IPCS INCHEM Home


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, ENZYMES, FLAVOUR
    ENHANCERS, THICKENING AGENTS, AND
    CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES 6







    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    4-13 June 19741


    World Health Organization     Geneva     1975






              

    1  Eighteenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557.
    FAO Nutrition Meetings Report Series, 1974, No. 54.

    GLUCONO-DELTA-LACTONE

    Explanation

         This compound has 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 expanded and is reproduced
    in its entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Glucono-delta-lactone, in an aqueous medium, readily forms an
    equilibrium mixture of the lactone and gluconic acid. These are
    intermediates in the oxidation of glucose through the pentose
    phosphate cycle, which, while not the main pathway of glucose
    metabolism, is well recognized.

         When three men were given 10 g (167 mg/kg) of glucono-delta-
    lactone orally as a 10% solution, the amounts recovered in the urine
    in seven hours represented 7.7-15% of the dose. No pathological urine
    constituents were noted. When 5 g (84 mg/kg) was given orally none
    was recovered in the urine. The largest dose given to man was 30 g
    (500 mg/kg (Chenoweth et al., 1941).

         Groups of six rats each were fed a diet in which the limiting
    factor was inadequate caloric value. When the basal diet was
    supplemented with either glucose or d-glucono-delta-lactone, as a
    source of additional calories, an increased growth rate was observed.
    Glucose and d-glucono-delta-lactone were almost equally effective in
    the promotion of growth (Eyles & Lewis, 1943).

         Sodium gluconate uniformly labelled with C14 and D was
    administered (i.p.) to normal rats for three successive days. In the
    case of the normal rat, 57% of the administered C14 was excreted
    uncharged into the urine, and 14% of the C14 label appeared in
    expired CO2. Only a small fraction of gluconate carbon could be
    recovered as urinary saccharate. When labelled gluconate was
    administered to phlorizinized rat, about 10% of the total C14 label
    appeared in the expired CO2. Urinary glucose from the phlorizinized
    rat and liver glycogen from the normal rat were shown to be uniformly
    labelled with respect to C14 (Stetten & Stetten, 1950).

    TOXICOLOGICAL STUDIES

    Special studies on teratogenicity

    Mouse

         Six groups of 25 pregnant mice were given continuously from day
    6-15 of gestation 0, 6.95 mg/kg bw, 32.5 mg/kg bw, 150 mg/kg bw,
    695 mg/kg bw GDL by oral intubation. A positive control group of
    150 mg/kg aspirin was included. No clearly discernible effects were
    seen on nidation or on maternal or fetal survival. The number of
    abnormalities seen in either soft or skeletal tissues of the test
    groups did not differ from the number occurring spontaneously in the
    sham-treated controls (Anonymous, 1974).

    Rat

         Six groups of 22 to 25 pregnant rats were given continuously from
    day 6-15 of gestation 0, 5.94, 27.6, 128 and 594 mg/kg bw GDL by oral
    intubation. A positive control group of 250 mg/kg aspirin was
    included. No clearly discernible effects were seen on nidation or on
    maternal or fetal survival. The number of abnormalities seen in either
    soft or skeletal tissues of the test groups did not differ from the
    number occurring spontaneously in the sham-treated controls
    (Anonymous, 1974).

    Hamster

         Six groups of approximately 25 pregnant hamsters were given
    continuously from day 6-10 of gestation 0, 5.6, 26, 121 or 560 mg/kg
    bw GDL by oral intubation. A positive control group of 250 mg/kg
    aspirin was included. No clearly discernible effects were seen on
    nidation or on maternal or fetal survival. The number of abnormalities
    seen on either soft or skeletal tissues of the test groups did not
    differ from the number occurring spontaneously in the sham-treated
    controls (Anonymous, 1974).

    Rabbit

         Six groups of 10 pregnant rabbits were given continuously
    from day 6 to 18 of gestation 0, 7.8, 36.2, 168.5 or 780 mg/kg b
    w GDL by oral intubation. A positive control of 2.5 mg/kg bw
    6-aminonicotinamide was included. No clearly discernible effects on
    nidation or on maternal or skeletal tissues of the test groups were
    seen. The number of abnormalities seen in either soft or skeletal
    tissues of the test groups did not differ from the number occurring
    spontaneously in the sham-treated controls (Anonymous, 1974).

    Acute toxicity
                                                                        

                                            LD50
    Animal    Compound            Route     (mg/kg bw)     Reference
                                                                        

    Rabbit    Sodium gluconate    i.v.      7 630          Gajatto, 1939
                                                                        

         The administration for three to six days of large oral doses
    (5-10 g/day) of gluconic acid to five normal humans did not produce
    any renal changes, as shown by the absence of blood, protein, casts
    and sugar in the urine (Chenoweth et al., 1941).

    Short-term studies

    Rat

         Groups of 20 male and 20 female rats were fed gluconic acid
    (as glucono-delta-lactone) for 26 weeks at levels of 0 and 10 000 ppm
    in the diet without ill-effects or demonstrable changes in the main
    organs on microscopic examination (Harper & Gaunt, 1962).

    Long-term studies

    Rat

         As part of another experiment groups of 30 male and 30 female
    rats were fed diets containing meat treated with 1% glucono-delta-
    lactone (GDL) and untreated meat for 29 months. This was equivalent to
    feeding 0.4% GDL. Growth, food intake and mortality were not different
    from controls. Haematology, clinical biochemistry, liver function
    tests and histopathology revealed no differences from controls (Van
    Logten et al., 1972).

    OBSERVATIONS IN MAN

         Sixteen persons (seven with urologic conditions) were
    administered 5 g doses of glucono-delta-lactone at two-hour intervals,
    up to total doses of 15 to 25 g daily, and subsequently 10 g doses, up
    to total doses of from 20 to 50 mg daily. pH and specific gravity of
    the urine was determined on test and controls. In 8 of the 16
    patients, the urine became more acid, and in the other half it became
    more alkaline during the period of treatment. Eleven of the 16
    patients developed diarrhoea without nausea during the course of the
    study (Gold & Givin, 1939).

    Comments:

         Consideration of glucono-delta-lactone may be based on the
    metabolic evidence as intermediates of normal glucose metabolism in
    mammalian species. There is considerable experience with gluconates in
    man and animals. A single long-term test at one level showed no
    evidence of carcinogenicity. Teratogenic tests have shown no
    abnormalities in four species.

    EVALUATION

    Estimate of acceptable daily intake for man

         0-50 mg/kg bw*

    REFERENCES

    Anonymous (1974) Unpublished report submitted by the United States
         Food and Drug Administration

    Chenoweth, M. B. et al. (1941) J. Lab. Clin. Med., 26, 1574

    Eyles, R. & Lewis, H. B. (1943) J. Nutri. 26, 309

    Gajatto, S. (1939) Arch. Farmacol. Sper., 68, 1

    Gold H, & Givin, M. S. (1939) J. Lab. Clin. Chem., 24, 1139

    Harper, K. H. & Gaunt, I. F. (1962) Unpublished report of Huntingdon
         Research Centre

    Stetten, M. R. & Stetten, D. jr (1950) J. Biol. Chem., 187, 241

    Van Logten, M. J. et al. (1972) Food Cosmet. Toxicol., 10, 475

              

    *    Calculated as total gluconic acid from all sources.


    See Also:
       Toxicological Abbreviations
       glucono-delta-lactone (SIDS)