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Ammonia

This chapter reviews physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on ammonia. The Subcommittee on Submarine Escape Action Levels used the information to assess health risk to Navy personnel aboard a disabled submarine and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and research relevant for determining the health risk attributable to exposure to ammonia.

BACKGROUND INFORMATION

The subcommittee reviewed data that came primarily from human experimental studies and from toxicity studies in various animal species. The evaluation focused on inhalation exposure studies that measured respiratory irritation and tolerance to odor. Human case studies, accident reports, and epidemiologic studies of industrial exposures were extensive but of limited use to the subcommittee because they lack quantitative exposure measurements. Controlled human experiments were most important to the subcommittee for establishing the SEALs for ammonia. There appears to be a broad range of sensitivity to ammonia’s pungent odor and in irritation caused by exposures to low concentrations



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Review of Submarine Escape Action Levels for Selected Chemicals 2 Ammonia This chapter reviews physical and chemical properties and toxicokinetic, toxicologic, and epidemiologic data on ammonia. The Subcommittee on Submarine Escape Action Levels used the information to assess health risk to Navy personnel aboard a disabled submarine and to evaluate the submarine escape action levels (SEALs) proposed to avert serious health effects and substantial degradation in crew performance from short-term exposures (up to 10 d). The subcommittee also identifies data gaps and research relevant for determining the health risk attributable to exposure to ammonia. BACKGROUND INFORMATION The subcommittee reviewed data that came primarily from human experimental studies and from toxicity studies in various animal species. The evaluation focused on inhalation exposure studies that measured respiratory irritation and tolerance to odor. Human case studies, accident reports, and epidemiologic studies of industrial exposures were extensive but of limited use to the subcommittee because they lack quantitative exposure measurements. Controlled human experiments were most important to the subcommittee for establishing the SEALs for ammonia. There appears to be a broad range of sensitivity to ammonia’s pungent odor and in irritation caused by exposures to low concentrations

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Review of Submarine Escape Action Levels for Selected Chemicals of ammonia. The odor threshold for ammonia is reported at 5–50 ppm (parts per million); the perception threshold for irritation is reported at 30–50 ppm (Wands 1981; WHO 1986). Intense irritation to the eyes, nose, and throat can occur at 100 ppm, but at that concentration, there is no evidence of a decrease in pulmonary or central nervous system (CNS) function, nor is there evidence of injury or lasting effects (Ferguson et al. 1977). Adaptation to the odor and to the effects of ammonia at low concentrations (<100 ppm) has been demonstrated in occupational exposure studies of workers who were able to carry out job-related functions during extended periods of exposure (Vigliani and Zurlo 1955; Ferguson et al. 1977). Ammonia is a colorless gas with a distinctive, penetrating, pungent odor that is often described as “drying urine.” Exposure to ammonia vapor can cause symptoms that range from mild eye and throat irritation at low concentrations to severe respiratory injury and death at high concentrations. Ammonia is highly soluble in water, forming ammonium hydroxide through an exothermic reaction (Budavari et al. 1996). Exothermic reaction of ammonia with water can cause thermal and chemical burns because of the alkalinity of ammonium hydroxide. Contact with refrigerated liquid ammonia can cause cryogenic skin injury (Hathaway et al. 1991). In addition to being a potent respiratory irritant, ammonia is a potent ocular irritant, and it can rapidly penetrate the corneal epithelium. Severe ocular exposures can lead to corneal ulceration, corneal perforations, and persistent corneal opacity (NRC 1979). Heating ammonia to decomposition produces ammonia vapor, hydrogen gas, nitrogen gas, and oxides of nitrogen (OSHA 1992; Sax and Lewis 1987). Under some conditions, mixtures of ammonia and air will explode when ignited, and fires and explosions can occur upon mixing of ammonia with other chemicals, such as chlorine, hypochlorites, and chlorine bleach (OSHA 1992). The National Fire Protection Association has assigned the flammability rating of 1 (slight fire hazard) to ammonia (New Jersey Department of Health 1998). The chemical and physical properties of ammonia are shown in Table 2–1. Ammonia is found in the environment as the result of natural and industrial processes. It is released into the environment by the breakdown of organic wastes, and it is a constituent of the soil, the atmosphere, and bodies of water. Ammonia is also a key intermediate in the nitrogen cycle and is a product of amino acid metabolism (WHO 1986). Anhydrous ammonia is used in the production of nitric acid, explosives, synthetic fibers, and fertilizers (Budavari 1989). It is used as a refrigerant; as a corrosion inhibitor; in the purification of water supplies; in steel production; as a catalyst for polymers; as a preservative for latex; and in the production of nitrocellulose, urea formaldehyde, sulfite cooking liquors, and nitroparaffins (ACGIH 1991; Lewis 1993). Ammonium hydroxide (10–35% ammonia) is a major constituent of many cleaning solutions. Ammonia

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 2–1 Chemical and Physical Properties CAS number 7664–41–7 Molecular formula NH3 Molecular weight 17.03 Color Colorless Odor Pungent Odor threshold 5–53 ppm Boiling point –33.35°C Melting point –77.7°C Gas density 0.7714 g/L Vapor density 0.5967 (air=1) Solubility Water, alcohol, chloroform, ether Conversion factors at 25°C at 760 mm Hg 1 mg/m3=1.41 ppm; 1 ppm=0.708 mg/m3 Abbreviations: g/L, grams per liter; mg/m3, milligrams per cubic meter; ppm, parts per million. Sources: Budavari (1989), ACGIH (1991), Hathaway et al. (1991). is a potential combustion product of fires on disabled submarines. Examples of materials that can produce ammonia gas upon pyrolysis include wool, polyacrylonitrile, synthetic fabrics, and insulating foams (Hilado et al. 1977). TOXICOKINETIC CONSIDERATIONS Absorption Short-term inhalation studies (<2 min) in human volunteers have demonstrated that ammonia is almost completely retained (83–92%) in the nasal mucosa (Landahl and Herrmann 1950). With longer exposures (500 ppm for 30 min), retention of ammonia in the nasal mucosa decreases progressively until reaching equilibrium at 23% (range: 4–30%) after 10–27 min of exposure (Silverman et al. 1949). The authors reported that the concentration of ammonia in exhaled air remained stable after this period and returned to pre-exposure levels within 3–8 min after the exposure. Localized irritation in the nose and pharynx was further

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Review of Submarine Escape Action Levels for Selected Chemicals evidence that ammonia is absorbed primarily in the upper respiratory tract. There was no evidence in this same study of lower airway irritation nor was there a significant increase in urine or blood ammonia concentrations or urea and nonprotein nitrogen concentrations. Studies with laboratory animals support that conclusion. Egle (1973) exposed male and female mongrel dogs to ammonia at concentrations of 214–714 ppm. Retention in the whole respiratory tract ranged from 73% to 83%, and was not affected by concentration, respiratory rate, or tidal volume. When the lower and upper respiratory tracts were studied separately, retention was found to be approximately 78% in each. In a study using rats, Schaerdel et al. (1983) exposed 4 groups of animals to ammonia at concentrations of 15, 32, 310, or 1,157 ppm for 24 h. Blood samples were taken 0, 8, 12, and 24 h after exposure. A significant increase in blood ammonia was found at the two highest concentrations after 8 h, but the increase was less marked at 12 or 24 h, suggesting an increase in ammonia metabolism. In another study, female rabbits were exposed to ammonia at concentrations of 50 or 100 ppm for 2.5–3 h (Mayan and Merilan 1972). No increase in blood pH was found, but there was a significant increase in blood urea nitrogen (BUN) in rabbits exposed to 100 ppm. In a study that exposed male Holstein calves to ammonia at concentrations of 50 and 100 ppm for 2.5 h, there was no increase in BUN or pH (Mayan and Merilan 1976). No animal or human studies were located on the quantitative absorption of ammonia through the skin. However, dermal toxicity studies indicate that little or no ammonia is absorbed into the blood through the skin. Ammonia can rapidly penetrate the corneal epithelium (NRC 1979). Distribution Ammonia is normally present in all tissues of the body. The distribution and metabolic fate of absorbed ammonia depends on the route of administration. The distribution of endogenous and absorbed ammonia in various body compartments is influenced by pH. The lower the pH of a compartment, the greater its total ammonia content (NRC 1979). The normal concentration of ammonia in human blood is approximately 1 milligram per liter (mg/L) (Wands 1981). Total ammonia concentrations in humans are 70–113 micromoles (µmol) in arterial blood and plasma, 5–40 µmol in venous blood and plasma, and 20–100 µmol in cerebrospinal fluid (Cooper and Plum 1987). No quantitative studies were available on the distribution of ammonia after inhalation. Inhaled ammonia is mostly absorbed in the upper respiratory tract;

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Review of Submarine Escape Action Levels for Selected Chemicals only a small amount is absorbed into the systemic circulation. Silverman et al. (1949) demonstrated that when human subjects were exposed to 500 ppm for 30 min there was no effect on blood nitrogen concentrations. In contrast, Kustov (1967) demonstrated a significant increase in BUN in human subjects exposed to 20 ppm for 8 h. It is likely that exogenous ammonia absorbed into the blood would be processed similarly to endogenously produced ammonia (excreted in the urine, converted to glutamine and urea, used in protein synthesis). Metabolism Ammonia is formed as a product of protein and amino acid metabolism, and the rapid metabolism of ammonia in the liver maintains the isotonic system (Pierce 1994; Visek 1972). In humans, approximately 50 milligrams per kilogram (mg/kg) of ammonia is produced in the body each day from the metabolism of dietary protein and amino acids (ATSDR 1990). No studies were available on the metabolism of ammonia after inhalation or dermal exposure. Ingested ammonia is metabolized to urea and glutamine, primarily in the liver (Fürst et al. 1969; Pitts 1971), but it also can be converted to glutamine in the brain (Takagaki et al. 1961; Warren and Schenker 1964). The route of exposure affects the metabolism of ammonia. It is almost completely converted by the liver to urea after oral exposure, but it is metabolized in body tissues to glutamine or tissue protein after intraperitoneal and subcutaneous administration (Duda and Handler 1958; Fürst et al. 1969; Vitti et al. 1964). The nitrogen fixed in glutamine is eventually used in protein synthesis (Duda and Handler 1958; Fürst et al. 1969; Vitti et al. 1964). Duda and Handler (1958) administered 15N-labeled ammonium acetate intravenously at a dose of 0.03 mg/kg to rats. Approximately 90% of the administered dose was converted to glutamine and urea within 30 min. Glutamine was the major early product. The investigators detected labeled nitrogen in amino acids, purines, pyrimidines, and other nitrogenous compounds. Saul and Archer (1984) demonstrated that ammonia is oxidized to nitrate in the rat. Three male Sprague-Dawley rats were administered 15N-labeled ammonium chloride by gavage at a dose of 1,000 µmol for 5 d. A significant amount (0.28±0.03 µmol, mean ± SE) of excess 15N-labeled nitrate was found in the urine. Because the CNS is sensitive to ammonia, its metabolism in the brain and the neurotoxicity associated with hyperammonia and hepatic encephalopathy (the proximate source of damage in the latter is also ammonia) is reviewed here. Hepatic encephalopathy (HE) or congenital and acquired hyperammonemia result in excessive ammonia accumulation within the CNS. The condition is due

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Review of Submarine Escape Action Levels for Selected Chemicals to liver failure. Experimental studies in vivo have shown that the effects of ammonia on the CNS vary with its concentration. High concentrations within the CNS produced seizures, resulting from its depolarizing action on cell membranes; lower concentrations produced stupor and coma, consistent with its hyperpolarizing effects. Ammonia intoxication is commonly associated with astrocytic swelling. In addition, astrocytes undergo morphologic changes following chronic exposure to ammonia, yielding the so-called Alzheimer type II astrocytes common to most hyperammonemic conditions. Notably, the astrocytic changes precede any other morphologic change in the CNS (Norenberg 1981). The exclusive site for the detoxification of glutamate to glutamine occurs within the astrocytes. This process requires adenosine-triphosphate-dependent amidation of glutamate to glutamine, a process mediated by the astrocyte-specific enzyme, glutamine synthetase (Norenberg and Martinez-Hernandez 1979). In vivo chronic exposure to ammonia leads to diminished glutamine metabolism within the astrocytes and to impairment of astrocytic energy metabolism (Albrecht 1996). It has been reported that the reduced astrocytic capacity to metabolize ammonia leads to ammonia-induced cytotoxicity in juxtaposed neurons, promoting accumulation of glutamine. This accumulation leads to decreased cerebral glucose consumption and amino acid imbalances (Hawkins and Jessy 1991; Hawkins et al. 1993). Increased intracellular ammonia concentrations also have been implicated in the inhibition of neuronal glutamate precursor synthesis, resulting in diminished glutamatergic neurotransmission, changes in neurotransmitter (glutamate) uptake, and changes in receptor-mediated metabolic responses of astrocytes to neuronal signals (Albrecht 1996). Elimination When absorbed into the systemic circulation, ammonia is primarily excreted by the kidney as urea and urinary ammonium compounds (Gay et al. 1969; Pitts 1971). Absorbed ammonia also can be excreted as urea in feces (Richards et al. 1975) and as a perspiration constituent (Guyton 1981; Wands 1981). In a study of male subjects exposed to ammonia at concentrations up to 500 ppm for 30 min, Silverman et al. (1949) found that 70–80% of inhaled ammonia was excreted in expired air. Ammonia in expired air returned to normal concentrations within 3 to 8 min after exposure was stopped. The investigators calculated that if all the retained ammonia were absorbed into the blood, there would be no significant change in blood or urine urea, ammonia, or nonprotein nitrogen.

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Review of Submarine Escape Action Levels for Selected Chemicals HUMAN TOXICITY DATA Experimental Studies Henderson and Haggard (1943) reviewed the early data on ammonia exposure in humans, primarily that of Flurry and Zernick (1931) and Lehmann (1886), and reported responses to various concentrations of ammonia as listed in Table 2–2. Pierce (1994) reported the odor threshold for ammonia can range from 5 to 53 ppm. Pedersen and Selig (1989) presented a summary of literature on human response to gaseous ammonia as presented by Markham (1986) (Table 2–3). Mild and reversible effects of inhaling ammonia have been documented in several studies of human subjects exposed to ammonia at various concentrations and durations. Those studies are outlined in Table 2–4. Industrial Bio-Test Laboratories, Inc. (1973, cited in WHO 1986), determined the irritation threshold in ten human volunteers exposed to ammonia at concentrations of 32, 50, 72, or 134 ppm for 5 min. Irritation was defined as any discomfort in the nose, throat, eyes, mouth, or chest. The subjects showed dose-related responses for chest irritation and dryness of the eye, nose, and throat. The severity of the effects was not noted. MacEwen et al. (1970) studied the effect of head-only exposure to ammonia at concentrations of 30 and 50 ppm for 10 min in six human volunteers. Each subject rated irritation responses on a scale of 0 to 4 (not detectable, just perceptible, moderate irritation, discomforting or painful, exceedingly painful) and odor perception on a scale of 0 to 5 (not detectable, positively perceptible, readily perceptible, moderate intensity, highly penetrating, and intense or very strong). At 30 ppm, three subjects reported irritation as not detectable, two subjects reported the irritation as just perceptible, and one subject gave no response. At 30 ppm, the odor was highly penetrating for three subjects, and moderately TABLE 2–2 Ammonia Exposure in Humans Concentration (ppm) Effect 53 Least detectable odor 408 Lowest concentration causing throat irritation 698 Lowest concentration causing ocular irritation 1,720 Lowest concentration that caused coughing 2,000–6,500 Dangerous for short (0.5 h) exposures 5,000–10,000 Rapidly fatal for short exposures   Source: Adapted from Henderson and Haggard (1943).

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 2–3 Human Response to Gaseous Ammonia Concentration (ppm) Exposure time (min) Effect 72 5 Some irritation 330 30 Concentration tolerated 600 1–3 Eyes streaming within 30 s 1,000 1–3 Eyes streaming immediately; Vision impaired but not lost; Breathing intolerable to most 1,500 1–3 Instant reaction is to escape   Source: Adapted from Pederson and Selig (1989). intense for two subjects. The sixth subject gave no response. At 50 ppm, four subjects reported the irritation as moderate, one as just perceptible, and one as not detectable. The odor was highly penetrating or intense for all six subjects inhaling 50 ppm of ammonia. Silverman et al. (1949) measured responses from six healthy human subjects in response to 30-min exposures to 500 ppm and from one subject exposed to 500 ppm for 15 min. The subjects hyperventilated and reported decreased sensitivity of the skin around the nose and mouth that disappeared soon after the end of the exposure. Two subjects reported irritation of the nose and throat starting at the beginning of the exposure and lasting 24 h. The irritation reported was likened to persistent nasal stuffiness. Two subjects were able to continue nasal breathing throughout the 30 min; the others changed to mouth breathing. There was no difference in the effects noted in the subject inhaling ammonia for 15 min and those inhaling ammonia for 30 min. Ferguson et al. (1977) reported that some industrial workers did not voluntarily use gas masks until ammonia concentrations reached 400 or 500 ppm in the workplace. The authors also reported that, before 1951, workers were routinely subjected to continuous workplace concentrations ranging from 150 to 200 ppm. In an effort to measure the responses of human subjects to concentrations of ammonia reportedly often encountered in industrial settings, three groups of two subjects each were exposed at 25, 50, and 100 ppm ammonia for 6 h/d, 5 d/wk, for 6 weeks. These exposures followed exposure to the same concentrations for a 1-wk practice period. Observations were made of irritation to the conjunctiva of the eyes and mucous membranes of the nose and throat. Vital signs (pulse, blood pressure, respiratory rate) were measured, as were parameters of pulmonary function. With exposures up to 100 ppm there were no significant differences between experimental and control subjects in the parameters measured. The authors further demonstrated that after a period of acclimation, exposures

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Review of Submarine Escape Action Levels for Selected Chemicals to ammonia at up to 100 ppm produced no increase in observed or reported irritation. The only complaints were lacrimation and nasal dryness during brief excursions above 150 ppm. Transient exposures of subjects to 200 ppm produced temporary discomfort with no lasting health effects. These workers were able to perform tasks during the exposure and carried out their daily operations in the workplace without consequence from the experimental exposures. In another study designed to establish limits of exposure and to examine adaptation to ammonia, Verberk (1977) exposed 16 healthy subjects to 50, 80, 110, and 140 ppm for 2 h. None of the subjects had previously been exposed to ammonia in experiments or at work; however, eight subjects (“expert” group) had experience in toxicology and were aware of the effects of ammonia exposure. Pulmonary function was measured, as were subjective assessments of irritation and discomfort parameters (irritation of eyes, throat, tightness of chest, urge to cough, tolerance to odor). There were no effects on lung function in any exposed individual at the concentrations used. Many subjects reported increases in subjective measures at the higher concentrations, with a non-expert group rating its effects as more severe. At 140 ppm, none of the non-expert group remained in the exposure chamber for the entire 2-h period, whereas all of the expert subjects remained for the entire exposure period. The greatest difference in responses between the expert and non-expert groups was in general discomfort. The expert group perceived no general discomfort even after exposure to the highest concentration for 2 h, whereas the non-expert subjects perceived general discomfort that ranged from “distinctly perceptible” to “unbearable” after 1 h. There were no differences detected between smokers and nonsmokers. No subjects were considered to be hypersensitive to nonspecific irritants. Cole et al. (1977) studied the effect of ammonia exposure in 18 subjects exposed to concentrations of 101, 151, 206, and 336 ppm for brief periods before and during exercise. Statistically significant decreases in minute volume and exercise tidal volume were detected at 151 ppm and above; respiratory frequency was increased at 206 ppm and above. Holness et al. (1989) compared effects in a group of 58 workers chronically exposed to ammonia vapor (9.2±1.4 ppm, mean ± standard deviation) with the effects in a group of plant workers who had no exposure to ammonia (0.3±0.1 ppm, mean ± standard deviation). During a 1-wk period, the workers were assessed, based on a questionnaire, on sense of smell and respiratory function. There were no reported differences between the two groups. Erskine et al. (1993) measured the threshold concentration of ammonia required to elicit reflex glottis closure, which is a protective response stimulated by inhaling irritant or noxious vapors at concentrations too small to produce cough. Glottis closure was measured in 102 healthy nonsmoking subjects between the ages of 17 and 96. The results showed a strong correlation between age

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 2–4 Human Toxicity Data, Experimental Exposure to Ammonia Subjects Route Concentration (ppm) Duration Effect Reference EXPERIMENTAL STUDIES 10 healthy volunteers Whole body 32, 50, 72, 134 5 min 32 ppm: 1 reported dryness of the nose. 50 ppm: 2 reported dryness of the nose. 72 ppm: 3 reported eye irritation; 2 reported nasal irritation; 3 reported throat irritation. 134 ppm: 5 reported eye irritation; 7 reported nasal irritation; 8 reported throat irritation; 1 reported chest irritation Industrial Bio-Test Laboratories, Inc. 1973 (as cited in WHO 1986) 6 healthy volunteers Whole body 30, 50 10 min At 50 ppm: 4 subjects reported moderate irritation; but none found that concentration to be discomforting or painful. MacEwen et al. 1970 (as cited in WHO 1986) 7 healthy volunteers Inhalation 500 30 min All of the subjects exhibited an increase in respiratory rate and minute volumes. Hyperventilation occurred immediately in 3 subjects, and after 10–30 min in 4 subjects. Respiratory minute volumes were 50–250% greater than control values, and exhibited a cyclic variation, decreasing by about 25% at 4–7 min intervals. Subjects reported nose and throat irritation, hypesthesia (decreased sensitivity to simulation) of the skin of the nose and mouth. Silverman et al. 1949 16 healthy volunteers Whole body 50, 80, 110, 140 2h Subjects were divided into 8 “experts” (familiar with the effects of ammonia) and 8 “non-experts” (unfamiliar with effects). Verberk 1977

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Review of Submarine Escape Action Levels for Selected Chemicals Subjects Route Concentration (ppm) Duration Effect Reference   Effects on respiratory function were measured by vital capacity, forced inspiratory volume, and forced expiratory volume immediately after exposure; subjective responses were taken at 15-min intervals. No effects on respiratory function were found. Subjects reported irritation of the eyes and throat, objectionable odor, and general discomfort. Non-experts rated their effects as more severe than did the experts. At the highest concentration, none of non-experts stayed in exposure chamber for 2 h; all of the experts remained in the chamber.   6 workers Whole body 25, 50, 100 2–6 h/d; 5 d/wk for 6 wk In 3 groups of 2 workers each, no effects observed on the eyes, nose, throat, pulse rate, respiratory function (under either normal or exercise conditions). No effects on physical or mental ability to perform work duties. Subjective responses were lacrimation and dryness of the nose and throat at 150–200 ppm. (In some tests in the exposure chamber, concentration rose briefly to 200 ppm.) Ferguson et al. 1977 18 volunteers under exercise conditions Whole body 101, 151, 206, 336 9 min preexposure; 8– 11 min during exercise Respiratory effects measured by respiratory rate, minute volume, tidal volume, oxygen uptake. Statistically significant decrease in ventilation minute volume and exercise tidal volume at 151 and 206 ppm, respiratory frequency increased at 206 and 336 ppm. Cole et al. 1977

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Review of Submarine Escape Action Levels for Selected Chemicals onstrated in humans and appears to be a common occurrence in past occupational settings (Ferguson et al. 1977). Even more remarkable are the findings of Verberk (1977) who demonstrated that simple knowledge of the nature of the odor and the irritant effects of low concentrations of ammonia can significantly alter a subject’s tolerance to the effects of the gas. The Navy should consider putting this later phenomenon to practice in training submarine crews for potential disabled submarine operations. NAVY’S RECOMMENDED SEALS The Navy proposes to set a SEAL 1 of 25 ppm for exposure to ammonia. This value is based on a report that some irritation can result from concentrations of 25 ppm (NIOSH 1974). The Navy has proposed a SEAL 2 of 75 ppm for ammonia. This value was based on reports of significant irritation at concentrations of 100 ppm (Vigliani and Zurlo 1955). ADDITIONAL RECOMMENDATIONS FROM THE NRC AND OTHER ORGANIZATIONS Table 2–9 presents exposure limits for ammonia recommended by the NRC and other organizations. The 24-h emergency exposure guidance level (EEGL) is the most relevant guidance level to compare to the SEALs. EEGLs were developed for healthy military personnel for emergency situations. An important difference between the EEGLs and the SEALs is that EEGLs allow mild, reversible health effects, whereas SEALs allow moderate, reversible health effects. That is, SEALs allow effects that are somewhat more intense or potent than those for the EEGLs. Therefore, the SEAL values are higher than the corresponding EEGL values. SUBCOMMITTEE ANALYSIS AND RECOMMENDATIONS Submarine Escape Action Level 1 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 1 of 25 ppm for ammonia is too conservative. The Navy’s proposed SEAL 1 could be below the threshold for odor or perception for some crew members, and it is well below the concentrations shown consistently to cause minimal eye and throat irritation. The subcommittee recommends 75 ppm for SEAL 1. The

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Review of Submarine Escape Action Levels for Selected Chemicals TABLE 2–9 Exposure Recommendations from Other Organizations Organization Type of Exposure Recommendation Exposure Limit, ppm Reference EPA RfC (lifetime) 0.14 IRIS 1991 ACGIH TLV-TWA (8 h/d during 40-h workweek) 25 ACGIH 1999   TLV-STEL (15 min) 35   AIHA ERPG1 25 AIHA 2001   ERPG2 150     ERPG3 750   ATSDR MRL (≤14 d) 0.5 ATSDR 1990   MRL (>14 d) 0.3   DFG MAK (8 h/d during 40 h workweek) 20 DFG 1997   Peak Limit (5 min maximum duration, 8 times per shift) 40   NASAb SMAC (1 h) 30 NRC 1994   SMAC (24 h) 20     SMAC (7 d) 10     SMAC (30 d) 10     SMAC (180 d) 10   NIOSH REL-TWA (10 h/d during 40-h workweek) 25 NIOSH 1992, 1997

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Review of Submarine Escape Action Levels for Selected Chemicals Organization Type of Exposure Recommendation Exposure Limit, ppm Reference   REL-STEL (15 min) 35     IDLH 300   NRCa EEGL (1 h) 100 NRC 1987   EEGL (24 h) 100     CEGL (90 d) 50   OSHA PEL-TWA (8 h/d during a 40-h workweek) 50 OSHA 1999c aThese guidelines were established for use by the military. bThese guidelines were established for use on spacecraft. cOccupational Safety and Health Standards. Code of Federal Regulations. Part 1910.1000, Air Contaminants. Abbreviations : ACGIH, American Conference of Governmental Industrial Hygienists; AIHA, American Industrial Hygiene Association; ATSDR, Agency for Toxic Substances and Disease Registry, CEGL, continuous exposure guidance level; DFG, Deutsche Forschungsgemeinschaft; EEGL, emergency exposure guidance level; EPA, U.S. Environmental Protection Agency, ERPG, emergency response planning guidelines; IDLH, immediately dangerous to life and health; MAK, maximum concentration values in the workplace; MRL, minimal risk level; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; RfC, reference concentration; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

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Review of Submarine Escape Action Levels for Selected Chemicals subcommittee’s value is based on two controlled human studies. In one study, volunteers exposed to ammonia at concentrations above 100 ppm for 2–6 h/d, 5 d/wk for 6 wk experienced transient irritation of the eyes and throat but no decreased pulmonary function or impaired mental ability, no adverse effects were reported in volunteers exposed at 100 ppm or below (Ferguson et al. 1977). The other human study showed that exposure at 110 ppm for 2 h can cause irritation of the eyes and respiratory tract (Verberk 1977). Because adaptation to ammonia at low concentrations has been shown, minimal irritant effects that can occur from exposure below 75 ppm are not expected to worsen with a longer exposure (up to 10 d). Submarine Escape Action Level 2 On the basis of its review of human and experimental animal health-effects and related data, the subcommittee concludes that the Navy’s proposed SEAL 2 of 75 ppm for ammonia is too conservative. The subcommittee recommends a SEAL 2 of 125 ppm. This value is based on a controlled human study in which volunteers exposed to ammonia at 140 ppm experienced severe throat irritation and left the exposure chamber within 1.25 h, while volunteers exposed at 110 ppm reported eye and throat irritation but did not leave the exposure chamber for the duration of the experiment (2 h) (Verberk 1977). Ferguson et al. (1977) observed only transient irritation of the eyes and throat after extended exposures (2–6 h/d, 5 d/wk for 110 ppm), and there was no evidence that such exposure caused decreased pulmonary function or affected mental ability. The crew of a disabled submarine should be able to tolerate the irritant effects from exposure to ammonia at concentrations below 125 ppm for up to 24 h. DATA GAPS AND RESEARCH NEEDS Because most of the controlled human studies on ammonia are of relatively short durations (5–120 min), the subcommittee recommends that additional controlled studies of longer exposure durations (e.g., for at least 24 h, and if possible, for up to 10 d) be conducted. There are data available on the interaction (altered toxicity) of ammonia with various chemicals, but there are little data available on the interaction of ammonia with other irritant gasses or airborne contaminants that are likely to be found in disabled submarines. Without evidence to the contrary, it might be assumed that the irritant effects of ammonia gas are at a minimum additive to the effects of other irritant gases that could be released simultaneously during a fire on a dis-

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Review of Submarine Escape Action Levels for Selected Chemicals abled submarine. However, the mechanism of irritation could be a saturable process, and the additive or synergistic nature of the effect might be an incorrect assumption. To address these questions, the subcommittee recommends that studies be conducted to examine the effects on respiratory-tract and eye irritation, and on pulmonary function of simultaneous exposures to multiple irritant gases. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Ammonia. Pp. 58–59 in Documentation of the Threshold Limit Values and Biological Exposure Indexes, Vol. 1., 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hygienists). 1999. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents. Biological Exposure Indices. Cincinnati, OH: ACGIH. AIHA (American Industrial Hygiene Association). 2001. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook Fairfax, VA: American Industrial Hygiene Association. Alarie, Y. 1973. Sensory irritation by airborne chemicals. CRC Crit. Rev. Toxicol. 2(3): 299–363. Alarie, Y. 1981. Bioassay for evaluating the potency of airborne sensory irritants and predicting acceptable levels of exposure in man. Food Cosmet. Toxicol. 19(5):623– 626. Albrecht, J. 1996. Astrocytes and ammonia neurotoxicity. Pp. 137–153 in The Role of Glia in Neurotoxicity, M.Aschner and H.K.Kimelberg, eds. Boca Raton: CRC Press. Anderson, D.P., C.W.Beard, and R.P.Hanson. 1964. The adverse effects of ammonia on chickens including resistence to infection with Newcastle disease virus. Avian Dis. 8:369–379. Appelman, L.M., W.F.ten Berge, and P.G.J.Reuzel. 1982. Acute inhalation toxicity study of ammonia in rats with variable exposure periods. Am. Ind. Hyg. Assoc. J. 43(9):662–665. ATSDR (Agency for Toxic Substancs and Disease Registry). 1990. Toxicological Profile for Ammonia. Prepared by Syracuse Research Corporation, for U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry. December. Barrow, C.S., Y.Alarie, and M.F.Stock. 1978. Sensory irritation and incapacitation evoked by thermal decomposition products of polymers and comparisons with known sensory irritants. Arch. Environ. Health 33(2):79–88. Boyd, E.M., M.L.MacLachlan, and W.F.Perry. 1944. Experimental ammonia gas poisoning in rabbits and cats. J. Ind. Hyg. Toxicol. 26(1):29–34. Broderson, J.R., J.R.Lindsey, and J.E.Crawford. 1976. The role of environmental ammonia in respiratory mycoplasmosis of rats. Am. J. Pathol. 85(1):115–130.

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Review of Submarine Escape Action Levels for Selected Chemicals Flury, F., and F.Zernick 1931. Noxious Gases, Vapors, Mist, Smoke and Dust Particles. Berlin: Springer. Flury, K.E., D.E.Dines, J.R.Rodarte, and R.Rodgers. 1983. Airway obstruction due to inhalation of ammonia. Mayo Clin. Proc. 58(6):389–393. Fürst, P., B.Josephson, G.Maschio, and E.Vinnars. 1969. Nitrogen balance after intravenous and oral administration of ammonium salts to man. J. Appl. Physiol. 26(1):13–22. Gamble, M.R., and G.Clough. 1976. Ammonia build-up in animal boxes and its effect on rat tracheal epithlium. Lab. Anim. 10(2):93–104. Gay, W.M.B., C.W.Crane, and W.D.Stone. 1969. The metabolism of ammonia in liver disease: a comparison of urinary data following oral and intravenous loading of [15N] ammonium lactate. Clin. Sci. 37(3):815–823. Guyton, A.C. 1981. Pp. 456–458, 889 in Textbook of Medical Physiology, 6th Ed. Philadelphia, PA: W.B.Sanders. Hathaway, G.J., N.H.Proctor, J.P.Hughes, and M.L.Fischman. 1991. Pp. 83–84 in Proctor and Hughes’ Chemical Hazards of the Workplace, 3rd Ed. New York Van Nostrand Reinhold. Hatton, D.V., C.S.Leach, A.L.Beaudet, R.O.Dillman, and N.DiFerrante. 1979. Collagen breakdown and ammonia inhalation. Arch. Environ. Health 34(2):83–87. Hawkins, R.A., and J.Jessy. 1991. Hyperammonemia does not impair brain function in the absence of net glutamine synthesis. Biochem. J. 277 (Pt.3):697–703. Hawkins, R.A., J.Jessy, A.M.Mans, and M.R.De Joseph. 1993. Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J. Neurochem. 60(3):1000–1006. Henderson, Y., and H.W.Haggard. 1927. Pp. 87, 113–126 in Noxious Gases and the Principles of Respiration Influencing Their Action. New York Chemical Catalog Company, Inc. Henderson, Y., and H.W.Haggard. 1943. Characteristics of irritant gases. Pp. 125–126 in Noxious Gases, 2nd Ed. New York Reinhold. Hilado, C.J., C.J.Casey, and A.Furst. 1977. Effect of ammonia on Swiss albino mice. J.Combust. Toxicol. 4:385–388. Hoeffler, H.B., H.I.Schweppe, and S.D.Greenberg. 1982. Bronchiectasis following pulmonary ammonia burn. Arch. Pathol. Lab. Med. 106(13):686–687. Holness, D.L., J.T.Purdham, and J.R.Nethercott. 1989. Acute and chronic respiratory effects of occupational exposure to ammonia. Am. Ind. Hyg. Assoc. 50(12):646– 650. Industrial Bio-Test Laboratories, Inc. 1973. Irritation Threshold Evaluation Study with Ammonia, Industrial Bio-Test Laboratories, Inc. (Report to International Institute of Ammonia Refrigeration, Publication No. 663–03161). IRIS. 1991. Ammonia. Integrated Risk Information System (IRIS), U.S. Environmental Protection Agency). [Online]. Available: http://www.epa.gov/iris [June 20, 2000]. Kapeghian, J.C., H.H.Mincer, A.B.Jones, A.J.Verlangieri, and I.W.Waters. 1982. Acute inhalation toxicity of ammonia in mice. Bull. Environm. Contam. Toxicol. 29(3):371–378.

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Review of Submarine Escape Action Levels for Selected Chemicals Kass, I., N.Zamel, D.A.Dobry, and M.Holzer. 1972. Bronchiectasis following ammonia burns of the respiratory tract. A review of two cases. Chest 62(3):282–285. Kirhov, V. 1977. Neuroautonomic responses of workers in the ammonia industry [in Bulgarian]. Suvrem. Med. 28(10):10–13. Kustov, V.V. 1967. Means of determining the maximum allowable concentration of toxic products of natural human metabolism. Pp. 63–65 in General Questions of Industrial Toxicology, Moscow [in Russian]. NASA TT F-11,358. Landahl, H.D., and R.G.Herrmann. 1950. Retention of vapors and gases in the human nose and lung. Arch. Ind. Hyg. Occup. Med. 1:36–45. Leduc, D., P.Gris, P.Lheureux, P.A.Gevenois, P.De Vuyst, and J.C.Yernault. 1992. Acute and long term respiratory damage following inhalation of ammonia. Thorax 47(9):755–757. Lehmann, K.B. 1886. Arch. F. Ind. Hyg. 5:68. Levy, D.M., M.B.Divertie, T.J.Litzow, and J.W.Henderson. 1964. Ammonia burns of the face and respiratory tract. JAMA 190(10):95–98. Lewis, R.J., ed. 1993. Hawle’s Condensed Chemical Dictionary, 12th Ed. New York Van Nostrand Reinhold. MacEwen, J.D., J.Theodore, and E.H.Vernot. 1970. Human exposure to EEL concentrations of monomethylhydrazine. Pp. 355–363 in Proceedings of the 1st Annual Conference on Environmental Toxicology, Ohio, Wright-Patterson Air Force Base, 9–11 September, 1970. AMRL-TR-70–102, Paper No. 23. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. MacEwen, J.D., and E.H.Vernot. 1972. Toxic Hazards Research Unit Annual Technical Report: 1972. AMRL-TR-72–62. NTIS AD755–358. Aerospace Medical Research Laboratory, Air Force Systems Command, Wright-Patterson Air Force Base, OH. Mangold, C.A. 1971. Investigation of Occupational Exposure to Ammonia. Record of Industrial Hygiene Division Investigation, Puget Sound Naval Shipyard, Washington. 29 November 1971 . Manninen, A., S.Anttila, and H.Savolainen. 1988. Rat metabolic adaptation to ammonia inhalation. Proc. Soc. Exp. Biol. Med. 187(3):278–281. Markham, R.S. 1986. A Review of Damage from Ammonia Spills. Paper presented at the 1986 Ammonia Symposium, Safety in Ammonia Plants and Related Facilities. A.I.Ch.E., Boston, MA, August 1986. (Cited in Pedersen and Selig 1989). Mayan, M.H., and C.P.Merilan. 1972. Effects of ammonia inhalation on respiration rate of rabbits. J. Anim. Sci. 34(3):448–452. Mayan, M.H., and C.P.Merilan. 1976. Effects of ammonia inhalation on young cattle. N.Z. Vet. J. 24(10):221–224. Montague, T.J., and A.R.Macneil. 1980. Mass ammonia inhalation. Chest 77(4):496– 498. Mulder, J.S., and H.O.Van der Zalm. 1967. A fatal case of ammonia poisoning. [In Dutch]. Tijdschrift voor Sociale Geneeskunde 45:458–460. Neumann, R., G.Mehlhorn, I.Buchholz, U.Johannsen, and D.Schimmel. 1987. Experimental studies on the effect of chronic aerogenous toxic gas burden of suckling pigs with different ammonia concentrations. II. The reaction of cellular and humoral

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