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    GLUCONO DELTA-LACTONE

    EXPLANATION

         Glucono delta-lactone (GDL) was evaluated for acceptable daily
    intake at the tenth and eighteenth meetings of the Joint FAO/WHO
    Expert Committee on Food Additives (Annex 1, references 13 and 35).
    Toxicological monographs were published after both of these meetings
    (Annex 1, references 12 and 36).

         Since the previous evaluation, at which time an ADI of 0-50 mg/kg
    b.w. was established, 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

         GDL, 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.

         GDL was reported to inhibit competitively mannosidase and
    glucosidase isolated from rat epididymis and limpet tissue
    (Levvy et al., 1964). These findings were confirmed using acid
    alpha-glucosidase from rabbits (Palmer, 1971).

         GDL is a non-competitive inhibitor of polysaccharide
    phosphorylase in in vitro assays (Tu et al., 1971).

         The enzyme gluconolactonase (E.C. 3.1.1.17) has been isolated
    from porcine liver; it was found to catalyze the hydrolysis of GDL to
    gluconic acid with maximum activity at pH 7.5 (Roberts et al.,
    1978).

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

         Sodium gluconate uniformly labelled with 14C and 2H was
    administered i.p. to normal rats for three successive days.
    Approximately 57% of the administered 14C 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 rats, about 10% of the total 14C label appeared in the
    expired CO2. Urinary glucose from phlorizinized rats and liver
    glycogen from normal rats were shown to be uniformly labelled with
    respect to 14C (Stetten & Stetten, 1950).

         Radioactivity was measured in the blood of normal and
    alloxan-diabetic Wistar rats after the oral administration of
    (U-14C)-GDL or (U-14C)-gluconate. Radioactivity was also measured
    in the intestinal contents and faeces 5 hours after ingestion of the
    radioactive materials. The authors concluded that the lactone is
    better-absorbed from the intestine than is the gluconate anion.
    Because of enhanced membrane permeation and higher concentrations of
    the lactone in blood, the distribution space of the lactone is larger
    than that of gluconate (50 and 41% of the body weight, respectively);
    a higher retention in tissues and a greater loss in urine was also
    observed after administration of the lactone. Incorporation into liver

    glycogen was higher after the administration of the lactone than after
    the administration of gluconate, particularly in diabetic animals. The
    initial deficit in the oxidation of gluconate compared to that of the
    lactone, caused by a lag period of 7 and 4 hours, respectively, was
    completely compensated for during the following 8-9 hours. The
    oxidative turnover of both compounds was significantly enhanced in
    diabetic animals. The better utilization in diabetic metabolism is in
    part explained by a rise of glycolytic intermediates in the liver,
    which are decreased in starvation and diabetes. Initial
    phosphorylation is the limiting step of gluconate metabolism
    (Tharandt et al., 1979.

         When three men were given 10 g (167 mg/kg b.w.) of GDL orally as
    a 10% solution, the amounts recovered in the urine in 7 hours
    represented 7.7-15% of the dose. No pathological urine constituents
    were noted. When 5 g (84 mg/kg b.w.) was given orally, none was
    recovered in the urine. The largest dose given was 30 g (500 mg/kg
    b.w.) (Chenoweth et al., 1941).

    Toxicological studies

    Special study on mutagenicity

         The mutagenic effects of GDL were assessed in Saccharomyces
    cerevisiae and Salmonella typhimurium strains TA1535 and TA1537,
    with and without metabolic actuation. GDL was not mutagenic in these
    assays at doses of 0.25 and 0.5% (Litton Bionetics, Inc., 1974).

    Special studies on teratogenicity

    Mice

         Six groups of 25 pregnant mice were given continuously from days
    6-15 of gestation 0, 6.95, 32.5, 150, or 695 mg/kg b.w./day GDL by
    oral intubation. A positive control group that was administered
    150 mg/kg b.w./day 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
    animals in the test groups did not differ from the number occurring
    spontaneously in the sham-treated controls (FDRL, 1974).

    Rats

         Six groups of 22 to 25 pregnant rats were given continuously from
    days 6-15 of gestation 0, 5.94, 27.6, 128, or 594 mg/kg b.w./day GDL
    by oral intubation. A positive control group that was administered
    250 mg/kg b.w./day 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
    animals in the test groups did not differ from the number occurring
    spontaneously in the sham-treated controls (FDRL, 1974).

    Hamsters

         Six groups of approximately 25 pregnant hamsters were given
    continuously from days 6-10 of gestation 0, 5.6, 26, 121, or 560 mg/kg
    b.w./day GDL by oral intubation. A positive control group that was
    administered 250 mg/kg b.w./day 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 animals in the test groups did not differ from the
    number occurring spontaneously in the sham-treated controls
    (FDRL, 1974).

    Rabbits

         Six groups of 10 pregnant rabbits were given continuously from
    days 6-18 of gestation 0, 7.8, 32.2, 168, or 780 mg/kg b.w./day GDL by
    oral intubation. A positive control group that was administered
    2.5 mg/kg b.w./day 6-aminonicotinamide 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 animals in the test groups did not differ from the number
    occurring spontaneously in the sham-treated controls (FDRL, 1974).

    Acute toxicity
                                                                        
                                             LD50
    Species    Compound            Route     (mg/kg b.w.)    Reference
                                                                        

    Rabbit     Sodium gluconate    i.v.      7630          Gajatto, 1939
                                                                        

    Short-term studies

    Rats

         Groups of 20 male and 20 female rats were fed gluconic acid
    (as GDL) for 26 weeks at levels of 0 or 1% in the diet without
    ill-effects or demonstrable changes in the main organs on microscopic
    examination (Harper & Gaunt, 1962).

    Cats and dogs

         Gluconic acid was administered as a 10% solution by stomach tube
    to 5 cats and 3 dogs at a daily dose of 1.0 g/kg b.w. for 14 days.
    Urine was examined daily for protein, blood, casts, and sugar. Gross
    examination of lungs, heart, liver, kidneys, gastrointestinal tract,
    bladder, ureters, and spleen as well as histological examination of
    lungs, liver, and kidneys were performed. No evidence of toxicity was
    found. (Chenoweth et al., 1941).

    Long-term study

    Rats

         Groups of 30 male and 30 female rats were fed diets containing
    meat treated with 1% GDL (equivalent to feeding 0.4% GDL) or untreated
    meat for 29 months. Growth, food intake, and mortality were not
    affected. Haematology, clinical biochemistry, liver function tests,
    and histopathology revealed no differences between treated animals and
    controls (Van Logten et al., 1972).

     Observations in man

         Sixteen persons (7 with urologic conditions) were administered
    5-g doses of GDL at 2-hour intervals, up to total doses of 15 to 25 g
    daily, and subsequently 10-g doses, up to total doses of 20 to 50 g
    daily. The pH and specific gravity of the urine from those on test and
    from the controls were determined. In g 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 & Civin, 1939).

         The administration for 3 to 6 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,
    or sugar in the urine (Chenoweth et al., 1941).

    Comments

         GDL, 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.

         A single long-term test in rats with 1 level of GDL in the diet
    showed no evidence of carcinogenicity. Teratogenicity studies have
    shown no abnormalities in several species. GDL was not mutagenic in
    microbial tests.

         GDL makes an insignificant contribution to the normal
    carbohydrate diet and is metabolized into normal body constituents.
    Single doses of GDL in excess of 20 grams exert a laxative effect in
    man.

    EVALUATION

    Estimate of acceptable daily intake for man

         ADI "not specified". The fact that high doses of GDL exert a
    laxative effect in man should be taken into account when considering
    its level of use.

    REFERENCES

    Chenoweth, M.B., Civin, H., Salzman, C., Cohn., & Gold H. (1941).
         Further studies on the behaviour of gluconic acid and ammonium
         gluconate in animals and man. J. Lab. Clin. Med.,
         26, 1574-1582.

    Eyles, R. & Lewis, H.B. (1943). The utilization of
         d-glucono-delta-lactone by the organism of the young white rat.
         J. Nutr., 26, 309-317.

    FDRL, (1974). Teratologic evaluation of FDA 71-72 (glucono
         delta-lactone). Prepared under Contract No. FDA 71-260 by Food
         and Drug Research Laboratories, Inc. 58 pp. Available from:
         National Technical Information Service, Springfield, VA, USA;
         No. PB-223,830.

    Gajatto, S. (1939). Richerche farmacologiche sul gluconato di sodio,
         Arch. di Farmacol. sper., 68, 1-13.

    Gold, H. & Civin, H. (1939). Gluconic acid as a urinary acidifying
         agent in man. J. Lab. Clin. Chem., 24, 1139-114b.

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

    Levvy, G.A., Hay, A.J., & Conchie, J. (1964). Inhibition of
         glycosidases by aldonolactones of corresponding configuration.
         4. Inhibitors of mannosidase and glucosidase. Biochem. J.,
         91, 378-384.

    Litton Bionetics, Inc. (1974). Mutagenic evaluation of compound 71-72
         glucono delta-lactone. 37 pp. Available from: National Technical
         Information Service, Spingfield, VA, USA; No. PB-245,498.

    Palmer, T.N. (1971). The maltase, glucoamylase and transglucosylase
         activities of acid delta-glucosidase from rabbit muscle.
         Biochem. J., 124, 713-724.

    Roberts, B.D., Bailey, G.D., Buess, C.M., & Carper, W.R. (1978).
         Purification and characterization of hepatic porcine
         gluconolactonase. Biochem. Biophys. Res. Commun., 84, 322-327.

    Stetten, M.R. & Stetten, D. Jr. (1950). The metabolism of gluconic
         acid. J. Biol. Chem., 187, 241-252.

    Tharandt, L., Hubner, W., & Holman, S. (1979). Untersuchugen uber die
         Verwertung von D-Gluconat und D-Glucono-delta-lacton im
         Stoffwechsel der normalen und alloxandiabetischen Ratte.
         J. Clin. Chem. Clin. Biochem., 17, 237-267.

    Tu, J.I., Jacobson, G.R., & Graves, D.J. (1971). Isotopic effects and
         inhibition of polysaccharide phosphorylase by 1,5-glucono-
         lactone. Relationship to the catalytic mechanism. Biochemistry,
         10, 1229-1236.

    Van Logten, M.J., den Tonkelaar, E.M., Kroes, R., Berkvens, J.M., &
         van Esch, G.J. (1972). Long-term experiment with canned meat
         treated with sodium nitrite and glucono-delta-lactone in rats.
         Food Cosmet. Toxicol., 10, 475-488.
    


    See Also:
       Toxicological Abbreviations
       GLUCONO delta-LACTONE (JECFA Evaluation)