*>EPA
EPA/635/R-18/041
IRIS Assessment Plan
www.epa.gov/iris
IRIS Assessment Plan for Ammonia and Ammonium Salts:
Noncancer Assessment for Oral Exposure
(Scoping and Problem Formulation Materials)
[CASRN 7664-41-7]
April 2018
NOTICE
This document is a Problem Formation Draft. This information is distributed solely for the
purpose of pre-dissemination peer review under applicable information quality guidelines. It has
not been formally disseminated by EPA. It does not represent and should not be construed to
represent any Agency determination or policy. It is being circulated for review of its technical
accuracy and science policy implications.
Integrated Risk Information System
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

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IRIS Assessment Plan for Ammonia (Oral Exposure)
DISCLAIMER
This document is a preliminary draft for review purposes only. This information is
distributed solely for the purpose of pre-dissemination review under applicable information quality
guidelines. It has not been formally disseminated by EPA. It does not represent and should not be
construed to represent any Agency determination or policy. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ammonia (Oral Exposure)
CONTENTS
AUTHORS | CONTRIBUTORS	vi
1.	INTRODUCTION	1
2.	SCOPING AND INITIAL PROBLEM FORMULATION	3
2.1. BACKGROUND	3
2.2.SCOPING SUMMARY	6
2.3.	PROBLEM FORMULATION	9
2.4.	KEY SCIENCE ISSUES	14
3.	OVERALL OBJECTIVE, SPECIFIC AIMS, AND DRAFT POPULATIONS, EXPOSURES,
COMPARATORS, AND OUTCOMES (PECO) CRITERIA	15
3.1.	SPECIFIC AIMS	15
3.2.	DRAFT PECO CRITERIA	16
REFERENCES	19
This document is a draft for review purposes only and does not constitute Agency policy.
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TABLES
Table 1. EPA program and regional office interest in an assessment of oral exposure to
ammonia	7
Table 2. Approximate number of primary studies likely to be cited in the assessment	12
Table 3. Draft PECO (Populations, Exposures, Comparators, Outcomes) Criteria for assessing
noncancer hazards of oral exposure to ammonia and ammonium salts	17
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science,
Toxline)	22
FIGURES
Figure 1. Integrated Risk Information System systematic review problem formulation and
method documents	2
Figure 2. Ammonia concentrations in groundwater in the United States	5
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Ammonia (Oral Exposure)
ABBREVIATIONS
CERCLA	Comprehensive Environmental Response, Compensation, and Liability Act
EPA	Environmental Protection Agency
FDA	Food and Drug Administration
IAP	IRIS Assessment Plan
IRIS	Integrated Risk Information System
PECO	populations, exposures, comparators, and outcomes
SAB	Science Advisory Board
WHO	World Health Organization
This document is a draft for review purposes only and does not constitute Agency policy.
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AUTHORS | CONTRIBUTORS
Assessment Team
Vincent Cogliano
Audrey Galizia
Amina Wilkins
U.S. EPA/ORD/NCEA (assessment manager)
U.S. EPA/ORD/NCEA
U.S. EPA/ORD/NCEA
Executive Direction
Tina Bahadori
Mary Ross
Emma Lavoie
Samantha Jones
Kris Thayer
James Avery
NCEA Center Director
NCEA Deputy Center Director
NCEA Assistant Center Director for Scientific Support
NCEA Associate Director for Health (acting)
NCEA/IRIS Division Director
NCEA/IRIS Deputy Director (acting)
Contributors and Production Team
Carolyn (Beth) Gatling
Satoru Ito
Ryan Jones
Vicki Soto
Dahnish Shams
Maureen Johnson
Ingrid Druwe
Roman Mezencev
Marian Rutigliano
HERO Librarian
HERO Librarian
HERO Director
Project Management Team
Project Management Team
Webmaster
Systematic Review Support
Systematic Review Support
Systematic Review Support
This document is a draft for review purposes only and does not constitute Agency policy.
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1. INTRODUCTION
The Integrated Risk Information System (IRIS) Program is undertaking an assessment of the
noncancer effects of oral exposure to ammonia. Ammonia (oral exposure) was included on the
December 2015 IRIS Program multiyear agenda1 as a high priority for assessment development
Oral exposure was specified because the IRIS Program was at that time completing an evaluation of
the noncancer hazards of inhalation exposure to ammonia (U.S. EPA. 2016). IRIS assessments
provide high quality, publicly available information on the toxicity of chemicals to which the public
might be exposed. These assessments are not regulations, but provide a critical part of the
scientific foundation for decisions made in Environmental Protection Agency (EPA) program and
regional offices to protect public health.
Prior to efforts to develop an IRIS assessment of oral exposure to ammonia, EPA's Office of
Water had been preparing a Health Advisory for ammonia and ammonium salts as technical
guidance for federal, state, and local officials, as well as managers of public or community water
systems in protecting public health should emergency spills or contamination situations occur. The
draft Health Advisory fU.S. EPA. 2013al was superseded by the IRIS effort to address these needs.
The peer-review draft of the 2016 IRIS assessment fU.S. EPA. 2013cl had included
evaluations of both oral and inhalation exposure to ammonia and ammonium hydroxide. In its
review of that draft, EPA's Science Advisory Board (SAB) recommended that the revised assessment
consider studies of ammonium salts and the potential for increased ammonia in blood to induce
neurotoxicity, especially in individuals with abnormal liver function fU.S. EPA. 2015bl. Because
these recommendations would entail new analyses and further peer review for oral exposure, the
IRIS Program separated and expedited the inhalation module fU.S. EPA. 20161. which was
completed and released in September 2016.
As part of the initial steps in assessment development, the IRIS Program undertakes scoping
and initial problem formulation activities. During scoping activities, the IRIS Program consults with
EPA program and regional offices to identify the nature of the hazard characterization needed, the
most important exposure pathways, and the level of detail required to inform Agency decisions. A
broad, preliminary literature survey may also be conducted to assist in identifying the extent of the
evidence and health effects that have been studied for the chemical of interest
Based on the preliminary literature survey and the scope defined by EPA, the IRIS Program
undertakes problem formulation activities to frame the scientific questions that will be the focus of
the assessment A summary of the IRIS Program's scoping and problem formulation conclusions
are contained in the IRIS Assessment Plan (IAP).
URIS multiyear agenda: https: //www.epa.gov/iris/iris-agenda
This document is a draft for review purposes only and does not constitute Agency policy.
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The IAP is followed by development of a Systematic Review Protocol, which presents
detailed methods for conducting the full systematic review and dose-response analysis, including
any adjustments made to the IAP in response to public input The IAP describes what will be
assessed, and the chemical-specific protocol describes how the assessment will be conducted.
Figure 1 graphically displays the context of the IAP and Systematic Review Protocol in the
systematic review process.
This document presents the draft IAP for oral exposure to ammonia—a summary of the IRIS
Program's scoping and initial problem formulation conclusions. It describes Agency need for the
assessment; objectives and specific aims of the assessment; draft Populations, Exposures,
Comparators, and Outcomes (PECO) criteria that outline the evidence considered most pertinent to
the assessment; and identification of key areas of scientific complexity. Brief background
information on uses and potential for human exposure is provided for context
Systematic
Review Protocol
Literature
Inventory
Study
Evaluation
Data
Extraction
Evidence
Integration
Derive Toxicity
Values
Initial Probten
Formulation

l l l l l 1 \
Literature Preliminary Organize Evidence Anal/sis select a rid Model | /
search Analysis plan Hazard Review and synthesis Studies 1/
Assessment


Plans:
What the
w
Protocols: How the assessment will be conducted (specific
assessment

procedures and approaches for each assessment component, with
will cover

rationale where needed)
ฆ Assessment
Developed
Figure 1. Integrated Risk Information System systematic review problem
formulation and method documents.
This document is a draft for review purposes only and does not constitute Agency policy.
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2.SCOPING AND INITIAL PROBLEM FORMULATION
2.1. BACKGROUND
Ammonia (NH3) is a clear caustic gas with a pungent odor. It is highly soluble in water and
in blood, with solubility decreasing as temperature or pH increases. The water-based solution is
called ammonium hydroxide or aqueous ammonia. The gas is also called anhydrous ammonia.
Ammonia is used in the disinfection of drinking-water by the process of chloramination,
whereby chlorine and ammonia are added to water to form the disinfectant chloramine (NH2CI).
The use of ammonia in drinking-water disinfection limits the production of chlorinated byproducts
(mainly trihalomethanes and haloacetic acids) that are suspected of causing cancer. Ammonia,
ammonium chloride, ammonium hydroxide, and ammonium sulfate are certified as treatment
chemicals in drinking water for the purposes of disinfection, chloramination, oxidation, ozone
reduction, pH adjustment, and as an antioxidant fNSF. 20121. Ammonia is also used in other areas
of water or wastewater treatment.
U.S. production of ammonia and ammonium salts totals tens of billions of pounds per year.
The major use is in fertilizers for agriculture. Ammonium nitrate is also used to produce explosives.
Ammonia has many other uses in smaller amounts. For example, several ammonium salts2
are used as food additives and in food processing and the Food and Drug Administration (FDA) has
determined these uses to be "Generally Recognized as Safe" (FDA. 19741. Ammonium chloride is an
FDA-approved prescription drug for lowering excess alkalinity in the blood. In addition, ammonia
and ammonium sulfate are EPA-registered pesticides for controlling micro-organisms (algae,
bacteria, fungi), and ammonium sulfamate was an EPA-registered herbicide. Several ammonium
compounds are inert ingredients in pesticide formulations.
2Ammonium bicarbonate, ammonium carbonate, ammonium chloride, ammonium hydroxide, mono and
dibasic ammonium phosphate, and ammonium sulfate.
This document is a draft for review purposes only and does not constitute Agency policy.
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Occurrence in environmental media is difficult to summarize, as concentrations depend on
proximity to agriculture and season of the year, and measurements often reflect specific local
conditions that are not widely representative. The U.S. Geological Survey reported that ammonia
concentrations are usually less than 0.1 mg/L in groundwater and stream samples from
background sites fMueller and Helsel. 20161. Figure 2 shows a range of ammonia concentrations in
groundwater in the United States, with most values in the lowest category, but elevated in some
areas. A World Health Organization report prepared by EPA estimated typical concentrations of
ammonia in surface water at 0.2-0.5 mg/L, but up to 12 mg/L near farms. Concentrations in
outdoor air were estimated at 5-25 |J.g/m3 in urban areas, 2-6 |ig/m3 in nonagricultural rural areas,
and up to some hundreds of ng/m3 in agricultural areas flPCS. 19861.3 Ammonia is present in
cigarette smoke, with a median yield in mainstream smoke of 37 |ig per cigarette and a range of
10-88 ng flARC. 20121. Comparison of oral exposure to exposure in air shows that oral exposure
generally is the principal route of human exposure.
3IPCS T19861 appears to be the most recent survey of ammonia occurrence in environmental media. It is the
primary reference cited for this purpose by WHO f20031. by ATSDR (20041. by a draft Health Advisory
prepared by EPA's Office of Water fU.S. EPA. 2013al. and by a summary of environmental concentrations
prepared by EPA's National Center for Environmental Assessment fU.S. EPA. 2013bl. Recent reports (see
table in this footnote] are consistent with the ranges reported by IPCS.
Recent reports of ammonia in surface water or groundwater
Concentration of ammonia
Location
Reference
31-43 ppb (head of bay)
Ochlocknee Bay, Florida
Seitzinger (1987)
8.5-26 ppb (mouth of bay)

as cited bv ATSDR (2004)
<1 mg/L (upstream)
Municipal-sewage-treatment facility,
Crumpton and Isenhart (1988)
16 mg/L (downstream, peak)
South Skunk River, Iowa
as cited by ATSDR (2004)
0-2.3 mg/L (1.2 m depth)
Groundwater in The Netherlands
Krajenbrink et al. (1988)
Nondetect (12.6 m depth)

as cited bv ATSDR (2004)
>0.020 mg/L for >6 months
Hamilton Harbour, Ontario
Barica (1990)
0.3 mg/L often exceeded

as cited bv ATSDR (2004)
As high as 3 mg/L
Groundwater rich in humic
Dieter and Moller (1991)

substances or iron, or in forests
as cited bv WHO (2003)
0.0025 mg/L (municipal well)
Area in Idaho with high nitrogen
Wicherski (2000)
3.25 mg/L (deep private well)
concentrations
as cited bv ATSDR (2004)
>2 mg/L in >50% of wells
Groundwater wells (Quaternary) in
Schilling (2002)
>5 mg/L in >5% of wells
Iowa

>2 mg/L in ~5% of bedrock wells
Groundwater wells (bedrock) in Iowa
Schilling (2002)
3.3 mg-nitrogen/L (mean)
Palo, Iowa
U.S. EPA (2014)
Up to 5-10 mg/L
Groundwater wells in Iowa
U.S. EPA (2014)
This document is a draft for review purposes only and does not constitute Agency policy.
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•mMki
•K tisjt
f M	* j
H ซ•ป> k'"> • ฆ • fJk
52	t,
Ammonia
Concentration (mg/L)
0 .500 and less
ฎ .500-1.00
ง 1.00-2.00
• 2.00-5.00
t 5.00-34.0
Figure 2. Ammonia concentrations in groundwater in the United States.
Source: Map created for U.S. EPA (2013a), based on U.S. Geological Survey National Water-Quality Assessment
Program data from 2011
Based on the ranges reported by the World Health Organization (WHO), and in the absence
of sources that would cause ammonia concentrations to be elevated, typical human intake would be
estimated at less than 1 mg/day from drinking water (but could exceed 2 0 mg/day near farms] and
less than 0.5 mg/day by inhalation (but proximity to farms or to cigarette smoke can add several
times that amount],4 Average intake of ammonium salts in foods was estimated at 18 mg/day (IPCS.
19861.
Ingested ammonia is transferred to the liver, where it is converted to urea (CfNH-Ji'O),
which is excreted by the kidneys. Ammonia can enter the systemic circulation and cross cell
membranes; it can also cross the blood-brain barrier.
Ammonia is also produced in the body at rates (more than 4 g/day) that are substantially
higher than typical intake rates (approximately 20 mg/day, discussed above]. Most of this
endogenous ammonia is produced in the intestines during digestion of meat and other sources of
protein. A smaller amount is produced in the mouth in the presence of food particles.
Oral exposure to ammonia has been linked to chemical burns in the mouth, throat, and
stomach fATSDR. 2004] and metabolic acidosis fPHE, 20151. but no national or international health
agency has yet derived a health-based reference value for chronic oral exposure. Chronic inhalation
exposure to ammonia can increase the risk of respiratory irritation, impaired lung function, and
other respiratory symptoms (U.S. EPA. 2016: PHE. 2015: ATSDR. 2004: CalEPA, 1999: U.S. EPA.
19871. but also adverse effects in the liver, kidney, and spleen fU.S. EPA. 19891. IRIS has derived an
Calculated as follows: surface-water concentrations of 0.2-0.5 mg/L times 2 L/day high-end drinking-water
intake yields a high-end estimate of 0.4-1 mg/day intake via drinking water; ambient air concentrations of
5-25 mg/m3 times 20 m3 air intake yields an estimate of 0.1-0.5 mg/day intake via air.
This document is a draft for review purposes only and does not constitute Agency policy,
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inhalation reference concentration of 0.5 mg/m3 based on decreased lung function and increased
respiratory symptoms in exposed workers (U.S. EPA. 20161. Short-term exposure to high air
concentrations can not only cause irritation and serious burns in the respiratory tract and eyes, but
also convulsions, pulmonary edema, coma, and death (U.S. EPA. 19891. To date, no health agency
has concluded that there is evidence of carcinogenic potential by any route of exposure.
In general, most health agencies have concluded that ammonia does not pose a direct health
concern at concentrations expected in drinking water (that is, below 0.2 mg/L) (WHO. 20031. but
some regions in the United States have elevated levels in their drinking-water sources (U.S. EPA.
20141. and there is also a concern for higher concentrations that might follow emergency spills or
contamination situations fU.S. EPA. 2013al.
2.2. SCOPING SUMMARY
During scoping, the IRIS Program consults with EPA program and regional offices that had
interest in an IRIS assessment of oral exposure to ammonia to discuss specific assessment needs.
Table 1 provides a summary of input from this outreach.
This document is a draft for review purposes only and does not constitute Agency policy.
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Table 1. EPA program and regional office interest in an assessment of oral
exposure to ammonia
EPA program or
regional office3
Oral
Inhalation
Statutes/regulations
Anticipated uses/Interest
Office of Water
Need
Completed,
2016
Safe Drinking Water Act:
to inform the Office of
Water Health Advisories,
which serve as technical
guidance to assist federal,
state, and local officials, as
well as managers of public
or community water
systems in protecting
public health when
emergency spills or
contamination situations
occur
Clean Water Act: potential
human health criteria
development
Ammonia is certified for use in water and
wastewater treatment, most notably in
disinfection of drinking water by chloramination.
Ammonia is also a high-priority contaminant due
to its use in fertilizers and presence in runoff
water from agricultural fields.
Health authorities need a reference dose to
ensure protection of public health after
emergency spills or contamination situations.
Elevated ammonia is associated with elevated
nitrate concentrations in drinking water sources.
aEPA's Office of Land and Emergency Management also has an interest in ammonia. Ammonia and several
ammonium compounds (ammonium acetate, benzoate, bicarbonate, bichromate, bifluoride, bisulfite,
carbamate, carbonate, chloride, chromate, citrate [dibasic], fluoborate, fluoride, hydroxide, oxalate, picrate,
silicofluoride, sulfamate, sulfide, sulfite, tartrate, thiocyanate, vanadate) are listed as hazardous substances
under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) section 102(a)
(U.S. EPA, 2015a). Ammonia is a chemical of concern at 135 sites on the National Priorities List for EPA's
Superfund program (ATSDR, 2015), and risk assessments for these sites conducted by EPA regional offices or by
state environmental agencies are often based on less-than-lifetime exposure scenarios. In addition, many
regions in the United States have excessive levels of ammonia in their drinking-water sources (ground and
surface waters) (U.S. EPA. 2014).
The assessment will meet the Office of Water's need for an evaluation of oral exposure to
ammonia and ammonium salts. In doing so, the assessment also will be mindful of the Science
Advisory Board's outstanding recommendations on oral exposure (U.S. EPA. 2015b). The scope of
the assessment is to develop an oral reference dose for noncancer effects (including neurotoxicity,
which the SAB had stressed as important). This will be the first oral reference dose for ammonia
under the IRIS Program.5
Ammonia is highly soluble in water and in blood, consequently, it will occur in the body as
the ammonium ion (NH4+). Many ammonium salts also are soluble in water and in blood, and the
ammonium moiety will dissociate and occur in the body as the ammonium ion. Accordingly, the
assessment will derive a reference value in terms of the ammonium ion. This may be converted
5EPA's Health Effects Assessment for Ammonia (U.S. EPA. 19871 derived reference values based on taste and
odor thresholds, but not on health hazards.
This document is a draft for review purposes only and does not constitute Agency policy.
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into a reference value for each ammonium salt by considering the fraction, by weight, of the
molecule that dissociates into an ammonium ion.
The reference value for the ammonium ion will be derived from results from suitable
studies of ammonia and various ammonium salts. In addition to ammonia (7664-41-7), studies
have been found on several ammonium salts in which the responses may be reasonably attributable
to the ammonium moiety.
•	ammonium hydroxide (1336-21-6)
•	ammonium acetate (631-61-8)
•	ammonium chloride (12125-02-9)
•	ammonium sulfate (7783-20-2)
•	ammonium phosphate (diammonium phosphate) (7783-28-0)
•	ammonium dihydrogen phosphate (7722-76-1)
•	ammonium carbonate (506-87-6)
•	ammonium nitrate (6484-52-2)
•	ammonium bicarbonate (1066-33-7)
•	ammonium citrate (7632-50-0)
There are also numerous complex ammonium compounds in which the non-ammonium
moiety is expected to be toxic. Although there are toxicity studies of several such compounds (e.g.,
aluminum ammonium sulfate, ammonium metavanadate, ammonium perchlorate), disentangling
the toxicity of the ammonium and non-ammonium moieties would be difficult Accordingly, the
assessment will not review studies of such ammonium compounds, especially as toxicity studies are
available for compounds where the non-ammonium moiety is relatively nontoxic (e.g., ammonium
hydroxide and acetate).
The assessment will not undertake an evaluation of carcinogenicity. The cancer studies
identified by preliminary survey of assessments from national and international health agencies
(see Section 2.3) identified no studies that could be used to derive cancer toxicity values. Briefly,
this information includes:
•	Two occupational case-control studies that mention ammonia in the abstract:
o one found an association with non-Hodgkin lymphoma in males in Montreal fFritschi
and Siemiatvcki. 1996).
This document is a draft for review purposes only and does not constitute Agency policy.
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1	o one found an association with colon cancer in males in British Columbia fFang etal..
2	20111.
3	The complex exposures inherent in the occupations and the small numbers of cases make it
4	unlikely that these cancers can be confidently attributed to ammonia. Moreover, there are
5	no quantitative exposure estimates that could be used to characterize exposure-response
6	relationships.
7	• Four studies of cancer in experimental animals:
8	o ammonium hydroxide in the drinking water of both sexes of Swiss mice fToth. 19721.
9	o ammonium hydroxide in the drinking water of both sexes of C3H mice fToth. 19721.
10	o ammonium chloride in the diet of both sexes of Wistar rats (Lina and Kuijpers. 2004).
11	o ammonium sulfate in the diet of both sexes of F344 rats (Ota etal.. 2006).
12	Each study found no increase in tumors. EPA has not derived cancer toxicity values from
13	negative studies of carcinogenicity.
14	• Three initiation-promotion studies:
15	o drinking-water administration of ammonia promoted gastric cancer in initiated
16	Sprague-Dawley rats (Tsuiii etal.. 1995: Tsuiii etal.. 1992).
17	o intrarectal administration of ammonium acetate promoted colon cancer in initiated
18	Sprague-Dawley rats fClinton etal.. 1988).
19	EPA has not derived cancer toxicity values from initiation-promotion studies. Moreover, it
20	would be difficult to translate the quantitative effect of initiation in rats to a human
21	population.
22
23	As there are no studies that can be used to derive toxicity values for cancer, the assessment
24	will not evaluate carcinogenicity.
25	2.3. PROBLEM FORMULATION
26	The literature searches conducted for the 2016 IRIS assessment of inhalation exposure
27	were insufficient to assess oral exposure. Although the searches conducted before 2013 did include
28	oral studies (because the 2013 peer-review draft addressed oral and inhalation exposures), no
29	systematic search for studies on ammonium salts was conducted (because the 2016 assessment
30	addressed only ammonia and ammonium hydroxide).
31	To obtain information on the ammonium salts, a preliminary survey began with a review of
32	assessments from national and international health agencies, including FDA (1974). IPCS (1986).
33	U.S. EPA f 19871. U.S. EPA f 19891. CalEPA f 19991. ATSDR f2 0041. PHE (20151. and U.S. EPA (20161.
34	These assessments were reviewed to identify health outcomes that have been associated with oral
This document is a draft for review purposes only and does not constitute Agency policy.
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exposure to ammonia or ammonium salts, and to identify the studies that provided the principal
support for these findings.
The preliminary survey also included a review of articles on the ability of some ammonium
salts to induce metabolic acidosis6 or hyperammonemia.7 These articles discuss the linkage
between metabolic acidosis and the subsequent development of bone loss or osteoporosis, and the
linkage between hyperammonemia and the subsequent development of hepatic encephalopathy or
other manifestations of neurotoxicity. Metabolic acidosis and hyperammonemia are well
established in the medical literature as hazards of exposure to high doses of ammonia. Accordingly,
this assessment will not expend resources on systematic reviews of the evidence for these hazards.
Rather, the assessment will accept that metabolic acidosis and hyperammonemia are known
hazards of ammonia exposure and will focus the review of these studies at a survey level to
characterize the doses or durations of exposure that could induce these effects.
To identify studies of these and other possible health hazards, literature search strategies
are using key terms and words related to the forms of ammonia outlined in the PECO criteria (see
Section 3). Literature search strategies were developed for the PubMed, Web of Science, and
Toxline databases, tailoring the strategies to the unique search functionality of each database. No
date or language restrictions are being applied. The initial search was conducted in May 2017 and
returned approximately 39,000 studies.
Given the size of the evidence base, refined searches were conducted to focus on standard
experimental animal species (e.g., rats; mice, rabbitsฆ, hamsters, dogs; monkeys), oral administration
(e.g., oral ingestion, gavage, diet, food, feed, drinking water), and on a subset of ammonium salts
(e.g., hydroxide, acetate, bicarbonate, carbonate, chloride, phosphate, diphosphate, sulfate, citrate)
where toxicity could reasonably be attributable to the ammonium ion. For epidemiologic studies,
searches focused on occupations with potential exposure to ammonia (e.g., brewers, janitors,
cleaners, exterminators, cosmetologists, hairstylists, morticians, embalmers, agricultural workers,
farmworkers, and fertilizer manufacture). Eventually, the refined searches (see Appendix A)
reduced the number of potentially pertinent studies to approximately 4,000. The refined searches
did not target in-vitro studies of mechanisms of ammonia toxicity because the review of
assessments by national and international health agencies or of comprehensive review articles did
not identify any questions in which data on mechanisms would affect the identification of hazards
or the modeling of dose-response for those hazards.
6Metabolic acidosis is a condition of excess acid in the body. It can arise from increased acid intake (e.g.,
ammonium chloride or sulfate), increased endogenous acid production, or decreased acid excretion.
Metabolic acidosis is a serious medical condition that can lead to impaired growth of infants and children and
loss of bone and muscle mass in adults. Metabolic acidosis is characterized by blood plasma pH <7.35, serum
bicarbonate <22 mmol/L fWingfield. 20011 or total carbon dioxide <22 mmol/L fMonsen. 19871
hyperammonemia means an excess of ammonia in the blood. Hyperammonemia is a serious medical
condition that can result in hepatic encephalopathy, characterized by altered mental state and potentially
leading to brain edema, seizures, coma, or death.
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The search results of approximately 4,000 studies include numerous studies in which an
ammonium salt was administered at a single high dose level only as an established means to induce
metabolic acidosis or hyperammonemia in experimental animals. These studies provide no
information on lower dose levels that could induce these effects and, thus, have little utility for this
assessment As indicated above, these studies will only be surveyed in the assessment to describe
the doses or durations of exposure that could induce these effects. Thus, these studies will be
tagged as supplemental material during screening, except for those studies that are useful for
setting an oral reference dose; that is, animal experiments that included multiple doses or exposure
durations and studies of controlled human exposure will be fully evaluated. This restriction greatly
reduces the number of studies considered most pertinent to this assessment
Based on the literature searches and screening done to date, Table 2 presents the
approximate number of primary studies likely to be cited for each broad health outcome to be
addressed in the assessment
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Table 2. Approximate number of primary studies likely to be cited in the assessment

Occupational
cohort and
case-control
studies (in
humans)
Population-based
cohort and
case-control
studies (in
humans)
Case
reports of
ingestion
(by
humans)
Intentional
dosing
studies in
humans by
ingestion
Multigenerational
animal studies
Chronic
animal
studies
Subchronic
animal
studies
Short-term
and acute
animal
studies
Gastric irritation


~20



l
3
Systemic toxicity





2
3

Metabolic acidosis3
(may be related to
musculoskeletal
toxicity)



5-10

1
1
3
Hyperammonemia3
(may be related to
neurotoxicity)



1

~5
~5
~5
Developmental toxicity


1

l



Cancer (carcinogenicity
studies)
1
1



4
N/A
N/A
Cancer
(initiation-promotion
studies)
N/A
N/A
N/A
N/A
N/A
3

N/A
N/A: Study design does not exist (e.g., there are never initiation-promotion studies in humans).
aDoes not include studies described as supplemental, in which an ammonium compound was administered at a single high dose only to induce acidosis or
hyperammonemia in animals.
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1	Based on the literature searches and screening done to date, several health outcomes are
2	likely to warrant inclusion in the assessment
3
4	• Gastric irritation
5	• Systemic toxicity
6	• Metabolic acidosis (and potentially musculoskeletal toxicity)8
7	• Hyperammonemia (and potentially neurotoxicity)8
8	• Developmental toxicity
9
10	A preliminary reading of review articles and assessments by other health agencies suggests
11	some potentially susceptible populations or life stages that are likely to warrant consideration in
12	the assessment, to the extent that suitable data are available.
13
14	• Individuals with impaired liver or kidney function: The liver converts ammonia to urea,
15	which enters the systemic circulation and is excreted by the kidneys. Individuals with
16	impaired liver or kidney function (e.g., through liver cirrhosis or a urea-cycle disorder)
17	would experience reduced clearance of ammonia, and hence, excess levels in the blood.
18	• Individuals at risk for osteoporosis: Metabolic acidosis can result in bone loss, potentially
19	exacerbating this condition in individuals at risk for osteoporosis (IPCS. 1986).
20	• Infants and children: Ammonia can cross the blood-brain barrier, possibly inducing
21	hepatic encephalopathy or other manifestations of neurotoxicity. The brain is not efficient
22	at excreting ammonia. It is thought that infants and children may be more susceptible than
23	adults to these effects (Braissantetal.. 2013: Gropman et al.. 2007). Experimental evidence
24	in rats suggests that developing offspring are susceptible to exposure during pregnancy and
25	lactation, providing further support fMinana et al.. 1995). In addition, bone loss resulting
26	from metabolic acidosis can be of concern early in life, which is a crucial period for bone
27	development
28	• Individuals infected with Helicobacter pylori: H. pylori, a bacterium estimated to infect
29	more than 30% of Americans (IARC. 2012). is a major cause of stomach ulcers and nearly
30	90% of noncardia stomach cancers (Plummer etal.. 2012). H. pylori survives in the stomach
31	by reducing acidity through the production of ammonia. Subsequent ingestion of ammonia
8As discussed in the main text of this section, metabolic acidosis and hyperammonemia are known hazards of
ammonia exposure. The assessment will not review evidence to re-establish these hazards and will fully
evaluate only the studies that are useful for setting an oral reference dose, that is, animal experiments that
included multiple doses or exposure durations and studies of controlled human exposure.
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could further increase stomach concentrations and potentially exacerbate the risk of
stomach irritation or stomach cancer.
2.4. KEY SCIENCE ISSUES
Based on the preliminary survey of health agency assessments and authoritative review
articles, several key science issues will warrant consideration in the assessment.
Attribution of responses to the ammonium cation or to the anion (for example, is a
response to ammonium chloride due to its ammonium cation or to its chloride anion?): Some
studies included an anion control (for example, a study of ammonium chloride that included control
animals exposed to equimolar concentrations of potassium chloride). These studies will be
especially informative for determining whether responses are attributable to the ammonium ion or
to the anion (in this example, the chloride ion).
The palatability of ammonia to experimental animals: Ammonia is unpalatable to
humans, which suggests that ammonia in food or water might cause experimental animals to
reduce intake, leading to adverse health outcomes that would not necessarily be due to ammonia
toxicity. The assessment will examine dose-related trends in body weight and in food or water
intake to estimate concentrations of ammonia that make food or water unpalatable to experimental
animals. In addition, the assessment will consider studies in which ammonia was administered
directly via oral gavage, in which the dose of ammonia does not depend on food or water intake.
Endogenous production of ammonia: The body produces ammonia during the
metabolism of amino acids. Most production occurs in the intestines during the digestion of meat
and other sources of protein, and a smaller amount occurs in the mouth from the reaction of saliva
with food particles. The rate of production of ammonia in the intestines is substantially higher than
typical intake rates (see Section 2.1). Ammonia is a toxic product with no apparent health benefits;
the body converts ammonia to urea and eliminates it
It would be difficult to investigate effects of oral exposure in the intestines. Such studies
have not been located, and the assessment will not evaluate the intestines as a target organ. On the
other hand, studies have been able to investigate the effects of oral exposure in the mouth,
esophagus, and stomach. These studies have reported clear dose-response relationships following
oral exposure to ammonia and have not attributed any part of these effects to endogenous
production. Similarly, numerous studies have investigated and shown a relationship between oral
exposure and hyperammonemia or metabolic acidosis, with subsequent effects on neurotoxicity or
bone loss, respectively.
Infection with Helicobacter pylori is a separate source of endogenous production of
ammonia. Oral intake of ammonia would directly add to the burden of ammonia produced in the
stomachs of infected individuals (see Section 2.3). The assessment will review studies that
investigated the effect that oral intake could have on this potentially susceptible population.
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1
2	3.OVERALL OBJECTIVE, SPECIFIC AIMS, AND DRAFT
s POPULATIONS, EXPOSURES, COMPARATORS,
4 AND OUTCOMES (PECO) CRITERIA
5	The overall objective of this assessment is to identify adverse noncancer outcomes of oral
6	exposure to ammonia and ammonium salts, to characterize exposure-response relationships, and to
7	derive an oral reference dose. The assessment will use systematic review methods to evaluate the
8	pertinent epidemiologic and experimental animal studies, including consideration of relevant
9	mechanistic evidence. The evaluations conducted in the assessment will be consistent with
10	relevant EPA guidance.9 The systematic review protocol will be disseminated after review of the
11	draft assessment plan and will reflect changes made to the specific aims and PECO criteria in
12	response to public input
13	3.1. SPECIFIC AIMS
14	• Identify epidemiologic and experimental animal studies pertinent to the health hazards of
15	ammonia, as outlined in the PECO criteria. This will include noncancer effects of oral
16	exposure to ammonia or ammonium salts. Identifying individual mechanistic studies is not
17	considered critical for this assessment and therefore not included in the PECO criteria.
18	Other published authoritative sources, such as public health agency reports and expert
19	review articles, will be the primary basis for providing mechanistic context in the
20	assessment
21	• Conduct study evaluations (risk of bias and insensitivity) for individual epidemiologic and
22	experimental animal studies. Studies with critical deficiencies will be considered
23	uninformative and will not be considered further.
24	• Extract data on relevant health outcomes from epidemiological and experimental animal
25	studies included based on the study evaluation.
26	• Synthesize the evidence across studies, assessing similar health outcomes using a narrative
27	approach or quantitative analysis (if appropriate).
28	• For each health outcome, express confidence in conclusions across studies (or subsets of
29	studies) within human and animal evidence streams, evaluating each evidence stream
30	(human and animal) separately. Metabolic acidosis and hyperammonemia are known
31	hazards of ammonia exposure (see Section 2.3); accordingly, the assessment will focus on
9EPA guidance documents: http://www.epa.gov/iris/basic-information-about-integrated-risk-information-
svstem# guidance /
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1	studies that provide information on doses or durations of exposure that could induce these
2	effects.
3	• For each health outcome, integrate results across evidence streams (human and animal) to
4	conclude whether a substance is hazardous to humans. Identify and discuss issues
5	concerning potentially susceptible populations and life stages. Biological support from
6	mechanistic studies will be summarized primarily by relying on other sources and targeted
7	literature searches that might be conducted later, if warranted, to address specific topics
8	that may arise when conducting the assessment.
9	• Derive oral reference doses as supported by the available data. If the data permit, also
10	derive oral reference doses for less-than-lifetime exposure to better serve risk assessment
11	needs at hazardous waste sites.
12	• Characterize uncertainties and identify key data gaps and research needs, such as
13	limitations of the evidence base, limitations of the systematic review, and consideration of
14	dose relevance and toxicokinetic differences when extrapolating findings from higher dose
15	animal studies to lower levels of human exposure.
16
17	3.2. DRAFT PECO CRITERIA
18	A PECO will be used as an aid to focus the research questions, search terms, and
19	inclusion/exclusion criteria in a systematic review. The draft PECO criteria for ammonia (see Table
20	3) was based on (1) nomination of the agent for assessment, (2) discussions with scientists in EPA
21	program and regional offices to determine the scope of the assessment that will best meet Agency
22	needs, and (3) a preliminary survey of the health effects literature (primarily health agency
23	assessments and authoritative review articles). These served to identify the major health hazards
24	and the key areas of scientific complexity.
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IRIS Assessment Plan for Ammonia (Oral Exposure)
Table 3. Draft PECO (Populations, Exposures, Comparators, Outcomes)
Criteria for assessing noncancer hazards of oral exposure to ammonia and
ammonium salts
PECO element
Evidence
Populations3
Human: Anv population and life stage (occupational or general population, including children
and other potentially susceptible populations or life stages). The following study designs will
be considered most informative: controlled exposure, cohort, case-control, cross-sectional, and
ecological.
Note: Case reports and case series will be tracked during study screening, but are not the
primary focus of this assessment. They may be retrieved for full-text review and subsequent
evidence synthesis if no or few informative study designs are available. Case reports also can
be used as supportive information to establish biologic plausibility for some target organs and
health outcomes.

Animal: Nonhuman mammalian animal species (whole organism) of anv life stage (including
preconception, in utero, lactation, peripubertal, and adult stages).
Exposures
•	Ingested ammonia (7664-41-7) or ammonium salts, including ammonium hydroxide
(1336-21-6), ammonium acetate (631-61-8), ammonium chloride (12125-02-9),
ammonium sulfate (7783-20-2), ammonium phosphate (7783-28-0), ammonium
dihydrogen phosphate (7722-76-1), ammonium carbonate (506-87-6), ammonium
bicarbonate (1066-33-7), and ammonium citrate (7632-50-0)
•	Studies of urea or of mixtures containing ammonia are not expected to be useful for
deriving toxicity values. These are outside the scope of the assessment.
•	Studies of complex ammonium salts in which the non-ammonium moiety could
contribute significant toxicity (e.g., aluminum ammonium sulfate, ammonium
metavanadate, ammonium perchlorate; see Section 2.2) are not expected to be useful
for deriving toxicity values for ammonia. These are outside the scope of the
assessment.

Human: Exposure based on biomonitoring data (e.g.. urine, blood, or other specimens),
environmental or occupational-setting measures (e.g., air, water levels), or job title, or
residence. Occupations in which exposure to ammonia is expected include brewers, janitors,
cleaners, exterminators, cosmetologists, hairstylists, morticians, embalmers, agricultural
workers, farmworkers, and fertilizer manufacture. All single-dose human studies will be
included.

Animal: Exposure routes to ammonia via dietarv. drinking water, gavage. or intraperitoneal
administration. Studies employing one or more exposed groups will be considered the most
informative (i.e., studies with multiple doses and multiple durations of exposure). Other
exposures (e.g., including single-dose studies) will be tracked during title and abstract as
"supplemental material." Studies involving exposures to mixtures will be included only if they
include an arm with exposure to ammonia or an ammonium salt alone.
Comparators
Human: A comparison or reference population exposed to lower levels (or no
exposure/exposure below detection levels) of ammonia (or ammonia salts) or for shorter
periods.

Animal: Quantitative exposure vs. lower or no exposure or for a shorter duration with vehicle
control. Historical controls, preferably from the same laboratory and close in time, may be
considered if needed.
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Table 3. Draft Population, Exposure, Comparator, and Outcome criteria for
the assessment of noncancer hazards of oral exposure to ammonia and
ammonium salts (continued)
PECO element
Evidence
Outcomes
Human and animal: All noncancer health outcomes, or precursors. In general, endpoints
related to clinical diagnostic criteria, disease outcomes, histopathological examination, or other
apical/phenotypic outcomes will be prioritized for evidence synthesis over outcomes such as
biochemical measures. Metabolic acidosis and hyperammonemia are established hazards of
ammonia exposure. The assessment will not review evidence to re-establish these hazards and
will fully evaluate only the studies that are useful for setting an oral reference dose, that is,
animal experiments that included multiple doses or exposure durations and studies of
controlled human exposure.
identifying individual mechanistic studies is not considered critical for this assessment and therefore not
included in the PECO criteria. Other published authoritative sources, such as public health agency reports and
expert review articles, will be the primary basis for providing mechanistic context in the assessment.
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REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). (2004). Toxicological profile for
ammonia [ATSDR Tox Profile], Atlanta, GA: U.S. Department of Health and Human Services,
Public Health Service, http://www.atsdr.cdc. gov/toxprofiles/tp.asp?id=ll&tid=2
ATSDR (Agency for Toxic Substances and Disease Registry). (2015). Summaiy data for 2015
priority list of hazardous substances. Washington, DC: Division of Toxicology and Human
Health, https://www.atsdr.cdc.gov/spl/resources/atsdr 2015 spl detailed data table.pdf
Braissant. 0: McLin. VA: Cudalbu. C. (2013). Ammonia toxicity to the brain [Review], J Inherit Metab
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CalEPA (California Environmental Protection Agency). (1999). 0EHHA chemical database:
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from https://oehha.ca.gov/chemicals/ammonia
Clinton. SK: Bostwick. DG: Olson. LM: Mangian. HI: Visek. WT. (1988). Effects of ammonium acetate
and sodium cholate on N-methyl-N'-nitro-N-nitrosoguanidine-induced colon carcinogenesis
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FDA (U.S. Food and Drug Administration). (1974). Evaluation of the health aspects of certain
ammonium salts as food ingredients. (SC0GS-34). Washington, DC: Bureau of Foods,
Department of Health, Education, and Welfare.
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34%20Ammonium%2 OSalts.pdf
Fritschi. L: Siemiatycki. 1. (1996). Lymphoma, myeloma and occupation: Results of a case-control
study. Int J Cancer 67: 498-503. http://dx.doi.org/10.1002/fSICniQ97-
0215fl9960807167:4<498::AID-ITC6>3.0.CQ:2-N
Gropman. AL: Summar. M: Leonard. TV. (2007). Neurological implications of urea cycle disorders
[Review], J Inherit Metab Dis 30: 865-879. http://dx.doi.org/10.1007/sl0545-007-07Q9-5
IARC (International Agency for Research on Cancer). (2012). Helicobater pylori. In IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans A Review of Human
Carcinogens: Biological Agents (pp. 385-435). Lyon, France: World Health Organization,
IARC. http://monographs.iarc.fr/ENG/Monographs/vollOOB/index.php
IPCS (International Programme on Chemical Safety). (1986). Environmental health criteria:
Ammonia. (EHC 54). Geneva, Switzerland: World Health Organization.
http://www.inchem.org/documents/ehc/ehc/ehc54.htm
Lina. BAR: Kuiipers. MHM. (2004). Toxicity and carcinogenicity of acidogenic or alkalogenic diets in
rats; effects of feeding NH(4)C1, KHC0(3) orKCl. Food Chem Toxicol 42: 135-153.
http://dx.doi.Org/10.1016/i.fct.2003.08.011
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Mi nana. MP: Marcaida. G: Grisoli'a. S: Felipo. V. (1995). Prenatal exposure of rats to ammonia
impairs NMDA receptor function and affords delayed protection against ammonia toxicity
and glutamate neurotoxicity. J Neuropathol Exp Neurol 54: 644-650.
http://dx.doi.Org/10.1097/00005072-199509000-00005
Monsen. ER. (1987). The journal adopts SI units for clinical laboratory values. J Am Diet Assoc 87:
356-358.
Mueller. KD: Helsel. DR. (2016). Nutrients in the nations waterstoo much of a good thing? (USGS
Circular 1136). U.S. Geological Survey, National Water-Quality Assessment (NAWQA)
Program. https://piibs.iisgs.gOv/circ/circri36/circri36.html#AMM
NSF (National Science Foundation). (2012). Search for NSF certified drinking water treatment
chemicals [Database], Retrieved from http://info.nsf.org/Certified/PwsChemicals/
Ota. Y: Hasumura. M: Okamura. M: Takahashi. A: Ueda. M: Onodera. H: Imai. T: Mitsumori. K: Hi rose.
M. (2006). Chronic toxicity and carcinogenicity of dietary administered ammonium sulfate
in F344 rats. Food Chem Toxicol 44: 17-27. http://dx.doi.Org/10.1016/i.fct.2005.06.001
PHE (Public Health England). (2015). Ammonia: toxicological overview. UK: PHE Centre for
Radiation, Chemical and Environmental Hazards.
https://www.gov.iik/government/uploads/svstem/iiploads/attachment data/file/455704
/Ammonia TO PHE 240815.pdf
Plummer. M: Franceschi. S: Vignat. 1: For man. D: de M artel. C. (2012). Global burden of gastric
cancer attributable to Helicobacter pylori. Int J Cancer 136: 487-490.
Schilling. KE. (2002). Occurrence and distribution of ammonium in Iowa groundwater. Water
Environ Res 74: 177-186.
Toth. B. (1972). Hydrazine, methylhydrazine and methylhydrazine sulfate carcinogenesis in Swiss
mice. Failure of ammonium hydroxide to interfere in the development of tumors. Int J
Cancer 9: 109-118.
Tsuiii. M: Kawano. S: Tsuii. S: Nagano. K: Ito. T: Havashi. N: Fusamoto. H: Kamada. T: Tamura. K.
(1992). Ammonia: a possible promoter in helicobacter-pylori related gastric carcinogenesis
[abstract]. Gastroenterology 65: 15-18.
Tsuiii. M: Kawano. S: Tsuii. S: Takei. Y: Tamura. K: Fusamoto. H: Kamada. T. (1995). Mechanism for
ammonia-induced promotion of gastric carcinogenesis in rats. Carcinogenesis 16: 563-566.
http://dx.doi.Org/10.1093/carcin/16.3.563
U.S. EPA (U.S. Environmental Protection Agency). (1987). Health effects assessment for ammonia
[EPA Report], (600/8-88/017). Cincinnati, OH: Environmental Criteria and Assessment
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U.S. EPA (U.S. Environmental Protection Agency). (1989). Summary review of health effects
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U.S. EPA (U.S. Environmental Protection Agency). (2013a). Drinking water health advisory for
ammonia and ammonium salts. Washington, DC: Office of Water.
U.S. EPA (U.S. Environmental Protection Agency). (2013b). IRIS exposure summary white paper:
ammonia. Washington, DC: National Center for Environmental Assessment Exposure and
Risk Characterization Team.
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U.S. EPA (U.S. Environmental Protection Agency). (2013c). Toxicological review of ammonia.
(CASRN 7664-41-7). In support of summary information on the Integrated Risk Information
System (IRIS). (EPA635R13139A).
http://ofmpub.epa.gov/eims/eimscomm.getfile7p download id=515194
U.S. EPA (U.S. Environmental Protection Agency). (2014). Engineering design and operation report:
Biological treatment process for the removal of ammonia from a small drinking water
system in Iowa: pilotto full-scale. (EPA/600/R-14/336). Cincinnati, OH: National Risk
Management Research Laboratory, Water Supply and Water Resources Division.
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11 /documents/palo full scale report 9-23-14.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2015a). List of lists: Consolidated list of
chemicals subject to the Emergency Planning and Community Right- To-Know Act (EPCRA),
Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) and
Section 112(r) of the Clean Air Act [EPA Report], (EPA 550-B-15-001). Wasington, DC:
Office of Solid Waste and Remedial Response.
https://www.epa.gOv/sites/production/files/2015-03/dociiments/list of lists.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2015b). SAB review of the EPAs draft
toxicological review of ammonia [EPA Report], (EPA-SAB-15-011). Washington, DC.
http://yosemite.epa.gOv/sab/sabproduct.nsf/368203f97al5308a852574ba005bbd01/2fe
334e0bec7a3cf85257b65005c500b!QpenDocument&TableRow=2.3#2
U.S. EPA (U.S. Environmental Protection Agency). (2016). Toxicological review of ammonia
noncancer inhalation: executive summary. (EPA/635/R-16/163Fc). Washington, DC:
National Center for Environmental Assessment, Integrated Risk Information System.
https://cfpub.epa.gov/ncea/iris/iris documents/documents/subst/0422 summarv.pdf#na
meddest=rfc.
WHO (World Health Organization). (2003). Ammonia in drinking-water. Background document for
development of WHO Guidelines for drinking-water quality. (WHO/SDE/WSH/03.04/01).
http://www.who.int/water sanitation health/dwq/ammonia.pdf
Wingfield. WE. (2001). Veterinary Emergency Medicine Secrets (Second ed.). Philadelphia, PA:
Hanley & Belfus.
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i APPENDICES
2 APPENDIX A. LITERATURE SEARCH TERMS
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science, Toxline)
Database
Terms
Date and Results
PUBMED
7664-41-7" OR ammonia "7783-18-8" OR ammonium thiosulfate OR ammonium thiosulfate OR ammonium
thiosulphate OR "6484-52-2" OR ammonium nitrate OR ammonium salt OR "5421-46-5" OR ammonium thioglycolate
OR "1111-78-0" OR ammonium carbamate OR "7773-06-0" OR ammonium sulfamate OR ammate OR ammonium
sulphamate OR "7632-50-0" OR ammonium citrate OR "53956-04-0" OR ammonium glycyrrhizate OR ammonium
glycyrrhizinate OR "12124-97-9" OR ammonium bromide OR "12125-02-9" OR ammonium chloride OR "7783-20-2"
OR ammonium sulfate OR "12125-01-8" OR ammonium fluoride OR "12027-06-4" OR ammonium iodide
27 Apr 2017: 36,314
PUBMED
(("7664-41-7" OR ammonia "7783-18-8" OR ammonium thiosulfate OR ammonium thiosulfate OR ammonium
thiosulphate OR "6484-52-2" OR ammonium nitrate OR ammonium salt OR "5421-46-5" OR ammonium thioglycolate
OR "1111-78-0" OR ammonium carbamate OR "7773-06-0" OR ammonium sulfamate OR amate OR ammonium
sulphamate OR "7632-50-0" OR ammonium citrate OR "53956-04-0" OR ammonium glycyrrhizate OR ammonium
glycyrrhizinate OR "12124-97-9" OR ammonium bromide OR "12125-02-9" OR ammonium chloride OR "7783-20-2"
OR ammonium sulfate OR "12125-01-8" OR ammonium fluoride OR "12027-06-4" OR ammonium iodide)) AND (live
animal studies OR rats OR mice OR rabbits OR hamsters OR dogs OR monkeys OR pigs OR guinea pigs)
27 Apr 2017: 15,301
Batch# 21468
PUBMED
((("7664-41-7" OR ammonia "7783-18-8" OR ammonium thiosulfate OR ammonium thiosulfate OR ammonium
thiosulphate OR "6484-52-2" OR ammonium nitrate OR ammonium salt OR "5421-46-5" OR ammonium thioglycolate
OR "1111-78-0" OR ammonium carbamate OR "7773-06-0" OR ammonium sulfamate OR ammate OR ammonium
sulphamate OR "7632-50-0" OR ammonium citrate OR "53956-04-0" OR ammonium glycyrrhizate OR ammonium
glycyrrhizinate OR "12124-97-9" OR ammonium bromide OR "12125-02-9" OR ammonium chloride OR "7783-20-2"
OR ammonium sulfate OR "12125-01-8" OR ammonium fluoride OR "12027-06-4" OR ammonium iodide)) AND (live
animal studies OR rats OR mice OR rabbits OR hamsters OR dogs OR monkeys OR pigs OR guinea pigs)) AND (oral OR
gavage OR ingestion OR inhal* OR diet OR food)
27 Apr 2017:1898
Batch # 21470
This document is a draft for review purposes only and does not constitute Agency policy.
22	DRAFT-DO NOT CITE OR QUOTE

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IRIS Assessment Plan for Ammonia (Oral Exposure)
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science, Toxline) (continued)
Database
Terms
Date and Results
PUBMED
(("7664-41-7" OR ammonia "7783-18-8" OR ammonium thiosulfate OR ammonium thiosulfate OR ammonium
thiosulphate OR "6484-52-2" OR ammonium nitrate OR ammonium salt OR "5421-46-5" OR ammonium
thioglycolate OR "1111-78-0" OR ammonium carbamate OR "7773-06-0" OR ammonium sulfamate OR ammate OR
ammonium sulphamate OR "7632-50-0" OR ammonium citrate OR "53956-04-0" OR ammonium glycyrrhizate OR
ammonium glycyrrhizinate OR "12124-97-9" OR ammonium bromide OR "12125-02-9" OR ammonium chloride OR
"7783-20-2" OR ammonium sulfate OR "12125-01-8" OR ammonium fluoride OR "12027-06-4" OR ammonium
iodide OR ammonium iodide)) AND (brewer OR brewery OR janitor OR housekeeper OR exterminator OR
cosmetologist OR hairstylist OR mortician OR embalmer OR agricultural workers OR farm workers OR fertilizer
manufacturers)
27 Apr 2017: 40
batch# 21471
PUBMED
((("7664-41-7" OR ammonia "7783-18-8" OR ammonium thiosulfate OR ammonium thiosulfate OR ammonium
thiosulphate OR "6484-52-2" OR ammonium nitrate OR ammonium salt OR "5421-46-5" OR ammonium
thioglycolate OR "1111-78-0" OR ammonium carbamate OR "7773-06-0" OR ammonium sulfamate OR ammate OR
ammonium sulphamate OR "7632-50-0" OR ammonium citrate OR "53956-04-0" OR ammonium glycyrrhizate OR
ammonium glycyrrhizinate OR "12124-97-9" OR ammonium bromide OR "12125-02-9" OR ammonium chloride OR
"7783-20-2" OR ammonium sulfate OR "12125-01-8" OR ammonium fluoride OR "12027-06-4" OR ammonium
iodide OR ammonium iodide)) AND (brewer OR brewery OR janitor OR housekeeper OR exterminator OR
cosmetologist OR hairstylist OR mortician OR embalmer OR agricultural workers OR farm workers OR fertilizer
manufacturers)) AND (cancer OR neoplasm OR malignancy OR tumor*)
27 Apr 2017: 1
Batch# 21472
WEB OF
SCIENCE
(TS=("7764-41-7") OR TS="ammonia" ORTS=("7783-18-8") OR TS="ammonium thiosulfate" ORTS="ammonium
thiosulfate" OR TS="ammonium thiosulphate" OR TS=("6484-52-2") OR TS="ammonium nitrate" OR TS="ammonium
salt" OR TS=("5421-46-5") OR TS="ammonium thioglycolate" ORTS=("llll-78-0") ORTS="ammonium carbamate"
ORTS=("7773-06-0") OR TS="ammonium sulfamate" ORTS="ammate" ORTS="ammonium sulphamate" OR
TS=("7632-50-0") OR TS="ammonium citrate" ORTS=("53956-04-0") ORTS="ammonium glycyrrhizate" OR
TS="ammonium glycyrrhizinate" OR TS=("12124-97-9") ORTS="ammonium bromide" ORTS=("12125-02-9") OR
TS="ammonium chloride" OR TS=("7783-20-2") ORTS="ammonium sulfate" ORTS=("12125-01-8") OR
TS="ammonium fluoride" ORTS=("12027-06-4") ORTS="ammonium iodide")
27 Apr 2017:
151,702
This document is a draft for review purposes only and does not constitute Agency policy.
23	DRAFT-DO NOT CITE OR QUOTE

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IRIS Assessment Plan for Ammonia (Oral Exposure)
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science, Toxline) (continued)
Database
Terms
Date and Results
WEB OF
SCIENCE
(TS=("7764-41-7") OR TS="ammonia" ORTS=("7783-18-8") OR TS="ammonium thiosulfate" ORTS="ammonium
thiosulfate" OR TS="ammonium thiosulphate" OR TS=("6484-52-2") OR TS="ammonium nitrate" OR TS="ammonium
salt" OR TS=("5421-46-5") OR TS="ammonium thioglycolate" ORTS=("llll-78-0") ORTS="ammonium carbamate"
ORTS=("7773-06-0") OR TS="ammonium sulfamate" ORTS="ammate" ORTS="ammonium sulphamate" OR
TS=("7632-50-0") OR TS="ammonium citrate" ORTS=("53956-04-0") ORTS="ammonium glycyrrhizate" OR
TS="ammonium glycyrrhizinate" OR TS=("12124-97-9") ORTS="ammonium bromide" ORTS=("12125-02-9") OR
TS="ammonium chloride" OR TS=("7783-20-2") ORTS="ammonium sulfate" ORTS=("12125-01-8") OR
TS="ammonium fluoride" OR TS=("12027-06-4") OR TS="ammonium iodide") AND (TS="live animal studies" OR
TS="rats" ORTS="mice" ORTS="rabbits" OR TS="hamsters" ORTS="dogs" ORTS="monkeys" ORTS="pigs" OR
TS="guinea pigs"))
27 Apr 2017:4885
Batch# 21476
WEB OF
SCIENCE
((((TS=("7764-41-7") OR TS="ammonia" ORTS=("7783-18-8") OR TS="ammonium thiosulfate" ORTS="ammonium
thiosulfate" OR TS="ammonium thiosulphate" OR TS=("6484-52-2") OR TS="ammonium nitrate" OR TS="ammonium
salt" OR TS=("5421-46-5") OR TS="ammonium thioglycolate" ORTS=("llll-78-0") ORTS="ammonium carbamate"
ORTS=("7773-06-0") OR TS="ammonium sulfamate" ORTS="ammate" ORTS="ammonium sulphamate" OR
TS=("7632-50-0") OR TS="ammonium citrate" ORTS=("53956-04-0") ORTS="ammonium glycyrrhizate" OR
TS="ammonium glycyrrhizinate" OR TS=("12124-97-9") ORTS="ammonium bromide" ORTS=("12125-02-9") OR
TS="ammonium chloride" OR TS=("7783-20-2") ORTS="ammonium sulfate" ORTS=("12125-01-8") OR
TS="ammonium fluoride" OR TS=("12027-06-4") OR TS="ammonium iodide") AND (TS="live animal studies" OR
TS="rats" ORTS="mice" ORTS="rabbits" OR TS="hamsters" ORTS="dogs" ORTS="monkeys" ORTS="pigs" OR
TS="guinea pigs") AND (TS="oral" ORTS="gavage" ORTS="ingestion" ORTS="inhal*" ORTS="diet" ORTS="food"))))
27 Apr 2017:1301
Batch # 21478
WEB OF
SCIENCE
((TS=("7764-41-7") OR TS="ammonia" OR TS=("7783-18-8") OR TS="ammonium thiosulfate" OR TS="ammonium
thiosulfate" OR TS="ammonium thiosulphate" OR TS=("6484-52-2") OR TS="ammonium nitrate" OR TS="ammonium
salt" OR TS=("5421-46-5") OR TS="ammonium thioglycolate" ORTS=("llll-78-0") ORTS="ammonium carbamate"
ORTS=("7773-06-0") OR TS="ammonium sulfamate" ORTS="ammate" ORTS="ammonium sulphamate" OR
TS=("7632-50-0") OR TS="ammonium citrate" ORTS=("53956-04-0") ORTS="ammonium glycyrrhizate" OR
TS="ammonium glycyrrhizinate" OR TS=("12124-97-9") ORTS="ammonium bromide" ORTS=("12125-02-9") OR
TS="ammonium chloride" OR TS=("7783-20-2") ORTS="ammonium sulfate" ORTS=("12125-01-8") OR
TS="ammonium fluoride" OR TS=("12027-06-4") OR TS="ammonium iodide") AND (TS="brewer" OR TS="brewery"
ORTS="janitor" OR TS="housekeeper" OR TS="exterminator" ORTS="cosmetologist" ORTS="hairstylist" OR
TS="mortician" OR TS="embalmer" OR TS="agricultural workers" OR TS="farm workers" OR TS="fertilizer
manufacturers"))
27 Apr 2017: 88
Batch# 21480
This document is a draft for review purposes only and does not constitute Agency policy.
24	DRAFT-DO NOT CITE OR QUOTE

-------
IRIS Assessment Plan for Ammonia (Oral Exposure)
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science, Toxline) (continued)
Database
Terms
Date and Results
WEB OF
SCIENCE
((TS=("7764-41-7") OR TS="ammonia" OR TS=("7783-18-8") OR TS="ammonium thiosulfate" OR TS="ammonium
thiosulfate" OR TS="ammonium thiosulphate" OR TS=("6484-52-2") OR TS="ammonium nitrate" OR TS="ammonium
salt" OR TS=("5421-46-5") OR TS="ammonium thioglycolate" ORTS=("llll-78-0") ORTS="ammonium carbamate"
ORTS=("7773-06-0") OR TS="ammonium sulfamate" ORTS="ammate" ORTS="ammonium sulphamate" OR
TS=("7632-50-0") OR TS="ammonium citrate" ORTS=("53956-04-0") ORTS="ammonium glycyrrhizate" OR
TS="ammonium glycyrrhizinate" OR TS=("12124-97-9") ORTS="ammonium bromide" ORTS=("12125-02-9") OR
TS="ammonium chloride" OR TS=("7783-20-2") ORTS="ammonium sulfate" ORTS=("12125-01-8") OR
TS="ammonium fluoride" OR TS=("12027-06-4") OR TS="ammonium iodide") AND (TS="brewer" OR TS="brewery"
ORTS="janitor" OR TS="housekeeper" OR TS="exterminator" ORTS="cosmetologist" ORTS="hairstylist" OR
TS="mortician" OR TS="embalmer" OR TS="agricultural workers" OR TS="farm workers" OR TS="fertilizer
manufacturers") AND TS="cancer" OR TS="neoplasm" OR TS="malignancy" OR Ts="tumor")
27 Apr 2017: 1
Batch# 21481
TOXLINE
@OR+("ammonium+salt"+@TERM+@rn+7664-41-7+"ammonia"+@TERM+@rn+7783-18-8+"ammonium+
thiosulfate"+"ammonium+ thiosulfate"+"ammonium+ thiosulphate"+@TERM+@rn+6484-52-2+"ammonium+
nitrate"+@TERM+@rn+5421-46-5+"ammonium+ thioglycolate"+@TERM+@rn+llll-78-0+"ammonium+
carbamate"+@TERM+@rn+7773-06-0+"ammonium+ sulfamate"+"ammate"+"ammonium+
sulphamate"+@TERM+@rn+7632-50-0+"ammonium+citrate"+@TERM+@rn+53956-04-0+"ammonium+
glycyrrhizate"+"ammonium+ glycyrrhizinate"+@TERM+@rn+12124-97-9+"ammonium+
bromide"+@TERM+@rn+12125-02-9+"ammonium+ chloride"+"ammonium+hydrochloride"+@TERM+@rn+7783-
20-2+"ammonium+ sulfate"+@TERM+@rn+12125-01-8+"ammonium+ fluoride"+@TERM+@rn+12027-06-
4"+"ammonium+ iodide")
27 Apr 2017: 73
Batch# 21482
TOXLINE
@AND+@OR+("ammonium+salt"+@TERM+@rn+7664-41-7+"ammonia"+@TERM+@rn+7783-18-8+"ammonium+
thiosulfate"+"ammonium+ thiosulfate"+"ammonium+ thiosulphate"+@TERM+@rn+6484-52-2+"ammonium+
nitrate"+@TERM+@rn+5421-46-5+"ammonium+ thioglycolate"+@TERM+@rn+llll-78-0+"ammonium+
carbamate"+@TERM+@rn+7773-06-0+"ammonium+ sulfamate"+"ammate"+"ammonium+
sulphamate"+@TERM+@rn+7632-50-0+"ammonium+citrate"+@TERM+@rn+53956-04-0+"ammonium+
glycyrrhizate"+"ammonium+ glycyrrhizinate"+@TERM+@rn+12124-97-9+"ammonium+
bromide"+@TERM+@rn+12125-02-9+"ammonium+ chloride"+"ammonium+hydrochloride"+@TERM+@rn+7783-
20-2+"ammonium+ sulfate"+@TERM+@rn+12125-01-8+"ammonium+ fluoride"+@TERM+@rn+12027-06-
4"+"ammonium+ iodide")+@AND+@OR+("live+animal+studies"+"rats"+"mice"+"rabbits"
+"hamsters"+"dogs"+"monkeys"+"pigs"+"guinea+pigs")+@SYN+@OR+("oral"+"gavage"+"ingestion"+"inhal*"+"food
"+"diet")
27 Apr 2017: 13
Batch# 21483
This document is a draft for review purposes only and does not constitute Agency policy.
25	DRAFT-DO NOT CITE OR QUOTE

-------
IRIS Assessment Plan for Ammonia (Oral Exposure)
Table A-l. Summary of detailed search strategies for Ammonia (PubMed, Web of Science, Toxline) (continued)
Database
Terms
Date and Results
TOXLINE
@OR+("ammonium+salt"+@TERM+@rn+7664-41-7+"ammonia"+@TERM+@rn+7783-18-8+"ammonium+
thiosulfate"+"ammonium+ thiosulfate"+"ammonium+ thiosulphate"+@TERM+@rn+6484-52-2+"ammonium+
nitrate"+@TERM+@rn+5421-46-5+"ammonium+ thioglycolate"+@TERM+@rn+llll-78-0+"ammonium+
carbamate"+@TERM+@rn+7773-06-0+"ammonium+ sulfamate"+"ammate"+"ammonium+
sulphamate"+@TERM+@rn+7632-50-0+"ammonium+citrate"+@TERM+@rn+53956-04-0+"ammonium+
glycyrrhizate"+"ammonium+ glycyrrhizinate"+@TERM+@rn+12124-97-9+"ammonium+
bromide"+@TERM+@rn+12125-02-9+"ammonium+ chloride"+"ammonium+hydrochloride"+@TERM+@rn+7783-
20-2+"ammonium+ sulfate"+@TERM+@rn+12125-01-8+"ammonium+ fluoride"+@TERM+@rn+12027-06-
4"+"ammonium+ iodide")+@AND+@OR+("cancer"+"neoplasm"+"malignancy"+"tumors")
27 Apr 2017: 2
TOXLINE
@OR+("ammonium+salt"+@TERM+@rn+7664-41-7+"ammonia"+@TERM+@rn+7783-18-8+"ammonium+
thiosulfate"+"ammonium+ thiosulfate"+"ammonium+ thiosulphate"+@TERM+@rn+6484-52-2+"ammonium+
nitrate"+@TERM+@rn+5421-46-5+"ammonium+ thioglycolate"+@TERM+@rn+llll-78-0+"ammonium+
carbamate"+@TERM+@rn+7773-06-0+"ammonium+ sulfamate"+"ammate"+"ammonium+
sulphamate"+@TERM+@rn+7632-50-0+"ammonium+citrate"+@TERM+@rn+53956-04-0+"ammonium+
glycyrrhizate"+"ammonium+ glycyrrhizinate"+@TERM+@rn+12124-97-9+"ammonium+
bromide"+@TERM+@rn+12125-02-9+"ammonium+ chloride"+"ammonium+hydrochloride"+@TERM+@rn+7783-
20-2+"ammonium+ sulfate"+@TERM+@rn+12125-01-8+"ammonium+ fluoride"+@TERM+@rn+12027-06-
4"+"ammonium+ iodide")+@AND+@OR+("brewer"+"brewery"+"janitor"+"housekeeper"+"exterminator"+
"cosmetologist"+"hairstylist"+"mortician"+"embalmer"+"agricultural workers"+"farm workers"+"fertilizer
manufacturers")
27 Apr 2017:0
Batch # 21484
TOXLINE
@OR+("ammonium+salt"+@TERM+@rn+7664-41-7+"ammonia"+@TERM+@rn+7783-18-8+"ammonium+
thiosulfate"+"ammonium+ thiosulfate"+"ammonium+ thiosulphate"+@TERM+@rn+6484-52-2+"ammonium+
nitrate"+@TERM+@rn+5421-46-5+"ammonium+ thioglycolate"+@TERM+@rn+llll-78-0+"ammonium+
carbamate"+@TERM+@rn+7773-06-0+"ammonium+ sulfamate"+"ammate"+"ammonium+
sulphamate"+@TERM+@rn+7632-50-0+"ammonium+citrate"+@TERM+@rn+53956-04-0+"ammonium+
glycyrrhizate"+"ammonium+ glycyrrhizinate"+@TERM+@rn+12124-97-9+"ammonium+
bromide"+@TERM+@rn+12125-02-9+"ammonium+ chloride"+"ammonium+hydrochloride"+@TERM+@rn+7783-
20-2+"ammonium+ sulfate"+@TERM+@rn+12125-01-8+"ammonium+ fluoride"+@TERM+@rn+12027-06-
4"+"ammonium+ iodide")+@AND+@OR+("brewer"+"brewery"+"janitor"+"housekeeper"+"exterminator"+
"cosmetologist"+"hairstylist"+"mortician"+"embalmer"+"agricultural workers"+"farm workers"+"fertilizer
manufacturers")+@AND+@OR+("cancer"+"neoplasm"+"malignancy"+"tumors")
27 Apr 2017:0
Batch# 21485
This document is a draft for review purposes only and does not constitute Agency policy.
26	DRAFT-DO NOT CITE OR QUOTE

-------