AMMONIUM CARBONATE AND AMMONIUM HYDROGEN CARBONATE
(formerly AMMONIUM BICARBONATE)
Explanation
These food additives were previously evaluated by JECFA in 1966
(see Annex I, Ref. 8). No toxicological monograph was published.
Introduction
Available data on ammonium carbonate and ammonium hydrogen
carbonate (bicarbonate) are summarized and discussed in the following
monograph. Because toxicological studies are limited for these
compounds, data on related ammonium salts (primarily ammonium
chloride) and carbonate salts (primarily sodium and potassium
carbonate and hydrogen carbonate (bicarbonate)) are also summarized
and discussed.
AMMONIUM SALTS
BIOCHEMICAL ASPECTS
The principal source of ammonia in the body is the oxidation of
glutamate by glutamate dehydrogenase, which is present in liver and
other tissues. Less important contributions are made by oxidative
deamination of amino acids (via L- and D- amino acid oxidases) and
endogenous amines (e.g., dopamine, epinephrine, etc., via monoamine
and diamine oxidases). Some ammonia also is produced by non-oxidative
deamination of certain amino acids by pyridoxal phosphate-dependent
dehydratase enzymes.
Ammonia is utilized in three major pathways:
(1) by reversal of the glutamate dehydrogenase reaction;
(2) in synthesis of glutamine and asparagine;
(3) in synthesis of carbamoyl phosphate, a key intermediate in the
synthesis of arginine and pyrimidines.
Hydrolysis of arginine by arginase produces urea, the final
metabolic product of mammalian nitrogen metabolism.
TOXICOLOGICAL STUDIES
Short-term studies
Rat
Groups of 5 weanling Holbrook rats (sex unspecified) were
administered 0 and 5% ammonium carbonate in the diet for 5 weeks.
Limited study parameters were examined. Test animals experienced
depressed growth and elevated BUN (Finlayson & Baumann, 1956).
Groups of 6 Sprague-Dawley rats, 225-275 g (sex unspecified) were
administered 0 or 1.28 g/kg/day of ammonium chloride for 5 days either
via drinking-water or by gavage. Treatment-related renal hypertrophy
was observed, but no increase occurred in uptake of radioactive
thymidine by the kidney, implying that no increase in DNA synthesis or
cell division occurred during renal enlargement. No other treatment-
related effects were observed (Janicki, 1970).
Groups of 6 female Holtzman rats, 200-250 g, were administered 0
or 1.5% ammonium chloride in the drinking-water for 7 days. Renal
hypertrophy was observed, along with increases in total DNA and total
RNA of kidney. No other treatment-related effects were reported
(Lotspeich, 1965). Similar effects were observed in another study in
which rats were fed ammonium chloride in the diet at 0 or 3% for a
period of 6 days (Thompson & Halliburton, 1966).
Groups of 7-12 adult male Sprague-Dawley rats were administered 0
or 1.5% ammonium chloride in their drinking-water for 330 days. In a
concurrent study by the same laboratory, similar animals in groups of
5-9 were administered 0 or 2% ammonium chloride in their drinking-
water for 6 months. Test animals developed osteoporosis due to a loss
of organic bone substance and bone minerals. Growth depression also
occurred in treated animals. The ammonium chloride-induced
osteoporosis was reversible with supplements of bicarbonate, but not
by calcium supplementation of the diet (Barzel & Jowsey, 1969; Barzel,
1969).
Rabbit
Groups of 5-7 female chinchilla rabbits, 8-14 months old, were
given 0 and 100-200 mg/kg ammonium carbonate by gavage for time
periods varying from 5 months to 16 months. The test compound was
given every other day in treatment cycles consisting of 3 weeks on and
1 week off the test compound. Treatment-related effects included
enlargement of adrenals, ovaries, mammary glands and womb as well as
lactation and proliferation of ovarian follicles and corpora lutea.
These effects were attributed to increased gonadotropin production by
the hypophysis, which, in turn, was stimulated by treatment-related
acidosis (Fazekas, 1949).
Similar studies by the same laboratory were carried out with
groups of 6 male and female chinchilla rabbits, 8-10 months old, that
were given 0 and 0.1-0.2 g/kg ammonium carbonate in their drinking-
water for periods ranging from 5 to 26 months. The treatment cycle was
for 3 weeks, followed by 1 week without the test compound. The only
notable effect was parathyroid hypertrophy (Fazekas, 1954b).
Rabbits were administered ammonium hydroxide (0, 83-200 mg/kg) by
stomach tube over periods of time varying from 1 to 17 months.
Hypertrophy of the adrenals, ovaries and parathyroid was noted, as was
hyperthyroidism (Fazekas, 1939, 1949, 1954a).
A group of 9 rabbits (sex and strain unspecified) was given by
gavage 0.6-1.0 g doses of ammonium chloride daily for a period of
4 weeks. A 20-30% reduction was observed in serum CO2; no other
adverse effects were reported (Jobling & Meeker, 1936).
A group of 9 rabbits averaging 2 kg in weight were given ammonium
chloride by stomach tube in doses ranging from 16.6 to 166 g for
periods from 11 days to 11 months; 6 controls were used. Severe
acidosis was observed, with casts and albumen in the urine.
Histological studies of the kidneys showed acute degeneration of the
convoluted tubules and marked pyknosis of nuclei. These effects were
reversible upon discontinuance of the acidotic diet (Seegal, 1927).
Dog
Four male mongrel dogs were fed 6 g of ammonium chloride by
capsule daily for 7 days. A fifth dog served as control. Increased
acidity and ammonia were observed in the urine. No other treatment-
related effects were reported (Pollak et al., 1965).
In another study, adult male mongrel dogs (1 dog/treatment level)
were given by capsule doses of 0, 25.5, 45.6, 91.0 or 170.0 mg/kg
ammonium chloride daily for 7 days. A treatment-related decrease in
urinary pH and specific gravity was observed, with only a mild
systemic acidosis (Short & Hammond, 1964).
OBSERVATIONS IN MAN
A number of clinical studies of duration less than 1 week have
been carried out with ammonium chloride. In one report, a man was
given 62 g of ammonium chloride in the diet over a 3-day period. No
effects were reported except for increased red cell count, increased
BUN and decreased plasma pH (Guest & Rapoport, 1940). In another
study, 3 young men were given ammonium chloride in drinking-water at
doses ranging from 52 to 105 g over 3-5 days. Headache, insomnia,
nausea and diarrhoea occurred along with increased urinary acidity and
ammonia. A reduction in glucose tolerance was also noted, consisting
of hyperglycaemia and a slow return of blood sugar to fasting levels
following glucose ingestion (Thompson et al., 1933).
Pregnant women (6 normal, 8 toxaemic, 3 hypertensive) were given
15 g/day of ammonium chloride in their beverage for a period of
3 days. Treated women experienced hyperventilation, anorexia,
diminished thirst, nausea, and loss in weight. Urinary chloride,
potassium, acidity and volume all increased, blood pH and CO2
decreased while haematocrit increased (Assali et al., 1955).
Eleven men, 21-38 years of age, given daily oral doses of 6-8 g
ammonium chloride for 6-9 days, showed a mild metabolic acidosis (Owen
& Robinson, 1963). A similar dosage of ammonium chloride was employed
in a study with 5 women of unspecified age suffering from rheumatoid
arthritis, who were administered the test compound for 23-33 days.
Some fluid loss was noted, but no other adverse effects were reported
(Owen & Robinson, 1963; Jacobson et al., 1942).
Three women and 3 men, aged 23-37, were given daily an oral
dose of 8 g of ammonium chloride for 5 days. The treatment group
experienced increased urinary excretion of magnesium, calcium and
phosphate and decreased urinary pH. No other effects were attributed
to ammonium chloride (Martin & Jones, 1961). These results were
corroborated in a 24-hour study in which 18 men and 6 women, age
unspecified, were given 0.1 kg of ammonium chloride by capsule (Lavan,
1969).
No adverse effects were reported in a 3-day study in which 4-5
patients, middle aged and older, were given a daily oral dose of 8 g
of ammonium chloride (Jailer et al., 1947).
Thirteen women and 2 men, aged 22-60, were given an oral dose of
ammonium chloride, 3 g/day, for 20 consecutive days a month for a
period of 3 months. Increased appetite and fat deposition were noted
which were attributed by the author to treatment-related acidosis and
resulting stimulation of adrenal cortical function. No other effects
due to ammonium chloride administration were reported (Fazekas, 1955).
CARBONATES/HYDROGEN CARBONATES (BICARBONATES)
BIOCHEMICAL ASPECTS
Bicarbonate enters the body from dietary sources and from carbon
dioxide through the carbonic anhydrase-catalysed equilibrium with
carbonic acid. Bicarbonate may be eliminated by conversion to carbon
dioxide and subsequent expiration, as well as by excretion in the
urine and faeces.
TOXICOLOGICAL STUDIES
Special studies on mutagenicity - Microbial systems
Microbial assay systems (plate and suspension test) with and
without activation were used to determine the mutagenic potential of
ammonium bicarbonate, potassium carbonate, calcium carbonate,
potassium bicarbonate and sodium bicarbonate. One strain of yeast,
Saccharomyces cerevisiae and three strains of the bacteria
Salmonella typhimurium were used in the studies, which employed
positive and negative controls. None of the compounds exhibited
mutagenic activity in any of the assay systems employed (Litton
Bionetics, 1974, 1975, 1977).
Special studies on reproduction and teratogenicity
Mouse
Groups of 24, 21, 22, 23 and 30 pregnant CD-1 outbred mice
received, respectively, 0, 6, 27, 125 and 580 mg/kg of sodium
bicarbonate by gavage daily during days 6-15 of gestation. Similar
studies were conducted with sodium and potassium carbonate by the same
laboratory. No adverse treatment-related effects were observed in test
and control groups (Food and Drug Research Laboratories, 1973b, 1975).
Rat
Groups of 20, 20, 21, 21 and 22 pregnant Wistar rats received,
respectively, 0, 3.4, 15.8, 73.3 and 340 mg/kg of sodium bicarbonate
by gavage daily during days 6-15 of gestation. Similar studies were
conducted with sodium and potassium carbonate by the same laboratory.
No adverse treatment-related effects were observed in nidation or on
maternal or foetal survival. Incidence of skeletal and soft-tissue
anomalies was comparable in test and control groups (Food and Drug
Research Laboratories, 1973b, 1975).
Rabbit
Groups of 11, 13, 12, 11 and 12 pregnant Dutch-belted rabbits
received, respectively, 0, 3.3, 15.3, 71.2 and 330 mg/kg of sodium
bicarbonate by gavage daily during days 6-18 of gestation. A similar
study was conducted with sodium carbonate, in which groups of 11, 12,
13, 14 and 12 rabbits received, respectively, daily gavage doses of 0,
1.8, 8.3, 38.6 and 179 mg/kg during days 6-18 of gestation. No adverse
treatment-related effects were observed on nidation or on maternal or
foetal survival. Incidence of skeletal and soft-tissue anomalies was
comparable in test and control groups (Food and Drug Research
Laboratories, 1974b).
Acute toxicity
Substance Animal Route LD50 Reference
(mg/kg bw)
Potassium Mouse Oral 2 900 Food and Drug Research
carbonate Laboratories, 1974a
Rat Oral 1 800 Food and Drug Research
Laboratories, 1974a
Oral 1 870 Smyth et al., 1969
Sodium Mouse Oral 5 650 Food and Drug Research
bicarbonate Laboratories, 1973a
Rat Oral 3 400 Food and Drug Research
Laboratories, 1973a
Oral 4 300 Informatics, Inc., 1972
Oral 6 000 Informatics, Inc., 1972
Oral 5 500 Informatics, Inc., 1972
Oral 4 850 Informatics, Inc., 1972
Oral 5 900 Informatics, Inc., 1972
OBSERVATIONS IN MAN
Comments
These compounds (ammonium ion and bicarbonate ion) are normal
metabolites in man. Although specific toxicological data for ammonium
carbonate and ammonium bicarbonate are limited, extrapolation of
results from studies with ammonium compounds (primarily ammonium
chloride) and with sodium or potassium carbonate provide a basis for
evaluation. Clinical studies in man show that administration of high
doses of ammonium chloride or of sodium bicarbonate results in changes
in the acid-base balance. This is the normal physiological response.
The levels of ammonium carbonate and bicarbonate in the diet from food
additive use are extremely small compared to the levels required to
cause physiological changes and pose no toxicological hazard.
EVALUATION
Estimate of acceptable daily intake for man
Not specified.*
* The statement "ADI not specified" means that, on the basis of the
available data (toxicological, biochemical, and other), the total
daily intake of the substance, arising from its use or uses at the
levels necessary to achieve the desired effect and from its acceptable
background in food, does not, in the opinion of the Committee,
represent a hazard to health. For this reason, and for the reasons
stated in individual evaluations, the establishment of an acceptable
daily intake (ADI) in mg/kg bw is not deemed necessary.
REFERENCES
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See Also:
Toxicological Abbreviations