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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION





    SAFETY EVALUATION OF CERTAIN 
    FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES: 42





    Prepared by the Fifty-first meeting of the Joint FAO/WHO
    Expert Committee on Food Additives (JECFA)





    World Health Organization, Geneva, 1999
    IPCS - International Programme on Chemical Safety

    GLUCONO-delta-LACTONE AND THE CALCIUM, MAGNESIUM, POTASSIUM, AND 
    SODIUM SALTS OF GLUCONIC ACID

    First draft prepared by Dr C. Whiteside and Dr M. Bonner
    Division of Health Effects Evaluation
    Office of Premarket Approval
    Center for Food Safety and Applied Nutrition
    Food and Drug Administration
    Washington DC, USA

           Explanation
           Biological data
                Biochemical aspects 
                      Absorption, distribution, and excretion
                Toxicological studies 
                      Acute toxicity 
                      Short-term studies of toxicity 
                      Long-term studies of toxicity 
                      Reproductive and developmental toxicity
                      Genotoxicity 
                Observations in humans 
           Comments 
           Evaluation 
           References 


    1.  EXPLANATION

          Glucono-delta-lactone was previously evaluated by the Committee
    at its tenth, eighteenth, and thirtieth meetings (Annex 1, references
    13, 35, and 73). At the tenth meeting, the Committee established an
    ADI of 0-50 mg/kg bw for glucono-delta-lactone. At its thirtieth
    meeting, the Committee changed the ADI for glucono-delta-lactone to an
    ADI 'not specified' on the basis of biochemical and metabolic data on
    glucono-delta-lactone and gluconic acid, noting that in an aqueous
    medium glucono-delta-lactone exists in equilibrium with D-gluconic
    acid. These compounds are intermediates in the oxidation of glucose
    through the pentose phosphate cycle. Data from studies that were
    evaluated previously by the Committee showed no evidence for the
    carcinogenicity, teratogenicity, or genotoxicity of
    glucono-delta-lactone.

          Since the last toxicological evaluation of glucono-delta-lactone,
    a new study of acute toxicity and two new 28-day studies of the oral
    toxicity of sodium gluconate in rats have become available. These
    studies are evaluated in order to determine whether the ADI 'not
    specified' for glucono-delta-lactone could be extended to a group ADI
    'not specified' for glucono-delta-lactone and the calcium, magnesium,
    potassium, and sodium salts of gluconic acid. The calcium, magnesium,
    potassium, and sodium gluconates were previously evaluated by the
    Committee as individual compounds or in other group categories as
    inorganic salts and salts of organic acids. The Committee concluded 

    that they are freely ionizable and that it was appropriate to allocate
    ADIs on the basis of data on their corresponding anion (gluconic
    acid).


    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

          In studies previously evaluated by the Committee,
    glucono-delta-lactone was reported to readily form an equilibrium
    mixture of 55-60% D-gluconic acid and 40-45% delta- and
    gamma-D-lactones. The rate of hydrolysis is accelerated by heat and
    high pH (Pocker & Green, 1973). These breakdown products are
    intermediates in the normal pathway of glucose metabolism through the
    pentose phosphate cycle in mammalian species. 

          Groups of six rats receiving a low-calorie basal diet had an
    increased growth rate when the diet was supplemented with either
    glucose or glucono-delta-lactone. The two compounds were of almost
    equal effectiveness in promoting growth (Eyles & Lewis, 1943; Annex 1,
    references 36 and 74). 

    2.1.1  Absorption, distribution, and excretion

          Intraperitoneal administration of calcium gluconate resulted in
    excretion of primarily unchanged gluconate anion in the urine; the
    remainder was metabolized. Twenty percent of a dose of calcium
    gluconate was absorbed from the intestine (AkzoChemie, Inc., undated).

          When uniformly labelled 14C, 3H-sodium gluconate was
    administered intraperitoneally to normal rats for three successive
    days, 37% of the administered 14C was excreted unchanged in the
    urine, 14% appeared in expired carbon dioxide, and a fraction
    (gluconate carbon) was recovered as urinary saccharate. When labelled
    gluconate was administered to phlorizinized rats, about 10% of the
    total 14C label appeared in expired carbon dioxide. Urinary glucose
    from the phlorizinized rats and liver glycogen from the normal rats
    was uniformly labelled with 14C (Annex 1, references 36 and 74).

          Radiolabel was measured in the blood, intestinal content, and
    faeces of normal and alloxan-diabetic Wistar rats 5 h after oral
    administration of 14C-glucono-delta-lactone (0.8 g/kg) or 14C-sodium
    gluconate. The authors concluded that glucono-delta-lactone is
    absorbed more rapidly from the intestine than sodium gluconate;
    initial oxidation occurred after 7 h with the gluconate and 4 h for
    the lactone. The oxidative turnover of lactone and gluconate was
    significantly enhanced in diabetic animals (Tharandt et al., 1979). 

          When three men were given an oral dose of 10 g (equivalent to
    167 mg/kg bw) of a 10% solution of glucono-delta-lactone, 7.7-15% of
    the dose was recovered over the succeeding 24 h, most excretion
    occurring within 7 h. No toxic urinary metabolites were observed. When

    5 g (84 mg/kg bw) were given orally, none was recovered in the urine.
    The largest dose given was 30 g, equivalent to 500 mg/kg bw (Chenoweth
    et al., 1941).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

          Studies of the acute toxicity of glucono-delta-lactone and other
    salts of gluconic acid in several species are summarized in Table 1. 

        Table 1. Acute toxicity of derivatives of gluconic acid

                                                                                                

    Species    Compound                  Route            LD50           Reference
                                                          (mg/kg bw)
                                                                                                

    Rat        Sodium gluconate          Oral, gavage     > 2000         Mochizuki (1995a)
    Rat        Glucono-delta-lactone     Oral             5940           Food & Drug Research
                                                                         Laboratories (1973a)
    Mouse      Calcium gluconate         Intravenous      950            Coulston et al. (1962)
    Mouse      Glucono-delta-lactone     Oral             6800           FOod & Drug Research
                                                                         Laboratories (1973a)
    Rabbit     Sodium gluconate          Intravenous      7630           Gajatto (1939)
    Rabbit     Glucono-delta-lactone     Oral             7850           Food & Drug Research
                                                                         Laboratories (1973a)
    Hamster    Glucono-delta-lactone     Oral             5600           Food & Drug Research
                                                                         Laboratories (1973a)
                                                                                                
    

          Groups of five Sprague-Dawley rats of each sex were given sodium
    gluconate orally by gavage as single doses of 500, 1000, or 2000 mg/kg
    bw after an overnight fast. The rats were then observed for 14 days
    for mortality, abnormal clinical signs, body-weight changes (on days
    1, 2, 3, 7, 10, and 14), and gross pathological changes in brain,
    pituitary, thyroid, salivary gland, thymus, heart, lung, liver,
    spleen, kidney, adrenals, stomach, small and large intestine,
    pancreas, gonads, urinary bladder, and lymph nodes. None of the rats
    died during the study. Soft faeces and diarrhoea, seen in one male and
    three females at 2000 mg/kg bw, were the only clinical effects
    observed 2-3 h after treatment. The body weights of treated rats were
    comparable to those of controls. No gross abnormalities were observed
    at necropsy. The minimum lethal dose was > 2000 mg/kg bw, although a
    transient, initial laxative effect was observed in rats at doses
    > 1000 mg/kg bw (Mochizuki, 1995a).

    2.2.2  Short-term studies of toxicity

     Rats

          Groups of 12 male and 12 female Sprague-Dawley rats were given
    sodium gluconate by gavage at doses of 0, 500, 1000, or 2000 mg/kg bw
    per day in water at a volume of 1 ml/100 g bw for four weeks. The
    doses were selected on the basis of the results of the study of acute
    toxicity described above (Mochizuki, 1995a). Satellite groups of four
    rats of each sex were included to determine the plasma concentrations
    of sodium gluconate. Body weight and food consumption were measured on
    day 1 and every third or fourth day of the study. Ophthalmological
    examinations were performed on all of the animals at the start of the
    study and on six animals of each sex per group at week 4.
    Haematological and clinical chemical parameters were measured at the
    end of treatment on blood collected from fasted surviving rats and on
    all animals at necropsy. Qualitative and quantitative urinalyses were
    performed on six rats of each sex from each group at the end of
    treatment (week 4), with a one-day water intake measurement. The
    weights of the brain, pituitary, thyroids, salivary glands, thymus,
    heart, lungs, liver, spleen, kidneys, adrenals, testes, prostate,
    seminal vesicle, ovaries, and uterus were recorded. Detailed
    histopathological examinations were performed on representative
    tissues from all control animals and those receiving 2000 mg/kg bw per
    day and on all gross lesions. 

          No deaths or signs of clinical abnormality were observed in any
    of the groups. Body weights, food consumption, and water intake were
    comparable in the treated and control animals. The ophthalmological
    examinations revealed a persistent hyaloid artery (bilateral) in the
    transparent body in all rats in the control and treated groups, which
    was considered to be an incidental physiological change during
    development of the eyeball. 

          The quantitative urinary analyses showed a significant increase
     (p < 0.01) in urinary sodium excretion in males and females at
    2000 mg/kg bw per day. Although the urine volume was increased in
    treated males and in females at the high dose, the increases were not
    statistically significant. Specific gravity and potassium and chloride
    excretion were not affected by sodium gluconate. The qualitative
    urinary analyses showed increased prevalences of urinary ketone bodies
    (ranging from - to +/- to + to ++), urobilogen (ranging from +/- to
    +), and phosphate sedimentation (ranging from - to +/- to +) and
    increased urinary protein concentrations in all treated animals. The
    author reported that the increased urinary protein concentrations were
    due to interference in the assay. Urinary pH and triglyceride and
    glucose concentrations were comparable to those in the control group.
    Bilirubin, blood urea nitrogen, and creatinine concentrations were not
    affected by treatment.

          None of the haematological parameters measured in this study were
    affected by sodium gluconate. The only statistically significant
    effect on blood chemistry was a decrease in serum sodium concentration
    in males at 500 mg/kg bw per day and in males and females at
    2000 mg/kg bw per day. Statistically significant increases were noted
    in the relative weights of the kidneys of males at 1000 and 2000 mg/kg
    bw per day and in the absolute weights of the adrenal glands of males
    at 1000 mg/kg bw per day, but these differences were not dose-related.
    The only treatment-related histopathological effect reported was an
    increased incidence of thickening of the limiting ridge of the stomach
    in 5/12 males at 2000 mg/kg bw per day. As the limiting ridge is a
    tissue specific to rodents, this lesion is not toxicologically
    significant for humans. Other lesions occurred incidentally and were
    not related to treatment. 

          The author concluded that the NOEL was 1000 mg/kg bw per day;
    however, because of the small group sizes and the positive findings in
    the qualitative analyses, the Committee concluded that this study was
    not suitable for identifying a NOEL (Mochizuki, 1995b). 

          Groups of 10 male and 10 female Crj:CD(SD) Sprague-Dawley SPF
    rats were fed basal diet containing sodium gluconate at concentrations
    of 0, 1.25, 2.5, or 5% w/w for 28 days, equal to 0, 1000, 2000, and
    4100 mg/kg bw per day for males and 0, 1000, 2000, and 4400 mg/kg bw
    per day for females. A control group was fed basal diet containing
    1.35% w/w NaCl, equivalent to the sodium concentration of the group
    receiving 5% sodium gluconate (equal to 1100 mg/kg bw per day in males
    and 1200 mg/kg bw per day in females). The doses were selected on the
    basis of the results of the four-week study of toxicity described
    above (Mochizuki, 1995b). Body weights and food consumption were
    measured on day 1 and every third or fourth day of the study. Food
    efficiency was calculated from the body-weight gain and food
    consumption. Ophthalmological examinations were performed on all
    animals at the start of the study and on six rats of each sex per
    group at week 4. Haematological and clinical chemical examinations
    were performed on all animals at necropsy. Qualitative and
    quantitative urinary examinations were performed at the end of
    treatment (week 4), and water intake was measured over 24 h. The
    weights of the brain, pituitary, thyroids, salivary glands, thymus,
    heart, lungs, liver, spleen, kidneys, adrenals, testes, prostate,
    seminal vesicles, ovaries, and uterus were recorded. Detailed
    histopathological examinations were performed on representative
    tissues from all animals at 0 and 5% sodium gluconate and the NaCl
    control group and on all gross lesions. 

          No deaths or clinical abnormalities were observed in any group.
    The body weights and food consumption of treated animals were
    comparable to those of controls on the basal diet. While there was a
    significant decrease (82% of the basal diet control,  p < 0.05) in
    the mean feed efficiency of males at 5% sodium gluconate at week 4,
    the overall mean feed efficiency for the entire treatment period was
    comparable to that of control males. The mean feed efficiencies of
    females treated with sodium gluconate were comparable to that of

    females on the basal control diet. Water intake was significantly
    increased (by 26%) in males at 5% sodium gluconate relative to that in
    the basal diet control group. There was also an insignificant increase
    in water intake (by 20%) in the group receiving 1.35% NaCl. The water
    intake of treated females was comparable to that of females given
    basal diet. 

          Statistically significant differences in some urinary parameters
    were reported in animals receiving 2.5 or 5% sodium gluconate when
    compared with those on basal diet; however, these differences were
    comparable to those observed in the NaCl control group and appeared to
    be related to the high sodium concentration of the sodium gluconate.
    Sodium excretion was significantly  (p < 0.05) increased in both
    males and females at 2.5 and 5% sodium gluconate relative to that in
    the basal diet control group; however, the sodium concentrations were
    not significantly different from that in the group given 1.35% NaCl.
    Urine volumes were not significantly affected by sodium gluconate.
    Qualitative measurements of urinary protein showed significantly
    increased concentrations in females at 2.5 and 5% sodium gluconate
    when compared with those on basal diet. Males at 5% showed a tendency
    for increased urinary protein concentrations, while the concentrations
    in males at 2.5% were not affected. The author reported that the
    increases in urinary protein were due to assay interference.
    Qualitative measurements of urinary ketone bodies also showed
    increases in males at 2.5% sodium gluconate. 

          Prothrombin times were significantly decreased (8%) in males at
    2.5 and 5% in comparison with the basal diet controls. There were no
    other significant haematological effects. Statistically significant
    alterations in blood chemistry were increased blood urea nitrogen in
    males at 2.5%, decreased serum chloride in females at 1.25 or 2.5% and
    in rats given 1.35% NaCl, and decreased total protein in males at
    1.25% and males and females at 2.5%. None of these differences was
    related to dose or treatment. 

          Gross histopathological examination revealed only incidental,
    insignificant findings. Significant increases were seen in the
    relative weights of the kidneys of males at 5% and of females at 2.5%
    when compared with those of rats on the basal diet. There was no
    dose-response relationship. The authors concluded that the NOEL was 5%
    (equal to 4100 mg/kg bw per day); however, because of the small group
    sizes and the positive findings in the qualitative analyses, the
    Committee concluded that this study was not suitable for identifying a
    NOEL (Mochizuki, 1997).

          The findings from a short-term study on calcium gluconate and
    calcium chloride that were initially published by Smith (1940) were
    summarized in a report on calcium salts by the Select Committee on
    GRAS Substances (1975). In this study, groups of 10 rats weighing
    200 g were given a suspension of calcium gluconate (0.4 g/kg calcium)
    or calcium chloride by gavage for 70 days. Two of the rats treated
    with calcium gluconate died before sacrifice. None of the treated rats
    showed histopathological alterations of the heart, kidney, or liver.

    The authors concluded that calcium chloride was more toxic to rats
    than calcium gluconate. 

     Cats and dogs

          In a study previously reviewed by the Committee, five cats and
    three dogs received a daily dose of 1 g gluconic acid (10% solution)
    by stomach intubation for 14 days. No changes were observed in general
    appearance or in the urine of either species. Several incidences of
    vomiting and diarrhoea were reported in three of the cats. Gross
    examination of the lungs, heart, liver, kidneys, gastrointestinal
    tract, urinary bladder, ureter, and spleen of treated animals showed
    that they were normal. No histological abnormalities were observed in
    the livers, lungs, or kidneys. The blood pressure of cats given
    intravenous injections of gluconic acid and ammonium gluconate (500
    mg/kg) fell temporarily but returned to normal within 5 min (Chenoweth
    et al., 1941). 

    2.2.3  Long-term studies of toxicity

     Rats

          In a study previously evaluated by the Committee, groups of
    20 rats of each sex were fed diets containing 40% meat treated with 1%
    glucono-delta-lactone (equivalent to 0.4% glucono-delta-lactone) or
    untreated meat for 29 months. Neither growth, survival, nor food
    intake was affected. Haematological, clinical biochemical, liver
    function, and histopathological examinations revealed no differences
    between treated animals and controls (van Logten et al., 1972). 

    2.2.4  Reproductive and developmental toxicity

          In a study previously evaluated by the Committee,
    glucono-delta-lactone was administered to pregnant mice, rats,
    hamsters, and rabbits by oral intubation on days 6-15 of gestation
    (days 6-18 for rabbits). Six groups of 25 CD-1 mice received doses of
    0, 7, 32, 150, or 700 mg/kg bw; groups of 22-25 Wistar rats received
    doses of 0, 5.9, 28, 130, or 590 mg/kg bw; groups of 25 hamsters
    received doses of 0, 5.6, 120, or 560 mg/kg bw; and groups of 10 Dutch
    belted rabbits received doses of 0, 7.8, 36, 170, or 780 mg/kg bw. No
    skeletal or developmental abnormalities (nidation, maternal, or fetal
    survival) were seen (Food & Drug Research Laboratories, 1973b). 

    2.2.5  Genotoxicity

          The results of tests for the genotoxicity of
    glucono-delta-lactone and gluconic acid and some of its salts are
    summarized in Table 2. Glucono-delta-lactone was not mutagenic in
    either  Saccharomyces cerevisiae or  Salmonella typhimurium strains
    when tested at doses of 0.25 or 0.5% with and without metabolic
    activation (Litton Bionetics, Inc., 1974). 

        Table 2.  Results of assays for the genotoxicity of gluconic acid

                                                                                                  
    Substance and end-point    Test object         Concentration    Result      Reference
                                                                                                  

    Glucono-delta-lactone
      Reverse mutation         S. cerevisiae D4    0.25 and 0.5%    Negativea   Litton Bionetics,
                               S. typhimurium                                   Inc. (1974)
                               TA 1535, TA 1537,
                               TA 1538

    Manganese gluconate
      Reverse mutation         S. typhimurium      0.033, 0.1,      Negativea   Prival et al.
                               TA 98, TA 100,      0.33, 1, 3.3,                (1991)
                               TA 1535, TA 1537,   10 mg/plate
                               TA 1538

      Tryptophan reversion     E. coli WP2         0.033, 0.1,      Negative    Prival et al.
                                                   0.33, 1, 3.3,                (1991)
                                                   10 mg/plate
                                                                                                  

    a With and without metabolic activation
    

          Manganese gluconate was not mutagenic in  S. typhimurium strains
    or  Escherichia coli (Prival et al., 1991). 

    2.3  Observations in humans

          Single doses of > 20 g glucono-delta-lactone have a laxative
    effect in humans (Annex 1, references 36 and 74). Sixteen persons,
    seven of whom had urological conditions, were given 5 g
    glucono-delta-lactone at 2-h intervals up to total doses of 20-50 g
    daily. The pH and specific gravity of the urine were monitored in the
    treated group and in an untreated group. Acidic urine was observed in
    eight of the treated subjects, and alkaline urine was observed in the
    others. Diarrhoea without nausea occurred in 11 of the 16 subjects
    during the study (Gold & Civin, 1939).

          Oral administration of gluconic acid at doses of 5-10 g/day to
    five volunteers induced no renal changes; i.e. no blood, protein
    casts, or sugar was observed in the urine (Chenoweth et al., 1941). 

          Four of 45 premature infants developed localized necrosis of the
    scalp after receiving a 5% solution of calcium gluconate intravenously
    into the scalp for 15 days, at a rate of 5 mg calcium per kg bw per
    hour, as therapy for hypocalcaemia. The necrosis was observed within
    48 h after the end of the 15-day infusion (Weiss et al., 1975). 

          The toxic effects of glucono-delta-lactone, gluconic acid, and
    its magnesium, sodium, potassium, and ferrous salts were compared by
    Prescott et al. (1953) on the basis of data reported by Nugent (1940),
    Bernhard (1951), Parker (1940), and Teeter (1945). Prescott concluded
    that gluconic acid and its derivatives are nontoxic and well tolerated
    in humans, since there had been no evidence of gastric or renal
    irritation in patients treated with these compounds. Potassium
    gluconate induced less gastric irritation than potassium chloride when
    administered orally as a 3-g dose (Parker, 1940). Bernhard (1951)
    stated that gluconic acid is well tolerated by the digestive system,
    is of relatively low toxicity when injected parenterally, and has no
    obvious physiological action. Unlike mandelic acid, gluconic acid
    induced no gastric irritation when used to treat pyelonephritis 
    (Nugent, 1940). A dose of 2 g ferrous gluconate did not cause
    gastrointestinal upset in anaemic patients (Teeter, 1945).


    3.  COMMENTS

          The results of the new study of acute toxicity provided no
    evidence of toxicity in rats given single doses of 500, 1000, or 2000
    mg/kg bw sodium gluconate.

          In two new four-week studies in rats, sodium gluconate was
    administered orally either by gavage at doses of 0, 500, 1000, or
    2000 mg/kg bw per day or by feeding at doses of 0, 1, 1.25, 2.5, or 5%
    w/w (equal to 1000, 2000, and 4100 mg/kg bw per day). A further group
    received 1.35% w/w sodium chloride (equal to 1100 mg/kg bw per day),
    equivalent to the concentration of sodium in 5% sodium gluconate.
    After gavage, a significant increase in the relative weight of the
    kidneys (unilateral) was seen in males at 1000 or 2000 mg/kg bw per
    day. No treatment-related or dose-related effect was observed on any
    of the other parameters examined in this study. The effects observed
    in the feeding study, i.e. increased water intake, increased
    prothrombin time, and increased relative kidney weights, were not
    dose-related. Qualitative urine analyses revealed effects in both
    four-week studies that were considered by the Committee to be related
    to the high sodium intake arising from the sodium gluconate.


    4.  EVALUATION

          On the basis of a re-evaluation of data previously considered by
    the Committee and new data on the short-term toxicity of sodium
    gluconate, the Committee extended the previous ADI 'not specified' for
    glucono-delta-lactone to a group ADI for glucono-delta-lactone and the
    calcium, magnesium, potassium, and sodium salts of gluconic acid.


    5.  REFERENCES

    AkzoChemie, Inc. (undated) Gluconates. Unpublished data sheet.
    Submitted to WHO by the US Food and Drug Administration  (GRP 6T0151,
    pp. 000130-143). 

    Bernhard, A. (1951) The use of potassium glucose in hypopotassemia.
     Science, 113, 751.

    Chenoweth, M.D., Civin, H., Salzman, C., Cohn, M. & 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.

    Coulston, F., Hulmue, N.A., Milens, L.E. & Minatoya, H. (1962)
    Comparison of parenterally administered calcium kinate gluconate with
    calcium gluconate and calcium chloride.  Toxicol. Appl. Pharmacol., 
    4, 492-503. 

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

    Food & Drug Research Laboratories (1973a) Acute LD50 data in mice,
    rats, hamsters and rabbits. Unpublished data, report No. FDA 71-260
    FDRL, Maspeth, New York, USA. Submitted to WHO by the US Food and Drug
    Administration GRM 000069.

    Food & Drug Research Laboratories (1973b) Teratologic evaluation of
    FDA 71-72 (glucono-delta-lactone). Unpublished data, contract No.
    FDA71-260, FDRL, Maspeth, New York, USA. Available from National
    Technical Information Service, Springfield, Virginia, USA, No. PB-223,
    830.

    Gajatto, S. (1939) [Pharmacological research on sodium gluconate.]
     Arch. Farmacol. Sper., 68, 1-13 (in Italian).

    Gold, H. & Civin, H. (1939) Gluconic acid as a urinary acidifying
    agent in man.  J. Lab. Clin. Chem., 24, 1139-1146.

    Litton Bionetics, Inc. (1974) Mutagenic evaluation of compound 71-72
    glucono-delta-lactone. Unpublished report No. PB-245,498 from National
    Technical Information Service, Springfield, VA, USA. Submitted to WHO
    by the US Food and Drug Administration GRP 9T0242, volume 1, pp.
    000292-000334.

    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. 

    Mochizuki, M. (1995a) A toxicity study of sodium gluconate (FR2531) by
    single oral administration in rats. Final report No. BOZO/B-2965 from
    Gotemba Laboratory, Bozo Research Center, Inc., Setagaya-Ku, Tokyo
    156, Japan.

    Mochizuki, M. (1995b) A 4-week oral toxicity study of sodium gluconate
    (FR2531) in rats. Final report No. BOZO/B-2966 from Gotemba
    Laboratory, Bozo Research Center, Inc., Setagaya-Ku, Tokyo 156, Japan.

    Mochizuki, M. (1997) A 28-day toxicity study in rats fed diet
    containing sodium gluconate (FR2531). Final report No. BOZO/B-3731
    from Gotemba Laboratory, Bozo Research Center, Inc., Setagaya-Ku,
    Tokyo 156, Japan.

    Nugent, J.J. (1940) Pyelonephritis.  J. Florida Med. Assoc., 27,
    18-23.

    Parker, F.P. (1940) Blood potassium studies in allergic states.
     South. Med. J., 33, 1301-1309. 

    Prescott, F.J., Shaw, J.K., Bilello, J.P. & Cragwall, G.O. (1953)
    Gluconic acid and its derivatives.  Ind. Eng. Chem., 45, 338-342.

    Pocker, Y. & Green, E. (1973) Hydrolysis of D-glucono-delta-lactone.
    I. General acid-base catalysis, solvent deuterium isotope effects and
    transition state characterization.  J. Am. Chem. Soc., 95, 113-119.

    Prival, M.J., Simmon, V.F. & Mortelmans, K. (1991) Bacterial
    mutagenicity testing of 49 food ingredients gives very few positive
    results.  Mutat. Res., 260, 321-329.

    Select Committee on GRAS Substances (1975) Tentative evaluation of the
    health aspects of certain calcium salts as food ingredients.
    FASEB-SCOGS Report No. 6T3135. Life Science Research Office.
    Federation of American Societies for Experimental Biology, Bethesda,
    Maryland, USA.

    Smith, E.R.B. (1940) A comparison of the effects of large doses of
    calcium gluconate-iodonate, calcium gluconate, and calcium chloride.
     J. Lab. Clin. Med., 25, 1018-1021.

    Teeter, E.J. (1945) Anemia therapy.  J. Am. Med. Assoc., 127,
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    See Also:
       Toxicological Abbreviations