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    Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents



    WHO FOOD ADDITIVES SERIES NO. 5







    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization
    Geneva
    1974

              

    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.

    ASCORBIC ACID AND ITS POTASSIUM AND SODIUM SALTS

    Explanation

         Ascorbic acid and sodium ascorbate were evaluated for acceptable
    daily intake by the Joint FAO/WHO Expert Committee on Food Additives
    (see Annex 1, Ref. No. 6) in 1961.

         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.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         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).

    TOXICOLOGICAL STUDIES

    Acute toxicity
                                                                        

                                     LD50
    Animal              Route       (mg/kg bw)       Reference
                                                                        

    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

    Mouse

         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).

    Guinea-pig

         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

    Rat

         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 analyses, 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 rate in control animals and in those treated (Surber & Cerioli,
    1971).

    OBSERVATIONS IN MAN

         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
    shown any progressive changes. Further, no harmful effects were
    observed in these four subjects during the three months (Lowry et al.,
    1952).

         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).

    Comments:

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

         Studies in man indicate that ascorbic acid has a diuretic effect
    at 5 mg/kg bw in children and adults and glycosuria was observed with
    doses of 30-100 mg/kg. Daily doses, of the order of 200 mg/kg, have
    been taken over periods of time for a therapeutic effect which has not
    been unequivocably demonstrated. The recommended dietary allowances
    range from 30-75 mg with a minimum of 5-10 mg/day. It is estimated
    that the daily intake of ascorbic acid is between 30-100 mg from
    natural sources.

    EVALUATION

    Estimate of acceptable daily intake for man

         0-15 mg/kg bw

    REFERENCES

    Abbasy, M. A. (1937) Biochem. J., 31, 339

    Abt, A. F. & Farmer, C. J. (1938) J. Amer. med. Ass., 111, 1555

    Curtin, C. O' H. & King, C. G. (1955) J. biol. Chem., 216, 539

    Demole, V. (1934) Biochem. J., 28, 770

    Evans, W. (1938) Lancet, 1, 308

    Lowry, O. H., Bessy, O. A. & Bunch, H. B. (1952) Proc. Soc. exp.
         Biol., 80, 361

    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

    Widenbauer, F. (1936) Klin. Wschr., 33, 1157


    See Also:
       Toxicological Abbreviations