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).



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2 Ammonia This chapter summarizes the relevant epidemiologic and toxicologic stud- ies 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 recom- mendations 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 re- search 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 nitro- gen cycle. Average global ammonia concentrations are estimated to range from 0.6 ppb to 3 ppb (ATSDR 2004). 20

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21 Ammonia 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% (0EC), 38% (15EC), 28% (30EC), 18% (50EC); soluble in chloroform and ether 1 ppm = 0.7 mg/m3; 1 mg/m3 = 1.44 ppm Conversion factors 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, decompo- sition 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. Mul- tiple 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 Hygien- ists (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 imme- diately on contact with moist mucous membranes of the eyes, mouth, and respi- ratory tract. It reacts with moist tissues to form ammonium hydroxide in an exo- thermic 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.

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22 Exposure Guidance Levels for Selected Submarine Contaminants Ammonia is a respiratory and ocular irritant; high concentrations can cause res- piratory tissue injury and necrosis and penetrate the corneal epithelium. Because of its appreciable water solubility, ammonia is largely retained in the nasal mu- cosa, another common site of tissue injury after vapor exposure. Because of its widespread commercial use and transport, accidental expo- sure to ammonia during industrial, farm, or transport accidents is not uncom- mon, 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 informa- tion regarding dose-response relationships, do not characterize exposure condi- tions expected on board a modern submarine, and hence will be given little con- sideration 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, be- havioral changes, reductions in respiration rates (such as RD50 values), poten- tially 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 va- por 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 am- monia, although sensory fatigue often occurs after continuous or repetitive exposures. Effects in Humans Accidental Exposures No reliable concentration data are available for characterizing human ex- posures sustained during the many transportation, industrial, and agricultural accidents in which injurious or lethal ammonia concentrations have been re- leased. 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 pul- monary 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

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23 Ammonia 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” (produc- tive 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” af- fected 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 denu- dation 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 sus- tained in a farming accident (Sobonya 1977). The autopsy report noted damage to the bronchial epithelium, bronchiectasis, mucus plugging and mural thicken- ing of the smallest bronchi and bronchioles, fibrous obliteration of small air- ways, and a purulent cavitary pneumonia characterized by large numbers of No- cardia 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

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24 Exposure Guidance Levels for Selected Submarine Contaminants edema. She required mechanically assisted respiration throughout her remaining life. Bronchiectasis was detected 2 years after exposure and confirmed at au- topsy, 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 sub- jects—including allergic and nonallergic people, those with asthma, and smok- ers—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 car- diac function, airway resistance, granulocytes and monocytes in peripheral blood, cell concentrations in nasal lavage fluids, and various subjective meas- urements of ocular and respiratory irritancy and systemic effects. Although re- sults of some of the earlier (such as 1940s) studies may be compromised by what is now considered limited analytic characterization of exposure concentra- tions, there are sufficient multiple and well-conducted clinical studies suitable for exposure-guideline estimation. The more quantitative studies are summa- rized in Tables 2-2 and 2-3 and the following text. Verberk (1977) examined dose-response relationships of signs and symp- toms 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 lit- erature on ammonia effects and unfamiliar with experiments in laboratory situa- tions (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 docu- mented 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 re- sponses (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 meas- ured before and after each exposure. Chamber concentrations were monitored instantaneously with an infrared spectrometer. No subject inhaling any test con- centration for any exposure duration exhibited more than a 10% decrease in VC, FEV1, or FIV1. Verberk (1977) considered that small percentage to be “no ef- fect.” The committee agrees that such small differences have minimal clinical significance. Furthermore, there was no group effect on those measures. Subjec- tive-response scores did exhibit group effects and dose- and duration-response

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25 Ammonia TABLE 2-2 Subjective-Response Scoresa of Informedb and Naiveb Human Subjects Exposed to Ammonia Vapor at Various Concentrations 140 ppmc (mean) Perception and 50 ppm (mean) 80 ppm (mean) 110 ppm (mean) Exposure Duration Informed Naive Informed Naive Informed Naive Informed Naive Smell: 3.8 3.0 2.0 2.5 2.0 3.0 2.2 ½h 2.0 4.0 3.0 2.0 2.5 2.0 3.0 2.1 1h 2.0 2.0 WD 2.1 3.0 3.0 1.5 3.0 2h 2.0 Eye irritation: 3.0 2.6 3.0 1.6 1.6 2.7 ½h 1.5 0.8 3.2 2.7 2.5 2.9 0.8 1.7 1.6 1h 1.5 2.3 WD 2.2 2.5 1.3 1.5 2.0 2h 1.0 Throat irritation: 1.0 3.8 1.4 2.0 0.5 0.8 1.1 ½h 0.5 1.3 4.5 1.4 2.6 1.0 1.5 1h 0.5 0.7 1.2 WD 1.0 3.0 0.8 2.0 2h 0.7 1.6 Urge to cough: 0.6 2.3 0.8 1.7 0.2 0.4 0.7 ½h 0.2 2.0 0.9 1.8 0.1 0.5 1.0 0.7 1h 0.2 WD 2.0 0.6 0.7 0.6 1.5 0.5 2h 0.3 General discomfort: 0.2 0.0 1.1 ½h 0.0 0.0 1.0 0.0 2.5 0.0 1.2 1h 0.0 0.2 0.2 1.0 0.0 3.3 1.2 0.0 1.2 2h 0.0 WD 0.3 1.8 0.0 a Based on a scale of 0-5: 0 = “no sensation,” 1 = “just perceptible,” 2 = “distinctly per- ceptible,” 3 = “nuisance,” 4 = “offensive,” 5 = “unbearable.” b Informed subjects were academically familiar with the effects of ammonia but not accus- tomed to regular exposure to it; naive subjects were unfamiliar with literature document- ing effects and had not experienced regular exposure. See Table 2-3 for additional details of experimental protocol. c Only 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 ex- posure 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 sub- jects 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

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26 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 5 males and 7 females; healthy adults, 21-28 years old (mean, 25); smoking Sundblad et al. resting + 1.5 h history unreported; n = 12 2004 exercising) 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” 10 4h 43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, Ihrig et al. 2006 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 20 4h 43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, Ihrig et al. 2006 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

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20, 40 20 ppm for 3 h with 43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, Ihrig et al. 2006 two 30-min peaks at 21-47 years old; smoking history unreported; n = 43 40 ppm 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 25 3-h exposure (1.5 h 5 males and 7 females; healthy adults, 21-28 years old (mean, 25 years); Sundblad et al. resting + 1.5 h smoking history unreported; n = 12 2004 exercising) 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” 30 10 min 6 fit males, 23-44 years old (mean, 31 years) MacEwen et al. Odor moderately intense to highly penetrating; irritation faint or not detectable 1970 32 5 min 10 healthy volunteers Industrial Bio-Test 1 had nasal dryness Lab 1973 (as cited in ATSDR 2004 and WHO 1986) 50 5 min 10 healthy volunteers Industrial Bio-Test 2 had nasal dryness; NOAEL identified by ATSDR (2004) Lab 1973 (as cited in ATSDR 2004 and WHO 1986) (Continued) 27

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28 TABLE 2-3 Continued Concentration (ppm) Time Subjects and Effects Reference 50 10 min 6 fit males, 23-44 years old (mean, 31 years) MacEwen et al. Highly penetrating odor; moderate irritation 1970 50 30 min 16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 Verberk 1977 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 50 1h 16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 Verberk 1977 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 50 2h 16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 Verberk 1977 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

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50 2-6 h/day, 6 weeks; 2 unacclimated subjects: 1 male, 1 female, 24-29 years old; 1 smoker Ferguson et al. workplace exposures, No significant difference in respiratory rates, pulse, systolic and diastolic BP, 1977 standard workplace FVC, and FEV1; physician-observed mild eye, nose, and throat irritation not physical activities significantly different from control; no evidence of abnormal chest sounds, heart murmur, neurologic change, or weight change; no impairment 50 4h 43 male volunteers (33 naive subjects, 10 ammonia workers); healthy adults, Ihrig et al. 2006 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 72 5 min 10 healthy volunteers Industrial Bio-Test 3 had nasal, eye, and throat irritation; LOAEL identified by ATSDR (2004) Lab 1973 (as cited in ATSDR 2004 and WHO 1986) Verberk 1977 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 (Continued) 29

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30 TABLE 2-3 Continued Concentration (ppm) Time Subjects and Effects Reference 80 1h 16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 Verberk 1977 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 80 2h 16 adults: 8 informed (7 males, 1 female, 29-53 years old); 8 naive (6 males, 2 Verberk 1977 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 25, 50, 100: ascending 2-6 h/day, 6 weeks; Ferguson et al. 4 unacclimated subjects: males, 26-46 years old; 2 smokers and descending workplace exposures; No adverse effects on respiratory function; no increase in frequency of eye, nose, 1977 sequentially weekly; 2 normal workplace throat irritation; only statistically significant increase was in FEV1 weeks at each (“improvement”) with increasing ammonia concentration; no subjective reports of physical and mental concentration irritation; physician examinations indicate “mild” irritation of eyes, nose, and tasks 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) 100 5, 10, 15, 20, 30 sec Individual, forced-air nostril delivery at 100 ppm (at 9 newtons/cm2) for McLean et al. 1979 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

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53 Ammonia 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 mar- ginally 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 sub- jects 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 ex- perienced subjects reported fewer symptoms than naive subjects. Medical ex- aminations were conducted for tear-flow rates, lung function, bronchial respon- siveness, cognitive function, and related end points after each exposure. Except for three subjects in the 50-ppm group who exhibited “slight conjunctival hy- peremia,” 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 aug- ment the human database. Animal studies include repeat-exposure and sub- chronic-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 consid- ered unusually sensitive to the toxic effects of exposure to such respiratory irri- tants 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 multi- ples 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 in- clude those on exercising human subjects and smokers (Ferguson et al. 1977;

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54 Exposure Guidance Levels for Selected Submarine Contaminants 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 estimat- ing 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 hu- man 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 (“nui- sance” 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 am- monia exposure for 24 h during emergency situations, given the present insuffi- ciency 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 sig- nificant 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 dura- tion. After continuous exposure at 375 ppm for 90 days, Coon et al. (1970) re- ported “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 ammo- nia.

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55 Ammonia because Coon and colleagues did not perform histopathologic evaluations of the nasal cavity to confirm the presence or absence of irritation response. More con- temporary 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 com- pared with controls (Done et al. 2005). Furthermore, daily clinical monitoring for respiratory, gastrointestinal, and ocular signs demonstrated that the experi- mental 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). Fer- guson et al. (1977) evaluated skilled and experienced repair workers at a chemi- cal 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 subjec- tive and physiologic responses of naive vs experienced subjects (the latter com- monly experienced workplace exposures to ammonia) to successive concentra- tions 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 me- dian 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.

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56 Exposure Guidance Levels for Selected Submarine Contaminants 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 dis- comfort 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. Re- ported 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 in- creased 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 popula- tions of an appropriate age and thus comparable with the submarine-crew popu- lation 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 se- lects that range as the minimal LOAEL for irritancy due to odor and incorpo- rates a factor of 3 to accommodate adjustment of the minimal LOAEL to a no- observed-adverse-effect level (NOAEL) for odor perception. The resulting esti- mate 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 indi- cate 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

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57 Ammonia 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 rela- tively 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 con- tinuously exposed at 37 ppm for 5 weeks. As for the previous 1-h and 24-h EEGL estimates, there is little justifica- tion 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 asthmat- ics, smokers, elderly people, and children—and laboratory animals, including such susceptible species as mice and rats. Most human studies suitable for quan- titative assessment used short-term exposure (up to 2 h; one study incorporated exposure of 4 h and 6 h), which necessitate assumptions regarding the concen- tration-dependent nature of the toxic response to ammonia. Controlled human- exposure 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 quantifi- cation of such subjective end points as irritation and nuisance is needed; how- ever, 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, cor- roborating 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 prop- erties 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.

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58 Exposure Guidance Levels for Selected Submarine Contaminants REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Ammonia. Documentation of the Threshold Limit Values and Biological Exposure Indi- ces, 7th Ed. American Conference of Governmental Industrial Hygienists, Cin- cinnati, OH. Albrecht, J. 1996. Astrocytes and ammonia neurotoxicity. Pp. 137-153 in The Role of Glia in Neurotoxicity, M. Aschner, and H.K. Kimelberg, eds. Boca Raton, FL: CRC Press. Anderson, D.P., C.W. Beard, and R.P. Hanson. 1964. The adverse effects of ammonia on chickens including resistance to infection with Newcastle disease virus. Avian Dis. 8:369-379. Appelman, L.M., W.F. ten Berge, and P.G. Reuzel. 1982. Acute inhalation toxicity study of ammonia in rats with variable exposure periods. Am. Ind. Hyg. Assoc. J. 43(9):662-665. ATSDR (Agency for Toxic Substances and Disease Registry). 2004. Toxicological Pro- file for Ammonia. Agency for Toxic Substances and Disease Registry, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. September 2004 [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/ tp126.pdf [accessed June 5, 2007]. Ballal, S.G., B.A. Ali, A.A. Albar, H.O. Ahmed, and A.Y. al-Hasan. 1998. Bronchial asthma in two chemical fertilizer producing factories in eastern Saudi Arabia. Int. J. Tuberc. Lung Dis. 2(4):330-335. Barrow, C.S., Y. Alarie, and M.F. Stock. 1978. Sensory irritation and incapacitation evoked by thermal decomposition products of polymers and comparisons with known sensory irritants. Arch. Environ. Health 33(2):79-88. Boyd, E.M., M.L. MacLachlan, and W.F. Perry. 1944. Experimental ammonia gas poi- soning in rabbits and cats. J. Ind. Hyg. Toxicol. 26(1):29-34. Broderson, J.R., J.R. Lindsey, and J.E. Crawford. 1976. The role of environmental am- monia in respiratory mycoplasmosis of rats. Am. J. Pathol. 85(1):115:130. Buckley, L.A., X.Z. Jiang, R.A. James, K.T. Morgan, and C.S. Barrow. 1984. Respira- tory tract lesions induced by sensory irritants at the median respiratory rate de- crease concentration. Toxicol. Appl. Pharmacol. 74(3):417-429. Budavari, S., M.J. O’Neil, A. Smith, and P.E. Heckelman, eds. 1989. Ammonia. P. 81 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 11th Ed. Rahway, NJ: Merck. Caplin, M. 1941. Ammonia-gas poisoning. Forty-seven cases in a London shelter. Lancet 241(July 26):95-96. Capuco, A.V. 1977. Ammonia: A modulator of 3T3 cell growth. Diss. Abstr Int B 38(9):4085. Carlile, F.S. 1984. Ammonia in poultry houses: A literature review. World Poult. Sci. J. 40(2):99-113. Choudat, D., M. Goehen, M. Korobaeff, A. Boulet, J.D. Dewitte, and M.H. Martin. 1994. Respiratory symptoms and bronchial reactivity among pig and dairy farmers. Scand. J. Work Environ. Health 20(1):48-54. Cole, T.J., J.E. Cotes, G.R. Johnson, H.D. Martin, J.W. Reed, and M.J. Saunders. 1977. Ventilation, cardiac frequency and pattern of breathing during exercise in men exposed to o-chlorobenzylidene malonitrile (CS) and ammonia gas in low con- centrations. Q. J. Exp. Physiol. Cogn. Med. Sci. 62(4):341-351.

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59 Ammonia Coon, R.A., R.A. Jones, L.F. Jenkins, Jr., and J. Siegel. 1970. Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol. Appl. Pharmacol. 16(3):646-655. Cormier, Y., E. Israel-Assayag, G. Racine, and C. Duchaine. 2000. Farming practices and the respiratory health risks of swine confinement buildings. Eur. Resp. J. 15(3):560-565. Crawl, J.R. 2003. Review/Updating of Limits for Submarine Air Contaminants. Presenta- tion at the First Meeting on Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, January 23, 2003, Washington, DC. Czuppon, T.A.,S.A. Knez, and J.M. Rovner. 1992. Ammonia. Pp. 638-691 in Kirk- Othmer Encyclopedia of Chemical Technology, 4th Ed., Vol. 2. New York: Wiley. Dalhamn, T. 1956a. Mucous flow and ciliary activity in the trachea of healthy rats and rats exposed to respiratory irritant gases (S02, H3N, HCHO). A functional and morphologic (light microscopic and electron microscopic) study, with special reference to technique. VIII. The reaction of the tracheal ciliary activity to sin- gle exposure to respiratory irritant gases and studies of the pH. Acta Physiol. Scand. 36 Suppl. 123):93-105. Dalhamn, T. 1956b. Mucous flow and ciliary activity in the trachea of healthy rats and rats exposed to respiratory irritant gases (S02, H3N, HCHO). A functional and morphologic (light microscopic and electron microscopic) study, with special reference to technique. Acta Physiol. Scand. 36 (Suppl. 123):1-161. Dalton, P. 2002. Odor, irritation and perception of health risk. Int. Arch. Occup. Environ. Health 75(5):283-290. Diamondstone, T.I. 1982. Amino acid metabolism. I. P. 544 in Textbook of Biochemistry with Clinical Correlations, T.M. Devlin, ed. New York, NY: John Wiley & Sons. Dodd, K.T., and D.R. Gross. 1980. Ammonia inhalation toxicity in cats: A study of acute and chronic respiratory dysfunction. Arch. Environ. Health 35(1):6-14. Done, S.H., D. J. Chennells, A.C. Gresham, S. Williamson, B. Hunt, L.L. Taylor, V. Bland, P. Jones, D. Armstrong, R.P. White, T.G. Demmers, N. Teer, and C.M Wathes. 2005. Clinical and pathological responses of weaned pigs to atmos- pheric ammonia and dust. Vet. Rec. 157(3):71-80. Donham, K.J., S.J. Reynolds, P. Whitten, J.A. Merchant, L. Burmeister, and W.J. Popen- dorf. 1995. Respiratory dysfunction in swine production facility workers: Dose- response relationships of environmental exposures and pulmonary function. Am. J. Ind. Med. 27(3):405-418. Donham, K.J., D. Cumro, S.J. Reynolds, and J.A. Merchant. 2000. Dose-response rela- tionships between occupational aerosol exposures and cross-shift declines of lung function in poultry workers: Recommendations for exposure limits. J. Oc- cup. Environ. Med. 42(3):260-269. Duda, G.D., and P. Handler. 1958. Kinetics of ammonia metabolism in vivo. J. Biol. Chem. 232:303-314. EPA (U.S. Environmental Protection Agency). 1991. Ammonia. Integrated Risk Informa- tion System, U.S. Environmental Protection Agency [online]. Available: http:// www.epa.gov/iris/subst/0422.htm [accessed June 7, 2007]. Erskine, R.J., P.J. Murphy, J.A. Langton, and G. Smith. 1992. Upper air reactivity in smokers and non-smokers. Abstract 197 in 10th World Congress of Anesthesi- ologists, The Hague, Netherlands.

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60 Exposure Guidance Levels for Selected Submarine Contaminants Erskine, R.J., P.J. Murphy, J.A. Langton, and G. Smith. 1993. Effect of age on the sensi- tivity of upper airways reflexes. Br. J. Anaesth. 70(5):574-575. Ferguson, W.S., W.C. Koch, L.B. Webster, and J.R. Gould. 1977. Human physiological response and adaptation to ammonia. J. Occup. Med. 19(5):319-326. Fürst, P., B. Josephson, G. Maschio, and E. Vinnars. 1969. Nitrogen balance after intra- venous and oral administration of ammonium salts to man. J. Appl. Physiol. 26(1):13-22. Gaafar, H., R. Girgis, M. Hussein, and F. el-Nemr. 1992. The effect of ammonia on the respiratory nasal mucosa of mice. A histological and histochemical study. Acta Otolaryngol. 112(2):339-342. Gay, W.M.B., C.W. Crane, and W.D. Stone. 1969. The metabolism of ammonia in liver disease: A comparison of urinary data following oral and intravenous loading of [15N] ammonium lactate. Clin. Sci. 37(3):815-823. Guyton, A.C. 1981. Pp. 456-458, 889 in Textbook of Medical Physiology, 6th Ed. Phila- delphia, PA: W.B. Saunders. Hansen, J.B., L. Wilsgard, and B. Osterud. 1991. Biphasic changes in leukocytes induced by strenuous exercise. Eur. J. Appl. Physiol. Occup. Physiol. 62(3):157-161. Hatton, D.V., C.S. Leach, A.L. Beaudet, R.O. Dillman, and N. Di Ferrante. 1979. Colla- gen breakdown and ammonia inhalation. Arch. Environ. Health 34(2):83-87. Hilado, C.J., C.J. Casey, and A. Fürst. 1977. Effect of ammonia on Swiss albino mice. J. Combust. Toxicol. 4:385-388. Hilado, C.J., H.G. Cumming, A.M. Machado, C.J. Casey, and A. Fürst. 1978. Effect of individual gaseous toxicants on mice. Proc. West. Pharmacol. Soc. 21:159-160. Hoeffler, H.B., H.I. Schweppe, and S.D. Greenberg. 1982. Bronchiectasis following pul- monary ammonia burn. Arch. Pathol. Lab. Med. 106(13):686-687. Holness, D.L., J.T. Purdham, and J.R. Nethercott. 1989. Acute and chronic respiratory effects of occupational exposure to ammonia. Am. Ind. Hyg. Assoc. J. 50(12):646-650. HSDB (Hazardous Substances Data Bank). 2005. Ammonia (CASRN 7664-41-7). TOXNET, Specialized Information Services, U.S. National Library of Medi- cine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/ htmlgen?HSDB [accessed March 14, 2007]. IARC (International Agency for Research on Cancer). 1995. Dry Cleaning, Some Chlo- rinated Solvents and Other Industrial Chemicals. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans Vol. 63. Lyon, France: Interna- tional Agency for Research on Cancer, World Health Organization. Ihrig, A., J. Hoffman, and G. Triebig. 2006. Examination of the influence of personal traits and habituation on the reporting of complaints at experimental exposure to ammonia. Int. Arch. Occup. Environ. Health 79(4):332-338. Industrial Bio-Test Labs, Inc. 1973. Irritation Threshold Evaluation Study with Ammo- nia. Industrial Bio-Test Laboratories, Inc. (Report to International Institute of Ammonia Refrigeration, Publication No. 663-03161) (as cited in NRC 2002). Kapeghian, J.C., H.H. Mincer, A.B. Jones, A.J. Verlangieri, and I.W. Waters. 1982. Acute inhalation toxicity of ammonia in mice. Bull. Environ. Contam. Toxicol. 29(3):371-378. Landahl, H.D., and R.G. Herrmann. 1950. Retention of vapors and gases in the human nose and lung. Arch. Ind. Hyg. Occup. Med. 1:36-45. Leduc, D., P. Gris, P. Lheureux, P.A. Gevenois, P. de Vuyst, and J.C. Yernault. 1992. Acute and long term respiratory damage following inhalation of ammonia. Thorax 47(9):755-757.

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61 Ammonia Lewis, R.J., ed. 1993. P. 62 in Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold. MacEwen, J.D., and E.H. Vernot. 1972. Toxic Hazards Research Unit Annual Technical Report: 1972. AMRL-TR-72-62. NTIS AD-755 358. Aerospace Medical Re- search Laboratory, Wright-Patterson Air Force Base, OH. MacEwen, J.D., J. Theodore, and E.H. Vernot. 1970. Human exposure to EEL concentra- tions of monomethylhydrazine. Pp. 355-363 in Proceedings of the 1st Annual Conference Environmental Toxicology, September 9-11, 1970, Wright- Patterson Air Force Base, OH. AMRL-TR-70-102, Paper No 23. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. Manninen, A., S. Anttilla, and H. Savolainen. 1988. Rat metabolic adaptation to ammonia inhalation. Proc. Soc. Exp. Biol. Med. 187(3):278-281. McLean, J.A., K.P. Mathews, W.R. Solomon, P.R. Brayton, and N.K. Baynel. 1979. Effect of ammonia on nasal resistance in atopic and nonatopic subjects. Ann. Otol. Rhinol. Laryngol. 88(2 Pt.1):228-234. Mulder, J.S., and H.O. Van der Zalm. 1967. A fatal case of ammonia poisoning [in Dutch]. Tijdsch. Soc. Geneeskd. 45:458-460 (as cited in NIOSH 1974). Neumann, R., G. Mehlhorn, I. Buchholz, U. Johannsen, and D. Schimmel. 1987. Experi- mental studies of the effect of chronic exposure of suckling pigs with different ammonia concentrations. II. The reaction of cellular and humoral infection de- fense mechanisms of NH3-exposed suckling pigs under the conditions of an experimental Pasteurella multocida infection with and without thermomotor stress [in German]. Zentralbl. Veterinarmed. B. 34(4):241-253. NIOSH (National Institute for Occupational Safety and Health). 1974. Criteria for a Rec- ommended Standard Occupational Exposure to Ammonia. HEW74-136. Na- tional Institute for Occupational Safety and Health, Public Health Service, U.S. Department of Health, Education and Welfare, Cincinnati, OH. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 2005-149. Na- tional Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, Cincinnati, OH [online]. Available: http://www.cdc.gov/niosh/npg/ [accessed June 14, 2007]. Norenberg, M.D. 1981. The astrocyte in liver disease. Pp. 303-352 in Advances in Cellu- lar Neurobiology, Vol. 2, S. Fedoroff,, and L. Hertz, eds. New York, NY: Aca- demic Press. Norenberg, M.D., and A. Martinez-Hernandez. 1979. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res. 161(2):303-310. NRC (National Research Council). 1966. Report on Advisory Center on Toxicology Pro- ject 390. Washington, DC: National Academy of Sciences. 5pp (as cited in NRC 1987). NRC (National Research Council). 1987. Ammonia. Pp. 7-15 in Emergency and Con- tinuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 7. Ammonia, Hydrogen Chloride, Lithium Bromide, and Toluene. Washington, DC: National Academy Press. NRC (National Research Council). 1988. Submarine Air Quality: Monitoring the Air in Submarines; Health Effects in Divers of Breathing Submarine Air Under Hy- perbaric Conditions. Washington, DC: National Academy Press. NRC (National Research Council). 1994. Ammonia. Pp. 39-59 in Spacecraft Maximum

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62 Exposure Guidance Levels for Selected Submarine Contaminants Allowable Concentrations for Selected Airborne Contaminants, Vol. 1. Wash- ington, DC: National Academy Press. NRC (National Research Council). 2002. Ammonia. Pp. 22-68 in Review of Submarine Escape Action Levels for Selected Chemicals. Washington, DC: National Academy Press. NRC (National Research Council). 2007. Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 6. Ammonia (CAS No. 7664-41-7). Washington, DC: The National Academies Press. O’Kane, G.J. 1983. Inhalation of ammonia vapor: A report on the management of eight patients during the acute stages. Anaesthesia 38(12):1208-1213. Pierce, J.O. 1994. Ammonia. Pp. 756-782 in Patty=s Industrial Hygiene and Toxicology, 4th Ed., Vol. II, Pt. A Toxicology, G.D. Clayton, and F.E. Clayton, eds. New York, NY: John Wiley & Sons. Pinson, D.M., T.R. Schoeb, J.R. Lindsey, and J.K. Davis. 1986. Evaluation of scoring and computerized morphometry of lesions of early Mycoplasma pulmonis in- fection and ammonia exposure in F344/N rats. Vet. Pathol. 23(5):550-555. Pitts, R.F. 1971. The role of ammonia production and excretion in regulation of acid-base balance. New Engl. J. Med. 284(1):32-38. Reynolds, S.J., K.J. Donham, P. Whitten, J.A. Merchant, L.F. Burmeister, and W.J. Popendorf. 1996. Longitudinal evaluation of dose-response relationships for environmental exposures and pulmonary function in swine production workers. Am. J. Ind. Med. 29(1):33-40. Richard, D., G. Bouley, and C. Boudene. 1978. Effects of continuous inhalation of am- monia in the rat and mouse [in French]. Bull. Eur. Physiopathol. Respir. 14(5):573-582. Rosenfeld, M. 1932. Experimental modification of mitosis by ammonia [in German]. Arch. Exp. Zellforsch. Besonders. Gewebezvecht. 14:1-13 (as cited in ATSDR 2004). Schaerdel, A.D, W. J. White, C.M. Lang, B.H. Dvorchik, and K. Bohner. 1983. Localized and systemic effects of environmental ammonia in rats. Lab. Anim. Sci. 33(1):40-45. Shimkin, M.B., A.A. de Lormier, J.R. Mitchell, and T.P. Burroughs. 1954. Appearance of carcinoma following single exposure to a refrigeration ammonia-oil mixture. Arch. Ind. Hyg. Occup. 9(3):186-193. Silver, S.D., and F.P. McGrath. 1948. A comparison of acute toxicities of ethylene imine and ammonia to mice. J. Ind. Hyg. Toxicol. 30(1):7-9. Silverman, L., J.L. Whittenberger, and J. Muller. 1949. Physiological response of man to ammonia in low concentrations. J. Ind. Hyg. Toxicol. 31(2):74-78. Slot, G.M. 1938. Ammonia gas burns: An account of six cases. Lancet 2(Dec.):1356- 1357. Sobonya, R. 1977. Fatal anhydrous ammonia inhalation. Hum. Pathol. 8(3):293-299. Sundblad, B.M., B.M. Larsson, F. Acevedo, L. Ernstgard, G. Johanson, K. Larsson, and L. Palmberg. 2004. Acute respiratory effects of exposure to ammonia on healthy persons. Scand. J. Work Environ. Health 30(4):313-321. Swotinsky, R.B., and K.H. Chase. 1990. Health effects of exposure to ammonia: Scant information. Am. J. Ind. Med. 17(4): 515-521. Targowski, S.P., W. Klucinski, S. Babiker, and B.J. Nonnecke. 1984. Effect of ammonia on in vivo and in vitro immune responses. Infect. Immun. 43(1):289-293.

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63 Ammonia ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309. Tepper, J.S., B. Weiss, and R.W. Wood. 1985. Alterations in behavior produced by in- haled ozone or ammonia. Fundam. Appl. Toxicol. 5(6 Pt.1):1110-1118. Uzvölgyi, E., and F. Bojan. 1980. Possible in vivo formation of a carcinogenic substance from diethyl pryocarbonate and ammonia. J. Cancer Res. Clin. Oncol. 97(2):205-207. Verberk, M.M. 1977. Effects of ammonia on volunteers. Int. Arch. Occup. Environ. Health. 39(2):73-81. Visek, W.J. 1972. Effects of urea hydrolysis on cell life-span and metabolism. Fed. Proc. 31(3):1178-1193. Walton, M. 1973. Industrial ammonia gassing. Br. J. Ind. Med. 30(1):78-86. Wands, R.C. 1981. Alkaline materials. Pp. 3045-3070 in Patty’s Industrial Hygiene and Toxicology, Vol. 2B, Toxicology, G.D. Clayton, and F.E. Clayton, eds, 3rd Rev. Ed. New York, NY: John Wiley and Sons. White, A., P. Handler, E.L. Smith, R.L. Hill, and I.R. Lehman. 1978. Amino acid me- tabolism. II. Pp. 695-700 in Principles of Biochemistry. New York, NY: McGraw-Hill. WHO (World Health Organization). 1986. Ammonia. Environmental Health Criteria 54. IPCS International Programme on Chemical Safety. Geneva: World Health Or- ganization. Wong, K.L. 1994. Ammonia. Pp. 39-59 in Spacecraft Maximum Allowable Concentra- tions for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press. Yadav, J.S., and V.K. Kaushik. 1997. Genotoxic effect of ammonia exposure on workers in a fertilizer factory. Indian J. Exp. Biol. 35(5):487-492. Zissu, D. 1995. Histopathological changes in the respiratory tract of mice exposed to ten families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213. Zimber, A., and W.J. Visek. 1972. Effect of urease injections on Ehrlich ascites tumor growth in mice. Proc. Soc. Exp. Biol. Med. 139(1):143-149.