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2
Ammonia1
Acute Exposure Guideline Levels
PREFACE
Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicological and other scientific data and develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals.
AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could
1
This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory) and Susan Ripple (Chemical Manager and National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances member). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001).
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experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
Ammonia is a colorless, corrosive, alkaline gas that has a very pungent odor. The odor detection level ranges from 5 to 53 ppm. Ammonia is used as a compressed gas and in aqueous solutions. It is also used in household cleaning products, in fertilizers, and as a refrigerant. Exposure to ammonia occurs as a result of accidents during highway and railway transportation, accidental releases at manufacturing facilities, and farming accidents.
Ammonia is very soluble in water. Because of its exothermic properties, ammonia forms ammonium hydroxide and produces heat when it contacts moist surfaces, such as mucous membranes. The corrosive and exothermic properties of ammonia can result in immediate damage (severe irritation and burns) to the eyes, skin, and mucous membranes of the oral cavity and respiratory tract. In addition, ammonia is effectively scrubbed in the nasopharyngeal region of the respiratory tract because of its high solubility in water.
The database for ammonia consisted primarily of case reports, human studies, and experimental studies on lethality and irritation in animals. The case reports were of limited use for quantitative evaluation, but the human and animal studies contained quantitative data useful for deriving AEGL values.
No reliable quantitative exposure data were available for humans dying as a result of accidental exposure to ammonia. One case report noted the death of
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an individual exposed to a high unknown concentration of ammonia. Other case reports also contained no exposure estimates but showed that high concentrations of ammonia caused severe damage to the respiratory tract, particularly in the tracheobronchial and pulmonary regions. Death was most likely to occur when damage caused pulmonary edema. Nonlethal, irreversible, or long-term effects occurred when damage progressed to the tracheobronchial region, manifested by reduced performance on pulmonary function tests, bronchitis, bronchiolitis, emphysema, and bronchiectasis. Nondisabling reversible effects were manifested by irritation to the eyes, throat, and nasopharyngeal region of the respiratory tract. The odor of ammonia can be detected by humans at concentrations >5 ppm; the odor is highly penetrating at 50 ppm (10 min). Human volunteers exposed to ammonia showed slight irritation at 30 ppm (10 min); moderate irritation to the eyes, nose, throat, and chest at 50 ppm (10 min to 2 h); moderate to highly intense irritation at 80 ppm (30 min to 2 h); highly intense irritation at 110 ppm (30 min to 2 h); unbearable irritation at 140 ppm (30 min to 2 h), and excessive lacrimation and irritation at 500 ppm. Reflex glottis closure, a protective response to inhaling irritant vapors, occurred at 570 ppm for 21- to 30-year-old subjects, 1,000 ppm for 60-year-old subjects, and 1,790 ppm for 86- to 90-year-old subjects.
Acute lethality studies in animals showed that the lethal concentration in 50% (LC50) of the rats ranged from 40,300 ppm for a 10-min exposure to 7,338 and 16,600 ppm for 60-min exposures. For the mouse, LC50 values were 21,430 ppm for a 30-min exposure (almost all animals died in less than 13 min), 10,096 ppm for a 10-min exposure, and 4,230 and 4,837 ppm for 60-min exposures. Comparative data for the same exposure duration show that mice were more sensitive than rats to the acute exposure to ammonia (10-min LC50 values for mice and rats are 10,096 and 40,300 ppm, respectively). The lowest lethal concentration was 1,000 ppm for a cat exposed via an endotracheal tube, which probably exacerbated the effects in the tracheobronchial region (bronchopneumonia, bronchitis, bronchiolitis, and emphysema) by bypassing the scrubbing action of the nasopharyngeal region. Rats exposed by inhalation to lethal concentrations of ammonia showed signs of dyspnea, irritation to the eyes and nose, and hemorrhage in the lungs. Mice exposed to lethal concentrations of ammonia showed signs of irritation to the eyes and nose, along with tremors, ataxia, convulsions, seizures, and pathological lesions in the alveoli. Effects at nonlethal concentrations in mice and rats consisted of mild effects on the respiratory epithelium of the nasal cavity (mice and rats), reduction in the respiratory rate (mice), and evidence of eye irritation (rat). The RD50 (concentration causing a 50% reduction in respiratory rate) for the mouse was 300 ppm for a 30-min exposure.
The AEGL-1 value was based on a study in which 2/6 human subjects experienced faint irritation after exposure to ammonia at 30 ppm for 10 min (MacEwen et al. 1970). An interspecies uncertainty factor is not applied because human data are used to derive the AEGL-1. An intraspecies uncertainty factor of 1 was applied because ammonia is a contact irritant and is efficiently scrubbed
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in the upper respiratory tract, particularly at the low AEGL-1 concentration. Irritation would be confined to the upper respiratory tract, and members of the population are not expected to respond differently. Atopic subjects, including asthmatics, responded similarly to nonatopics to brief nasal exposure to ammonia, and exercising subjects experienced only nonsignificant clinical changes in pulmonary function after exposure to ammonia. Asthmatic and exercising individuals are not expected to respond differently from nonasthmatic or resting individuals. Time scaling is not applied because upper respiratory tract irritation at low ammonia concentrations is not expected to become more severe with duration of exposure; adaptation may occur during prolonged exposure to ammonia. Therefore, the AEGL-1 value is 30 ppm for all exposure durations.
The AEGL-2 values were based on “offensive irritation” to the eyes and respiratory tract experienced by nonexpert human subjects (unfamiliar with the effects of ammonia or with laboratory studies) exposed to 110 ppm of ammonia for 2 h (Verberk 1977). The response of the nonexpert subjects ranged from “no sensation” to “offensive” eye irritation, cough, or discomfort and from “just perceptible” or “distinctly perceptible” to “offensive” throat irritation. However, AEGL-2 derivation was based on the response of the most sensitive nonexpert subjects. No residual effects were reported after termination of exposure, and pulmonary function was not affected by exposure. At the next higher concentration, some subjects reported the effects as unbearable and left the chamber after 30 min to 1 h; none remained for the full 2 h. An intraspecies uncertainty factor of 1 was selected because ammonia is a contact irritant, it is efficiently scrubbed in the upper respiratory tract, and any perceived irritation is not expected to be greater than that of the most sensitive nonexpert subject. The range of responses for this group is considered comparable to the range of responses that would be encountered in the general population, including asthmatics. Investigations have shown a link between nasal symptoms or allergic rhinitis and asthma, with rhinitis preceding the development of asthma, and studies have shown that atopic subjects, including asthmatics, and nonatopic subjects do not respond differently to a brief nasal exposure to ammonia. Exposure to exercising subjects showed only nonsignificant clinical changes in pulmonary function during exposure to ammonia at concentrations up to 336 ppm. In addition, a child experienced less severe effects than an adult exposed to very high concentrations of ammonia. The equation Cn × t = k, where n = 2, was used to extrapolate to 5-, 10-, and 30-min exposure durations. This equation was based on mouse and rat lethality data. The AEGL-2 values are 220, 220, 160, 110, and 110 ppm for exposure durations of 10 and 30 min and 1, 4, and 8 h, respectively. The value of 110 ppm was adopted for the 4- and 8-h values, because the maximum severity rating for irritation in the Verberk (1977) study changed very little between 30 min and 2 h and is not expected to change for exposures up to 8 h. The 30-min value was also adopted as the 10-min AEGL-2 value because time scaling would yield a 10-min AEGL-2 of 380 ppm, which might impair escape.
The AEGL-3 values were based on LC01 values of 3,317 and 3,374 ppm derived by probit analysis of mouse lethality data reported by Kapeghian et al.
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(1982) and MacEwen and Vernot (1972), respectively. An interspecies uncertainty factor of 1 was applied to the mouse data because the mouse was the most sensitive species among mammals and the mouse is considered unusually sensitive to respiratory irritants. An uncertainty factor of 3 was applied to account for intraspecies variability because concentrations of ammonia that are life threatening cause severe tracheobronchial and pulmonary damage and these effects are not expected to be more severe in asthmatics than in nonasthmatics, in children than adults, or in exercising than nonexercising individuals (see rationale for AEGL-2), but tracheobronchial and pulmonary effects may occur at a lower concentration in the elderly. Investigations showed that reflex glottis closure (protective mechanism) is 3-fold less sensitive in the elderly than in young subjects; this mechanism may be applicable only when concentrations of ammonia exceed 570 ppm. In addition, a larger interspecies or intraspecies uncertainty factor would lower the 30-min AEGL-3 to approximately 500 ppm, which was tolerated by humans without lethal or long-term consequences. ten Berge’s equation (Cn × t = k) was used to extrapolate to the relevant exposure durations. The value of n was calculated from the regression coefficients (b1/b2) for the mouse lethality data reported by ten Berge et al. (1986). The 5-min AEGL value was requested by the ammonia industry. The AEGL values and toxicity end points are summarized in Table 2-1.
1.
INTRODUCTION
Ammonia is a colorless, corrosive, alkaline gas that has a very pungent odor, detectable by humans at concentrations >5 ppm. It can be liquefied under pressure. Ammonia is very soluble in water; it forms ammonium hydroxide when it contacts moist surfaces, producing heat because of its exothermic prop-
TABLE 2-1 Summary of AEGL Values for Ammonia
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (nondisabling)
30 ppm
(21 mg/m3)
30 ppm
(21 mg/m3)
30 ppm
(21 mg/m3)
30 ppm
(21 mg/m3)
30 ppm
(21 mg/m3)
Mild irritation (MacEwen et al. 1970)
AEGL-2 (disabling)
220 ppm
(154 mg/m3)
220 ppm
(154 mg/m3)
160 ppm
(112 mg/m3)
110 ppm
(77 mg/m3
110 ppm
(77 mg/m3)
Irritation: eyes and throat; urge to cough (Verberk 1977)
AEGL-3 (lethal)
2,700 ppm
(1,888 mg/m3)
1,600 ppm
(1,119 mg/m3)
1,100 ppm
(769 mg/m3)
550 ppm
(385 mg/m3)
390 ppm
(273 mg/m3)
Lethality (Kapeghian et al. 1982; MacEwen and Vernot 1972)
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erty. Ammonia and air will explode when ignited under some conditions (not otherwise described). Although it is generally regarded as nonflammable, ammonia is classified as a flammable gas by the National Fire Protection Association (Budavari et al. 1989; Lewis 1993; Pierce 1994). Table 2-2 summarizes the physical and chemical properties of ammonia.
TABLE 2-2 Physical and Chemical Data
Property
Descriptor or Value
Reference
Chemical name
Ammonia
Synonyms
Anhydrous ammonia, ammonia gas, AM-Fol, nitro-sil, R 717, spirit of hartshorn, UN1005 (DOT)
CAS registry no.
7664-41-7
Chemical formula
NH3
Weast et al 1984
Molecular weight
17.03
Weast et al 1984
Physical state
colorless gas (or liquid)
Lewis 1993
Vapor pressure
8.5 atm at 20°C
Lewis 1993
Density (liquid)
0.6818 at 33.35°C, 1 atm
0.6585 at 15°C, 2.332 atm
0.6386 at 0°C, 4.238 atm
0.6175 at 15°C, 7.188 atm
0.5875 at 35°C, 13.321 atm
O’Neil et al. 2001
Specific volume
22.7 ft3/lb at 70°C
Lewis 1993
Critical temperature
132.9°C
Pierce 1994
Pressure at critical temperature
111.5 atm
Pierce 1994
Solubility
89.9 g/100 mL cold water
Weast et al. 1984
Boiling/freezing point
−33.5°C/−77°C
Lewis 1993
Autoignition temperature
650°C (1,204°F)
Lewis 1993
Explosive limit
16-25% by volume in air
Pierce 1994
Ionization constants
Kb 1.774 × 10−5
Ka 5.637 × 10−10 at 25°C
Pierce 1994
Alkalinity
1% solution, pH = 11.7
Pierce 1994
Conversion
1 ppm = 0.7 mg/m3 at 25°C, 1 atm
1 mg/m3 = 1.43 ppm
Pierce 1994
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Ammonia is produced commercially by a modified Haber reduction process using atmospheric nitrogen and a hydrogen source. Ammonia is used as a compressed gas, as an aqueous solution (28%) called aquammonia, and as a household cleaning product (10%). It is widely used as a fertilizer, where the anhydrous gas or aqueous solution is injected directly into the soil. Ammonia is also used as a refrigerant in commercial installations, and it is used in the manufacture of other chemicals (Pierce 1994).
Ammonia is transported on highways (in tanker trucks), by railways, in pipelines, and on barges. Exposure to the general public can occur from accidents during transportation on highways and railways, during transfer between transportation vessels and storage vessels, by accidental releases at manufacturing facilities, and from farming accidents during soil application.
The data evaluated for AEGL derivation were obtained from case studies of accident victims exposed to high concentrations of ammonia, experimental studies in humans exposed to lower but irritating concentrations of ammonia, and experimental studies on lethality and irritation in animals. Additional data are available on long-term exposure to ammonia in the agricultural industry (feeding lots and poultry houses) but are not considered relevant for deriving acute exposure values for ammonia.
2.
HUMAN TOXICITY DATA
2.1.
Human Lethality
Quantitative exposure estimates of acute lethality of ammonia in humans are not well documented. In one case study the exposure concentration was estimated, but the duration was not. Another study reconstructs the exposure due to an accidental spill resulting in deaths. The remaining studies document the types of effects encountered when humans are acutely exposed to lethal concentrations of ammonia.
A worker was exposed to a very high concentration of ammonia vapor, estimated as 10,000 ppm. Duration of exposure was not reported, but it could have been a few minutes; nevertheless, the worker continued to perform his duties for an additional 3 h after the exposure. He experienced coughing, dyspnea, and vomiting soon after exposure. Three hours after initial exposure, his face was “red and swollen,” his mouth and throat were “red and raw,” his tongue was swollen, his speech was difficult, and he had conjunctivitis. 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).
Caplin (1941) reported on 47 persons accidentally exposed to ammonia in an enclosed area (air raid shelter). The patients were divided into three groups depending on the degree to which they were affected: mildly, moderately, or severely. No deaths occurred among the nine mildly affected patients. Three of
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27 moderately affected patients showed signs and symptoms similar to pulmonary edema and died within 36 h. Nine moderately affected patients developed bronchopneumonia within 2-3 days, and three died 2 days after the onset. The mortality rate for the moderately affected patients was 22% (6/27). The 11 severely affected patients developed pulmonary edema; seven died within 48 h. The mortality rate for the severely affected patients was 63% (7/11). Walton (1973) reported on the death of one of seven workers exposed to ammonia in an industrial accident. The autopsy report noted marked laryngeal edema, acute congestion, pulmonary edema, and denudation of the bronchial epithelium. These studies show that individuals who develop pulmonary edema (evidence of damage to alveolar region) after inhaling ammonia are more likely to die than those who do not.
Individuals who are acutely exposed to high concentrations of ammonia and survive the immediate effects may die weeks to months later, probably due to secondary effects of exposure. A 25-year-old man died 60 days after exposure to a high concentration of ammonia in a farming accident (Sobonya 1977). The autopsy report noted damage to the bronchial epithelium, bronchiectasis, mucus 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 accident died immediately. Hoeffler et al. (1982) reported on the 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 (Houston accident). Her injuries resulted in severe immediate respiratory effects, including pulmonary edema. She required mechanically assisted respiration throughout her remaining life. Bronchiectasis was detected 2 years after exposure and confirmed on autopsy. The autopsy examination also showed bronchopneumonia and cor pulmonale (heart disease secondary to pulmonary disease). According to the authors, the bronchiectasis may have been due to bacterial bronchitis or to the chemical injury.
In the Houston accident, the crash of a tanker truck released 17.2 tonnes of pressurized anhydrous ammonia. The chemical cloud extended 1,500 m downwind and was 550 m wide. Five people were killed, 178 were injured, some with permanent disabling injuries (not otherwise described). The fatalities and disabling injuries occurred within about 70 m of the accident (NTSB 1979). The Potchefstroom, South Africa accident involved a pressurized ammonia storage tank that failed and instantaneously released 38 tonnes of anhydrous ammonia into the atmosphere. Eighteen people died and an unknown number were injured (Lonsdale 1975). A visible cloud extended about 300 m wide and about 450 m downwind; all deaths occurred within 200 m of the release point (Pedersen and Selig 1989). Pedersen and Selig used the WHAZAN gas dispersion model, which incorporated meteorological data and physicochemical data for ammonia to predict the concentration isopleths for ammonia released during both the Houston and Potchefstroom accidents. For the Houston accident, a 10,000-ppm isopleth extended 600 m long and 350 m wide, the 5,000-ppm isopleth was
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835 m long and 430 m wide, the 2,500-ppm isopleth was 875 m long and 420 m wide, and the 1,200-ppm isopleth was to 1,130 m long and 400 m wide. The investigators reported that their model overestimated the distance to zero deaths (200m) by 2.9 times for the Houston accident and by 2.5 times for the Potchefstroom accident. Pederson and Selig estimated the risk due to a few minutes, exposure to ammonia as very high for the general population at 10,000 ppm, as high for risk of fatalities among the general population and as very high for the vulnerable population (elderly people, children, and people with respiratory or heart disorders) at 5,000 ppm, and as some risk to the general population and high risk to the vulnerable population at 2,500 ppm.
Pedersen and Selig estimated the LC50 for a 30-min exposure to the general population to be 11,500 ppm. They did not report their actual LC50 estimate for the vulnerable population, but it would be lower than that estimated for the general population.
Mudan and Mitchell (1996) used the HGSYSTEM gas dispersion model to estimate atmospheric ammonia concentrations generated at the time of the ammonia accident in Potchefstroom. They provided upper-bound (wind speed = 1 m/s) and lower-bound (wind speed = 2 m/s) estimates of ammonia concentration based on distance from the release point and the time after release. Instantaneous concentrations were estimated to be in excess of 500,000 ppm (upper bound) within 50 m of the release point. The model predicted rapidly decreasing concentrations, such that, by 1 min after the release, concentrations would fall below 100,000 ppm. Mudan and Mitchell estimated that personnel were exposed to ammonia concentrations exceeding 50,000 ppm for the first 2 min, decreasing to 10,000 ppm during the next 3-4 min. The charts provided by Mudan and Mitchell of the South Africa accident showed that 10 workers were in Zone 1 (50 m of the release point) at the time of release; seven died (100% mortality for workers exposed outside). All survivors in Zone 1 remained sheltered inside buildings and therefore would not have experienced the outside atmospheric ammonia concentrations predicted by the model. Five deaths occurred in Zone 2 (50-100 m). Workers in Zone 2 who were upwind and outside at the time of the release survived, as did those who escaped in an upwind direction. Workers in Zone 2 who were downwind and outside at the time of release or attempted to escape downwind did not survive (except for one worker who escaped downwind; 83% mortality of workers exposed). All Zone 2 victims who died were outside; whereas individuals who were inside buildings survived. Five deaths occurred in Zone 3 (100 to ~200 m). Four victims were found downwind and >150 m from the release point, and another victim was found <150 m from the release point and in a crosswind location. The charts did not show the location or number of any survivors downwind and inside or outside buildings in Zone 3 (i.e., no data were available from the charts to determine if there were individuals who remained outside buildings in Zone 3 and survived). Therefore, the mortality rate cannot be calculated for Zone 3. It appears that within 150 m of the release point, individuals downwind of the ammonia cloud and outside a building were not likely to survive, but individuals downwind and sheltered indoors
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or those upwind whether or not they were sheltered indoors were likely to survive. Thus, the lack of data on survivors in the path of the plume precludes estimating ammonia concentrations associated with zero mortality. RAM TRAC (1996) used the results of the HGSYSTEM gas dispersion model to predict 5-min ammonia concentrations of 87,479 ppm for 60% mortality, 73,347 ppm for 26% mortality, and 33,737 ppm for zero mortality for the Potchefstroom accident. RAM TRAC estimated a 5-min LC50 of 83,322 ppm. See Section 7.1 for details of the evaluation of dose reconstruction models.
Henderson and Haggard (1943) reported that, exposure to ammonia at concentrations >2,500 ppm for durations ≥30 min is dangerous to humans. They noted that concentrations ≥5,000 ppm are rapidly fatal to humans.
2.2.
Nonlethal Toxicity
2.2.1.
Experimental Studies, Case Reports, and Anecdotal Data
The available literature detailing the disabling, long-term, or irreversible effects of inhaling ammonia gas or vapor is quite extensive. However, none of the studies contain quantitative exposure data. The acute effects of inhaling high nonlethal concentrations of ammonia include burns to the eyes and oral cavity and damage to the nasopharyngeal and tracheobronchial regions of the respiratory tract. Manifestations of damage include conjunctivitis, corneal burns, visual impairment, pain in the pharynx and chest, cough, dyspnea, hoarseness, aphonia, rales, wheezing, rhonchi, hyperemia and edema of the pharynx and larynx, tracheitis, bronchiolitis, and purulent bronchial secretions (Levy et al. 1964; Walton, 1973; Hatton et al. 1979; Montague and Macneil 1980; Flury et al. 1983; O’Kane 1983). Cyanosis, tachycardia, convulsions, and abnormal electroencephalograms also have been described for some patients (Kass et al. 1972; Walton 1973; Hatton et al. 1979; Montague and Macneil 1980). Pulmonary edema occurred in some patients who survived (Caplin 1941) but is most often seen in fatal cases. A few case studies are described below to document some of the disabling or irreversible injuries seen in individuals who inhaled high concentrations of ammonia. Some of the injuries would probably have resulted in death without rescue and medical treatment. The duration of exposure is reported when known.
Short-term recovery from serious injury due to inhaling ammonia is exhibited by three children and a 17-year-old female exposed to high but unknown concentrations of ammonia in the Houston accident (Hatton et al. 1979). These patients suffered second- or third-degree burns to the body, damage to the eyes, burns to the oral mucosa, upper-airway obstruction (probably due to damage to the laryngeal and tracheobronchial regions), and some pulmonary damage. All four patients recovered within 7-32 days. Nine of 14 patients exposed to an unknown concentration ammonia by inhalation for only a few seconds or few min-
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utes showed moderate symptoms of chest abnormalities or airway obstruction and recovered within 6.3 days (average) (Montague and Macneil 1980).
Two young women accidentally exposed to anhydrous ammonia fumes (concentration unknown) for 30 or 90 min continued to show effects more than 2 years after exposure (Kass et al. 1972). One woman was found unconscious 90 min after the accident, and the other woman was exposed when she went outdoors for 30 min after the accident. The accident in which these two women were injured involved a railroad tanker car carrying 33,000 gal of anhydrous ammonia; 8 people died and 70 were injured. A heavy fog kept the ammonia vapors close to the ground for a long period of time after the accident. Damage to the eyes caused marked visual deterioration. Bronchiectasis was detected 2 years after exposure, and pulmonary function tests showed abnormalities indicative of small-airway obstruction. Various tests and examinations showed areas of atelectasis and emphysema in the lungs, thickened alveolar walls with histiocytic infiltration into the alveolar spaces, and mucous and desquamated cells in the bronchiolar lumen. Some of these effects may be secondary to the damage caused by ammonia. The woman exposed for 90 min was carrying her 1-year-old child, who was exposed at the same time. The child became “quite ill” but recovered completely except for a chemical scar on his abdomen (Kass et al. 1972).
In another accident, four patients (three farm workers and one refrigeration technician) who had been struck in the face and upper body with liquid ammonia had damage to their tracheobronchial regions, causing upper-airway obstruction and injury to the respiratory tract persisting for 2 years after the accident (Levy et al. 1964). A man splashed with liquid ammonia during a refrigeration accident showed evidence of peripheral (possibly bronchiolitis) and central airway obstruction 5 years after the accident (Flury et al. 1983). Tubular bronchiectasis was detected 8 years after exposure of a 28-year-old man to a high concentration of anhydrous ammonia in an industrial accident. Twelve years after exposure, the man continued to have a productive cough, frequent bronchial infections, dyspnea upon exertion, and severe airflow obstruction (62% reduction in forced expiratory volume at 1 s, FEV1; Leduc et al. 1992). O’Kane (1983) described several patients who had been exposed to ammonia vapor by inhalation for 5 min. One developed necrotizing pneumonia and was “left with chronic infective lung disease”, one had persistent hoarseness and a productive cough for several months, and a third was left with a diffusion defect that was 75% of normal. Finally, Shimkin et al. (1954) described a man who developed epidermoid carcinoma 6 months after ammonia was splashed on his upper lip and nose. The authors postulated that the carcinoma was due to a single-exposure chemical trauma that exteriorized a latent cutaneous carcinoma. There was no evidence that ammonia caused the carcinoma.
Nondisabling and reversible effects of inhaling ammonia have been documented in several experimental studies of human subjects exposed to ammonia at various concentrations and durations. These studies are summarized below.
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Hoeffler, H.B., H.I. Schweppe, and S.D. Greenberg. 1982. Bronchiectasis following pulmonary ammonia burn. Arch. Pathol. Lab. Med. 106(13):686-687.
Holness, D.L., J.T. Purdham, and J.R. Nethercott. 1989. Acute and chronic respiratory effects of occupational exposure to ammonia. Am. Ind. Hyg. Assoc. J. 50(12):646-650.
Industrial Bio-Test Laboratories, Inc. 1973. Irritation Threshold Evaluation Study with Ammonia. Publication IBT 663-03161. Report to International Institute of Ammonia Refrigeration by Industrial Bio-Test Laboratories, Inc. March 23, 1973 (as cited in NIOSH 1974).
Kapeghian, J.C., H.H. Mincer, and 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.
Kapeghian, J.C., A.B. Jones, and I.W. Waters. 1985. Effects of ammonia on selected hepatic microsomal enzyme activity in mice. Bull. Environ. Contam. Toxicol. 35(1):15-22.
Kass, I., N. Zamel, C.A. Dobry, and Holzer. 1972. Bronchiectasis following ammonia burns of the respiratory tract: A review of two cases. Chest 62(3):282-285.
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(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.
Legters, L. 1980. Biological Effects of Short High-Level Exposure to Gases: Ammonia. Phase Report, May 1979-May 1980. DAMD 17-79-C-9086. AD A094501. Prepared for U.S. Army Medical Research and Development Command, Fort Detrick, Frederick, MD, by Environ Control, Inc, Rockville, MD.
Levy, D.M., M.B. Divertie, T.J. Litzow, and J.W. Henderson. 1964. Ammonia burns of the face and respiratory tract. J. Am. Med. Assoc. 190:873-876.
Lewis, R.J., Sr., ed. 1993. Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold. .
Lonsdale, H. 1975. Ammonia Tank Failure-South Africa. American Institute of Chemical Engineers, Ammonia Plant Safety 17:126-131 (as cited by RAM TRAC 1996).
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 Research Laboratory, Wright-Patterson Air Force Base, OH.
MacEwen, J.D., J. Theodore, and E.H. Vernot. 1970. Human exposure to EEL concentrations of monomethylhydrazine. Pp. 355-363 in Proceedings of the 1st Annual Conference 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.
Mahlum, D.D., and L.B. Sasser. 1991. Evaluation of Exposure Limits to Toxic Gases for Nuclear Reactor Control Room Operators. NUREG/CR-5669. PNL -7522. Prepared by Pacific Northwest Laboratory, Richland, WA, for the Nuclear Regulatory Commission, Office of Nuclear Regulatory Research, Division of Safety Issue Resolution, Washington, DC.
Manninen, A., S. Anttila, and H. Savolainen. 1988. Rat metabolic adaptation to ammonia inhalation. Proc. Soc. Exp. Biol. Med. 187(3):278-281.
Markham, R.S. 1986. A Review of Damage from Ammonia Spills. Paper presented at the 1986 Ammonia Symposium, Safety in Ammonia Plants and Related Facilities,
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American Institute of Chemical Engineers Boston, MA, August 1986 (as cited in Pedersen and Selig 1989).
Mayan, M.H., and C.P. Merilan. 1972. Effects of ammonia inhalation on respiration rate of rabbits. J. Anim. Sci. 34(3):448-452.
Mayan, M.H., and C.P. Merilan. 1976. Effects of ammonia inhalation on young cattle. N.Z. Vet. J. 24(10):221-224.
Mazzola, C. 1996. Inherent Uncertainties in Dose Reconstructions Using Dispersion Models. Presented to the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances, December 16, 1996, Washington, D.C.
Mazzola, C. 1997. Potchefstroom Dose Reconstruction: Inherent Uncertainties that Significantly Limit Effective Application to Human Health Standards Process. Prepared for the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL), by Stone & Webster Engineering Corporation. May, 1997.
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.
Michaels, R.A. 1998. Emergency planning: Critical evaluation of proposed AEGLs for ammonia. Process Saf. Prog. 17(2): 134-137.
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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).
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O’Kane, G.J. 1983. Inhalation of ammonia vapor: A report on the management of eight patients during the acute stages. Anesthesia 38(12):1208-1213.
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Weatherby, J.H. 1952. Chronic toxicity of ammonia fumes by inhalation. Proc. Soc. Exp. Biol. Med. 81(1):300-301.
Wong, K.L. 1994. Ammonia. Pp. 39-59 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 1. Washington, DC: National Academy Press.
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APPENDIX A
Derivation of AEGL-1 Values
Key study:
MacEwen et al. 1970
Toxicity end point:
Faint or irritation (humans)
Time scaling:
None
Uncertainty factors:
Interspecies: NA
Intraspecies: 1
Calculations:
10-min: AEGL-1:
30 ppm/UF = 30 ppm/L = 30 ppm
30-min, 1-, 4-, and 8-h:
AEGL-1: Same as AEGL-1: 30 ppm
Derivation of AEGL-2 Values
Key study:
Verberk 1977
Toxicity end point:
Irritation: eyes and upper respiratory tract in humans
Time scaling:
Cn × t = k; n = 2 (ten Berge et al. 1986)
Uncertainty factors:
1 for intraspecies variability; not applicable for interspecies sensitivity
Calculations:
Point of departure:
110 ppm for 2 h
10-min AEGL:
Same as the 30-min value = 220 ppm
30-min AEGL-2:
Cn × t = k; C = 110 ppm, t = 120 min, n = 2
C = (k/t)1/2 = (1.45 × 106 ppm•min/30 min)1/2
C = 220 ppm
1-h AEGL-2:
C = (k/t)1/2 = (1.45 × 106 ppm•min/30 min)1/2
C = 160 ppm
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4-h AEGL-2:
C = 110 ppm, same as the POD
8-h AEGL-2:
C = 110 ppm, same as the POD
Derivation of AEGL-3 Values
Key study:
Kapeghian et al. 1982; MacEwen and Vernot 1972
Toxicity end point:
Lethality: the LC50 for the two sets of mouse data were extrapolated to an LC01
Time scaling:
Cn × t = k; n = 2 (ten Berge et al. 1986)
Uncertainty factors:
Three for intraspecies variability; one for interspecies sensitivity
Calculations:
1-h AEGL-3:
C = 3,317 ppm/3 (uncertainty factor) = 1,106 ppm
C = 3,374 ppm/3 (uncertainty factor) = 1,125 ppm
Kapeghian et al. 1982
Cn × t = k; C = 1,106 ppm, t = 60 min, n = 2, k = 7.335 107 ppm•min
C = (k/t)1/2 = (7.335 × 107 ppm•min/60 min)1/2
C = 1,106 ppm = 1,100 ppm
MacEwen and Vernot 1972
Cn × t = k; C = 1,125 ppm, t = 60 min, n = 2, k = 7.59 × 107 ppm•min
C = (k/t)1/2 = (7.59 × 107 ppm•min/60 min)1/2
C = 1,125 ppm = 1,100 ppm
10-min AEGL -3:
C = (k/t)1/2 = (7.335 × 107 ppm•min/10 min)1/2
C = 2,708 ppm = 2,700 ppm
C = (k/t)1/2 = (7.59 × 107 ppm•min/10 min)1/2
C = 2,755 ppm = 2,700 ppm
30-min AEGL-3:
C = (k/t)1/2 = (7.335 × 107 ppm•min/30 min)1/2
C = 1,564 ppm = 1,600 ppm
C = (k/t)1/2 = (7.59 × 107 ppm•min/30 min)1/2
C = 1,591 ppm = 1,600 ppm
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4-h AEGL-3:
C = (k/t)1/2 = (7.335 × 107 ppm•min/240 min)1/2
C = 553 ppm = 550 ppm
C = (k/t)1/2 = (7.59 × 107 ppm•min/240 min)1/2
C = 562 ppm = 560 ppm
8-h AEGL-3:
C = (k/t)1/2 = (7.335 × 107 ppm•min/480 min)1/2
C = 391 ppm = 390 ppm
C = (k/t)1/2 = (7.59 × 107 ppm•min/480 min)1/2
C = 398 ppm = 400 ppm
APPENDIX B
Acute Exposure Guideline Levels for Ammonia
Derivation Summary for Ammonia AEGLS
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
30 ppm
30 ppm
30 ppm
30 ppm
30 ppm
Reference: MacEwen, J.D.; J. Theodore, and E. H. Vernot. 1970. Human exposure to EEL concentrations of monomethylhydrazine, AMRL-TR-70-102, Paper No. 23. In: Proc. 1st Ann. Conf. Environ. Toxicol., September 9-11, 1970, Wright-Patterson AFB, OH. Pp. 355-363.
Test species/Strain/Sex/Number: Humans.
Exposure route/Concentrations/Durations: Inhalation.
Effects: 30 ppm for 10 min: 2/6 subjects reported faint irritation; 3/6 reported no irritation; 1/6 provided no response.
End point/Concentration/Rationale: Faint irritation in human subjects exposed to 30 ppm of ammonia for 10 min. The responses by all subjects exposed to 30 ppm of ammonia were consistent with the definition of AEGL-1 or below the definition of AEGL-1.
Uncertainty factors/Rationale:
Total uncertainty factor: 1.
Interspecies: Not applicable.
Intraspecies: 1; Ammonia is a contact irritant and is efficiently scrubbed in the upper respiratory tract, particularly at the low AEGL-1 concentration; therefore, members of the population are not expected to respond differently to effects confined to the upper respiratory tract. Atopics, including asthmatics, and nonatopics responded similarly to a brief nasal exposure to ammonia. Exercising subjects showed only a clinically nonsignificant decrease in pulmonary function after exposure to ammonia.
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10 min
30 min
1 h
4 h
8 h
30 ppm
30 ppm
30 ppm
30 ppm
30 ppm
Modifying factor: 1.
Animal to human dosimetric adjustment: Not applicable.
Time scaling: The severity of upper respiratory tract irritation is not expected to increase with duration of exposure to low concentrations of ammonia; therefore, the same value is applied to all AEGL-1 exposure duration.
Data adequacy: Upper respiratory tract irritation at 30 ppm and above is well documented in the literature. Therefore, sufficient data were available to document the irritation threshold.
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
220 ppm
220 ppm
160 ppm
110 ppm
110 ppm
Reference: Verberk, M.M. 1977. Effects of ammonia on volunteers. Int. Arch. Occup. Environ. Health 39:73-81.
Test species/Strain/Sex/Number: Humans, mixed sex; 8 expert and 8 nonexpert subjects.
Exposure route/Concentrations/Durations: Inhalation; 50, 80, 110, or 140 ppm for durations up to 2 h.
Effects: 50 ppm: just perceptible to offensive odor; no sensation to nuisance eye, nose, and throat irritation; no sensation to distinctly perceptible urge to cough, chest irritation, or general discomfort.
80 ppm: just perceptible to offensive odor; no sensation to offensive eye, nose, throat, and chest irritation and urge to cough; no sensation to nuisance general discomfort;
110 ppm: distinctly perceptible to offensive odor; no sensation to offensive eye, nose, throat, and chest irritation, urge to cough, or general discomfort;
140 ppm: just perceptible to offensive odor; just perceptible to unbearable eye irritation; no sensation to offensive nose, throat, and chest irritation, urge to cough, or general discomfort;
severity ratings: 0 = no sensation, 1 = just perceptible, 2 = distinctly perceptible, 3 = nuisance, 4 = offensive, and 5 = unbearable.
End point/Concentration/Rationale: 110 ppm for 2 h; respiratory tract and eye irritation and urge to cough ranged from “no sensation” to “offensive” during the 2-h exposure of the nonexpert subjects. The AEGL-2 derivation was based on the response (offensive irritation) of the most sensitive nonexpert subjects. The responses changed very little between 30 min and 2 h. The nonexperts considered the effects to be near the maximum response (offensive), whereas the expert responses were always of a lesser degree.
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10 min
30 min
1 h
4 h
8 h
220 ppm
220 ppm
160 ppm
110 ppm
110 ppm
Uncertainty factors/Rationale:
Total uncertainty factor: 1.
Interspecies: Not applicable.
Intraspecies: 1; Ammonia is a contact irritant and is efficiently scrubbed in the upper respiratory tract, and any perceived irritation experienced by the general public including sensitive individuals at low AEGL-2 concentrations is not expected to be greater than that of the most sensitive nonexpert subject. Atopics, including asthmatics, and nonatopics responded similarly to a brief nasal exposure to ammonia; a child experienced less severe effects than that of an adult exposed to high concentrations of ammonia; and exercising subjects showed only a nonclinically significant decrease in pulmonary function after exposure to ammonia.
Modifying factor: 1; POD was from a controlled exposure study on human subjects.
Animal to human dosimetric adjustment: Not applicable.
Time scaling: Cn × t = k, where n = 2 based on an analysis of empirical mouse and rat lethality data in which the times of exposure ranged from 10 to 60 min (ten Berge et al. 1986). Values for 4 and 8 h are the same as the POD because the responses of the subjects did not change considerably between 30 min and 2 h and are not expected to change for exposures up to 8 h. The 10-min AEGL-2 is the same as the 30-min AEGL-2 because the time-scaled value of 380 ppm might impair escape.
Data adequacy: The AEGL-2 values were based on a study using human subjects exposed to ammonia for 2 h; the responses of the subjects ranged from “no sensation” to “offensive,” which is expected to be comparable to the range of responses in the general public, including sensitive individuals. Case reports of long-term or irreversible effects in humans with exposure estimates were not available in the literature.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
2,700 ppm
1,600 ppm
1,100 ppm
550 ppm
390 ppm
References: MacEwen, J.D., and E.H. Vernot. 1972. Toxic Hazards Research Unit Annual Technical Report. SysteMed Report No. W-72003, AMRL-TR-72-62. Sponsor: Aerospace Medical Research Laboratory, Wright-Patterson AFB, OH. (I);
Kapeghian, J.C., H.H. Mincer, and A.B. Hones et al. 1982. Acute inhalation toxicity of ammonia in mice. Bull. Environ. Contam. Toxicol. 29:371-378. (II)
Test species/Strain/Number: CF1 or ICR male mice, 10 or 12 per group.
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10 min
30 min
1 h
4 h
8 h
2,700 ppm
1,600 ppm
1,100 ppm
550 ppm
390 ppm
Exposure route/Concentrations/Durations:
Inhalation: 0, 3,600, 4,550, or 5,700 ppm for 1 h (I).
Inhalation: 0; 1,190; 1,340; 2,130; 3,400; 3,950; 4,220; 4,860 ppm for 1 h (II).
Effects:
(I): Clinical signs: nasal and eye irritation, labored breathing, gasping, convulsions, and low body weight gain.
Mortality: 3,600 ppm (0/10), 4,500 ppm (3/10), and 5,720 ppm (9/10); LC01: 3,374 ppm.
(II): Clinical signs: eye and nasal irritation, hypoactivity, labored breathing, ataxia, convulsions, weight loss.
(III): Mortality: ≤3,440 ppm (0/12), 3,950 ppm (3/12), 4,220 ppm (5/12), 4,490 ppm (8/12), and 4,860 ppm (12/12); LC01: 3317 ppm.
End point/Concentration/Rationale: Lethality; LC01 = 3,374 ppm (I) and 3,317 ppm (II) for 1 h are the estimated thresholds for lethality derived by probit analysis of the data. Both numbers when divided by an uncertainty factor of 3 give the same result when the AEGL value is expressed to two significant figures.
Uncertainty factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, The mouse was unusually sensitive to ammonia compared with other mammalian species. An UF of 3 would yield a 30 min AEGL-3 value below a level that humans can tolerate (500 ppm) for 30 min.
Intraspecies: 3, Life-threatening concentrations of ammonia cause severe tracheobronchial and pulmonary effects and these effects, are not expected to be more severe in asthmatics than in nonasthmatic individuals, more severe in children than in adults, or more severe in exercising than resting individuals, but tracheobronchial and pulmonary effects may occur at a lower concentration in the elderly than in young adults. Reflex glottis closure (protective mechanism) is 3-fold less sensitive in the elderly than in young subjects; this mechanism may only be applicable when concentrations of ammonia exceed 570 ppm.
Modifying factor: 1.
Animal to human dosimetric adjustment: 1.
Time scaling: Cn × t = k where n = 2 based on an empirical analysis of mouse and rat lethality data in which the durations of exposure ranged from 10 to 60 min (ten Berge et al. 1986).
Data adequacy: No quantitative exposure data were available for humans who died from exposure to ammonia. Lethality data were available for two animal species—mice and rats. The AEGL-3 values were based on two mouse studies that were in close agreement, although they were conducted 12 years apart by two different laboratories.
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APPENDIX C
CATEGORY PLOT FOR AMMONIA
FIGURE 2-1 Chemical toxicity TSD all data—ammonia.