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Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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2
Ammonia

This chapter summarizes the relevant epidemiologic and toxicologic studies of ammonia. Selected chemical and physical properties, toxicokinetic and mechanistic data, and inhalation-exposure levels from the National Research Council (NRC) and other agencies are also presented. The committee considered all that information in its evaluation of the Navy’s current and proposed 1-h, 24-h, and 90-day exposure guidance levels for ammonia. The committee’s recommendations for ammonia exposure levels are provided at the end of this chapter with a discussion of the adequacy of the data for defining the levels and the research needed to fill the remaining data gaps.

PHYSICAL AND CHEMICAL PROPERTIES

Ammonia is a corrosive alkaline gas at room temperature (Budavari et al. 1989). It is colorless and has a distinctive odor that has been described as sharp, pungent, and irritating (HSDB 2005). The odor threshold has been reported to range from 5 to 53 ppm (NRC 2002). Selected chemical and physical properties are listed in Table 2-1.

OCCURRENCE AND USE

Ammonia has several important industrial uses (Czuppon et al. 1992). It is a primary feedstock in the fertilizer industry, which is the largest consumer of ammonia. It is also used to synthesize explosives and products in the fibers and plastics industry. Ammonia also is a naturally occurring compound, an essential component of many biologic processes, and an intermediate in the global nitrogen cycle. Average global ammonia concentrations are estimated to range from 0.6 ppb to 3 ppb (ATSDR 2004).

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 2-1 Physical and Chemical Properties of Ammonia

Synonyms

Anhydrous ammonia, ammonia gas

CAS registry number

7664-41-7

Molecular formula

NH3

Molecular weight

17.03

Boiling point

−33.35°C

Melting point

−77.7°C

Flash point

NA

Explosive limits

NA

Specific gravity

0.639 at 0°C

Vapor pressure

8.5 atm at 20°C

Solubility

Solubility in water: 47% (0°C), 38% (15°C), 28% (30°C), 18% (50°C); soluble in chloroform and ether

Conversion factors

1 ppm = 0.7 mg/m3; 1 mg/m3 = 1.44 ppm

Abbreviations: NA, not available or not applicable.

Sources: Specific gravity from Czuppon et al. 1992; vapor pressure from Lewis 1993; all other data from Budavari et al. 1989.

Sources of ammonia on submarines include the sanitary system, decomposition of monoethanolamine (a chemical used in the carbon dioxide removal system), and decomposition of insulation blowing agents (Crawl 2003). NRC (1988) listed ammonia as a possible air contaminant on board submarines and reported a concentration of 2 ppm. No information was provided on sampling protocol, location, operations, or duration. No other exposure data were located.

SUMMARY OF TOXICITY

The database to characterize ammonia toxicity is sufficient and includes human and animal data suitable for derivation of exposure guidance levels. Multiple toxicologic reviews are available, including evaluations by the NRC (1966, 1987, 1994, 2002, 2007), the Agency for Toxic Substances and Disease Registry (ATSDR 2004), the American Conference of Governmental Industrial Hygienists (ACGIH 2001), and the National Institute for Occupational Safety and Health (NIOSH 1974). Information from those reviews is summarized in the following paragraphs.

Ammonia is a corrosive, alkaline, irritant gas that produces effects immediately on contact with moist mucous membranes of the eyes, mouth, and respiratory tract. It reacts with moist tissues to form ammonium hydroxide in an exothermic reaction; the thermal and chemical burns resulting from high-concentration exposures are a consequence of the heat of reaction and of the corrosive properties of the alkaline reaction product ammonium hydroxide.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Ammonia is a respiratory and ocular irritant; high concentrations can cause respiratory tissue injury and necrosis and penetrate the corneal epithelium. Because of its appreciable water solubility, ammonia is largely retained in the nasal mucosa, another common site of tissue injury after vapor exposure.

Because of its widespread commercial use and transport, accidental exposure to ammonia during industrial, farm, or transport accidents is not uncommon, and the toxicology literature contains numerous case studies and accident reports involving human exposures to high, but unknown, concentrations that have caused deaths or severe and long-lasting injuries. Although they contain useful background information, such reports provide little quantitative information regarding dose-response relationships, do not characterize exposure conditions expected on board a modern submarine, and hence will be given little consideration in the present analysis.

In addition to accident case reports, the ammonia database contains human experimental-exposure studies, epidemiologic studies, and laboratory animal experimental studies that characterize respiratory and ocular tissue injury, behavioral changes, reductions in respiration rates (such as RD50 values), potentially increased infectivity with pathogen challenge, or lethality.

As stated above, the human odor threshold for ammonia ranges from 5 to 53 ppm, and sensory fatigue (“adaptation” or “inurement”) is documented. There is some subjective debate regarding the concentration at which respiratory and ocular irritation occurs, but there is a consensus that tissue is injured at vapor concentrations in excess of those at which ammonia can be detected by odor or ocular irritation; thus odor and ocular irritation have warning value for ammonia, although sensory fatigue often occurs after continuous or repetitive exposures.

Effects in Humans

Accidental Exposures

No reliable concentration data are available for characterizing human exposures sustained during the many transportation, industrial, and agricultural accidents in which injurious or lethal ammonia concentrations have been released. Most case reports contain no exposure estimates but demonstrate that high vapor concentrations have caused severe damage to the respiratory tract. Death was most likely to occur when exposures were high enough to cause pulmonary edema. Nonlethal, irreversible, or long-term effects occurred when damage progressed to the tracheobronchial region, as manifested in reduced performance on pulmonary-function tests, bronchitis, bronchiolitis, emphysema, and bronchiectasis. Nondisabling, reversible effects were manifested as irritation to the eyes, throat, and nasopharyngeal region. A few of the many accident case reports are summarized below. Additional case reports and details are presented

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

in NRC (2002; see Table 2-5, “Human Toxicity Data, Accidental Exposure to Ammonia,” pp. 34-41) and ATSDR (2004).

Caplin (1941, as cited in NIOSH 1974) reported effects observed in 47 persons accidentally exposed to ammonia in an air-raid shelter when a transfer pipe containing ammonia was ruptured. Casualties were divided into three groups according to the degree to which they were affected: “mildly” (slight upper respiratory tract and eye irritation and hoarseness), “moderately” (productive cough and moist rales and more pronounced respiratory tract irritation), or “severely” (pulmonary edema with cyanosis, intense dyspnea, and persistent cough with frothy sputum). No deaths occurred among the nine “mildly” affected patients. Of the 27 “moderately” affected patients, three exhibited signs and symptoms similar to pulmonary edema and died within 36 h. Nine of the “moderately” affected patients developed bronchopneumonia within 2-3 days, and three died 2 days after the onset; mortality rate for the “moderately” affected patients was 22% (six of 27). The 11 “severely” affected patients developed pulmonary edema, and seven died within 48 h after exposure; mortality rate for the “severely” affected group was 64% (seven of 11).

Walton (1973) reported on the death of one of seven workers exposed to ammonia for an undefined duration in an industrial accident. The autopsy report noted marked laryngeal edema, acute congestion, pulmonary edema, and denudation of the bronchial epithelium. Survivors exhibited difficulty in breathing and burns of the eyes, mucous membranes, and skin; reduced pulmonary gas transfer and airway damage were apparent in survivors followed for 3 years after exposure.

A worker exposed to high concentrations of ammonia vapor estimated at 10,000 ppm for an undefined duration (perhaps a few minutes) experienced coughing, dyspnea, and vomiting soon after exposure (Mulder and Van der Zalm 1967). Three hours after initial exposure, the worker’s face was “red and swollen,” his mouth and throat were “red and raw,” his tongue was swollen, speech was difficult, and conjunctivitis was present; he died of cardiac arrest 6 h after exposure. An autopsy revealed marked respiratory irritation, denudation of the tracheal epithelium, and pulmonary edema (Mulder and Van der Zalm 1967).

People acutely exposed to high concentrations of ammonia who survive immediate effects may die of complications weeks to months later. A 25-year-old man died 60 days after exposure to a high concentration of ammonia sustained in a farming accident (Sobonya 1977). The autopsy report noted damage to the bronchial epithelium, bronchiectasis, mucus plugging and mural thickening of the smallest bronchi and bronchioles, fibrous obliteration of small airways, and a purulent cavitary pneumonia characterized by large numbers of Nocardia asteroides (nocardial pneumonia). Three co-workers exposed in the same accident died immediately. Hoeffler et al. (1982) reported on a case of a 30-year-old woman who died 3 years after exposure to ammonia during an accident involving a tanker truck carrying anhydrous ammonia in Houston, Texas. Her injuries resulted in severe immediate respiratory effects, including pulmonary

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

edema. She required mechanically assisted respiration throughout her remaining life. Bronchiectasis was detected 2 years after exposure and confirmed at autopsy, which also showed bronchopneumonia and cor pulmonale.

Experimental Studies

Numerous clinical studies—summarized in NRC (1987, 2002, 2007), ATSDR (2004), and elsewhere—have been conducted in healthy human subjects—including allergic and nonallergic people, those with asthma, and smokers—exposed to monitored concentrations of ammonia for various durations in controlled settings. Clinical data on reversible and nondisabling effects include responses from resting and exercising subjects and address respiratory and cardiac function, airway resistance, granulocytes and monocytes in peripheral blood, cell concentrations in nasal lavage fluids, and various subjective measurements of ocular and respiratory irritancy and systemic effects. Although results of some of the earlier (such as 1940s) studies may be compromised by what is now considered limited analytic characterization of exposure concentrations, there are sufficient multiple and well-conducted clinical studies suitable for exposure-guideline estimation. The more quantitative studies are summarized in Tables 2-2 and 2-3 and the following text.

Verberk (1977) examined dose-response relationships of signs and symptoms after exposure to ammonia vapor at 50-140 ppm in an exposure chamber over increasing durations (30 min to 2 h). Respiratory function and subjective responses of two groups of adults were recorded. One group consisted of eight people familiar with the literature on ammonia effects but “not accustomed…by personal contact” to ammonia exposures (the informed group, 29-53 years old). The second group consisted of eight university students unfamiliar with the literature on ammonia effects and unfamiliar with experiments in laboratory situations (the naive group, 18-30 years old). All subjects had the opportunity to leave the exposure chamber at any time during the test. Histamine threshold challenge tests performed on each subject before ammonia exposure documented the absence of hypersusceptibility to nonspecific irritants. Four members of each group were smokers. Each group was exposed at 1-week intervals to ammonia at 50, 80, 110, or 140 ppm for 30 min, 1 h, or 2 h. Subjective responses (such as smell, eye irritation, throat irritation, and cough) were recorded every 15 min, and respiratory function—vital capacity (VC), forced expiratory volume at 1 sec (FEV1), forced inspiratory volume at 1 sec (FIV1)—was measured before and after each exposure. Chamber concentrations were monitored instantaneously with an infrared spectrometer. No subject inhaling any test concentration for any exposure duration exhibited more than a 10% decrease in VC, FEV1, or FIV1. Verberk (1977) considered that small percentage to be “no effect.” The committee agrees that such small differences have minimal clinical significance. Furthermore, there was no group effect on those measures. Subjective-response scores did exhibit group effects and dose- and duration-response

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 2-2 Subjective-Response Scoresa of Informedb and Naiveb Human Subjects Exposed to Ammonia Vapor at Various Concentrations

Perception and Exposure Duration

50 ppm (mean)

80 ppm (mean)

110 ppm (mean)

140 ppmc (mean)

Informed

Naive

Informed

Naive

Informed

Naive

Informed

Naive

Smell:

 

 

 

 

 

 

 

 

½ h

2.0

2.5

2.0

3.0

2.2

3.0

2.0

3.8

1 h

2.0

2.5

2.0

3.0

2.1

3.0

2.0

4.0

2 h

2.0

3.0

1.5

3.0

2.1

3.0

2.0

WD

Eye irritation:

 

 

 

 

 

 

 

 

½ h

1.5

0.8

1.6

1.6

2.7

2.6

3.0

3.0

1 h

1.5

0.8

1.7

1.6

2.7

2.5

2.9

3.2

2 h

1.0

1.3

1.5

2.0

2.2

2.5

2.3

WD

Throat irritation:

 

 

 

 

 

 

 

 

½ h

0.5

0.5

0.8

1.1

1.4

2.0

1.0

3.8

1 h

0.5

0.7

1.0

1.5

1.4

2.6

1.3

4.5

2 h

0.7

1.6

0.8

2.0

1.0

3.0

1.2

WD

Urge to cough:

 

 

 

 

 

 

 

 

½ h

0.2

0.2

0.4

0.7

0.8

1.7

0.6

2.3

1 h

0.2

0.1

0.5

1.0

0.7

2.0

0.9

1.8

2 h

0.3

0.7

0.6

1.5

0.5

2.0

0.6

WD

General discomfort:

 

 

 

 

 

 

 

 

½ h

0.0

0.0

0.0

1.1

0.2

1.0

0.0

2.5

1 h

0.0

0.2

0.0

1.2

0.2

1.0

0.0

3.3

2 h

0.0

1.2

0.0

1.2

0.3

1.8

0.0

WD

aBased on a scale of 0-5: 0 = “no sensation,” 1 = “just perceptible,” 2 = “distinctly perceptible,” 3 = “nuisance,” 4 = “offensive,” 5 = “unbearable.”

bInformed subjects were academically familiar with the effects of ammonia but not accustomed to regular exposure to it; naive subjects were unfamiliar with literature documenting effects and had not experienced regular exposure. See Table 2-3 for additional details of experimental protocol.

cOnly four of the naive subjects tolerated 140 ppm for 1 h; none tolerated 140 ppm for 2 h.

Abbreviations: WD, self-withdrawn from chamber.

Source: Adapted from NRC 2007; data from Verberk 1977.

relationships and are summarized in Table 2-2. In general, the informed group submitted response scores lower than the naive group.

Ihrig et al. (2006) evaluated the dose-response relationship of signs and symptoms (irritative, olfactory, and respiratory) during and after ammonia vapor exposures at 10-50 ppm in an exposure chamber according to the following exposure protocol: (a) 0 ppm for 4 h/day on day 1, (b) 10 ppm for 4 h/day on day 2, (c) 20 ppm for 4 h/day on day 3, (d) 20 ppm for 3 h/day with two 30-min peak exposures at 40 ppm (referred to hereafter as 20/40), and (e) 50 ppm for 4 h/day on day 5. The subjects were 43 male volunteers, 21-47 years old: 33 naive subjects unfamiliar with ammonia odor and 10 subjects who were regularly exposed to ammonia in the workplace; their smoking history was unreported. Subjective responses were elicited from them every hour of exposure at 10-40 ppm; at

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

TABLE 2-3 Summary of Experimentally Determined Human Nondisabling and Reversible Effects of Inhaled Ammonia

Concentration (ppm)

Time

Subjects and Effects

Reference

5

3-h exposure (1.5 h resting + 1.5 h exercising)

5 males and 7 females; healthy adults, 21-28 years old (mean, 25); smoking history unreported; n = 12

When compared with 0-ppm control, no inflammatory reaction in upper respiratory tract, no alteration in exhaled nitric oxide concentration, no alteration in bronchial response to methacholine; subjective reports of eye discomfort and smell (p < 0.01), headache, dizziness, and “feeling of intoxication” (p < 0.05) significantly greater than control; tendency toward sensory adaptation to subjective “solvent smell”

Sundblad et al. 2004

10

4 h

43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, 21-47 years old; smoking history unreported; n = 43.

Subjects examined by physician before and after exposure; tear-flow rates measured with paper strips; lung-function examinations included bronchial responsiveness; individual attention, reaction time, and powers of concentration tested at end of each exposure day; “no relevant effects of the ammonia exposure in these physical and neurophysiological examination could be found”

Median rank of olfactory symptoms 0.2 (less than 1 = “hardly at all”) in experienced subjects and 1.8 (2 = “somewhat”) in naive subjects

Ihrig et al. 2006

20

4 h

43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, 21-47 years old; smoking history unreported; n = 43

Subjects examined by physician before and after exposure; tear-flow rates measured with paper strips; lung-function examinations included bronchial responsiveness; individual attention, reaction time, and powers of concentration tested at end of each exposure day; “no relevant effects of the ammonia exposure in these physical and neurophysiological examination could be found”

Median rank of olfactory symptoms 0.5 (less than 1 = “hardly at all”) in experienced subjects and about 2.5 (2 = “somewhat”) in naive subjects

Ihrig et al. 2006

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

20, 40

20 ppm for 3 h with two 30-min peaks at 40 ppm

43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, 21-47 years old; smoking history unreported; n = 43

Subjects examined by physician before and after exposure; tear-flow rates measured with paper strips; lung-function examinations included bronchial responsiveness; individual attention, reaction time, and powers of concentration tested at end of each exposure day; “no relevant effects of the ammonia exposure in these physical and neurophysiological examination could be found”

Median rank of olfactory symptoms 0.9 (less than 1 = “hardly at all”) in experienced subjects and 3 (“rather much”) in naive subjects

Ihrig et al. 2006

25

3-h exposure (1.5 h resting + 1.5 h exercising)

5 males and 7 females; healthy adults, 21-28 years old (mean, 25 years); smoking history unreported; n = 12

When compared with 0-ppm control, no inflammatory reaction in upper respiratory tract, no alteration in exhaled nitric oxide concentration, no alteration in bronchial response to methacholine; subjective reports of irritation in eye and upper airways increased over control in all categories (p < 0.01); headache, dizziness, “feeling of intoxication, etc.” (p < 0.01 or p < 0.05); no tendency toward sensory adaptation to subjective reports of “solvent smell”

Sundblad et al. 2004

30

10 min

6 fit males, 23-44 years old (mean, 31 years)

Odor moderately intense to highly penetrating; irritation faint or not detectable

MacEwen et al. 1970

32

5 min

10 healthy volunteers

1 had nasal dryness

Industrial Bio-Test Lab 1973 (as cited in ATSDR 2004 and WHO 1986)

50

5 min

10 healthy volunteers

2 had nasal dryness; NOAEL identified by ATSDR (2004)

Industrial Bio-Test Lab 1973 (as cited in ATSDR 2004 and WHO 1986)

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Time

Subjects and Effects

Reference

50

10 min

6 fit males, 23-44 years old (mean, 31 years)

Highly penetrating odor; moderate irritation

MacEwen et al. 1970

50

30 min

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-2.5 (5 = “unbearable”); eye irritation ranked 0.8-1.5; throat irritation ranked 0.5; slight urge to cough; slight general discomfort; pre-exposure and postexposure measurements of FVC and FEV1 exhibited no change from control; participants recorded subjective response every 15 min of exposure; in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

50

1 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-2.5 (5 = “unbearable”); eye irritation ranked 0.8-1.5; throat irritation ranked 0.5-0.7; mild urge to cough; slight general discomfort; pre-expsoure and postexposure measurement of FVC and FEV1 exhibited no change from control; in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

50

2 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-3.0 (5 = “unbearable”); eye irritation ranked 1.0-1.3; throat irritation ranked 0.7-1.6; mild urge to cough; mild general discomfort; pre-exposure and postexposure measurement of FVC and FEV1 exhibited no change from control; in general, naive subjects rated effects more severely than informed subjects, at all exposures

Verberk 1977

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

50

2-6 h/day, 6 weeks; workplace exposures, standard workplace physical activities

2 unacclimated subjects: 1 male, 1 female, 24-29 years old; 1 smoker

No significant difference in respiratory rates, pulse, systolic and diastolic BP, FVC, and FEV1; physician-observed mild eye, nose, and throat irritation not significantly different from control; no evidence of abnormal chest sounds, heart murmur, neurologic change, or weight change; no impairment

Ferguson et al. 1977

50

4 h

43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, 21-47 years old; smoking history unreported; n = 43

Subjects examined by physician before and after exposure; tear-flow rates measured with paper strips; lung-function examinations included bronchial responsiveness; individual attention, reaction time, and powers of concentration tested at end of each exposure day; “no relevant effects of the ammonia exposure in these physical and neurophysiological examination could be found”

3 participants exhibited “slight conjunctival hyperemia”; irritative symptom median of 1 (“hardly at all”) and largely unchanged over 4-h exposure; median rank of olfactory symptoms about 1.7 (2 = “somewhat”) in experienced workers and about 3.2 (3 = “rather much”) in naive subjects

Ihrig et al.2006

72

5 min

10 healthy volunteers

3 had nasal, eye, and throat irritation; LOAEL identified by ATSDR (2004)

Industrial Bio-Test Lab 1973 (as cited in ATSDR 2004 and WHO 1986)

80

30 min

16 adults; 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-3.0 (5 = “unbearable”); eye irritation ranked 1.6; throat irritation ranked 0.8-1.1; mild urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Time

Subjects and Effects

Reference

80

1 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-3.0 (5 = “unbearable”); eye irritation ranked 1.6-1.7; throat irritation ranked 1.0-1.5; mild urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

80

2 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 1.5-3.0 (5 = “unbearable”); eye irritation ranked 1.5-2.0; throat irritation ranked 0.8-2.0; urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

25, 50, 100: ascending and descending sequentially weekly; 2 weeks at each concentration

2-6 h/day, 6 weeks; workplace exposures; normal workplace physical and mental tasks

4 unacclimated subjects: males, 26-46 years old; 2 smokers

No adverse effects on respiratory function; no increase in frequency of eye, nose, throat irritation; only statistically significant increase was in FEV1 (“improvement”) with increasing ammonia concentration; no subjective reports of irritation; physician examinations indicate “mild” irritation of eyes,, nose, and throat at 50, 100 ppm (0.11), not significantly different from control (0.09); after acclimation, continuous exposure at 100 ppm (with occasional excursions to 200 ppm) easily tolerated; exposure effects on workplace mental and physical tasks normally performed by chemical operator also evaluated (none)

Ferguson et al. 1977

100

5, 10, 15, 20, 30 sec

Individual, forced-air nostril delivery at 100 ppm (at 9 newtons/cm2) for designated exposure periods separated by 15-min measurement of NAR; concentration-dependent increase in NAR but no significant differences between mean response in nonatopic and atopic (including those with allergic rhinitis) subjects

McLean et al. 1979

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Mean, 102-336 (range, 71.5-492)

Apparently 95-120 min

18 healthy servicemen, mean 24.1 years old; exercising on cycle ergometer at 20 to 120 W; considered “submaximal” exercise

“No material discomfort ” but dryness of mouth and prickling sensation in nose; reversible ventilatory responses; ventilation minute volume significantly reduced at 151-336 ppm; no effect on respiratory minute volume at 102 ppm; exercise tidal volume significantly increased at 152 ppm; average reduction in ventilation minute volume of 6% (range, 3.5-10.0%) at all concentrations

Cole et al. 1977

110

30 min

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.2-3.0 (5 = “unbearable”); eye irritation ranked 2.6-2.7; throat irritation ranked 1.4-2.0 of 5; mild urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

110

1 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.1-3.0 (5 = “unbearable”); eye irritation ranked 2.5-2.7; throat irritation ranked 1.4-2.6; moderate urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

110

2 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old), 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.1-3.0 (5 = “unbearable”); eye irritation ranked 2.2-2.5; throat irritation ranked 1.0-3.0; urge to cough; general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
×

Concentration (ppm)

Time

Subjects and Effects

Reference

140

30 min

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-3.8 (5 = “unbearable”); eye irritation ranked 3.0; throat irritation ranked 1.0-3.8; mild urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

140

1 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Odor perception ranked 2.0-4.0 (5 = “unbearable”); eye irritation ranked 2.9-3.2; throat irritation ranked 1.3-4.5; moderate urge to cough; moderate general discomfort; no measurable change from control in respiratory function (FVC, FEV1); part of naive population withdrew; in general, naive subjects rated effects more severely than informed subjects at all exposures

Verberk 1977

140

2 h

16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 females, 18-30 years old)

Naive group withdrew; odor perception ranked 2.0 by informed group; eye irritation ranked 2.3 by informed group; throat irritation ranked 1.2 by informed group; urge to cough; general discomfort; no measurable change from control in respiratory function (FVC, FEV1).

Verberk 1977

143

5 min

10 healthy volunteers

Nose, eye, throat, and chest irritation; lacrimation

Industrial Bio-Test Lab 1973 (as cited in ATSDR 2004 and WHO 1986)

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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500

15, 30 min (1 for 15 min, 6 for 30 min)

7 adult males at rest

Increase in minute volume compared with control (+50-250%); nose and throat irritation (2) with nasal dryness and stuffiness; excessive lacrimation (2); immediate hyperventilation (3); change to mouth breathing (5); transient hypoesthesia of skin around nose and mouth (7); no significant change in blood or urinary urea, ammonia, blood-protein nitrogen; “slight” increase in pulse rate, BP in 1 of 2; nasopharyngeal irritation persisted for 24 h in 2; authors consider 500 ppm “physiologically undesirable”

Silverman et al. 1949

571 (mean NH3TR; SEM, 41.5)

Single breath

14 subjects, 21-30 years old from cohort of 102 healthy, nonsmoking males, females

Threshold for reflex glottis closure

Erskine et al. 1993

1,791 (mean NH3TR; SEM, 52)

Single breath

14 subjects, 86-95 years old from cohort of 102 healthy, nonsmoking males, females

Threshold for reflex glottis closure

Erskine et al. 1993

Note: See also Table 2-4 of NRC (2002) and Table 3-1 of ATSDR (2004) for additional detail. For full description of rankings used in Verberk (1977), see Table 2-2 of this chapter.

Abbreviations: ATSDR, Agency for Toxic Substances and Disease Registry; BP, blood pressure; FEV1, forced expiratory volume at 1 sec; FVC, forced vital capacity; LOAEL, lowest observed-adverse-effect level; NAR, nasal airway resistance; NOAEL, no-observed-adverse-effect level.

Source: Adapted from NRC 2007.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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50 ppm, responses were elicited every 30 min. Subjective-response scores were to ammonia in the workplace; their smoking history was unreported. Subjective responses were elicited from them every hour of exposure at 10-40 ppm; at 50 ppm, responses were elicited every 30 min. Subjective-response scores were ranked as 0 = “not at all,” 1 = “hardly at all,” 3 = “somewhat,” 4 = “considerably,” and 5 = “very much.” Medical examinations conducted before and after each exposure assessed physical response of the eyes and respiratory tract and cognitive skills (for example, lung-function test, including bronchial responsiveness; neuropsychologic examination for reaction time, attention, and concentration; and nasal resistance and lacrimation). Ihrig et al. (2006) report that, with the exception of three subjects in the 50-ppm exposure group who exhibited “slight conjunctival hyperemia,” “no relevant effects of the ammonia exposure in these physical and neuropsychological examinations could be found.” Furthermore, comparison of subjective symptoms reported by naive subjects vs ammonia workers indicated that habituation strongly influenced complaint reporting (for example, naive subjects reported more symptoms than experienced subjects at a given exposure).

McLean et al. (1979) examined the effect of ammonia on nasal airway resistance (NAR) in atopic and nonatopic human subjects and the potential inhibition of such effects by atropine or chlorpheniramine administration. Ammonia (100 ppm at 9 newtons/cm2) was serially introduced into each nostril (successive exposure durations for each subject of 5, 10, 15, 20, and 30 sec/nostril followed by 15-min intervals). Exposures were followed by NAR measurement with a pneumotachograph attached to a facemask every minute for 5 min and then every 2 min for 10 min (total of 10 measurements over a 15-min period). Nonatopic subjects were screened on the basis of strict criteria that included a questionnaire, physical examination, spirometry, a nasal smear for eosinophils, and a battery of 19 prick and six intracutaneous allergen tests. Nonatopic subjects could possess no personal or immediate family history of atopic disease (allergic rhinitis, asthma, or atopic dermatitis), could have no more than 5% eosinophils in their nasal smears, and had to exhibit negative reactions on the battery of prick and intracutaneous allergen tests. Atopic subjects were screened on the basis of a characteristic history of allergic rhinitis and positive allergen-test reactions. Some subjects determined to be atopic had a history of asthma. All subjects had been symptom-free for several weeks before the study, and none was judged to be taking medications that would influence skin or mucosal tests. Individual baselines were obtained by collection of NAR measurements during a 15-min pre-exposure period. Additional tests included introduction of 0.1 mL of aerosolized phosphate-buffered saline, 0.1 mL of atropine sulfate, or 0.1 mL of chlorpheniramine maleate into the nostrils, each followed by exposure to 100-ppm ammonia vapor for 20 sec. NAR measurements after exposure increased significantly with increase in exposure duration from 5 to 20 sec. Negligible increases were noted in subjects exposed for 30 sec compared with 20 sec. There was no significant difference in NAR increase between atopic and nonatopic subjects exposed to ammonia, nor was there any significant difference between

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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the allergic-rhinitis subjects with and without a history of asthma. Atropine sulfate administration inhibited the NAR response to ammonia in atopic and nonatopic subjects by up to 89%, whereas administration of the antihistamine chlorpheniramine had no effect on ammonia-induced NAR. The study authors noted that the results of atropine and chlorpheniramine administration suggest that ammonia irritancy is mediated primarily by a parasympathetic reflex effect on the nasal vasculature and not by histamine release.

Industrial Bio-Test Laboratories, Inc. (1973, as cited in ATSDR 2004 and WHO 1986) determined the irritation threshold in 10 human volunteers exposed to ammonia vapor at 32, 50, 72, or 143 ppm for 5 min. Irritation was subjectively defined as annoyance to the nose, throat, eyes, mouth, or chest. Subjects demonstrated dose-related response of those subjective end points; effect severity was not noted.

MacEwen et al. (1970) studied six male workers, 23-44 years old (average, 31 years); all were considered “fit” in that each had passed either class II U.S. Air Force (USAF) or class II Federal Aviation Administration (FAA) physical examinations for flying. The test population included “nonsmokers, reformed smokers, and heavy smokers.” Each subject underwent head-only exposure to ammonia at 30 or 50 ppm for 10 min and reported the degree of intensity and description of irritation of the nose and eyes on a subjective scale. Study results demonstrated a dose-related increase in the subjective response to ammonia at 30 and 50 ppm. At 30 ppm, irritation was reported by two of the six subjects as faint (grade 1) and by three as not detectable (grade 0), and one gave no response; for odor characteristics at 30 ppm, three subjects reported odor as strong or highly penetrating (grade 4), two reported odor as easily noticeable or moderate (grade 3), and one gave no response. At 50 ppm, irritation was reported by four subjects as moderate (grade 2), by one as faint or just perceptible (grade 1), and by one as not detectable (grade 0); odor was characterized as strong or highly penetrating (grade 4) for by all six subjects at 50 ppm.

Silverman et al. (1949) studied seven male subjects exposed to 500-ppm anhydrous ammonia through a nose and mouth mask for 30 min (six subjects) or 15 min (one subject). Respiratory rates, minute volumes, blood pressure, pulse rates, blood urea, serum nonprotein nitrogen, and urinary urea and ammonia were measured in each subject, and each subject provided subjective reactions. Results were as follows: increase (50-250%) of minute volume in all seven subjects; nose and throat irritation (two subjects) with nasal dryness and stuffiness; excessive lacrimation (two subjects); immediate hyperventilation (three subjects); change to mouth breathing (five subjects); transient hypoesthesia (decreased sensitivity) of skin around nose and mouth (seven subjects); no significant change in blood or urinary urea, ammonia, or blood-protein nitrogen; and “slight” increase in pulse rate and systolic and diastolic blood pressure in one of two measured subjects. Nasopharyngeal irritation persisted for 24 h in two subjects. Silverman et al. (1949) concluded from their results that exposure to 500-ppm ammonia was “physiologically undesirable.”

Cole et al. (1977) studied the effects of exercise on 18 servicemen exposed

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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to ammonia vapor at 102, 152, 206, and 336 ppm in an exposure chamber while cycling under a load of 20 W increased to 180 W in 20-W increments for various durations that apparently were 95-120 min (based on assumptions of “zero time” and extrapolation from figures in the report). Subjects served as their own controls. Measurements of respiratory function (respiratory rate, minute volume, tidal volume, and oxygen uptake) and cardiac frequency were taken during each experimental period and compared with control values. Measured minute volume was decreased by 8%, 10%, and 6% at 152, 206, and 336 ppm, respectively. However, no clear dose-related trend was observed relative to the controls. Tidal volume was significantly decreased by 9% and 8% and respiratory frequency was increased by 10% and 8% at 206 and 336 ppm, respectively, compared with the control values. Those changes may indicate that vagal stimulation may have occurred; however, no clear dose-response relationship was observed. The small changes in tidal volume and respiratory frequency are unlikely to be clinically significant. During exposures, subjects noted “no material discomfort” but mouth dryness and prickling in the nose; these effects were reversible on cessation of exposure.

Sundblad et al. (2004) investigated the acute effects of repeated low-concentration ammonia exposures in chamber experiments, incorporating both rest and ergometric exercise. Seven females and five male healthy atopic adults, 21-28 years old (mean, 25 years), with no reported present or past symptoms of allergy or airway disease were exposed to ammonia in randomized order at 0, 5, and 25 ppm for 3 h on three occasions; the exposures were separated by at least 1 week in which subjects did not undergo experimental ammonia exposures. During each 3-h exposure, 1.5 h was spent at seated rest and 1.5 h in exercising on a bicycle ergometer at 50 W. Subjects ranked 10 subjective and transient symptoms selected to characterize irritation—such as eye, nose, and throat discomfort—and systemic response—such as headache, dizziness, nausea, and “feeling of intoxication.” The latter symptoms were characterized by Sundblad and co-workers as “CNS [central nervous system] effects.” Sundblad et al. (2004) offered no neurophysiologic measurements or other experimental data to support categorization of the latter symptoms as adverse CNS responses. The committee concludes that the systemic responses may be consequences of irritation or odor. Moreover, the exposure protocol meant that each subject was exposed to two ammonia concentrations, which may or may not have been separated by a sham exposure, depending on the randomized exposure sequence. Therefore, because of sensory fatigue, a subject’s response to the second ammonia exposure may have been less vigorous than it would have been in previously unexposed subjects.

Sundblad et al. (2004) also evaluated changes resulting from exposure in the following parameters: lung function; bronchial responsiveness to methacholine; exhaled nitric oxide; cell composition in nasal lavage fluids; and peripheral blood profiles for leukocytes, monocytes, lymphocytes, basophilic granulocytes, eosinophils and complement factor C3b. Under the experimental conditions, ammonia exposures at 5 or 25 ppm did not induce detectable upper airway in-

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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flammation or increased bronchial response to methacholine according to any analytic measure used; an observed increase in number of blood granulocytes after exposure was considered an exercise effect by the investigators and has been noted by other investigators (Hansen et al. 1991).

Subjective-symptom rankings on a questionnaire exhibited a dose-response relationship. On the basis of questionnaire results, Sundblad et al. (2004) noted a tendency toward sensory adaptation to “solvent smell” in those exposed at 5 ppm but not those exposed at 25 ppm. Rankings of all 10 measured symptoms that characterized irritation and systemic response were significantly greater than in controls in the 25-ppm exposure group, but the 5-ppm exposure group exhibited higher rankings of only five symptoms. All symptomatic effects ranked were transient.

In the controlled workplace-exposure study of Ferguson et al. (1977), effects of ammonia vapor on three groups of two industrial workers exposed at 25, 50, or 100 ppm were evaluated after practice exposure at the same concentrations during a 1-week period. Subjects underwent exposure at a sodium bicarbonate plant in areas where ammonia concentrations of 25 and 50 ppm were achieved; controlled 100-ppm exposures took place in an exposure chamber. Exposure periods ranged from 2 to 6 h/day for 5 weeks. No adverse effects on respiratory function and no increase in frequency of eye, nose, and throat irritation were noted. The only statistically significant increase was an unexplained FEV1 (“improvement”) with increasing ammonia concentration. Participants contributed no subjective reports of irritation; physician examinations indicated that the resulting signs of “mild” eye, nose, and throat irritation at 50 and 100 ppm were not significantly different from control findings. After acclimation, exposure for up to 6 h at at least 100 ppm (averages of 103-140 ppm with occasional excursions to 200 ppm) was “easily tolerated” by subjects (Ferguson et al. 1977).

Erskine et al. (1993) used an inspiratory pneumotachograph to measure the concentration of ammonia required to elicit reflex glottis closure in 102 healthy nonsmoking subjects, 17-96 years old, after single intermittent breaths of ammonia vapor at about 500 to 2,000 ppm. The results demonstrated a strong positive correlation (coefficient, 0.85) between age and the ammonia concentration needed to trigger reflex glottis closure (NH3TR). The mean NH3TR for the group 86-95 years old was 1,791 ppm (SEM, 52; n = 14), and the mean NH3TR for the group 21-30 years old was 571 ppm (SEM, 41.5; n = 14).

Occupational and Epidemiologic Studies

Most available occupational and epidemiologic studies were not designed to discriminate between ammonia and other workplace contaminants—such as endotoxins, fungi, bacteria, and respirable dusts—in their relative contributions to the development of observed adverse respiratory effects. Minor pulmonary-function deficits have been observed in swine workers exposed to ammonia in

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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combination with dust and endotoxin (Reynolds et al. 1996). Although ammonia concentrations as high as 200 ppm have been reported (Carlile 1984), mean exposure concentrations of 4-7 ppm were more typical for the swine workers examined (Reynolds et al. 1996; Donham et al. 1995). Other occupational cohort studies have examined farmers and farm workers employed in enclosed livestock buildings; substances measured include not only ammonia but also dusts, endotoxins, and various microorganisms and fungi (Cormier et al. 2000; Choudat et al. 1994; Donham et al. 1995, 2000; Ballal et al. 1998, all as cited in ATSDR 2004). The utility of the data from those studies is limited because of confounding by multiple exposures, fragmentary exposure-duration characterization, and lack of information on clinical signs and symptoms.

Holness et al. (1989) compared respiratory effects in a group of 58 workers (51 production and six maintenance workers at an industrial soda-ash production facility) chronically exposed to airborne ammonia vapor (mean ± standard deviation, 9.2 ± 1.4 ppm) with effects in a group of 31 plant workers with essentially no exposure to airborne ammonia (0.3 ± 0.1 ppm). During a 1-week period, the workers were assessed on the basis of a questionnaire (reporting of cutaneous or respiratory symptoms), sense of smell, baseline pulmonary function (FVC [forced vital capacity], FEV1, FEF50 [forced expiratory flow at 50% FVC], and FEF75), or change in lung function over a workshift at the beginning and end of a workweek. There were no differences between the two groups in the characteristics studied and no relationship between concentration and duration of ammonia exposure and lung function. Holness and colleagues pointed out that study weaknesses included “lack of adequate exposure data” and the difficulties in accounting for both concentration and duration of exposure. In addition, there was no characterization of historical occupational ammonia exposures during years before the short period in which they measured workplace concentrations.

Effects in Animals

Thorough reviews of the results of controlled experimental exposures can be found in NRC (2002, 2007) and ATSDR (2004).

Acute Toxicity

Lethality values (LC50 and lowest experimental concentrations) for mice, rats, and cats receiving inhalation exposures are presented in Table 2-4; data on other exposure routes, such as rabbit intratracheal cannulation (Boyd et al. 1944), are not summarized here because of their limited application. Cats are the least characterized of the experimental species tested. The LC50 for rats ranged from 7,338 and 16,600 ppm for 60-min exposures to 40,300 ppm for a 10-min exposure (MacEwen and Vernot 1972; Appelman et al. 1982). The LC50 for mice ranged from 4,230 ppm for a 60-min exposure to 10,096 ppm for a 10-min

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 2-4 Summary of Acute-Lethality Inhalation Data on Ammonia Exposure of Laboratory Animals

Species

Concentration (ppm)

Time

Effects

Reference

Rat

40,300

10 min

LC50

Appelman et al. 1982

33,433

10 min

10% mortality

28,595

20 min

LC50

26,155

20 min

30% mortality

20,300

40 min

LC50

18,047

40 min

20% mortality

16,600

60 min

LC50

14,114

60 min

30% mortality

Rat

7,338

60 min

LC50

MacEwen and Vernot 1972

Mouse

10,152

10 min

LC50

Silver and McGrath 1948

8,723

10 min

25% mortality

Mouse

4,837

60 min

LC50

MacEwen and Vernot 1972

4,550

60 min

30% mortality

Mouse

4,230

60 min

LC50

Kapeghian et al. 1982

3,950

60 min

25% mortality

4,380

240 min

25% mortalitya

1,350

240 min

100% survival

Mouse

21,430

30 min

LC50

Hilado et al. 1977, 1978

19,048

30 min

25% mortality

Cat

1,000

10 min

5% mortality

Dodd and Gross 1980

aNo observation period after exposure.

Abbreviations: LC50; statistically determined lethal concentration for 50% of sample population.

Source: Adapted from NRC 2007.

exposure (Silver and McGrath 1948; MacEwen and Vernot 1972; Kapeghian et al. 1982; Hilado et al. 1977, 1978).

Rats exposed to lethal ammonia concentrations exhibited signs of dyspnea and of irritation of the eyes and nose and lung hemorrhage on necropsy (Appelman et al. 1982). Mice exposed to lethal concentrations showed signs of irritation of the eyes and nose, labored breathing, and gasping with tremors, ataxia, convulsions, and seizures; pathologic lesions occurred in the alveoli (Silver and McGrath 1948; MacEwen and Vernot 1972; Kapeghian et al. 1982). Signs of toxicity in cats included death, poor general condition, severe dyspnea, anorexia, dehydration, bronchial breath sounds, sonorous and sibilant rhonchi, and coarse rales (Dodd and Gross 1980). Pulmonary-function tests provided evidence of airway damage throughout the experiment and of central lung damage on observation day 21. Gross lung examination showed congestion, hemorrhage, edema, and evidence of interstitial emphysema and collapse. Bronchopneumonia, which caused the death of one animal, was common after observation day 7.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Species comparisons of LC50 data by ten Berge et al. (1986) documented that mice are usually more sensitive to lethal concentrations of irritants in general, and ammonia in particular, than other experimental laboratory animals. ten Berge et al. also suggested that toxicity data on mice “do not provide an appropriate basis for predicting…the mortality response in humans” to many locally irritant gases, including ammonia. Data summarized in NRC (2007) indicate that the mouse is 2.7-4 times more susceptible than the rat to the toxic effects of ammonia inhalation exposure.

Acute sublethal toxicity after controlled experimental exposure to ammonia has been well summarized in the previous NRC (2002) report Review of Submarine Escape Action Levels for Selected Chemicals (Chapter 2, pp. 22-68, “Ammonia”; see Table 2-8, “Experimental Animal Toxicity Data…” pp. 44-56) and ATSDR report (2004; see Table 3-1, “Levels of Significant Exposure to Ammonia and Ammonium Compounds—Inhalation,” pp. 27-40) and will not be presented at the same level of detail here. The database on acute sublethal exposure includes studies on mice, rats, and cats exposed at various concentrations (3-1,157 ppm) of ammonia for 10 min to 24 h.

In general, nondisabling, reversible effects in laboratory animals were mild after single exposure. Rats exhibited concentration-dependent cessation of tracheal ciliary activity during exposure at 3-90 ppm for 10 min (Dalhamn 1956 a,b): at 3, 6.5, and 90 ppm, ciliary activity ceased in 7-8 min, 150 sec, and 5 sec, respectively. Schaerdel et al. (1983) exposed rats to ammonia at 15-1,157 ppm for 24 h; no behavioral changes or irritation of the eyes or mucous membranes were exhibited, and no changes were noted in blood pCO2 and pH. Small changes in pO2 occurred “within the normal range for rats.” A 50% reduction in the respiration rate (RD50) was noted in mice exposed at about 300 ppm for 30 min (Barrow et al. 1978).

There was no evidence of pulmonary lesions in mice or rats exposed at single nonlethal concentrations.

Repeated Exposure and Subchronic Toxicity

Effects in laboratory animals were mild and transient after repeated exposure (subchronic duration) to ammonia and are summarized in Table 2-5. Only minimal effects on respiratory epithelium of the upper respiratory tract were observed after continuous exposure at up to 714 ppm for several days (Schaerdel et al. 1983). Repeated exposure of Swiss-Webster mice to the experimental RD50 of 303 ppm for 6 h/day for 3 or 7 days was associated with reversible and minimal to moderate changes in respiratory epithelium that were not considered pathologic lesions (Buckley et al. 1984). Exposure of Swiss OF1 mice at 711 ppm, which is about 3 times the experimental RD50 of 257 ppm in this mouse breed, resulted in slight to moderate exfoliation, erosion, ulceration, and necrosis of the respiratory epithelium of the nasal cavity; no lower respiratory tract le-

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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sions were produced (Zissu 1995). Additional supportive studies (for example, Tepper et al. 1985; Manninen et al. 1988) are summarized in Table 2-5.

Except for nonspecific inflammation of the lungs at 1,101 ppm, repeated daily exposure of rats at 57 ppm for 114 days or at 222 or 1,101 ppm for 6 weeks (8 h/day) produced no effects (Coon et al. 1970). Almost all rats died after continuous exposure at 651 or 672 ppm for 65 days. Repeated exposure at 1,101 ppm for 6 weeks (8 h/day) produced transient dyspnea and lacrimation in dogs and rabbits, whereas continuous exposure at 672 ppm for 90 days resulted in signs of irritation of the eyes and nose and pathologic lesions in the lungs of dogs and rabbits and pneumonitis in several species (dog, rabbit, guinea pig, and monkey) (Coon et al. 1970).

Subchronic inhalation-exposure studies of male mice provide inconclusive evidence of nasal carcinoma (Gaafar et al. 1992), and gavage exposure of laboratory mice to ammonium ion at 42 mg/kg per day for 4 weeks provided no evidence of carcinogenicity (Uzvolgyi and Bojan 1980, as cited in ATSDR 2004).

The longest exposure in the available literature was 114 days of continuous exposure of male and female Sprague-Dawley and Long-Evans rats at 57 ppm (Coon et al. 1970); this protocol resulted in no clinical signs and no significant effects when compared with the control.

Done et al. (2005) evaluated continuous ammonia exposure (at 0.6, 10.0, 18.8, or 37.0 ppm) of weanling pigs (commercial herd) in combination with generated inspirable (artificial) dust (at 1.2, 2.7, 5.1, or 9.9 mg/m3) for 5 weeks in a controlled-ventilation facility. The ammonia and dust concentrations evaluated were considered representative of commercial piggeries in the United Kingdom. Done and co-workers used a multifactorial design incorporating a total of 560 weanling pigs over 2 years. Daily clinical examination for respiratory, gastrointestinal, and ocular signs documented that the experimental exposures had no significant effects. Postmortem turbinate scores were low (for example, low clinical rhinitis), as were lung scores; neither turbinate nor lung scores were affected by exposure to ammonia or dust when compared with the controls. No significant differences in any monitored characteristic were noted when experimental pigs were compared with controls (Done et al. 2005).

Overall, studies of repeated exposure indicate that mice are more susceptible than other mammals tested repeatedly or for subchronic exposure durations.

Chronic Toxicity

No information characterizing chronic toxicity of ammonia exposure was located.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 2-5 Summary of Repeated and Subchronic Ammonia Exposure Studies in Laboratory Animals

Species

Concentration (ppm)

Exposure Duration

Effects

Reference

Rat (male, female Sprague-Dawley, Long-Evans)

222

8 h/day for 6 weeks

No deaths or clinical signs

Coon et al. 1970

1,101

8 h/day for 6 weeks

Nonspecific inflammatory changes in lungs (colony infection); no deaths or clinical signs

57

Continuous, 114 days

No clinical signs; no significant effects when compared with controls

182

Continuous, 90 days

No clinical signs

375

Continuous, 90 days

“Mild” nasal discharge in 25% of test population

651

Continuous, 90 days

Day 25: mild dyspnea, nasal irritation, 63% mortality

Day 65: 98% mortality

672

Continuous, 90 days

87% mortality

Rabbit, guinea pig, dog, monkey

222

8 h/day for 6 weeks

Focal pneumonitis in one of three monkeys; no other signs or clinically significant effects

Coon et al. 1970

1,101

8 h/day for 6 weeks

Dogs and rabbits exhibited transient lacrimation and dyspnea in week 1; nonspecific inflammatory changes in guinea pig lungs

Rabbit, guinea pig, dog, monkey

57

Continuous, 90 days

No signs or clinically significant effects

Coon et al. 1970

672

Continuous, 90 days

Dogs: heavy lacrimation, nasal discharge, hemorrhagic lung lesions in one of two

Rabbits: erythema, discharge, corneal opacity, moderate lung congestion in two of three

Guinea pigs: four of 15 died

All (also in controls, but less severe): focal or diffuse interstitial pneumonitis; calcification in renal tubules and bronchial epithelium; cell proliferation in renal epithelium; myocardial fibrosis

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Rat

Serial exposure at 100, 300, 300, 100

6 h/day, with 2 days separating exposure concentrations

Measurements of running-wheel activity indicated decrease after more than 1 h at 100 ppm, decrease throughout 300-ppm exposures; authors attributed activity change to sensory irritation; activity depression transient; running-wheel activity increased after exposure cessation.

Tepper et al. 1985

Mouse

Serial exposure at 100, 300, 300, 100

6 h/day, with 2 days separating exposure concentrations

Similar to rat experience, as described above; at comparable concentrations, activity of mice decreased less than that of rats

Tepper et al. 1985

Weanling pig (commercial herd)

0.6, 10.0, 18.8, or 37.0 (in combination with artificial dust at 1.2, 2.7, 5.1 or 9.9 mg/m3)

Continuous for 5 weeks

Multifactorial experiment performed on 560 weanling pigs over 2 years; daily inspections and clinical monitoring and postmortem examinations of 40 pigs in each of eight batches revealed “minimal gross pathology and …minor pathological changes of little significance”; low turbinate scores (for example, low clinical rhinitis) and low lung scores observed and unaffected by exposure to ammonia and dusts; no differences between control and exposed pigs in any respiratory, gastrointestinal, or ocular measure monitored, including nasal discharge and sneezing

Done et al. 2005

Rat

4, 24, 44, 165, 714

Continuous for 3 or 7 days

Minimal lesions in nasal-cavity respiratory epithelium at 7 days (undefined concentration); no change in trachea or lungs; no significant effects on blood gases or pH

Schaerdel et al. 1983

Rat (female)

25, 300

6 h/day for 5, 10, or 15 days

No treatment-related changes observed in lung, kidney, or liver; 300 ppm considered NOAEL

Manninen et al. 1988

Mouse (Swiss-Webster)

303 (RD50)

6 h/day for 5 days

Observed subjects exhibited no clinical signs; no lesions in tracheobronchial or pulmonary areas; nasal-cavity epithelium exhibited minimal exfoliation and other tissue changes, moderate squamous metaplasia and inflammatory changes

Buckley et al. 1984

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Species

Concentration (ppm)

Exposure Duration

Effects

Reference

Mouse (Swiss OF1)

78 (0.3 RD50); 257 (RD50), 711 (2.8 RD50)

6 h/day for 4, 9, or 14 days

Observed subjects exhibited no clinical signs; respiratory tract exhibited rhinitis with metaplasia and necrosis in nasal-cavity epithelium only at 3 times RD50, with increasing severity at greater exposure duration (very severe on day 14); no lesions at RD50 for any exposure duration

Zissu 1995

Abbreviations: NOAEL, no-observed-adverse-effect level; RD50; statistically estimated concentration resulting in 50% reduction in respiratory rate.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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Reproductive Toxicity in Males

No information characterizing reproductive toxicity of inhalation, ocular, oral, or dermal exposure to ammonia of male humans or laboratory animals was located.

Immunotoxicity

Although secondary infections of respiratory lesions and skin burns can occur after exposure to concentrated ammonia vapors or aerosols (Caplin 1941; Sobonya 1977; Slot 1938; O’Kane 1983), there is no evidence that ammonia exposure impairs the human immune system (ATSDR 2004).

Laboratory animal studies of a variety of species indicate that repeated inhalation or whole-body exposure to some concentrations of ammonia is associated with a decrease in immune response—a decrease in “cell-mediated immune response” in guinea pigs challenged with tuberculin derivative after exposure to 90-ppm ammonia 24 h/day for 3 weeks (Targowski et al. 1984, as cited in NRC 2002) or a decrease in resistance when challenged with an infective bacterial dose. Examples of the latter include increased mortality in male mice exposed to the LD50 of Pasteurella multocida after exposure to 500-ppm ammonia 24 h/day for 7 days (Richard et al. 1978, as cited in ATSDR 2004), increased severity of clinical signs in rats inoculated with Mycoplasma pulmonis either before a 4-week exposure to 25-ppm ammonia 24 h/day (Broderson et al. 1976, as cited in ATSDR 2004) or before a 3- to 9-day exposure to 100-ppm ammonia 24 h/day (Pinson et al. 1986), and increased Newcastle disease infection rate in chickens exposed to the 48-h lowest observed-adverse-effect level (LOAEL) of 50 ppm and to the 72-h LOAEL of 20 ppm (Anderson et al. 1964, as cited in NRC 2002). Neumann et al. (1987, as cited in ATSDR 2004) noted a reduced gamma globulin concentration in pigs exposed to ammonia at 100 ppm 24 h/day for 31-45 days. It is thought that the experimental findings in laboratory animals represent the consequences of an effect secondary to tissue injury and inflammation resulting from the ammonia exposure.

Genotoxicity

ATSDR (2004) considers that the data on ammonia and ammonium ion exposures may indicate the presence of mutagenic and clastogenic properties.

A retrospective examination of fertilizer-factory workers with different occupational histories of ammonia exposure compared the frequencies of chromosomal aberrations and sister-chromatid exchanges (SCEs) and mitotic index; findings indicated increased chromosomal-aberration and SCE frequencies with “increasing length of exposure” (Yadav and Kaushik 1997, as cited in ATSDR 2004).

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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The frequency of mouse micronuclei increased after single intraperitoneal administration of ammonia at 12, 25, and 50 mg/kg in Swiss albino mice (Yadav and Kaushik 1997, as cited in ATSDR 2004).

Among the several cellular assays that were not lethal to the test system, positive results were observed in the following: chromosomal aberrations in chick fibroblasts exposed to buffered ammonia-ammonium chloride solutions, reduced cell division in mouse fibroblasts cultured in media with added ammonia and ammonium chloride, DNA-repair inhibition in mouse fibroblasts in media with added ammonium chloride, and decreased rate of DNA synthesis in mucosal cells of mouse ileum and colon in culture with added ammonium chloride (Rosenfeld 1932; Visek 1972; Capuco 1977; Zimber and Visek 1972, all as cited in ATSDR 2004).

Carcinogenicity

The Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) has not evaluated ammonia for evidence of human carcinogenic potential, because there are “no data,” and so has made no formal determination regarding the carcinogenicity of ammonia (EPA 1991).

The International Agency for Research on Cancer (IARC) considered “aqueous ammonia” as one of several materials used for spot removal in its monograph on dry cleaning (IARC 1995). However, ammonia was not specifically examined for carcinogenic potential in the monograph, which focused on chlorinated and other industrial solvents (IARC 1995). IARC has not published an evaluation of the potential human carcinogenicity of ammonia.

ATSDR reported a case of epidermal carcinoma of the nasal septum in the survivor of a serious industrial accident in which the exposed person’s upper lip and nose were accidentally splashed with a refrigeration mixture containing ammonia (Shimkin et al. 1954, as cited in ATSDR 2004). There was no evidence that the ammonia exposure was causal. ATSDR (2004) examined other cases of human inhalation exposure that followed ammonia spills but found no other case reports of carcinogenicity.

Adult male mice repeatedly exposed to ammonia vapor (“ammonia vapour of 12% ammonia solution,” 15 min/day, 6 days/week, 8 weeks) exhibited “mitotic figures” and nasal carcinoma (one of 10) or nasal mucosal adenocarcinoma (one of 10) (Gaafar et al. 1992). There is no conclusive evidence that the ammonia exposures induced the observed carcinomas (ATSDR 2004).

Examination of mice exposed by gavage to ammonia dissolved in water at 42 mg of ammonium ion per kilogram per day for 4 weeks provided “no evidence of a carcinogenic effect” (Uzvolgyi and Bojan 1980, as cited in ATSDR 2004).

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TOXICOKINETIC AND MECHANISTIC CONSIDERATIONS

Toxicokinetics and mechanisms of action for ammonia have been thoroughly summarized in recent publications—such as NRC 2002, 2007, and ATSDR 2004—and will not be detailed here.

Metabolism and Toxicokinetics

Ammonia is a product of amino acid and dietary-protein metabolism and is found naturally in human blood and tissues. In the large intestine, bacterial degradation of urea can also form ammonia (Diamondstone 1982, as cited in NRC 1994). Synthesis of some amino acids (glutamine, asparagine, and arginine) requires the presence of ammonia (White et al. 1978, as cited in NRC 1994).

Depending on the route of exposure, ammonia can be metabolized to urea and glutamine in the liver (ingestion exposure; Visek 1972; Furst et al. 1969; Pitts 1971, as cited in NRC 2002) or metabolized to glutamine or protein in tissues (after subcutaneous or intraperitoneal exposures; Duda and Handler 1958; Furst et al. 1969, as cited in NRC 2002). Of more immediate interest to the present analysis is inhalation exposure, during which ammonia is largely retained and absorbed by tissues of the upper respiratory tract. For short-term exposure (less than 2 min), 83-92% of inhaled ammonia is retained in the nasal mucosa (Landahl and Hermann 1950), and only small amounts are absorbed in the systemic circulation. With longer and more concentrated inhalation exposure, retention in the nasal mucosa decreases until it attains equilibrium (4-30%) with the inhaled-air concentration after exposure of 10-27 min (Silverman et al. 1949). Within 3-8 min after exposure termination, ammonia in expired air decreases to pre-exposure concentrations. After inhalation exposure during an industrial accident to ammonia at concentrations sufficient to induce first- and second-degree burns, blood ammonia concentration in the exposed patient remained stable, and chest x-ray films were normal (Leduc et al. 1992); it is thought that this finding indicates either a lack of appreciable ammonia absorption from the respiratory tract or rapid detoxification of inhaled ammonia (NRC 2007).

It has been speculated that people with impaired liver function may have increased blood-ammonia concentrations after inhalation exposure (Swotinsky and Chase 1990).

Systemic ammonia is largely excreted by the kidney as urea and ammonium compounds and voided in urine. Systemic ammonia can also be excreted as urea in feces (Gay et al. 1969; Pitts 1971, both as cited in NRC 2002) and perspiration (Guyton 1981; Wands 1981, both as cited in NRC 2002). Silverman et al. (1949) reported no changes in blood or urinary ammonia, urea, or nonprotein nitrogen in seven human subjects exposed to ammonia vapor at 350-500 ppm for 30 min. Within the first 30 min, about 70-80% of inhaled ammonia was expired; Silverman and colleagues thought that this indicated ammonia satura-

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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tion of upper respiratory tract tissues. Depending on the subject, equilibrium was attained within 10-27 min after exposure at 350-400 ppm, when the concentration of ammonia in expired air remained stable. Silverman et al. (1949) calculated that if all retained ammonia had been absorbed into the blood, there would have been no significant change in blood or urinary urea, ammonia, or nonprotein nitrogen; this is consistent with the human experimental data.

The data of Silverman et al. (1949) also indicate that retention of ammonia in the human nasopharynx is concentration- and time-dependent.

Mechanism of Toxicity

Ammonia is a corrosive, alkaline, locally irritant gas that produces effects immediately on contact with moist mucous membranes of the eyes, mouth, and respiratory tract. It reacts with those and other moist tissues to form ammonium hydroxide in an exothermic reaction (Wong 1994); the thermal and chemical burns that result from high-concentration exposures are considered to be a consequence of the heat of reaction and of the corrosive properties of the alkaline reaction product ammonium hydroxide. Ammonia is a respiratory and ocular irritant; case reports of accidental industrial and agricultural releases of high (but unquantified) concentrations document the presence of respiratory tissue injury and necrosis and penetration of corneal epithelium with resulting corneal scarring (Leduc et al. 1992; Mulder and van der Zalm 1967; Sobonya 1977; Hatton et al. 1979. For additional cases, see ATSDR 2004; NRC 1987, 2007).

Although there is no evidence that CNS function is compromised by inhalation exposure to ammonia at about 100 ppm, persons with depressed liver function or liver failure (for example, hepatic encephalopathy or congenital or acquired hyperammonemia) accumulate excessive ammonia in the CNS (NRC 2002). Depending on concentration, low or high CNS ammonia accumulations can induce “stupor and coma” (consistent with hyperpolarization) or seizures (consistent with depolarization), respectively (NRC 2002). Ammonia intoxication in the CNS is associated with astrocyte swelling and morphologic change (for example, Alzheimer II astrocytes observed in cases of hyperammonemia) and adverse changes in astrocyte metabolism (Norenberg 1981; Albrecht 1996; Norenberg and Martinez-Hernandez 1979, as cited in NRC 2002).

The human odor threshold for ammonia is about 5-53 ppm (Pierce 1994), and sensory fatigue (adaptation) occurs with prolonged exposure. The study conducted by Ferguson et al. (1977) demonstrated adaptation to ammonia at up to 150 ppm, with excursions to 200 ppm, in people acclimated to ammonia at 25-100 ppm for 1 week. When subjects were exposed to mixed odors, the odor threshold for ammonia was 10-20 ppm (Ferguson et al. 1977). At a concentration of 30 ppm in a Rochester chamber (head-only exposures), fit and healthy male workers (who passed class II USAF or class II FAA flying physicals) described the odor as “easily noticeable, moderate intensity” (two of five subjects) or “strong, highly penetrating” (three of five); that indicated that the odor

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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threshold had been exceeded at 30 ppm (MacEwen et al. 1970). When groups of naive and informed subjects were exposed to ammonia for 30 min in a whole-body exposure chamber and mean results were compared, the naive group subjectively judged 50 ppm to be greater than “distinctly perceptible” but less than a “nuisance;” the judgement of informed subjects rated concentrations of 50 and 80 ppm as only “distinctly perceptible” after a 30-min exposure (Verberk 1977). After a 2-h exposure, the naive group judged 50, 80, and 110 ppm as a “nuisance” (Verberk 1977).

A more recent study of naive vs informed (workers familiar with workplace ammonia) subjects (Ihrig et al. 2006) evaluated the response of 43 male volunteers (21-47 years old) repeatedly exposed to ammonia at 10-50 ppm 4 h/day for 5 days in an exposure chamber. The median reported intensity of irritative symptoms and respiratory symptoms remained below 1 (“hardly at all”) at all exposure concentrations (even at 50 ppm) for both naive and informed subjects. For olfactory symptoms, the median score of the naive group for the 20/40-ppm and 50-ppm exposure was between 3 and 4 (between “rather much” and “considerably”), whereas the median score of the informed group for the 20/40-ppm exposure was less than 1 (1 = “hardly at all”) and for the 50-ppm exposure was less than 2 (2 = “somewhat”) (Ihrig et al. 2006). Median annoyance rankings displayed by the naive group exceeded 4 (“rather much”) at 50 ppm, whereas the median annoyance rankings by the informed group exposed at 50 ppm remained under 2. Habituation was evident in the informed group of subjects.

Although there are variable results and some debate regarding the concentrations at which respiratory and ocular irritation occurs, there is a consensus that tissue injury occurs at vapor concentrations higher than those at which ammonia can be detected by odor or irritation; thus, sensitivity to the odor of ammonia vapor imparts warning properties via odor and ocular irritation.

Susceptible Populations In tests of concentrations required to stimulate reflex glottis closure (NH3TR) in healthy nonsmokers, Erskine et al. (1993) determined that the closure reflex of elderly people (86-95 years old) with a mean NH3TR of 1,791ppm (SEM ,52 ppm) is less responsive to ammonia vapor than that of younger people (21-30 years old) with a mean NH3TR of 571 ppm (SEM, 41.5 ppm). Erskine et al. (1993) point out that their earlier work (Erskine et al. 1992) indicated that “smokers have considerably more sensitive upper airway reflexes than non-smokers.”

The human-subjects study of McLean et al. (1979) documented that nonatopic and atopic subjects, some of whom had a history of asthma, responded similarly on a NAR test to ammonia at 100 ppm introduced into each nostril under pressure for up to 30 sec. McLean and colleagues noted that experimental results suggest attenuation of NAR after ammonia exposure and that the attenuation is mediated primarily by parasympathetic reflex effects on the nasal vasculature, not by histamine release. Collectively, the results indicate that, at about 100 ppm, ammonia coming into contact with tracheobronchial or pulmonary regions would not be expected to induce a different effect on asthmatic people.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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INHALATION EXPOSURE LEVELS FROM THE NATIONAL RESEARCH COUNCIL AND OTHER ORGANIZATIONS

A number of organizations have established or proposed inhalation-exposure levels or guidelines for ammonia. Selected values are summarized in Table 2-6.

COMMITTEE RECOMMENDATIONS

The committee’s recommendations for EEGL and CEGL values for ammonia are summarized in Table 2-7. The current and proposed U.S. Navy values are provided for comparison.

The literature contains human-exposure data derived from multiple clinical and monitoring studies that were carried out at ammonia concentrations and for exposure durations of interest and are thus suitable for direct estimation of exposure guidance levels. Over 100 adults were subjects of the clinical studies summarized in Tables 2-2 and 2-3, and 58 workers were monitored for the occupational epidemiologic study of Holness et al. (1989). Evaluated subjects were healthy people participating in a variety of activities (and thus uptake rates), including resting, working, and exercise. Groups represented were nonatopic and atopic people, including asthmatics (McLean et al. 1979; Sundblad et al. 2004); smokers and nonsmokers (MacEwen et al. 1970; Ferguson et al. 1977); and those with various thresholds for reflex glottis closure (Erskine et al. 1993). Given the breadth of data available on ammonia that include evaluation of a variety of groups involved in various activities, the committee concludes that the uncertainty surrounding the variability in susceptibility of the submarine crew to ammonia is most likely small.

1-Hour EEGL

On the basis of human data summarized in Table 2-3, the highest concentrations (102-140 ppm) in exposures of about 1 h resulted in minimal or no physiologic change in respiratory function (FVC, FEV1, minute volume, and respiratory rate) or cardiac function (pulse rate and diastolic and systolic blood pressure) compared with control values (Verberk 1977; Ferguson et al. 1977; Cole et al. 1977). The protocol of Ferguson et al. (1977) incorporated serial daily exposures for 2 weeks. The exercise regimen incorporated into the study of Cole et al. (1977) and the workplace physical activity incorporated into the study of Ferguson et al. (1977) take into account the physical stress that may occur during an emergency situation onboard. The Ferguson et al. evaluation of potential exposure effects on a worker’s ability to perform physical and mental tasks required in the course of daily duties of a chemical-plant operator is pertinent to tasks performed by submarine crew (for example, data-logging, computational tasks, and walking up and down flights of stairs).

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 2-6 Selected Inhalation Exposure Levels for Ammonia from the NRC and Other Agenciesa

Organization

Type of Level

Exposure Level (ppm)

Reference

Occupational

 

 

 

ACGIH

TLV-TWA

25

ACGIH 2001

TLV-STEL

35

NIOSH

REL-TWA

25

NIOSH 2005

REL-STEL

35

OSHA

PEL-TWA

50

29 CFR 1910.1000

Spacecraft

 

 

 

NASA

SMAC

 

NRC 1994

1-h

30

24-h

20

30-day

10

180-day

10

Submarine

 

 

 

NRC

EEGL

 

NRC 1987

1-h

100

24-h

100

CEGL

 

 

90-day

50

 

SEAL 1 (10 days)

75

NRC 2002

SEAL 2 (24 h)

125

General Public

 

 

 

ATSDR

Acute MRL

1.7

ATSDR 2004

Chronic MRL

0.1

NAC/NRC

AEGL-1 (1-h)

30

NRC 2007

AEGL-2 (1-h)

160

AEGL-1 (8-h)

30

AEGL-2 (8-h)

110

aThe comparability of EEGLs and CEGLs with occupational-exposure and public-health standards or guidance levels is discussed in Chapter 1 (“Comparison with Other Regulatory Standards or Guidance Levels”).

Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; AEGL, acute exposure guideline level; ATSDR, Agency for Toxic Substances and Disease Registry; CEGL, continuous exposure guidance level; EEGL, emergency exposure guidance level; MRL, minimal risk level; NAC, National Advisory Committee; NASA, National Aeronautics and Space Administration; NIOSH, National Institute for Occupational Safety and Health; NRC, National Research Council; OSHA, Occupational Safety and Health Administration; PEL, permissible exposure limit; REL, recommended exposure limit; SMAC, spacecraft maximum allowable concentration; STEL, short-term exposure limit; TLV, Threshold Limit Value; TWA, time-weighted average.

The preponderance of data from clinical studies indicates that even a multihour exposure to ammonia at about 100 ppm would result in few substantial

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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TABLE 2-7 Emergency and Continuous Exposure Guidance Levels for Ammonia

Exposure Level

U.S. Navy Values (ppm)

Committee Recommended Values (ppm)

Current

Proposed

EEGL

 

 

 

1-h

100

30

100

24-h

100

20

50

CEGL

 

 

 

90-day

50

10

10

Abbreviations: CEGL, continuous exposure guidance levels; EEGL, emergency exposure guidance level.

physiologic effects. Among naive populations tested (Verberk 1977), exposure at 110 ppm for 1 h was judged to be at a “nuisance” level and to generate perceptible eye and throat irritation and perceptible urge to cough. Those effects are known to be reversible on cessation of exposure. Thus, a concentration of about 100 ppm is judged to be minimal and would not interfere with performance of critical tasks during an onboard emergency.

The weight of evidence from the strong human experimental data, including exercising subjects (Cole et al. 1977) and exercising smoking subjects (Ferguson et al. 1977) for the exposure duration of concern indicates a 1-h EEGL of 100 ppm for ammonia. The use of human data precludes the application of an interspecies uncertainty factor. Furthermore, that concentration does not induce significant differences in NAR when the response of atopic subjects, including asthmatics, is compared with that of nonatopic subjects in studies of direct (forced-air) ammonia-vapor contact with intranasal tissues (McLean et al. 1979). Therefore, no intraspecies uncertainty factor has been applied.

24-Hour EEGL

Pertinent, multihour, human exposure studies include those of Ferguson et al. (1977), Sundblad et al. (2004), Verberk (1977), and Ihrig et al. (2006). For ammonia exposure 2-6 h/day, 5 days/week for 2 weeks at 100 ppm, Ferguson et al. (1977) observed no eye, nose, or throat irritation significantly different from controls and no other effects except for FEV1 improvement. Ferguson et al. (1977) observed that repeated exposure at 100 ppm as above, with excursion to 200 ppm, was “easily tolerated” by the human subjects. Sundblad et al. (2004) observed no detectable inflammation in upper airways (on the basis of multiple physiologic measurements) and no increased bronchial responsiveness to methacholine challenge in healthy and atopic subjects exposed to ammonia continuously for 3 h at 0, 5, or 25 ppm with exposures separated by an interval of at least a week; each subject exercised at 50 W for half of each exposure period. Sundblad et al. (2004) noted a dose-response relationship for multiple and transient symptoms of irritation and systemic response as reported on subject ques-

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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tionnaires. Verberk (1977) exposed informed and naive subjects to ammonia for 2 h at 110 or 140 ppm. At 110 ppm, informed and naive subjects reported marginally nuisance eye irritation and perceptible (informed) or nuisance (naive) odor; at 140 ppm, naive subjects withdrew from the exposure chamber before the passage of 2 h because of “offensive” concentrations, but no informed subjects withdrew (the informed group reported “perceptible” and “nuisance” odor and eye irritation at 140 ppm for 2 h ) (see Table 2-3).

Ihrig et al. (2006) exposed naive and informed male volunteers (the latter “regularly exposed to ammonia in the workplace”) to ammonia at 10-50 ppm 4 h/day for 5 days. Habituation was noted during the course of the study, and experienced subjects reported fewer symptoms than naive subjects. Medical examinations were conducted for tear-flow rates, lung function, bronchial responsiveness, cognitive function, and related end points after each exposure. Except for three subjects in the 50-ppm group who exhibited “slight conjunctival hyperemia,” no relevant physical or neurophysiologic effects (such as reaction time, attention, and power of concentration) were observed (see Table 2-3).

The short-term (10-min) exposure studies of fit, male, military or military-contractor personnel (MacEwen et al. 1970) also provide valuable background regarding irritancy.

Pertinent animal studies were evaluated for valuable insight and to augment the human database. Animal studies include repeat-exposure and subchronic-toxicity estimates in rats, mice, rabbits, guinea pigs, and rabbits (Coon et al. 1970; Tepper et al. 1985; Manninen et al. 1988; Buckley et al. 1984; and Zissu 1995) (see Table 2-5). Preference is given to consideration of the rat and mouse data because these species are obligate nose-breathers; mice are considered unusually sensitive to the toxic effects of exposure to such respiratory irritants as ammonia (Ten Berge et al. 1986).

Coon et al. (1970) reported no deaths or clinical signs after exposure of rats at 222 ppm 8 h/day for 6 weeks and no deaths or attributable clinical signs at 1,101 ppm with the same exposure regimen. Tepper et al. (1985) observed transient changes in running-wheel activity in rats with exposure durations greater than 1 h at ammonia concentrations of 100 ppm and for all exposure durations at 300 ppm; mice undergoing the same protocol exhibited a similar but smaller activity-profile change; Tepper and colleagues attributed the changes to sensory irritation. The related mouse studies of Buckley et al. (1984) and Zissu (1995) examined the effects of ammonia exposure at various fractions or multiples of the RD50 (Swiss-Webster mouse RD50 of 303 ppm, Buckley et al.; Swiss OF1 mouse RD50 of 257 ppm, Zissu); subjects exhibited no clinical signs. At the RD50, histopathologic examination identified minimal exfoliation and erosion, and moderate metaplasia and inflammation were exhibited in the nasal cavity epithelium. Rats continuously exposed at 182 ppm for 90 days exhibited no clinical signs and had normal hematologic, organ, and tissue values not different from control values for any measure examined (Coon et al. 1970; see Table 2-4).

The weight of evidence exhibited by the experimental data—which include those on exercising human subjects and smokers (Ferguson et al. 1977;

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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MacEwen et al. 1970; Sundblad et al. 2004), naive and informed human subjects (Verberk 1977; Ihrig et al. 2006), and mice and rats1 exercising for multiple hours (Tepper et al. 1985; ten Berge et al. 1986)—provides the basis for estimating the 24-h EEGL for ammonia. It is important to note that close examination of data from MacEwen et al. (1970) and Verberk (1977) indicates that the human irritancy response (for example, eye and throat irritation) tends to “flatten” after exposure at 50 ppm for 30 min to 1 h even among naive subjects (“nuisance” concentrations of 50 ppm; Verberk 1977). The same naive subjects ranked exposure at 80-100 ppm as “offensive.” Such irritancy effects are fully reversible on cessation of ammonia exposure. It is further noted that the recent and carefully collected human-exposure data of Ihrig et al. (2006) indicate threshold physiologic effects at 50 ppm (4 h/day for 5 days) by documenting transient conjunctival irritation (three subjects) and olfactory irritation rankings considered moderate (“somewhat” for experienced subjects and “rather much” for naive subjects); habituation was evident (Ihrig et al. 2006). Therefore, the human data led the committee to consider 50 ppm as a protective level of ammonia exposure for 24 h during emergency situations, given the present insufficiency of data for assessing human accommodation to 80-100 ppm for 24 h of continuous exposure.

The use of human data precludes application of an interspecies uncertainty factor. Furthermore, it is known that exposure at 100 ppm does not induce significant differences in NAR when the response of atopic subjects, including asthmatics, is compared with that of nonatopic subjects in studies of direct (forced-air) ammonia-vapor contact with intranasal tissues (McLean et al. 1979). Therefore, no intraspecies uncertainty factor has been applied. The committee’s recommended 24-h EEGL is 50 ppm, which the committee judges sufficient to prevent a level of irritancy that could interfere with crew alertness and efficient work performance during an emergency.

90-Day CEGL

There are no reliable human experimental data on exposure durations greater than about 6 weeks (Ferguson et al. 1977; see Table 2-3). The committee considered subchronic experimental data on a susceptible laboratory species (rat) in which there are no documented clinical signs after continuous exposure at 57 ppm for 114 days or at 182 ppm for 90 days (Coon et al. 1970); the study’s continuous-exposure protocol included “downtime” for animal feeding and chamber servicing equal to less than 2.2% of the experimental exposure duration. After continuous exposure at 375 ppm for 90 days, Coon et al. (1970) reported “mild” nasal discharge as the only noteworthy sign in rats (see Table 2-5). The committee did not use the latter finding regarding nasal tissue effects,

1

Both rodents are obligate nose breathers, and mice are considered sensitive to ammonia.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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because Coon and colleagues did not perform histopathologic evaluations of the nasal cavity to confirm the presence or absence of irritation response. More contemporary studies have shown that 5-week continuous exposure of weanling pigs at 37 ppm in combinations with dust at concentrations up to 9.9 mg/m3 was associated with no significant changes in turbinate or lung tissue when compared with controls (Done et al. 2005). Furthermore, daily clinical monitoring for respiratory, gastrointestinal, and ocular signs demonstrated that the experimental exposures had no significant effect. Swine are increasingly considered a reasonable surrogate for human physiologic and tissue responses; thus, the study of Done et al. (2005) adds particular insight to human-exposure considerations.

It is reported that rodents exposed repeatedly to ammonia vapor at 711 ppm over a period of days develop lesions in the nasal respiratory epithelium (Zissu 1995).

Human data indicate that exposure to ammonia concentrations at up to 140 ppm over a period of hours or days is unlikely to cause irreversible systemic effects. Nevertheless, it appears that exposure at over about 110 ppm would be expected to generate eye, nose, throat, and chest irritation in naive or untrained human populations exposed for 90 days (Verberk 1977), even when sensory fatigue is accounted for. Although not yet experimentally characterized in long-term human studies, available dose-response data indicate that systemic toxicity at that concentration is not expected to be clinically significant (NRC 1987).

It is known that “most, if not all, individuals who are regularly exposed to ammonia develop a tolerance to its irritant effects” (Ferguson et al. 1977). Ferguson et al. (1977) evaluated skilled and experienced repair workers at a chemical manufacturing facility who underwent workplace exposure in areas where ammonia concentrations of 25 and 50 ppm were achieved; controlled 100-ppm exposure took place in an exposure chamber. Exposure periods ranged from 2 to 6 h/day for 5 weeks. No adverse effects on respiratory function and no increase in frequency of eye, nose, and throat irritation were noted by participants and examining physicians. After acclimation, up to 6 h of continuous exposure at at least 100 ppm (average, 103-140 ppm, with occasional excursions to 200 ppm) was “easily tolerated” (Ferguson et al. 1977). In the years before the Ferguson et al. study, facility workers did not voluntarily don respiratory protection until workplace ammonia reached 400-500 ppm. Persons who are naive with respect to ammonia do not exhibit such tolerance.

The human-exposure study of Ihrig et al. (2006) also compared the subjective and physiologic responses of naive vs experienced subjects (the latter commonly experienced workplace exposures to ammonia) to successive concentrations of 0, 10, 20, 20/40, or 50 ppm 4 h/day over 5 days. At all concentrations, the experienced subjects reported fewer symptoms than naive subjects. At 10 ppm, the median ranking of olfactory symptoms by naive subjects lay between the qualitative score of 1 (“hardly at all”) and 2 (“somewhat”), whereas the median ranking by naive subjects at 20 ppm lay between 2 and 3 (“rather much”). The median ranking of olfactory symptoms by experienced subjects was less than 1 at 10, 20, and 20/40 ppm (Ihrig et al. 2006). Habituation was evident.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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On the basis of response to questionnaires, the subjects of the Sundblad et al. (2004) study exposed at 25 ppm for 3 h (serial exposures) did not appear to exhibit sensory fatigue to “solvent smell”; sensory fatigue to odor was noted in subjects exposed at 5 ppm. Subjects exposed at 25 ppm ranked perceived discomfort for all 10 possible questionnaire symptoms significantly higher than during the sham exposure or when exposed at 5 ppm; however, no subjects are reported to have terminated the 25-ppm exposure prematurely. Nevertheless, the committee considers the Sundblad et al. (2004) study to be flawed in that it lacked control for odor perception and is thus confounded by the potential for irritancy as a consequence of generic odor perception rather than any sensory-irritancy response peculiar to ammonia. An ideal study protocol would have masked the odor of ammonia or used subjects who had no sense of smell. Reported irritation effects and breathing difficulties for the 5-ppm exposure group are recognized as small, odor-related, and generic.

The data of MacEwen et al. (1970) indicate that ammonia at 30 ppm was associated with “just perceptible” nasal and ocular effects in two of five naive volunteers exposed for 10 min. The data of Sundblad et al. (2004) indicate that ammonia at 25 ppm (3-h exposure) is associated with transient irritation of eyes, nose, and upper airways but no “detectable upper-airway inflammation or increased bronchial responsiveness to methacholine.” When compared with sham exposures, ammonia at 25 ppm was also associated with increased reports of sensations of nausea, headache, and sensation of intoxication in some subjects. The symptomatology is consistent with an odor response, and the committee considers 25 ppm to be an odor-irritancy threshold in healthy, exercising populations of an appropriate age and thus comparable with the submarine-crew population of concern.

It is acknowledged that rigorous measurements of sensory fatigue have not been collected for continuous exposure approaching 90 days, so some degree of speculation is appropriate.

The human-subjects data of Sundblad et al. (2004), MacEwen et al. (1970), and Ihrig et al. (2006) are convergent in demonstrating irritancy in young adults in response to ammonia at about 20-30 ppm. The committee selects that range as the minimal LOAEL for irritancy due to odor and incorporates a factor of 3 to accommodate adjustment of the minimal LOAEL to a no-observed-adverse-effect level (NOAEL) for odor perception. The resulting estimate of 6.7-10 ppm is rounded to 10 ppm.

To minimize potential complaints regarding discomfort, annoyance, or ocular irritation among submariners confined for multiple weeks in ammonia atmospheres, the committee recommends a 90-day CEGL of 10 ppm. That CEGL should prevent potential degradation in submarine-crew performance resulting from sustained exposure to intense odor and nuisance concentrations and is below the human experimental concentrations associated with “moderate” irritation considered as an adverse effect. The Sundblad et al. (2004) data indicate that sensory fatigue for ammonia odor perception is likely to occur at some (undefined) ammonia concentration greater than 5 ppm but less than 25 ppm and

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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are indicative of the protective nature of a 10-ppm CEGL. Furthermore, the committee’s recommended CEGL of 10 ppm is supported by the results of Sundblad et al. (2004), Verberk (1977), and Ihrig et al. (2006) indicating relatively static effects over time at 20-50 ppm; the results of Coon et al. (1970) documenting no signs or clinically significant effects in nonhuman primates continuously exposed for 90 days at 57 ppm; and the results of Done et al. (2005) showing no signs or clinically significant effects in weanling pigs continuously exposed at 37 ppm for 5 weeks.

As for the previous 1-h and 24-h EEGL estimates, there is little justification for application of an intraspecies uncertainty adjustment to accommodate asthmatics exposed to ammonia. Given the weight of evidence from workplace and clinical exposure studies, an ammonia concentration of 10 ppm as the CEGL is protective for submarine crews.

DATA ADEQUACY AND RESEARCH NEEDS

Quantitative exposure data are available on humans—including asthmatics, smokers, elderly people, and children—and laboratory animals, including such susceptible species as mice and rats. Most human studies suitable for quantitative assessment used short-term exposure (up to 2 h; one study incorporated exposure of 4 h and 6 h), which necessitate assumptions regarding the concentration-dependent nature of the toxic response to ammonia. Controlled humanexposure studies for extended exposure (especially 24-h continuous and multi-day exposure) are lacking in the database available for study. In addition, controlled experimental studies of humans are restricted to small numbers of subjects and exhibit incomplete protocols. Greater and more objective quantification of such subjective end points as irritation and nuisance is needed; however, evaluations using appropriate psychophysical methods also need to assess cognitive and emotional factors that affect subjective responses (Dalton 2002). Finally, there are few contemporary studies of long-term ammonia exposure of laboratory animals; the 90-day studies available for assessment were published in the early 1970s. Although they are sufficient for the current evaluation, corroborating evidence based on modern analytic and vapor-generation techniques would have been highly useful for application to the 90-day assessment.

The results of Verberk (1977; Table 2-2) and Ihrig et al. (2006) indicate that mere knowledge of and exposure experience with the irritant and odor properties of ammonia vapor can effectively reduce human avoidance behavior and increase tolerance to concentrations as great as 140 ppm for exposure as long as 2 h. That finding has operational significance for naval submarine command and warrants further serious consideration as a training opportunity for submarine crews. The committee echoes the previous recommendation of the Committee on Submarine Escape Action Levels regarding application of Verberk’s (1977) findings to submarine-crew training curricula (NRC 2002) and recommends inclusion of the more recent Ihrig et al. (2006) human-exposure data.

Suggested Citation:"2 Ammonia." National Research Council. 2008. Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants: Volume 2. Washington, DC: The National Academies Press. doi: 10.17226/12032.
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