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    MALTITOL AND MALTITOL SYRUP

    First draft prepared by
    Dr J.L. Herrman
    International Programme on Chemical Safety
    World Health Organization
    Geneva, Switzerland

    1.  EXPLANATION

         Hydrogenated glucose syrups were evaluated at the
    twenty-fourth, twenty-seventh, and twenty-ninth meetings of the
    Committee (Annex 1, references 53, 62, and 70).  A temporary ADI was
    allocated at the twenty-seventh meeting, with the requirement that
    the results of a lifetime feeding study be submitted.  At the
    twenty-ninth meeting the Committee concluded that the previously-
    requested lifetime feeding study was not necessary because
    hydrogenated glucose syrups are fully metabolized to natural body
    constituents.  An ADI "not specified" was allocated, which applied
    to hydrogenated glucose syrups that met the established
    specifications.

         At the thirty-third meeting (Annex 1, reference 83) the
    specifications for hydrogenated glucose syrups were revised and
    retitled "maltitol syrup".  The Committee confirmed that the ADI
    "not specified" previously allocated to hydrogenated glucose syrups
    applied to maltitol syrup meeting the revised specifications.  In
    addition, an ADI "not specified" was allocated to maltitol, which
    was specified as having a minimum 98% purity.

         A combined long-term toxicity/carcinogenicity study in rats
    using a commercial product has now been completed, which is
    summarized in this monograph addendum.

    2.  BIOLOGICAL DATA

    2.1  Biochemical aspects

         No new information.

    2.2  Toxicological studies

    2.2.3  Long-term toxicity/carcinogenicity study

    2.2.3.1  Rats

         In a combined long-term toxicity/carcinogenicity study a
    commercial preparation containing approximately 87% maltitol was fed
    to Crl:CD(SD)BR male and female rats at doses equal to 0, 0.5, 1.5,
    or 4.5 g/kg bw/day.  [The highest dose corresponded to an average of
    about 10% of the commercial product in the diet.]  Rats were
    maintained on these diets for 52 weeks in the long-term study (20
    animals/sex/group) or for 106 weeks in the carcinogenicity study (50
    animals/sex/group), after which they were killed.

         In both experiments animals were examined daily for signs of
    ill health or behavioral changes.  Food consumption and body weights
    were recorded immediately prior to the start of administration of
    the test compound, at weekly intervals for the first 12 weeks, and
    then every 4 weeks until the end of the experiment.  Animals were
    inspected twice daily for mortality, and those found dead or
    sacrificed "in extremis", as well as those killed at the end of the
    study, were subjected to complete necropsies and organs were
    removed, weighed, and histologically examined.  Caecum and colon
    diameters were measured in the long-term study.

         Ten animals/sex/group were subjected to ophthalmoscopic
    examination prior to the start of treatment and at weeks 13, 26, and
    52 in the long-term study.  Haematological examinations, blood
    chemistry tests, and urinalyses were performed on 10
    animals/sex/group at weeks 14, 26, and 51 in this study.

    Results of the long-term toxicity study

         No animals in the mid- or high-dose groups died.  Three animals
    in the control group and four in the low-dose group died, most of
    which were caused by accidents; none of these deaths was related to
    treatment.  No treatment-related clinical signs were noted. 
    Treatment had no effect on body weight.  Sporadic differences in
    food consumption were noted in males, with no apparent trend.  Mean
    food consumption was significantly less in high-dose females at 12
    and 52 weeks than in the other groups.  No treatment-related eye
    abnormalities were observed.  Sporadic differences were observed in
    haematological parameters but, except for a decrease in leukocytes
    in mid-dose females, none of these differences were observed at all

    observation times.  Occasional significant differences were observed
    in blood chemistry and urinalysis parameters, but none of these
    differences were major and most of them were not dose-related.  No
    treatment-related effects were observed after gross or
    histopathological examination.  A significant increase in the caecum
    diameter of high-dose males was observed, which was due to higher
    values in 3 out of 20 rats.  A trend toward a decrease in caecum
    diameter was observed in low- and high-dose females when compared to
    controls.  The NOEL in this study was the highest dose tested, 4.5 g
    commercial product/kg bw/day (Conz & Fumero, 1989).

    Results of the carcinogenicity study

         Mortality was not affected by treatment.  No treatment-related
    clinical signs were noted.  Body weights of all treated males and of
    high-dose females were comparable to those of animals in their
    respective control groups.  Mean body weights of low- and mid-dose
    females were slightly lower than those of controls, which reached
    statistical significance only occasionally, including weeks 100 and
    104.  Food intake was not affected by treatment.  No gross
    pathological treatment-related changes were observed in any organs,
    including the intestine and caecum.  Occasional masses or nodules of
    the adrenal glands were observed, but they were not dose-related and
    the highest frequencies were within the control incidences observed
    in 2-year carcinogenicity studies in rats of the same strain
    performed in the same laboratory.

         Histopathological changes related to treatment were observed in
    the adrenal gland.  The findings are summarized in Table 1.  Both
    benign and malignant phaeochromocytomas, when considered either
    separately or together, occurred with higher incidence in both males
    and females in the high-dose group when compared with the control
    group.  In addition, slight to moderate medullary hyperplasia
    occurred at an increased frequency in all treated groups when
    compared to controls.  The trend test showed a significant increase
    in females, with a significant difference between high-dose females
    and the control group.

    Table 1.  Histopathological changes observed in the adrenal gland in
              the carcinogenicity study in rats

                                                                      

      Sex/                           M                F

      Dose Level1        0    0.5   1.5   4.5   0    0.5   1.5   4.5
                                                                      

    Phaeochromocytoma

       Benign            8     4    10    20    2     2     4    10

       Malignant         6    12     4    10    2     2     2     4

       Total            14    16    14    30    4     4     6    14

    Medullary
     hyperplasia        24    32    38    32   14    22    24    34
                                                                      

    1  50 adrenal glands/sex/group were examined except for the
       mid-dose males, in which  49 were examined.

         An increased incidence of mammary gland adenocarcinomas was
    observed in females: 4/50 (8.0%), 2/43 (4.6%), 8/50 (18.6%,
    P=0.054), and 10/50 (20.0%, P=0.044) in the controls and low-, mid-,
    and high-dose animals, respectively.  Although the trend was
    significant (P=0.013), the incidences at the two highest doses were
    barely significantly different than the controls.  Increased
    incidences of mammary gland adenomas or fibroadenomas were not
    observed.  The incidences of mammary gland adenocarcinomas were
    within the historical control incidences of mammary gland
    adenocarcinomas in female rats in the same laboratory in 7 studies
    carried out between 1978 and 1989, which have ranged from 0 to 22%
    (Conz & Maraschin, 1992).

    3.  COMMENTS

         At its present meeting, the Committee reviewed a recently
    completed combined long-term toxicity/carcinogenicity study, in
    which a commercial preparation containing approximately 87% maltitol
    was administered in the diet of Sprague-Dawley rats at levels equal
    to 0, 0.5, 1.5, or 4.5 g/kg bw/day for either 52 weeks (toxicity
    study) or 106 weeks (carcinogenicity study).  No adverse effects
    were observed in the toxicity study.  In the carcinogenicity study,
    histopathological changes related to treatment were observed in the
    adrenal gland, which included increased incidences of both benign
    and malignant phaeochromocytomas in male and female rats in the
    high-dose group and an increased frequency of slight to moderate
    adrenal medullary hyperplasia in all treated groups.  A slightly
    increased incidence of mammary gland adenocarcinomas was observed in
    female rats at the 1.5 and 4.5 g/kg bw/day doses, however the
    incidence was within the range reported in the historical control. 
    Increased incidences of mammary gland adenomas or fibroadenomas were
    not observed, and the combined incidences of mammary gland
    adenocarcinomas and adenomas were not increased.  For these reasons,
    the Committee did not consider the increase in mammary gland
    adenocarcinomas to be related to treatment.

    4.  EVALUATION

         Previous Committees have taken cognisance of adrenal medullary
    lesions in rats associated with high intake levels of poorly-
    absorbed polyols when allocating ADIs to them (Annex 1, reference
    62).  In line with earlier conclusions regarding the significance of
    these lesions, the Committee confirmed the ADI "not specified" for
    maltitol and maltitol syrup that meet the specifications established
    at the present meeting.  The Committee recommended that the
    information database on adrenal medullary hyperplasia and
    phaeochromocytomas associated with polyols and other poorly-absorbed
    carbohydrates be reviewed and that mechanisms of the appearance of
    these lesions and their toxicological significance be assessed at a
    future meeting.

    5.  REFERENCES

    CONZ, A. & FUMERO, S. (1989). Combined chronic
    toxicity/carcinogenicity study in Sprague Dawley Crl:CD(SD)BR rats
    treated with the test article MALBITR (crystal powder)
    administered at the dosages of 0, 0.5, 1.5, and 4.5 g/kg/day in the
    diet: chronic toxicity study.  Unpublished report from RBM, Istituto
    di Richerche Biomediche, Ivrea, Italy.  Submitted to WHO by Cerestar
    Research & Development, Vilvoorde, Belgium.

    CONZ, A. & MARASCHIN, R. (1992).  Combined chronic
    toxicity/carcinogenicity study in Sprague Dawley Crl:CD(SD)BR rats
    treated with the test article MALBITR (crystal powder)
    administered at the dosages of 0, 0.5, 1.5, and 4.5 g/kg/day in the
    diet: carcinogenicity study.  Unpublished report from RBM, Istituto
    di Richerche Biomediche, Ivrea, Italy.  Submitted to WHO by Cerestar
    Research & Development, Vilvoorde, Belgium.


    See Also:
       Toxicological Abbreviations