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or EPA ID for final]
www.epa.gov/iris
4>EPA
ANNOTATED REFERENCE OUTLINE
FOR THE TOXICOLOGICAL REVIEW
OF
Ammonia
(CAS No. 7664-41-7)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
12/12/08
NOTICE
This document is an Agency Review 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.
U.S. Environmental Protection Agency
Washington, DC
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REVIEWS
Clayton, GD; Clayton, FE; eds. (1993) Ammonia. In: Patty's industrial hygiene and toxicology.
New York, NY: John Wiley & Sons; pp. 756-762.
ACGIH (American Conference of Governmental Industrial Hygienists). (1991) Ammonium
chloride fume. 6th edition. Cincinnati, OH: American Conference of Governmental Industrial
Hygienists; p. 58.
AGCIH. (2001) Threshold limit values for chemical substances and physical agents and
biological exposure indices. Cincinnati, OH: American Conference of Governmental Industrial
Hygienists.
ACGIH. (1991) Ammonia. In: Documentation of the threshold limit values and biological
exposure indices. Cincinnati, OH: American Conference of Governmental Industrial Hygienists
Inc; pp. 58-59.
Albrecht, J. (1996) Astrocytes and ammonia neurotoxicity. In: Role of Glia in Neurotoxicity.
2nd edition. New York, NY: CRC Press; pp. 137-153.
Amshel, CE; Fealk, MH; Phillips, BJ; et al. (2000) Anhydrous ammonia burns case report and
review of the literature. Burns 26(5):493-497.
ATSDR (Agency for Toxic Substances and Disease Registry). (2004) Toxicological profile for
ammonia (update). Atlanta, GA.
Budavari, S. (1996) Ammonium bicarbonate. In: Budavari, S; ed. The Merck index-an
encyclopedia of chemicals, drugs, and biologicals. 12th edition. Whitehouse Station, NJ: Merck
and Co., Inc.; p. 87.
Butterworth, RF. (2002) Pathophysiology of hepatic encephalopathy: A new look at ammonia.
Metab Brain Dis 17(4):221-227.
Cole, D; Todd, L; Wing, S. (2000) Concentrated swine feeding operations and public health: A
review of occupational and community health effects. Environmental Health Perspectives
108(8):685-699.
European Commission. (2000) Iuclid dataset Cas no. 6484-52-2. European Chemicals Bureau,
European Commission. Available online at http://ecb.jrc.ec.europa.eu/esis/index.php. Accessed
on December 10, 2008.
European Commission. (2000) Iuclid dataset Cas no. 12125-02-9. European Chemicals Bureau,
European Commission. Available online at http://ecb.jrc.ec.europa.eu/esis/index.php. Accessed
on December 10, 2008.
Faint, V. (2006) The pathophysiology of hepatic encephalopathy. Nurs Crit Care ll(2):69-74.
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Felipo, V; Butterworth, RF. (2002) Neurobiology of ammonia. Progress in Neurobiology
67:259-279.
Gantilli, R. (1991) Drinking water health advisory for ammonia. Environmental Protection
Agency, Office of the Assistant Administrator for Water. Washington, DC. PB 92 135 425.
Gosselin, RE; Smith, RP; Hodge, HC. (1984) In: Clinical toxicology of commercial products.
Baltimore, MD: Williams and Wilkins; p. Ill - 22.
Heidelberger, C; Freeman, AE; Pielka, RJ; et al. (1983) Cell transformation by chemical agents -
a review and analysis of the literature. Mutation Research 114:283-385.
International Programme on Chemical Safety. (1990) Ammonia - health and safety guide. World
Health Organization, Distribution and Sales Service. Available online at
http://www.inchem.org/documents/hsg/hsg/hsg037.htm. Accessed on December 12, 2008.
IRIS (Integrated Risk Information System). (1988) Ammonia. Integrated Risk Information
System. U.S. Environmental Protection Agency, Washington, DC.
IRIS. (2002) Ammonia. Integrated Risk Information System. U.S. Environmental Protection
Agency, Washington, DC.
Jalan, R; Shawcross, D; Davies, N. (2003) The molecular pathogenesis of hepatic
encephalopathy. Int JBiochem Cell Biol 35(8): 1175-1181.
Johanson, G; Alexandrie, A; Jarnberg, J; et al. (2006) Nordic expert group: Evaluation of health
risks of ammonia. Toxicol Sci 90(1-S):332.
Karim, Z; Szutkowska, M; Vernimmen, C; et al. (2005) Renal handling of NH3/NH4+: Recent
concepts. Nephron Physiol 101(4):p77-81.
Katayama, K. (2004) Ammonia metabolism and hepatic encephalopathy. Hepatol Res 30S:73-
80.
Latenser, BA; Lucktong, TA. (2000) Anhydrous ammonia burns: Case presentation and literature
review. Journal of Burn Care and Rehabilitation 21(1 PT l):40-42.
Lehninger, AL. (1975) Oxidative degradation of amino acids. In: Biochemistry: The molecular
basis of cell structure and function. 2nd edition. Worth Publishers, Inc.; pp. 579-585.
Lewis, RJ. (1996) Ammonia. In: Sax's dangerous properties of industrial materials. New York,
NY: p. 210.
Liesivuoru, J; Nordic Expert, G. (2005) The nordic expert group for criteria documentation of
health risks from chemicals. 137. Ammonia. Arbete och Halsa 13.
Makarovsky, I; Markel, G; Dushnitsky, T; et al. (2008) Ammonia—when something smells
wrong. Isr Med Assoc J 10(7):537-543.
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Marcaggi, P; Coles, JA. (2001) Ammonium in nervous tissue: Transport across cell membranes,
fluxes from neurons to glial cells, and role in signaling. Progress in Neurobiology 64:157-183.
NIOSH (National Institute for Occupational Safety and Health). (1974) Criteria for a
recommended standard: Occupational exposure to ammonia. Cincinnati, OH: National Institute
for Occupational Safety and Health. Hew publication number 74-136.
O'Neil, MJ. (2001) Potential symptoms of overexposure to fumes are irritation of eyes, skin,
respiratory system; cough, dyspnea, pulmonary sensitization. In: O'Neil, MJ; ed. The Merck
index- an encyclopedia of chemicals, drugs, and biologicals. Whitehouse Station, NJ: Merck and
Co., Inc.; p. 89.
Pierce, JO. (1993-1994) Biological effects. In: Clayton, GD and Clayton, FE; eds. Patty's
industrial hygiene and toxicology. 4th edition. New York, NY: John Wiley & Sons, Inc.; p. 758.
Pierce, JO. (1993-1994) Absorption, metabolism, and excretion. In: Clayton, GD and Clayton,
FE; eds. Patty's industrial hygiene and toxicology. 4th edition. New York, NY: John Wiley &
Sons, Inc.; p. 760.
Prager, JC. (1995) Ammonia. In: Environmental contaminant reference databook. New York,
NY: Van Nostrand Reinhold; p. 137.
Ryer-Powder, JE. (1991) Health effects of ammonia. Plant/Operations Progress 10(4):228-232.
Seiler, N. (2002) Review: Ammonia and Alzheimer's disease. Neurochemistry International
41:189-207.
Tonelli, AR; Pham, A. (2008) Bronchiectasis, a long-term sequela of ammonia inhalation: A
case report and review of the literature. Burns Jun 5. [Epub ahead of print]
U.S. EPA (Environmental Protection Agency). (1999) Ambient water quality criteria for
ammonia, 1999 update. Office of Water. Washington, DC. EPA-822-R-99-014.
Verschueren, K. (1983) Ammonium acetate. In: Handbook of environmental data on organic
chemicals. 2nd edition. VanNorstrand Reinhold Company; p. 196.
Visek, WJ. (1968) Some aspects of ammonia toxicity in animal cells. J Dairy Sci 51(2):286-295.
Visek, WJ. (1984) Ammonia: Its effects on biological systems, metabolic hormones, and
reproduction. Journal of Dairy Science 67(3):481-498.
Walaszek, DR. (2003) Occupational ammonia injuries and sodium thiosulfate treatment: A
review. Ammonia Plant Safety & Related Facilities 44:119-126.
Weiner, ID; Hamm, LL. (2007) Molecular mechanisms of renal ammonia transport. Annu Rev
Physiol 69:317-340.
White, CE; Park, MS; Renz, EM; et al. (2007) Burn center treatment of patients with severe
anhydrous ammonia injury: Case reports and literature review. J Burn Care Res 28(6):922-928.
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Winek, CL. (1985) Drug and chemical blood-level data 1985. Pittsburgh, PA: Allied Fischer
Scientific.
World Health Organization. (1986) Ammonia. Geneva, Switzerland: World Health
Organization.
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1	2. CHEMICAL AND PHYSICAL INFORMATION
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3. TOXICOKINETICS
3.1. ABSORPTION
ACGIH. (1991) The average nasal retention of ammonia by human subjects was found to be
83%. Cincinnati, OH: American Conference of Governmental Industrial Hygienists; p. 58.
Boyd, EM; MacLachlan, ML; Perry, WF. (1944) Experimental ammonia gas poisoning in rabbits
and cats. Journal of Industrial Hygiene and Toxicology 26(l):29-34.
Castell, DO; Moore, EW. (1971) Ammonia absorption from the human colon. Gastroenterology
60:33-42.
Dalhamn, T. (1963) Effect of ammonia alone and combined with carbon particles on ciliary
activity in the rabbit trachea in vivo, with studies of the absorption capacity of the nasal cavity.
International Journal of Air and Water Pollution 7:531-539.
Egle, JL. (1973) Retention of inhaled acetone and ammonia in the dog. American Industrial
Hygiene Association Journal 34:533-539.
Landahl, HD; Hermann, RG. (1950) Retention of vapors and gases in the human nose and lung.
Archives of Industrial Hygiene and Occupational Medicine 1:36-45.
Manninen, A; Anttila, S; Savolainen, H. (1988) Rat metabolic adaptation to ammonia inhalation.
Proceedings of the Society for Experimental Biology and Medicine 187(3):278-281.
Metges, CC; Petzke, KH; El-Khoury, AE; et al. (1999) Incorporation of urea and ammonia
nitrogen into ileal and fecal microbial proteins and plasma free amino acids in normal men and
ileostomates. American Journal of Clinical Nutrition 70(6): 1046-1058.
Mossberg, SM; Ross, G. (1967) Ammonia, movement in the small intestine: Preferential
transport by the ileum. Journal of Clinical Investigation 46(4):490-498.
Schaerdel, AD; White, WJ; Lang, CM; et al. (1983) Localized and systemic effects of
environmental ammonia in rats. Laboratory Animal Science 33(l):40-45.
3.2. DISTRIBUTION
Brown, RH; Duda, GD; Korkes, S; et al. (1957) A colorimetric micromethod for determination
of ammonia; the ammonia content of rat tissues and human plasma. Archives of Biochemistry
and Biophysics 66:301-309.
Conn, HO. (1972) Studies of the source and significance of blood ammonia iv. Early ammonia
peaks after ingestion of ammonia salts. Yale Journal of Biology and Medicine 45:543-549.
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da Fonseca, J; Brito, MJ; Freitas, J; et al. (1998) Acute colitis caused by caustic products.
American Journal of Gastroenterology 93(12):2601-2602.
da Fonseca-Wollheim, F. (1995) The influence of ph and various anions on the distribution of
NH4+ in human blood. European Journal of Clinical Chemistry and Clinical Biochemistry
33(5):289-294.
Huizenga, JR; Tangerman, A; Gips, CH. (1994) Determination of ammonia in biological fluids.
Annals of Clinical Biochemistry 31(6): 529-543.
Jozwik, M; Pietrzycki, B; Chojnowski, M; et al. (2005) Maternal and fetal blood ammonia
concentrations in normal term human pregnancies. Biol Neonate 87(l):38-43.
Pitts, RF. (1971) The role of ammonia production and excretion in regulation of acid-base
balance. New England Journal of Medicine 284:32-38.
Salvatore, F; Bocchinti, V; Cimino, F. (1963) Ammonia intoxication and its effects on brain
ammonia levels. Biochemical Pharmacology 12:1-6.
Stabenau, JR; Warren, KS; Rail, DP. (1958) The role of ph gradient in the distribution of
ammonia between blood and cerebro-spinal fluid, brain and muscle. Journal of Clinical
Investigation 38:373-383.
Takagaki, G; Berl, S; Clarke, DD; et al. (1961) Glutamic acid metabolism in brain and liver
during infusion with ammonia labeled with nitrogen-15. Nature 189:326.
Vitti, TG; Vukmirovich, R; Gaebler, OH. (1964) Utilization of ammonia nitrogen, administered
by intragastric, intraperitonal, and subcutaneous routes: Effects of growth hormone. Archives of
Biochemistry and Biophysics 106:475-482.
Warren, KS; Nathan, DG. (1958) The passage of ammonia across the blood-brain-barrier and its
relation to blood ph. Journal of Clinical Investigation 37:1724-1728.
3.3. METABOLISM
Cooper, AJ; Freed, BR. (2005) Metabolism of [13N]ammonia in rat lung. Neurochem Int 47(1-
2): 103-118.
Duda, GD; Handler, P. (1958) Kinetics of ammonia metabolism in vivo. Journal of Biological
Chemistry 232:303-314.
Gay, WMB; Crane, CW; Stone, WD. (1969) The metabolism of ammonia in liver disease: A
comparison of urinary data following oral and intravenous loading of [15n]ammonium lactate.
Clinical Science 37:815-823.
Katayama, K. (2004) Ammonia metabolism and hepatic encephalopathy. Hepatol Res 30S:73-
80.
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Keiding, S; Sorensen, M; Bender, D; et al. (2006) Brain metabolism of 13n-ammonia during
acute hepatic encephalopathy in cirrhosis measured by positron emission tomography.
Hepatology 43(l):42-50.
Lockwood, AH. (2007) Controversies in ammonia metabolism: Implications for hepatic
encephalopathy. Metab Brain Dis 22(3-4):285-289.
Mohanachari, V; Reddy, KS; Indiri, K. (1984) Metabolic fate of ammonia in the rat after ethanol
loading. Toxicology Letters 20:225-228.
Morimoto, Y; Ukida, M; Tsuji, T. (1988) Dynamic relationship between urea and glutamine
synthesis in the mechanism of ammonia detoxication: A tracer study using 15NH4C1 in fulminant
hepatic failure rats. Gastroenterologia Japonica 23(5):538-545.
Saul, RL; Archer, MC. (1984) Oxidation of ammonia and hydroxylamine to nitrate in the rat and
in vitro. Carcinogenesis 5(1):77-81.
Schenker, S; Warren, KS. (1962) Effect of temperature variation on toxicity and metabolism of
ammonia in mice. Journal of Laboratory and Clinical Medicine 60(2):291-301.
Souba, WW. (1987) Interorgan ammonia metabolism in health and disease: A surgeon's view.
Journal of Parenteral and Enteral Nutrition 11(6):569-579.
Summerskill, WHJ; Wolpert, E. (1970) Ammonia metabolism in the gut. American Journal of
Clinical Nutrition 23:633-639.
Zange, J; Gronczewski, J; Jans, AWH. (1993) NH4+ metabolism and the intracellular ph in
isolated perfused rat liver. Biochemical Journal 293:667-673.
3.4. ELIMINATION
Barrow, CS; Steinhagen, WH. (1980) NH3 concentrations in the expired air of the rat:
Importance to inhalation toxicology. Toxicology and Applied Pharmacology 53:116-121.
Benyajati, S; Goldstein, L. (1975) Renal glutaminase adaptation and ammonia excretion in infant
rats. American Journal of Physiology 228:693-698.
Davies, BMA; Yudkin, J. (1952) Studies in biochemical adaptation. The origin of urinary
ammonia as indicated by the effect of chronic acidosis and alkalosis on some renal enzymes in
the rat. Biochemical Journal 52:407-412.
Flessner, MF; Wall, SM; Knepper, MA. (1992) Ammonium and bicarbonate transport in rat
outer medullary collecting ducts. American Journal of Physiology 262(1 Pt 2):F1-F7.
Giroux, M; Bremont, F; Salles, JP; et al. (2002) Exhaled NH3 and excreted NH4+ in children in
unpolluted or urban environments. Environment International 28:197-202.
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Han, KH; Croker, BP; Clapp, WL; et al. (2006) Expression of the ammonia transporter, rh C
glycoprotein, in normal and neoplastic human kidney. J Am Soc Nephrol 17(10):2670-2679.
Handlogten, ME; Hong, SP; Westhoff, CM; et al. (2005) Apical ammonia transport by the mouse
inner medullary collecting duct cell (mimcd-3). Am J Physiol Renal Physiol 289(2):F347-F358.
Hunt, RD. (1977) Measurement of partial pressure of ammonia in breath and arterial blood:
Evidence for secretion of ammonia into expired gas by metabolism of monoamines in the lung.
Dissertation Abstracts International Section B Physical Sciences and Engineering 37:3279.
Karim, Z; Szutkowska, M; Vernimmen, C; et al. (2005) Renal handling of NH3/NH4+: Recent
concepts. Nephron Physiol 101(4):77-81.
Kupprat, I; Johnson, RE; Hertig, BA. (1976) Ammonia: A normal constituent of expired air
during rest and exercise. Federation Proceedings 35:478.
Larson, TV; Covert, DS; Frank, R; et al. (1977) Ammonia in the human airways: Neutralization
of inspired acid sulfate aerosols. Science 197:161-163.
Lotspeich, WD. (1965) Renal hypertrophy in metabolic acidosis and its relation to ammonia
excretion. American Journal of Physiology 208:1135-1142.
Muntwyler, E; Iacobellis, M; Griffin, GE. (1956) Kidney glutaminase and carbonic anhydrase
activities and renal electrolyte excretion in rats. American Journal of Physiology 184:83-90.
Richards, P; Brown, CL; Houghton, BJ; et al. (1975) The incorporation of ammonia nitrogen into
albimum in man: The effects of diet, uremia and growth hormone. Clinical Nephrology
3(5):172-179.
Robin, ED; Travis, DM; Bromberg, PA; et al. (1959) Ammonia excretion by mammalian lung.
Science 129:270-271.
Turner, C; Spanel, P; Smith, D. (2006) A longitudinal study of ammonia, acetone and propanol
in the exhaled breath of 30 subjects using selected ion flow tube mass spectrometry, sift-ms.
Physiol Meas 27(4):321-337.
Utell, MJ; Mariglio, JA; Morrow, PE; et al. (1989) Effects of inhaled acid aerosols on respiratory
function: The role of endogenous ammonia. Journal of Aerosol Medicine 2:141-147.
Van Slyke, DD; Phillips, RA; Hamilton, PB; et al. (1943) Glutamine as source material of
urinary ammonia. Journal of Biological Chemistry 150:481-482.
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
Diack, C; Bois, FY. (2005) Pharmacokinetic-pharmacodynamic models for categorical toxicity
data. Regul Toxicol Pharmacol 41(l):55-65.
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4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
Ali, BA. (2001) Pulmonary function of workers exposed to ammonia: A study in the eastern
province of Saudi Arabia. International Journal of Occupational and Environmental Health
7(1): 19-22.
Altmann, L; Berresheim, H; Kruell, H; et al. (2006) Odor and sensory irritation of ammonia
measured in humans. Naunyn Schmiedebergs Arch Pharmacol 372(Suppl. 1):99.
Amshel, CE; Fealk, MH; Phillips, BJ; et al. (2000) Anhydrous ammonia burns case report and
review of the literature. Burns 26(5):493-497.
Andersson, BO. (1991) Lithuanian ammonia accident, March 20th 1989. Institution of Chemical
Engineers Symposium Series 124:15-17.
Ballal, SG; Ali, BA; Albar, AA; et al. (1998) Bronchial asthma in two chemical fertilizer
producing factories in eastern Saudi Arabia. International Journal of Tuberculosis and Lung
Disease 2(4):330-335.
Brautbar, N; Wu, MP; Richter, ED. (2003) Chronic ammonia inhalation and interstitial
pulmonary fibrosis: A case report and review of the literature. Arch Environ Health 58(9):592-
596.
Buff, R; Koller, EA. (1974) Studies on mechanisms underlying the reflex hyperpnoea induced by
inhalation of chemical irritants. Respiration Physiology 21:371-383.
Burns, TR; Greenberg, SD; Mace, ML; et al. (1985) Ultrastructure of acute ammonia toxicity in
the human lung. American Journal of Forensic Medicine and Pathology 6:204-210.
Caplin, M. (1941) Ammonia-gas poisoning: Forty-seven cases in a London shelter. Lancet
241:95-96.
Choudat, D; Goehen, M; Korobaeff, M; et al. (1994) Respiratory symptoms and bronchial
reactivity among pig and dairy farmers. Scandinavian Journal of Work Environment and Health
20(l):48-54.
Christesen, HB. (1995) Prediction of complications following caustic ingestion in adults.
Clinical Otolaryngology 20(3):272-278.
Cole, TJ; Cotes, JE; Johnson, GR. (1977) Ventilation, cardiac frequency and pattern of breathing
during exercise in men exposed to o-chlorobenzylidene malonitrile (CS) and ammonia gas in low
concentrations. Quarterly Journal of Experimental Physiology and Cognate Medical Sciences
62:341-351.
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Cormier, Y; Israel-Assayag, E; Racine, G; et al. (2000) Farming practices and the respiratory
health risks of swine confinement buildings. European Respiratory Journal 15(3):560-565.
Counturier, Y; Barbotin, M; Bobin, P; et al. (1971) Apropos of three cases of toxic lung caused
by vapors of ammonia and hydrogen sulfide. Bulletin de la Societe Medicale d'Afrique Noire de
Langue Francaise 16(2):250-252.
Crook, B; Robertson, JF; Travers Glass, SA; et al. (1991) Airborne dust, ammonia,
microorganisms, and antigens in pig confinement houses and the respiratory health of exposed
farm workers. American Industrial Hygiene Association Journal 52(7):271-279.
de la Hoz, RE; Schlueter, DP; Rom, WN. (1996) Chronic lung disease secondary to ammonia
inhalation injury: A report on three cases. American Journal of Industrial Medicine 29(2):209-
214.
Dilli, D; Bostanci, I; Tiras, U; et al. (2005) A non-accidental poisoning with ammonia in
adolescence. Child Care Health Dev 31(6):737-739.
Donham, KJ; Cumro, D; Reynolds, SJ; et al. (2000) Dose-response relationships between
occupational aerosol exposures and cross-shift declines of lung function in poultry workers:
Recommendations for exposure limits. Journal of Occupational and Environmental Medicine
42(3):260-269.
Donham, KJ; Knapp, LW; Monson, R; et al. (1982) Acute toxic exposure to gases from liquid
manure. Journal of Occupational Medicine 24:142-145.
Donham, KJ; Reynolds, SJ; Whitten, P; et al. (1995) Respiratory dysfunction in swine
production facility workers: Dose-response relationships of environmental exposures and
pulmonary functions. American Journal of Industrial Medicine 27(3):405-418.
Douglas, RB; Coe, JE. (1987) The relative sensitivity of the human eye and lung to irritant gases.
Annal Occup Hyg 31(2):265-267.
Duke-Elder, S; MacFaul, PA. (1972) Injuries: Non-mechanical injuries. In: Duke-Elder, S; ed.
System of ophthalmology. St. Louis, MO: C. V. Mosby Company; pp. 1079-1085.
Dworkin, MS; Patel, A; Fennell, M; et al. (2004) An outbreak of ammonia poisoning from
chicken tenders served in a school lunch. J Food Prot 67(6): 1299-1302.
Ferguson, WS; Koch, WC; Webster, LB; et al. (1977) Human physiological response and
adaption to ammonia. Journal of Occupational Medicine 19:319-326.
Flury, KE; Dines, DE; Rodarte, JR; et al. (1983) Airway obstruction due to inhalation of
ammonia. Mayo Clinic Proceedings 58:389-393.
Furst, P; Josephson, B; Maschio, G; et al. (1969) Nitrogen balance after intravenous and oral
administration of ammonium salts to man. Journal of Applied Physics 26:13-22.
George, A; Bang, RL; Lari, AR; et al. (2000) Liquid ammonia injury. Burns 26(4):409-413.
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Gilbert, GJ. (1988) Acute ammonia intoxication 37 years after ureterosigmoidostomy. Southern
Medical Journal 81(11): 1443-1445.
Gomzi, M. (1999) Indoor air and respiratory health in preadolescent children. Atmospheric
Environment 33(24-25):4081-4086. (Note: Will also be discussed in Section 4.8)
Gomzi, M; Saric, M. (1997) Respiratory impairment among children living in the vicinity of a
fertilizer plant. International Archives of Occupational and Environmental Health 70(5):314-
320. (Note: Will also be discussed in Section 4.8)
Gueye, L; Samb, A; Ciss, M; et al. (2001) [ammonia-gas poisoning: Respiratory troubles
evaluated by functional exploration], Dakar Med 46(1):8-11.
Hatton, DV; Leach, CS; Beaudet, AL; et al. (1979) Collagen breakdown and ammonia
inhalation. Archives of Environmental Health 34:83- 86.
Heederik, D; van Zwieten, R; Brouwer, R. (1990) Across-shift lung function changes among pig
farmers. American Journal of Industrial Medicine 17(l):57-58.
Holness, DL; Purdham, JT; Nethercott, JR. (1989) Acute and chronic respiratory effects of
occupational exposure to ammonia. American Industrial Hygiene Association Journal
50(12):646-650.
Ihrig, A; Hoffmann, J; Triebig, G. (2006) Examination of the influence of personal traits and
habituation on the reporting of complaints at experimental exposure to ammonia. Int Arch
Occup Environ Health 79(4):332-338.
Kalandarov, S; Bychkov, VP; Frenkel, ID; et al. (1984) Effect of an increased ammonia content
in an enclosed atmosphere on the adrenocortical system in man. Kosmicheskaya Biologiya i
Aviakosmicheskaya Meditsina 18:75-77.
Kass, I; Zamel, N; Dobry, CA; et al. (1972) Bronchiectasis following ammonia burns of the
respiratory tract. Chest 62(3):282-285.
Latenser, BA; Lucktong, TA. (2000) Anhydrous ammonia burns: Case presentation and literature
review. Journal of Burn Care and Rehabilitation 21(1 PT l):40-42.
Leduc, D; Gris, P; Lheureux, P; et al. (1992) Acute and long term respiratory damage following
inhalation of ammonia. Thorax 47(9):755-757.
Lee, HS; Chan, CC; Tan, KT; et al. (1993) Burnisher's asthma-a case due to ammonia from
silverware polishing. Singapore Medical Journal 34(6):565-566.
Levy, DM; Divertie, MB; Litzow, TJ; et al. (1964) Ammonia burns of the face and respiratory
tract. JAMA the journal of the American Medical Association 190(10):95-98.
Lopez, G; Dean, BS; Krenzelok, EP. (1988) Oral exposure to ammonia inhalants: A report of 8
cases. Veterinary and Human Toxicology 30:350.
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MacEwen, JD; Theodore, J; Vernot, EH. (1970) Human exposure to EEL concentrations of
monomethylhydrazine. Wright-Patterson Air Force Base, OH: Aerospace Medical Research
Laboratory; pp. 355-363.
Melbostad, E; Eduard, W. (2001) Organic dust-related respiratory and eye irritation in
Norwegian farmers. American Journal of Industrial Medicine 39(2):209-217.
Megarbane, B; Brunneel, F; Bedos, JP; et al. (2000) Ammonium chloride poisoning: A
misunderstood cause of metabolic acidosis with normal anion gap. Intensive Care Medicine
26(12): 1869.
Montague, TJ; Macneil, AR. (1980) Mass ammonia inhalation. Chest 77:496-498.
Morton, K. (2005) Fatal exposure to anhydrous ammonia in a food manufacturing plant. J
Occup Environ Hyg 2(6):D40-D43.
Mulder, JS; Van der Zalm, HO. (1967) Fatal case of ammonia poisoning. Tijdschrift voor
Sociale Geneeskunde 45:458-460.
Petrova, M; Diamond, J; Schuster, B; et al. (2008) Evaluation of trigeminal sensitivity to
ammonia in asthmatics and healthy human volunteers. Inhal Toxicol 20(12): 1085-1092. (Note:
Will also be discussed in Section 4.8)
Price, S. (2008) Ammonia gas incident. Anaesthesia 63(8):894-895.
Price, SK; Hughes, JE; Morrison, SC; et al. (1983) Fatal ammonia inhalation- a case report with
autopsy findings. South African Medical Journal 64:952-955.
Prudhomme, JC; Shusterman, DJ; Blanc, PD. (1998) Acute-onset persistent olfactory deficit
resulting from multiple overexposures to ammonia vapor at work. Journal of the American
Board of Family Practitioners ll(l):66-69.
Rahman, MH; Bratveit, M; Moen, BE. (2007) Exposure to ammonia and acute respiratory effects
in a urea fertilizer factory. Int J Occup Environ Health 13(2): 153-159.
Reynolds, SJ; Donham, KJ; Whitten, P; et al. (1996) Longitudinal evaluation of dose-response
relationships for environmental exposures and pulmonary function in swine production workers.
American Journal of Industrial Medicine 29(l):33-40.
Sigurdarson, ST; O'Shaughnessy, PT; Watt, JA; et al. (2004) Experimental human exposure to
inhaled grain dust and ammonia: Towards a model of concentrated animal feeding operations.
Am J Ind Med 46(4):345-348.
Silverman, L; Whittenberger, JL; Muller, J. (1949) Physiological response of man to ammonia in
low concentrations. Journal of Industrial Hygiene and Toxicology 31:74-78.
Sobonya, R. (1977) Fatal anhydrous ammonia inhalation. Human Pathology 8:293-299.
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Sotiropoulos, G; Kilaghbian, T; Dougherty, W; et al. (1998) Cold injury from pressurized liquid
ammonia: A report of two cases. Journal of Emergency Medicine 16(3):409-412.
Stroud, S. (1981) Ammonia inhalation- a case report. Critical Care Nurse 1:23-26.
Suh, HH; Spengler, JD; Koutrakis, P. (1992) Personal exposures to acid aerosols and ammonia.
Environmental Science and Technology 26(12):2507-2517.
Sundblad, BM; Larsson, BM; Acevedo, F; et al. (2004) Acute respiratory effects of exposure to
ammonia on healthy persons. Scand J Work Environ Health 30(4):313-321.
Tepper, A; Constock, GW; Levine, M. (1991) A longitudinal study of pulmonary function in fire
fighters. American Journal of Industrial Medicine 20(3):307-316.
Tonelli, AR; Pham, A. (2008) Bronchiectasis, a long-term sequela of ammonia inhalation: A
case report and review of the literature. Burns Jun 5. [Epub ahead of print],
Tsimakuridze, M; Saakadze, V; Tsereteli, M. (2005) [the characteristic state of health of
ammonia nitrate producing workers], Georgian Med News (122):80-83.
Tunnicliffe, WS; Harrison, RM; Kelly, FJ; et al. (2003) The effect of sulphurous air pollutant
exposures on symptoms, lung function, exhaled nitric oxide, and nasal epithelial lining fluid
antioxidant concentrations in normal and asthmatic adults. Occup Environ Med 60(1 l):el5.
Tuskes, PM; Tilton, MA; Graff, RM. (1988) Ammonia exposures of blue-line printers in
Houston, Texas. Applied Industrial Hygiene 3:155-157.
Verberk, MM. (1977) Effects of ammonia in volunteers. International Archives of Occupational
and Environmental Health 39:73-81.
Vogelzang, PFJ; van der Gulden, JWJ; Preller, L; et al. (1997) Bronchial hyperresponsiveness
and exposure in pig farmers. International Archives of Occupational and Environmental Health
70(5):327-333.
Vogelzang, PFJ; van der Gulden, JWJ; Folgering, H; et al. (2000) Longitudinal changes in
bronchial responsiveness associated with swine confinement dust exposure. Chest 117(5): 1488-
1495.
Voisin, C; Guerrin, F; Robin, H; et al. (1970) Sequelles fonctionnelles respiratoires des
intoxications par l'ammoniac (a propos de 8 observations). Le Poumon et le Coeur 26:1079-
1095.
Walton, M. (1973) Industrial ammonia gassing. British Journal of Industrial Medicine 30:78-86.
Ward, K; Costello, GP; Murray, B. (1983) Acute and long-term pulmonary sequelae of acute
ammonia inhalation. Irish Medical Journal 76(6):279-281.
Wason, S; Stepman, M; Breide, C. (1990) Ingestion of aromatic ammonia smelling salts
capsules. American Journal of Diseases of Children 144(2): 139-140.
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Weir, DC; Robertson, AS; Jones, S; et al. (1989) Occupational asthma due to soft corrosive
soldering fluxes containing zinc chloride and ammonium chloride. Thorax 44(3):220-223.
Weiser, JR; Mackenroth, T. (1989) Acute inhalatory mass ammonia intoxication with fatal
course. Experimental Pathology 37(l-4):291-295.
Wen, SL; Shao, JY; Wu, XH. (2004) [acute and long term respiratory damage following severe
ammonia poisoning], Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 22(l):75-76.
White, CE; Park, MS; Renz, EM; et al. (2007) Burn center treatment of patients with severe
anhydrous ammonia injury: Case reports and literature review. J Burn Care Res 28(6):922-928.
White, ES. (1971) A case of near fatal ammonia gas poisoning. Journal of Occupational
Medicine 13:543-550.
Wise, PM; Canty, TM; Wysocki, CJ. (2005) Temporal integration of nasal irritation from
ammonia at threshold and supra-threshold levels. Toxicol Sci 87(1):223-231.
Yang, GY. (1987) An industrial mass ammonia exposure. Veterinary and Human Toxicology
29:476-477.
Zhang, YX; Chen, SF; Wang, FJ; et al. (2003) [detection of myocardial lesion in patients with
acute ammonia poisoning], Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi 21(4):247-249.
4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN
ANIMALS—ORAL AND INHALATION
4.2.1. ORAL
Barzel, US; Jowsey, J. (1969) The effects of chronic acid and alkali administration on bone
turnover in adult rat. Clinical Science 36:517-524.
Barzel, US. (1975) The effect of chronic ammonium chloride ingestion on parathyroid hormone
function. Nephron 14:339-346.
Bodansky, A; Jaffe, HL; Chandler, JP. (1932) Serum phosphatase changes in calcium deficiency
and in ammonium chloride osteoporosis. Proceedings of the Society for Experimental Biology
and Medicine 29:871-873.
Bodega, G; Suarez, J; Boyano, MC; et al. (1993) High ammonia diet: Its effect on the glial
fibrillary acidic protein (GFAP). Neurochemical Research 18(9):971-975.
Boyano-Adanez, MC; Bodega, G; Barrios, V; et al. (1996) Response of rat cerebral
somatostatinergic system to a high ammonia diet. Neurochemical Research 29(5):469-476.
Gupta, BN; Khanna, RN; Data, KK. (1979) Toxicological studies of ammonium sulfamate in rat
after repeated oral administration. Toxicology 13:45-49.
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Janicki, RH. (1970) Renal adaptation during chronic NH4C1 acidosis in the rat: No role for
hyperplasia. American Journal of Physiology 219:613-618.
Kawano, S; Tsujii, M; Fusamoto, H; et al. (1991) Chronic effect of intragastric ammonia on
gastric mucosal structures in rats. Digestive Diseases and Sciences 36(l):33-38.
Kienzle, E; Wilms-Eilers, S. (1994) Struvite diet in cats: Effect of ammonium chloride and
carbonates on acid base balance of cats. Journal of Nutrition 124(Suppl 12):2652S-2659S.
Konsenko, E; Kaminsky, YG; Felipo, V; et al. (1993) Chronic hyperammonemia prevents
changes in brain energy and ammonia metabolites induced by acute ammonium intoxication.
Biochimica etBiophysica Acta 1180(3):321-326.
Lina, BA; Kuijpers, MH. (2004) Toxicity and carcinogenicity of acidogenic or alkalogenic diets
in rats; effects of feeding NH(4)C1, KHCO(3) or KC1. Food Chem Toxicol 42(1): 135-153.
Ota, Y; Hasumura, M; Okamura, M; et al. (2006) Chronic toxicity and carcinogenicity of dietary
administered ammonium sulfate in f344 rats. Food Chem Toxicol 44(1): 17-27.
Seegal, BC. (1927) Chronic acidosis in rabbits and in dogs. Archives of Internal Medicine
39:550-563.
Tsujii, M; Kawano, S; Tsuji, S; et al. (1992) Ammonia: A possible promoter in helicobacter
pylori-related gastric carcinogenesis. Cancer Lett 65(1):15-18.
Tsujii, M; Kawano, S; Tsujii, S; et al. (1993) Cell kinetics of mucosal atrophy in rat stomach
induced by long-term administration of ammonia. Gastroenterology 104(3):796-801.
Tsujii, M; Kawano, S; Tsujii, S; et al. (1995) Mechanism for ammonia-induced promotion of
gastric carcinogenesis in rats. Carcinogenesis 16(3):563-566.
Uzvolgyi, E. (1985) In vivo formation of a carcinogenic substance from diethyl pyrocarbonate in
the presence of ammonia. Archives of Toxicology. Supplement 8:490-493.
Uzvolgyi, E; Bojan, F. (1980) Possible in vivo formation of a carcinogenic substance from
diethyl pyrocarbonate and ammonia. Journal of Cancer Research and Clinical Oncology 97:205-
207.
4.2.2. INHALATION
Broderson, JR; Lindsey, JR; Crawford, JE. (1976) The role of environmental ammonia in
respiratory mycoplasmosis of rats. American Journal of Pathology 85:115-130.
Coon, RA; Jones, RA; Jenkins, LJ; et al. (1970) Animal inhalation studies on ammonia, ethylene,
glycol, formaldehyde, dimethylamine and ethanol. Toxicology and Applied Pharmacology
16:646-655.
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Dodd, KT; Gross, DR. (1980) Ammonia inhalation toxicity in cats: A study of acute and chronic
respiratory dysfunction. Archives of Environmental Health 35:6-14.
Done, SH; Chennells, DJ; Gresham, AC; et al. (2005) Clinical and pathological responses of
weaned pigs to atmospheric ammonia and dust. Vet Rec 157(3):71-80.
Donham, KJ. (1991) Association of environmental air contaminants with disease and
productivity in swine. American Journal of Veterinary Research 52(10): 1723-1730.
Drummond, JG; Curtis, SE; Simon, J; et al. (1980) Effects of aerial ammonia on growth and
health of young pigs. Journal of Animal Science 50(6): 1085-1091.
Gaafar, H; Girgis, R; Hussein, M; et al. (1992) The effect of ammonia on the respiratory nasal
mucosa of mice. A histological and histochemical study. Acta Oto Laryngologica Stockholm
112(2):339-342.
Gustin, P; Urbain, B; Prouvost, JF; et al. (1994) Effects of atmospheric ammonia on pulmonary
hemodynamics and vascular permeability in pigs: Interaction with endotoxins. Toxicology and
Applied Pharmacology 125(1): 17-26.
Inoiatov, F. (2004) [morphologic features of the liver changes in rats of both gender exposed to
aerogenic toxicants for a long period of time], Lik Sprava (3-4):78-83.
Kamildzhanov, AK; Dadazhanov, SN; Inoyatov, FS; et al. (2002) Some indicators of the
functional state of liver and reproductive organs exposed to ammonia inhalation.
Toksikologicheskii Vestnik (3): 17-21.
Neumann, R; Mehlhorn, G; Buchholz, I; et al. (1987) Experimental studies of the effect of
chronic exposure of suckling pigs to aerogenous toxic gas with ammonia of varying
concentrations. Zentralblatt fur Veterinaermedizin Reihe B 34:241-253.
Smith, LG; Busch, RH; Buschbom, RL; et al. (1989) Effects of sulfur dioxide or ammonium
sulfate exposure, alone or combined, for 4 or 8 months on normal and elastase-impaired rats.
Environmental Research 49(l):60-78.
Weatherby, JH. (1952) Chronic toxicity of ammonia fumes by inhalation. Proceedings of the
Society for Experimental Biology and Medicine 81:300-301.
4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Diekman, MA; Scheidt, AB; Sutton, AL; et al. (1993) Growth and reproductive performance,
during exposure to ammonia, of gilts afflicted with pneumonia and atrophic rhinitis. American
Journal of Veterinary Research 54(12):2128-2131.
Minana, MD; Marcaida, G; Grisolia, S; et al. (1995) Prenatal exposure of rats to ammonia
impairs NMDA receptor function and affords delayed protection against ammonia toxicity and
glutamate neurotoxicity. Journal of Neuropathology and Experimental Neurology 54(5):644-
650.
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4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES
Allen, WM. (1993) Bovine deaths associated with ammoniated straw. Veterinary Record
132(16):419.
Ambrose, AM. (1943) Studies on the physiological effects of sulfamic acid and ammonium
sulfamate. Journal of Industrial Hygiene and Toxicology 25(l):26-28.
Appelman, LM; ten Berge, WF; Reuzel, PGJ. (1982) Acute inhalation toxicity of ammonia in
rats with variable exposure periods. American Industrial Hygiene Association Journal
43(9):662-665.
Bajpai, A; Tikaria, A; Kabra, SK; et al. (2004) Hyperchloraemic acidosis consistent with
ammonium chloride administration. Arch Dis Child 89(1):92.
Beare, JD; Wilson, RS; Marsh, RJ. (1988) Ammonia burns of the eye: Old weapon in new hands.
British Medical Journal 296:590.
Benson, RA; Slobody, LB; et al. (1949) The treatment of ammonia dermatitis with diaparene;
report on 500 cases. J Pediatr 34(l):49-51.
Boyd, EM; MacLachlan, ML; Perry, WF. (1944) Experimental ammonia gas poisoning in rabbits
and cats. Journal of Industrial Hygiene and Toxicology 26(l):29-34.
Boyd, EM; Seymour, KGW. (1946) Ethylenediamine dihydrochloride or chlor-ethamine. Ii.
Untoward and toxic reactions. Experimental Medicine and Surgery:223-227.
Buckley, LA; Jiang, XJ; James, RA; et al. (1984) Respiratory tract lesions induced by sensory
irritants at the rd50 concentration. Toxicol Appl Pharmacol 74:417-429.
Capuco, AV. (1977) Ammonia: A modulator of 3t3 cell growth. Dissertation Abstracts
International Section B Physical Sciences and Engineering 38(9):4085.
Close, LG; Catlin, FI; Cohn, AM. (1980) Acute and chronic effects of ammonia burns of the
respiratory tract. Archives of Otolaryngology 106:151-158.
Doig, PA; Willoughby, RA. (1971) Response of swine to atmospheric ammonia and organic
dust. Journal of the American Veterinary Medical Association 159:1353-1361.
Fazekas, IG. (1939) Experimental suprarenal hypertrophy induced by ammonia. Endokrinologie
21:315-337.
Gamble, MR; Clough, G. (1976) Ammonia build-up in animal boxes and its effect on rat tracheal
epithelium. Lab Anim. 10:93-104.
Garcia, MV; Lopez-Mediavilla, C; Juanes de la Pena, MC; et al. (2003) Tolerance of neonatal rat
brain to acute hyperammonemia. Brain Res 973(1):31-38.
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Garcia, MV; Lopez-Mediavilla, C; Juanes de la Pena, MC; et al. (2004) Antioxidant defence of
the neonatal rat brain against acute hyperammonemia. Brain Res 1001(1-2): 159-163.
Greenlee, AR; Ellis, TM; Berg, RL. (2004) Low-dose agrochemicals and lawn-care pesticides
induce developmental toxicity in murine preimplantation embryos. Environ Health Perspect
112(6):703-709.
Hagiwara, A; Tanaka, H; Tamano, S; et al. (1994) Inhibiting effects of diethylmaleate or NH4C1
on nahco3, but not butylated hydroxyanisole, promotion of urinary bladder carcinogenesis in
male 344 rats initiated with n-butyl-n-(4-hydroxybutyl)nitrosamine. J Toxicol Sci 19(4): 189-
195.
Hawkins, RA; Miller, AL; Nielsen, RC; et al. (1973) The acute action of ammonia on rat brain
metabolism in vivo. Biochemical Journal 134:1001-1008.
Heifer, U. (1971) [Casuistic contribution to acute lethal inhalation poisoning by ammonia],
Lebensversicherungsmedizin 22:60-62. (German)
Helmers, S; Top, FH; Knapp, LW. (1971) Ammonia injuries in agriculture. Journal of the Iowa
Medical Society 61(5):271-280.
Hilado, CJ; Casey, CJ; Furst, A. (1977) Effect of ammonia on Swiss albino mice. Journal of
Combustion Toxicology 4:385-388.
Jarudi, MD; Golden, MD. (1973) Ammonia eye injuries. Journal of the Iowa Medical Society
63:260-263.
Jones, JB; Burgess, LR; Webster, AJF; et al. (1996) Behavioral responses of pigs to atmospheric
ammonia in a chronic choice test. Animal Sci 63(3):437-445.
Kane, LE; Barrow, CS; Alarie, Y. (1979) A short-term test to predict acceptable levels of
exposure to airborne sensory irritants. Am Ind Hyg Assoc J 40:207-229.
Kapeghian, JC; Jones, AB; Waters, IW. (1985) Effects of ammonia on selected hepatic
microsomal enzyme activity in mice. Bulletin of Environmental Contamination and Toxicology
35:15-22.
Kapeghian, JC; Mincer, HH; Jones, AL; et al. (1982) Acute inhalation toxicity of ammonia in
mice. Bulletin of Environmental Contamination and Toxicology 29:371-378.
Kerstein, MD; Schaffzin, DM; Hughes, WB; et al. (2001) Acute management of exposure to
liquid ammonia. Military Medicine 166(10):913-914.
Klein, J; Olson, KR; McKinney, HE. (1985) Caustic injury from household ammonia. American
Journal of Emergency Medicine 3:320.
Klendshoj, NC; Rejent, TA. (1966) Tissue levels of some poisoning agents less frequently
encountered. Journal of Forensic Sciences ll(l):75-80.
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Klucinski, W; Targowski, SP. (1984) Ammonia toxicity for mammalian and avian lymphocytes
from blood. Immunopharmacology 8(l):47-52.
Koenig, H; Koenig, R. (1949) Production of acute pulmonary edema by ammonium salts.
Proceedings of the Society for Experimental Biology and Medicine 70(3):375-380.
Konsenko, E; Felipo, V; D., MM; et al. (1991) Ammonium ingestion prevents depletion of
hepatic energy metabolites induced by acute ammonium intoxication. Archives of Biochemistry
and Biophysics 290(2):484-488.
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20
21
22	4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS
23
24	4.6.1. Oral
25
26	4.6.2. Inhalation
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28	4.6.3. Mode of Action Information
29
30	4.7. EVALUATION OF CARCINOGENICITY
31
32	4.7.1. Summary of Overall Weight-of-Evidence
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34	4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence
35
36	4.7.3. Mode of Action Information
37
38	4.7.2.1. Hypothesized Mode of Action
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40	4.7.2.2. Experimental Support for the Hypothesized Mode of Action
41
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1	4.7.2.3. Other Possible Modes of Action
2
3	4.7.2.4. Conclusions About the Hypothesized Mode of Action
4
5
6	4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES
7
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10
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14
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16	exposures on symptoms, lung function, exhaled nitric oxide, and nasal epithelial lining fluid
17	antioxidant concentrations in normal and asthmatic adults. Occup Environ Med 60(1 l):el5.
18
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