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    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 (Koėter, 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 (Koėter, 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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         Wuppertal, F.R.G. Submitted to WHO by Bayer A.G.

    Patzschke, K., Wegner, L., & Horster, F.A. (1975b). Bay i 3930-14C:
         Reabsorption und elimination - Experiments conducted on humans.
         Unpublished pharmaceutical report No. 5635 from Bayer A.G.,
         Wuppertal, F.R.G. Submitted to WHO by Bayer A.G.

    Petzoldt, R., Lauer, P., Spengler, M., & Schöffling, K. (1982).
         Palatinit(R) in type II diabetics. Dtsch. Med. Wschr., 107,
         1910-1913.

    Pometta, D. & Trabichet, C. (1983). Report on utilization of
         Palatinit(R) in type II diabetics treated by diet alone.
         Unpublished study from Cantonal Hospital of the University of
         Geneva. Submitted to WHO by Bayer A.G.

    Pütter, J. & Spengler, M. (1975). Tolerance to a single dose of
         Palatinit(R) (Bay i 3930). Unpublished pharmaceutical report 
         No. 5475 from Bayer A.G., Wuppertal, F.R.G. Submitted to WHO by 
         Bayer A.G.

    Schlüter, G. (1984). Palatinit(R): Embryotoxicity studies on rats.
         Unpublished pharmaceutical report No. 12,451 from Bayer A.G.,
         Wuppertal, F.R.G. Submitted to WHO by Bayer A.G.

    Siebert, G. (1972). Personal communication submitted to WHO
         by Suddentsche Zucher A.G.

    Siebert, G. (1977). Study on the reabsorption of Palatinit(R) in 6
         human volunteers. Unpublished pharmaceutical report from Bayer
         A.G., Wuppertal, F.R.G. Submitted to WHO by Bayer A.G.

    Siebert, G. & Grupp, U. (1978). alpha-D-Glucopyranosido-1,6-sorbitol
         and alpha-D-Glucopyranosido-1,6-mannitol (Palatinit(R)). Health
         and Sugar Substitutes. Proc. ERGOB Conf. Geneva, 109-113,
         Karger, Basle.

    Siebert, G., Grupp, U., & Heinkel, K. (1975). Studies on
         isomaltitol. Nutr. Metabol., 18 (Suppl.1), 191-196.

    Sinkeldam, E.J. (1983). Effects of Palatinit(R) ingestion on the gut
         flora and the gut contents of rats. Unpublished report No. V
         83.007/212651 from Centraal Instituut voor Voedingsonderzoek
         (CIVO/TNO), Zeist, The Netherlands. Submitted to WHO by Bayer
         A.G.

    Sinkeldam, E.J. & Dreef-van der Meulen, H.C. (1982). Multigeneration
         study with Palatinit(R) in rats. Unpublished report No. V
         82.244/292310 from Centraal Instituut voor Voedingsonderzoek
         (CIVO/TNO), Zeist, The Netherlands. Submitted to WHO by Bayer
         A.G.

    Sinkeldam, E.J. & Dreef-van der Meulen, H.C. (1983). Life-span oral
         toxicity and carcinogenicity study with Palatinit(R) in rats.
         Unpublished report No. V 83.412/292021 from Centraal Instituut
         voor Voedingsonderzoek (CIVO/TNO), Zeist, The Netherlands.
         Submitted to WHO by Bayer A.G.

    Sinkeldam, E.J., Woutersen, R.A., & Hoetmer, A. (1981). One-year
         feeding study with Palatinit(R) in rats. Unpublished report No. V
         81.416/212021 from Centraal Instituut voor Voedingsonderzoek
         (CIVO/TNO), Zeist, The Netherlands. Submitted to WHO by Bayer
         A.G.

    Spengler, M. (1978). Palatinit(R), tolerance test carried out at the
         Children's Clinic, City Hospital, Wuppertal-Barmen. Unpublished
         report submitted to WHO by Bayer A.G.

    Spengler, M. (1979a). Palatinit(R) tolerance study (sorbitol control)
         on 36 metabolically healthy patients at the Children's Clinic,
         Barmen. Unpublished report submitted to WHO by Bayer A.G.

    Spengler, M. (1979b). Palatinit(R), tolerance study (controls:
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         Pediatrics Clinic. Unpublished report submitted to WHO by Bayer
         A.G.

    Spengler, M. & Schmitz, H. (1979). Comparison of Palatinit(R)
         tolerance with sorbitol tolerance after 14-day oral
         administration to healthy adult patients. Unpublished
         pharmaceutical report No. 8449 from Bayer A.G., Wuppertal, F.R.G.
         Submitted to WHO by Bayer A.G.

    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
         report No. 8457 from Bayer A.G., Wuppertal, F.R.G. Submitted to
         WHO by Bayer A.G.

    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)