TECHNICAL REPORT DATA
fflttte ntd Instruction! on tht r-wit btfort compltiuig)
1. REPORT NOi
EPA/600/8-88/017
3. RECIPIENT'S ACCESSION NO.
PB88-179437/AS
4. TITLE AND SUBTITLE
C. REPORT DATE
Health Effects Assessment for Ammonia
«. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
*. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME ANO ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
6. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order J2991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants fcr which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there Is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS ANO DOCUMEN1 ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
8. DISTRIBUTION STATEMENT
Public
1*. SECURITY CLASS (Thit Report)
Unclassified
21. NO. OF PAGES
9. SECURITY CLASS (Thit page)
Unclassified
22. PRICE
EPA f»rm 2220-1 (*». 4-77) PREVIOUS EDITION OMOUKTC
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EPA/600/8-88/017
June. 1987
HEALTH EFFECTS ASSESSMENT
FOR AMMONIA
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
U.S. Environjaental Protection Agency
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DISCLAIMER
This document has been reviewed In accordance with the U.S
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with ammonia.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary reflecting limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document Is current up to Hay,
1986. Secondary sources of Information have also been relied upon 1n the
preparation of this report and represent large scale health assessment
efforts that entail extensive peer and Agency review. The following Office
of Health and Environmental Assessment (OHEA) sources have been extensively
utilized:
U.S. EPA. 1980a. Hazard Profile for Ammonia. Prepared by the
Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of
Solid Waste, Washington, DC.
U.S. EPA. 1981. Ambient Water Quality Criterion for the Protec-
tion of Human Health: Ammonia. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Water Regulations and
Standards, Washington, DC.
U.S. EPA. 1983. Reportable Quantity Document for Ammonia.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
The Intent 1n these assessments Is to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the llfespan).
111
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This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD§ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$i) and oral (RfD$o)
exposures.
The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfOo) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained In U.S.
EPA (1984).
For compounds for which there 1s sufficient evidence of carclnogenlclty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed. If appro-
priate, based on oral and Inhalation data If available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Ammonia, a by-product of metabolism absorbed by the gut, normally
combines with carbon dioxide to form urea. Only when this process Is
saturated are toxic effects of ammonia observed. Data were Inadequate to
develop an RfD$o or RfDg. A taste threshold of 34 mg/l Is proposed,
consistent with U.S. EPA (1981).
When Inhaled, ammonia acts as an Irritant on the upper respiratory
tract. To protect against this effect, an RfO$i or RfOj value of 7.0
mg/day for a 70 leg human or 0.49 mg/kg/day Is recommended, based on the
lower-bound limit of the range for odor detection of 0.36 mg/rn3 (Carson et
al., 1981). A CS of 19, based on hlstopathologlcal lesions In the liver,
spleen and kidney of guinea pigs exposed Intermittently to 119 mg/m3
(Weatherby, 1952) was chosen to represent the toxldty of ammonia.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati. OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . ,
2.1. ORAL ,
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT .
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcT)
Page
. . . . 1
. . . . 4
. . . . 4
. . . . 5
. . . . 7
. . . . 7
. . . . 7
. . . . 9
. . . 14
. . . 14
. . . . 14
. . . 14
. . . 15
... 16
... 16
... 16
... 16
... 17
... 17
... 17
... 18
... 18
... 19
... 21
... 21
... 21
... 21
V11
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TABLE OF CONTENTS
Page
6.2. REFERENCE DOSE (RfD) -. 23
6.2.1. Oral (RfD0) 23
6.2.2. Inhalation (RfDj) 25
6.3. CARCINOGENIC POTENCY (q-|*) 29
7. REFERENCES. 30
APPENDIX 40
V111
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and Half-Lives
for Ammonia 2
3-1 Effects of Subchronlc Inhalation Exposure on Hammals 11
6-1 Composite Scores for the Oral Toxlclty of Ammonia 26
6-2 Composite Scores for the Inhalation Toxldty of Ammonia ... 28
1x
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LIST OF ABBREVIATIONS
BUN Blood urea nitrogen
bw Body weight
CS Composite score
LCso Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
LOAEL Lowest-observed-adverse-effect level
LOEL Lowest-observed-effect level
MED Minimum effective dose
PEL Permissible exposure level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDn, Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfDso Subchronlc oral reference dose
RQ Reportable Quantity
RV
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected physical and chemical properties of ammonia are presented In
Table 1-1.
The atmospheric residence time of ammonia 1s relatively brief. Gener-
ally, combination with sulfate or washout from rainfall accounts for Us
rapid return to water and son (NRC, 1979).
Ammonia Is a basic compound, which commonly occurs In the environment as
the positively charged ammonium Ion. Ammonia/ammonium 1on 1s an Integral
part of the nitrogen cycle, and Its concentration 1n water and soil Is 1n
constant flux (NRC, 1979).
Nitrification 1s Important In reducing the accumulation of ammonia In
receiving waters. The process of nitrification proceeds In two steps each
mediated by different bacterial genera:
NUrosomonas
NH{ >- NO?
NUrobacter
NO? *- N03
This process depends upon available oxygen, temperature, pH and the
mlcroblal population (WHO, 1986). Nitrification may lead to depletion of
dissolved oxygen and acidification. In addition to nitrification, physical
adsorption and chemical binding to suspended solids and sediments, volatili-
zation to the atmosphere, and assimilation by algae and macrophytes can also
be Important removal processes. Thus, 1t appears that the half-life of
ammonia In water 1s highly variable, depending upon such factors as dis-
solved oxygen content, type of mlcroblal species and microbe concentrations,
pH, temperature, current speed and wind velocity as well as other factors
(U.S. EPA, 1981).
0075h -1- 10/16/86
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TABLE 1-1
Selected Physical and Chemical Properties and Half-Lives for Ammonia
Property
Value
Reference
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
PKD:
Half-lives:
A1r:
Soil:
Inorganic nitrogenous
compound
17.03
10 atm at 25°C
5.29xlO» mg/l at 20°C
4.77 at 20°C
16 days (less In polluted air)
days to weeks (1n the
unadsorbed form 1n warm,
moist soils)
Oones, 1973
Jones, 1973
HSDB, 1986
NRC, 1979
007 5h
-2-
10/16/86
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In soil, the ammonium Ion Is fairly Immobile. The ammonium Ion Is
adsorbed onto the negative adsorption sites of clay found In all soils, and
the Ions that are not clay-fixed undergo bacterial fixation to nitrate In
soil (t,/? - days to weeks In warm, moist soils). In addition, relatively
small quantities of ammonia are mineralized and transferred to plants. If
fertilizers are applied without thorough Incorporation Into the soil,
relatively large amounts (up to 50%) of ammonia nitrogen as gaseous NH_
0
may volatilize rapidly under hot, dry and windy conditions (NRC, 1979).
0075h -3- 10/16/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Ammonia, which 1s a by-product of protein and nucleic acid metabolism,
Is readily absorbed by the gastrointestinal tract. Summersklll and Wolpert
(1970) estimated that of the 3080 mg ammonia produced 1n the human gut/day,
-99% 1s absorbed. In healthy Individuals, absorbed ammonia 1s mainly con-
verted to urea In the liver so that relatively small amounts reach systemic
circulation.
In a study by Conn (1972), 9 mg ammonium chloride/kg was administered
orally to 20 healthy adult men and women and to 50 male patients with
cirrhosis of the liver. Normal Individuals showed only a transient Increase
In ammonia concentrations 1n arterial blood. Concentrations peaked (mean,
140 tig ammonia/100 ml) at 15 minutes and returned to fasting levels
(mean, 105 yg ammonia/100 mi) by 30 minutes. About SOX of the subjects
showed no significant rise In arterial ammonia concentrations. Individuals
with cirrhosis of the liver, who had higher fasting ammonia levels (mean,
150 yg ammonia/100 ml), showed much higher blood ammonia concentrations
(mean, 370 yg ammonia/100 ml) at 15 minutes, followed by a slow decrease
that reflected Impaired hepatic urea synthesis. In drrhotlc patients with
portacaval anastomoses, ammonia blood levels were significantly higher than
In patients without shunts.
Absorption of ammonia from the human colon, the major site of ammonia
production. Increases with Increasing pH of the lumlnal contents (Castell
and Moore, 1971). As pH Increases more ammonia Is In the non-Ionized form
and can diffuse from the gut.
0075h -4- 10/16/86
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There 1s also evidence for the active transport of ammonium ion from the
gut. At a lumlnal pH of 5, a pH at which un-1on1zed ammonia would be
virtually absent. Castell and Moore (1971) showed that ammonia transport by
the colon, although greatly diminished, still occurred. Hossberg and Ross
(1967) studied the absorption of ammonia from Isolated Intestinal loops of
the golden hamster and concluded that the preferential site for ammonia
uptake Is 1n the lleum. In the Heum, but not In the jejunum, ammonia was
found to move against a concentration gradient. Cyanide, d1n1trophenol and
anaeroblosls Inhibited ammonia movement In the 1leum, suggesting that an
energy-dependent transport system was operable In the 1leum but not In the
jejunum. Heal transport was not found to be dependent on pH or ammonia
gradients but was observed to be dependent on carbon dioxide and carbonate
concentration, providing additional evidence that Ionic NH* was the
species being actively transported (Hossberg and Ross, 1967; Hossberg, 1967).
2.2. INHALATION
Because 1t Is water soluble, low concentrations of ammonia are largely
absorbed In the mucous coating of the upper respiratory tract, thus protect-
ing the lungs from exposure. Landahl and Herrmann (1950) found nasal reten-
tion of ammonia to be "83% In humans with mean minute volumes of 6-7 l,
exposed to 0.05 mg/i ammonia for short durations (<120 seconds). Total
retention determined at ammonia concentrations between 0.04 and 0.35 mg/i
(40 and 350 mg/m3) was 92+2% for two male subjects tested 4 times.
Retention was Independent of ammonia concentration over the range tested.
Sllverman et al. (1949) exposed seven male volunteers to 500 ppm (350
mg/m3) for 30 minutes. Average Initial ammonia retention was not report-
ed, but In the one example shown, Initial retention was -75%. Retention
decreased progressively until equilibrium was reached In 10-27 minutes.
0075H -5- 10/16/86
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Retention at equilibrium averaged 23% (range 4-30%). Some Irritation was
observed In the nose and throat, leading the authors to suggest that at the
concentration used, ammonia was primarily absorbed by the upper respiratory
tract. BUN, nonproteln nitrogen, urinary urea and urinary ammonia remained
normal 1n these subjects. This 1s In contrast to results reported In an
abstract of a Russian study (Kustov, 1967} In which human subjects were
exposed to 20 ppm (14 mg/m3) for 8 hours and significant Increases In BUN
were observed.
Egle (1973) studied ammonia retention In anesthetized mongrel dogs
(7-37/experlment). Total respiratory tract retention averaged 78% and was
not related to changes In ventilation rate (5-30/m1nute) or ammonia concen-
tration (214-714 ppm or 150-500 mg/m3). The duration of exposure was not
reported. To measure ammonia retention for the upper and lower respiratory
tracts separately, Egle (1973) severed the trachea just above the bifurca-
tion. Retention In the lower tract alone averaged 78%. Retention again
averaged 78% when ammonia vapor was drawn through the nose and out the
trachea and then returned. In one-way passage from the nose through the
trachea, retention averaged 88%, Indicating that concentrations of Inhaled
ammonia reaching the lungs were substantially lower than ambient concen-
trations.
Schaerdel et al. (1983) exposed four groups of rats (8/group) to average
ammonia concentrations of 11, 23, 220 or 826 mg/m3. Ammonia In the blood
was measured at 0, 8, 12 and 24 hours. At the two lowest concentrations,
there was no Increase In blood ammonia. At the two higher doses, signifi-
cant Increases at the 8-hour time point were noted. After 12 and 24 hours
the Increases were not as marked.
0075h -6- 10/16/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC TOXICITY
3.1.1. Oral. The oral toxlclty of ammonia has been studied using ammo-
nium salts as the dosing agents, and the results of these studies will be
presented 1n this document even though many effects such as metabolic addo-
sls observed were the result of the anlon rather than effects attributable
to ammonia. Only those studies performed at doses sufficiently low to
suggest thresholds are discussed here.
Lemann et al. (1966) studied the electrolyte balance of five men who
received ammonium chloride. After control observations were made, the men
were given total oral doses of 733 mEq ammonium chloride over a 6-day
"loading period" (-93 mg/kg/day), followed by a total of 2771 mEq from days
7-18 (-177 mg/kg/day). Serum bicarbonate levels dropped Initially but
stabilized by day 12 of treatment and rose slightly between days 12 and 18,
despite the retention of add that occurred throughout the study. Calcium
and phosphorus were lost during treatment, suggesting to the authors that
the slow resorptlon of bone mineral was providing an additional buffering
capacity. The U.S. EPA (1981) reviewed several short-term studies 1n humans
that Indicated that metabolic acldosls, Impaired glucose tolerance and
reduced tissue sensitivity to Insulin may result from doses of ammonium
chloride >100 mg/kg/day. Although frank effects were not reported, the U.S.
EPA (1981) expressed concern for the potential for bone demlnerallzatlon as
a result of Impaired acid-base balance. The U.S. EPA (1981) calculated 100
mg/kg/day of ammonium chloride to be equivalent to 31.8 mg/kg/day ammonia.
0075h -7- 10/16/86
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Freedman and Beeson (1961) gave 12 adult male Sprague-Dawley rats 1.6X
ammonium chloride In their drinking water for up to 3 weeks and examined
them for evidence of renal Injury. Ur1nalys1s and gross and hlstopatho-
loglcal examinations of the kidneys at necropsy revealed no abnormalities.
Glutamlnase activity per g of kidney Increased with duration of exposure.
Indicating a physiological adaption to addosls. An additional 10 rats were
treated as above, but were then given drinking water containing 1% ammonium
chloride for an additional 2.5 months. These rats also had no gross or
microscopic renal abnormalities. No data on water consumption or body
weights of the rats were provided; therefore, a precise dally Intake cannot
be calculated. Assuming the rats weighed 250 g and drank 25 ml of water/
day, the rats given the 1.6X concentration or the IX concentration In drink-
Ing water could have Ingested as much as 1.6 and 1.0 g/kg bw/day, respec-
tively, resulting In a TWA Intake of ammonia of "360 mg/kg/day. Actual
Intakes may have been lower because ammonium chloride 1s known to affect the
appetite and may render the water less palatable.
In a study by Gupta et al. (1979), ammonium sulfamate was given "orally"
to adult female rats and weanling male and female rats ITRC colony-bred
albino) at 100, 250 or 500 mg/kg bw/day, 6 days/week for 30, 60 or 90 days
as a 10% solution 1n water. Twenty rats/sex/age/dose leve< were used. The
effective dose of ammonia at each dose level 1s difficult to determine,
since under certain conditions, sulfamate Ion 1s hvdrolyzed-to blsulfate 1on
and ammonia, and whether this hydrolysis occurs 1n the *at Intestine Is
uncertain. Assuming no hydrolysis, the ammonia doses can be estimated to be
15.0, 37.3 or 74.8 mg ammonia/kg bw/day. The effect of the anlon, sulfamate
and sulfate on the action of ammonium Is a matter of conjecture. According
0075h -8- 10/16/86
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to Gupta et al. (1979) ammonium sulfamate would be expected to produce
metabolic addosls on the basis of Us structure, but this result does not
appear to have been verified experimentally.
The treated and control rats appeared to be healthy, and the only
significant weight difference was a slight depression In the highest-dose
adult females at 60 and 90 days. Food and water consumption were unaffected
except In the highest-dose weanlings of both sexes, which had lower food and
higher water consumption than did control weanlings. At necropsy, hemato-
logical and hlstologlcal examinations were conducted. No significant
differences In selected hematologlcal values were observed. Relative organ
weights of all treated groups were not significantly different from
controls. Hlstologlcal examination of selected major organs and tissues
showed no abnormalities except slight hepatic fatty degeneration In one
adult female at 90 days.
3.1.2. Inhalation. Ferguson et al. (1977) exposed six volunteers (five
male and one female) to ammonia for 5 weeks. The volunteers were divided
Into three groups and were exposed 2-6 hours/day to respective ammonia
levels of 25, 50 and 100 ppm (17, 35 and 70 mg/m3}. Exposure patterns
varied among groups, complicating the Interpretation of results. A statis-
tically significant Increase In forced expiratory volume as ammonia concen-
tration Increased was reported. This Increase averaged only 4X from the low
to the high dose. No differences were reported among groups for respira-
tion, forced vital capacity, pulse or blood pressure. For the group exposed
to a constant pattern to 50 ppm over 6 weeks, none of the variables varied
significantly. The authors claimed that subjects became Inured to eye, nose
and throat Irritation, but this conclusion was not clearly shown by data
presented (U.S. EPA, 1981).
0075h -9- 10/16/86
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Effects of subchronlc Inhalation exposure on laboratory animals are
summarized In Table 3-1. Only two of these studies (Coon et a!., 1970;
Broderson et al.t 1976) were performed at doses low enough to define thresh-
olds and were reported 1n sufficient detail to permit evaluation for risk
assessment.
Coon et al. (1970) exposed rats and guinea pigs of both sexes and male
rabbits, monkeys and dogs to ammonia, 8 hours/day, 5 days/week for 6 weeks
or continuously for 65-114 days. Ammonia concentrations used were 155 or
770 mg/m3 for Intermittent exposures and 40 or 470 mg/m3 for continuous
exposure, except for rats, which were also exposed to 455, 262 or 127
mg/m3 continuously. The parameters examined were hlstochemlcal determina-
tions, blood analyses, visible signs of toxldty and hlstopathologlcal
examination of heart, lung, liver, kidney and spleen from all species, and
brain, spinal cord and adrenals from monkeys and dogs, as well as thyroid
tissue from dogs.
.The only abnormality observed In any species exposed to 155 mg/m3
Intermittently was evidence of focal pneumonltls In the lung of one of the
three monkeys. At the 770 mg/m3 Intermittent exposures, rabbits and dogs
had mild to moderate lacMmatlon and dyspnea during the first week. These
signs disappeared during the second week and no further signs of Irritation
or toxlclty were observed. The only other observation noted was rather
consistent nonspecific Inflammatory changes In the lungs of exposed rats and
guinea pigs that were more extensive than 1n control animals.
No signs of toxlclty were observed In any species exposed continuously
to ammonia at 40 mg/m3 for 114 days. R?ts exposed continuously to ammonia
at 127 mg/m3 also showed no specific chemically-Induced changes. At 262
0075h -10- 10/20/86
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mg/m3, -25% of the 49 rats exposed had mild nasal discharge. Nonspecific
circulatory and degenerative changes In lungs and kidneys were observed but
were difficult to relate specifically to ammonia Inhalation.
At 455 mg/m3, 32/51 rats died by day 25 of exposure and by day 65,
when the experiment was terminated, 50 had died. All rats showed mild signs
of dyspnea and nasal Irritation. H1stopatholog1cal examinations were not
performed on these rats.
At 470 mg/m3, 13/15 rats and 4/15 guinea pigs died. Oogs and rabbits
showed marked eye Irritation. At necropsy, moderate lung congestion was
observed 1n two rabbits, and one dog had a hemorrhaglc lesion of a lung. In
all animals examined, hlstopathologlcal examination showed focal or diffuse
Interstitial pneumonltls. Also observed In several animals of each species
were calcification of renal tubular and bronchial epHhella, proliferation
of renal tubular epithelium, myocardlal flbrosls and fatty changes of the
liver plate cells. These changes were also observed 1n control animals but
were less severe. Throughout these experiments (Coon et al., 1970), no
pathological examinations of the upper respiratory tract were made.
In a study by Broderson et al. (1976), Sherman and Fischer pathogen-free
rats In groups of 10-12 of each sex were exposed to ammonia from soiled
bedding at 153+35 ppm (105 mg/m3) for 75 days or to purified ammonia at
250±8 ppm (175 mg/m3) for 35 days. Pathological changes were observed In
the nasal passages of all exposed rats. The changes observed were Increased
thickness of the respiratory and olfactory epithelium with pyknotlc nuclei
In many cells along the basement membrane and hyperplasla of epithelial
cells with the formation of glandular crypts. These lesions decreased 1n
Intensity posteriorly. The submucosa of the nasal passages was widened by
dilation of small vessels and edema. Replacement of submucosal glands with
collagen was observed and a few lymphocytes and neutrophlls were present.
0075h -13- 10/20/86
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312. CHRONIC
3.2.1. Oral. In a study by Fazekas (1939), rabbits were treated with
ammonium hydroxide by gavage at 100 mg/kg bw on alternate days and then
dally for up to 17 months. This treatment resulted 1n enlarged adrenal
glands and an Increase In blood pressure to 10-30 mm Hg above baseline after
several months of treatment.
Barzel and Jowsey (1969) gave male Sprague-Oawley rats (250 g, 10-12/
group) 1.5% ammonium chloride 1n their drinking water and a regular or
calcium-deficient diet for 330 days. Rats on both diets showed statisti-
cally significant decreases 1n bone (femur) fat-free solid and calcium
content as compared with controls. Bone length and plasma calcium and
phosphorus levels were unaffected. Blood pH and plasma carbon dioxide were
decreased only In the regular diet group. Rats 1n both treated groups
weighed significantly less and had smaller accumulations of body fat than
did control rats receiving the same diets. Similar results were obtained In
Intact or ovarlectomlzed female rats treated with 1.5% ammonium chloride In
the drinking water for 300 days (Barzel, 1975). A regular diet was used In
both groups of rats.
Lifetime studies with ammonium hydroxide In drinking water were
conducted 1n two strains of mice by Toth (1972). This study did not address
noncarclnogenlc endpolnts and 1s not discussed further In this section.
3.2.2. Inhalation. Pertinent data regarding the effects of chronic Inha-
lailoi exposure to ammonia could not be located In the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the teratogenlc and reproductive effects of
ammonia by either the oral or Inhalation routes of exposure could not be
located In the available literature.
0075h -14- 10/20/86
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3.4. TOXICANT INTERACTIONS
Dalhamn (1963) found no synerglstlc effect of ammonia and carbon
particles on the breathing rate of rabbit tracheal c1Ua. In the study a
technique was used In which an air pollutant mixture could be drawn Into the
nostrils and out through a tracheal cannula Implanted In a live rabbit
breathing through another tracheal opening.
Zleve et al. (1974) found that simultaneous Injection of an ammonium
salt and a fatty add Into normal rats or cats produced coma at lower plasma
levels of ammonia and free fatty adds than single Injections of the
compounds. In rats, Injected sodium octanoate or Inhaled methanethlol
Interfered with the metabolism of an Injected dose of ammonium acetate, as
evidenced by higher blood ammonia levels than those resulting from the
ammonium dose alone. The authors suggested that the synerglsm of these
compounds plays a role In human hepatic coma.
Broderson et al. (1976) Inocculated pathogen-free Sherman and Fischer
rats Intranasally with Hycoplasma pulmonls and then exposed the rats to
ammonia at concentrations of 25-250 ppm. A dose-related Increase 1n the
prevalence of pneumonia, but not the other respiratory lesions caused by M.
pulmonls. was observed.
0075h -15- 06/16/87
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4. CARCINOGENICITY
4.1. HUNAN DATA
No conclusive evidence of the carcinogenic potential of ammonia In
humans was found; however, evidence that suggests the possibility of ammonia
playing an Indirect role In Inducing cancer In humans Is available.
4.1.1. Oral. The higher Incidence of colonlc cancer In countries with
populations that consume diets high In animal protein and low In fiber may
provide some evidence that ammonia has an etlologlc role In this cancer
(Vlsek et a!., 1978) . A major detoxification product of protein 1s urea.
Approximately 25X of this urea 1s excreted Into the Intestinal tract where
It 1s hydrolyzed by bacterial urease to ammonia (U.S. EPA, 1981). BurkHt
(1975) noted that the Incidence of polyps and cancers are highest 1n areas
of the large bowel where ammonia concentrations are highest. BurkHt (1978)
hypothesized that the role of fiber In reducing colon cancer Is a result of
Its ability to enhance excretion of nitrogenous products. Fiber also
provides an Increased level of fatty acids, which decreases the pH of the
colon and provide anlons to trap free ammonia (Cunnings, 1981).
Tannenbaum et al. (1978, 1980) and Tannenbaum and Young (1980) also
suggested that amonla may be converted to nitrite In the small Intestines by
heterotrophlc nitrification and then react to form N-nHroso carcinogens.
This suggestion has been disputed by Witter et al. (1981); the role of
ammonia In such a process has not been proven.
4.1.2. Inhalation. Shlmkln et al. (1954) reported an Isolated case of a
white male who showed evidence of epidermal carcinoma of the nasal septum
within 6 months after being accidentally .burned by a ammonia-oil mixture.
This case may represent a coincidental chain of events.
0075h -16- 06/16/87
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Blttersohl (1971) commented on the numerous cancer cases occurring In
workers who deal with ammonia In an East German factory. Ammonia exposure
levels were described and concomitant exposures to asbestos were mentioned,
but no Information concerning the population exposed, exposure duration or
cancer rates was provided.
4.2. BIOASSAYS
4.2.1. Oral. Toth (1972) administered ammonium hydroxide 1n drinking
water at 0.1, 0.2 or 0.3% to male and female Swiss mice for their lifetime.
Inbred male and female C3H mice were provided with drinking water containing
1.0% ammonium hydroxide throughout their lifetime. Average water consump-
tion/day was reported for each sex and dose group, but animal weights were
not reported. Using an average mouse weight of 30 g, respective dose
estimates are 290, 490 and 565 mg/kg bw/day for Swiss mice exposed at 0.1,
0.2 and 0.3%, and 270 mg/kg bw/day for C3H mice exposed at 1%. These
estimates are likely to be low 1f dose-related weight reduction occurred.
No carcinogenic effect was noted In this study (Toth, 1972). Ammonium
hydroxide did not Increase or Inhibit the development of adenocardnoma of
the mammary gland In C3H females, a tumor commonly occurring In this strain.
In a study by Uzvdlgl and Bojan (1980), no significant Increase In lung
tumors was observed In mice with a high sensitivity to lung tumors after
receiving 42 mg/kg ammonia 2 times/week by gavage for 4 weeks. Uzvdlgl and
Bojan (1985) also found that mice treated repeatedly with dlethyl
pyrocarbonate and ammonia by gavage developed tumors. Dlethyl pyrocarbonate
alone did not cause lung tumors.
4.2.2. Inhalation. Pertinent data regarding the carcinogenic potential
of ammonia following Inhalation exposure could not be 1oca led 1n the
available literature.
0075h -17- 10/20/86
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4>.3. OTHER RELEVANT DATA
Litton Blonetlcs, Inc. (1975) reported that ammonium sulfate was not
mutagenlc In the Salmonella and Saccharomyces systems. Other tests have
suggested that ammonia may have weak mutagenlc activity 1n lower organisms.
Ammonia was found to Induce back-mutations from streptomycin dependence to
nondependence In EscheMchla coll but only 1n treatment that left <2X
survivors (Demerec et al., 1951). Lobashov and Smlrnov (1934) and Lobashov
(1937) found that ammonia showed slight mutagenlc activity 1n DrosophUa In
tests where survival was <2X after treatment. Auerbach and Robson (1947)
observed 0.5X sex-Hnked lethal mutations In Drosophlla exposed to ammonia
vapor 1n small glass containers, also suggesting a very slight mutagenlc
response. Rosenfeld (1952) reported that ammonia can Induce clumping of
chromosomes, arrest spindle formation and result In polyploldy 1n chick
flbroblasts in vitro.
4.4. WEIGHT OF EVIDENCE
No conclusive evidence was found to show that ammonia 1s carcinogenic 1n
humans or experimental animals. Hutagenlclty assays Indicate that ammonia
may have slight mutagenlc activity In lower organisms. Ammonia has not been
tested for mutagenlc potential In mammals.
Because of the lack of evidence concerning the carcinogenic potential of
ammonia, ammonia can be placed In IARC Group 3, Inadequate evidence nf
carclnogenlclty. According to the EPA classification system (U.S. EPrt,
1986b), ammonia Is a Group D chemical, meaning that there Is Inadequate
animal evidence of carclnogenlclty.
0075H -18- 05/16/87
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5. REGULATORY STANDARDS AND CRITERIA
The ambient water quality criterion for ammonia (NH3 and NH^)
for the protection of human health Is 35 mg/l when expressed as NH3, or
28.8 mg/l as ammonia-nitrogen (U.S. EPA, 1981). Because ammonia In
ambient water 1s a greater threat to aquatic life than to human health, a
maximum value for un-1on1zed ammonia of 0.02 mg/l as NH has been
-------
The ACGIH (1948) reported the maximum acceptable concentration for
ammonia to be 100 ppm (70 mg/m'). which later became a TLV. The TLV was
reduced to 50 ppm (35 mg/m3) to protect against respiratory Irritation
(ACGIH, 1963). The ACGIH (1971) recommended a TWA of 25 ppm (17.5 mg/m3)
as the TLV, which was then adopted by ACGIH (1973) as the 'maximum accept-
able concentration without severe complaints)" and Is now the present TLV
(ACGIH. 1986). The ACGIH (1986) adopted 35 ppm as a STEL; the OSHA (1985)
PEL 1s also 35 ppm (50 mg/m3).
0075H -20- 10/20/86
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfD-g). Several subchronlc studies using animals and one
with humans on the effects of ammonia salts were reviewed by the U.S. EPA
(1981); the more pertinent data were reviewed In Section 3.2.1. Generally,
effects occurred In humans at dosages lower than those that caused effects
In animals. Gupta et al. (1979) reported reduced body weight In adult
female rats treated with ammonium sulfamate for up to 90 days at 500
mg/kg/day, corresponding to 74.8 mg ammonla/kg/day. Lemann et al. (1966),
however, noted disturbed acid-base balance 1n humans receiving ammonium
chloride at -149 mg/kg/day (ammonia equivalent of -47.4 mg/kg/day). The
U.S. EPA (1980a) reviewed shorter-term studies In humans In which ammonium
chloride at 100 mg/kg/day,' equivalent to 31.8 mg/kg/day ammonia, was
associated with disturbed add-base balance, glucose tolerance and tissue
sensitivity to Insulin. Animal models may, therefore, be an Inappropriate
model for the toxldty of ammonia to humans. This Issue Is further confused
by the fact that the toxldty of ammonia has not been tested; oral studies
used various ammonium salts, and the contribution of the anlon to the
toxldty of the compound Is difficult to determine.
The WHO (1986) has suggested a taste threshold of 35 mg/l, which Is
felt to be protective for health endpolnts.
6.1.2. Inhalation (RfO-,). The pharnuicoklnetlcs of Inhalation exposure
to ammonia differs from that oral of exposure. Ammonia 1s absorbed by the
mucous of the upper respiratory tract, with very little reaching the lungs
(see Section 2.2.). Because ammonia concentrates In the upper respiratory
tract, the first signs of toxldty are observed at this site. Unfortu-
nately, the Inhalation studies of Coon et al. (1970) and Ueatherby (1952)
0075h -21- 06/16/87
-------
did not examine the upper respiratory tract for signs of toxldty. Upper
respiratory tract toxldty was observed 1n the studies by Richard et al.
(1978) and Broderson et al. (1976), which both used pathogen-free rats.
Pathological changes of the respiratory tract were observed at a lower
concentration In the study by Broderson et al. (1976); therefore, that study
1s the best animal study available for use In Inhalation risk assessment.
Broderson et al. (1976) exposed 10 male and 10 female pathogen-free
Sherman rats to ammonia at an average concentration of 105 mg/m3 continu-
ously for 75 days. The pathological changes observed were Increased thick-
ness of olfactory and respiratory epHhella of the nasal cavity, showing
pyknotlc nuclei and hyperplasla. These lesions decreased In Intensity
posteriorly. The submucosa of the nasal cavity had edema and small vessels
were dilated.
The LOEL observed 1n rats Is calculated by multiplying 105 mg/m3, the
exposure concentration, by the reference rat Inhalation rate 0.223 mVday
and by dividing by 0.35 kg, the reference rat weight (U.S. EPA, 1980b) to
obtain 66.9 mg/kg/day as a LOEL. Applying an uncertainty factor of 1000 (10
for Interspecles extrapolation, 10 for Individual variability, 10 for calcu-
lating an RfD-j from a LOEL), a possible human RfD-, for ammonia of 0.07
mg/kg/day of 4.9 mg/day may be calculated for a 70 kg human. This value 1s
slightly less than the RfDj of 7.0 mg/day calculated from the odor
threshold as described 1n Section 6.2.2. Since the choice of the odor
threshold as the basis for the RfO. reflects the Inadequacies associated
with the animal toxldty studies, the RfD, of 0.1 mg/kg/day or 7.0 mg/day
for ammonia Is adopted as f.he RfD-j for ammonia. Since this Is an odor
threshold 1t Is most appropriately expressed as 0.36 mg/m3.
0075h -22- 06/16/87
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6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfOQ). Three chronic oral animal studies with ammonium
salts were available. In one, rabbits treated by gavage with ammonium
hydroxide at -100 mg/kg/day (-48.6 mg ammonla/kg/day) by gavage for up to 17
months had enlarged adrenal glands and elevated blood pressure (Fazekas,
1939). In the other two experiments (Barzel and Jowsey, 1969; Barzel, 1975)
rats of both sexes consuming ammonium chloride at 1.5X of their drinking
water (estimated to be 477 mg ammonla/kg/day) for 300-330 days had decreased
bone content of fat-free solid and decreased bone content of calcium. These
studies fall to define thresholds for toxldty to ammonia below that (31.8
mg/kg/day) associated with disturbed acid-base balance, glucose tolerance
and tissue response to Insulin In humans In very short-term studies.
Ammonia Is an endogenous molecule produced In the catabollsm of proteins
and nucleic acid and used In the synthesis of these compounds. In humans,
excess ammonia 1s combined with carbon dioxide by the urea cycle.
Because ammonia Is endogenous, a tox1c1ty-based criterion should be
derived from an estimate of the amount of excess ammonia that can be
tolerated without saturating homeostatlc control mechanisms. Unfortunately,
studies us^ng oral exposure to address this Issue are not available. The
following discussion will attempt to define a clearly undesirable level of
oral exposure-to ammonia, as well as levels that are clearly tolerable.
The normal human absorbs -4 g of ammonia/day, primarily from urea and
protein catabollsm 1n the gut (Summerskill and Wolpert, 1970). Using an
average body weight of 70 kg, 50-60 mg/kg Is a reasonable estimate of dally
ammonia uptake.
0075h -23- 06/16/87
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The amount of excess ammonia that can be safely Ingested Is difficult to
define. Most studies have used ammonium chloride as the dosing agent;
effects In these studies are often the result of metabolic acldosls rather
than effects of ammonia. In the study by Lemann et al. (1966), metabolic
acldosls was Induced In five human males after a TWA dally dose of 149 mg/kg
ammonium chloride over an 18-day period. In shorter studies (1-8 days)
[reviewed In U.S. EPA (1981)]. metabolic acldosls as well as Impaired
glucose tolerance and tissue sensitivity to Insulin has been Induced In
humans at doses of ammonium chloride as low as 100 mg/kg/day (OeFronzo and
Beckles, 1979; Hahnensmlth et al., 1979; Edelmann et al., 1967). In longer-
term studies In experimental animals (see Section 3.1.1.), no adverse
effects were reported at higher levels of ammonia Intake.
In theory, an RfO can be calculated from the LOAEL In previous studies
using accepted methodology (U.S. EPA, 1980b). RfOs calculated by this
methodology (uncertainty factor of 100 for short-term human data and a
factor of 1-10 for using a LOAEL) would range from 0.032-0.32 mg/kg/day, and
have been rejected by the U.S. EPA (1981) as being unreasonably low when
compared with dally absorption of 50-60 mg/kg ammonia from the gut. In
addition, there are no reports of adverse effects associated with the
1ngest1on of ammonia salts as food additives. Ammonia Ingestlon from food
additives Is estimated to average -0.25 mg/kg/day (18 mg/day) and could
reach -20 mg/kg/day (-1400 mg/day) In some diets (FASEB, 1974). From this
Information, It Is evident that an RfO somewhat higher than that calculated
by normal procedures will be protective.
In lieu of adequate health data, the U.S. EPA (1981) used organoleptlc
data to help pinpoint acceptable ammonia Intake. In a study by Campbell et
al. (1958) using taste "difference tests of the triangle type," the taste
0075H -24- 12/31/86
-------
threshold was determined to be 34 mg/t. A summary by Pfaffmann (1959)
states that thresholds have been determined for ammonium chloride 1n water
at 53.5, 107 and 482 mg/l (17-153 mg/l as ammonia). How much the
chloride Ion contributes to the detection of ammonium chloride Is uncertain.
Details of the studies finding these thresholds were not available; there-
fore, a meaningful comparison with the Campbell et al. (1958) study cannot
be made. Because of the uncertainty In taste threshold determination, the
U.S. EPA (1981) concluded that the palatabHUy of water Is not likely to be
significantly affected by total ammonia levels <35 mg/l (as NH-). This
J
Is the same conclusion reached by WHO (1986).
The U.S. EPA (1981) recommended 35 mg/l (28.8 mg/l as ammonium
nitrogen) as the ambient water quality criterion to protect human health.
Since this criterion level Is based upon an organoleptlc level rather than
upon systemic toxlclty It would be Inappropriate to extrapolate an RfDQ
value 1n units of mg/kg/day. However, there 1s consensus that the 35 mg/l
level Is below that which would contribute to adverse health effects as an
additional ammonia Increment from contaminated water. The actual "accept-
able" level In terms of health endpolnts may be higher but cannot be
accurately projected based upon available data.
In determining the RQ for ammonia, CS values were calculated (U.S. EPA,
1983). The values calculated from oral data are presented 1n Table 6-1.
The highest CS for ammonia was from an Inhalation study and will be
presented In Section 6.2.2.
6,2.2. Inhalation (RfO,). There were no chronic Inhalation studies
available for ammonia. One approach for deriving an RfO, Is to d1v1.de the
RfDSI by an additional uncertainty factor of 10. An RfD, of 0.007
0075H -25- 06/16/87
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mg/kg/day or 0.49 mg/day for a 70 kg human can be calculated. Because of
the large amount of uncertainty In this value and because the value seems
unreasonably low, U Is not recommended as the RfDj.
In a review of all the ammonia Inhalation studies, Carson et al. (1981)
recommended that, because of the lack of studies of the effects of ammonia
at low concentrations, the odor threshold, 3.6 mg ammonla/m3, should be
the upper bound of the range of concern. Applying an uncertainty factor of
10, 0.36 mg ammonla/m3 was recommended as the lower bound limit of the
range of concern. In contrast, WHO (1986) concluded that the best estimate
for an odor threshold was 35 mg/m3 with sensitive Individuals potentially
able to detect -3.5 mg/m3. WHO (1986) did not draw any conclusions
concerning limits for acceptable exposure. The concentration In air of 3.6
mg/m3 1s substantially below the TLV of 25 ppm (-18 mg/m3) recommended
by ACGIH (1986) Intended to protect against ocular and respiratory Irrita-
tion and may serve as the basis for an RfD,. Since 0.36 mg/m3 1s the
lower bound limit of the range of concern, 1t should not be necessary to
apply an uncertainty factor of 10 for unusually sensitive Individuals.
Using a 70 kg human reference body and an Inhalation rate of 20 mVday,
the corresponding dosage Is 0.1 mg/kg/day or 7.0 mg/day for ammonia. This
value 1s slightly larger than 4.9 mg/day calculated as a possible RfDSj-
Since this value 1s based on potential Irritation and odor detection follow-
ing Inhalation exposure, 1t Is most appropriately expressed as the air
concentration.
CSs for ammonia from Inhalation studies are presented In Table 6-2, and
were calculated using the method Indicated. U.S. EPA (1983) calculated CSs
using an older methodology. HEDs were calculated assuming th?t Inhalation
exposures result In equivalent absorbed doses 1n mg/kg/day among species and
0075h -27- 06/16/87
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using an absorption efficiency of 0.5 (U.S. EPA, 1983). Because of the
different methods of calculating HEDs, the CSs 1n this document are higher
than those reported In U.S. EPA (1983). The highest CS, 19, was calculated
for hlstopathologlcal effects 1n the liver, kidney, adrenal and spleen of
guinea pigs exposed Intermittently to 119 mg/m3 (Heatherby, 1952).
6.3. CARCINOGENIC POTENCY (q^)
Ammonia has not been shown to be carcinogenic by either the oral or
Inhalation routes of exposure; therefore, no q,* values can be calculated.
0075h -29- 06/16/87
-------
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1948.
Transactions of the 10th Annual Meeting, Boston, March 27-30. p. 30.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1963.
Threshold Limit Values for 1963. Cincinnati, OH. p. 3.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1971.
Documentation of the Threshold Limit Values for Substances 1n Workroom A1r.
Cincinnati, OH. p. 11.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1973.
THreshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1973. Cincinnati, OH. p. 10.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
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Auerbach, C. and J.M. Robson. 1947. Tests of chemical substances for
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Barzel, U.S. 1975. Effect of chronic ammonium chloride 1ngest1on on
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0075h -30- 06/16/87
-------
Barzel, U.S. and J. Jowsey. 1969. Effects of chronic add and alkali
administration on bone turnover 1n adult rats. Clln. Sc1. 36(3): 517-524.
BUtersohl, G. 1971. Ep1dem1olog1cal studies of cancer In chemical
Industries. Arch. Geschwulstforsch. 38: 198. (Cited 1n U.S. EPA, 1981)
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environmental ammonia In respiratory mycoplasmosls of rats. Am. J. Pathol.
85: 115-130.
Burkltt, D.P. 1975. Benign and malignant tumors of large bowel, in:
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Burkltt, D.P. 1978. Workshop V - Fiber and cancer: Summary and recommenda-
tions. Am. J. Cl1n. Nutr. 31: 312. (Cited In U.S. EPA, 1981)
Campbell, C.L., R.K. Dawes, S. Deolalkar and H.C. Merrltt. 1958. Effect of
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0075h -31- 06/16/87
-------
.Castell, DoO. and E.W. Moore. 1971. Ammonia absorption from the human
colon. Gastroenterology. 60(1): 33-42. (Cited fn WHO, 1986)
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Conn, H.O. 1972. Studies of the source and significance of blood ammonia.
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Med. 45: 543-549.
Coon, R.A., R.A. Jones, L.J. Jenkins, Jr. and J. Slegel. 1970. Animal
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and ethanol. Toxlcol. Appl. Pharmacol. 16: 646-655.
Cummlngs, J.H. 1981. Dietary fiber. Br. Med. Bull. 37: 65. (Cited In
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Dalhamn, T. 1963. Effect of ammonia alone and combined with carbon
particles on ciliary actlvHy 1n the rabbit trachea jjn vivo, with studies of
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531-539. (Cited In WHO, 1986)
DeFronzo, R.A. and A.P. Bec
-------
Ecological Analysts, Inc. 1981. The sources, chemistry, fate and effects
of ammonia In aquatic environments. American Petroleum Institute, Wash-
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Edelman, C.M., Jr., H. Bolchls, J.R. Soriano and H. Stark. 1967. The renal
response of children to acute ammonium chloride addosls. Red 1 at. Res. 1:
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Egle, J.L. 1973. Retention of Inhaled acetone and ammonia In the dog. Am.
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Fazekas, I.G. 1939. Experimental suprarenal hypertrophy Induced by ammo-
nium hydroxide. Endokrlnologle. 21: 314-337. (Ger.) (CUed 1n WHO, 1986)
Ferguson, W.S., W.C. Koch, L.B. Webster and J.R. Gould. 1977. Human
physiological response and adaptation to ammonia. J. Occup. Hed. 19:
319-326.
Freedman, L.R. and P.B. Beeson. 1961. Experimental pyelonephritis. VIII.
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0075h -33- 06/16/87
-------
Gupta, B.N., RoN. Khanna and K.K. Datta. 1979. Toxlcologlcal studies of
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HSDB (Hazardous Substance Data Bank. 1986. Report No. 162. National
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Jones, K. 1973. Ammonia. In: Comprehensive Inorganic Chemistry, J.C.
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Kustov, V.V. 1967. Means for determining the maximum allowable concentra-
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Lemann, J., Jr., J.R. LUzow and E.J. Lennon. 1966. The effects of chronic
acid loads tn normal man: Further evidence for the participation of bone
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0075h -34- 06/16/87
-------
Litton Blonetlcs. Inc. 1975. Mutagenlc evaluation of compound FOA 73-42
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auf der Mutations prozess de: DrosophUa melanoqaster. Genetlca. 19: 200.
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non-disjunction and Transgenatlonen b1e DrosophUa melanoqaster. Dokl.
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U.S. EPA, 1983)
MahnensmHh, R., S.O. Thler, C.R. Cooke, A. Broadus and R.A. DeFronzo.
1979. Effect of acute metabolic addenda on renal electrolyte transport In
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0075h -35- 06/17/87
-------
NRC (National Research Council). 1979. Ammonia, University Park Press,
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0075h -36- 06/16/87
-------
Sllverman, L., J.L. WhHtenberger and J. Huller. 1949.. Physiological
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0075h -37- 06/16/87
-------
U.S. EPA. 1980b. Guidelines and Methodology for the Preparation of Health
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0075h -38- 06/17/87
-------
*
Uzvdlgl, E. and F. Bojan. 1980. Possible In vivo formation of a cardno-
r ~~ ~-^~
genie substance from dlethyl pyrocarbonate and ammonia. J. Cancer Res.
Cl1n. Oncol. 97: 205-207. (Cited 1n U.S. EPA, 1986b)
Uzvolgl, E. and F. Bojan. 1985. ln_ vivo formation of a carcinogenic
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WHO (World Health Organization). 1986. Environmental Health Criteria. 54.
Ammonia. WHO, Geneva, Switzerland.
Witter, J.P., S.J. Gatley and E. Ballsh. 1981. Evaluation of nitrate
synthesis by Intestinal microorganisms J^ vivo. Science. 213: 449-450. .
Z1eve, L., W.M. Oo1zak1 and F.J. Z1eve. 1974. Synerglsm between mercaptans
and ammonia or fatty adds In the production of coma: A possible role for
mercaptans In the pathogenesls of hepatic coma. J. Lab. Clln. Med. 83:
16-28. (Cited 1n WHO, 1986)
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