Review of Submarine Escape Action Levels for Selected Chemicals (2002)

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.

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

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

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).

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

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).

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;

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).

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

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).

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.

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

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

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

and the threshold concentration. The younger subjects were more sensitive, with the reflex response occurring at 571 ppm in subjects aged 21–30 and at 1,791 ppm in subjects aged 86–95. The threshold was about 1,000 ppm for 60-yr-old subjects. The decreased reflex activity of the glottis suggests that protection of the airways in elderly people could be less than that of much younger people.

Collectively, these studies show that ammonia at concentrations as high as 140 ppm has no effect on pulmonary function, but it causes irritation of the eyes, nose, and throat at concentrations as low as 72 ppm. Those studies provide the critical data on which to base both SEAL 1 and SEAL 2.

Table 2–5 presents the details of studies related to accidental exposures to ammonia. All studies involved inhalation and dermal exposure to ammonia at high concentrations, although it was not possible to quantify them. Accidental exposure has resulted in both immediate and delayed mortality (Caplin 1941; Hoeffler et al. 1982; Mulder and Van der Zalm 1967; Sobonya 1977). Other exposure cases have resulted in injury to the respiratory tract, including mild to severe irritation, tracheal and bronchial burns, and airway obstruction (Close et al. 1980; Sobonya 1977; Walton 1973); burns or irritation to the skin, eyes, and mucous membranes of the nasal and oral passages (Hatton et al. 1979; Mulder and Van der Zalm 1967); and cardiac effects (Hatton et al. 1979; Montague and Macniel 1980). Hematological and musculoskeletal effects have also been documented (White 1971). In cases of severe exposure, respiratory effects can persist for years (Levy et al. 1964; Kass et al. 1972; Flury et al. 1983; Leduc et al. 1992). The respiratory dysfunction caused by acute high-level ammonia exposure can be biphasic: Immediate effects can lead to severe pulmonary damage, edema, and death. But if there is initial recovery, secondary effects can lead to death or debilitating chronic respiratory disease (Dodd and Gross 1980). Because of the high concentrations of ammonia exposure, further discussion of these case reports is of limited usefulness in deriving either SEAL 1 or SEAL 2.

Table 2–6 provides details of occupational and epidemiologic studies of workers exposed to ammonia. Overall, differences were found in pulmonary function among workers exposed to ammonia compared with non-exposed workers. Some studies reported increased subjective reports of respiratory, dermal, or ocular irritation, but it is unclear whether these effects can be attrib-

uted solely to ammonia. Some of the studies were poorly conducted or documented, and co-exposures to other chemicals often were involved.

Acute inhalation experiments with ammonia have demonstrated lethal and nonlethal toxic effects in a variety of laboratory animals. Table 2–7 lists LC₅₀ (the concentration that is lethal to 50% of test animals) reported for ammonia in various species. Mice are particularly sensitive to ammonia and other irritant gasses (Alarie 1973; Alarie 1981; Kapeghian et al. 1982).

Of particular relevance is the work of Buckley et al. (1984). Respiratory lesions induced by sensory irritants were compared in mice exposed at RD₅₀ (the

concentration that causes a 50% decrease in respiratory rate). In this study, the effects of exposure to the RD₅₀ concentrations for ammonia (303 ppm) and hydrogen chloride (309 ppm) were compared (Barrow et al. 1978). Even though hydrogen chloride and ammonia have similar water solubility and RD₅₀ values, the injury caused by hydrogen chloride was extensive, whereas there were no observable histopathologic changes in the respiratory tracts of mice exposed to ammonia at 303 ppm. Thus, in the case of ammonia, significant irritation does not necessarily translate into pathology. Studies in rabbits also indicate that because of its water solubility, ammonia is absorbed by the mucous coating of the upper respiratory tract, thus reducing exposure to the lower respiratory tract. For example, Boyd et al. (1944) reported less toxic effects (e.g., damage to trachea, effects on bronchioles) in rabbits exposed to ammonia inhaled through the nose and mouth compared with rabbits whose exposures were directly into the trachea. Table 2–8 describes acute animal toxicity studies with ammonia.

Repeated or continuous exposure over several days or weeks has been studied in several animal species. The details of those studies are also presented in Table 2–8. As in acute studies, the primary effects caused by exposure are irritation of the upper respiratory tract, eyes, and skin. The results of the study by Buckley et al. (1984) are supported by the work by Zissu (1995), who repeatedly exposed mice to various concentrations of ammonia 6 h/d for up to 14 d. The minimum concentration of ammonia causing histopathologic changes in respiratory epithelium was 711 ppm. No changes were seen in the olfactory epithelium, lung, or trachea at this concentration.

Some studies indicate that ammonia can increase susceptibility to pathogens (Anderson et al. 1964; Broderson et al. 1976; Schoeb et al. 1982; Targowski et al. 1984) and could affect behavior (Tepper et al. 1985). There are no animal toxicity studies specifically on dermal exposure to ammonia gas, but most of the inhalation studies outlined in Table 2–8 involved whole body exposures. Those studies report burns and irritation of the skin, eyes, and mucous membranes of the upper respiratory system. In general, the severity of the damage is related to the concentration and duration of exposure.

Ammonia is an irritant gas that produces effects immediately upon contact with moist mucous surfaces of the eyes and respiratory tract via the formation of ammonium hydroxide and the production of heat (NRC 1994). Because of its offensive odor and irritant properties, a person who is exposed to ammonia

vapor (or gas) will try to escape as quickly as possible (Swotinsky and Chase 1990). The odor threshold for ammonia is lower than is the threshold for irritation, and it can serve as a warning of ammonia’s presence, but not as a determinant of its concentration. In the case of human deaths reported after massive inhalation exposures, laryngeal swelling resulting from fluid engorgement and edema restricted airflow (see Table 2–5). Further, in the first tissues exposed to the irritant gas, plasma exudes from the vascular walls into the respiratory passages causing additional blockage to airflow and leading to respiratory failure and death (Henderson and Haggard 1927). Hyperammonemia is an unlikely sequela from inhalation exposure to ammonia; however, the mechanism of hyperammonemia-induced CNS injury was discussed earlier.

There are no known specific biomarkers for exposure to ammonia. Plasma concentrations cannot serve this purpose, as relatively large amounts of ammonia are produced endogenously. Previously discussed studies (Schaerdel et al. 1983; Silverman et al. 1949) have demonstrated that inhalation of relatively high concentrations of ammonia do not significantly alter blood or urinary ammonia. Biomarkers of effect from ammonia exposure are limited to resultant tissue injuries from contact with the irritant gas. Unfortunately, the lesions are nonspecific and are consistent with exposure to other irritant gasses and caustic compounds.

Persons who suffer from hepatic or renal insufficiency can become susceptible to ammonia toxicity. Toxicity from ammonia in these cases, however, results from endogenously produced ammonia. The limited systemic absorption of ammonia following inhalation exposure would be insignificant when compared with concentrations produced within the body (WHO 1986). Persons with hyperactive airway disease or other conditions that alter airway function (colds, cough, nasal congestion) are expected to be more susceptible to irritant effects of ammonia.

Adaptation to the odor and mild irritant effects of ammonia has been dem-

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.

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).

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.

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

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).

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.

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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