Prepared by:
          The forty-ninth meeting of the Joint FAO/WHO Expert
          Committee on Food Additives (JECFA)

        World Health Organization, Geneva 1998


    First draft prepared by
    Ms. E. Vavasour
    Dr. R. Rotter
    Chemical Health Hazard Assessment Division
    Bureau of Chemical Safety
    Food Directorate, Health Protection Branch
    Health Canada, Ottawa, Ontario, Canada

        1.  Explanation
        2.  Biological data
            2.1 Biochemical aspects
            2.2 Toxicological studies
                2.2.1   Short-term toxicity studies
                2.2.3   Special studies on genotoxicity
        4.  Evaluation
        5.  References


        The safety of hydrogenated glucose syrups (also referred to as
    maltitol syrups) were evaluated at the twenty-fourth, twenty-seventh,
    twenty-ninth, thirty-third and forty-first meetings of the Committee
    (Annex 1, references 53, 62, 70, 83 and 107), such syrups are a
    subgroup of the hydrogenated starch hydrolysates (HSHs) having a
    composition which conforms to specifications designated at the
    twenty-ninth meeting. These specifications require that the glucose
    syrups used as starting materials have a glucose content of less than
    8%, a maltose content greater than 50% and a maltotriose content not
    greater than 25%, with the remainder being longer chain glucose
    polymers. An ADI "not specified" has been allocated for maltitol
    syrups that meet these specifications.

        At the forty-sixth meeting of the Committee (Annex 1 reference
    122), a review of the specifications for polyol ingredients was
    undertaken. It recommended that a joint review of pertinent
    toxicological data and specifications was required to support the use
    of a broader range of starch hydrogenation products in maltitol syrup
    than are currently permitted. By deletion of the specification tests
    for hydrogenated saccharides other than maltitol, the theoretical
    contents of any of these components in maltitol syrups (sorbitol,
    maltotriitol and higher order polyols) could be as high as 49% and
    maltitol content could vary from 50 to 98%. Maltitol and sorbitol have
    already been evaluated and have been allocated ADIs "not specified".
    This monograph addendum reviews the metabolic fate of HSH components
    and considers the results of 90-day feeding studies employing two HSHs
    that contain more than 49% hydrogenated polysaccharides.


    2.1  Biochemical aspects

        A number of studies (published and unpublished) that have examined
    the metabolic fate of maltitol and higher order polyols were reviewed.
     In vitro and  in vivo studies, including some utilizing human
    intestinal mucosa, indicated that the available glucosidic linkages of
    the higher-order polyols in HSH syrups covering a range of polyol
    compositions were readily hydrolysed by digestive enzymes to glucose
    and maltitol. The glucose units were absorbed in the upper intestine.
    Hydrolysis of maltitol occurred more slowly. It was degraded primarily
    in the jejunum, but also in the ileum and duodenum. In humans,
    metabolism of maltitol was primarily through fermentation by the
    intestinal flora. Some absorption of maltitol occurred, but it was
    quickly excreted in the urine with little evidence of metabolism.

        Human digestion of two HSH syrups (7:60:33 and 14:8:78) in
    diabetic (Type I and Type II) and non-diabetic subjects indicated that
    they were less glycaemic than glucose in all three test groups. This
    was explained by decreased bioavailability of glucose from the HSHs
    due to its the slower release in the gastrointestinal tract compared
    with directly ingested glucose (Modderman, 1993).

    2.2  Toxicological studies

    2.2.1  Short-term toxicity studies  Rats

        A 90-day oral toxicity study was conducted with Lycasin 65/63
    (10.5% D-sorbitol, 7.5% maltitol, 25% tri- to hexasaccharide alcohols
    and 57% higher-than-hexasaccharide alcohols; 10:8:82) with male and
    female Charles River albino rats. Test material was included in
    standard rat diets at levels of 0, 2, 5 or 15% (equal to 2.2, 6.2 and
    15 g/kg bw per day for males and 2.6, 7.8 and 18 g/kw bw per day for
    females) and fed to 15 rats/sex per dose. Each rat was weighed at the
    start of the experiment and at weekly intervals thereafter. Feed
    consumption was recorded for 5 individual animals/sex per dose each
    week during the experiment. The rats were observed daily for signs of
    abnormal behaviour or mortality. Blood and urine samples were
    collected from 5 fasted rats/sex from the control and high-dose
    Lycasin diet groups on days 45 and 84 of exposure (duration of fast
    not stated). The blood samples were analysed for: haematocrit, red
    blood cell count, haemoglobin, total and differential leukocyte
    counts, blood urea nitrogen, serum alkaline phosphatase and serum
    glutamic-pyruvic transaminase (alanine aminotransferase) activities
    and fasted blood glucose. Urine samples were analysed for glucose,
    albumin, microscopic elements, pH and specific gravity. At the end of
    the experiment, all surviving animals were sacrificed and necropsied.
    The following organs from all animals were weighed: liver, kidneys,
    spleen, testes/ovaries, heart and brain. Histological examinations

    were performed on 37 tissues/organs (including the adrenal glands and
    caecum) from 10 rats/sex fed the control and high-dose Lycasin diets.

        No animals died as a result of treatment and there were no effects
    of treatment on body weight gain, food consumption, haematological,
    clinical chemistry or urinary parameters, organ weights or
    histopathogy. The results of this experiment suggest that Lycasin
    65/63 was not toxic in rats under the test conditions used. The NOEL
    was the highest dose tested, 15% of the diet. This experiment was
    conducted by Industrial BIO-TEST Laboratories, Inc. in 1969, prior to
    the implementation of GLP. It was audited in 1982 by an independent
    auditor and concluded to be substantially accurate. However, many of
    the raw data were not available for examination (Industrial BIO-TEST
    Laboratories, Inc., 1969a).

        Male and female OFA rats (derived from Sprague Dawley rats) were
    randomized into 4 treatment groups (20 rats/sex per dose) and fed
    diets containing 0, 1.25, 2.5 or 5% hydrogenated dextrin (0:0:100)
    (equal to 0, 1.0, 2.0 or 4.0 g/kg bw per day for males and 0, 1.4, 2.8
    or 5.2 g/kg bw per day for females) for 13 weeks. The rats were housed
    two per cage according to sex. At first exposure, the male rats
    weighed an average of 192 g and the females weighed 157 g. The animals
    were examined at the start of the experiment and they were observed
    daily. Body weight was recorded once each week and feed and water
    consumption were noted twice weekly. Ophthalmological examinations
    were conducted on all animals after 4 weeks of exposure and at
    sacrifice. Under anaesthesia, blood samples were collected from fasted
    animals from the orbital sinus after 4 weeks of exposure and from the
    vena cava prior to sacrifice. Urine samples were collected after 4
    weeks of exposure and on the day of sacrifice. All blood samples were
    analysed for cholesterol, triglycerides, glucose, total protein,
    aspartate aminotransferase (ASAT), alanine animotransferase (ALAT),
    alkaline phosphatase,  gamma-glutamyl transferase, urea, creatinine,
    sodium, potassium, chloride, magnesium, calcium, inorganic phosphorus
    and uric acid. The blood samples collected prior to sacrifice were
    also analysed for prothrombin time, cephaline activated time,
    cholinesterase activity, albumin, total bilirubin, lactase
    dehydrogenase and amylase. All urine samples were analysed for the
    following: total protein, glucose, urea, uric acid, sodium, potassium,
    creatine, chloride, volume, pH, nitrite, ketone bodies, urobilinogen,
    bilirubin and blood. At the end of the experiment, all animals were
    sacrificed and necropsied. The following organs were weighed:
    encephalon, thymus, heart, liver, spleen, kidneys, adrenal glands,
    caecum and testes/ovaries. Histological examination of 36
    organs/tissues including adrenal glands and caecum were performed.
    Only tissues from the control and high dose groups were examined.

        No treatment-related effects were observed on animal health,
    weight gain, food or water consumption, no eye abnormalities were
    detected and no mortalities occurred during the experiment. No
    abnormalities were seen at necropsy and there were no
    treatment-related differences in organ weights. Some statistically
    significant differences were seen in several blood parameters, but

    they were only observed at one time point and in one sex. Many of the
    parameters were still within normal ranges and none of the effects
    were dose-related. Consequently, these differences were not considered
    to be of toxicological significance. The data suggest that
    hydrogenated dextrin was not toxic in rats up to the highest dose
    tested, 5% of the diet (Roquette Frčres Biology and Toxicology
    Department, 1995).  Dogs

        Pure-bred male (6.7-11.5 kg bw) and female beagle dogs (5.3-9.2 kg
    bw), 6.0-6.5 months old, were assigned to 4 treatment groups (4
    dogs/sex per dose). The dogs were fed diets containing 0, 2, 5 or 15%
    Lycasin 65/63 (10:8:82) (equal to 0, 5, 14 and 43 g/kg bw per day,
    respectively) for 90 days. All dogs of the same sex were housed
    together according to treatment group. In addition to feeding the
    Lycasin-containing food, each dog had unrestricted access to untreated
    diet for an addition 3 hours per day. The Lycasin was from the same
    lot used in the IBT study on rats described above. The dogs were
    observed daily for signs of toxicity. Individual body weight and a
    pen-based average food consumption were recorded weekly. Blood samples
    were collected on days 0, 42 and 90 of the experiment, and urine
    samples were collected on days 0, 42 and 84. Haematological analysis
    of the blood samples included determination of haematocrit,
    haemoglobin, red blood cells and total and differential white blood
    cells. Clinical chemistry analyses of the blood samples were also
    conducted to determine blood urea nitrogen, serum alkaline
    phosphatase, serum glutamic-oxaloacetic transaminase (aspartate
    aminotransferase), serum glutamic-pyruvic transaminase (alanine
    aminotransferase) and serum glucose. The urine samples were analysed
    for albumin, glucose, pH and microscopic elements. All animals were
    sacrificed on day 91 of the experiment and subjected to necropsy. The
    following organs/tissues were weighed: liver, lungs, kidneys, heart,
    brain, pituitary, spleen, ovary/testes, adrenals and thyroid. Samples
    of 30 organs/tissues were removed and prepared for histological

        Body weight gain in male and female dogs receiving the low and mid
    doses of Lycasin was lower than in the control animals. The mean
    weekly feed consumption was also 14 and 12% lower in the low- and
    mid-dose female dogs, respectively. The authors of the report
    attributed this to problems with behavioural incompatibility in these
    groups rather than an effect of treatment. This is supported by the
    lack of dose relationship for these effects. All haematological and
    blood chemistry parameters measured were similar across the treatment
    groups. No treatment-related lesions or differences in organ weights
    were noted. The results of this experiment indicated that Lycasin
    65/63 was not toxic in Beagle dogs under the test conditions used.
    This experiment was conducted by Industrial BIO-TEST Laboratories
    prior to the implementation of GLP. A 1982 audit of the data concluded
    that the conclusions of the study were supported by the data. However,
    no summary data were supplied with the study and statistics were not
    performed (Industrial BIO-TEST Laboratories, Inc., 1969b).

    2.2.3  Special studies on genotoxicity

        The results of studies on the genotoxicity of hydrogenated dextrin
    are presented in Table 1.

        Table 1. Results of tests for the genotoxicity of hydrogenated dextrin


    End-point           Test object             Concentration of         Results       Reference
                                                hydrogenated dextrin 

    Reverse mutation    S. typhimurium          50-5000                  Negative1     Institute Pasteur 
                        TA98, TA100, TA1535,                                           de Lille (1995)

                        E. coli                 50-5000                  Negative1     Institute Pasteur 
                        WP2pKM101,                                                     de Lille (1995)

    1 In the presence and absence of S9 metabolic activation.

        The results of metabolic studies in rats and humans indicated that
    the higher-order polyol components in HSHs of differing composition
    were efficiently hydrolysed in the gastrointestinal tract to glucose
    and a small amount of maltitol. Maltitol was hydrolysed less readily
    by endogenous enzymes and a considerable portion undergoes
    fermentation in the lower gastrointestinal tract. The small amount
    that is absorbed is quickly excreted unchanged in the urine.

        Animal studies with maltitol syrups composed of up to 41% higher
    order polyols were reviewed at the twenty-ninth meeting of the
    Committee (Annex 1, reference 70). The toxic potential of two
    materials that contain more than 49% of the hydrogenated
    polysaccharides, the first containing 10% sorbitol, 8% maltitol and
    82% higher-order polyols and the second containing 100% hydrogenated
    dextrin, were evaluated in animal feeding studies, and the mutagenic
    potential of hydrogenated dextrin was also examined in bacterial
    assays. Ingestion of up to 5.2 g hydrogenated dextrin/kg bw per day
    for 13 weeks did not result in any treatment-related effects in rats.
    No treatment-related toxicity was seen in rats or dogs fed Lycasin
    65/63 up to dose levels of 18 and 43 g/kg bw per day, respectively,
    for 90 days. Hydrogenated dextrin was not mutagenic in either 
     S. typhimurium or  E. coli bacteria strains in the absence or
    presence of rat S9 activation. 


        On the basis of the above considerations, the Committee confirmed
    the previous ADI "not specified" and concluded that it could be
    applied to substances meeting the revised specifications.


    Industrial BIO-TEST Laboratories, Inc. (1969a) Ninety-day subacute
    oral toxicity of Lycasin. Albino rats - BTL-68-25. Unpublished report
    No. B6874 from Industrial Bio-Test, dated April 16, 1969 (Submitted to
    WHO by Roquette Frčres, Lestrem, France; validated by Booz, Allen and
    Hamilton Inc.).

    Industrial BIO-TEST Laboratories, Inc. (1969b) Ninety-day subacute
    oral toxicity of Lycasin in Beagle dogs - BTL-68-25. Unpublished
    report No. C6875 from Industrial Bio-Test, dated May 7, 1969
    (Submitted to WHO by Roquette Frčres, Lestrem, France; validated by
    Booz, Allen and Hamilton Inc.).

    Institute Pasteur de Lille (1995) Mutagenicity test on bacteria
     (Salmonella typhimurium his- and  Esherichia coli trp-) using
    B.N. Ames technique with hydrogenated dextrin. Unpublished report No.
    IPL-R 95-0305 from Institute Pasteur de Lille, France, dated  March
    21, 1995 (Submitted to WHO by Roquette Frčres, Lestrem, France).

    Modderman, J.P. (1993) Safety assessment of hydrogenated starch
    hydrolysates.  Regul. Toxicol. Pharmacol., 18: 80-114.

    Roquette Frčres Biology and Toxicology Department (1995) Subchronic
    toxicity (13 weeks) by the oral route of Lab 2204 in rats. Unpublished
    report No.95041 from Roquette Frčres Biology and Toxicology
    Department, dated September 12, 1995 (Submitted to WHO by Roquette
    Frčres, Lestrem, France).


    See Also:
       Toxicological Abbreviations
       MALTITOL SYRUP (JECFA Evaluation)