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
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
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
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;
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
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.
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). |
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
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
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 |
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 |
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.
Accidental Exposures
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.
Occupational and Epidemiologic Studies
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-
TABLE 2–5 Human Toxicity Data, Accidental Exposure to Ammonia
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
6 ice cream factory workers |
Whole body |
NR |
NR |
Subjects exhibited shock, acute inflammation of the respiratory tract, and burns to the skin and eyes. One subject died 1 mo after exposure; autopsy revealed acute laryngotracheitis, tracheobronchitis, and bronchopneumonia. |
Slot 1938 |
1 worker |
Whole body |
NR |
NR |
Death by cardiac arrest 6 h after exposure; autopsy revealed marked respiratory irritation, denudation of tracheal epithelium, pulmonary edema. Before death, effects included coughing dyspnea, vomiting, reddened and swollen face, red and raw mouth and throat, conjunctivitis. |
Mulder and Van der Zalm 1967 (as cited in NIOSH 1974) |
7 workers |
Whole body |
NR |
NR |
1 death; autopsy and histologic examination revealed obstructed airway, acute congestion and edema of the lungs, denudation of the bronchial epithelium, red blood cells and edema fluid in the alveoli. Survivors suffered burns of the mucous membranes, skin, and eyes; difficulty breathing. Airway damage and reduced gas transfer observed for up to 3 yr after exposure. |
Walton 1973 |
47 subjects |
Whole body |
NR |
NR |
Subjects classified as “mildly,” “moderately,” or “severely” affected. Mildly affected: No deaths among 9 subjects; acute pharyngitis and tracheitis. Moderately affected: 6 of 27 died; 3 subjects exhibited symptoms similar to pulmonary edema and died within 36 h; 9 subjects developed bronchopneumonia within 2–3 d and 3 died 2 d after onset. Severely affected: 7 of 11 died; all subjects had pulmonary edema, and 7 died within 48 h. |
Caplin 1941 |
1 worker |
Whole body |
NR |
NR |
Immediate effects included bilateral conjunctival edema; respiratory distress, wheezing, rhonchi, rales; skin burns; pulmonary edema. Subject died 60 d after exposure. Autopsy revealed bronchiectasis, fibrous obliteration of small airways, terminal nocardial pneumonia, mucous plugging and mural thickening of the smallest bronchi and some bronchioles. |
Sobonya 1977 |
1 subject |
Whole body |
NR |
NR |
Female exposed in trucking accident died 3 yr after exposure. She suffered from severe respiratory effects (pulmonary edema) immediately after exposure and required mechanical-assisted respiration until death. Autopsy revealed bronchiectasis and bacterial bronchitis. |
Hoeffler et al. 1982 |
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
2 subjects |
Whole body |
NR |
NR |
Both subjects died of acute ammonia exposure; light microscopy of pulmonary tissues revealed denudation of tracheobronchial epithelium; edema of lamina propria; and marked alveolar edema, congestion, and hemorrhage. Electron microscopy of tissues showed marked swelling and imbitional edema of Type I alveolar epithelial cells, no effect on alveolar basement membranes and capillary endothelial cells. |
Burns et al. 1985 |
9 subjects |
Whole body |
NR |
NR |
Subjects divided into 2 groups: Those exposed to high concentrations over a short period (n=3) and those exposed to lower concentrations over a prolonged period (n= 6). One highly exposed individual died, and the other 2 had upper airway obstruction that necessitated early intubation or tracheostomy, burns to the skin and mucous membranes of the upper airway, and epithelial defects of the cornea; Individuals recovered with few respiratory sequelae. Subjects who experienced longer-term exposure had burns of the face, eyes, and |
Close et al. 1980 |
|
skin; had burns of the upper respiratory tract. None had upper airway obstruction but did suffer long-term pulmonary sequelae. |
||||
1 subject |
Whole body |
NR |
3 min |
Immediate effects included burns of the face, eyes, and oral cavity. Subject developed clinical and radiologic features of pulmonary edema, respiratory failure with tachypnoea and arterial hypoxaemia, airflow obstruction. Death occurred 12 wk after exposure. Autopsy revealed bronchiectasis and obliterative bronchiolitis. |
Price et al. 1983 |
4 subjects |
Whole body |
NR |
NR |
Upper airway obstruction; second- or third-degree burns to the skin; burns or irritation of the mouth, nose, throat, eyes; some pulmonary damage. One subject (6 mo) suffered cardiorespiratory arrest). All recovered between 7 and 32 d. |
Hatton et al. 1979 |
14 fishermen |
Whole body |
NR |
NR |
Respiratory distress, pharyngeal or pleuritic chest pain, cough, dyspnea, ocular irritation. Some exhibited tachypnea, rales, rhonchi, wheezing, tachycardia. |
Montague and Macneil 1980 |
1 subject |
Whole body |
NR |
NR |
Loss of consciousness; rapid and heavy respiration; burns on the neck, eyes, skin; elevated blood pressure and pulse; lungs with fine and harsh rales; spastic extremities; increased white blood cell count. |
White 1971 |
Subject |
Route |
Concentration (ppm) |
Duration |
Effect |
Reference |
8 subjects |
Whole body |
NR |
NR |
Immediate effects included eye and throat irritation, difficulty breathing. Some had burns of the skin, tachycardia, tachypnoea. Severely affected subjects showed evidence of impaired pulmonary function up to 2 yr after exposure. |
Ward et al. 1983 |
1 subject |
Whole body |
NR |
NR |
Male subject splashed with liquid ammonia suffered burns of the skin and upper airway obstruction. Follow-up examinations for 5 yr indicate persistent central and peripheral airway obstruction. |
Flury et al. 1983 |
8 workers |
Whole body |
NR |
NR |
Subjects described as having “mild,” “moderate,” and “heavy” exposure. Mildly exposed subjects had burns of the oral cavity, pharynx, eyes. Moderately exposed subjects exhibited bronchospasm, labored breathing, transient bilateral rhonchi. Heavily exposed subjects severe irritation of the eyes, oral cavity, pharynx; inspiratory and expiratory rhonchi. 1 subject needed mechanical ventilation and tracheostomy. |
O’Kane 1983 |
1 subject |
Whole body |
NR |
NR |
Immediate effects included burns of the respiratory tract, eyes, skin; dyspnea; labored breathing. Tubular bronchiectasis 8 yr after the accident. Airflow obstruction, cough, frequent bronchial infections, dyspnea upon |
Leduc et al. 1992 |
|
exertion persisted for 12 yr after exposure. |
|
|||
2 subjects |
Whole body |
NR |
30, 90 min |
Immediate effect included burns of the respiratory tract, eyes, skin. Both suffered from residual effects more than 2 yr after exposure. Effects included bronchiectasis, visual deterioration, small airway obstruction, atelectasis, emphysema in the lungs; thickened alveolar walls with histiocytic infiltration into alveolar spaces,; mucous and desquaminated cells in the bronchiolar lumen. |
Kass et al. 1972 |
1 subject |
Whole body |
NR |
NR |
Irritation of the eyes, dyspnea, pharyngeal edema, and bilateral diffuse rhonchi and rales. 2 yr after exposure, subject needed traceostomy and mechanical ventilation, eventually permanent traceostomy. |
Stroud 1981 |
4 subjects |
Whole body |
NR |
NR |
Subjects sprayed on the face and upper body with liquid ammonia had upper airway obstruction, burns to the skin, mucous membranes of the oral cavity and pharynx, and eyes. |
Levy et al. 1964 |
TABLE 2–6 Human Toxicity Data, Occupational and Epidemiology Studies of Exposure to Ammonia
Subjects |
Route |
Concentration, ppm |
Duration |
Effect |
Reference |
Worker |
Whole body |
20–100 |
NR |
Irritation of the upper respiratory tract, eyes. Workers accustomed to 20 ppm showed redness of the conjuctiva but did not report irritation; unaccustomed workers reported irritation. No other details provided. No information on methods used to survey workers. |
Vigliani and Zurlo 1955 (as cited in NIOSH 1974) |
73 workers in ammonia production plant |
Whole body |
13–51 |
NR |
Exposed workers reported more headaches, vertigo, staggering, and tremors. Unclear whether effects can be attributed solely to ammonia, because the workers were exposed to other compounds and because of possible selection and/or reporting bias. |
Kirhov 1977 (as cited in Swotinsky and Chase 1990) |
41 workers in ice-manufacturing plant |
Whole body |
NR |
NR |
Questionnaires administered before and after work shifts were compared with those from 28 nonexposed workers. Chronic bronchitis was found in 20% of exposed workers and 14% of nonexposed workers. No differences between the groups in ventilatory function tests or chest examinations. |
el-Sewefy and Awad 1971 (as cited in NRC 1987) |
8 workers in blueprint shop |
Whole body |
4–29 |
NR |
Ocular irritation reported in an unspecified number of workers. |
Mangold 1971 (as cited in NIOSH 1974) |
58 sodium carbonate industry workers |
Whole body |
9.2±1.4 (mean ± SD) |
12.2 yr |
Workers exposed during production of sodium carbonate compared with 31 control workers (mean concentration, 0.3± 0.1 ppm). Investigators assessed subjective respiratory, ocular, dermal responses; sense of smell; baseline lung function at the beginning and end of a work week; changes in lung function over a work shift. No significant differences between the exposure groups, no relationship found between concentration or length of ammonia exposure and lung function. |
Holness et al. 1989 |
Abbreviations: SD, standard deviation; NR, not reported. |
TABLE 2–7 LC50 for Exposure to Ammonia
Species |
Duration |
LC50 (ppm) |
Reference |
Rat |
10 min |
40,300 |
Appelman et al. 1982 |
|
15 min |
17,401 |
Prokop’eva et al. 1973 (as cited in ATSDR 1990) |
|
20 min |
28,595 |
Appelman et al. 1982 |
|
40 min |
20,300 |
Appelman et al. 1982 |
|
60 min |
16,600 |
Appelman et al. 1982 |
|
60 min |
7,338 |
MacEwen and Vernot 1972 (as cited in WHO 1986) |
|
960 min |
1,000 |
Weedon et al. 1940 (as cited in ATSDR 1990) |
Mouse |
10 min |
9,960 |
Silver and McGrath 1948 |
|
30 min |
21,430 |
Hilado et al. 1977 |
|
60 min |
4,837 |
MacEwen and Vernot 1972 (as cited in WHO 1986) |
|
60 min |
4,230 |
Kapeghian et al. 1982 |
|
960 min |
1,000 |
Weedon et al. 1940 (as cited in ATSDR 1990) |
Rabbit |
60 min |
9,870 |
Boyd et al. 1944 |
Cat |
60 min |
9,870 |
Boyd et al. 1944 |
Abbreviation: LC50, median lethal concentration. |
uted solely to ammonia. Some of the studies were poorly conducted or documented, and co-exposures to other chemicals often were involved.
EXPERIMENTAL ANIMAL TOXICITY DATA
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.
OTHER CONSIDERATIONS
Mechanism of Action
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
TABLE 2–8 Experimental Animal Toxicity Data, Exposure to Ammonia
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
ACUTE EXPOSURE |
||||||
Rat: 2–3 |
Inhalation (mouth only) |
10, 20, 45, 90 |
8 min |
Ciliary movement in the trachea stopped in a concentration-dependent fashion. |
LOAEL: 10 |
Dalhamn 1956 |
Rat: 10 |
Inhalation |
13, 920– 53, 330 |
10 min-1 h |
Mortality was concentration related. LC50 significantly lower for males than females. Animals exhibited restlessness, nasal and eye irritation, dyspnea. Hemorrhagic lungs found in animals that died and those that survived. |
NA |
Appelman et al. 1982 |
Rat: 10 |
Inhalation |
6,210, 7,820, 9,840 |
1 h |
8 and 9 deaths in the mid- and high-concentration groups, respectively. Nasal and eye irritation, labored breathing in all groups. Surviving rats necropsied after 14 d exhibited fatty livers. |
LOAEL: 6,210 |
MacEwen and Vernot 1972 (as cited in WHO 1986) |
Rat: 3 |
Inhalation |
100–300 |
6 h |
Behavioral activity assessed by wheel running. At low concentration, free-access wheel running was decreased by 61%. At high concentration, activity ceased throughout exposure. Activity steadily increased after exposure stopped. |
LOAEL: 100 |
Tepper et al. 1985 |
Rat: 8 |
Inhalation |
15, 32, 310, 1,157 |
24 h |
No significant effects. |
NOAEL: 1,157 |
Schaerdel et al. 1983 |
Mouse: 20 |
Inhalation |
8,600–12,690 |
10 min |
25% of the mice died at the lowest concentration; 80% died at the highest concentration. Animals exhibited excitement, nasal and eye irritation, convulsions. |
NA |
Silver and McGrath 1948 |
Mouse: 4 |
Inhalation |
303 |
30 min |
50% reduction in respiratory rate. |
NA |
Barrow et al. 1978 |
Mouse: 4 |
Inhalation |
7,143–28,571 |
30 min |
4 deaths each at 26,190 ppm and 28,571 ppm; 3 deaths at 23,810 ppm; 2 deaths at 21,429 ppm; 1 death at 19,048 ppm. No deaths at 14,286 ppm and lower. |
NA |
Hilado et al. 1977 |
Mouse: 10 |
Inhalation |
3,600, 4,550, 5,720 |
1 h |
3 and 9 deaths in mid- and high-concentration groups, respectively. Nasal and eye irritation, dyspnea, convulsions. Surviving animals had lower body weight at 14 d. At necropsy, mild liver congestion found in mid- and high-concentration groups. |
LOAEL: 3,600 |
MacEwen and Vernot 1972 (as cited in WHO 1986) |
Mouse: 12 |
Inhalation |
3,440–4,860 |
1 h |
Significant number of deaths occurred at concentrations of 3,950 ppm and greater. No deaths occurred at 3,440 ppm and lower. Animals exhibited ataxia, tremors, convulsions, excited |
LOAEL: 3,440 |
Kapeghian et al. 1982 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
behavior, eye and nose irritation, dyspnea before death. Pathologic examination of dead animals showed acute vascular congestion, diffuse intraalveolar hemorrhage, congestion of hepatic sinusoids and blood vessels. Pathologic examination of surviving animals revealed mild to moderate chronic focal pneumonitis, focal atelectatic changes (high-concentration only), hepatic cellular damage. |
|
||||
Chicken: 12 |
Inhalation |
50 |
48 h |
Exposure increased infection rate with Newcastle disease virus. |
LOAEL: 50 |
Anderson et al. 1964 |
Chicken: 12 |
Inhalation |
20 |
72 h |
Exposure increased infection rate of chickens to Newcastle disease virus. |
LOAEL: 20 |
Anderson et al. 1964 |
Rabbit: 8– 17 |
Inhalation |
9,870 |
1 h |
Exposure occurred before or after intratracheal cannulation to collect respiratory tract fluid. Mean survival time was 18 h for animals exposed after cannulation and 33 h for those exposed before cannulation. Histopathologic changes were different in the groups: Animals exposed after cannulation had |
NA |
Boyd et al. 1944 |
|
tracheal and bronchial damage; none of those effects were found in animals exposed before cannulation. Damage to the bronchioles and alveoli was similar in both groups. |
|
||||
Rabbit: 7–9 |
Inhalation |
50, 100 |
2.5–3 h |
Respiratory rate decreased 34% and 32%, respectively. No histopathologic changes in lunch, liver, spleen, kidneys. |
LOAEL: 50 |
Mayan and Merilan 1972 |
Cat: 4–5 |
Inhalation (endotracheal tube) |
1,000 |
10 min |
Severe dyspnea, anorexia, dehydration, bronchial breath sounds, sonorous and sibulent ronchi, coarse rales. Pulmonary function tests indicated increased pulmonary resistance throughout the study and significantly increased functional residual capacity on day 21. At necropsy, lungs were congested, hemorrhagic, edematous; there was interstitial emphysema, collapse. Histopathologic changes included necrosis and sloughing of bronchial epithelium on day 1; healing of the bronchial epithelium was detected on day 7. On days 21 and 35, there was evidence of bronchitis, bronchiolitis, bronchopneumonia, bulbous emphysema, thought to be caused by opportunistic infections. |
LOAEL: 1,000 |
Dodd and Gross 1980 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
REPEATED OR CONTINUOUS EXPOSURE |
||||||
Rat: 7 |
Inhalation |
4, 24, 44, 165, 714 |
3–7 d |
No significant effects in blood pH, blood gases, hepatic-drug-metabolizing enzyme activity. Histologic examination showed minor lesions of the respiratory epithelium in animals exposed for 7 d; no changes observed in trachea or lungs. The concentrations at which those lesions occurred was not specified. |
NA |
Schaerdel et al. 1983 |
Rat: 5 |
Inhalation |
435 |
7d |
Trachea effects included inflammation, infiltration of neutrophils, large mononucleated cells, monocytes, immature fibroblasts. |
LOAEL: 435 |
Gamble and Clough 1976 |
Rat: 5 |
Inhalation |
200 |
4–12 d |
Tracheal hyperplasia damage increased with duration. |
LOAEL: 200 |
Gamble and Clough 1976 |
Rat: 5 |
Inhalation |
25, 300 |
6 h/d, for 5–15 d |
Metabolic acidosis observed at day 5 but not thereafter. No treatment-related effects observed in the lung, liver, kidney. |
NOAEL: 300 |
Manninen et al. 1988 |
Rat: 12 |
Inhalation |
250 |
35 d |
No clinical symptoms observed. Pathologic examination revealed nasal lesions, predominantly in the anterior of the nasal passages. Histopathological |
LOAEL: 250 |
Broderson et al. 1976 |
|
changes included thickening of respiratory, olfactory epithelium. Cells along the basement membrane had pyknotic nuclei, eosinophilic cytoplasm. |
|
||||
Rat: 12 |
Inhalation |
25, 50, 100, 250 |
35–49 d, continuous |
Rats were inoculated with Mycoplasma pulmonis on day 7. Animals exposed to ammonia showed significantly increased symptoms of murine respiratory mycoplasmosis; severity of rhinitis, otitis media, tracheitis, pneumonia was increased. Pathologic and microscopic changes characteristic of infection also increased in exposed rats. |
LOAEL: 25 |
Broderson et al. 1976 |
Rat: 49 |
Inhalation |
2,100 |
4 wk, continuous |
Pathogen-free rats inoculated with M. pulmonis and exposed to ammonia had greater bacterial growth and immunologic responses than unexposed inoculated rats. Effects were considered secondary to effects in the nasal passages. |
LOAEL: 100 |
Schoeb et al. 1982 |
Rat: 15 |
Inhalation |
220, 1,090 |
8 h/d, 5 d/wk for 6 wk |
Nonspecific inflammatory changes observed in the lungs of the 1,090 ppm group. |
NOAEL: 220 LOAEL: 1,090 |
Coon et al. 1970 |
Rat: 48–51 |
Inhalation |
180, 370, 640 |
90 d, continuous |
At 640 ppm, 50 of 51 rats died by day 65. Animals exhibited dyspnea and nasal irritation. No significant effects observed at the other concentrations. |
NOAEL: 370 |
Coon et al. 1970 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
Rat: 15 |
Inhalation |
660 |
90 d, continuous |
13 of 15 animals died. Histopathologic examination revealed focal or diffuse interstitial pneumonitis, calcification of renal tubules, calcification of bronchial epithelial, renal tubular epithelial proliferation, myocardial fibrosis; fatty changes of the liver in several animals. Changes were also found in control animals, but were of lesser severity. |
LOAEL: 660 |
Coon et al. 1970 |
Rat: 15 |
Inhalation |
60 |
114 d, continuous |
No significant effects. |
NOAEL: 60 |
Coon et al. 1970 |
Mouse: 16–24 |
Inhalation |
303 |
6 h/d for 5 d |
Histopathologic changes in respiratory epithelium of nasal cavity included minimal exfoliation, erosion, ulceration, necrosis; moderate inflammation; minimal squamous metaplasia. No lesions found in tracheobronical or pulmonary regions. |
LOAEL: 303 |
Buckley et al. 1984 |
Mouse: 10 |
Inhalation |
78, 257, 711 |
6 h/d for 4–14 d |
No clinical signs of toxicity. Lesions of respiratory epithelium (rhinitis with metaplasia and necrosis) observed at highest concentration. Severity increased |
NOAEL: 257 LOAEL: 711 |
Zissu et al. 1995 |
|
with exposure duration. No lesions found in trachea or lungs. |
|
||||
Mouse: 20 |
Inhalation |
20 |
6 wk, continuous |
No clinical or pathologic effects observed up to 4 wk. At 6 wk, evidence of pulmonary edema, congestion, hemorrhage. |
LOAEL: 20 |
Anderson et al. 1964 |
Chicken: 12 |
Inhalation |
1,000 |
2 wk |
At 3 d, animals had photophobia and nasal secretion. At 8 d, corneal opacity evident. Pathologic examination at 2 wk revealed pulmonary congestion, edema, hemorrhage; congestion of liver and spleen. |
LOAEL: 1,000 |
Anderson et al. 1964 |
Chicken: 14 |
Inhalation |
200 |
3 wk |
Ocular irritation, increased mucous secretion, anorexia, weight loss observed between 1 and 2 wk. At 2–3 wk, lungs congested, edematous, and hemorrhagic; liver congested; and corneas slightly clouded. |
LOAEL: 200 |
Anderson et al. 1964 |
Chicken: 21 |
Inhalation |
20 |
12 wk |
No clinical or pathologic effects observed up to 4 wk. At 6 wk, lungs darkened, edematous, congested, hemorrhagic. |
LOAEL: 20 |
Anderson et al. 1964 |
Guinea pig: 8 |
Inhalation |
50, 90 |
3 wk |
No evidence of distress, ocular irritation, respiratory diseases, no effects on erythrocyte, leukocyte counts. Significant decrease in cell-mediated immune responses to challenge with a derivative of tuberculin at 90 ppm. |
NOAEL: 50 |
Targowski et al. 1984 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
Guinea pig: 15 |
Inhalation |
220, 1,090 |
8 h/d, 5 d/wk for 6 wk |
Nonspecific inflammatory changes observed in the lungs of the 1,090-ppm group. |
NOAEL: 220 LOAEL: 1,090 |
Coon et al. 1970 |
Guinea pig: 10 |
Inhalation |
20 |
6 wk, continuous |
No clinical or pathologic effects observed up to 4 wk At 6 wk, lungs darkened, edematous, congested, hemorrhagic. |
LOAEL: 20 |
Anderson et al. 1964 |
Guinea pig: 6 |
Inhalation |
50 |
6 wk, continuous |
Grossly enlarged spleen; congested liver spleen, lungs; pulmonary edema. |
LOAEL: 50 |
Anderson et al. 1964 |
Guinea pig: 15 |
Inhalation |
660 |
90 d, continuous |
4 of 15 animals died. Histopathologic examination revealed focal or diffuse interstitial pneumonitis, calcification of renal tubules, calcification of bronchial epithelial, renal tubular epithelial proliferation, myocardial fibrosis, fatty changes of the liver in several animals. Changes also found in control animals, but of lesser severity. |
LOAEL: 660 |
Coon et al. 1970 |
Guinea pig: 15 |
Inhalation |
60 |
114 d, continuous |
No significant effects. |
NOAEL: 60 |
Coon et al. 1970 |
Guinea pig: NS |
Inhalation |
170 |
6 h/d, 5d/wk for 18 wk |
No adverse effects up to 12 wk At necropsy at 18 wk, mild changes observed in spleen, kidney suprarenal glands, livers. No effects found in lungs. |
LOAEL: 170 |
Weatherby 1952 (as cited in IRIS) |
Rabbit: 3 |
Inhalation |
220, 1,090 |
8 h/d, 5 d/wk for 6 wk |
Mild to moderate lacrimation and dyspnea during wk 1 in the 1,090-ppm group, disappeared during wk 2. |
NOAEL: 1,090 |
Coon et al. 1970 |
Rabbit: 3 |
Inhalation |
660 |
90 d, continuous |
Marked eye irritation. At necropsy, moderate lung congestion in 2 rabbits. Histopathologic examination revealed focal or diffuse interstitial pneumonitis, calcification of renal tubules, calcification of bronchial epithelial, renal tubular epithelial proliferation, myocardial fibres is, fatty changes of the liver in several animals. Changes also found in control animals, but of lesser severity. |
LOAEL: 660 |
Coon et al. 1970 |
Rabbit: 3 |
Inhalation |
60 |
114 d, continuous |
No significant effects. |
NOAEL: 60 |
Coon et al. 1970 |
Dog: 2 |
Inhalation |
220, 1,090 |
8 h/d, 5 d/wk for 6 wk |
Mild to moderate lacrimation and dyspnea during wk 1 in 1,090 ppm group, but disappeared during wk 2. |
NOAEL: 1,090 |
Coon et al. 1970 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
Dog: 2 |
Inhalation |
660 |
90 d, continuous |
Marked eye irritation and nasal discharge. 1 of 2 dogs had a hemorrhagic lesion of the lung. Histopathologic examination revealed focal or diffuse interstitial pneumonitis, calcification of renal tubules, calcification of bronchial epithelial, renal tubular epithelial proliferation, myocardial fibrosis, fatty changes of the liver in several animals. Changes also found in control animals, but of lesser severity. |
LOAEL: 660 |
Coon et al. 1970 |
Dog: 2 |
Inhalation |
60 |
114 d, continuous |
No significant effects. |
NOAEL: 60 |
Coon et al. 1970 |
Pig: 8 |
Inhalation |
50, 100, 150 |
4 wk |
At 100 and 150 ppm, lethargy, nasal secretions, coughing, tracheal inflammation. Excessive lacrimation; reduced weight gain observed in all exposure groups. |
LOAEL: 50 |
Drummond et al. 1980 |
Pig: 6 |
Inhalation |
100 |
1–6 wk |
Ocular irritation at wk 1, but not thereafter. No effects on appetite, mean daily weight gains, frequency of |
LOAEL: 100 |
Doig and Willoughby 1971 |
|
coughing, hemograms, total serum lactic dehydrogenase activity. Histopathologic changes included thickening of the tracheal epithelium, decrease in number of tracheal epithelial goblet cells in pigs exposed for 2–6 wk |
|
||||
Pig: 8 |
Inhalation |
50, 100, 150 |
4 wk |
Lethargy and an acute inflammatory reaction in the tracheal epithelium of pigs exposed at 100 or 150 ppm. |
NOAEL: 50 |
Drummond et al. 1980 |
Pig: 9 |
Inhalation |
10, 50, 100, 150 |
5 wk |
Up to 50 ppm, coughing; irritation of the mouth, nose, eyes; reduced feed intake; and reduced weight gain. No effects observed at 10 ppm. |
NOAEL: 10 |
Stombaugh et al. 1969 |
Pig: NS |
Inhalation |
100 |
3 1–45 d |
Increased concentration of gamma globulin. |
LOAEL: 100 |
Neumann et al. 1987 (as cited in ATSDR 1990) |
Monkey: 3 |
Inhalation |
220, 1,090 |
8 h/d, 5 d/wk for 6 wk |
Histopathologic examination revealed focal pneumonitis in the lung of 1 of 3 animals at 220 ppm. |
LOAEL: 220 |
Coon et al. 1970 |
Monkey: 3 |
Inhalation |
660 |
90 d, continuous |
Histopathologic examination revealed focal or diffuse interstitial pneumonitis, calcification of renal tubules, calcification of bronchial epithelial, renal tubular epithelial proliferation, |
LOAEL: 660 |
Coon et al. 1970 |
Species: No. per Group |
Route |
Concentration (ppm) |
Duration |
Effect |
NOAEL, LOAEL (ppm) |
Reference |
|
myocardial fibrosis, fatty changes of the liver in several animals. Changes were also found in control animals, but of lesser severity. |
|
||||
Monkey: 3 |
Inhalation |
60 |
114 d, continuous |
No significant effects. |
NOAEL: 60 |
Coon et al. 1970 |
Abbreviations: LC50, median lethal concentration; LOAEL, lowest observable adverse effect level; NOAEL, no observable adverse effect level; NS, not specified. |
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.
Biomarkers of Exposure
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.
Susceptible Populations
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
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.
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
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 |
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. |
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-
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.
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