INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN
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
Absorption, distribution, and excretion
Short-term studies of toxicity
Long-term studies of toxicity
Reproductive and developmental toxicity
Observations in humans
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
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
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
Rat Sodium gluconate Oral, gavage > 2000 Mochizuki (1995a)
Rat Glucono-delta-lactone Oral 5940 Food & Drug Research
Mouse Calcium gluconate Intravenous 950 Coulston et al. (1962)
Mouse Glucono-delta-lactone Oral 6800 FOod & Drug Research
Rabbit Sodium gluconate Intravenous 7630 Gajatto (1939)
Rabbit Glucono-delta-lactone Oral 7850 Food & Drug Research
Hamster Glucono-delta-lactone Oral 5600 Food & Drug Research
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
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
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
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).
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
Reverse mutation S. cerevisiae D4 0.25 and 0.5% Negativea Litton Bionetics,
S. typhimurium Inc. (1974)
TA 1535, TA 1537,
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
Tryptophan reversion E. coli WP2 0.033, 0.1, Negative Prival et al.
0.33, 1, 3.3, (1991)
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).
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.
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.
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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)
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calcium gluconate and calcium chloride. Toxicol. Appl. Pharmacol.,
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.
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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.
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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.
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
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.
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Nugent, J.J. (1940) Pyelonephritis. J. Florida Med. Assoc., 27,
Parker, F.P. (1940) Blood potassium studies in allergic states.
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Prescott, F.J., Shaw, J.K., Bilello, J.P. & Cragwall, G.O. (1953)
Gluconic acid and its derivatives. Ind. Eng. Chem., 45, 338-342.
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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.
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health aspects of certain calcium salts as food ingredients.
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calcium gluconate-iodonate, calcium gluconate, and calcium chloride.
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