HYDROGENATED GLUCOSE SYRUPS (HGS)
EXPLANATION
Hydrogenated glucose syrups (HGS) are a mixture of polymers of
glucose obtained from starch by hydrolysis which, upon hydrogenation,
results in chemical reduction of the end-group glucose molecule to
sorbitol. HGS consists primarily of maltitol and sorbitol, with lower
portions of hydrogenated oligo- and polysaccharides.
Hydrogenated glucose syrups were evaluated for acceptable daily
intake by the Committee at its twenty-fourth and twenty-seventh
meetings (Annex 1, references 53 & 62). At the twenty-seventh meeting,
the Committee decided, on the basis of acute and subacute tests and
reproduction and metabolism studies, to allocate a temporary ADI of
0-25 mg/kg b.w. to hydrogenated glucose syrups containing 50-90%
maltitol. The Committee at that time requested that the results of a
lifetime feeding study should be made available.
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, biotransformation, and excretion
In male Swiss mice given single oral doses of either 14C-
maltitol or 14C-glucose, expired 14CO2, faecal 14C, and blood 14C-
concentrations were determined from 5 to 240 minutes post-
administration. Labelled 14C from maltitol was absorbed into the
blood from the gastrointestinal tract much more slowly, exhaled
substantially less, and excreted via the faeces significantly more
than 14C from glucose. Glucose and sorbitol, but not maltitol, were
detected in the blood of treated animals (Kamoi, 1975).
Five to 10 male or female Sprague-Dawley rats/group were given
single oral doses, by gastric intubation, of 200, 400, or 600 mg
sorbitol, maltitol, or HGS (containing 6-8% sorbitol, 50-55% maltitol,
20-25% hydrogenated tri- to hexasaccharide, and 15-20% hydrogenated
polysaccharide of more than 6 units) and were killed 1.5, 3, or 7
hours post-administration. Only a small quantity of non-hydrolysed
maltitol crossed the intestinal barrier, since its concentration in
blood was very small. Urinary excretion of sorbitol, maltitol, or HGS
accounted for about 1% of the ingested quantity over a 7-hour period.
Administration of increasing doses of maltitol or HGS resulted in
increased concentrations of sorbitol and decreased concentrations of
maltitol in the gastrointestinal tract, which demonstrates that the
alpha-l,4 glucose-sorbitol linkage of maltitol is hydrolysed and
liberates glucose and sorbitol (Verwaerde & Dupas, 1982a).
Two series of 10 male Sprague-Dawley rats (5 treated and 5
control rats) were housed individually in metabolic cages. The treated
rats drank a solution of HGS (18% W/V) for 10 days, and thereafter
pure water until sacrifice. The control animals received water only.
One series of rats was sacrificed on day 11; the other series was
sacrificed on day 21. Sorbitol and maltitol were determined daily in
urine and plasma, and the liver, kidneys, and spleen were removed from
the animals at terminal sacrifice. After maltitol ingestion per day
ranging from 2.97-4.27 g in males, the maximum quantity of maltitol
excreted per day was 6.27 ± 4.50 mg (the maximum excretion coefficient
was 0.14%); in females, the amount ingested ranged from 2.46-3.03
g/day, and the maximum quantity of maltitol excreted per day was 2.04
± 1.2 mg (the maximum excretion coefficient was 0.09%). The ingestion
of HGS resulted in very small quantities of maltitol in the urine.
Twenty-four hours following the removal of HGS from the rats, the
quantity of maltitol excreted in the urine was reduced to essentially
nil. Maltitol was absent in the plasma, liver, kidneys, and spleen of
treated animals. In addition, the ingestion of HGS did not affect the
sorbitol content in the examined organs (Verwaerde & Dupas, 1982b).
Groups of 35 male Wistar rats (about 200 g each) received by
gavage 1.2 ml of a 50%-aqueous solution of maltitol, xylitol,
sorbitol, or glucose, and their blood glucose and residual sugar
alcohols in the digestive tract were determined hourly for 6
consecutive hours. Animals given the sugar alcohols exhibited lower
blood glucose values than animals receiving glucose itself. Maltitol
disappeared from the digestive tract the most quickly of the sugars
that were investigated (Takae et al., 1972).
Weanling Wistar rats placed on diets containing 13 or 26%
maltitol for 9 weeks had reduced body-weight gains and increased
intestinal weights as compared with controls. Enzymatic tests in dosed
rats indicated that the alpha-glycosidic linkage of maltitol was not
hydrolysed with pancreatic enzymes or enzymes of the intestinal
mucosa. Maltitol dehydrogenase was not observed in liver-cell
cytoplasm and prolonged maltitol administration did not induce hepatic
sorbitol dehydrogenase (Inoue, 1970).
Maltitol was administered to rats either by gastric probe at a
dosage of 2 g/kg or i.v. at a dosage of 1 g/kg. Blood glucose and
insulin levels and the liver glycogen content were measured at
4.5 hours. Maltitol induced hyperglycemia similar to that observed by
the administration of an equivalent amount of glucose or sucrose
(Lederer et al., 1974).
Ten grams maltitol was given to fasted germ-free or normal rats
by stomach tube. Urine and faeces were collected for 24 hours after
intubation and analysed for sorbitol and maltitol. No glucose was
detected in the urine or faeces of any of the animals, and there was
no significant difference in the maltitol content of the urine. The
sorbitol content of the urine was higher in germ-free than in normal
animals, but no statistical differences were found. In normal animals
there was a 96% utilization of maltitol, while in germ-free animals,
utilization was 84%, indicating that microbial utilization is not the
major factor in maltitol metabolism. Maltitol injected i.v.
(0.25 g/animal) was excreted almost quantitatively (88%) in the urine,
producing no significant rise in blood glucose. No sorbitol was
detected in the blood. The small amount of sorbitol in the urine
indicated slight utilization of maltitol in body tissues (Kearsley
et al., 1982).
Intestinal perfusions were carried out with 6 rats (WAG/Rij),
5 females and 1 male, monoassociated with aerobic bacilli that are
unable to metabolize maltitol. A solution (0.18 ml/min) containing
85 mM maltitol and 0.1% (w/v) polyethylene glycol 4000 was infused in
the duodenum. Maltitol and polyethylene glycol were estimated in the
lower ileum during a period of 4 hours. The portion of maltitol
absorbed over the distance of the whole small intestine was found to
be 19 ± 4%. Therefore, under the experimental conditions used,
2.9 µmol maltitol/min, was hydrolysed (the ingested amount was
15.3 µmol/min) (Zunft et al., 1983).
By stomach tube 5 ml of an aqueous solution of 30% (w/v,
4.36 mmole) maltitol and 1% (w/v) polyethylene glycol were introduced
into the stomachs of 8 gnotobiotic rats. For comparison, the same
amount of maltose was administered to 3 rats. The animals were killed
by decapitation 60-120 min. after application. Maltitol, maltose, and
polyethylene glycol were found only above the ileocaecal valve. The
maltitol:polyethylene glycol quotient decreased in going from the
stomach to the small intestine. Only 31% of the ingested maltitol was
found in the ileum after 2 hours (Zunft et al., 1983).
Rats (groups of 3 or 6) were given a single oral dose of 1 or 2 g
maltitol. Very little of either maltitol or sorbitol appeared in the
faeces, but appreciable amounts of sorbitol found in the urine
indicate that the maltitol had been hydrolised. When HGS was
administered, the pattern of excretion was similar, but the quantities
of both maltitol and sorbitol in the urine were significantly higher
(Lian-Loh et al., 1982).
Excretion of maltitol and sorbitol were compared in germ-free and
normal rats given oral doses of 2 g maltitol. Significantly less of
both substances was recovered in the faeces of normal rats, but
urinary excretion was similar in both groups. Three rats were injected
with maltitol (250 mg/animal). The dose was virtually cleared from the
blood within 1 hour, and at most the equivalent of approximately 30 mg
was recovered as sorbitol in the excreta after 24 hours. There was no
evidence of a rise in blood glucose after injection of maltitol.
Little or no metabolism of maltitol had occurred in the tissues
because hydrolysis was catalyzed by gastric or intestinal enzymes
(Lian-Loh et al., 1982).
Wistar rats were dosed orally with a 20%-maltitol solution
(320 mg/kg, containing about 1.28 µCi maltitol-U-14C per 100 g b.w.).
A second group was dosed with maltitol-U-14C and fasted 24 hours.
Urine, faeces, and 14CO2 were collected. The rate of 14CO2
excretion in respired air of the fed group was more rapid than that of
the fasted group; of the CO2 excreted within 24 hours (18.0%), 90%
was excreted within 8 hours after dosing. The 14CO2 excretion per
unit time was high in the fed group between 2 and 4 hours after
dosing. The fasted group showed a high excretion rate between 2 and 6
hours after dosing, and the decline thereafter was more moderate than
that observed with the fed group. About 22% of the dosed maltitol was
hydrolysed in the fed group, while that of the fasted group was about
33%. Excretion in the urine of 14C-derivatives was more rapid in the
fasted group than in the fed group. About 50% of the 14C excreted in
the urine was maltitol, while the figure for the fed group was about
34%. The results show that a portion of the administered maltitol was
not metabolized, but was absorbed in the intestinal tract and quickly
excreted in the urine (Oku et al., 1981).
Five Charles-River rats (both sexes represented) were dosed with
radioactive maltitol solution by intubation (125-260 mg/kg, 49.7 µCi).
After dosing, 1 animal was placed in a breath collection chamber; the
other 4 were placed in individual metabolism cages. Exhaled carbon
dioxide was collected over a period of 14 hours. Urine and faeces were
collected either over a period of 48 hours (2 rats) or 72 hours
(3 rats). The rapid (1-2 hours) and appreciable appearance of 14CO2
(45.5% in 14 hours) in the breath indicates that a portion of the
maltitol was hydrolised in the stomach and the resulting components,
glucose and sorbitol, were absorbed and catabolically utilized. The
calculated caloric utilization was 76%. Radioactivity in the urine
varied from 3.94 to 9.40% in 72 hours. The faeces contained
4.38-13.22% of the ingested radioactivity at 72 hours. Thirteen
percent of the total faecal radioactivity was due to volatile fatty
acids (Rennhard & Bianchine, 1975).
HGS or maltitol (400 mg) was administered by gastric intubation
to groups of 10 male rats (5 fasted and 5 fed). Rats were sacrificed
after 7 hours. The tested products and their metabolites were then
examined in the digestive tract and in the urine. The results showed
that the alpha-1,4 glucose-sorbitol linkage was hydrolysed in rats,
whether fasted or not. Seven hours after the administration of either
HGS or maltitol, small quantities of free maltitol were detected in
the digestive tract of fasted and fed rats (2.5 (fasted) and 3.8 mg
after HGS administration, 6.2 (fasted) and 4 mg after maltitol
administration). Sorbitol liberated by digestive hydrolysis of
maltitol or HGS was more rapidly absorbed by fed rats than by fasted
rats. However, this does not seem to affect maltitol or sorbitol
urinary excretion (Verwaerde & Dupas, 1984).
Two male beagle dogs were given maltitol-U-14C (51.2 µCi) by
stomach tube. Blood samples were collected until 32 hours after
dosing. The peak radiolabel concentration in plasma was 2 hours after
maltitol administration (304 and 263 µg/ml, expressed as maltitol
equivalent in the 2 dogs). The radioactivity present in the urine
after 48 hours was 7.8 and 3.8% of the administered dose in the
2 animals (Rennhard & Bianchine, 1975).
In vitro investigations on maltitol utilization by human
intestinal flora indicate that some strains of Lactobacillae,
Enterobacteriaceae klebsiella, Bacteroidaceae, and
Catanabacterium utilize maltitol (Mitsuoka, 1982a; 1982b).
In an in vitro study of 14C-U-maltitol in everted intestinal
sacs, the highest transport of 14C-maltitol was displayed in the
jejunum, followed by the ileum and duodenum. Twenty-four hours after
oral administration of 14C-U-maltitol, 60% of the radioactivity was
detected in the caecum, large intestine, and faeces. Five percent was
excreted in the urine and 1.2% was expired as CO2 within 24 hours.
When 14C-U-maltitol was injected i.v., over 35, 60, and 85% of the
administered dose was excreted in the urine within 1, 3, and 24,
hours, respectively (Oku et al., 1971).
In vitro digestion of HGS and its main components was
investigated using enzymes from human and rat intestinal mucosa for
periods of 0.5 to 24 hours. The amount of maltitol present in HGS
governed the enzymatic hydrolysis of its components. Maltitol was
hydrolysed slowly by the intestinal mucosa of man (3.56%) and rat (7%)
when compared with maltose, of which 76% and 26%, respectively, was
hydrolysed (Verwaerde, 1982).
High disaccharidase activity for sucrose, maltose, and maltitol
was found in the jejunum of female Wistar rats. Less was observed in
the ileum and duodenum. Disaccharidase activity for maltitol was
extremely low compared with that for sucrose and maltose. Kinetic data
indicate that both maltose and maltitol compete for the same
intestinal disaccharidase (Yoshizawa et al., 1975).
Pieces of New Zealand rabbit small intestine were everted and
incubated with 100 mM substrate (maltitol, sucrose, or glucose). After
removal at different times (20, 40, or 60 min.) of incubation, the
volume of serosal fluid and the dry mass of the gut pieces were
determined. Maltitol was hydrolysed, and the hydrolysis products were
absorbed by the everted sacs. No maltitol was detected in the serosal
fluid. The serosal glucose concentration increased at a slower rate
after incubation with maltitol than after incubation with glucose or
sucrose. The rate of hydrolysis and absorption decreased with the
longer time of incubation (Zunft et al., 1983).
An enzymatic maltase/glucoamylase system isolated from the
intestinal mucosa of the rat was used in an hydrolysis study. After
40 hours of incubation with different substrates, the percentage of
hydrolysis was 100% for maltose, 91% for maltitol, and 79-95% for HGS.
The maltase/glucoamylase system hydrolysed maltose more quickly than
maltitol (200 and 15 nmoles/minute, respectively) (Montreuil et al.,
1983).
Toxicological studies
Special studies on mutagenicity
HGS was evaluated in a series of assays for assessing the
mutagenic potential of chemicals.
HGS did not induce a significant increase in genetic mutations in
the Schizosaccharomyces pombe strain in a host-mediated assay
(mouse) at doses up to 1 g/kg (Mondino et al., 1979a).
HGS was not mutagenic against 4 strains of Salmonella
typhimurium at concentrations of 0.01 to 1 ml/plate (0.2-20 mg),
with or without activation by rat liver microsomes (Fouillet et al.,
1978a; 1978b; Hofnung, 1978).
Eight male Sprague-Dawley rats (4 controls) received daily by
gavage doses of HGS equivalent to 0, 2.5, 5, 10, 15, or 20% in the
diet for 15 consecutive days. Urine from each rat was collected on day
15. Urine that had been concentrated and purified was assayed for
mutagenic activity against Salmonella typhimurium strains TA98,
TA100, TA1535, TA1537, and TA1538 using the Ames test with or without
metabolic activation. No mutagenic effects were found (Farrow, 1983d).
A micronucleus test was conducted in which HGS was administered
orally to adult male mice at doses of 10 or 50 ml/kg on 2 consecutive
days. The animals were killed 6 hours after the second administration
of HGS. Femoral bone marrow was taken, and 2000 polychromatic
erythrocytes per animal were counted and scored for micronuclei. The
administration of HGS did not significantly increase the mean
percentage of polychromatic erythrocytes carrying micronuclei (Siou
et al., 1981).
HGS at concentrations of 0.5 to 1000 µg/plate was not mutagenic
in the Ames test with Salmonella typhimurium strains TA98, TA100,
TA1535, TA1537, or TA1538 with and without metabolic activation
(Mondino et al., 1979b).
HGS did not induce a significant increase in the incorporation of
3H-thymidine into human heteroploid fibroblasts at concentrations up
to 300 µg/ml (Mondino, 1980).
HGS was added in vitro to C3H/10T 1/2 (Clone 8) mouse
fibroblast cells using concentrations from 10 to 1000 µg/ml with or
without metabolic activation. There was a significant increase in the
prevalence of morphologically transformed foci due to exposure to HGS
(Farrow & Sernau, 1982; Farrow, 1982c).
The potential of HGS to induce forward mutations at the thymidine
kinase locus in the L5178Y mouse lymphoma cell line was assessed at
concentrations ranging from 27 to 1000 µg/ml in the presence or
absence of metabolic activation. HGS induced a slight increase in
mutation frequency, but the increase was not dose-related (Farrow,
1982b).
The ability of HGS to induce mutations in Chinese hamster ovary
cells in vitro was investigated at concentrations ranging from 49 to
4900 µg/ml. No significant increase in the frequency of structural
chromosomal aberrations was seen at any of the concentrations tested,
either with or without metabolic activation (Farrow, 1982a).
Special study on reproduction
Rats
A multigeneration reproduction study in Sprague-Dawley rats was
conducted, in which males received 5.4-8.5 g HGS per day and females
received 5.3-13.5 g of the same compound per day in drinking water as
an 18% (dry weight/volume) aqueous solution for 3 successive
generations, each comprising 2 consecutive litters. Concurrent
controls were given water only. The initial number of animals in each
generation was 10 males and 10 females.
During the study, food consumption was lower for treated animals
than for controls, but without irreversible effect on the growth rate
except for females of the F2 generation. Animals from most groups may
not have had decreased growth rates due to the caloric compensation of
HGS in the drinking water. No abnormal behaviour was detected during
treatment.
Among the organ weights recorded, the kidneys of treated rats had
lower weights and caeca had higher weights than concurrent controls.
Haematology and gross pathology of parents were not remarkable.
Fertility, length of gestation, litter size, number of live and
stillborn pups, post-natal survival, and the lactation index were not
affected by treatment. Sex ratios of treated litters exhibited an
approximate 10% decrease in the number of female pups (Leroy & Dupas,
1983).
Special study on teratogenicity
Rats
HGS was administered by gavage to groups of 30 pregnant Sprague-
Dawley rats from day 6 to day 15 of gestation, inclusive, at dosage
levels of 0, 3000, 5000, or 7000 mg/kg/day. A control group received
the vehicle, distilled water, at the same dosage volume through the
same period. On day 20 of gestation, all rats were killed and the
number of corpora lutea in each ovary and the number, position, and
condition of implantations were recorded. Viable foetuses were
weighed, sexed, and examined externally. The thoracic and abdominal
cavities of the remainder were dissected, examined, and then processed
for subsequent skeletal examination. No adverse effects were observed
on pregnant females or on litter responses (litter size, foetal
weight, or pre- and post-implantation losses). No visceral or skeletal
abnormalities in the foetuses attributable to the treatment were
observed (Dupas & Siou, 1985).
Acute toxicity
LD50
Species Route (mg/kg b.w.) Reference
Mouse, male oral 24,370 Dupas, 1982a
& female
Mouse oral 16,000 Yamasaki et al.,
1973a
Mouse, male i.p. 10,640 Dupas, 1982a
Mouse, female i.p. 12,430 Dupas, 1982a
Mouse i.p. 18,500 Yamasaki et al.,
1973b
Mouse, male i.v. 6,390 Dupas, 1982a
Mouse, female i.v. 8,150 Dupas, 1982a
Mouse i.v. 12,000 Yamasaki et al.,
1973b
Mouse s.c. 24,000 Yamasaki et al.,
1973b
Rat, male & oral 24,370 Dupas, 1982b
female
Rat, male & oral 24,000 Nishibori, 1968
female
Rat oral 24,130 Kotani & Chiba,
1968
Rat, male & i.p. 13,000 Dupas, 1982b
female
Short-term studies
Rats
Groups of 20 Sprague-Dawley rats, evenly divided by sex, were fed
diets containing 1, 15, or 20% HGS for 3 consecutive months. The diet
of the controls was supplemented with 20% sucrose. No effects on
mortality, growth, or food consumption were observed. No diarrhoea or
other clinical symptoms were noted. No treatment-related effects were
reported after ophthalmological examination, and organ weights were
normal. Slight decreases in haemoglobin levels and erythrocyte counts
occurred in both sexes of the 15%- and 20%-groups at week 4 and week
13 of treatment. Blood urea concentrations increased slightly in all
treated females at week 4. Moderate elevation of blood urea and
glucose were noted in all treated rats at week 13. Slight elevation of
blood phosphous occurred in both sexes fed 15 and 20% of the test
material at week 13 of the test. Gross and histopathological changes
observed were not remarkable (Coquet et al., 1980).
Forty weanling Sprague-Dawley rats, equally divided by sex,
were fed 20% HGS for 90 consecutive days. The same number of controls
were fed a diet supplemented with 20% sorbitol. No mortality or
noteworthy clinical symptoms occurred. No effects on haematology,
blood chemistry, urinalysis, or organ weights were noted. Gross and
microscopic examination revealed no histopathological alterations in
organs or tissues at termination (Stevens et al., 1980).
Dogs
Four male or 4 female beagle dogs received 4.95 g/kg HGS every
day for 13 weeks. Clinical examinations were performed daily and all
animals were autopsied. Food intake in the treated animals was
slightly decreased throughout the study, without any effect on the
animals' body-weight gain. Ophthalmologic examinations did not reveal
any abnormalities caused by the treatment. The only significant
effects that were observed involved the occurrence of diarrhoea.
Haematological and urinary analyses did not reveal any abnormalities
linked with treatment. At autopsy, no lesions signifying an effect of
treatment were observed. Organ weights were not modified (Virat,
1982).
Long-term studies
Rats
Weanling Wistar-derived male rats were divided into groups of 10
each and fed 0, 5, 10, 20, or 30% of either maltitol or sucrose, or
20% HGS, for 31 weeks. Body weights were reduced at week 4 in groups
of 20 and 30% maltitol and 20% HGS, but were similar between the
treated and control groups at week 8. At termination, body weights and
selected organ weights of groups fed 5 to 30% maltitol were similar to
rats fed 5 to 30% sucrose (Wada, 1972).
Groups of 15 male or 15 female young Wistar rats were fed diets
containing 0, 1, 3, or 10% HGS for up to 13 months. Mortality, food
and water consumption, body weights, haematology, blood chemistry,
urinalysis, and organ weights were similar between the treated and
control rats. At the 6-month interim sacrifice, about half of the
treated rats exhibited dilation of the stomach. Slight edema of the
colonic mucosa in half of the treated rats was observed at month 3 and
in about 10% of the treated rats at month 6. At termination, the
histopathological changes were comparable between the dosed and
control animals (Yamasaki et al., 1973c).
Three groups of 26 male or 26 female Wistar rats were fed diets
containing 0, 3, or 10% HGS for 78 weeks. An interim sacrifice of
3 males and 4 females per group was carried out at week 52. After week
50, mortality increased in both groups of dosed males, but only in the
high-dose female group. Males of the high-dose group weighed
substantially less than controls after week 60. Haematology, blood
chemistry, and organ weights at interim and terminal sacrifices were
similar between the dosed and control rats. The incidence of
non-neoplastic lesions was not remarkable. Increased incidences of
neoplasms of adrenal glands occurred in the dosed females and of the
thyroid gland in the dosed males. Tumours of the skin and mammary
region were not compound-related. Neoplasms of internal organs and
tissues other than the above endrocine glands were not observed
(Shimpo, 1977).
HGS was administered in drinking water to groups of 100 Sprague-
Dawley rats (50 males and 50 females) at concentrations of 0 or 18%
(w/v) for 24 months. The HGS consumption measured during the study
was: 13.9 g/kg/day and 21.5 g/kg/day for males and females,
respectively.
Weight gains in both groups were essentially identical, except
for during a short preliminary period of adaptation. Subsequently, the
treated female body weights were nearly always slightly higher than of
the control females. The treated male body weights, which were
slightly lower during the first year, increased during the second year
to slightly exceed those of the control group.
Diarrhoea, which appeared from the first week of the study, and
which decreased from the fourth week in treated animals, is usual in
animals receiving drinking water with high osmotic properties.
Adaptation to the diet was also the cause of considerable caecum
hypertrophy.
Haematological and clinical chemical parameters did not reveal
changes related to the test material. The only significant variation
observed in treated males and females as compared with the control
groups was a decrease in urea levels due to considerably higher water
consumption by treated rats.
Urinalysis did not show treatment-related differences.
Histopathological examination did not show any tissue changes
related to HGS ingestion.
The spontaneous mortality rate recorded during the study was
lower for treated males than for control males (5 vs. 13,
respectively). Among females, mortality was slightly higher in the
treated group than in the control group (11 vs. 8, respectively).
Neoplasms of internal organs and tissues occurred with the same
frequency in control and treated animals (Dupas et al., 1984).
Observations in man
Six fasted normal volunteers (3 men and 3 women) and 4 diabetics
(1 man and 3 women) were given orally 30 g of maltitol or 30 g of
sucrose, and at 0.5-, 1-, 1.5-, 2-, and 3-hour periods post-
administration the glucose and maltitol concentrations in blood and
urine were analysed. Maltitol administration induced lower blood
glucose levels than the sucrose administration, both in normal and
diabetic volunteers. Urinary excretion of maltitol was also low
(Atsuji et al., 1982).
Three normal volunteers, 3 diabetics, and 1 subject infected with
acute hepatitis, were administered orally 50 g of glucose, sorbitol,
or maltitol in aqueous solution, and at 0-, 0.5-, 1-, 2-, and 3-hour
intervals post-administration the blood concentrations of these sugars
were measured. Maltitol concentrations peaked at 0.5 hour and
decreased sharply thereafter. Glucose followed a similar pattern, but
its concentration was significantly higher than maltitol, especially
in diabetics (Nishikawa, 1982).
Twenty-seven children, 3 to 14 years of age, consumed 18 to 42 g
of hard candies made either from sucrose or HGS within one hour. At
this dosage, the children developed slight nausea and "hate to eat
more" symptoms, whether the candies were made from sucrose or from
HGS. Only 3 children, from both groups, developed mild flatulence
(Leroy, 1982b).
Twenty, 30, 40, or 60 g HGS or sucrose were consumed in bolus
form by groups of 6-10 volunteers in a double-blind study. Ingestion
of a single dose of 60 g HGS resulted in 80% of the volunteers
reporting either abdominal discomfort, watery diarrhoea, colic, or an
increase in flatus production. At lower doses, incidences of these
symptoms were marginal. In another experiment, 10 different volunteers
consumed intermittently 30, 60, or 120 g HGS or 64 g sucrose daily for
2 days in divided doses. The highest dose produced abdominal symptoms
in 50% of the subjects, whereas at the lowest dose, symptoms occurred
in about 20% of the volunteers. In yet another experiment, groups of
10 volunteers took either 30 g HGS or 30 g sucrose daily for 21 days,
while groups of 12 subjects consumed 15 g HGS, 15 g sorbitol, or 15 g
sucrose daily for 28 days. In all subjects taking HGS for 21-28 days,
no adverse symptomology other than mild flatulence in 5 subjects at
the higher dose was observed. Haematological and biochemical indices
(liver function, glucose, cholesterol, lipoproteins, plasma insulin,
and triglycerides) were not remarkable (Abraham et al., 1981).
Nine diabetics (5 men and 4 women) each received a single oral
dose of 50 g maltitol, 50 g glucose, or 7 consecutive daily doses of
50 g each of sucrose, powdered starch syrup, or maltitol. At 0, 1, 2,
and 3 hours post-administration the blood levels of glucose, immuno-
reactive insulin (IRI), free fatty acids (FFA), and triglycerides (TG)
were determined. Single doses of maltitol produced lower blood glucose
and IRI levels but higher FFA and TG concentrations than glucose
administration itself. The presentation of results from the multiple
administration are unclear for the purpose of evaluation (Takeuchi &
Yamashita, 1972).
In a similar study, blood glucose and IRI concentrations
exhibited flatter curves when 10 normal volunteers and 5 diabetics
received a single oral dose of 50 g HGS than when 50 g glucose was
administered (Yamakubi, 1971).
In a preference test on the sweetening power and quality of
sweetness of HGS compared with sucrose, 20 young women preferred
sucrose over HGS for its sweetening power, but both sugars scored
identically in terms of the quality of sweetness (Yamakubi, 1971).
Eleven diabetics (6 men and 5 women) and 9 healthy control
volunteers (7 men and 2 women) were given single oral doses of 50 g
maltose or 50 g maltitol. Lower increases in blood glucose and
IRI were observed with maltitol administration than with the
administration of maltose. An additional 10 diabetics and 10 healthy
control volunteers were offered "Zenzai", a thick bean syrup sweetened
either with maltitol or with sucrose. Lower increases in blood glucose
levels were observed in subjects that consumed "Zenzai" sweetened with
maltitol than with sucrose. In the preference test, no significant
differences were recorded in the intensity and quality of sweetness of
"Zenai" sweetened with either substance. No unfavourable side effects
were observed (Mimura et al., 1972).
The influence on carbohydrate metabolism of HGS (containing 89%
maltitol) has been studied in healthy humans by measuring blood
glucose and insulin levels after various oral dosages of HGS. Subjects
given oral doses of glucose were used as controls. Six volunteers were
given on different occasions 50 g of glucose or HGS at dosages of 10,
25, or 50 g. Blood glucose levels after the administration of maltitol
were much less than after the administration of glucose; the area
under the blood glucose curve after the administration of 50 g HGS
represented about 25% of the area under the curve after glucose
administration. Similarly, insulin levels were significantly lower
after HGS ingestion than after glucose ingestion. At a dose of 10 g
HGS, practically no increase in blood glucose or insulin was observed
(Secchi et al., 1982).
Groups of 16 to 36 volunteers per dose level ingested daily 12 to
60 g of maltitol for 3 consecutive days. Ingestion of 50 or 60 g of
maltitol induced diarrhoea in 15 and 30% of the volunteers,
respectively (Nikken Chemicals, 1982).
Chemical changes in the blood induced by maltitol were compared
with those induced by glucose in both healthy people and patients with
several disorders, including diabetes mellitus. Blood glucose levels
of healthy subjects were determined after the administration of
glucose (12.5, 25, or 50 g) or maltitol (50 g). Based on the glucose
absorption curve, 38% of the maltitol that was orally administered was
absorbed through the intestinal tract, but the absorption of maltitol
was more delayed than that of glucose.
After administration of maltitol to the groups with diabetes and
the other diseases with impaired glucose tolerance, blood glucose
levels were higher than in healthy people. Elevation of blood glucose
levels by maltitol was 25 to 50% of the elevation by glucose, and
there was a correlation between the elevation of blood glucose by
glucose and by maltitol.
The peak blood glucose level after administration of a mixture of
50 g glucose and 50 g maltitol was lower than after the administration
of 50 g glucose alone. Diarrhoea was frequently observed in healthy
people and in patients with a borderline glucose tolerance test
pattern after oral administration of maltitol. However, the frequency
of diarrhoea was very low in patients with diabetes or the other
disease with impaired glucose tolerance patterns (Kamoi et al.,
1975).
Ten men and 7 women volunteers consumed daily 20 hard candies
containing about 80 g/day of sweet product, for 2 consecutive weeks in
a blind trial. Each volunteer was offered for 1 week sucrose control
candies and for the other week the candies made from HGS. A majority
of volunteers complained during both trial weeks of digestive
disorders, such as loss of appetite, occasional diarrhoea, cramps, and
a "bloated feeling". At the dosage level of 80 g/day of hard candies
made from HGS, the limit of tolerance was exceeded (Leroy, 1982a).
Five normal men, 23 to 56 years old, ingested in the early
morning on an empty stomach 0.5 g/kg/day maltitol for 30 consecutive
days. On days 1, 7, and 30 at 1, 2, and 3 hours after the daily
administration of maltitol, the concentrations of maltitol and glucose
in the blood were measured and serum levels of protein, cholesterol,
bilirubin, uric acid, urea nitrogen, SGOT, SGPT, LDH, sodium,
potassium, and calcium were determined. Diarrhoea was not observed. In
3 volunteers, blood glucose levels increased by about 20% 1 hour after
maltitol administration. No other changes were observed (Itoya et
al., 1974).
One hundred seven men (including 11 diabetics) and 20 women
(including 2 diabetics) were offered daily 30 to 180 ml of a 50% HGS
solution in 2 equal daily doses for periods up to 4 months. They were
examined daily and subjected to extensive monthly blood chemistry
analyses. Occasional diarrhoea or accelerated intestinal transit
occurred at higher doses, more frequently in women than in men. Both
sexes tolerated 30 ml/day for up to 4 months without any clinical or
digestive manifestations (Tacquet & Devulder, 1978).
Fifteen subjects received single oral doses of 50 g glucose or
40-50, 80, or 100 g HGS. At 0-, 0.5-, 1-, 1.5-, 2-, 2.5-, and 3-hour
intervals post-administration, the blood concentrations of glucose and
insulin were determined. Maltitol excretion was measured in urine 3
hours after administration. Blood glucose and insulin peaked at 0.5
hour after administration of either glucose or HGS, but the increases
after administration of HGS were less than after glucose
administration. The data on maltitol excretion in urine were not
conclusive (Debry, 1983).
Five healthy women and 5 diabetics (3 males and 2 females) were
offered single oral doses of either 50 g glucose or 50 g HGS on 2
different occasions. Another group of 5 normal volunteers (1 male and
4 females) and 5 diabetics (3 males and 2 females) were given orally
25 g sucrose, 25 g sorbitol, or 33 g HGS on 3 different occasions. At
0-, 0.5-, 1-, 1.5-, 2-, and 3-hour periods post-administration, the
concentrations of serum glucose and insulin were determined.
Administration of glucose produced the highest serum glucose
concentrations. Insulin levels in normal volunteers given HGS varied
between insulin levels in those volunteers administered sucrose and
sorbitol. Among diabetics, there were virtually no differences
observed after the administration of the different sugars (Vessby,
1982).
Thirty-five subjects (10 females and 25 males) were divided into
3 groups and given 50, 85, or 125 g/day HGS. Subjects were required to
ingest each solution in 6 equal doses, 1 every 2.5 hours, and were
asked to record any intestinal discomfort, flatulence or diarrhoea. Of
the 12 subjects that consumed 50 g/day, 2 had diarrhoea, flatulence,
and abdominal pain. At 85 g/day, 3/12 subjects had diarrhoea,
flatulence, and abdominal pain. At 125 g/day, 6/11 subjects had
diarrhoea, flatulence, and abdominal pain.
No differences were noted between male and female subjects. The
authors concluded that over 85 g HGS could be tolerated without undue
problems to most subjects if taken over a period of one day.
Intestinal discomfort, flatulence, and diarrhoea increased in severity
with intake of HGS (Kearsley et al., 1982).
Sixteen subjects (8 females and 8 males) who had fasted overnight
received 0.5 g/kg of one of 5 different substances (HGS, maltitol,
glucose, glucose and sorbitol in the ratios found in HGS, or high-
maltitol syrup). No glucose was detected in the urine of any of the
subjects after ingestion of any of the test carbohydrates. There were
no significant differences in polyol levels in the urine among
subjects administered HGS, the glucose/sorbitol mixture, or high-
maltitol syrup. Blood glucose and serum insulin profiles indicated no
differences among subjects administered HGS, maltitol, and the
glucose/sorbitol mixture. All these substances induced lower peak
values for glucose and insulin than did glucose. The results indicate
that HGS and high-maltitol syrup are metabolized to approximately the
same extent as their basic components (Kearsley et al., 1982).
Six male subjects were placed on a strictly-controlled diet
containing 40% carbohydrate and 60% protein for 10 days. No lipids
were included except when part of a protein source. Total daily
caloric intake was about 1800 calories. The carbohydrate in the diet
consisted of HGS, high-maltitol syrup, 43% glucose syrup, or glucose
(the standard). Total sample intake was about 160 g/day, in 6 equal
doses. The results of blood glucose and serum insulin analyses
indicate that prolonged consumption of high-maltitol syrup or HGS
leads to some adaption to these compounds as judged by elevated blood
glucose and insulin peak values at the end of the trial. Diarrhoea and
flatulence gradually disappeared after 4-5 days of consuming these
hydrogenated samples. No problems were encountered with either glucose
or 43% glucose syrup, and urine and faeces analysis revealed no
carbohydrate present after ingestion of these samples. Subjects
ingesting HGS or high-maltitol syrup excreted up to 10 g sorbitol and
0.5 g maltitol in the urine and up to 8 g sorbitol and 11 g maltitol
in the faeces over the trial period. Over 99% of the hydrogenated test
materials were retained in the body and were therefore presumably
utilized. This was substantiated by the steady body weights exhibited
by all subjects throughout the trial (Kearsley et al., 1982).
Two healthy volunteers (aged 30 and 35 years) each received a
test meal of 69.5 g maltitol on an empty stomach. Twenty minutes after
oral administration, blood glucose concentrations had increased by 20
and 30 mg/dl, respectively. They remained at this level for 2 hours
and started to normalize 3 hours after maltitol application. At that
time, the 2 individuals suffered from diarrhoea (2 and 3.5 hours,
respectively) (Zunft et al., 1983).
Daily amounts of 35 g maltitol were given with meals for a period
of 10 days to 4 subjects aged 34-53 years. Subjective signs
(flatulence, gripes, and nausea) and faecal parameters (amount,
frequency, pH, and content of maltitol) were compared with data from a
control period without maltitol application. During the 10-day test
period, there were no significant alterations of frequency and amount
of faeces or of the pH. No maltitol was detected in the excreta by
thin-layer chromatography (Zunft et al., 1983).
Four healthy men (21-23 years of age) were given daily doses of
10 g maltitol containing 79.65 µCi 14C-U-maltitol for a period of 7
days. Expired breath, blood, urine, and faeces were collected. An
average of 17% of the total 14CO2 recovered was exhaled within the
first 2 hours, and 43% of the total 14CO2 was exhaled within 4
hours. The total recovery of 14CO2 suggests a caloric utilization of
maltitol in man of approximately 90%. This value is substantiated by
the low radioactivity levels found in the faeces (5%) and by the
presence of appreciable quantities of radioactive metabolites in the
blood and urine 7 days after administration (Rennhard & Bianchine,
1975).
Comments
Several metabolic studies have been performed in rats and in man
with HGS containing 50-90% maltitol. HGS is metabolized to glucose and
sorbitol by disaccharidases in the intestinal mucosa. Data on the
velocity of hydrolysis in comparison to the natural substrate maltose
show that the maltitol hydrolysis rate corresponds to 5-7% that of
maltose; maltose inhibits the hydrolysis of maltitol. Maltitol is
absorbed in trace amounts, with a maximum of 0.05% of the ingested
dose excreted as maltitol in human urine. Sorbitol, a hydrolysis
product of maltitol, is absorbed very slowly. The second cleavage
product, glucose, is produced at a slow rate due to the slow
hydrolysis of maltitol; it is partially metabolized, like sorbitol, by
the bacteria of the lower intestine. Sorbitol inhibits the absorption
of glucose.
After the administration of 14C-maltitol, 13% and 5% of the
administered radioactivity was recovered in rat and human faeces,
respectively; 13% of the total radioactivity found in rat faeces was
represented by volatile fatty acids. The total urinary excretion of
the administered radioactivity (4-5%) was comparable for rats and
humans. A further indication that 14C-maltitol is hydrolysed in the
stomach and that the resulting components, glucose and sorbitol, are
absorbed and catabolically utilized, is given by the rapid (1-2 hours)
and appreciable appearance of 14CO2 in the breath of rats. In rats,
43% of the total 14CO2 was exhaled within 4 hours. The recovery of
radioactivity as 14CO2 within 24 hours of administration of
14C-maltitol was 49% and 38-59% of the administered dose for rats and
humans, respectively.
Studies in animals and humans revealed that HGS or its major
component maltitol produced significantly lower blood-glucose levels
and more stable insulin levels than glucose or sucrose due to slow
metabolism of maltitol.
HGS was examined in in vitro and in vivo genetic toxicity
assays. The results from the in vitro assays, with and without
metabolic activation, suggest that HGS does not induce a mutagenic,
clastogenic, genotoxic, or neoplastic transformation response. No
in vivo clastogenic effects were observed.
Acute and short-term animal studies indicate that HGS is not
toxic after single or repeated oral administration of large doses. In
rats, no evidence of toxic effects of prolonged feeding of up to
15-20% of the diet was observed. A 90-day study in dogs showed no
evidence of adverse effects, except for diarrhoea, at a level of
4.95 g/kg b.w./day. A multigeneration reproduction study in rats, in
which HGS was administered in drinking water as an 18% aqueous
solution, did not reveal any toxicologically-significant effects.
Human tolerance studies conducted with HGS in healthy and diabetic
subjects showed a laxative effect at intake levels of 30-50 g/day.
EVALUATION
Estimate of acceptable daily intake for man
ADI "not specified". The fact that high doses of HGS exert a
laxative effect in man, which is a common feature of polyols, should
be taken into account when considering appropriate levels of use of
polyols, alone and in combination.
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See Also:
Toxicological Abbreviations