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    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

    Assali, N. S., Herzig, D. & Singh, B. P. (1955) Renal response to
         ammonium chloride acidosis in normal and toxemic pregnancies,
         J. Appl. Physiol., 7, 367-374

    Barzel, U. S. (1969) Effect of excessive acid feeding on bone,
         Calcif. Tissue Res., 4(2), 94-100

    Barzel, U. S. & Jowsey, J. (1969) The effects of chronic acid and
         alkali administration on bone turnover in adult rats, Clin.
         Sci., 36, 517-524

    Fazekas, I. G. (1939) Experimental suprarenal hypertrophy induced by
         ammonium hydroxide, Endokrinologie, 21, 315-337

    Fazekas, I. G. (1949) Experimental data on influencing ovarian
         functions by simple compounds, Orvosi Hetilap, 90, 777-781

    Fazekas, I. G. (1954a) Enlargement of the parathyroid by treatment
         with simple acidotic compounds, Virchow's Arch. Pathol. Anat.
         u. Physiol., 324, 531-542

    Fazekas, I. G. (1954b) The influence of acidotic compounds on
         parathyroid function (serum Ca and P), Endokrinologie, 32,
         45-57

    Fazekas, I. G. (1955) Gain in weight (fat accumulation) in man
         following treatment with ammonium chloride, Endokrinologie,
         32, 289-295

    Finlayson, J. S. & Baumann, C. A. (1956) Responses of rats to urea and
         related substances. The use of spaced-feeding technique,
         J. Nutrition, 59, 211-221

    Food and Drug Research Laboratories, Inc. (1973a) FDA 71-79 (sodium
         bicarbonate). Approximate acute LD50 in mice, rats and rabbits.
         Three reports prepared for FDA under contract No. 71-260.
         Waverly, NY. Submitted by FDA to World Health Organization, 1982

    Food and Drug Research Laboratories, Inc. (1973b) Teratologic
         evaluation of FDA 71-84 (sodium carbonate) and FDA 71-79 (sodium
         bicarbonate) in mice and rats. Four final reports prepared for US
         Food and Drug Administration under DHEW contract No. FDA 71-260.
         Waverly, NY. Submitted by FDA to World Health Organization, 1982

    Food and Drug Research Laboratories, Inc. (1974a) FDA 73-76 (potassium
         carbonate). Approximate acute LD50 in mice and rats. Two reports
         prepared for FDA under contract No. 223-74-2176. Waverly, NY.
         Submitted by FDA to World Health Organization, 1982

    Food and Drug Research Laboratories, Inc. (1974b) Teratologic
         evaluation of FDA 71-79 (sodium bicarbonate) and FDA 71-84
         (sodium carbonate) in rabbits. Two final reports prepared for US
         Food and Drug Administration under DHEW contract No. FDA 71-260.
         Waverly, NY. Submitted by FDA to World Health Organization, 1982

    Food and Drug Research Laboratories, Inc. (1975) Teratologic
         evaluation of FDA 73-76 (potassium carbonate) in rats and mice.
         Two final reports prepared for US Food and Drug Administration
         under DHEW contract No. FDA 223-74-2176. Waverly, NY. Submitted
         by FDA to World Health Organization, 1982

    Guest, G. M. & Rapoport, S. (1940) Clinical studies of the organic
         acid-soluble phosphorus of red blood cells in different acidotic
         states, J. Lab. Clin. Med., 26, 190-198

    Informatics, Inc. (1972) Food ingredients - carbonates. Report
         prepared for US Food and Drug Administration under contract No.
         FDA 72-104. Rockville, MD

    Jacobson, S. D., Leichtentritt, B. & Lyons, R. H. (1942) The effect of
         acid and alkaline salts on some patients with rheumatoid
         arthritis, Amer. J. Med. Sci., 204, 540-546

    Jailer, J. W., Rosenfeld, M. & Shannon, J. A. (1947) The influence of
         orally administered alkali and acid on the renal excretion of
         quinacrine, chloroquine and santoquine, J. Clin. Invest., 26,
         1168-1172

    Janicki, R. H. (1970) Renal adaptation during chronic NH4Cl acidosis
         in the rat: no role for hyperplasia, Am. J. Physiol., 219,
         613-618

    Jobling, J. W. & Meeker, D. R. (1936) Further investigations on
         experimental atherosclerosis, Arch. Pathol., 22, 293-300

    Kirsner, J. C. & Palmer, W. L. (1943) Studies on the effect of massive
         quantities of sodium bicarbonate on the acid-base equilibrium and
         on renal function, Ann. Internal Med., 13, 100-104

    Lavan, J. N. (1969) The effect of oral ammonium chloride on the
         urinary excretion of calcium, magnesium and sodium in man,
         Irish J. Med. Sci., 2, 223-227

    Litton Bionetics, Inc. (1974) Mutagenic evaluation of sodium
         bicarbonate (compound FDA 71-79). Prepared for US Food and Drug
         Administration under DHEW contract No. FDA 223-74-2104.
         Kensington, MD. Submitted by FDA to World Health Organization,
         1982

    Litton Bionetics, Inc. (1975) Mutagenic evaluation of potassium
         bicarbonate (compound FDA 73-76). Prepared for US Food and Drug
         Administration under DHEW contract No. FDA 223-74-2104.
         Kensington, MD. Submitted by FDA to World Health Organization,
         1982

    Litton Bionetics, Inc. (1977a) Mutagenic evaluation of FDA 75-90
         (potassium bicarbonate) and FDA 75-97 (calcium carbonate). Two
         final reports prepared for US Food and Drug Administration under
         DHEW contract No. FDA 223-74-2104. Kensington, MD. Submitted by
         FDA to World Health Organization, 1982

    Litton Bionetics, Inc. (1977b) Mutagenic evaluation of FDA 75-85
         (ammonium bicarbonate). Prepared for US Food and Drug
         Administration under DHEW contract No. FDA 223-74-2102.
         Kensington, MD. Submitted by FDA to World Health Organization,
         1982

    Lotspeich, W. D. (1965) Renal hypertrophy in metabolic acidosis and
         its relation to ammonia excretion, Am. J. Physiol., 208(6),
         1135-1142

    Martin, H. E. & Jones, R. (1961) The effect of ammonium chloride and
         sodium bicarbonate on the urinary excretion of magnesium, calcium
         and phosphate, Amer. Heart J., 62, 206-210

    Owen, E. E. & Robinson, R. R. (1963) Amino acid extraction and ammonia
         metabolism by the human kidney during the prolonged
         administration of ammonium chloride, J. Clin. Invest., 42,
         263-276

    Pollak, V. E. et al. (1965) Experimental metabolic acidosis. The
         enzymic basis of ammonia production by the dog kidney, J. Clin.
         Invest., 44, 169-181

    Seegal, B. C. (1927) Chronic acidosis in rabbits and in dogs, with
         relation to kidney pathologic changes, Arch. Internal Med.,
         39, 550-563

    Short, E. C. & Hammond, P. B. (1964) Ammonium chloride as a urinary
         acidifier in the dog, J. Am. Vet. Med. Assoc., 144, 864-867

    Smyth, H. F., Jr et al. (1969) Range-finding toxicity data. VII. Am.
         Ind. Hyg. Ass. J., 30(5), 470-476

    Thompson, G., Mitchell, D. M. & Kolb, L. C. (1933) The influence of
         variations in systemic acid-base balance upon carbohydrate
         tolerance in normal subjects, Biochem. J., 27, 1253-1256

    Thompson, R. Y. & Halliburton, I. W. (1966) Effect of diet on the
         composition of the kidney, Biochem. J., 99(3), 44P

    Van Goidsenhoven, G. M. T. et al. (1954) The effect of prolonged
         administration of large doses of sodium bicarbonate in men,
         Clin. Sci. (London), 13, 383-401

    Yoshida, J., Nakame, K. & Nakamura, R. (1957) Toxicity of urea and its
         control. II. Toxicity of ammonium salts and urea in rabbits and
         goats, Nippon Chikusangaku Kaiho, 28, 185-191
    


    See Also:
       Toxicological Abbreviations