r=%„	United States
Environmental Protection
VU * \Agency
EPA/690/R-05/006F
Final
2-2-2005
Provisional Peer Reviewed Toxicity Values for
Ammonia
(CASRN 7664-41-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
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MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
AMMONIA (CASRN 7664-41-7)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. Once an IRIS value for a specific chemical
becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It
should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived
based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The HEAST (U.S. EPA, 1997) lists subchronic and chronic oral reference doses (RfDs)
of 34 mg/L for ammonia. A comment in the HEAST indicates that 34 mg/L is a concentration in
drinking water that is specifically related to the organoleptic (taste) threshold and that a safe
concentration for ammonia may be higher than 34 mg/L, but the data are inadequate to assess the
safe level. The source document for derivation of the HEAST subchronic and chronic oral RfD
values is the Health Effects Assessment (HEA) for Ammonia (U.S. EPA, 1987). The HEAST
subchronic and chronic RfD values are based on a determination of the organoleptic (taste)
threshold of ammonia in redistilled water by Campbell et al. (1958). The value selected for the
HEAST subchronic and chronic RfDs was supported by the closely similar value of 35 mg/L
identified as the taste threshold for ammonia in a World Health Organization Environmental
Health Criteria (EHC) document (WHO, 1986) and as the ambient water quality criterion to
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protect human health derived by U.S. EPA (1981). No oral assessment is included on IRIS (U.S.
EPA, 2003) or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). No
relevant documents other than the HEA and the AWQC document were included in the CARA
list (U.S. EPA, 1991, 1994a).
The HEAST includes a value of 1E-1 mg/m3 for the subchronic inhalation RfC. The
HEAST subchronic RfC used the same data and is the same as the RfC (1E-1 mg/m3) reported in
IRIS (U.S. EPA, 2003). The IRIS chronic RfC value was derived from a free-standing NOAEL
of 6.4 mg/m3 (9.2 ppm) identified for lack of evidence of decreased pulmonary function or
changes in subjective symptomatology in an occupational study of workers exposed to ammonia
in a soda ash (sodium carbonate) facility (Holness et al., 1989). A LOAEL was not identified in
the study. The NOAEL was adjusted for intermittent exposure to a value of 2.3 mg/m3 and
divided by a composite uncertainty factor (UF) of 30. The composite UF included a factor of 10
for protection of sensitive individuals and a factor of 3 for database deficiencies, including lack
of chronic data, proximity of the occupational NOAELm < to a LOAELm < observed in a
subchronic inhalation study in rats (Broderson et al., 1976), and lack of data on reproductive or
developmental toxicity. The RfD/RfC Workgroup verified the RfC on February 21, 1991. The
HEA had previously derived subchronic and chronic inhalation RfDs of 0.36 mg/m3 by dividing
the ammonia air odor threshold of 3.6 mg/m3 (Carson et al., 1981) by an uncertainty factor of 10
to obtain an estimate of the lower bound limit for odor detection.
The public review draft of the ATSDR Toxicological Profile on ammonia (ATSDR,
2002)	derived an intermediate oral minimal risk level (MRL) value of 0.3 mg/kg-day based on a
duration-adjusted NOAEL of 39.5 mg/kg-day for weight loss in rats exposed to ammonium
sulfamate in drinking water for 90 days (Gupta et al., 1979) and an uncertainty factor of 100 (10
for extrapolation from rats to humans and 10 to protect sensitive individuals). ATSDR (2002)
also derived a chronic inhalation MRL of 0.3 ppm (200 |ig/m3) based on a duration-adjusted
NOAEL of 3.1 ppm in the Holness et al. (1989) study and an uncertainty factor of 10 for human
variability. The State of California (OEHHA, 2002) has derived a chronic inhalation reference
exposure level of 200 |ig/m3 (0.3 ppm) for ammonia. This value (200 |ig/m3) is based on the
occupational study of Holness et al. (1989) with a duration adjusted NOAEL of 2 mg/m3 and an
uncertainty factor of 10 for intraspecies variability. The OEHHA (2002) used the same
methodology as ATSDR. ACGIH (2001) lists a TLV-TWA of 25 ppm (17 mg/m3) and a STEL of
35 ppm (24 mg/m3) for ammonia. These values are intended to minimize the potential for acute
ocular and respiratory tract irritation. NIOSH (2002) lists values of 25 ppm (18 mg/m3) and 35
ppm (27 mg/m3) for the REL-TWA and REL-ST, respectively. OSHA (2002) lists a value of 50
ppm (35 mg/m3) for the PEL-TWA.
Ammonia is not included in the HEAST (U.S. EPA, 1997) cancer table. IRIS (U.S. EPA,
2003)	and the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002) do not
provide a carcinogenicity assessment for ammonia. IARC (2002) has not evaluated the
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carcinogenicity of ammonia. NTP (2002) does not list ammonia among the chemicals it
considers to be known human carcinogens or reasonably anticipated to be human carcinogens.
Literature searches to identify studies relevant to the derivation of provisional toxicity
values for ammonia were conducted for the period 1988 through September 18, 2002. Databases
searched included: TOXLINE, MEDLINE, TSCATS, RTECS, CCRIS, DART,
EMIC/EMICBACK, HSDB, GENETOX and CANCERLU. Additional literature searches were
conducted through May 2004 by NCEA-Cincinnati using TOXLINE, MEDLINE, Chemical and
Biological Abstract databases and no relevant information was found.
REVIEW OF PERTINENT DATA
Human Studies
Holness et al. (1989) studied workers exposed to ammonia in a sodium carbonate
production plant. Fifty-two of the 64 available workers agreed to participate in the study. The
control group consisted of 31 office and stores workers employed at the plant who were without
previous exposure to ammonia. Information was collected on age, height, work history, smoking
history, respiratory symptoms, and skin and eye complaints. Respiratory questions were based
on an American Thoracic Society questionnaire. Sense of smell was evaluated at the beginning
and end of the work week. Pulmonary function tests were performed at the beginning and end of
each work shift on two test days. The parameters measured were forced vital capacity (FVC),
forced expiratory volume in one second (FEVj); and forced expiratory flow rate at 50% and 75%
of the vital capacity (FEF50 and FEF75). Mean time-weighted average (TWA) exposures to
ammonia were determined by personal air sampling over one shift following NIOSH
recommendations. The average sampling time was 8.4 hours. The mean age of the exposed
workers was 38.9 ± 11.7 years and the average duration of exposure was 12.2 ± 8.9 years. Only
weight differed significantly when demographics for the exposed and control workers were
compared. Time-weighted average airborne concentrations of ammonia were 9.2 ±1.4 ppm (6.4
mg/m3) and 0.3 ±0.1 ppm (0.2 mg/m3) for the exposed and control groups, respectively.
Although no significant difference was evident between exposed and control groups in reporting
of respiratory symptoms, workers reported that exposure at the plant aggravated specific
symptoms including coughing, wheezing, nasal complaints, eye irritation, throat discomfort, and
skin problems. No significant differences were evident between the exposed and control groups
in reporting of respiratory symptoms, sense of smell, baseline lung function, or change in lung
function at the beginning and end of a work week. No significant relationships between level or
length of ammonia exposure and lung function results were demonstrated. The NOAEL in this
study was 9.2 ppm (6.4 mg/m3), based on lack of evidence for decreased pulmonary function or
changes in subjective assessments of respiratory symptoms. A LOAEL was not identified in this
study.
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Ferguson et al. (1977) exposed healthy human volunteers (2/concentration) employed in
an alkali plant to ammonia concentration of 25 ppm, 50 ppm, or 100 ppm, 5 days/week for six
weeks. Conclusions of the study were actually based on 5 weeks of exposure as a result of
technical difficulties during the first week of the study. Toxicity was assessed by subjective and
objective indications of eye and respiratory tract irritation, pulse rate, respiration rate, pulmonary
function (FVC, FEV), physical examination, and the ability to perform routine tasks. Exposure
to ammonia did not result in abnormalities of the chest, heart, vital organs, neurological response,
task performance or significant weight changes as assessed during weekly medical examinations.
Transient irritation of the throat was observed at exposures of 50 ppm (4 hours/day).
More recently published occupational studies were examined to identify data potentially
suitable for calculation of a subchronic RfC. Ballal et al. (1998) reported the results of a cross-
sectional study of male workers employed in two fertilizer plants in Saudi Arabia. Exposure to
ammonia concentrations of 25 ppm and above were significantly associated with respiratory
symptoms including wheezing, cough, phlegm, dyspnea, and asthma. Ali et al. (2001) examined
the pulmonary function of workers (gender not specified) in an ammonia-producing factory in
Saudi Arabia. Cumulative exposure of greater than 50 mg/m3-years was associated with
significantly reduced FEVj and FVC. Symptomatic workers (i.e., those reporting cough, phlegm,
wheeze, and/or dyspnea) showed significantly reduced FEVjand FEV/FVC ratio when compared
to asymptomatic workers. Neither study adequately reported details of worker exposure, such as
the number of hours worked per week, and were not further considered for derivation of
reference doses.
A number of studies have examined the relationship between inhalation exposure to
pollutants (including ammonia) in livestock confinement buildings and occurrence of respiratory
symptoms and/or changes in pulmonary function in workers (Heerderik et al., 1990; Choudat et
al., 1994; Donham et al., 1995, 2000; Reynolds et al., 1996; Vogelzang et al. 1997, 2000;
Cormier et al., 2000). Exposure to ammonia concentrations of 2.3 to 20.7 ppm was associated
with symptoms of bronchial reactivity, inflammation, cough, wheezing, or shortness of breath
and decrements in pulmonary function as measured by FEVj, maximum expiratory flow rate, and
maximal mid-expiratory flow rate. These data are of limited use for derivation of a subchronic
toxicity reference value for ammonia because workers were concurrently exposed to other
potential respiratory toxicants such as dusts, endotoxins, and nitrogen dioxide.
The carcinogenic potential of ammonia via the inhalation route has not been assessed in
humans.
The experimental database for human oral exposure to ammonia consists of acute and
short-term studies of exposure to ammonium chloride. No subchronic or chronic duration oral
exposure studies were located in the literature examined. The availability of studies on
ammonium chloride is a result of its use for experimental induction of hyperchloremic metabolic
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acidosis. Few of the available studies have been designed or conducted to specifically assess the
toxicity of ammonia or ammonium ion in response to oral dosing.
U.S. EPA (1981) reviewed fifteen existing short-term studies of ammonium chloride in
humans. Administration of ammonium chloride to all age groups produced metabolic acidosis,
with increased susceptibility observed in infants. The results of these studies indicate that
metabolic acidosis, impaired glucose tolerance, and reduced tissue sensitivity to insulin may
result from doses of ammonium chloride greater than or equal to 100 mg/kg-day (31.8 mg
ammonia/kg-day, as estimated by U.S. EPA, 1981). Although frank toxicity was not reported,
U.S. EPA (1981) expressed concern for potential bone demineralization as a result of impaired
acid-base balance.
In the longest duration human study found, Lemann et al. (1966) investigated the
electrolyte balance of five men who were given doses of ammonium chloride to induce metabolic
acidosis. Each individual served as his own control. Following baseline observations, each
subject was given a small initial dose which was progressively increased over a period of six to
nine days, after which the dose remained constant until administration of ammonium chloride
was discontinued after day 18. U.S. EPA (1987) reported total doses of 733 mEq (approximately
93 mg/kg-day) for the initial loading period and 2771 mEq (approximately 177 mg/kg-day) for
the remainder of the experiment. During ammonium chloride loading, net fixed acid production
was increased by an average of 3425 mEq. Progressive acid retention was initially accompanied
by a progressive decrease in serum bicarbonate concentration. Serum bicarbonate levels dropped
as acid was retained during the first nine days of ammonium chloride dosing, stabilized at a
reduced level by about day 12, and rose slightly between days 13 to 18, but did not return to
baseline levels until after treatment with ammonium chloride was discontinued. Calcium and
phosphorus balances became negative as a result of urinary losses, suggesting to the study
authors that slow dissolution of bone mineral was occurring to provide additional buffering
capacity. The LOAEL in this study was the initial dose of 93 mg/kg-day.
The carcinogenic potential of ammonia via the oral route has not been assessed in
adequately designed epidemiological studies.
Animal Studies
Broderson et al. (1976) continuously exposed F344 rats (6 rats/sex/dose) to ammonia
concentrations of 25, 50, 150, or 250 ppm for seven days prior to inoculation with Mycoplasma
pulmonaris and for 28 to 42 days following inoculation. These exposures were conducted using
purified ammonia from a commercial source. In addition, one treatment group was exposed to
ammonia produced from a natural source (soiled bedding) for 30 days following inoculation.
Each treatment group had a corresponding control group that was inoculated with M. pulmonaris
and exposed only to background levels of ammonia. Additional groups were exposed to
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background or high levels of ammonia (trace and 250 ppm, respectively) without M. pulmonaris
inoculation. Toxicity was assessed by observation of clinical signs and histopathological
examination of nasal passages, middle ear, trachea, lungs, liver, kidney, adrenal, pancreas,
testicle, spleen, mediastinal nodes, and thymus. Clinical signs were similar in control and
exposed groups during the pre-inoculation exposure period. Signs of murine respiratory
mycoplasmosis (MRM) were observed in all groups approximately 10 days after inoculation. All
levels of ammonia from bedding or the commercial source increased the severity of the rhinitis,
otitis media, tracheitis, and pneumonia characteristic of MRM. The prevalence and extent of
gross atelectasis and consolidation were greater in rats exposed to high ammonia concentrations
(i.e., ammonia concentrations greater than background) and the prevalence of microscopic
respiratory lesions was also greater. The prevalence of gross and microscopic lung lesions
differed significantly from controls when data from all high exposure groups were summed and
compared with pooled control data. Regression analysis indicated a positive relationship
between ammonia concentration and prevalence of gross or microscopic lesions. Exposure of
uninoculated rats to ammonia resulted in lesions that were unlike those of MRM and which were
restricted to the nasal passages. A LOAEL of 25 ppm (17.4 mg/m3) was identified in this study.
Schoeb et al. (1982) inoculated pathogen-free F344 rats with M. pulmonis and exposed
groups to trace or 100 ppm (70 mg/m3) concentrations of ammonia for up to 28 days. Growth of
M. pulmonis was greater in ammonia-exposed rats than in controls and serum immunoglobulin
response to the inoculum was also greater in the exposed population. Results of an experiment
conducted in rats with cannulated tracheas demonstrated that the nasal passages absorbed
virtually all ammonia at administered concentrations of 500 ppm (348 mg/m3) or below.
Coon et al. (1970) continuously exposed male and female Sprague-Dawley and Long
Evans rats for a minimum of 90 days to ammonia concentrations of 0, 40, 127, 262, 455, or 470
mg/m3. A LOAEL of 262 mg/m3 was identified on the basis of nasal discharge in 25% of the rats
and nonspecific degenerative and circulatory changes in the lungs and kidneys. The upper
respiratory tract was not examined for microscopic lesions. In another series of experiments,
Coon et al. (1970) exposed rats, guinea pigs, rabbits, dogs and monkeys to ammonia
concentrations of 0, 155, or 770 mg/m3 for 8 hours/day, 5 days/week for a total of 30 exposures.
This study identified a LOAEL of 770 mg/m3 for lung inflammation in rats and guinea pigs and
ocular and nasal irritation in dogs and rabbits. The upper respiratory tract was not examined for
presence of lesions.
Anderson et al. (1964) conducted a series of experiments that included continuous
exposure of guinea pigs and Swiss albino mice to 20 ppm (13.9 mg/m3) ammonia for up to six
weeks and exposure of Leghorn chickens for up to 12 weeks. A separate group of guinea pigs
was exposed to 50 ppm (35 mg/m3) ammonia for six weeks. Although no effects were observed
after exposure to 20 ppm for four weeks, gross lesions including edema, congestion, and
hemorrhage were observed in the lungs of all three species after six weeks. Grossly enlarged and
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congested spleens, congested livers and lungs, and pulmonary edema were observed in guinea
pigs exposed to 50 ppm ammonia for six weeks.
Weatherby (1952) exposed guinea pigs to 0 or 170 ppm (118 mg/m3) 6 hours/day, 5
days/week for up to 18 weeks. No adverse effects were observed in animals exposed for 6 to 12
weeks. Mild changes were observed in the spleen, kidney suprarenal glands, and liver at 18
weeks. No effects on the lungs were observed. The upper respiratory tract was not examined for
lesions.
No effects on ovarian or uterine weights were observed in pigs exposed by inhalation to
approximately 5 or 35 ppm ammonia for 6 weeks (Diekman et al., 1993). Continuous exposure
of female pigs to approximately 35 ppm ammonia from 6 weeks prior to breeding through
gestation day 30 did not significantly affect age to puberty, number of live fetuses, fetus-to-
corpus luteum ratio, or fetal length when compared to females exposed to 7 ppm ammonia for
the same duration (Diekman et al., 1993).
Limited subchronic and chronic toxicity data are available for ammonia. In an early
study, Seegal (1927) administered ammonium chloride doses of 0 or 372 mg/kg-day to rabbits by
gavage for 36 days and observed episodes of severe metabolic acidosis and epithelial
degeneration in the renal tubules. Similar effects plus softening of the teeth, skull, and ribs were
observed at a dose of 234 mg/kg-day given by gavage for 11 months.
Freedman and Beeson (1961) exposed 12 adult male Sprague-Dawley rats to 1.6%
ammonium chloride in the drinking water for periods of up to three weeks to evaluate effects on
the kidney. Six control animals were provided with tap water. An additional group of 10 rats
was given drinking water containing 1% ammonium chloride for an additional 2.5 months to
assess subchronic effects. No abnormalities were detected by urinalysis, gross pathology or
histologic examination. Physiological adaptation to metabolic acidosis was indicated by
increased glutaminase activity per gram of kidney with duration of treatment. No data on water
consumption or body weight of the test animals were provided. Assuming that the rats weighed
250 grams and consumed 25 mL of drinking water per day, U.S. EPA (1987) estimated a time-
weighted average dose of approximately 360 mg/kg-day.
Gupta et al. (1979) conducted a subchronic exposure study in adult female and weanling
male and female ITRC rats (20/sex/age/dose). The test animals were treated with ammonium
sulfamate (NH4S03NH2) at doses of 0, 100, 250, or 500 mg/kg-day, 6 days per week for 30, 60,
or 90 days. The ammonium sulfamate was given as a 10% solution, but the study report did not
clearly indicate whether the dose was administered by gavage. Food and water consumption,
appearance, behavior, and body weight were monitored during the study. Hematological
parameters and organ weights were measured at interim and terminal sacrifices and tissue
samples were collected for histopathological examination. Food and water consumption were
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decreased in male and female weanlings at the 500 mg/kg-day dose relative to the controls. No
compound-related clinical signs of toxicity were observed in dosed rats. Body weight of adult
females receiving 500 mg/kg-day was significantly reduced at 60 day (9%) and 90 days (16%)
when compared to the control group. No significant differences were noted in hematological
parameters, organ weights, or histopathology. Although the study authors indicated that
ammonium sulfamate would be expected (on the basis of its structure) to cause metabolic
acidosis, this prediction does not appear to have been confirmed experimentally. These data
identify NOAEL and LOAEL values of 250 and 500 mg/kg-day as ammonium sulfamate,
respectively. The effective dose of ammonia at each of these dose levels is uncertain, because
under certain conditions the sulfamate ion is hydrolyzed to bisulfate ion and ammonia (U.S.
EPA, 1981, 1987). Assuming no hydrolysis of the sulfamate ion, these doses correspond to 37.3
and 74.8 mg/kg-day of ammonia, respectively.
Bodega et al. (1993) fed diets containing 0 or 20% ammonium acetate to pathogen-free
female Wistar rats (5 rats/group) for 3, 7, 15, 45, or 90 days to assess effects on glial fibrillary
acidic protein (GFAP) in the spinal cord. The ammonium acetate in the diet was supplemented
by addition of 5 mM ammonium acetate to the drinking water. The total exposure from the
combined food and water was not provided by the author. Exposure to ammonium acetate had
no effect on behavior, water consumption, or spinal GFAP levels of the test animals. Body
weight gain was significantly reduced in dosed animals at all time points. Body weight gain in
animals exposed to ammonia for 90 days was 69% of the control value.
Fazekas (1939, 1954a,b) conducted studies in rabbits that ranged from 3 to 17 months in
duration. The administration of various ammonium salts (carbonate, chloride, sulfate,
hydrophosphate, acetate, or lactate) or ammonium hydroxide resulted in enlargement of the
parathyroids. Similar results were obtained with a variety of other chemicals (sodium
dihydrophosphate, sodium ammonium phosphate, calcium chloride, hydrochloric acid, acetic
acid, lactic acid) (Fazekas, 1954a). The chemicals were given for three week periods separated
by one week intervals. The administered dose of ammonium salts in this study is unclear, but
based on descriptions in secondary sources is likely to be less than or equal to 0.4 mg/kg-day. In
a related study, similar treatment of rabbits with ammonium chloride or ammonium sulfate
resulted in fluctuations in serum calcium and phosphorus levels (Fazekas, 1954b). Rabbits given
gavage doses of 100 mg/kg by gavage on alternate days and then daily for 17 months developed
enlarged adrenal glands. An initial fall in blood pressure of 20 to 30 mg Hg was followed by a
gradual rise to levels 10 to 30 mg Hg after several months of treatment.
In a chronic study, Barzel and Jowsey (1969) exposed male Sprague-Dawley rats to 1.5%
ammonium chloride in the drinking water for 330 days. The effects of ammonium on animals
receiving a nutritionally complete diet included decreased bone content of fat-free solid and
calcium; decreased body weight and body fat; and decreased blood pH and plasma carbon
dioxide. Barzel (1975) reported effects on bone (decreased density, ash weight, and calcium
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content), but no effects on growth, in intact and ovariectomized female rats exposed to 1.5%
ammonium chloride in the drinking water for 300 days. U.S. EPA (1981) estimated an average
daily dose of 1500 mg/kg-day for both studies.
The carcinogenic potential of ammonia has been investigated in an oral bioassay
conducted in mice. Toth et al. (1972) exposed male and female Swiss mice (49-50/sex/dose) to
0.1, 0.2, or 0.3% ammonium hydroxide in the drinking water for their lifetime. U.S. EPA (1987)
estimated an average daily dose of 565 mg/kg-day at the highest concentration. Male and female
C3H mice (40/sex) were exposed to 0.1% ammonium hydroxide in the drinking water for their
lifetime. This concentration corresponded to average daily doses of approximately 270 mg/kg-
day, respectively, as calculated by U.S. EPA (1987). While data for a control group are reported
in the publication, it is not clear whether this group was run concurrently with the ammonia
treatment groups. The mice were examined and weighed at weekly intervals. Moribund animals
were humanely sacrificed. Complete necropsies were performed on all animals and the liver,
kidney, spleen, lung, and organs with gross lesions were processed for histopathological
examination. No evidence for carcinogenicity was observed in males or females of either strain.
Two studies have examined the interaction of ammonia with other compounds in the
induction of tumors. Uzvolgyi and Bojan (1980) investigated the interaction of ammonia with
diethyl pyrocarbonate (DEPC) in induction of lung tumors in CFPL mice (a urethane-sensitive
strain). Mice given gavage doses of either ammonia or DEPC alone did not develop lung tumors,
whereas development of lung tumors was observed in mice dosed with both ammonia and
DEPC. Induction of tumors in the sensitive CFPL strain may have resulted from formation of
urethane in vivo from ammonia and DEPC (Uzvolgyi and Bojan,1985). Tsujii et al. (1995)
studied the effect of ammonia on tumor development in male Sprague-Dawley rats pretreated
with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in the drinking water for 24 weeks and
subsequently exposed to drinking water containing 0 or 0.01% ammonia for an additional 24
weeks. Exposure to ammonia significantly increased the incidence, multiplicity, size, and depth
of tumors in the glandular stomach and stimulated cell proliferation in the gastric mucosa.
Reproductive and developmental toxicity data on ammonia from animal studies are
limited. Treatment of virgin female rabbits with oral doses of various ammonium salts
(carbonate, chloride, hydrophosphate, or sulfate) or ammonium hydroxide was associated with
enlargement of the ovaries, follicle maturation, and formation of corpora lutea (Fazekas, 1949).
Enlargement of the uterus, hypertrophy of the teats, and secretion of milk were also reported in
treated rabbits. However, several aspects of this study are poorly documented, including the use
of controls and exact method of dose administration.
Minana et al. (1995) examined the effect of prenatal exposure to 20% ammonium acetate
in the diet on NMD A receptor function in Wistar rats. As judged from graphically presented
data, offspring of dams treated from day 1 of pregnancy through lactation had body weights at
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birth that were comparable to the control group. The body weight of weanlings maintained on a
diet containing 20% ammonium acetate was reduced by approximately 27% and 26% in males
and females, respectively, at 120 days of age when compared to animals maintained on the
control diet. Rats exposed to ammonia during pregnancy and lactation and fed an
unsupplemented diet at weaning had a lower growth rate than the controls until day 60, indicating
persistent effects of prenatal and lactational exposure to ammonia. Prenatal exposure to
ammonia reduced binding of [3H]MK-801 to NMDA receptors in primary cultures of cerebellar
neurons by approximately 60%. No data were provided for feed intake in this study; therefore,
an average daily dose can not be reliably estimated.
Other Studies
Information on the toxicokinetic properties of ammonia have been reviewed and
summarized in ATSDR (2002). Inhalation exposure studies in humans show that ammonia
dissolves in the mucous of the upper respiratory tract. At low levels of exposure, most inhaled
ammonia is retained in the upper respiratory system. As the ammonia concentration increases,
the capacity of the upper respiratory system is saturated and a larger percentage is absorbed.
Development of nasal and pharyngeal irritation, but not tracheal irritation, following exposure is
consistent with retention of inhaled ammonia in the upper respiratory tract. Animal data provide
supporting evidence for high nasal retention. Quantitative differences in the amount of ammonia
in inhaled and exhaled air suggest that small amounts are absorbed across the nasopharyngeal
membranes into the systemic circulation. Limited systemic absorption is also inferred from lack
of change in blood nitrogen and urinary-ammonia compounds following exposure. The available
evidence suggests that ammonium absorbed via inhalation would be distributed to all body
compartments by the blood. Ammonium reaching the tissues would be used in protein synthesis
or as a buffer, with excess levels reduced by urinary excretion or conversion in the liver to
glutamine and urea. Absorbed ammonia is excreted by the kidneys as urea and urinary
ammonium compounds. Bioaccumulation to toxic levels is not expected to occur from chronic
inhalation exposure based on the low levels of absorption and existence of multiple effective
mechanisms for detoxification and excretion.
Human data indicate that ingested ammonium compounds are readily absorbed. The
absorbed ammonium ion is transported via the hepatic portal vein to the liver, where most is
metabolized to urea in healthy individuals. Data from animals and humans suggest that little of
the ingested compound reaches the systemic circulation as ammonia or ammonium
ion. Ingested ammonium compounds are excreted primarily in the urine as urea. Small amounts
may be excreted in the sweat or in exhaled air.
Genotoxicity data are available from studies in humans, mice, Escherichia coli,
Drosophila melanogaster, and cultured chick fibroblast cells. Yadav and Kaushik (1997)
conducted cytogenetic assays on blood samples collected from 22 workers exposed to ammonia
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gas (ambient level = 0.09 mg/m3) during production of nitrogen fertilizers and 42 unexposed staff
employed at the same facility. The exposed workers did not show clinical symptoms of ammonia
toxicity. The mitotic index, total number of chromosome aberrations (CA), and frequency of
sister chromatid exchange (SCE) were significantly increased in the exposed workers as
compared to their matched controls. The frequency of CA and SCE increased with the duration
of exposure. Concurrent exposure to other compounds such as nitrogen dioxide was not
addressed in the study report. The frequency of micronuclei was significantly increased in Swiss
albino mice treated with intraperitoneal doses of ammonia ranging from 12.5 to 50 mg/kg as
compared to controls (Yadav and Kaushik, 1997). Positive results were obtained for reverse
mutation in E. coli, but only at levels of ammonia that were cytotoxic (Demerec et al., 1951).
Negative results were reported for ammonium sulfate in Salmonella typhimurium and
Saccharomyces (Litton Bionetics, 1975). Positive results were observed for chromosomal
aberrations in chick fibroblasts treated with buffered ammonium chloride (Rosenfeld, 1932).
Reduced cell division and inhibition of DNA repair were observed in mouse fibroblasts treated
with ammonia and/or ammonium chloride (Visek et al., 1972; Capuco, 1977). Lobasov and
Smirnov (1934) reported slightly mutagenic activity in D. melanogaster. Auerbach and Robson
(1947) obtained doubtful, probably negative, results for sex-linked recessive mutations in D.
melanogaster and reported negative results for dominant lethality.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR AMMONIA
Adequate toxicity data for derivation of provisional subchronic or chronic RfD values are
not available. The human experimental database consists primarily of older acute and short-term
studies in which ammonium chloride was used to induce metabolic acidosis. The longest
duration of exposure among these studies was 18 days. The animal database includes one study
(Gupta et al., 1979) that was reasonably well-documented, evaluated appropriate endpoints, and
included a histopathological evaluation of potential target tissues. This study was not used to
derive p-RfD values for two reasons. First, the test article was ammonium sulfamate, which is
hydrolyzed under certain conditions to bisulfate ion and ammonia. It is not known whether
hydrolysis occurred when the compound was administered to rats; thus, the actual dose of
ammonia/ammonium ion administered to the test animals is uncertain. Second, comparison of
the data from this study to results from human studies suggests that health effects may occur in
humans at lower concentrations of ammonium salts. Gupta et al. (1979) identified a NOAEL
equivalent to 37.3 mg ammonia/kg-day and a LOAEL equivalent to 74.8 mg ammonia/kg-day
(assuming no hydrolysis of the sulfamate ion; the actual dose may differ). This LOAEL is higher
than the 31.8 mg/kg-day level of concern identified for humans by U.S. EPA (1981) for potential
bone demineralization. Route-to-route extrapolation is not feasible for derivation of oral
reference values because the toxicokinetic properties of ammonia differ significantly for the oral
and inhalation pathways. This evaluation of data adequacy is consistent with previous
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assessments conducted by U.S. EPA (1981, 1987), which did not use the existing toxicity data
for derivation of reference doses.
Because adequate data are lacking for oral exposure to ammonia, previous determinations
of toxicity reference values (U.S. EPA, 1981, 1987, 1997) have used organoleptic (taste) data to
estimate acceptable ammonium levels in drinking water at 34-35 mg/L. However, organoleptic
(taste) data are not reliable predictors of either toxicity or intake. Furthermore, WHO (1986) has
identified several limitations of the "triangle test" methodology used to derive the organoleptic
(taste) threshold for ammonia: 1) the definition of the threshold is somewhat arbitrary; 2)
McBride & Laing (1979) have reported significant positional bias in using the triangle test to
determine taste threshold; and 3) the triangle test is not intended to mimic environmental
exposures in which the taste thresholds could be substantially higher. Due to the high uncertainty
associated with use of the organoleptic (taste) data for ammonia, no oral subchronic or chronic
p-RfD is derived.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR AMMONIA
A chronic RfC of 1E-1 mg/m3 is listed for ammonia on IRIS (U.S. EPA, 2003) based on
lack of evidence of decreased pulmonary function in human workers exposed to an estimated
concentration of 6.4 mg/m3 for an average of 12.2 years (Holness et al., 1989). The presence of a
chronic RfC on IRIS precludes derivation of a provisional chronic RfC for this chemical.
The occupational study of Holness et al. (1989) and the subchronic study conducted in
rats by Broderson et al. (1976) were also considered to be an appropriate basis for derivation of a
provisional subchronic RfC. Holness et al. (1989) identified a NOAEL of 9.2 ppm (6.4 mg/m3)
for apparent lack of effect on pulmonary function or changes in subjective assessments of
symptoms in workers exposed to ammonia for a mean duration of 12.2 years while employed at a
sodium carbonate production plant. A LOAEL was not identified in this study. The NOAELm <
was calculated using the default dosimetric adjustment for human data (U.S. EPA, 1994b), as
follows:
NOAELadj = 6.4 mg/m3 x 5days/7days = 4.6 mg/m3
NOAEL^ = NOAELAI)[ X (VEho/VEh)
= 4.6 mg/m3 x (10 m3/20 m3)
= 2.3 mg/m3
where,
VEho = human occupational default minute volume (10 m3/8 hours; U.S. EPA, 1994b)
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VEh = human ambient default minute volume (20 m3/24 hours; U.S. EPA, 1994b)
A LOAELm c was calculated from the rat data of Broderson et al. (1976) for comparison
with the human NOAELm c. These researchers identified a LOAEL of 17.4 mg/m3, the lowest
concentration tested, for increased severity of rhinitis and pneumonia (with respiratory lesions) in
F344 rats inoculated with M. pulmonis and continuously exposed to ammonia. The LOAELm < is
calculated using the procedure for a respiratory effect of a category 1 gas in the extrathoracic
region (U.S. EPA, 1994b) as follows:
LOAELadj	= LOAELobserved = 17.4 mg/m3 (continuous exposure)
LOAELfjgc = LOAELAI)l x RGDRet
RDGRet	= (VE /SAet)a / (VE /SAet)h
= (0.14 m3/day / 15 cm2) / (20 m3/day/ 200 cm2) = 0.093
LOAELjjgc = 17.4 mg/m3 x 0.093
= 1.62 mg/m3 =1.6 mg/m3
where:
RDGRet = regional gas deposition ratio in the extrathoracic region
VE	= ventilation rate (m3/day)
SAet = surface area of extrathoracic region (cm2)
A, H = subscripts denoting laboratory animal and human, respectively
(VE)A = 0-14 m3/day (subchronic, female F344 rats; U.S. EPA, 1988)
(VE)H = 20 m3/day (U.S. EPA, 1988)
(SAet)a = 15 cm2 (U.S. EPA, 1994b)
(SAet)h = 200 cm2 (U.S. EPA, 1994b)
A subchronic p-RfC of 0.1 mg/m3 (1E-1 mg/m3) is derived by applying a composite
uncertainty factor of 30 to the human NOAEL of 2.3 mg/m3 (Holness et al., 1989). The
composite UF includes a factor of 10 to protect sensitive individuals and a factor of 3 for
proximity of the animal LOAEL to the human NOAEL and database limitations, including lack
of adequate reproductive and developmental toxicity studies. The UF is applied to the human
NOAELm < of 2.3 mg/m3, as follows:
subchronic p-RfC = NOAELm < / UF
= 2.3 mg/m3 / 30
= 0.1 mg/m3 or 1E-1 mg/m3
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The animal LOAEL of 1.62 mg/m3 is in close proximity to the human NOAEL of 2.3
mg/m3; however, the extrathoracic effects observed in the animal study were mild and reversible.
Furthermore, the animal LOAELm < of 1.6 mg/m3 gives a sixteen-fold comparative ceiling to the
p-sRfC of 0.1 mg/m3. This adds confidence to the human NOAEL. Thus, the human NOAEL is
considered for the derviation of this subchronic p-RfC. Thus the subchronic p-RfC, based on
pharmacokinetics, remained the same as the RfC.
Confidence in the principal study is medium because the study was conducted in humans
(but the sample size was relatively small), data were collected on males only, and a LOAEL was
not identified. Although complaints of exacerbated upper respiratory symptoms were recorded in
the principal study and support the extrathoracic region as the critical region for effects, an
objective assessment of the workers' nasal epithelium was not performed. However, the
observation of mild extrathoracic effects in animals at a HEC similar to the NOAEL support the
human findings.
Confidence in the database is medium. The developmental, reproductive, and chronic
toxicity of ammonia have not been tested, but toxicokinetic data suggest that ammonia is
absorbed by the nasal passages at concentrations comparable to the NOAELm < and systemic
distribution is unlikely (U.S. EPA, 2003). Medium confidence in the subchronic p-RfC follows.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR AMMONIA
Human data on the carcinogenic effects of ammonia or ammonia compounds are not
available. Among animals, no evidence for carcinogenicity was observed in two strains of mice
administered ammonium hydroxide in drinking water for two years or in a urethane-sensitive
strain of mice administered ammonia in water by gavage for 4 weeks. There is some indication
that ammonia contributes to the development of cancer when coadministered with DEPC (via
formation of urethane) or MNNG (via stimulation of cell proliferation in the gastric mucosa).
Limited genotoxicity testing of ammonia has produced mixed results. Under the proposed
guidelines (U.S. EPA, 1999), the data for carcinogenicity of ammonia are inadequate for an
assessment of human carcinogenic potential.
Derivation of quantitative estimates of cancer risk for ammonia is precluded by the
absence of data indicating a carcinogenic effect for this chemical.
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