ISOMALTITOL
Explanation
The material evaluated is an equimolecular mixture of
alpha-D-glucopyranosido-1,6-sorbitol (GPS) and alpha-D-
glucopyranosido-1,6-mannitol (GPM). The mixture is also known as
Palatinit and Isomalt B.P. The sweetness of isomaltitol is
approximately 0.5 that of sucrose.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Rat
Isomaltitol-14C was administered orally to rats in doses of 250,
1000, and 2500 mg/kg. Absorption of activity was dose-dependent
varying from 80% (250 mg/kg) to 45% (2500 mg/kg) (Patzschke, et al.,
1975a). Excretion of activity in expired air ranged from 62%
(250 mg/kg) to 33% (2500 mg/kg) and in faeces from 18% to 54% over a
period of 48 hours; approximately 5% of the administered activity
appeared in urine. It was pointed out in this study that the 14CO2
in expired air could have originated in two ways: the fraction of
isomaltitol hydrolysed in the gut and absorbed as glucose, sorbitol
and mannitol undergoes carbohydrate metabolism in the tissues while
the fraction remaining unhydrolysed undergoes microbial fermentation
in the caecum liberating 14CO2. Consequently, 14CO2 excretion could
not be used as a direct indication of energy utilization.
Grupp & Siebert (1978) investigated the fate of isomaltitol in
the gastrointestinal tract of female rats which had been adapted to
the compounds by increasing the dietary concentration from 10% to
34.5% over a period of three to four weeks. After administration of
1.7 g isomaltitol in 5 g feed, the contents of stomach, small
intestine, caecum and large intestine were examined at intervals up to
six hours. From the content of GPS, GPM, sorbitol, mannitol and
sucrose found in these organs it was concluded that GPS and GPM were
only partially hydrolysed by the carbohydrases in the small intestine
and a substantial proportion of these compounds reached the caecum
where further hydrolysis of the 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.
Musch et al. (1973) concluded that unhydrolysed isomaltitol was
absorbed to a small extent in rats given large doses orally since
small quantities were detectable in kidney and urine.
When isomaltitol was fed to rats for several weeks it was
observed that faecal excretion declined steadily while the caecum
enlarged and it was concluded that this resulted from adaptation and
metabolism by the gut microflora.
Similarly, during a 17-day feeding period in which six female
rats received 3.5 g isomaltitol 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 carried out in adult female rats
(250 g bw) infused with 1.8 g isomaltitol, GPS or GPM over a period of
three hours (Grupp & Siebert, 1978). 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
isomaltitol per day orally. Under infusion of isomaltitol or GPS, free
sorbitol was never detectable in blood or urine, and blood glucose
concentrations were unchanged, demonstrating the metabolic inertness
of the disaccharide alcohols. From the infusion and excretion rates
and the plasma concentrations observed, it was concluded that GPS
distributed in extracellular water but did not reach the intracellular
compartment.
Hydrolysis by intestinal glycosidases
Rat intestinal maltase was shown to be active against
isomaltitol, GPS and GPM but the rate of hydrolysis was slow (Grupp &
Siebert, 1978; Musch et al., 1975). The ratio of the rates of
hydrolysis of sucrose, isomaltulose and isomaltitol by rat intestinal
alpha-glucosidases were 100:30:12. Similarly sucrose was hydrolysed
about 20 times faster than GPS or GPM by disaccharidases from the
small intestine of the pig (Gau & Muller, 1976), and the relative
rates of hydrolysis of maltose, sucrose, isomaltulose and isomaltitol
by human intestinal alpha-glucosidases were 100:25:11:2 (Grupp &
Siebert, 1978).
Energy utilization
Using isocaloric diets, a 30-day maintenance study was carried
out on rats of 146 g bw 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 isomaltitol 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).
TOXICOLOGICAL STUDIES
Special studies on cytotoxicity
Isomaltitol was not cytotoxic to cultured mouse fibroblasts when
incorporated in the culture media at concentrations of 200 mM. glucose
consumption was unimpaired by a 30-fold molar excess of isomaltitol in
the medium in comparison with glucose (Nittinger et al., 1974).
Special studies on mutagenicity
Isomaltitol was non-mutagenic in the Ames' test at concentrations
up to 12 500 µg/plate (Herbold, 1978).
Special studies on tolerance
Rat
Four groups of eight rats received doses of 1.0 or 2.5 g
isomaltitol/kg i.v. or i.p.; the doses were well tolerated and no
abnormalities were seen in general behaviour, food intake or body
weight during a 10-day observation period.
Female Sprague-Dawley rats received diets containing 10%
isomaltitol for 14 days without adverse effects (Siebert, 1972). In
other dietary studies, 10% isomaltitol caused a transient diarrhoea
which disappeared after adaptation and associated caecal enlargement
(Musch et al., 1973). After caecectomy, the diarrhoea persisted four
to five times longer than in intact rats (Grupp & Siebert, 1978).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Rat i.v. >2 600 mg/kg Musch et al., 1973
i.p. >2 500 mg/kg Musch et al., 1973
Short-term studies
Rat
Groups of 15 male and 15 female rats received isomaltitol in the
diet at concentrations of 0, 3.3, 10, and 30% for three months; a
similar group received 30% sucrose in the diet (Bomhard et al., 1978).
The appearance, behaviour, growth and mortality were unaffected in the
3.3% group. Rats receiving 10% isomaltitol showed a mild diarrhoea in
the first two weeks which ceased as the study continued; rats given
30% isomaltitol had severe diarrhoea in the first two weeks which then
diminished in intensity. Body weight gain was impaired in the top dose
group, most markedly in males. Haematological parameters were
unaffected by treatment after five and 12 weeks. After five 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 of 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, GOT or GPT levels. Urinalysis
at five 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 thyroid,
thymus, heart, lungs, liver, spleen, adrenals, and testes or ovaries
(Note: caecal weights were not recorded). Kidney weights were lowered
in the 30% isomaltitol groups of both sexes which may have resulted
from reduced N-metabolism. Histopathological examination was carried
out on 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 marrow (sternum). No treatment-related effects were seen.
In this study, dietary concentrations of up to 10% isomaltitol
were tolerated without obvious organic damage and, if the transient
diarrhoea was taken into account, it was claimed that 3.3% dietary
isomaltitol 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-untoward-effect level.
Dog
Groups of four male and four female beagle dogs, 40-51 weeks of
age, received isomaltitol at dietary concentrations of 0, 5, 10 or 20%
for 13 weeks. No differences between control and test groups were
observed in general behaviour and appearance; food intake and body
weights were normal. Diarrhoea was observed in animals receiving 20%
isomaltitol and, occasionally, in the 10% dose group; normal faeces
were produced by animals given 5% isomaltitol. Measurement of body
temperature, pulse rate, reflexes and ophthalmoscopic investigations
after four, seven and 13 weeks of treatment showed no treatment-
dependent changes; haematological and clinical chemical parameters
were normal at these times. The 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 (Note:
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.
Concentrations of up to 20% isomaltitol in the diet did not show
any toxic injury. Allowing for the occasional ill-formed faeces in the
10% dose group, the no-untoward-effect level is conservatively placed
at 5% of the diet, equal to 1.67 g/kg per day for 13 weeks (Hoffmann
et al., 1978).
Long-term studies
No data available but lifespan studies in mice and rats are in
progress. Chronic toxicity experiments are proceeding in the dog. A
multigeneration study in the rat has also been commenced.
OBSERVATIONS IN MAN
Absorption and excretion
Six volunteers were each given 15 g 14C-isomaltitol orally. Only
about 10% of the administered radioactivity was excreted in the
faeces of five individuals. One volunteer had abnormally rapid
gastrointestinal transit (due to beer drinking) and excreted 40% of
the activity in faeces (Patzschke et al., 1975b). Approximately 5% of
the activity was excreted in the urine, principally in the first 24
hours. Serum levels of activity reached a maximum of the equivalent of
130 µg isomaltitol/ml within one hour. Small amounts of unhydrolysed
isomaltitol were found in the urine indicating that a minor proportion
of the dose was absorbed unchanged.
After oral doses of 100 g isomaltitol, an average of 0.1% of the
dose was excreted in the 24-hour urine in 19 studies; after 50 g an
average of 0.04% was voided in 2-hour urine in 37 studies (Siebert et
al., 1975).
Four female and two male volunteers, aged 20-56, took 3 × 20 g
isomaltitol daily for eight days in various foods. On average less
than 0.2% was excreted in the urine as disaccharide 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 eight 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 colectomized patients fitted with an ileostomy bag were
given 30 isomaltitol in 250 ml herbal/fruit tea at breakfast following
a 12-hour fast. An average of 58.9% of the dose was found in the
collecting bag indicating poor absorption of isomaltitol from the
small intestine (Kronenberg et al., 1979).
Action on blood sugar and insulin
Healthy volunteers were given 50 g (43 subjects) or 100 g (seven
subjects) isomaltitol on a fasting stomach. There was no significant
increase in blood glucose levels within two hours (Siebert et al.,
1975).
Six healthy volunteers with a mean weight of 80.5 kg were treated
in a cross-over trial with sucrose, isomaltitol or placebo at a dose
level of 1 g/kg bw. 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 dosing. Sucrose produced
the expected increase in blood glucose and insulin within 30 minutes,
returning to fasting levels within the observation period. In
contrast, after dosing with isomaltitol, blood glucose levels were
similar to the placebo study throughout. The serum insulin levels were
also similar up to four hours after dosing with the placebo or
isomaltitol but after isomaltitol the serum insulin increased between
four and six hours to double the fasting levels (Keup & Putter, 1974).
Tests on eight healthy female volunteers given 50 g isomaltitol in
400 ml water after overnight fast revealed practically no change in
blood glucose levels in the subsequent three hours (Mehnert et al.,
1977).
The effects of 30 g isomaltitol 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 two hours compared with an increase of 14 mg/ml produced
by isomaltitol (Jahnke & Gierlich, 1978). In similar studies, 24 adult
onset diabetics were given 50 g isomaltitol 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 isomaltitol, 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 isomaltitol or 50 g fructose in
400 ml water. The results confirmed that isomaltitol caused only a
small increase in blood glucose and had little effect on insulin
levels (Mehnert et al., 1979).
Tests on energy utilization
Measurements on human volunteers in a respiratory chamber
indicated that isomaltitol produced only about 35% of the energy
utilization of sucrose, i.e. 65% was not utilized as energy (Grupp &
Siebert, 1978).
Tolerance tests
Ten adult volunteers were given doses of isomaltitol of 250, 500
and 350 mg/kg bw at intervals of two days between doses. The dose of
250 mg/kg bw was well tolerated by all the subjects; 350 mg/kg
produced flatulence in 8/10 volunteers, two of whom had diarrhoea.
After 500 mg/kg only two subjects did not have diarrhoea. The maximum
tolerated dose for a single administration in aqueous solution was
250 mg/kg bw (Putter & Spengler, 1975).
Four groups of 10 children aged between four and 12 were given
doses of 15, 30, 45 or 60 g isomaltitol, spread over one day, in the
form of sweets. One child in the lowest dose group exhibited diarrhoea
but it was not clear that this was connected with dosage since doses
of 30 g and 45 g were tolerated without side-effects. Four children in
the highest dose group did not consume the full dose; of the remaining
six subjects, four developed diarrhoea (Spengler, 1978).
Administration of daily doses of 3 × 20 g isomaltitol to six
subjects for eight days produced flatulence in the first four days but
the symptom subsequently subsided, indicating an adaptive improvement
in tolerance (Siebert, 1973).
In a single-dose comparative study of isomaltitol and sorbitol
tolerance in 36 children aged 4-14 years, the test materials were
administered at single oral dosages of 10, 20 or 40 g with breakfast.
Diarrhoea was observed in 25% of the subjects receiving 40 g of either
isomaltitol or sorbitol but not at lower doses. No differences in
tolerance were observed between the two compounds (Spengler, 1979).
Multiple-dose comparisons were made between isomaltitol and
sorbitol over a period of 14 days during which two groups of 10 adult
volunteers received daily doses of 50 g of either isomaltitol or
sorbitol in three equal portions, morning, midday and evening. In the
isomaltitol group, mild diarrhoea was reported in one case on the
sixth day; in contrast, sorbitol produced mild diarrhoea in seven
cases, and on several successive days. In this respect, isomaltitol
was significantly better tolerated than sorbitol although the degree
of flatulence reported was similar in both groups. The symptoms
diminished during the treatment (Spengler & Schmitz, 1979).
Effects on faecal mircoflora
Two subjects received daily doses of 50 g isomaltitol orally
for 14 days. Faeces were examined microbiologically twice weekly over
a period of five weeks (two weeks prior to dosing, two weeks during
dosing and one week follow-up). Stools were or normal consistency
throughout and isomaltitol had no significant effect on faecal pH or
microflora. Both volunteers experienced flatulence in the first week
of isomaltitol treatment which diminished or disappeared on the second
week (Linzenmeier, 1978).
Comments
There are no long-term oral toxicity or reproduction studies with
this material, but these are in progress in mice, rats and dogs; a
multigeneration study in rats has also been commenced.
Hydrolysis of isomaltitol yields glucose (50%), sorbitol (25%)
and mannitol (25%) but hydrolysis by intestinal disaccharidases is
incomplete. Sorbitol was evaluated by the Joint FAO/WHO Expert
Committee on Food Additives in 1973 and 1978 and allocated a temporary
ADI not specified, pending adequate long-term studies (WHO, 1974;
1978); mannitol is metabolically inert and is used in kidney function
tests as a measure of glomerular filtration rate.
EVALUATION
Level causing no toxicological effect
Man: The evaluation is based on the lowest dose which was
observed to cause laxation in man, i.e. 250 mg/kg bw (Putter &
Spengler, 1975) to which a safety factor of 0.1 has been applied.
Estimate of temporary acceptable daily intake for man
0-25 mg/kg bw.
FURTHER WORK OR INFORMATION
Required by 1985.
Results of long-term feeding studies in mice and rats;
multigeneration studies in rats.
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