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
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
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.
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
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).
Animal Route (mg/kg bw)
Rabbit i.v. 50 (Na salt) Gillert, 1926
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 &
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.
Estimate of acceptable daily intake for man
0 to 1.25 mg/kg bw.
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
Ross, C. A. C. et al. (1955) Lancet, i, 1087