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


    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.



         These compounds have been 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.



         L(+)-lactate is a normal intermediary of mammalian metabolism. It
    arises from glycogen breakdown, from amino acids and from dicarboxylic
    acids, e.g. succinate. Some micro-organisms specifically produce
    lactic acid as major product of the metabolism; L. delbrueckii
    produces L(+)-lactic acid, the physiological isomer, and
    L. leichmanii, the D(-)-isomer.

         Various groups of rats were killed three hours after the
    administration of L(+), D(-) or DL-lactic acid (1700 mg/kg) orally or
    by s.c. injection. The L(+)-isomer produced the largest rise in liver
    glycogen; 40-95% of the L(+)-lactate absorbed in three hours being
    converted; practically none was formed from the D(-)-isomer.
    D(-)-lactate produced the highest blood lactate level and 30% of the
    amount absorbed was excreted in the urine; no L(+)-lactate was found.
    D(-)-lactate was utilized four times more slowly but both D(-) and
    L(+)-isomers were absorbed at the same rate from the intestine (Cori &
    Cori, 1929). The absorption of sodium DL-lactate from the intestine of
    groups of six male and female rats was determined at one, two, three
    and four hours after oral feeding of 215 mg/kw bw of material. The
    rate of absorption decreased with time and was roughly proportional to
    the amount of lactate present in the gut. Slow evacuation of the
    stomach limited the rate of absorption in some animals (Cori, 1930).
    At blood levels over 200 to 250 mg lactate, rabbits showed excitation,
    dyspnoea and tachycardia (Collazo et al., 1933).

         After oral administration to a human subject of 1 to 3000 mg
    lactate, 20 to 30% was excreted in the urine during 14 hours (Fürth &
    Engel, 1930).

         When sodium DL-lactate was given i.v. to starving dogs, 7 to 40%
    was recovered in the urine, none was found in the faeces (Abramson &
    Eggleton, 1927).  Rabbits were given orally 600 to 1600 mg/kg bw of
    racemic lactic acid. Most animals died within three days. Urinary
    excretion varied between 0.26 and 31%. Alkalosis did not affect the
    excretion (Fürth & Engel, 1930).

         In vitro studies have shown that mammalian tissue produces only
    L(+)-lactate although some tissues can oxidize both isomers. Rat liver
    tissue used almost entirely L(+) and practically no D(-)-isomer, as
    measured by oxygen consumption and carbohydrate synthesis. Rat kidney
    tissue used a definitely measurable amount of D(-)-isomer. Grey matter
    of rat brain was unable to utilize the D(-)-isomer. L(+)-lactate
    stimulated oxygen consumption and CO2 production of all rat tissues;
    similarly D(-)-lactate slightly stimulated respiration of liver and
    heart but not brain tissue. Similar effects occurred in duck tissue.
    Heart tissue is able to utilize both isomers almost equally well.
    14C-L(+)-lactate produces 14CO2 more rapidly than D(-)-lactate in
    the intact rat although the D(-) form is fairly well metabolized.
    After two hours, both isomers are oxidized at equal rates (Brin,
    1964). More recent studies have defined the cell sites for
    metabolizing the isomers in micro-organisms and higher animals and
    identified the pathways in normal animals, cattle with D(-)
    lactacidosis and mentally ill patients (Brin, 1964).

         L(+)-lactate was oxidized three to five times as rapidly as
    D(-)-lactate by duck and rat heart and liver slices and 10 to 20 times
    as rapidly by brain slices, using 14C labelled substrate, as shown by
    oxygen consumption and 14CO2 production. The D(-)-isomer was used
    equally as well as the L(+)-isomer by duck and rat heart slices,
    two-thirds as well by brain and one-third as well by duck and rat
    liver and duck brain. High utilization of D(-)-isomer requires special
    metabolic pathways (Brin et al., 1952).


    Acute toxicity

                                         LD50        References
    Animal         Route                 (mg/kg bw)

    Rat            i.p. (Sod. lactate)   2 000        Rhône-Poulenc, 1965

                   oral (lactic acid)    3 730        Smyth et al., 1941

    Guinea-pig     oral                  1 810        Smyth et al., 1941

    Mouse          oral                  4 875        Fitzhugh, 1945

         Rats have been stated to survive 2000 to 4000 mg/kw bw
    administered s.c. Mice were killed by subcutaneous doses of 2000 to
    4000 mg/kg bw whether or not alkalosis was present (Fürth & Engel,
    1930). In man, accidental intraduodenal administration of 100 ml 33%
    lactic acid was fatal within 12 hours (Leschke, 1932). Other workers
    quote an adult human maximum tolerated dose of 1530 mg/kg bw (Nazario,

    Short-term studies


         Groups of two animals received daily doses of 1000 and 2000 mg/kg
    bw of sodium lactate (as lactic acid) over 14 to 16 days; Body
    analyses showed no cumulation (Fürth & Engel, 1930).


         Two dogs received 600 to 1600 mg/kg bw of lactic acid orally 42
    times during 2.5 months without ill effects (Faust, 1910).


         Feeding of 10% lactic acid has been blamed for the development of
    polyneuritic crises resembling B1 deficiency on diets rich in
    carbohydrates, proteins or fats (Lecoq, 1936).

    Long-term studies

         No animal studies are available.



         Forty full-term newborn infants were given a commercial feeding
    formula containing 0.4% DL-lactic acid. No effect was observed on the
    rate of weight gain, from the second to the fourth week of life
    (Jacobs & Christian, 1957).

         Healthy babies were fed milk formulae acidified with 0.4 to 0.5%
    DL-lactic acid for periods of 10 days, during the first three months
    of their life. An increase in the titrable acidity of the urine and
    lowering of urinary pH was observed. Babies on "milk rich" formula
    (4/5 milk mixture) excreted twice as much acid in the urine as babies
    on diets containing less milk and approximately 33% developed
    acidosis. Clinical manifestations were: decrease in the rate of body
    weight gain and decrease in food consumption. On replacing the
    acidified diet with "sweet milk" diet these effects were reversed very
    rapidly (Droese & Stolley, 1962).

         When 0.35% DL-lactic acid was administered to healthy babies from
    the tenth to the twentieth day of life, a threefold increase in the
    urinary excretion of the physiological L(+)-lactic acid and a
    twelvefold increase in the D(-)-lactic acid was observed. On
    withdrawing lactic acid from the diet the level of lactic acid
    excreted in the urine returned to normal. Since the racemic mixture
    used consisted of 80% of the L(+) and 20% of the D(-) forms it seems
    that the metabolism of the D(-) form by the young full-term baby is
    more difficult than the L(+) form. The increase in the urinary
    excretion of either form of lactic acid indicated that the young
    infant cannot utilize lactic acid at a rate which can keep up with
    0.35% in the diet. A number of babies could not tolerate lactic acid.
    In such cases there was rapid loss of weight, frequent diarrhoea,
    reduction of plasma bicarbonate and increased excretion of organic
    acids in the urine. All these effects were reversed on withdrawing
    lactic acid from the diet (Droese & Stolley, 1965).

         Man has consumed fruits, sour milk and other fermented
    products containing DL-lactic acid for centuries, apparently
    without any adverse effects.


         In evaluating lactic acid, emphasis is placed on its well-
    established metabolic pathways after normal consumption in man. It is
    an important intermediate in carbohydrate metabolism. However, human
    studies determining the maximum load of lactate are not available.
    There is some evidence that babies in their first three months of life
    have difficulties in utilizing small amounts of DL and D(-) lactic


         No limit need be set for the acceptable daily intake for man.

    Estimate of acceptable daily intake

         Not limited*

         Neither D(-)-lactic acid nor (DL)-lactic acid should be used in
    infant foods.


         Desirable: Metabolic studies on the utilization of D(-) and
    DL-lactic acid in infants.


    *    See relevant paragraph.


    Abramson, H. A. & Eggleton, P. (1927) J. Biol. Chem., 75, 745, 753,

    Brin, M. (1964) J. Ass. Food and Drug. Off., 178

    Brin, M., Olson, R. E. & Stare, F. J. (1952) J. Biol. Chem., 199, 467

    Collazo, J. A., Puyal, J. & Torres, I. (1933) Anales Soc. Esp. Fis,
         Quim., 31, 672

    Cori, C. F. & Cori, G. T. (1929) J. Biol. Chem., 81, 389

    Cori, G. T. (1930) J. Biol. Chem., 87, 13

    Droese, W. & Stolley, H. (1962) Dtsch. med. J., 13, 107

    Droese, W. & Stolley, H. (1964) Symp. über die Ernäbrung der
         Frühgeborenen, Bad Schachen, May 1964, 63-72

    Faust, E. S. (1910) Cothener Chem. Z., 34, 57

    Fitzhugh, O. G. (1945) Unpublished data, submitted to WHO

    Fürth, O. & Engel, P. (1930) Biochem. Z., 228, 381

    Jacobs, H. M. & Christian, J. R. (1957) Lancet, 77, 157

    Lecoq, M. R. (1936) C.R. Acad. Sci., 202, 1304

    Leschke, E. (1932) Munch. Med. Wschr., 79, 1481

    Nazario, G. (1951) Rev. Inst. Adolfo Lutz, 11, 141

    Rhône-Poulenc (1965) Unpublished report

    Smyth, H. F. jr, Seaton, J. & Fischer, L. (1941) J. Ind. Hyg.
         Toxicol., 23, 59

    See Also:
       Toxicological Abbreviations