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.
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.
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).
Special studies on teratogenicity
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).
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
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).
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).
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).
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).
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).
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.
Estimate of acceptable daily intake for man
0-50 mg/kg bw*
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
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.