway changes in the remaining hamsters included acute bronchitis, acute bronchiolitis, obliter- ative bronchiolitis, bronchiolectasia, and bronchiectasis. These pathologic changes were accompanied by decreased lung volumes, decreased internal sur- face areas, increased lung weights, and increased elastin content. Airway dilata- tion and morphometric and biochemical changes persisted through day 60 post- treatment (the last day animals were examined). In a similar experiment, hamsters were exposed via intratracheal instilla- tion to 0.5 mL of nitric acid at 0.1 N. Up to 17 weeks post-exposure, histologic lesions in the lung included secretory cell metaplasia, interstitial fibrosis, bron- chiolectasis, and diffuse extension of hyperplastic bronchiolar epithelium into adjacent alveoli (Christensen et al. 1988). 3.2.4. Sheep 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 developing bronchospasm after inhalation challenge with Ascaris su- um antigen; the induced airway response is similar to that which occurs in hu- mans with allergic airway disease. Measurements of lung resistance were taken before exposure, after 20 breaths of carbachol at 2.5% (to induce bronchocon- striction), and after exposure to nitric acid vapor at 1.6 ppm (4.13 mg/m3) for 4 h. Immediately after treatment with nitric acid, sheep were given a second bron- chial challenge with aerosolized carbachol. Nitric acid exposure alone did not 

152 Acute Exposure Guideline Levels result in bronchoconstriction in either normal or allergic sheep, as measured by specific lung resistance. However, airway hyperreactivity to carbachol after ni- tric acid exposure occurred in allergic sheep. Pulmonary flow resistance from carbachol challenge before and after exposure 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 and Reproductive Toxicity No information regarding the developmental or reproductive toxicity of nitric acid in animals was found. 3.4. Genotoxicity Nitric acid at up to 0.008% was negative in mutagenicity tests with Esche- richia coli (Demerec et al. 1951). 3.5. Carcinogenicity No information regarding the carcinogenicity of nitric acid in animals was found. Lung damage in rats, induced by intratracheal instillation of 0.25 mL of nitric acid at 1%, 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 pulmonary changes in animal models of obstructive lung disease (Coalson and Collins 1985; Peters and Hyatt 1986; Fujita et al. 1988). Experi- ments with sheep (Abraham et al. 1982) have demonstrated the sensitivity of allergic individuals to acidic atmospheres. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No information regarding the pharmacokinetics of nitric acid was found. 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 or absorbed nitric-acid transport to the lower respiratory tract. 

Nitric Acid 153 4.2. Mechanism of Toxicity Nitric acid is a highly corrosive, strongly oxidizing acid (O’Neil et al. 2006). Contact with the liquid causes burns on the skin and corneal opacity (NIOSH 1976a). A 4-h occluded patch test induced skin corrosion in rabbits with nitric acid at 8%, but not 6% (Vernot et al. 1977). Respiratory irritation attributed to nitric acid 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. How- ever, 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 or absorbed nitric-acid transport to the lower respiratory tract. Reaction with endogenous ammonia and water may also produce particu- lates 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 (NO2) and nitric oxide (NO). Fuming nitric acid reacts with wood or metals and emits fumes of nitrogen diox- ide, which form equimolar amounts of nitrous and nitric acid when in contact with steam (NIOSH 1976a; O’Neil et al. 2006). In the presence of light, nitric acid undergoes an oxidation-reduction reaction to produce nitrogen dioxide, water, and oxygen. Nitric 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). In animal experiments, Lehmann and Hasagawa (1913) showed that up to a concentration of about 272 ppm (700 mg/m3), toxic response was the same whether the gas contained nitric acid alone or was a mixture of nitrous and nitric acid. As discussed in Section 3.1.2, Gray et al. (1954) compared the toxicities of nitrogen dioxide, RFNA, and WFNA in male rats. The dose-response curves for nitrogen dioxide and RFNA for 30-min exposures were parallel statistically, indicating a similar mode of action for the two gases. For both gases, deaths were from pulmonary edema. The 30-min LC50 value was 174 ppm (449 mg/m3) for nitrogen dioxide and 138 ppm as nitrogen dioxide (356 mg/m3) for RFNA. With exposures to WFNA, the authors stated that deaths were not as “predicta- ble as with the other gases”. The approximate LC50 for WFNA (244 ppm as ni- trogen dioxide [630 mg/m3]) indicates it is less toxic than either RFNA or nitro- gen dioxide. Therefore, the investigators concluded that the main toxic component of these oxides of nitrogen is nitrogen dioxide, and that RFNA is approximately 25% more toxic than nitrogen dioxide because of the contribution by the acid component. However, NIOSH (1976a) calculated LC50s for RFNA and WFNA of 310 ppm (800 mg/m3) and 334 ppm (862 mg/m3), respectively, 

154 Acute Exposure Guideline Levels on the basis of total nitric acid concentration. The calculations were based on molecular weights and the percentage of nitrogen dioxide in RFNA and WFNA. Because the values are very similar, it suggests the possibility of a synergistic effect between nitric acid vapor and nitrogen dioxide, because RFNA has a higher nitrogen dioxide content by weight than WFNA. The supposition that nitric acid and nitrogen dioxide interact to cause en- hanced toxicity is also supported, in part, by the inhalation toxicokinetics exper- iments of Goldstein et al. (1977) in Rhesus monkeys. Approximately 50-60% of inhaled nitrogen dioxide was retained by monkeys and distributed throughout the lungs. Radioactivity was retained in the lungs during a 21-min post-exposure period with extrapulmonary distribution (percent not quantified) via the blood- stream. The investigators speculate that the reaction of inhaled nitrogen dioxide 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 cannot be considered without taking into account the effects of nitrogen dioxide. However, nitric acid fumes will contain nitrogen dioxide upon contact with wa- ter, such that reports of experimental or accidental exposures to nitric acid fumes will account for the toxicity contributed by nitrogen dioxide. NIOSH (1976b) described the effects of nitrogen dioxide in humans as involving initial irritation with mild dyspnea during exposure followed by delayed onset of pulmonary edema after several hours of apparent recovery. A similar toxic response, includ- ing interstitial fibrosis, has been shown in five species of animals following acute inhalation exposure to nitrogen dioxide (Hine et al. 1970). This course of toxicity is identical to that described for nitric acid, but the concentrations elicit- ing responses are very different for the two chemicals. For example, 75 ppm is the concentration at which deaths were first observed in rats exposed to nitrogen dioxide for 1 h (Hine et al. 1970) whereas 1,300 ppm was the concentration for nitric acid (DuPont 1987). Also, on the basis of the LC50 values for the rat, ni- trogen dioxide appears to be more toxic than nitric acid. Therefore, using data from inhalation studies of nitrogen dioxide might be an overly conservative ap- proach for establishing AEGL values for nitric acid. If nitrogen dioxide is of concern, AEGL values for that chemical have been established (see NRC 2012). 4.4. Other Relevant Information 4.4.1. Species Variability There are no apparent species differences in the toxic response to acute in- halation exposure to nitric acid. Nitric acid fumes may cause immediate irrita- tion 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 from bronchopneumonia or pulmonary fibrosis (NIOSH 1976a; ACGIH 1991). Toxic 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 

Nitric Acid 155 models of obstructive airway disease, and experiments in sheep (Abraham et al. 1982) have demonstrated the sensitivity of allergic individuals to nitric acid. 4.4.2. Susceptible Populations Epidemiologic studies indicate that asthmatics may be more sensitive to acidic atmospheres (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 that of nitrous acid ranged from 0.1 to 1.4 ppb; these were combined as gaseous acids. Among chil- dren aged 8-12 years, these gaseous acids (but not nitric acid alone) were associ- ated 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 in an experimental study in which allergic adoles- cents were exposed to nitric acid were reported (Koenig et al. 1989). Abraham et al. (1982) showed that airway hyperreactivity to carbachol oc- curred in allergic sheep following a 4-h exposure to nitric acid at 1.6 ppm (4.13 mg/m3). Specific airway resistance before and after exposure to nitric acid in- creased 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 for nitric acid. The most reliable study (DuPont 1987) used a single duration over a large range of concentrations. However, lethality data in the rat indicates that 100% mortality is reached abruptly, indicating a steep concentra- tion-response. 5. DATA ANALYSIS FOR AEGL-1 5.1. Summary of Human Data Relevant to AEGL-1 A no-effect level of 1.6 ppm (4.13 mg/m3) was reported for changes in pulmonary function (vital capacity, respiratory resistance, and FEV1) in five healthy volunteers exposed at rest to nitric acid vapor for 10 min (Sackner and Ford 1981). That concentration is the highest no-observed-adverse-effect level available in humans. An experimental self-exposure to nitric acid at 62 ppm (160 mg/m3) for 1 h resulted in irritation of the larynx, thirst, and an objectiona- ble odor (Lehmann and Hasegawa 1913). 

156 Acute Exposure Guideline Levels 5.2. Summary of Animal Data Relevant to AEGL-1 Most animal studies of nitric acid involved lethal concentrations or were performed using intratracheal instillation, a route not comparable to inhalation exposure. 5.3. Derivation of AEGL-1 Values The highest no-effect level for AEGL-1 effects in humans of 1.6 ppm (4.13 mg/m3) for 10 min was used to derive AEGL-1 values. An uncertainty factor of 10 was applied to account for variability in response in the general population and possibly greater sensitivity of asthmatics to a direct-acting irri- tant. Time scaling was not performed because a no-effect level for irritation was used as the point of departure and such irritation is generally concentration de- pendent but not time dependent, so the 10-min value was applied to all the other AEGL durations. AEGL-1 values for nitric acid are presented in Table 5-4. 6. DATA ANALYSIS FOR AEGL-2 6.1. Summary of Human Data Relevant to AEGL-2 Human data relevant to AEGL-2 values were not found. Experimental studies in which results consistent with AEGL-2 end points were described did not expose individuals to pure nitric acid, but generated an atmosphere contain- ing a mixture of nitrogen oxides (Diem 1907; Lehmann and Hasegawa 1913). 6.2. Summary of Animal Data Relevant to AEGL-2 The most relevant animal data for deriving AEGL-2 values were those from a study by DuPont (1987). The study was well conducted and controlled for potential nitrogen dioxide contamination. Groups of five male and five fe- male Crl:CD®BR rats were exposed nose-only to nitric acid aerosol at 260-3,100 ppm for 1 h, 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 concentrations of 1,300 ppm and higher, lung noise and gasping at 1,600 ppm and higher, and extended weight loss for up to 12 days post-exposure at 1,500 ppm and greater for males and 1,600 ppm and greater for females. TABLE 5-4 AEGL-1 Values for Nitric Acid 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) 

Nitric Acid 157 No long-term effects from exposure to nitric acid were observed in rats exposed at up to 19 ppm for 6 h on alternate days for a total of six exposures (Ballou et al. 1978). 6.3. Derivation of AEGL-2 Values A study of rats exposed to nitric acid at 470 ppm for 1 h (DuPont 1987) was used to derive AEGL-2 values. The point of departure is a no-effect level for impaired ability to escape. Effects observed at 470 ppm were transient body weight loss 1-2 days post-exposure. At the next higher concentration, rats exhib- ited partially closed eyes (a possible sign of severe ocular irritation), which could definitely impair escape, and lung noise. Time scaling was performed us- ing the equation Cn × t = k (ten Berge et al. 1986). In the absence of an empiri- cally derived, chemical-specific value for n, scaling was performed using the default values of n = 3 for extrapolating to the shorter durations (10 and 30 min) and n = 1 for extrapolating to the longer durations (4 and 8 h). A total uncertain- ty factor of 10 was used: a factor of 3 for interspecies differences and 3 for intra- species variability. Larger uncertainty factors were considered unnecessary be- cause the mechanism of action of a direct ocular irritant and of a corrosive acid in the lung is not expected to differ greatly between species or among individu- als. In addition, a modifying factor of 2 was applied because clinical observa- tions were not well described, and the AEGL-2 values overlap AEGL-3 values, suggesting a very steep concentration-response relationship. AEGL-2 values for nitric acid are presented in Table 5-5. 7. DATA ANALYSIS FOR AEGL-3 7.1. Summary of Human Data Relevant to AEGL-3 Limited human data useful for deriving AEGL-3 values are available. Case reports of lethal exposures from accidents do not contain information on exposure concentrations. An experimental self-exposure was reported by Leh- mann and Hasegawa (1913). One of the researchers exposed himself to nitric acid at 74-101 ppm (190-260 mg/m3) for 1 h and then at 23-43 ppm (60-110 mg/m3) for another hour. He experienced immediate severe irritation with cough and an increase in pulse and respiratory rates after 40 min. Because severe symptoms were immediate, the average concentration of 88 ppm during the first hour of exposure was assumed to be close to intolerable but not lethal. The sub- ject was able to tolerate exposure to nitric acid at 158 ppm (408 mg/m3), but for only 10 min due to coughing, severe burning in the nose and throat, lacrimation, heavy mucous secretion from the nose, a feeling of suffocation, headache, dizzi- ness, and vomiting. 

158 Acute Exposure Guideline Levels TABLE 5-5 AEGL-2 Values for Nitric Acid 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) 7.2. Summary of Animal Data Relevant to AEGL-3 Animal data relevant to derivation of AEGL-3 values are limited to the LC50 study by DuPont (1987). This well-conducted study controlled for potential nitrogen dioxide contamination. 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, 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 1,300 ppm and higher, lung noise and gasping at 1,600 ppm and higher, and extended weight loss for up to 12 days post- exposure at 1,500 ppm and higher for males and 1,600 ppm and higher for fe- males. The 1-h LC50 for males and females combined was 2,500 ppm. Deaths occurred at concentrations of 1,300 ppm and higher (see Table 5-3). 7.3. Derivation of AEGL-3 Values A 1-h LC50 in rats was calculated by DuPont (1987). In this study, mortali- ty ratios at each concentration were determined. On the basis of these data, an LC01 of 919 ppm was calculated by log-probit analysis. Values were time scaled using the equation Cn × 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 value for n, time scaling was performed using default values of n = 3 for extrapolating to shorter durations (10 and 30 min) and n = 1 for longer durations (4 and 8 h). A total uncertainty factor of 10 was used: a factor of 3 for interspecies differences and 3 for intraspecies variability. Use of larger uncertainty factors was consid- ered unnecessary because the mechanism of action of a corrosive acid in the lung is not expected to differ greatly between species or among individuals. AEGL-3 values for nitric acid are presented in Table 5-6. 8. SUMMARY OF AEGLS 8.1. AEGL Values and Toxicity End Points AEGL values for nitric acid are presented in Table 5-7. AEGL-1 values were based on a no-effect level in humans. AEGL-2 values were based on a concentration which produced transient weight loss in rats, and AEGL-3 values on an estimated 1-h LC01 in rats. If nitrogen dioxide is of concern, AEGL values for that chemical are available (see NRC 2012). 

Nitric Acid 159 8.2. Comparison with Other Standards and Guidelines Standards and guidelines for workplace and community exposures to nitric acid are presented in Table 5-8. Some of the standards and guidelines have been developed on the basis of nitrogen dioxide or comparisons with other acids in the workplace. An occupational time weighted average (TWA) concentration of 2 ppm and a short term exposure limit (STEL) of 4 ppm have been adopted by several organizations (ACGIH 2003; OSHA [29 CFR 1910.1000 (2006)]; NIOSH 2011). ACGIH (2003) set the TWA as an intermediate value between that for hydrogen chloride and sulfuric acid and considers both the TWA and STEL to be sufficiently low to prevent ocular and upper respiratory tract irrita- tion. International standards for nitric acid are also 2 ppm for a workday and 2-5 ppm for short-term limits (DFG 2002; Swedish Work Environment Authority 2005). The German MAK value is based on the results of a study by Diem (1907). The immediately dangerous to life or health (IDLH) value of 25 ppm (NIOSH 1994) is based on acute toxicity data in humans (conversion of lethal oral dose to an equivalent inhalation concentration) and animals (secondary source). Emergency response planning guideline (ERPG) levels were developed for WFNA (AIHA 2001), and are based on toxicity data in animals exposed to nitric acid or nitrogen dioxide and dose-response estimates in humans exposed to nitrogen dioxide. 8.3. Data Adequacy and Research Needs Limited inhalation data were available for determining AEGL values. On- ly one well-conducted study in rats was available. Most animal data adminis- tered nitric acid by intratracheal instillation, a route that does not necessarily mimic inhalation exposures. Data from human case reports lacked exposure concentrations and durations. TABLE 5-6 AEGL-3 Values for Nitric Acid 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) TABLE 5-7 AEGL Values for Nitric Acid Classification 10 min 30 min 1h 4h 8h AEGL-1 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm (nondisabliing) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) (0.41 mg/m3) AEGL-2 43 ppm 30 ppm 24 ppm 6.0 ppm 3.0 ppm (disabling) (110 mg/m3) (77 mg/m3) (62 mg/m3) (15 mg/m3) (7.7 mg/m3) AEGL-3 170 ppm 120 ppm 92 ppm 23 ppm 11 ppm (lethal) (440 mg/m3) (310 mg/m3) (240 mg/m3) (59 mg/m3) (28 mg/m3) 

160 Acute Exposure Guideline Levels TABLE 5-8 Standards and Guidelines for Nitric Acid Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm 0.16 ppm (0.41 (0.41 (0.41 (0.41 (0.41 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-2 43 ppm 30 ppm 24 ppm 6.0 ppm 3.0 ppm (110 (77 (62 (15 (7.7 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 170 ppm 120 ppm 92 ppm 23 ppm 11 ppm (440 (310 (240 (59 (28 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) ERPG-1 (AIHA)a 1 ppm ERPG-2 (AIHA) 6 ppm ERPG-3 (AIHA) 78 ppm b IDLH (NIOSH) 25 ppm TLV-TWA (ACGIH)c 2 ppm d REL-TWA (NIOSH) 2 ppm PEL-TWA (OSHA) e 2ppm TLV-STEL (ACGIH) f 4ppm REL-STEL (NIOSH)g 4 ppm MAK (Germany)h 2 ppm MAK Peak Limit 2 ppm (Germany)i OELV-LLV (Sweden)j 2ppm OELV-STV (Sweden)j 5ppm a ERPG (emergency response planning guidelines, American Industrial Hygiene Associa- tion) (AIHA 2011). ERPG-1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing health effect more severe than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor. ERPG-2 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversi- ble or other serious health effects or symptoms that could impair an individual’s ability to take protection action. ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life- threatening health effects. 

Nitric Acid 161 b IDLH (immediately dangerous to life or health, National Institute for Occupational Safe- ty and Health) (NIOSH 1994) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irreversible health effects. c TLV-TWA (threshold limit value - time weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2003) is the time-weighted average con- centration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. d REL-TWA (recommended exposure limit - time weighted average, National Institute for Occupational Safety and Health) (NIOSH 2011) is defined analogous to the ACGIH TLV-TWA. e PEL-TWA (permissible exposure limit - time weighted average, Occupational Safety and Health Administration) ((29 CFR 1910.1000 [2006]) is defined analogous to the ACGIH TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week. f TLV-STEL (threshold limit value – short-term exposure limit, American Conference of Governmental Industrial Hygienists) (ACGIH 2003) is defined as a 15-min TWA expo- sure which should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than four times per day. There should be at least 60 min between successive exposures in this range. g REL-STEL (recommended exposure limit – short-term exposure limit) (NIOSH 2011) is defined analogous to the ACGIH TLV-STEL. h MAK (maximale arbeitsplatzkonzentration [maximum workplace concentration], Deutsche Forschungsgemeinschaft [German Research Association]) (DFG 2002) is de- fined analogous to the ACGIH TLV-TWA. i MAK spitzenbegrenzung (peak limit [Category I, 1], Deutsche Forschungsgemeinschaft [German Research Association]) (DFG 2002) constitutes the maximum average concen- tration to which workers can be exposed for a period up to 15 min with no more than four exposure periods per work shift and a minimum of 1 h between excursions. j OEL-LLV (occupational exposure limit – level-limit value ). OEL-STV (occupational exposure limit – short-term value) (Swedish Work Environment Authority 2005) is the maximum acceptable average concentration (time-weighted average) of an air contami- nant in respiratory air. An occupational exposure limit value is either a level-limit value (1 working day) or a ceiling-limit value (15 min or some other reference time period), and a short-time value is a recommended value consisting of a time-weighted average for exposure during a reference period of 15 min. 9. REFERENCES Abraham, W.M., C.S. Kim, M.M. King, W. Oliver, and L. Yerger. 1982. Effects of nitric acid on carbachol reactivity of the airways in normal and allergic sheep. Arch. En- viron. Health 37(1):36-40. ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Nitric acid. Pp. 1088-1089 in Documentation of the Threshold Limit Values and Biologi- cal Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 2003. P. 43 in TLVs and BEIs Based on the Documentation of the Threshold Limit Values for 

162 Acute Exposure Guideline Levels Chemical Substances and Physical Agents and Biological Exposure Indices. Amer- ican Conference of Governmental Industrial Hygienists, Cincinnati, OH. AIHA (American Industrial Hygiene Association). 2001. Nitric Acid WFNA. Emergency Response Planning Guidelines, American Industrial Hygiene Association, Fairfax, VA. AIHA (American Industrial Hygiene Association). 2011. Nitric Acid WFNA (7697-37- 2). P. 26 in Emergency Response Planning Guidelines and Workplace Environ- mental Exposure Level Guides Handbook. American Industrial Hygiene Associa- tion, Fairfax, VA [online]. Available: www.aiha.org/insideaiha/.../2011erpgweel handbook_table-only.pdf [accessed Jan. 29, 2013]. Aris, R., D. Christian, I. Tager, L. Ngo, W.E. Finkbeiner, and J.R. Balmes. 1993. Effects of nitric acid gas alone or in combination with ozone on healthy volunteers. Am. Rev. Respir. Dis. 148(4 Pt. 1): 965-973. Ballou, J.E., R.A. Gies, G.E. Dagle, F.G. Burton, and O.R. Moss. 1978. Toxicology of inhaled acid aerosols. Pp. 6.1-6.2 in Pacific Northwest Laboratory Annual Report to the DOE Assistant Secretary for Environment. Report No. 1978-PNL-2500ac (as cited in AIHA 2001). Blenkinsopp, W.K. 1968. Relationship of injury to chemical carcinogenesis in the lungs of rats. J. Natl. Cancer Inst. 40(4):651-661. Bur, A., A. Wagner, M. Röggla, A. Berzlanovic, H. Herkner, F. Sterz, and A.N. Laggner. 1997. Fatal pulmonary edema after nitric acid inhalation. Resuscitation 35(1):33- 36. Chen, L.C., and R.B. Schlesinger. 1996. Considerations for the respiratory tract dosime- try of inhaled nitric acid vapor. Inhal. Toxicol. 8(7):639-654. Christensen, T.G., E.C. Lucey, R. Breuer, and G.L. Snider. 1988. Acid-induced secretory cell metaplasia in hamster bronchi. Environ. Res. 45(1):78-90. Coalson, J.J., and J.F. Collins. 1985. Nitric acid induced injury in the hamster lung. Br. J. Exp. Pathol. 66(2):205-216. Demerec, M., G. Bertani, and J. Flint. 1951. A survey of chemicals for mutagenic action on E. coli. Am. Nat. 85(821):119-136. DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values, 2002. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 38. Weinheim, Federal Republic of Germany: Wiley-VCH. Diem, L. 1907. Experimentelle Untersuchungen über die Einatmung von Salpetersäure- Dämpfen. Thesis D-8700. Universität Würzburg, Würzburg, Germany. Dockery, D.W., J. Cunningham, A.I. Damokosh, L.M. Neas, J.D. Spengler, P. Koutrakis, J.H. Ware, M. Raizenne, and F.E. Speizer. 1996. Health effects of acid aerosols on North American children: Respiratory symptoms. Environ. Health Perspect. 104(5):500-505. DuPont (E. I. du Pont de Nemours and Company). 1987. One-hour Inhalation Median Lethal Concentration (LC50) Study with Nitric Acid. Report No 451-87. Haskell Laboratory, DuPont, Newark, DE. 26pp. EPA (U.S. Environmental Protection Agency). 1993. Monograph for Nitric Acid (CAS Reg. No. 7697-37-2). Prepared by Clement International Corporation for Office of Pollution Prevention and Toxics, U.S. Environmental Protection Agency, Wash- ington, DC. 17 pp. Fujita, M., M.A. Schroeder, and R.E. Hyatt. 1988. Canine model of chronic bronchial injury. Lung mechanics and pathologic changes. Am. Rev. Respir. Dis. 137(2): 429-434. 

Nitric Acid 163 Gardiner, T.H., and L.S. Schanker. 1976. Effect of oxygen toxicity and nitric acid- induced lung damage on drug absorption from the rat lung. Res. Commun. Chem. Pathol. Pharmacol. 15(1):107-120. 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(3):403-412. Gray, E.L., F.M. Patton, S.B. Goldberg, and E. Kaplan. 1954. Toxicity of the oxides of nitrogen. II. Acute inhalation toxicity of nitrogen dioxide, red fuming nitric acid, and white fuming nitric acid. AMA Arch. Ind. Health 10(5):418-422. Hajela, R., D.T. Janigan, P.L. Landrigan, S.F. Boudreau, and S. Sebastian. 1990. Fatal pulmonary edema due to nitric acid fume inhalation in three pulp-mill workers. Chest 97(2):487-489. Hall, J.N., and C.E. Cooper. 1905. The effects of the inhalation of the fumes of nitric acid with report of cases. JAMA 45(6):396-399. Hine, C.H., F.H. Meyers, and R.W. Wright. 1970. Pulmonary changes in animals ex- posed to nitrogen dioxide, effects of acute exposures. Toxicol. Appl. Pharmacol. 16(1):201-213. HSDB (Hazardous Substances Data Bank). 2012. Nitric acid (CAS Reg. No. 7697-37-2). TOXNET Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed Jan. 29, 2013]. Koenig, J.Q., D.S. Covert, and W.E. Pierson. 1989. Effects of inhalation of acidic com- pounds on pulmonary function in allergic adolescent subjects. Environ. Health Perspect. 79:173-178. Lehmann, K.B., and Hasegawa. 1913. Studies on the effects of technically and hygieni- cally important gases and vapors on man (31) - The nitrous gases - Nitric oxide, ni- trogen dioxide, nitrous acid, nitric acid [in German]. Arch. Hyg. 77:323-368. Millstein, J., F. Gilliland, K. Berhane, W.J. Gauderman, R. McConnell, E. Avol, E.B. Rappaport, and J.M. Peters. 2004. Effects of ambient air pollutants on asthma medication use and wheezing among fourth-grade school children from 12 south- ern California communities enrolled in the children’s health study. Arch. Environ. Health 59(10):505-514. Mink, S.N., J.J. Coalson, L. Whitley, H. Greville, and C. Jadue. 1984. Pulmonary func- tion tests in the detection of small airway obstruction in a canine model of bron- chiolitis obliterans. Am. J. Respir. Dis. 130(6):1125-1133. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Salpeterzuur. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Feb. 1, 2013]. Myint, S.S., and S.K. Lee. 1983. Pulmonary effects of acute exposure to nitrous fumes - A case report. Singapore Med. J. 24(5):312-313. NARSTO. 2004. Particulate Matter Assessment for Policy Makers: A NARSTO Assess- ment, P. McMurry, M. Shepherd, and J. Vickery, eds. Cambridge, UK: Cambridge University Press. NIOSH (National Institute for Occupational Safety and Health). 1976a. NIOSH Criteria for a Recommended Standard. Occupational Exposure to Nitric Acid. HEW(NIOSH) 76-141. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health, Washington, DC [online]. Available: http://www.cdc.gov/niosh/docs/1970/76-141. html [accessed Jan. 29, 2013]. 

164 Acute Exposure Guideline Levels NIOSH (National Institute for Occupational Safety and Health). 1976b. NIOSH Criteria for a Recommended Standard Occupational Exposure to Oxides of Nitrogen (Ni- trogen Dioxide and Nitric Oxide). HEW(NIOSH) 76-149. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Con- trol, National Institute for Occupational Safety and Health, Washington, DC [online]. Available: http://www.cdc.gov/niosh/docs/1970/76-149.html [accessed Jan. 29, 2013]. NIOSH (National Institute for Occupational Safety and Health). 1994. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLHs): Nitric acid. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/idlh/7697372.html [accessed Feb.1, 2013]. NIOSH (National Institute for Occupational Safety and Health). 2011. NIOSH Pocket Guide to Chemical Hazards: Nitric acid. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occu- pational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc. gov/niosh/npg/npgd0447.html [accessed Feb.1, 2013]. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 2012. Nitrogen oxides. Pp. 167-256 in Acute Expo- sure Guideline Levels for Selected Airborne Chemicals, Volume 11. Washington, DC: The National Academies Press. O’Neil, M.J., P.E. Heckelman, C.B. Koch, and K.J. Roman, eds. 2006. Nitric acid. P. 1138 in The Merck Index, 14th Ed. Whitehouse Station, NJ: Merck. Ostro, B.D., M.J. Lipsett, M.B. Wiener, and J.C. Selner. 1991. Asthmatic responses to airborne acid aerosols. Am. J. Public Health 81(6):694-702. Peters, S.G., and R.E. Hyatt. 1986. A canine model of bronchial injury induced by nitric acid. Lung mechanics and morphological features. Am. Rev. Respir. Dis. 133(6): 1049-1054. Peters, J.M., E. Avol, W. Navidi, S.J. London, W.J. Gauderman, F. Lurmann, W.S. Linn, H. Margolis, E. Rappaport, H. Gong, and D.C. Thomas. 1999a. A study of twelve southern California communities with differing levels and types of air pollution. I. Prevalence of respiratory morbidity. Am. J. Resp. Crit. Care Med. 159(3):760-767. Peters, J.M., E. Avol, W.J. Gauderman, W.S. Linn, W. Navidi, S.J. London, H. Margolis, E. Rappaport, H. Vora, H. Gong Jr., and D.C. Thomas.1999b. A study of twelve southern California communities with differing levels and types of air pollution. II. Effects on pulmonary function. Am. J. Resp. Crit. Care Med. 159(3):768-775. Raizenne, M., L.M. Neas, A.I. Damokosh, D.W. Dockery, J.D. Spengler, P. Koutrakis, J.H. Ware, and F.E. Speizer. 1996. Health effects of acid aerosols on North Ameri- can children: Pulmonary function. Environ. Health Perspect. 104(5):506-514. Sackner, M.A., and D. Ford. 1981. Effects of breathing nitrate aerosols in high concentra- tions 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(4 Part 2):151. 

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. 

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 

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 

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 

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) 

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: 

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. 

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) 

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. 

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 

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%