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.


    CHOLIC AND DESOXYCHOLIC ACID AND THEIR SALTS

    Explanation

         These substances were evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 13) in 1966.

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

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         The bile acids and their salts are found as natural constituents
    of the bile. The nucleus of the bile acids is closely related to
    cholesterol, from which they are formed in the liver, and this
    conversion depends on their relative concentrations. Between 90 and
    95% of bile acids are reabsorbed, mainly from the lower half of the
    small intestine, and undergo enterohepatic circulation; small
    quantities occur in the stools and very little is normally excreted in
    the urine. Bile salts affect the absorption of fats, fat-soluble
    vitamins, and various ions. In normal individuals, additional
    administration of moderate quantities of bile acids or salts by mouth
    has no demonstrable effect, since there are enough bile salts present
    in the intestinal lumen to carry out all the absorptive functions. If
    there is a deficiency of bile salts, administration may be beneficial.
    Bile salts stimulate excretion of bile and hence tend to hasten their
    own elimination. Bile salts may also cause some stimulation of
    intestinal movement.

         The daily output from a fistula in man ranged from 1 to 2.3 g
    daily; when stimulated by bile, the daily output was increased
    fourfold (Josephson, 1941).

    TOXICOLOGICAL STUDIES

    Acute toxicity
                                                                   

                                  LD50                References
    Animal              Route     (mg/kg bw)
                                                                   

    CHOLIC ACID

    Rabbit              i.v.      50 (Na salt)        Gillert, 1926

    DESOXYCHOLIC ACID

    Rabbit              i.v.      15 (Na salt)        Gillert, 1926
                                                                   

         In general, bile acids and salts have only a minor toxic
    potential when given by mouth. In large doses they are likely to have
    the same effects as saponins; the main action is likely to be
    irritation of mucous membranes. Parenterally they are much more toxic
    and may cause haemolysis, a digitalis-like action on the heart and
    effects on the central nervous system. Toxic effects that may be
    attributable to accumulation of bile acids or salts are also seen in
    obstructive jaundice, since they disappear if cholestyramine, which
    adsorbs bile acids in the intestinal lumen and prevents their
    reabsorption, is administered (van Itallie et al., 1961).

    OBSERVATIONS IN MAN

         Dehydrocholic acid is the most commonly employed of the bile
    acids for medicinal purposes. The dose range is 250 to 750 mg thrice
    daily. The only contraindications listed are biliary obstruction and
    severe hepatitis (Martindale, 1972).

         Two grams of ox bile salts were administered daily to a child of
    five years who had a congenital deficiency of bile salts, for a period
    of 11 months, with consequent improvement in fat absorption and no
    evidence of ill effects (Ross et al., 1955).

         Deoxycholic acid administered orally in doses of 400 mg thrice
    daily decreased appetite in four out of six patients (Bray &
    Gallagher, 1968).

    Comments:

         A 5% variation in the daily output of bile is equivalent to 75 mg
    bile salts daily (equivalent to 1.25 mg/kg bw). This amount is
    unlikely to affect the normal equilibrium of bile acid metabolism.

    EVALUATION

    Estimate of acceptable daily intake for man

         0 to 1.25 mg/kg bw.

    REFERENCES

    Bray, G. A. & Gallagher, T. F. (1968) Lancet, i, 1066

    Gillert, E. (1926) Z. Ges. exp, Med., 52, 779

    Itallie, T. B., van et al. (1961) New England J. Med., 265, 469

    Josephson, B. (1941) Physiol. Rev., 21, 435

    Martindale's Extra Pharmacopoeia, 26th Ed. (1972) The Pharmaceutical
         Press, London

    Ross, C. A. C. et al. (1955) Lancet, i, 1087

    See Also:
       Toxicological Abbreviations