Ascorbic acid and potassium and sodium ascorbate were evaluated
    for acceptable daily intake by the Joint FAO/WHO Expert Committee on
    Food Additives in 1974 (see Annex, Ref. 32). A Toxicological monograph
    was issued in 1974 (see Annex, Ref. 33).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.



         Ascorbic acid is readily absorbed and metabolized. However, after
    oral administration of large quantities only small amounts are
    excreted in the urine, while there is a steady rise in the level of
    ascorbic acid in the plasma. If the oral ingestion is continued for a
    sufficient period, the plasma concentration rises to a maximum, after
    which a rapid urinary excretion of a large part of the ingested
    ascorbic acid occurs (Abt & Farmer, 1938).

         Using 14C-labelled ascorbic acid, it was found that in the rat
    after intraperitoneal injection of 1.5-5.9 mg approximately 19 to 29%
    was converted to CO2 and only 0.4% was excreted as oxalate within 24
    hours (Curtin & King, 1955).

         A pharmacokinetic study of the oral administration of ascorbic
    acid to male volunteers indicated the half life of ascorbic acid was
    inversely related to the administered dose and total turnover of
    ascorbate. Under steady state conditions, approached the half life 10
    days at a total turnover of 70 mg/day (Kalluer et al., 1979).

         In a study involving three patients, the biological half life of
    ascorbate in man averaged 16 days; the body pool averaged 20 mg/kg bw
    and the turnover rate was about 1 mg/kg/day (Hellman & Burns, 1958).

         Metabolism of ascorbate to CO2 does not occur to any great
    extent in the human (Baker et al., 1962).

         In the 10 days following an i.v. dose of 1-14C-L-ascorbate to
    human subjects, 42% of the label was found in the urine, 1% in faeces
    and none in expired CO2. Oxalate was the major urinary metabolite,
    followed by ascorbate itself and then diketo-L-gulonic acid.

         A study carried out in a male volunteer administered
    4-3H-L-ascorbate showed that the label did not enter the body water
    pool but was excreted as ascorbate and other metabolites (Tolbert et
    al., 1967).


    Special studies mutagenicity

         Neither ascorbic acid or calcium ascorbate were mutagenic to
    Salmonella typhimurium strains TA-98, TA-100, 1535, 1537 or 1538 or
    to Saccharoymyces cervisiae strain D4 when tested in plate or
    suspension assay systems with or without metabolic activation (Litton
    Bionetics, 1975 & 1976).

    Special studies on teratogenicity

         Groups of 20 to 23 pregnant female CD-1 strain albino mice were
    given doses of 5.2-520 mg/kg of ascorbic acid by oral intubation for
    10 consecutive days starting on day 6 of pregnancy. Compared to
    concurrent controls, there were no adverse effects reported on
    maternal or foetal survival nor were there any increases in soft
    tissue or skeletal malformations as a result of treatment.

         Groups of 20 to 22 pregnant Wistar derived female rats were
    administered, by gavage, doses of 5.5-555 mg/kg of ascorbic acid daily
    from days 6 through 15 of gestation, compared to sham treated
    controls. No treatment related effects were observed with respect to
    maternal or foetal survival or soft tissue or skeletal malformations,
    although the incidence of incomplete closure of the skull was the
    greatest in the high dose foetuses (Food & Drug Research Laboratories,

    Acute toxicity

                                  LD50          Reference
    Animal          Route      (mg/kg bw)

    Mouse           Oral          5 000         Demole, 1934

                    i.v.          1 000

    Rat             Oral          5 000         Demole, 1934

                    i.v.          1 000

    Guinea-pig      Oral          5 000         Demole, 1934

                    i.v.           500

    Short-term studies


         Mice given ascorbic acid orally, subcutaneously and intravenously
    in daily doses of 500-1000 mg/kg bw for seven days, showed no
    difference in appetite, weight gain and general behaviour from
    controls receiving the same amount of the biologically inactive
    galacturonic acid. Histological examination of various organs showed
    no definite changes (Demole, 1934).


         Groups of six rats were given ascorbate added to the diet at 0,
    1, 5 or 10%. There was a dose related effect on weight gain. Two of
    six rats in the high dose group died, laxation also occurred at this
    level (De Albequerque & Henriques, 1970).


         Guinea-pigs given ascorbic acid orally, subcutaneously and
    intravenously in daily doses of 400-2500 mg/kg bw for six days, showed
    no difference in appetite, weight gain and general behaviour from
    controls receiving the same amounts of the biologically inactive
    galacturonic acid. Histological examination of various organs showed
    no definite changes (Demole, 1934).

    Long-term studies


         Four groups of 26 male and 26 female rats were given in their
    diet for two years daily doses of 0, 1000, 1500 or 2000 mg/kg bw of
    L-ascorbic acid. Haematological examinations, urine analysis, blood
    enzyme activity, liver and renal function tests yielded results within
    the normal range of values observed in the control group.

         No macro- or micropathologically detectable toxic organic lesions
    were observed which could be attributed to the daily ingestion of
    large doses of L-ascorbic acid. Age-dependent degenerative processes
    in organs, increasing predisposition of aging animals to intercurrent
    diseases and the appearance of spontaneous tumours occurred at the
    same rates in control animals as in those treated (Surber & Cerioli,


         One woman and three men were each given 1000 mg of ascorbic acid
    a day for three months. The ascorbic acid levels in the serum and in
    the white blood cells and the urinary excretion of this acid did not
    show any progressive changes. Further, no harmful effects were
    observed in these four subjects during the three months (Lowry et al.,

         After a daily dose of 5 mg/kg for three days a significant
    increase in urinary volume was observed in 30 children, 10 active
    rheumatic, 10 convalescent rheumatic patients and 10 controls (Abbasy,
    1937). This diuretic effect was confirmed in another study on nine
    patients with heart failure, given 300 mg of ascorbic acid daily
    (Evans, 1938).

         Doses up to 6000 mg of ascorbic acid were given to 29 infants, 93
    children of preschool and school age, and 20 adults for more than 1400
    days. With the higher doses, toxic manifestations were observed in
    five adults and four infants. The signs and symptoms in adults were
    nausea, vomiting, diarrhoea, flushing of the face, headache, fatigue
    and disturbed sleep. The main toxic reactions in the infants were skin
    rashes (Widenbauer, 1936).

         In order to test the efficacy of ascorbic acid therapy against
    the common cold there have been a number of human studies in which
    persons were given large daily doses of vitamin C. For example,
    Anderson et al. (1972) enrolled 1000 volunteers in a double blind
    study in which half the subjects took four tablets containing 250 mg
    each of ascorbic acid while the other half took four tablets daily of
    a placebo. The study lasted three months. Subjects were instructed to
    increase their intake to 16 tablets daily for the first three days of
    any illness. A total of 28 subjects dropped out of the study because
    of suspected side effects, 15 had been taking the vitamin and 13
    placebo. Specific complaints such as nausea, cramps, skin rash, etc.
    were approximately evenly divided between individuals ingesting
    ascorbate and placebo. Of the 818 persons who remained on the study
    for three months, 12% of these taking ascorbic and 11% of the placebo
    users reported unusual symptoms.

         A group of 311 subjects who took part in a double blind study
    were divided into four groups and received from 0 to 6 g daily of
    ascorbic acid in a series of divided doses. An additional 6 g (or
    placebo) were taken daily for five days if the subject was suffering
    from a cold. The study was continued for nine months. No side effects
    were noted in the placebo or ascorbate group. The report stated that
    no ascorbic acid "toxicity" was found in the following laboratory
    tests: albumin, globulin, alkaline phosphatase, total bilirubin,
    calcium, cholesterol, glucose, lactic acid, LDH, BUN, uric acid and
    alanine amino transferase (Lewis et al., 1975).

         A study carried out in school-age children utilized 44 pairs of
    identical twins. One member of each pair received, depending on body
    weight, 500, 750 or 1000 mg of vitamin C daily while the other member
    of the pair received a placebo. The study lasted five months. No
    significant effects of treatment were noted with respect to blood
    pressure, height, weight, tonsil or cervical node size, white or
    red cell count, liver function tests, uric acid, cholesterol,
    electrolytes, total protein, albumin and tests of mental alertness and
    cognitive processing (Miller et al., 1977).

         There are conflicting data in the literature regarding the
    question of destruction of vitamin B12 in food by large amounts of
    ascorbate (Newmark et al., 1976; Herbert & Jacob, 1974). However, one
    brief report indicated that vitamin B12 deficiency may occur in 2 or
    3% of adults who ingested 500 mg or more of ascorbate daily (Hines,

         Daily administration of ascorbic acid for three to five days to
    14 adult volunteers was reported to increase the lytic sensitivity of
    the subjects' erythrocytes to hydrogen peroxide (Mengel & Green,

         Five male patients were dosed daily with 200 mg of ascorbic acid
    for 15 days then with 2 g for an additional 15 days. Biochemical
    studies performed on leucocytes obtained from the subjects indicated
    stimulation of hexose monophosphate shunt activity in resting
    leucocytes, and significant impairment of bacterial killing by
    leucocytes. The effects were reversible (Shilotri & Seetharam, 1977).

         Long-term ingestion of very large doses of ascorbate may lead to
    a state of dependency upon these larger doses in guinea-pigs and man
    (Rhead & Schrauzer, 1971; Sorensen et al., 1974). The subject has
    recently been reviewed (SCOGS, 1979).

         Self-administration of ascorbate for a cold was reported to
    interfere with warfarin therapy in a female patient (Rosenthal, 1971).

         It was reported that a healthy young male receiving 4 g daily of
    ascorbate as a supplement excreted up to 622 mg daily of oxalate as
    compared to a value of 58 mg prior to supplementation. The usual
    increase in oxalate output following supplementation with 4 g
    ascorbate was reported to be 12 mg (Briggs, 1973).


         Animal studies reveal that ascorbic acid is not toxic after
    single or repeated administrations of relatively large doses.

         Oxalate is the major urinary metabolite of ascorbic acid.
    However, it is unlikely that the use of the Ca salt will increase the
    risk of crystalluria and the formation of calcium oxalate stones,
    since the intake of calcium from this source would be minor compared
    to the total diet intake of calcium.

         Some studies in man indicate that ascorbic acid has a diuretic
    effect at 5 mg/kg bw in the children and adults and glycosuria was
    observed with doses of 30-100 mg/kg. However, these effects were not
    noted in other large-scale double blind studies. Daily doses, of the
    order of 100 mg/kg or more, have been taken over periods of time for a
    therapeutic effect. In general no adverse effects were noted in these
    studies. The recommended dietary allowance ranges from 30-75 mg with a
    minimum of 5-10 mg per day. It is estimated that the daily intake of
    ascorbic acid is between 30-100 mg from natural sources.

         The Committee considered that the evaluation of ascorbic acid and
    its salts had relevance only with respect to the food-additive use of
    these substances, and their use as a vitamin C supplement in the
    usually accepted levels of intake for nutritional purposes. Since
    oxalate is a major metabolite of ascorbate, the use of the calcium
    salt in large amounts might increase the risk of crystalluria and the
    formation of calcium oxalate stones. However, the Committee concluded
    that in regard to food-additive and nutritional use, the intake of
    calcium from ascorbate would represent only a small fraction of the
    total dietary intake of calcium. Therefore it was not envisaged that
    the use of calcium ascorbate required any special restriction. The
    Committee concluded that the ADI for ascorbic acid and its potassium
    and sodium salts should be changed from 0-15 mg/kg bw to "not
    specified" and that the calcium salt should be included in this


    ADI 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


    Abbasy, M. A. (1937) The diuretic action of Vitamin C, Biochem. J.,
         31, 339-342

    Abt, A. F. & Farmer, C. J. (1938) Vitamin C pharmacology and
         therapeutics, J. Amer. Med. Ass., 111, 1555-1565

    Anderson, T. W., Reid, D. B. & Beaton, G. H. (1972) Vitamin C and the
         common cold: a double-blind study, Canadian Medical Assoc. J.,
         107, 503-508

    Baker, E. M. et al. (1962) Tracer studies of vitamin C utilization in
         men: Metabolism of D-glucolronolactone-6-C14, D-glucuronic-6-
         C14, and L-ascorbic-1-C14 acid, Proc. Soc. Exp. Med. Biol.,
         109, 737-741

    Briggs, M. H., Garcia-Webb, P. & Davies, F. (1973) Urinary oxalate and
         vitamin C supplements, Lancet, 2, 201

    Curtin, C. O. H. & King, C. G. (1955) The metabolism of ascorbic
         acid-1-C14 and oxalic acid-C14 in the rat, J. Biol. Chem.,
         216, 539-548

    Demole, V. (1934) CVII. On the physiological action of ascorbic acid
         and some related compounds, Biochem. J., 28, 770-773

    De Albuquerque, A. & Henriques, M. A. (1970) Toxicity of ascorbic
         acid, Rev. Port. Farm., 20, 41-46

    Evans, W. (1938) Vitamin C in heart failure, Lancet, I, 308-309

    Food and Drug Research Laboratories, Inc. (1974) Unpublished report.
         Teratologic evaluation of FDA 71-65 (ascorbic acid) in mice and
         rats. Final report submitted by the U.S. Food and Drug

    Hellman, L. & Burns, J. J. (1958) Metabolism of L-ascorbic acid-1-C14
         in man, J. Biol. Chem., 230, 923-930

    Herbert, V. & Jacob, E. (1974) Destruction of vitamin B 12 by ascorbic
         acid, J.A.M.A., 230, 241-242

    Hines, J. D. (1975) Letter: Ascorbic acid and vitamin B 12 deficiency,
         J.A.M.A., 234, 24

    Kallner, A., Hartmann, D. & Horbug, D. (1979) Steady-state turnover
         and body pool of ascorbic acid in man, Amer. J. Clin. Nut.,
         32, 530-539

    Lewis, T. L. et al. (1975) A controlled clinical trial of ascorbic
         acid for the common cold, Ann. N.Y. Acad. Sci., 258, 505-512

    Litton Bionetics, Inc. (1976) Mutagenic evaluation of calcium
         ascorbate. Final report submitted by the U.S. Food and Drug

    Litton Bionetics, Inc. (1975) Mutagenic evaluation of ascorbic acid.
         Final report submitted by the U.S. Food and Drug Administration

    Lowry, O. H., Bessey, O. A. & Burch, H. B. (1952) Effects of prolonged
         high dosage with ascorbic acid, Proc. Soc. Exp. Biol., 80,

    Mengel, C. E. & Greene, H. L., jr (1976) Letter: Ascorbic acid effects
         on erythrocytes, Ann. Int. Med., 84, 490

    Miller, J. Z. et al. (1977) Therapeutic effect of vitamin C. A co-twin
         control study, J.A.M.A., 237, 248-251

    Newmark, H. L. et al. (1976) Stability of vitamin B 12 in the presence
         of ascorbic acid, Amer. J. Clin. Nutr., 29, 645-649

    Rhead, W. J. & Schrauzer, G. N. C. (1971) Risks of long-term ascorbic
         acid overdosage, Nutr. Rev., 29, 262-263

    Rosenthal, G. (1971) Interaction of ascorbic acid and warfarin,
         J.A.M.A., 215, 1671

    SCOGS (1979) Evaluation of the health aspects of ascorbic acid, sodium
         ascorbate, calcium ascorbate, erythorbic acid, sodium
         erythorbate, and ascobyl palmilate as food ingestients SCOGS-59).
         Report prepared for U.S. Bureau of Foods, Food & Drug
         Administration. Contract No. FDA 223-75-2004

    Sorensen, D. I., Devine, M. M. & Rivers, J. M. (1974) Catabolism and
         tissue levels of ascorbic acid following long-term massive doses
         in the guinea pig, J. Nutr., 104, 1041-1048

    Surber, W. & Cerioli, A. (1971) A two-year toxicity study with
         L-ascorbic acid on the rats. Unpublished report of the Battelle
         Laboratories submitted by Hoffman-La Roche AG

    Tolbert, B. M. et al. (1967) Metabolism of L-ascorbic-4-3H acid in
         man, Amer. J. Clin. Nutr., 20, 250-252

    Widenbauer, F. (1936) Toxic secondary effects of ascorbic acid-C
         hypervitaminosis, Klin Worchschr., 15, 1158

    See Also:
       Toxicological Abbreviations