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.



    Absorption, distribution and excretion


         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

    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).


    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 g/plate (Herbold, 1978).

    Special studies on tolerance


         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

    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


         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.


         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.


    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 g 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.,

         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.,

         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).


         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.


    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.


    Required by 1985.

         Results of long-term feeding studies in mice and rats;
    multigeneration studies in rats.


    Bomhard, E., Luckhaus, G. & Muller, L. (1978) Palatinit (Bay; 3930),
         subchronic toxicology investigations in rats. Bayer AG Pharma-
         Report Nr. 8025 v.22.12.78. Unpublished report submitted to WHO
         by Bayer A.G.

    Gau, W. & Muller, L. (1976) Unpublished data submitted to WHO by Bayer

    Grupp, U. & Siebert, G. (1978) Metabolism of hydrogenated palatinose,
         an equimolecular mixture of alpha-D-glucopyranosido-1,6-sorbitol
         and alpha-D-glucopyranosido-1,6-mannitol, Res. Exp. Med.
         (Berl.), 173, 261-278

    Herbold, B. (1978) Palatanit (Bay; 3930) Salmonella/Microsome-Test to
         investigate point mutagenicity. Bayer A.G. Pharma-Report Nr. 7578
         v.7.6.1978. Unpublished report submitted to WHO by Bayer A.G.

    Hoffmann, K., Luckhaus, G., & Muller, L. (1978) Bay; 3930/Palatinit,
         sub-chronic toxicity study in dogs with administration in the
         feed (13-week feeding study). Bayer A.G. Pharma Report Nr. 7987
         v.6.12.1978. Unpublished report submitted to WHO by Bayer A.G.

    Jahnke, K. & Gierlich, P. (1978) Pilotstudie Palatinit Bericht
         vom 20.1.1978. Unpublished report submitted to WHO by Bayer A.G.

    Jahnke, K. & Gierlich, P. (1979) Wirkung einer oralen akuten
         Belastung mit Palatinitgegenuber Glucose auf Blutglucose und
         Seruminsulin und weitere Stoffswechsel-parameter bei Diabetikern.
         Prufplan u. statistische Auswertung der Ergebnisse dutch Bayer,
         PH-Dokumentation u. Biometric v.31.5.1979. Unpublished report
         submitted to WHO by Bayer A.G.

    Keup, U. & Putter, J. (1974) Serumglukose-und-insulinverlauf bei
         gesunden Probanden nach einmaliger oraler Palatinit - bzw.
         Saccharosebeiastung. Bayer A.G. Pharma-Bericht Nr 4781
         v.1.4.1974. Unpublished report submitted to WHO by Bayer A.G.

    Kronenberg, H.-G., Spengler, M. & Strohmeyer, G. (1979) Zur
         Resorptionen von Palantinit, dem Equimolekularen Gemisch von
         alpha-D-glucopyranoside-1,6-sorbit (GPS) und alpha-D-
         Glucopyranosido-1,6-mannit (GPM) in Dunndarm von colectomierten
         Patienten. Unpublished report submitted to WHO by Bayer A.G.

    Linzenmeier, G. (1978) The influence of 14 day oral administration of
         Palatinit on the stool flora of 2 healthy male volunteers.
         Unpublished report submitted to WHO by Bayer A.G.

    Mehnert, H., Haslbeck, M. & Bachmann, W. (1977) Palatinitbelastung
         gesunder Probanden. protokoll vom 16-29.11.1977. Unpublished
         report submitted to WHO by Bayer A.G.

    Mehnert, H., Haslbeck, M. & Bachmann, W. (1979) Eignung von Palatinit
         als Zucheraustauschstoff fur Diabetiker aus medizinischer Sicht
         im Vergleich zu Fructose. Prufplan u. statische Auswertung der
         Ergebnisse durch Bayer. PH-Dokumentation und Biometrie
         v.28.5.1977. Unpublished report submitted to WHO by Bayer A.G.

    Musch, V. K. et al. (1973) Ernahrungsphysiologische
         Untersuchungen mit isomaltit an der Ratte. Zeitschrift fur
         Ernahrungswissen-schaft Suppl., 15, 3-16

    Patzschke, K., Weber, H. & Wegner, L. (1975a) Bay; 3930-14C:
         Resorption und Elimination - orientierende Untersuchungen on
         Ratten. Pharmabericht Nr. 5636. Unpublished report submitted to
         WHO by Bayer A.G.

    Patzschke, K., Wegner, L. & Horster, F. A. (1975b) Bay; 3930-14C.
         Resportion und Elimination - Untersuchungen an Probanden. Bayer
         AG Pharmabericht Nr. 5635 v.30.9.1975. Unpublished report
         submitted to WHO by Bayer A.G.

    Putter, J. & Spengler, M. (1975) Zur Vertraglichkeit von Palatinit
         (Bay; 3930) als Einzeldosis Bayer AG Pharma-bericht Nr. 5475
         v.6.6.1975. Unpublished report submitted to WHO by Bayer A.G.

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

    Siebert, G. (1973) Resorptionversuch mit Palatinat an
         6 Versuchspersonen. Bericht vom 20.1.1973. Unpublished report
         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). Health
         and Sugar Substitutes. Proc. ERGOB Conf. Geneva,
         pp. 109-113, Basle, Karger

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

    Spengler, M. (1978) Paltinit, tolerance test carried out at the
         Children's Clinic, City Hospital, Wuppertal-Barmen Report
         5.7.1978. Unpublished report submitted to WHO by Bayer A.D.

    Spengler, M. (1979) Palatinit, Toleranzstudie (Kontrolle Sorbit) an 36
         stoffwechselgesunden Patienten der Kinderklinik Barmen. Berich
         vom 12.6.1979. Unpublished report submitted to WHO by Bayer A.G.

    Spengler, M. & Schmitz, H. (1979) Vergleich der Palantinit-Toleranz
         gegenuber der Sorbit-Toleranz gesunder Erwachsener nach
         14-tagiger oraler Gabe Bayer AG Pharma-Bericht Nr. 8449
         v.23.5.1979. Unpublished report submitted to WHO by Bayer A.D.

    See Also:
       Toxicological Abbreviations