A EPA
EPA/635/R-16/163 Fc
www.epa.gov/iris
Toxicological Review of Ammonia
Noncancer Inhalation:
Executive Summary
[CASRN 7664-41-7]
September 2016
Integrated Risk Information System
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

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Toxicological Review of Ammonia
EXECUTIVE SUMMARY
Occurrence and Health Effects
Ammonia occurs naturally in air, soil, and water. Ammonia is also produced
by humans and other animals as part of normal biological processes.
Ammonia is used as an agricultural fertilizer and in many cleaning products.
Exposure to ammonia occurs primarily through breathing air containing ammonia
gas, and may also occur via diet, drinking water, or direct skin contact Measured
concentrations of ammonia range from 0.28 to 15 |ig/m3 in ambient outdoor air and
from 0.09 to 166 |ig/m3 in indoor air.
Health effects of inhaled ammonia observed at levels exceeding naturally-
occurring concentrations are generally limited to the respiratory tract, the site of
direct contact with ammonia. Short-term inhalation exposure to high levels of
ammonia in humans can cause irritation and serious burns in the mouth, lungs, and
eyes. Chronic exposure to airborne ammonia can increase the risk of respiratory
irritation, cough, wheezing tightness in the chest, and impaired lung function in
humans. Studies in experimental animals similarly indicate that breathing ammonia
at sufficiently high concentrations can result in effects on the respiratory system.
Animal studies also suggest that exposure to high levels of ammonia in air may
adversely affect other organs, such as the liver, kidney, and spleen.
This assessment presents an evaluation of the noncancer health effects of ammonia by the
inhalation route of exposure.
Chemical Properties
Ammonia (NH3) is a colorless alkaline gas with a pungent odor. In solution, ammonia exists
as ammonium hydroxide, a weak base that is only partially ionized in water according to the
following equilibrium fATSDR. 20041: NH3 + H2O *± NH4+ + OH". A decrease in pH results in an
increase in the concentration of ammonium ion (NH4+) and a decrease in the concentration of the
un-ionized form (NH3). At physiological pH (7.4), this equilibrium favors the formation of NH4+.
Toxicokinetics
Inhaled ammonia is almost completely retained in the upper respiratory tract Ammonia
produced endogenously in the intestines through the use of amino acids as an energy source and by
bacterial degradation of nitrogenous compounds from ingested food is largely absorbed. At
physiological pH, 98.3% of ammonia is present in the blood as the ammonium ion (NH4+). Given its
importance in amino acid metabolism, the urea cycle, and acid-base balance, ammonia is
homeostatically regulated to remain at low concentrations in the blood. Ammonia is present in
fetal circulation and in human breast milk as a source of nonprotein nitrogen. Ammonia production
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Toxicological Review of Ammonia
occurs endogenously by catabolism of amino acids by glutamate dehydrogenase or glutaminase
primarily in the liver, renal cortex, and intestines, but also in the brain and heart. Ammonia is
metabolized to glutamine via glutamine synthetase in the glutamine cycle or incorporated into urea
as part of the urea cycle. The principal means of excretion of ammonia is as urinary urea; lesser
amounts are eliminated in the feces, through sweat production, and in expired air.
Effects Other Than Cancer Observed Following Inhalation Exposure
Respiratory effects have been identified as a human health hazard following inhalation
exposure to ammonia. This hazard determination is based on findings from multiple epidemiology
studies in human populations exposed to ammonia in different settings (workers in industrial,
cleaning, and agricultural settings, volunteers exposed for up to 6 hours under controlled
conditions, and case reports) and animals (short-term and subchronic studies in several species
and across different exposure regimes).
Cross-sectional occupational studies involving chronic exposure to ammonia in industrial
settings provide evidence of an increased prevalence of respiratory symptoms (Rahman etal..
2007: Ballal etal.. 1998) and decreased lung function (Rahman etal.. 2007: Ali etal.. 2001: Ballal et
al.. 1998: Bhat and Ramaswamv. 1993). Other studies of exposure to ammonia when used as a
disinfectant or cleaning product provide evidence of asthma, asthma symptoms, and impaired
pulmonary function, using a variety of study designs fCasas etal.. 2013: Arif and Delclos. 2012:
Dumas etal.. 2012: Lemiere etal.. 2012: Vizcava etal.. 2011: Zock etal.. 2007: Medina-Ramon et al..
2006: Medina-Ramon etal.. 2005). Further evidence of respiratory effects of ammonia is seen in
studies of pulmonary function in an agricultural setting specifically in studies that accounted for
effects of co-exposures to other agents such as endotoxin and dust (Donham etal.. 2000: Reynolds
etal.. 1996: Donham et al.. 1995: Preller etal.. 1995: Heederik et al.. 1990) and in one study that did
not control for co-exposures fLoftus etal.. 20151. Despite the variation in population
characteristics, level and pattern of exposure, and potential confounders across these three settings
of epidemiology studies, respiratory effects were consistently observed in these studies. Further,
but more limited, support for the respiratory system as a target of ammonia toxicity comes from
controlled human exposure studies of ammonia inhalation and case reports of injury in humans
with inhalation exposure to ammonia. Additionally, respiratory effects were observed in several
animal species following short-term and subchronic inhalation exposures to ammonia.
Overall, there are suggestions in experimental animals that ammonia exposure may be
associated with effects on organs distal from the portal of entry, but there is inadequate
information to draw conclusions about the liver, kidney, spleen, or heart as sensitive targets of
ammonia toxicity.
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Toxicological Review of Ammonia
Inhalation Reference Concentration (RfC) for Effects Other Than Cancer
Table ES-1. Summary of reference concentration (RfC) derivation
Critical effect
Point of departure3
UF
Chronic RfC
Decreased lung function and respiratory symptoms
Occupational epidemiology studies
Holness et al. (1989), supported bv Rahman et al.
(2007), Ballal et al. (1998), and Ali et al. (2001)
NOAELadj: 4.9 mg/m3
10
0.5 mg/m3
aAn estimate of the 95% lower confidence bound of the mean exposure concentration in the high-exposure group
of the Holness et al. (1989) study was used as the NOAEL. Because the study involved workplace exposure
conditions, the NOAEL of 13.6 mg/m3 was adjusted for continuous exposure based on the ratio of VEho (human
occupational default minute volume of 10 m3 breathed during an 8-hour workday) to VEh (human ambient
default minute volume of 20 m3 breathed during the entire day) and an exposure of 5 days out of 7 days.
NOAEL = no-observed-adverse-effect level; UF = uncertainty factor
The study of ammonia exposure in workers in a soda ash plant by Holness etal. (19891.
with support from three studies in urea fertilizer plants by Rahman etal. (20071. Ballal et al.
(19981. and Ali etal. (20011. was identified as the principal study for RfC derivation. Respiratory
effects, characterized as increased respiratory symptoms based on self-report (including cough,
wheezing, and other asthma-related symptoms) and decreased lung function in workers exposed to
ammonia, were selected as the critical effect Rahman etal. f20071 observed an increased
prevalence of respiratory symptoms and decreased lung function in workers exposed in a plant
with a mean ammonia concentration of 18.5 mg/m3, but not in workers in a second plant exposed
to a mean concentration of 4.9 mg/m3. Ballal etal. (19981 observed an increased prevalence of
respiratory symptoms among workers in one factoly with exposures ranging from 2 to 27.1
mg/m3,1 but no increase in another factory with exposures ranging from 0.02 to 7 mg/m3. A
companion study by Ali etal. f20011 also observed decreased lung function among workers
exposed to higher cumulative ammonia levels (>50 mg/m3-years), with an approximate 5-7%
decrease in FVC% predicted and FEVi% predicted (see definition of spirometry measures in Section
1.2.1). Holness etal. (19891. who investigated a plant with exposures generally lower than other
studies, found no differences in the prevalence of respiratory symptoms or lung function between
workers (mean exposure 6.5 mg/m3) and the control group, and no differences when stratified by
exposure level (highest exposure group, >8.8 mg/m3).
These four studies addressed smoking by a variety of methods (e.g., adjustment for
smoking, exclusion of smokers, stratification of the results by smoking status). Two of the
iThis concentration range does not include exposures in the urea store (number of employees = 6; range of
ammonia concentrations = 90-130.4 mg/m3) because employees in this area were required to wear full
protective clothing, thus minimizing potential exposure.
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Toxicological Review of Ammonia
studies—Rahman et al. (2007) and Holness etal. (1989)—addressed other potential confounders
as appropriate. In particular, a high level of control of exposures in the facility studied by Holness
etal. f!9891 was reported, suggesting a low potential for co-exposures. As discussed in more detail
in the Literature Search Strategy | Study Selection and Evaluation section, confounding by other
workplace exposures, although a potential concern, was unlikely to be a major limitation of these
studies.
Considerations in selecting the principal study for RfC derivation include the higher
confidence placed in the measures of ammonia exposure in Holness et al. (1989). evaluation of both
respiratory symptoms and lung function parameters in this study, and the fact that the estimate of
the no-observed-adverse-effect level (NOAEL) for respiratory effects of 13.6 mg/m3 from Holness et
al. (1989) was the highest of the studies with adequate exposure-response information. The
synthesis of findings from the full body of evidence demonstrates that there is a relationship
between ammonia exposure and respiratory effects. Although Holness etal. (1989) do not report
associations between ammonia exposure and respiratory effects, it is included in the body of
epidemiologic studies of industrial settings because it is informative of the levels above which
ammonia causes effects. Other epidemiology studies include those with higher workplace ammonia
concentrations associated with respiratory effects (i.e., higher concentrations relative to those
reported by Holness et al. (1989)) and for which lowest-observed-adverse-effect levels (LOAELs)
could be identified. The Holness etal. T19891 study is identified as the principal study for RfC
derivation based on the quality of the exposure data and other factors, as stated above.
In summary, the study of ammonia exposure in workers in a soda ash plant by Holness et al.
(1989) was identified as the principal study for RfC derivation, with support from Rahman et al.
(2007). Ballal etal. (1998). and Ali etal. (2001). and respiratory effects were identified as the
critical effect. The NOAEL, represented by an estimate of the 95% lower confidence bound of the
mean exposure concentration in the high-exposure group from the Holness etal. (1989) study, or
13.6 mg/m3, was used as the point of departure (POD) for RfC derivation. The NOAEL adjusted to
continuous exposure (NOAELadj) was 4.9 mg/m3.
An RfC of 0.5 (rounded) mg/m3 was calculated by dividing the POD (adjusted for
continuous exposure, i.e., NOAELadj) by a composite uncertainty factor (UF) of 10 to account for
potentially susceptible individuals in the absence of data evaluating variability of response to
inhaled ammonia in the human population.
Confidence in the Chronic Inhalation RfC
Study - medium
Database - medium
RfC - medium
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Toxicological Review of Ammonia
Consistent with Environmental Protection Agency (EPA) Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA. 19941. the
overall confidence in the RfC is medium and reflects medium confidence in the principal study
(adequate design, conduct, and reporting of the principal study; limited by small sample size and
identification of a NOAEL only) and medium confidence in the database, which includes
occupational, cleaner, agricultural, and human exposure studies and studies in animals that are
mostly of subchronic duration. There are no studies of developmental toxicity, and studies of
reproductive and other systemic endpoints are limited; however, the likelihood of reproductive,
developmental, and other systemic effects at the RfC is considered small because it is well
documented that ammonia is endogenously produced in humans and animals, and any changes in
blood ammonia levels at the POD would be small relative to normal blood ammonia levels. Further,
EPA is not aware of any mechanisms by which ammonia can exert effects at the point of contact
(i.e., respiratory system) that could directly or indirectly impact tissues or organs distal to the point
of contact
Susceptible Populations and Lifestages
Studies of the toxicity of ammonia in children that would support an evaluation of
childhood susceptibility are limited. Casas etal. f20131 and Loftus etal. f20151 reported evidence
of an association between ammonia exposure and decrements in lung function in children;
however, these studies did not report information that would allow a comparison of children and
adults.
A limited number of studies provides inconsistent evidence of greater respiratory
sensitivity to ammonia exposure in asthmatics (Loftus etal.. 2015: Petrova etal.. 2008: Sigurdarson
etal.. 2004: Preller etal.. 1995). Loftus etal. (2015) reported no increase in asthma symptoms and
medication use in asthmatic children living near animal feeding operations; however, ammonia
exposure was associated with lower FEVi.
Hyperammonemia is a condition of elevated levels of circulating ammonia that can occur in
individuals with severe diseases of the liver or kidney or with hereditary urea [CO(NH2)2] cycle
disorders. These elevated ammonia levels can predispose an individual to encephalopathy due to
the ability of ammonia to cross the blood-brain barrier; these effects are especially marked in
newborn infants. Thus, individuals with disease conditions that lead to hyperammonemia may be
more susceptible to the effects of ammonia from external sources, but there are no studies that
specifically support this susceptibility.
Key Issues Addressed in This Assessment
Comparison of Exhaled Ammonia to the RfC
Ammonia is generated endogenously in multiple organs and plays central roles in nitrogen
balance and acid-base homeostasis fWeiner etal.. 2014: Weiner and Verlander. 20131. Given its
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Toxicological Review of Ammonia
important metabolic role, free ammonia is homeostatically regulated to remain at low
concentrations in blood (Souba. 19871. Elimination of ammonia occurs primarily in urine and
exhaled breath. Consideration was given to the presence of ammonia in exhaled air because the
range of ammonia concentrations in exhaled breath (0.009-2 mg/m3) overlaps the ammonia RfC
(0.5 mg/m3).
In general, higher and more variable ammonia concentrations (0.03-2 mg/m3) are reported
in human breath exhaled from the mouth or oral cavity (Schmidt etal.. 2013: Smith etal.. 2008:
Spanel etal.. 2007a. b; Turner etal.. 2006: Diskin etal.. 2003: Smith etal.. 1999: Norwood etal..
1992: Larson etal.. 1977). Ammonia concentrations measured in breath derived from oral
breathing largely reflect the production of ammonia via bacterial degradation of food protein in the
oral cavity or gastrointestinal tract, and can be influenced by diet, oral hygiene, age, and saliva pH.
In contrast, concentrations of ammonia in breath exhaled from the nose and trachea of humans
(0.0092-0.1 mg/m3) are lower than those in air exhaled from the mouth (Schmidt etal.. 2013:
Smith etal.. 2008: Larson etal.. 1977). and are generally lower than the RfC by a factor of five or
more. Concentrations in breath exhaled from the nose appear to better represent levels at the
alveolar interface of the lung and are more relevant to understanding systemic levels of ammonia
than breath exhaled from the mouth f Schmidt etal.. 2013: Smith etal.. 20081: however,
concentrations in breath from neither the mouth nor the nose can be used to predict blood
ammonia concentration or previous exposure to environmental (ambient) concentrations of
ammonia (see Appendix C, Section C.1.4).
Regardless of the source of expired ammonia (mouth or nose), the level of ammonia in
breath, even at concentrations that exceed the RfC, does not necessarily raise questions about the
appropriateness of the RfC. The exhalation of ammonia is a clearance mechanism for a product of
metabolism that is otherwise toxic in the body at sufficiently high concentrations. Thus, ammonia
concentrations in exhaled breath may be higher than inhaled concentrations. However, the
presence of ammonia in exhaled breath is not considered an uncertainty in the RfC.
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