ISOMALT
EXPLANATION
Isomalt is an equimolar mixture of alpha-D-glucopyranosido-1,6-
sorbitol (GPS) (sometimes called alpha-D-glucopyranosido-1,6-glucitol)
and alpha-D-glucopyranosido-1,6-mannitol (GPM). Complete hydrolysis of
isomalt yields glucose (50%), sorbitol (25%), and mannitol (25%).
Isomalt was evaluated at the twenty-fifth meeting of the
Committee under the name "isomaltitol" (Annex 1, reference 56). On the
basis of the data available, the Committee allocated a temporary ADI
of 0-25 mg/kg b.w. Further results from lifetime feeding studies and
multigeneration reproduction studies were required by 1985.
Since the previous evaluation these data have become available
and are summarized and discussed in the following monograph. The
previously-published monograph has been expanded and is reproduced in
its entirety below.
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, and excretion
Isomalt-14C was administered orally to rats at doses of 250,
1000, or 2500 mg/kg b.w. Absorption of 14C-activity was dose-
dependent, varying from 80% in the low-dose group to 45% in the high-
dose group. 14CO2 in expired air 2 days after administration ranged
from 62% of the administered dose in the low-dose group to 33% in the
high-dose group. Elimination in the faeces ranged from 18-54% of the
administered dose over a period of 48 hours. Approximately 5% of the
administered 14C-activity appeared in urine. The authors pointed out
that the 14CO2 that they measured could have originated in 2 ways:
from the expired air due to metabolism of glucose, sorbitol, and
mannitol after their absorption from the gut, or from intestinal gases
due to microbial fermentation in the caecum. Consequently, 14CO2
excretion could not be used as a direct indication of energy
utilization (Patzschke et al., 1975a).
The fate of isomalt in the gastrointestinal tract of female rats
that had been adapted to the compound was investigated by increasing
its dietary concentration from 10% to 34.5% over a period of 3-4
weeks. After administration of 1.7 g isomalt in 5 g feed, the contents
of the stomach, small intestine, caecum, and large intestine were
examined at intervals up to 6 hours. From the content of GPS, GPM,
sorbitol, mannitol, and sucrose found in these organs, the authors
concluded that GPS and GPM were only partially hydrolysed by the
carbohydrases in the small intestine, while a substantial proportion
of these compounds reached the caecum where further hydrolysis of
glycosidic bonds occurred. Fermentation of the liberated hexitols
occurred in the caecum, which was enlarged, and only small amounts of
GPS, GPM, and hexitols reached the large intestine (Grupp & Siebert,
1978).
Small quantities of isomalt were detected in kidneys and urine of
rats after they were given large oral doses of isomalt. On this basis,
the authors concluded that unhydrolysed isomalt is absorbed to a small
extent (Musch et al., 1973).
When isomalt was fed to rats for several weeks it was observed
that faecal excretion declined steadily, while the caecum enlarged.
The authors concluded that this resulted from adaptation and
metabolism by the gut microflora. Similarly, during a 17-day feeding
period in which 6 female rats received 3.5 g isomalt daily, the faecal
content fell from 25% of the dose at the beginning to 1% at the end
(Musch et al., 1973; Grupp & Siebert, 1978).
Renal clearance studies were conducted in adult female rats
(250 g b.w.) infused with 1.8 g isomalt, GPS, or GPM over a period of
3 hours. Maximum plasma concentrations of 25 mM were obtained. These
compounds were readily cleared and urinary concentrations of up to
100 mg/ml were recorded, which compares with a maximum urinary
concentration of 0.6 mg/ml in rats receiving 5 g isomalt per day
orally. After the infusion of either isomalt or GPS, free sorbitol was
not detected in blood or urine, and blood glucose concentrations were
unchanged, demonstrating the metabolic inertness of these disaccharide
alcohols. From the infusion and excretion rates and the plasma
concentrations that were observed, the authors concluded that GPS is
distributed in extracellular water, but does not reach the
intracellular compartments (Grupp & Siebert, 1978).
Rat intestinal maltase was shown to be active against isomalt,
GPS, and GPM, but the rates of hydrolysis were slow (Grupp & Siebert,
1978; Musch et al., 1973).
The ratio of the rates of hydrolysis of sucrose isomaltulose, and
isomalt by rat intestinal alpha-glucosidases was 100:30:12. Similarly,
sucrose was hydrolysed about 20 times faster than GPS or GPM by
disaccharidases from the small intestine of the pig, and the relative
rates of hydrolysis of maltose, sucrose, isomaltulose and isomalt by
human intestinal alpha-glucosidases were 100:25:11:2 (Gau & Muller,
1976; Grupp & Siebert, 1978).
Using isocaloric diets, a 30-day maintenance study was conducted
on rats weighing 146 g and a 34-day growth study was performed on
rats initially weighing 94 g. In these experiments carbohydrate
(starch or sucrose) was partially replaced by isomalt, giving final
concentrations of 34.5% in test diets. In the maintenance study, the
food energy intake was 21% higher than in sucrose-containing diets and
in the growth experiment the test group received 38% more energy in
the feed than did control rats given starch. The fall in energy
utilization was between 53% and 75%, depending on the test protocol
(Grupp & Siebert, 1978; Siebert & Grupp, 1978).
Isomalt was fed to groups of rats (10 males and 10 females) at
levels of 0, 2.5, 5.0, or 10.0% of the diet; a group fed 10% sucrose
was used as an additional control. The following observations were
made during weeks 73-75 of the chronic toxicity/carcinogenicity study:
faeces production, moisture content and pH of faeces, apparent
digestibility of fat and protein, determination of isomalt and its
break-down products (maltitol and sorbitol) in the faeces, excretion
of lactic acid and short-chain fatty acids, and composition of the gut
flora.
From the results, it seems clear that isomalt is largely digested
or degraded in the gastrointestinal tract of the rat, since neither
isomalt nor its degradation products, such as sorbitol or mannitol,
could be detected in the faeces. If it is assumed that degradation
takes place mainly by bacterial flora in the large bowel, one may
expect an increased production of short-chain fatty acids, which
generally result from bacterial fermentation. The fact that in the
present study faecal excretion of short-chain fatty acids was not
increased and the pH of the faeces was not decreased indicates that
any short-chain fatty acids formed were absorbed through the gut wall,
thus providing energy to the body.
The feeding of isomalt resulted in a slight increase in the
production of faecal dry matter, accompanied by an increased excretion
of protein (nitrogen). The increased excretion of protein is probably
a reflection of an increased number of intestinal micro-organisms
resulting from the supply of an easily-fermentable substrate, as
isomalt probably is (Sinkeldam, 1983).
In the preparation phase of a metabolic study in rats, all the
animals were adapted to isomalt by feeding them a mixture of 95% basal
diet and 5% isomalt, then increasing the isomalt portion by increments
of 5% every 5 days until it ultimately amounted to 30% of the diet.
After 30 days, 24 rats were divided into 3 groups. The control group
was fed a casein starch diet. In the other 2 groups this basal diet
was supplemented with either 30% sucrose or 30% isomalt. Food
consumption and faecal and urinary excretion were quantitatively
measured for a period of 10 days. The prostprandial course of serum
insulin activity was determined in all groups up to 7 hours after
feeding.
The apparent digestibility and metabolisability of the energy of
isomalt were 91.3% and 90.1%, respectively. These values were 7% and
11%, respectively, lower than those of sucrose. Faecal excretion of
nitrogen after feeding isomalt was twice that of the sucrose group
because of increased microbial activity. Isomalt and its hexitols
were excreted in the urine, which represents a loss of potential
metabolisable energy. Altogether, the increased losses of
metabolisable energy after feeding isomalt as compared with sucrose
amounted to 20-30% in this experiment. In contrast to the control and
sucrose groups, there was no prostprandial increase in the activity of
serum insulin; the authors concluded that this is due to reduced and
delayed hydrolysis and absorption of isomalt in the gastrointestinal
tract (Kirchgessner et al., 1983).
The 2 isomalt components, GPM and GPS, were assayed for glucose
bioavailability using ketotic rats. With conversion rates into glucose
of 6 and 20%, respectively, for free mannitol and sorbitol, 39% for
GPM, and 42% for GPS, the metabolic glucose pool of the rat does not
receive the full carbohydrate complement of these compounds. Under
these conditions, 36% of the GPM and 32% of the GPS provided
bioavailable glucose; 50% is the theoretical maximum.
Less-than-theoretical bioavailability of glucose from isomalt was
ascribed by the authors to microbial attack in the hind-gut. The
authors concluded that the data on rats were valid for other species
demonstrating carbohydrate fermentation in the caecum and/or colon.
Differences between GPM and GPS are caused by a differential delay of
glucose absorption in the small intestine, which is also observed with
sorbitol. These studies point toward the important role played by the
mammal-microbial symbiosis in the large bowel (Ziesenitz, 1983).
Groups of 12 ileum re-entrant fistulated pigs and 12 normal pigs
(Dutch Landrace × large white) were fed 80% basal ration plus a
combination of 10% isomalt and 10% sucrose, 20% isomalt, or 20%
sucrose. After exposure to isomalt for 5 and 8 days, no isomalt could
be detected in the faeces. Although no detectable quantities of
sucrose reached the terminal ileum, 67% of the intact isomalt, plus
mannitol and sorbitol, reached the terminal ileum in the group fed 20%
isomalt; 54% reached the terminal ileum in the group fed 10% isomalt
plus 10% sucrose. This means that 33% and 46% of the ingested amount
of isomalt, respectively, was hydrolysed and absorbed in the small
intestine.
In pigs fed 10%, and especially 20%, isomalt, the flow of the
chyme along the small intestine was considerably accelerated during
the first 3-4 hours after feeding, and the amount of chyme appearing
at the terminal ileum was greatly increased compared with the animals
fed 20% sucrose. This accelerated and increased flow of the chyme
along the small intestine was ascribed by the authors as most likely
due to the osmotic properties of the non-absorbed isomalt and its
constituents.
Faecal digestibility of proteins and "nitrogen-free extract" in
the 10%, and especially the 20%, isomalt diets was depressed compared
with the 20% sucrose diet. As a result, energy digestibility with the
isomalt diets was also depressed. The authors concluded that the
lowered faecal digestibility of the isomalt diets is most likely due
to the increased excretion of bacterial mass resulting from the more
intensive fermentation in the large intestine in the isomalt-fed
groups (van Weerden et al., 1984a).
Fistulated and normal pigs were fed 10% sucrose between meals, 5
or 10% isomalt between meals, or 10% isomalt with meals. The passage
and absorption rate of these substances were determined at the
terminal ileum (10 pigs per treatment) or over the whole distance of
the digestive tract (4 pigs per treatment). Ten percent sucrose was
completely digested and absorbed in the small intestine. In the 3
isomalt treatments, 61-64% of the ingested compound passed the
terminal ileum in the form of intact isomalt plus free sorbitol, free
mannitol, and free glucose. None of these sugars was excreted in the
faeces, indicating that isomalt and its constituents passing the
terminal ileum are completely broken down in the large intestine. No
influence of isomalt on the consistency of the faeces was observed. An
increased flow of ileum chyme occurred in the period of 1-4 hours
after administration of isomalt, which is probably related to the
osmotic activity of non-absorbed isomalt and its constituents.
Consequently, the ileal digestibility of the proteins of the basal
diet was slightly negatively affected. The faecal digestibility of
energy-containing compounds in the isomalt treatments was
significantly lower than in sucrose treatment. This can be explained
by the increased excretion of bacterial mass resulting from the more
intensive fermentation in the large intestine in the isomalt-fed
groups. The results of the determination of metabolisable energy of
the diets indicate that the metabolisable energy value of isomalt is
lower than that of sucrose (van Weerden et al., 1984b).
The in vivo metabolism of isomalt in the large intestine was
simulated in an in vitro fermentation study to investigate its
degradation using chyme from pigs as basic substrate additionally
inoculated with faeces. In the first week, the fermentation of isomalt
(3.65%) by non-adapted microflora was investigated. In the second
week, isomalt fermentation by adapted microflora taken from pigs fed a
basic diet supplemented with isomalt was studied. In the third week,
both flora were studied in fermentation experiments with a high
concentration of isomalt (7.30%).
Isomalt was degraded to lactic acid, volatile fatty acids, and
gases (CO2, CH4, and H2). The energy loss through these gases is of
minor importance compared with the energy content of isomalt itself.
Depending upon the concentration of isomalt (and possibly the type of
flora), different amounts of intermediates (volatile fatty acids and
lactic acid) were formed. These intermediates can be reabsorbed in the
large intestine. A concentration of isomalt in chyme of 3.65% (which
corresponds to 20% in the feed) did not lead to higher levels of
intermediates in comparison with controls with no isomalt, suggesting
that no extra energy take-up by the body occurs through these
intermediates. A considerable part of the energy content of isomalt
entering the large intestine probably leaves the body in the form of
biomass (Bol & Knol, 1982).
Toxicological studies
Special studies on carcinogenicity
Mice
The carcinogenicity of isomalt was examined in a 2-year oral
study in Swiss mice, by feeding the material at dietary levels of 0
(control), 2.5, 5.0, or 10% to groups of 50 male and 50 female mice.
An additional control group was fed 10% sucrose.
General condition, behaviour, and mortality rates were not
unfavourably affected by the test substance in any of the groups. All
surviving male mice were killed during week 94, because mortality
exceeded 80% in both control groups. The female mice, which showed
better survival, remained in the study until the scheduled termination
date in week 104. Mean body weights of females in the mid- and high-
dose groups were relatively low from day 112 onwards. Mean food intake
figures were comparable in all groups. There were no changes in
haematological findings that could be ascribed to the feeding of
isomalt. The absolute and relative weights of the caecum (filled and
empty) were increased in both sexes fed 10% isomalt. Gross and
microscopic examination did not reveal pathological changes that could
be ascribed to the feeding of the test substance. High mortality in
males was probably caused by infectious urogenital disease.
From the results of this study, the authors concluded that the
feeding of isomalt at dietary levels up to 10% to mice throughout the
major part of their lifetimes failed to show carcinogenic properties
or any other effects of obvious toxicological significance (Dreef-van
der Meulen et al., 1983).
Rats
Isomalt was examined in an oral long-term toxicity/
carcinogenicity study by feeding groups of 50 male and 50 female rats
diets containing isomalt at levels of 0 (control), 2.5, 5.0, or 10%
for a lifetime period (males, 128 weeks; females, 130 weeks). A diet
containing 10% sucrose was included in the study as an additional
control. The rats were derived from parents that had been fed the same
diets before mating and during the gestation and lactation periods
(in utero exposure). Weanling rats obtained from the second mating
cycle (F1b-rats) described in the "Special study of reproduction"
were used for the carcinogenicity study.
Mortality rates were not affected in any of the treated groups.
During the last half-year of the study, there was a tendency towards
lower mortality in the group fed 5% isomalt and also, though to a
lesser extent, in the group fed 10% isomalt, both in males and
females. The overall mortality at the end of the study was 68% for
males and 63% for females.
Body weights were relatively low in the males fed 10% isomalt
during the major part of the study. However, the differences with the
controls were generally less than 5%. In females fed 5 or 10% isomalt,
body weights were generally slightly lower than those of the controls.
The greatest differences were observed after 2 years of feeding, but
amounted to no more than 10%. Food intake and food efficiency figures
did not show any obvious differences among the various groups.
However, males fed 10% isomalt tended to consume more food and to have
lower food efficiencies than controls. Water intake figures were
generally slightly higher in treated groups than in controls, but
there was no clear dose-related response. Haematological findings did
not reveal any effects related to the feeding of isomalt or sucrose.
At a number of stages, animals fed isomalt excreted greater volumes of
more diluted urine than the controls. Urine analyses and microscopic
examination of the sediment did not reveal any treatment-related
effects. Several blood plasma parameters showed statistically-
significant changes in animals fed isomalt, but none of these changes
were considered to be of toxicological importance. The relative
weights of the caecum, filled or empty, were increased in rats of both
sexes fed 10% isomalt. Macroscopic examination at autopsy did not
reveal any abnormalities that could be ascribed to the feeding of
isomalt.
Non-neoplastic and hyperplastic histopathological changes
occurred in the kidneys of animals fed isomalt. These changes
consisted of decreased nephrocalcinosis in the intercortico-medullary
layer of females, increased nephrocalcinosis in the pelvis of males
and females, and increased pelvic urothelial hyperplasia in females.
No indications were found of carcinogenic properties of the test
substance.
The authors concluded that the feeding of isomalt at levels up to
10% in the diet of rats that had been exposed to the test substance
in utero and then continuously during their lifetimes did not induce
any effects of obvious toxicological importance (Sinkeldam & Dreef-van
der Meulen, 1983).
Special study on mutagenicity
Isomalt was non-mutagenic in the Ames test at concentrations up
to 12,500 µg/plate (Herbold, 1978).
Special study on reproduction
Rats
A multigeneration study was conducted in groups of 20 male or
20 female rats to examine the effects of isomalt on reproductive
performance. Rats were fed diets containing 0 (control), 2.5, 5.0, or
10.0% isomalt over 3 successive generations. One group of rats fed a
diet containing 10.0% sucrose served as an additional control group.
Two litters from each generation were reared. Organ-weight
analyses and histopathological examinations were made on selected
offspring of the final (F3b) generation. There were no outstanding
differences in body weight, food intake, or food efficiency among the
groups of parent animals (F0, F1b, and F2b). A tendency toward lower
body weights occurred in the group fed 10% isomalt, but only in males
of the F0 and F1 generations. This tendency was also noticeable in
the food efficiency figures. The fertility of females, number of pups
per litter, general condition, appearance, sex ratio at birth, birth
weight, growth rate, and mortality of the pups were not adversely
affected by the feeding of isomalt. The resorption quotient did not
indicate any embryotoxic effects of isomalt.
F3b rats fed 10% isomalt for 4 weeks after weaning showed caecal
enlargement, which was attributed to poor digestibility of the
isomalt. Gross and microscopic examinations did not reveal any
treatment-related pathological changes. A slight increase in the
relative weight of the kidneys in males fed 10% sucrose was regarded
as not being of toxicological significance.
The authors concluded that the feeding of isomalt at levels up to
10% in the diet to rats over 3 successive generations did not affect
fertility, reproduction, or health and survival of the progeny
(Sinkeldam & Dreef-van der Meulen, 1982).
Special studies on teratogenicity
Rats
Isomalt was fed to female Wistar rats from day 0 to day 21 of
pregnancy at dietary levels of 0 (control), 2.5, 5.0, or 10%. No
abnormalities in the condition or behaviour of the animals fed isomalt
were observed during the experiment. Body weights, food intake,
autopsy findings, organ weights, and litter data were comparable
between the control group and all groups fed isomalt. Visceral and
skeletal examination of the foetuses did not indicate any effects that
could be related to the feeding of isomalt.
The authors concluded that under the conditions of the study,
isomalt did not induce any embryotoxic or teratogenic effects in rat
foetuses (Koëter, 1982).
Isomalt was administered in various concentrations from days 0-20
of gestation to groups of 25 female rats of the BAY:FB30 line (derived
from Long-Evans). The feed mixture consisted of 90% Altromin basic
feed plus 0, 2.5, 5.0, or 10% isomalt (supplemented with corn starch
to a total of 100% in each case). Two other groups were established;
one received a 10% sucrose-feed mixture and the other received
Altromin basic feed at a level of 80% of the amount consumed by the
control group (restricted diet). The daily food consumption of those
rats fed 5% or 10% isomalt was reduced significantly; these animals
did not consume much more food than the animals that received the
restricted diet. The number of foetuses with retarded development was
elevated as a function of dosage in the Caesarean-section groups that
had received 5% or 10% isomalt. The foetal weight and the number of
resorptions of embryos were slightly elevated in the group receiving a
restricted amount of feed.
An adequate number of gravid animals were allowed to deliver
their young vaginally in the control group and in the groups receiving
10% sucrose or 10% isomalt. They were then allowed to raise their
young without any treatment. Some of the pups were raised to sexual
maturity, mated within the groups, and then examined for delayed
damage in fertility or reproductive performance.
Both sucrose and corn starch (in the control group) were
tolerated without any signs of damage to the mother animals or their
young. In the isomalt group, there was a reduction in food consumption
during gestation (treatment period) and a reduction in weight gain of
the mothers during this period and during the phase of nurturing the
young. Prenatal losses and perinatal and postnatal mortality were
elevated among the pups. The surviving pups exhibited normal
development, however, and no signs of delayed damage were evident in
the F1 mating.
The question of whether these harmful effects were induced
prenatally or postnatally was investigated in an experiment in which
nursing mothers were exchanged, so that the control mother animals
nurtured newborn pups from mother animals that had been fed 10%
isomalt during gestation, and vice versa. Mortality of the pups
treated with isomalt before birth remained elevated even when nurtured
by control rats, whereas the newborn of untreated mothers were
nurtured by the previously-treated mothers without any signs of
toxicity. Therefore, damage to the foetuses due to isomalt must have
occured prenatally.
The immediate great reduction in food consumption in those groups
treated with isomalt led the authors of the study to the assumption
that the mothers were impaired by the acute dosage of isomalt.
Therefore, forced adaptation was accomplished over a period of 14 days
by first offering the animals feed that contained 5% isomalt, and then
10% isomalt, as the only food source. At the end of this adaptation
period, weight gains and feed consumption of the animals in the
isomalt group were essentially the same as those in the control group.
These animals were then mated and treated further with 10% isomalt
until the 20th day of gestation.
In contrast to the earlier studies in which the mothers were not
adapted to the diet, postnatal mortality in the isomalt group was not
elevated. Weight gains and physiological development of the pups were
comparable to those of both the concurrent controls and historical
controls of this strain of rats.
The author concluded that the embryotoxic effects observed in
this strain of rats were not a primary effect of the test substance,
but instead were a secondary embryotoxic effect due to maternal
intolerance to the acute doses of isomalt at the beginning of
gestation. When this maternal intolerance was avoided by adaptation of
the animals to isomalt mixed with the feed before gestation, no
embryotoxic effects were observed (Schlüter, 1984).
Rabbits
Isomalt was fed to female New Zealand white rabbits from day 0 up
to day 29 of pregnancy at dietary levels of 0 (control), 2.5, 5.0, or
10%. No abnormalities in condition or behaviour of the rabbits were
observed during the experiment. Maternal performance was comparable in
all groups; fertility indices ranged from 65.7 in the control group to
75.0 in the 5.0% group and the gestation indices ranged from 88.5 in
the 2.5% group to 100 in the 5.0% group. Body weights, food intake,
autopsy findings, organ weights, and litter data did not reveal any
consistent or significant group differences. Visceral and skeletal
examination of foetuses did not indicate any effects that could be
related to the feeding of isomalt.
Under the conditions of the study, isomalt at concentrations of
2.5, 5.0, or 10% in the diet was non-toxic to pregnant New Zealand
White rabbits and did not induce any teratogenic or embryo/foetotoxic
effects in rabbits (Koëter, 1983).
Acute toxicity
LD50
Species Route (mg/kg b.w.) Reference
Rat i.v. > 2,500 Musch et al., 1973
i.p. > 2,500 Musch et al., 1973
Short-term studies
Rats
Groups of 15 male and 15 female rats received isomalt in the diet
at concentrations of 0, 3.3, 10, or 30% for 3 months; a similar group
received 30% sucrose in the diet. Appearance, behaviour, growth, and
mortality were unaffected in the 3.3% group. Rats receiving 10%
isomalt showed mild diarrhoea in the first 2 weeks, which ceased as
the study continued; rats given 30% isomalt had severe diarrhoea in
the first 2 weeks, which then diminished in intensity. Body-weight
gains were impaired in the top-dose group, most markedly in males.
Haematological parameters were unaffected by treatment after 5 and
12 weeks. After 5 weeks, male rats in the top-dose group displayed
elevated plasma bilirubin levels and lowered concentrations of urea
and glucose; females in this dose group had raised alkaline
phosphatase and glucose levels, while urea and protein concentrations
were lowered. After 12 weeks, male rats in the top-dose group and
females in all treatment groups had elevated plasma bilirubin
concentrations; in the females, bilirubin levels increased in a dose-
dependent way.
In both sexes, blood urea concentrations were significantly
depressed at the highest-dose level. Blood oxalate concentrations were
significantly elevated in males of all dose groups, but were within
the range considered normal; no treatment-related changes were
observed in blood cholesterol, uric acid, creatine, SGOT, or SGPT
levels. Urinalysis at 5 and 12 weeks revealed no differences between
control and treated rats. Autopsy of all animals did not reveal any
treatment-related gross pathology, and organ weights were normal for
the thyroid, thymus, heart, lungs, liver, spleen, adrenals, and testes
or ovaries (caecal weights were not recorded). Kidney weights were
lowered in the 30%-isomalt groups of both sexes, which may have
resulted from reduced nitrogen metabolism. Histopathological
examination was carried out on the heart, lungs, liver, spleen,
kidneys, pituitary, thyroid, adrenals, testes, epididymis, prostate,
seminal vesicle, ovaries, uterus, salivary glands, pancreas,
oesophagus, stomach, intestine, lymph nodes, thymus, bladder, brain,
eyes, aorta, trachea, skeletal muscle, bone (femur), and bone marrow
(sternum). No treatment-related effects were seen.
In this study, dietary concentrations of up to 10% isomalt were
tolerated without obvious organic damage. The authors claimed that, if
the transient diarrhoea is taken into account, 3.3% dietary isomalt
was well-tolerated. However, due to the elevated plasma bilirubin
concentrations seen in female rats at all treatment levels, it is
difficult to establish a no-effect level (Bomhard et al., 1978).
Female Sprague-Dawley rats received diets containing 10% isomalt
for 14 days without adverse effects (Siebert, 1972).
In other dietary studies, 10% isomalt caused transient diarrhoea
that disappeared after adaptation; the feeding of isomalt was
associated with caecal enlargement (Musch et al., 1973).
After caecetomy, diarrhoea persisted 4 to 5 times longer than in
intact rats (Grupp & Siebert, 1978).
Dogs
Groups of 4 male and 4 female beagle dogs, 40-51 weeks of age,
received isomalt at dietary concentrations of 0, 5, 10, or 20% for
13 weeks. No differences between control and test groups were observed
in general behaviour or appearance; food intake and body weights were
normal. Diarrhoea was observed in animals receiving 20% isomalt and,
occasionally, in the 10%-dose group; normal faeces were produced by
animals given 5% isomalt. Measurement of body temperatures, pulse
rates, and reflexes and ophthalmoscopic investigations after 4, 7, and
13 weeks of treatment showed no treatment-related changes;
haematological and clinical chemical parameters were normal at these
times. Plasma urea concentrations were lower in the treated animals,
sometimes significantly so, but still within the range considered
physiologically normal. Urinalysis did not show treatment-related
differences. At autopsy, no compound-dependent abnormalities were
observed and organ weights were unaffected (the gastrointestinal tract
components were not weighed). Histopathological examination did not
detect any tissue changes related to the test material. Concentrations
of intestinal tissue alpha-glucosidases (maltase, sucrase, and
glucoamylase) were unchanged by treatment.
The authors concluded that concentrations of up to 20% isomalt in
the diet did not produce any toxic injury. Allowing for the occasional
ill-formed faeces in the 10%-dose group, the no-effect level was
conservatively placed at 5% of the diet, equal to 1.67 g/kg b.w./day
for 13 weeks (Hoffmann et al., 1978).
Long-term studies
Rats
A 1-year feeding study with isomalt in rats, which was part of a
long-term toxicity/carcinogenicity study, was conducted. Isomalt was
fed to groups of 10 male or 10 female rats at levels of 0 (control),
2.5, 5.0, or 10% in the diet. An additional control group was fed
sucrose at a level of 10% in the diet. The rats were derived from
parents that had been fed the same diets prior to mating and during
the gestation and lactation periods (in utero exposure).
Observations were made of general appearance and growth, and food and
water intakes were measured. After 52 weeks, all rats were killed and
examined for gross pathology. Seven different organs were weighed.
Tissue samples of a wide range of organs were examined
microscopically.
Body weights of males fed isomalt or sucrose tended to be higher
than those of males of the control group during the experimental
period. This is probably the result of relatively low body weights of
the control animals at the initiation of the study. In females, body
weights of the various groups were similar. Food intake of males fed
isomalt or sucrose was generally slightly higher than that of the
corresponding controls. In females, food intake of the various groups
was similar. Food-efficiency figures did not show any obvious
differences among the groups. There were no consistent differences in
water intake between the test groups and the controls. Gross and
microscopic examination did not reveal pathological changes which
could be ascribed to the ingestion of the test substance. The only
treatment-related change consisted of an increase in the relative
weights of the filled and empty caeca in males fed 10% isomalt.
The authors concluded that isomalt, fed at levels up to 10% in
the diet to rats that had been exposed to the test substance in
utero and then continuously during a 1-year period, did not induce
any effects of obvious toxicological importance (Sinkeldam et al.,
1981).
Dogs
Isomalt was administered orally to groups of 8 Beagle dogs
(4 males and 4 females), at concentrations of 0, 2.5, 5.0, or 10%
during a 1-year chronic toxicity study. As controls, 1 group of
animals was given 10% maize starch in place of 10% isomalt and another
group was given 10% sucrose.
Treatment with isomalt did not affect appearance or behaviour,
nor did it have an effect on food or water intake; it did not affect
body-weight gains. Likewise, there were no differences in body
temperature or pulse rates and neurologic and ophthalmoscopic
examination results showed no differences between control and treated
animals.
The only consequence of treatment with isomalt was an increased
occurrence of pappy to liquid faeces at all dose levels; this effect
was most pronounced in the animals fed 10% isomalt.
No evidence of blood lesions, nor any influence on coagulation,
was observed in treated animals. Clinical chemical examination, gross
pathological and histopathological liver examination, and comparisons
of organ weights showed no indication of hepatic deficiency. There was
no indication of renal deficiency on the basis of clinical chemical
blood or urine examination, gross pathological or histopathological
examination of the kidneys, or comparisons of organ weights. Apart
from the increased occurrence of pappy to liquid faeces during
treatment with isomalt, which the authors concluded on the basis of
the results is not of toxicological relevance, concentrations of
isomalt up to 10% administered orally over a period of 12 months were
tolerated by the dogs without harm (Hoffman et al., 1981).
Observations in man
Six volunteers were each given 15 g 14C-isomalt orally.
Approximately 10% of the administered radioactivity was excreted in
the faeces of 5 individuals. One volunteer had abnormally rapid
gastrointestinal transit (due to beer drinking) and excreted 40% of
the radioactivity in faeces. Approximately 5% of the radioactivity was
excreted in the urine, principally in the first 24 hours. Serum levels
of radioactivity reached a maximum (the equivalent of 130 µg
isomalt/ml) within 1 hour. Small amounts of unhydrolysed isomalt were
found in the urine, indicating that a minor proportion of the dose was
absorbed unchanged (Patzschke et al., 1975b).
After oral doses of 100 g isomalt, an average of 0.1% of the dose
was excreted in the urine within 24 hours in 19 studies; after the
administration of 50 g isomalt, an average of 0.04% was voided in
urine within 2 hours in 37 studies (Siebert et al., 1975).
Four female and 2 male volunteers, aged 20-56, took 3 × 20 g
isomalt daily for 8 days in various foods. On average, less than 0.2%
was excreted in the urine as disaccharides and less than 0.02% as
hexitols. Maximum values were less than 1% and 0.1%, respectively.
Less than 0.5% GPS and GPM together were found in faeces on any of the
8 days, and the daily mean amount of hexitol was never more than
0.07%. Excretion levels in faeces did not change significantly
throughout the study (Siebert, 1977).
Three colostomy patients fitted with ileostomy bags were given
30 g isomalt in 250 ml herbal or fruit tea at breakfast after fasting
for 12 hours. An average of 58.9% of the dose was found in the
collection bag, indicating poor absorption of isomalt from the small
intestine (Kronenberg et al., 1979).
Healthy volunteers were given either 50 g (43 subjects) or 100 g
(7 subjects) isomalt on fasting stomachs. There were no significant
increases in blood glucose levels within 2 hours after treatment
(Siebert et al., 1975).
Six healthy volunteers with mean body weights of 80.5 kg were
treated in a cross-over trial with sucrose, isomalt, or a placebo at a
dose level of 1 g/kg b.w. The test material was administered, after an
overnight fast, in 400 ml rose-hip tea, and a normal breakfast was
eaten 30 minutes later. Blood glucose and insulin concentrations were
determined 0, 0.5, 1, 2, 4, and 6 hours after treatment. Sucrose
produced the expected increase in blood glucose and insulin levels
within 30 minutes, returning to fasting levels within the observation
period. In contrast, after treatment with isomalt, blood glucose
levels were similar to the levels after treatment with the placebo
throughout the study. Serum insulin levels were also similar up to
4 hours after treatment with either the placebo or isomalt, but with
isomalt serum insulin levels increased to twice the fasting levels
between 4 and 6 hours after treatment (Keup & Pütter, 1974).
Tests on 8 healthy female volunteers given 50 g isomalt in 400 ml
water after fasting overnight revealed practically no change in blood
glucose levels in the subsequent 3 hours (Mehnert et al., 1977).
The effects of 30 g isomalt and 30 g glucose were compared in a
73-year-old male diabetic using the glucose tolerance test. Glucose
produced a maximal increase in blood glucose concentration of
77 mg/100 ml after 2 hours compared with an increase of 14 mg/ml after
the ingestion of isomalt (Jahnke & Gierlich, 1978).
In similar studies, 24 adult onset diabetics were given 50 g
isomalt or glucose in 250 ml rose-hip tea using a randomized, cross-
over protocol. In groups receiving glucose, blood glucose
concentrations increased by 123-141 mg/100 ml in 90 minutes and
maximum insulin levels increased by 22.6 to 25.1 mE/1; in contrast,
after dosing with isomalt, the increase in blood glucose was
10.5-12.7 mg/100 ml and insulin levels were similar to fasting
concentrations (Jahnke & Gierlich, 1979).
A randomized, cross-over study was performed on 12 tablet-
dependent diabetics given oral doses of 50 g isomalt or 50 g fructose
in 400 ml water. The results confirmed that isomalt caused only a
small increase in blood glucose levels and had little effect on
insulin levels (Mehnert et al., 1979).
Ten adult volunteers were given isomalt at doses of 250, 350, or
500 mg/kg b.w. at intervals of 2 days between doses. The dose of
250 mg/kg b.w. was well-tolerated by all the subjects; 350 mg/kg b.w.
produced flatulence in 8 of 10 volunteers, 2 of whom had diarrhoea. At
500 mg/kg b.w., only 2 subjects did not have diarrhoea. The maximum
tolerated dose for a single administration in aqueous solution was
250 mg/kg b.w. (Pütter & Spengler, 1975).
Four groups of 10 children aged 4 to 12 years were given doses of
15, 30, 45, or 60 g isomalt, spread over one day, in the form of
sweets. One child at the lowest dose exhibited diarrhoea, but it was
not clear that this was connected with treatment since children
consuming doses of 30 g and 45 g tolerated isomalt without side-
effects. Four children in the highest-dose group did not consume the
full regimen. Of the remaining 6 subjects, 4 developed diarrhoea
(Spengler, 1978).
Administration of daily doses of 3 × 20 g isomalt to 6 subjects
for 8 days produced flatulence in the first 4 days, but this symptom
subsequently subsided, indicating an adaptive improvement in tolerance
(Siebert, 1977).
In a single-dose comparative study, 36 children aged 4 to 14
years were tested for their tolerance to isomalt or sorbitol. The test
materials were administered at oral doses of 10, 20, or 40 g with
breakfast. Diarrhoea was observed in 25% of the subjects receiving
40 g of either isomalt or sorbitol, but not at lower doses. No
differences in tolerance were observed between the 2 compounds
(Spengler, 1979a).
Multiple-dose comparisons were made between isomalt and sorbitol
over a period of 14 days during which 2 groups of 10 adult volunteers
received daily doses of 50 g of either isomalt or sorbitol in 3 equal
portions in the morning, at mid-day, and in the evening. In the
isomalt group, mild diarrhoea was reported in 1 case on the sixth day;
in contrast, sorbitol produced mild diarrhoea in 7 cases, and on
several successive days. In this respect, isomalt was tolerated
significantly better than sorbitol, although the degree of flatulence
reported was similar in both groups. The symptoms diminished during
treatment (Spengler & Schmitz, 1979).
Two subjects received daily doses of 50 g isomalt orally for 14
days. Faeces were examined microbiologically twice weekly over a
period of 5 weeks (2 weeks prior to dosing, 2 weeks during dosing, and
1 week following). Stools were of normal consistency throughout, and
isomalt had no significant effect on faecal pH or microflora. Both
volunteers experienced flatulence in the first week of isomalt
treatment, which diminished or disappeared during the second week
(Linzenmeier, 1978).
Eight metabolically-healthy women each received 1 50 g oral dose
of isomalt, while 24 type II diabetics (2 groups of 12 each) received
either 50 g isomalt and 50 g fructose, or 50 g isomalt and 50 g
sucrose, as part of 2 controlled cross-over studies. The levels of
blood glucose, serum insulin, free fatty acids, lactate, and pyruvate
did not change in the next 3 hours in the healthy volunteers. In the
other 2 groups there were no increases in blood sugar or serum insulin
levels after consuming isomalt, in contrast with observations after
sucrose or fructose administration. Gastrointestinal symptoms
(meteorism, flatulence, and mild diarrhoea) occurred in 2-4 persons in
each of the 3 groups (Bachmann et al., 1984).
In a randomized cross-over study, the effects of oral loading
with 50 g isomalt on blood glucose, urinary sugar, and serum insulin
levels were compared with oral administration of 50 g glucose in 24
diabetics of the "maturity-onset" type. Isomalt, in contrast with
glucose, did not cause any changes in blood sugar levels nor an
increase in serum insulin levels. Glycosuria was reduced significantly
after isomalt ingestion compared with after glucose administration.
Diarrhoea and flatulence were reported more frequently after isomalt
ingestion (45.8%) than after the ingestion of glucose (12.5%) under
the experimental conditions (Drost et al., 1980).
Isomalt was compared to sucrose in a prospective double-blind
controlled cross-over study. The acute effects of the oral ingestion
of 30 g loads of isomalt or sucrose on plasma glucose, insulin, free
fatty acids, lactic acid, and carbohydrate and lipid oxidation were
studied over a period of 6 hours by means of continuous indirect
calorimetry in 10 healthy normal-weight subjects (21-30 years). Unlike
sucrose, the ingestion of which was followed by significant changes in
plasma glucose, insulin, and lactic acid during the first 60 minutes
of the test, no significant changes in these parameters were observed
following the administration of isomalt. The increase in carbohydrate
oxidation occuring between 30 and 150 minutes was significantly lower
(P < 0.01) following isomalt ingestion than after the ingestion of
sucrose. Conversely, the decrease in lipid oxidation was significantly
less (P < 0.01) after isomalt ingestion than after sucrose ingestion.
In contrast to other sugar substitutes, no increase in plasma lactic
acid was observed after isomalt administration (Thiebaud et al.,
1984).
In a randomized cross-over study, 24 type II diabetics were first
given 50 g isomalt and later 50 g glucose or vice versa in the
morning before breakfast. After the administration of glucose there
were definite increases in blood glucose, serum insulin, and C-peptide
concentrations. After isomalt ingestion, the rise in blood glucose,
serum insulin, and C-peptide concentrations were significantly less.
Gastrointestinal effects such as diarrhoea and flatulence were noted
only after a single high dose of isomalt. The authors concluded that
isomalt appears to be suitable as a sugar substitute in a diabetic
diet, since in comparison with glucose there were no significant
changes in blood sugar levels and additional insulin was not released
(Petzoldt et al., 1982).
In a controlled single-blind comparison study, 2 groups of 13 or
14 healthy, male adults received 24 g isomalt or sucrose per day for a
week. The incidence of subjective symptoms reported by the test
subjects after the ingestion of isomalt or sucrose, respectively,
were: diarrhoea, 15% versus 21%; flatulence, 38% versus 36%; and
stomach-ache, 31% versus 21%. All the test subjects in the isomalt
group were free of symptoms on day 8 (Spengler & Schmitz, 1983).
A controlled double-blind cross-over study was conducted to
compare tolerance to isomalt with tolerance to sorbitol after single
oral doses of 3 different amounts (10, 20, or 40 g) in 36
metabolically-healthy children between the ages of 6 and 14. Single
doses of 20 g isomalt or sorbitol were tolerated without diarrhoea,
but about 10% of the children reacted with mild diarrhoea after
receiving 40 g doses. Two cases of flatulence were observed after the
ingestion of 10 g of either isomalt or sorbitol. No differences
between the 2 substances were found (Spengler, 1979b).
In a 6-week controlled, randomized, cross-over study, 60 insulin-
dependent children received their regular diet or their regular diet
plus isomalt (20 g). The median age was 13 years. Twenty-six cases
were available for evaluation from each half of the median at the end
of the study. Daily doses of 20 g isomalt did not have any influence
on serum insulin levels, the frequency of hypoglycaemia, or the
incidence of glucosuria in type I diabetic children in either age
group. Consumption was accompanied, however, by a mild increase in
flatulence and soft or runny stools (Dorchy & Ernould, 1983).
Twenty-four grams isomalt were administered daily for 3 months to
12 type II diabetics managed by diet alone. Various parameters in
these patients were compared with those of a control group of 12
diabetic patients managed by diet alone who were not given isomalt.
The treatment with isomalt produced no differences in blood sugar
(fasting or postprandial), haemoglobin levels, or serum levels of
cholesterol, triglycerides, or high-density lipids compared with the
control group. The results of hepatic and renal function tests were
within normal limits before and at the end of the study in both groups
(Pometta & Trabichet, 1983).
In a double-blind cross-over study, 200 healthy adult volunteers
of both sexes received 50 g chocolate containing either 20 g isomalt
or 20 g sucrose at 8 o'clock in the morning after a standard breakfast
at intervals of 1 week. After isomalt ingestion, 16 of the volunteers
(8%) reacted with diarrhoea, whereas none experienced diarrhoea after
sucrose ingestion. The incidence of diarrhoea was 10.8% in female
volunteers versus only 4.5% in male volunteers. The subjects had been
informed of the possible gastrointestinal symptoms in advance, so it
is possible that the expectations of the female volunteers and also
their subjective evaluation of the resulting symptoms were different
than those of the male volunteers. A higher frequency of defecation
and increased flatulence were reported after isomalt ingestion
compared with the ingestion of sucrose (Spengler et al., 1983).
During a double-blind test, 12 volunteers ingested sorbitol, and
12 others isomalt, in 10, 20, or 40 g doses administered in 1-2 week
intervals. The internal neurological and cardiovascular examinations,
as well as haematology and blood chemistry analyses, revealed no
modifications in initial data or values which could be related to the
intake of either of the 2 sugar substitutes. The intestinal symptoms
(meteorism, flatulence, and diarrhoea) increased as the administered
dose-strength increased. After 10 g of either substance, light
abdominal pains were registered; after 20 g, these symptoms became
stronger, and flatulence and diarrhoea occurred; the 10 patients
having indicated no symptoms were equally divided between the 2 test
groups. From a clinical viewpoint, intestinal symptoms were
significantly higher in those volunteers given 40 g isomalt or
sorbitol, which represents the normal consumption level of a sugar
substitute, than in the other groups. The differences in response to
isomalt and sorbitol were not significant (Spengler et al., 1979).
Isomalt, placebo, sorbitol, or sucrose (20 g dissolved in 200 ml
water in the case of the placebo or 2 tablets of Natreen(R) dissolved
in the same amount of water) was administered to 24 type I diabetics
at 6 a.m., 10 a.m., 2 p.m., and 6 p.m. Each test substance was
administered 6 times at each of these 4 periods. Average and maximum
serum insulin levels and average and maximum blood sugar levels were
significantly higher after sucrose ingestion than after ingestion of
the other test substances. There were no significant differences
between sorbitol and isomalt. Side effects reported after isomalt
ingestion included vomiting in one patient, but diarrhoea was not
reported with any of the test substances (Irsigler et al., 1984).
Comments
Hydrolysis of isomalt yields glucose (50%), sorbitol (25%), and
mannitol (25%). Hydrolysis by intestinal disaccharidases in the small
intestine is incomplete. Further metabolism by the microbial flora of
the large intestine results in complete disappearance of the sweetener
from the faeces. After the administration of 14C-isomalt, excretion
of radiactivity in expired air ranged from 33 to 62%, and in the
faeces from 18 to 54% over a period of 48 hours, depending upon the
dose; approximately 5% of the administered radioactivity appeared in
the urine.
Isomalt was non-mutagenic in the Ames test.
A multigeneration reproduction study conducted in rats at levels
up to 10% in the diet did not affect fertility or reproduction, nor
did it affect the health or survival of the progeny.
It is unlikely that embryotoxic effects observed in strain FB30
rats were due to isomalt; these effects were probably the result of
maternal impairment caused by the elevated acute doses of isomalt at
the beginning of gestation. These effects were avoided by adaptation
of the animal to isomalt when it was mixed with the feed before
gestation. No embryotoxic or teratogenic effects were observed in
Wistar rats or in New Zealand White rabbits fed at the same dietary
levels as the strain FB30 rats.
The feeding of isomalt at levels up to 10% in the diet of rats
exposed in utero and then continuously during 1 year did not induce
any toxic effects. Concentrations of isomalt up to 10% administered
orally over a period of 12 months were tolerated by dogs without harm,
apart from the increased occurrence of liquid faeces.
Carcinogenicity was not demonstrated in rats that had been
exposed to isomalt at levels up to 10% in the diet in utero and then
continuously during their lifetimes. No evidence of carcinogenic
properties of isomalt were observed after feeding mice at dietary
levels up to 10% throughout the major part of their lifetimes.
Lifetime feeding studies of high doses of isomalt resulted in
caecal enlargement in mice and rats and renal pelvic nephrocalcinosis
in rats, effects common to other polyols.
Laxative effects in man were noted at 20-30 g/day.
EVALUATION
Estimate of acceptable daily intake for man
ADI "not specified". The fact that high doses of isomalt 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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feeding study with Palatinit(R) in rats. Unpublished report No. V
81.416/212021 from Centraal Instituut voor Voedingsonderzoek
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Spengler, M. (1978). Palatinit(R), tolerance test carried out at the
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report submitted to WHO by Bayer A.G.
Spengler, M. (1979a). Palatinit(R) tolerance study (sorbitol control)
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Spengler, M. & Schmitz, H. (1979). Comparison of Palatinit(R)
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Spengler, M. & Schmitz, H. (1983). Comparison of the tolerance
of healthy male adults towards Palatinit(R) (generic name:
isomalt) and sucrose after oral administration for 8 days.
Unpublished pharmaceutical report No. 11930 from Bayer A.G.,
Wuppertal, F.R.G. Submitted to WHO by Bayer A.G.
Spengler, M., Sommer, J., & Schmitz, H. (1979). Comparison between
tolerance to oral Palatinit(R) and sorbitol taken once in
increasing doses by healthy adults. Unpublished pharmaceutical
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Spengler, M., Schmitz, H., & Sommer, J. (1983). Comparison of the
tolerance of healthy adults towards Palatinit(R) and sucrose
after a single oral dosage. Unpublished pharmaceutical report No.
11892 from Bayer A.G., Wuppertal, F.R.G. Submitted to WHO by
Bayer A.G.
Thiebaud, D., Jacot, E., Schmitz, H., Spengler, M., & Felber, J.P.
(1984). Comparative study of isomalt of sucrose by means of
continuous indirect calorimetry. Metabolism, 33, 808-813.
van Weerden, E.J., Huisman, J., & van Leeuwen, P. (1984a). The
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pig. Unpublished report No. 528 from Institut voor Landbouwkundig
Onderzoek van Biochemische Producten (ILOB), Wageningen, The
Netherlands. Submitted to WHO by Bayer A.G.
van Weerden, E.J., Huisman, J., & van Leeuwen, P. (1984b).
Further studies on the digestive process of Palatinit(R) in the
pig. Unpublished report No. 530 from Institut voor Landbouwkundig
Onderzoek van Biochemische Producten (ILOB), Wageningen, The
Netherlands. Submitted to WHO by Bayer A.G.
Ziesenitz, S.C. (1983). Bioavailability of Glucose from Palatinit(R).
Z. Ernährungswiss., 22, 185-194.
See Also:
Toxicological Abbreviations
ISOMALT (JECFA Evaluation)