The data contained in this document were examined by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 3-12 April 1978

    Food and Agriculture Organization of the United Nations
    World Health Organization

    * Twenty-second Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1978, WHO Technical Report Series No. 631



         Sorbitol was evaluated at the seventeenth session of the Joint
    FAO/WHO Expert Committee on Food Additives in 1973. Since the previous
    evaluation new data were made available and are summarized below.


    Long-term studies


         A total of 75 male and 75 female Sprague-Dawley rats of the CD
    strain were included in each dosage group. Each group consisted of 50
    male and 50 female rats for tumorigenic evaluation, 15 male and 15
    female rats for laboratory investigation, and 10 males and 10 females
    for interim sacrifice of 5 male and female rats at 26 and 52 weeks.
    All animals were derived from parents exposed to the respective test
    diets. The test diets contained 0 or 20% sorbitol, or 20% sucrose. The
    diet of all groups was maintained at 20% carbohydrate supplementation
    through the use of rice starch in the 0% groups. Protein was
    maintained constant in all groups through the addition of casein. For
    the 20% sucrose groups, the carbohydrate was increased 5% per week
    until the desired level was attained.

         A lowered body weight gain was recorded through the first 78
    weeks of the study for males and females in the 20% sorbitol group.
    Coupled with the decreased body weight gain was an impairment of food
    utilization efficiency for the 20% sorbitol group. A higher water
    intake was seen in both male and female 20% sorbitol rats and was
    associated with increased urine excretion. No other treatment effect
    was observed on mortality, food intake, or clinical signs.

         Urinalysis indicated increased urine volumes for the 20% sorbitol
    All other urinalysis and haematological parameters, were within normal
    limits for sorbitol, sucrose, or rice starch. Sucrose treatment
    increased cholesterol in males at 52 weeks and males and females at 78
    weeks. No increase in cholesterol was noted at terminal sacrifice for
    the sucrose group. Both sucrose and sorbitol increased insulin levels
    at 26 and 52 weeks but returned to normal at 78 weeks. At terminal
    sacrifice the sorbitol group had normal insulin levels but the sucrose
    males had elevated insulin levels. No other consistent 
    treatment-related effects were noted on blood biochemistry for 20% 
    sorbitol, 20% sucrose, or 20% rice starch.

         At autopsy lower absolute and relative thyroid weights were
    recorded for males and females in the 20% sorbitol and 20% sucrose
    groups. Histological examination of the animals indicated no
    treatment-related effects on the major organ systems. However, the
    incidence of both unilateral and bilateral hyperplasia of the adrenal
    medulla was increased significantly for both males and females in the
    20% sorbitol group. Only unilateral hyperplasia was seen in the
    controls. Macroscopic examination indicated that 20% sorbitol caused
    caecal enlargement in both males and females. No other 
    treatment-related gross pathological changes were noted (Hunter et 
    al., 1978).


         Sorbitol 0 or 20% was administered in the diet of pure-bred
    beagle dogs (eight male and eight female animals per group). Another
    group received 20% sucrose for comparative purposes. Rice starch was
    included in the diets of the controls so that the diet consisted of
    80% normal diet and 20% carbohydrate. After 52 weeks there was an
    interim sacrifice of two males and two females per group. The study
    was terminated at 104 weeks.

         Mortalities, gross clinical signs, body weight, food consumption,
    food conversion ratio, water consumption, ophthalmoscopic signs,
    neurological signs and dental changes were determined. Haematology,
    clinical chemistry and urinalysis were conducted at -1, 12, 26, 38,
    50, 64, 76, 89 and 100 weeks.

         There was an increase in total serum protein, body weight, and
    organ weight in the 20% sorbitol groups as compared to the 0% group.
    There was a slight increase in the utilization of food in the 20%
    sorbitol group. There were no other significant findings (Heywood et
    al., 1977).

    Reproduction studies


         A three-generation study was conducted in Sprague-Dawley (CD)
    specific pathogen-free rats with 20 males and 20 females respectively
    per group. Each group received the test material by dietary
    administration. A control group received 20% rice starch. One group
    received 20% sorbitol and another group received 20% sucrose
    ad libitum.

         The pups of the F1a, F2a, and F3a generations were weighed
    and killed at four days and examined for sex determination of
    abnormalities. The F1b, F2b, and F3b pups were weighed, sexed, and
    litters culled to eight per dam. Pups were weighed at 8, 12, and 21
    days post partum. Observations were made to determine litter size,

    litter and pup weights, pup mortality, and gross abnormalities. Gross
    and histopathological observations were conducted on rats of the F3b
    generation, which were killed at three weeks of age. There were two
    deaths of parent animals of the F2b generation, among nine deaths
    which occurred in the study, which were attributed to chance
    occurrence. Marked inhibition of food consumption occurred.
    Suppression of weight gain was noted. Mating performance and pregnancy
    rate were not affected. Gestation period was increased (23-24 days) in
    36% of litters of the first mating versus 16.1% of controls and
    23.2% of second mating versus 7.3% of controls. At terminal necropsy
    caecal enlargement was noted.

         Litter size was decreased (total and viable pups) as was litter
    weight, but with increased mean pup weight. No terata were observed
    grossly. Statistical analysis of organ weights showed a number of
    statistically significant differences in absolute organ weights which
    reflected body weight differences as shown by co-variance analysis.
    Statistically significant decreased absolute thyroid weight did not
    reflect body weight changes. There was also lower adjusted heart
    weight and higher adjusted ovary weight. Distention of the caecum was
    observed in the F3b generation. Two rats derived from the same litter
    showed an absence of thymic tissue, cortical lymphocyte depletion and
    changes in a number of other tissues. The relationship to treatment is
    unknown. Two males and one female showed an absence of extramedullary
    haematopoiesis in the liver (Palmer et al., 1978).

    Special studies



         Groups of 31-33 CFT strain-specific pathogen-free female weanling
    rats received test diets containing either/or 20% rice starch
    (control), 20% sorbitol or 20% sucrose for comparison. The test diets
    were administered for five weeks before mating. Parameters
    investigated included food consumption, body weight change, and mating
    performance. Litter data included implantations, pre-implantation and
    post-implantation loss, litter and mean foetal weights, major
    malformations and minor abnormalities, and skeletal variants.

         There was a low overall pregnancy rate (approximately 50%) for
    all groups. No major malformations were noted. No skeletal variations
    were attributable to treatment. Other parameters were within normal
    limits (Palmer and Bottomley, 1977).


         Groups of 20 yellow-silver does of a closed, randomized, outbred
    rabbit strain, aged three to four months (2.7-3.0 kg) received test
    diets ad libitum containing 20% sorbitol or 20% sucrose baked into
    the food pellets. Males were untreated. The test diets were
    administered from days seven to 19 of gestation. Parameters
    investigated were body weights of does, litter data including
    implantations and pre-implantation loss, litter size and 
    post-implantation loss, litter and mean foetal weights, major and minor
    anomalies and skeletal variants. Young were incubated for 24 hours to
    determine neonatal viability. Gross and X-ray examinations were
    conducted to discover external and skeletal malformations. Alizarin
    red technique was utilized where necessary. The Wilson technique was
    used to examine for malformations of brain and skull. The incidence of
    skeletal malformations was similar in treatment and control (sucrose)
    groups. No major visceral abnormalities were noted. Food intake was
    decreased during the period of sorbitol administration. No other
    treatment effects were noted (Hummler, 1978).


    Heywood, R., Chesterman, H., Allen, T. R., Sheet, A. E., Kennedy, S.
    J., Majerd, S. K. and Prentice, D. E. (1977) Xylitol toxicity studies
    in the beagle dog. Unpublished report from Huntingdon Research Centre,
    submitted to World Health Organization by F. Hoffman La Roche Co.,
    Ltd., Basle, Switzerland

    Hummler, H. (1978) Reproduction study in rabbits in oral
    administration of Ro 06-7045-Xylitol, Phase II - Teratology study.
    Unpublished company report submitted to the World Health Organization
    by F. Hoffman La Roche Co., Ltd., Basle, Switzerland

    Hunter, B., Colley, J., Street, A., Heywood, R., Prentice, D. and
    Magnusson, G. (1978) Xylitol tumorigenicity and toxicity study in
    long-term dietary administration to rats. Unpublished report from
    Huntingdon Research Centre, submitted to World Health Organization by
    F. Hoffman La Roche Co., Ltd., Basle, Switzerland

    Palmer, A. K. and Bottomley, A. M. (1977) Effect of xylitol during a
    modified teratology study in rats. Final report. Unpublished report
    from Huntingdon Research Centre, Huntingdon, Cambridgeshire, England;
    submitted to the World Health Organization by Hoffman La Roche Co.,
    Ltd., Basle Switzerland

    Palmer, A. K., Bottomley, A.M., Wight, D. G. D. and Cherry, C. P.
    (1978) Effect of xylitol on reproductive functions of multiple
    generations in the rat. Final report. Unpublished report from
    Huntingdon Research Centre, Huntingdon, Cambridgeshire, England;
    submitted to the World Health Organization by F. Hoffman La Roche Co.,
    Ltd., Basle, Switzerland

    See Also:
       Toxicological Abbreviations
       Sorbitol (FAO Nutrition Meetings Report Series 40abc)
       Sorbitol (WHO Food Additives Series 5)
       SORBITOL (JECFA Evaluation)