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    MANNITOL

    EXPLANATION

         Mannitol was evaluated for acceptable intake at the tenth,
    eighteenth, twentieth, and twenty-ninth meetings of the Joint FAO/WHO
    Expert Committee on Food Additives (Annex 1, references 13, 35, 41,
    and 70). A toxicological monograph was published after the tenth
    meeting (Annex 1, reference 12). At its twenty-ninth meeting, the
    Committee extended the temporary ADI of 0-50 mg/kg b.w. to 1986
    pending submission of the results of a number of long-term studies
    completed but not submitted for evaluation. The previously-published
    monograph has been expanded and is reproduced in its entirety below.

    BIOLOGICAL DATA

    Biochemical aspects

         D-Mannitol occurs widely in nature in a variety of plants, algae,
    fungi and certain bacteria. L-Mannitol does not occur naturally.
    Traces of mannitol have been identified occasionally in human urine
    (Pitkänen & Pitkänen, 1964).

         When 14C-D-mannitol was given at a dose of 240 mg/rat orally to
    non-fasted rats, about 50% of the radioactivity was recovered in the
    expired 14CO2 (Wick et al., 1954).

         In similar experiments, also using 14C-D-mannitol at 500 mg/kg
    b.w., fasted rats oxidized 40% of the dose to 14CO2, non-fasted
    rats oxidized 68%; 9.74% was stored in the carcass, 1.28% in the
    liver, and 6.32% was excreted in the urine (Gongwer, 1963).

         Feeding D-mannitol to rats and dogs led to a small but
    significant increase of liver glycogen (Carr et al., 1933;
    Todd et al., 1939; Silberman & Lewis, 1933; Carr & Krantz, 1938).

         When 14C-D-mannitol was administered to rats by i.p. injection,
    77-97% of the dose was excreted in the urine within 24 hours, and only
    2-3% of the mannitol carbon was oxidized to 14CO2. Additional
    experiments, in which mannitol was injected directly into the portal
    vein, showed that mannitol could be oxidized only by the liver
    (Wick et al., 1954).

         D-Mannitol administered i.v. was completely cleared by the
    kidneys of 2 dogs at rates identical to inulin and creatinine
    (Smith et al., 1940).

         Mannitol at a dose of 22.5 g/dog did not elevate the blood sugar
    level of dogs after i.v. injection (Todd et al., 1939).

    Toxicological studies

    Special studies on carcinogenicity

    Mice

         Diets containing 0, 2.5, or 5% mannitol (0, 3750, or 7500 mg/kg
    b.w., respectively) were fed to groups of 50 B6C3F1 mice of each sex
    for 103 weeks. The mice were observed twice daily for clinical signs
    of toxicity and body weights were recorded weekly. The body weights of
    treated females were similar to those of controls, while those of the
    treated males were slightly but not significantly higher than those of
    controls; feed consumption was similar to controls in both dose
    groups. There were no significant differences in survival rates nor in

    tumour incidence between treated animals and controls. Mild nephrosis,
    characterized by focal vacuolation of the tubular epithelium, was
    observed in increased incidence in treated mice of both sexes (control
    males 30%, low-dose males 58%, high-dose males 64%, control females
    2%, low-dose females 6%, high-dose females 29%). The authors concluded
    that this vacuolation was probably caused by osmotic imbalance. Under
    the conditions of this bioassy, mannitol was noncarcinogenic to
    B6C3F1 mice (NTP, 1982; Abdo et al., 1983).

    Rats

         Groups of 50 male and female F344 rats were fed diets containing
    0, 2.5, or 5% mannitol for 103 weeks (corresponding to 0, 1250, or
    2500 mg/kg b.w./day). The body weights of treated males were similar
    to those of controls, while those of treated females were slightly but
    not significantly lower than those of controls; feed consumption was
    similar to controls in both dose groups. There were no significant
    differences in survival rates nor in tumour incidence between treated
    animals and controls. Retinopathy and cataracts occurred at increased
    incidences in high-dose male and mid- and high-dose female rats
    (retinopathy: males-17/50, 6/50, 42/50; females-10/50, 3/50, 33/50;
    cataracts: males-15/50, 6/50, 40/50, females-9/50, 40/50, 32/50; all
    for the controls, mid-, and high-dose groups respectively). This
    increase appears to be associated with the distance of the animals
    from sources of fluorescent light; however, a contributing effect of
    mannitol cannot be discounted completely. Dilatation of the gastric
    fundal gland was observed at increased incidences in dosed females
    (control, 6/50 (12%); low-dose, 23/50 (46%); high-dose, 23/50 (46%)).
    Under the conditions of the bioassay, mannitol was not carcinogenic to
    F344 rats (NTP, 1982; Abdo et al., 1983).

    Special studies on mutagenicity

         Mannitol was non-mutagenic in a host-mediated assay in mice using
    Salmonella typhimurium G46 and TA1530 and Saccharomyces cerevisiae
    strain D3, in a cytogenic assay in rat bone marrow, and in human W1-38
    cells (Green, 1977).

         Mannitol was not mutagenic in the Ames test using S. typhimurium
    strains TA98, TA100, TA1535, and TA1537 (NTP, 1981).

         Results of a dominant lethal assay in rats at doses of mannitol
    of 0, 20, 200, 2000, and 5000 mg/kg b.w. by gavage were negative
    (U.S. FDA, 1974).

    Special study on renal reabsorption

         Intravenous administration of mannitol at an initial dose of
    0.3 g followed by hourly injections of 1 g to Sprague-Dawley rats
    resulted in complete inhibition of salt and water reabsorption from
    the medullary collecting system of the kidney (Sonnenberg, 1978).

    Special studies on teratogenicity

         Mannitol was tested for teratogenic effects in mice, rats, and
    hamsters. Pregnant mice and rats given oral doses of mannitol up to
    1.6 g per kg for 10 consecutive days and hamsters up to 1.2 g per kg
    for 5 consecutive days showed no effects on maternal or fetal
    survival. Mannitol was not teratogenic under the test conditions
    (FDRL, 1972).

    Acute toxicity
                                                                        

                            LD50
    Animal      Route       (mg/kg b.w.)         Reference
                                                                        

    Mouse       oral        22,000               Gongwer, 1960
                i.v.        16,800               Robb, 1964
                i.p.        14,000-16,000        Beck et al., 1936

    Rat         oral        17,300               Gongwer, 1960
                                                                        

         Mice died with signs of central nervous system depression and
    gastrointestinal tract mucosal damage; rats died with predominantly
    gastrointestinal tract signs (Gongwer, 1960; Gongwer, 1961).

    Short-term studies

    Mice

         Groups of five male and five female B6C3F1 mice were fed diets
    containing 0.6, 1.25, 2.5, 5.0, or 10.0% mannitol for 14 days. No
    control groups were used. Animals were killed on days 16-20 and
    necropsies performed on all animals. All animals survived to the end
    of the dosing periods and all groups had similar increases in body
    weight. No compound-related effects were observed (NTP, 1952).

         Groups of 10 male and 10 female B6C3F1 mice were fed diets
    containing 0, 0.3, 0.6, 1.2, 2.5, or 5.0% mannitol for 13 weeks. On
    one day animals from the 0.3 and 0.6% dose groups were accidently
    given diets containing 0.3 or 0.6% Ziram. Animals were checked for
    mortality/ morbidity twice daily. Each animal was subjected to
    clinical examination and palpation weekly, and body weights and food
    intake were recorded weekly. Necropsies were performed on animals in
    the control and top two dose groups. Mean body-weight gain was higher
    than controls in all dose groups except males of the top-dose group,
    where weight gain was similar to controls. All animals survived to
    termination and no compound-related effects were observed at necropsy
    or on histopathological examination (NTP, 1982).

    Rats

         Groups of 20 rats were fed 35% sucrose plus 5% mannitol or 40%
    sucrose (control group) over a period of 3 months. The growth curves
    showed that mannitol was nutritionally inferior to sucrose (Ellis &
    Krantz, 1941). These results are in accord with earlier findings that
    mannitol is inferior to sucrose, as judged by weight gain of rats
    (Ariyama & Takahasi, 1929).

         Groups of 5 male and 5 female F344/N rats (6 weeks of age) were
    fed diets containing 0.6, 1.2, 2.5, 5.0, or 10% mannitol for 14 days.
    No control groups were used. Animals were killed on days 16-20 and
    necropsies performed on all animals. All animals survived to the end
    of the dosing period. Females fed diets containing 10% mannitol gained
    less weight than did other groups. Two of 5 males in the top-dose
    group developed diarrhoea from days 4 to 6. No gross lesions were
    reported at autopsy (NTP, 1982).

         Groups of 10 male and 10 female F344 rats were fed diets
    containing 0, 0.3, 0.6, 1.25, or 5.0% mannitol for 13 weeks. On one
    day, animals from the 0.3 and 0.6% dose groups were accidentally given
    diets containing 0.3 or 0.6% Ziram. Animals were checked for
    mortality/morbidity twice daily. Each animal was subjected to clinical
    examination and palpation weekly, and body weights and food intake
    were recorded weekly. Necropsies were performed at termination and
    haematological and histopathological examinations were performed on
    animals in the control and two highest-dose groups. Mean body-weight
    gains of the top-dose group males were depressed by 9.6% relative to
    controls; mean body-weight gains of other groups were similar to
    controls. All animals survived and no compound-related clinical signs
    or histopathologic effects were observed (NTP, 1982).

    Monkeys

         Three rhesus monkeys were fed 3 g mannitol daily for 3 months.
    Two animals were employed as controls. No toxic signs nor pathological
    changes were observed (Ellis & Krantz, 1941).

    Long-term studies

    Rats

         Wistar-derived SPF albino rats were fed 0, 1, 5, or 10% mannitol
    in their diets for 94 weeks (40 males and 40 females/group).
    Decreasing amounts of corn starch (10, 9, 5, or 0% respectively) were
    added to each diet. Body weights were generally decreased by
    approximately 5-7% in the medium- and high-dose male rats. Food
    consumption, haematology, haemochemistry, histopathology, and most
    urinalyses were unaffected by mannitol administration. Total urinary
    calcium and magnesium were elevated in a dose-related manner, but
    these were not considered to be pathological changes.

         Histopathological evaluation revealed that most neoplasms were
    unrelated to treatment, but a low incidence of benign thymomas in
    female rats was apparently treatment-related (2 benign thymic tumours
    in female controls, 6 in each of the 1 and 5% mannitol groups, and 10
    in the 10% mannitol group). No significant group differences occurred
    for thymomas in male rats (0 in controls, 3 at 1%, 1 at 5%, and 0 at
    10% of mannitol in the diet). No additional treatment-related
    neoplasms occurred in other lymphopoietic tissues (Saatman
    et al., 1978).

         Female rats of the Sprague-Dawley strain were administered
    mannitol at dose levels of 0, 1, 5, or 10% of the diet. All surviving
    rats were killed after 27 months of treatment, when mortality of the
    rats receiving 10% mannitol was 68%. Evaluation of mortality, general
    health and behaviour, body weight, food consumption, urinary
    chemistry, organ weights, and subcutaneous tissue masses observed
    in-life did not indicate any effects due to the administration of
    mannitol. In addition, evaluation of all gross necropsy findings, as
    well as histopathological evaluations of the thymus of all rats, and
    histomorphology of all other tissues of those rats with thymic
    abnormalities, resulted in the conclusion that there was no effect of
    mannitol on Sprague-Dawley rats in this study (Gongwer et al.,
    1978).

         Female rats of the Wistar strain (100 animals/group) were
    administered mannitol at dose levels of 0, 1, 5, or 10% of the diet
    for 30 months. Histopathological evaluations of the thymus of these
    rats revealed no effect of mannitol on the development of primary
    thymic neoplasms. Other findings in the thymus, and in other tissues
    examined histopathologically in those rats with thymic abnormalities,
    were not attributable to the administration of mannitol. There was no
    indication that the incidences of gross necropsy findings were related
    to the administration of mannitol. Slightly increased incidences of
    tissue masses in the cervix and/or uterus noted in the compound-
    treated groups as compared to the control were considered of
    no biological importance because of their low overall incidence. Mean
    adjusted body-weight values of the group which received 10% mannitol
    in the diet were lower (and occasionally statistically significant)
    than in the concurrent control group when all animals were weighed at
    weeks 26 and 52, and when rats of selected replicates were weighed at
    weeks 88-120. Most mean values of the rats receiving 1% of the
    compound in the diet were slightly lower than those of controls
    throughout the study; mean body weights of rats receiving 5% mannitol
    were slightly lower than control weights from approximately weeks
    88-120. Differences in these two groups, however, were slight and not
    statistically significant. Evaluation of mortality, general health and
    behaviour, food consumption, urinary chemistry and volume, terminal
    organ and body weights, and subcutaneous tissue masses observed
    in-life did not indicate any effects which could be attributed to the
    administration of mannitol at levels of 1, 5, and 10% of the diet
    (Gongwer et al., 1978).

         Female Fischer rats (100 animals/group) were administered
    mannitol at dose levels of 0, 1, 5, or 10% of the diet for 30 months.
    Histopathological evaluation of the thymus of these rats revealed no
    effect of mannitol on the development of primary thymic neoplasms.
    Other findings in the thymus, and in other tissues examined
    histopathologically in those rats with thymic abnormalities, were not
    attributable to the administration of mannitol. The incidences of
    gross necropsy findings were not related to the administration of
    mannitol.

         Slightly increased incidences of tissue masses in the anogenital
    area, cervix, and uterus were noted in the 10% Fischer rat group as
    compared to the control group. These findings were not considered to
    be of biological importance; the incidence of uterine masses in this
    study were well within the expected spontaneous incidence rate for
    this strain of rats. The combined incidence of focal medullary
    hyperplasia and medullary pheochromocytoma was higher in the high-dose
    group than in the control or other test groups. However, there 
    was no clear dose response of focal medullary hyperplasia and
    pheochromocytoma, and the investigating pathologists concluded that
    this increased incidence was probably a chance occurrence unrelated to
    the administration of mannitol.

         Mean body weights of Fischer rats receiving mannitol at dietary
    levels of 5 and 10% were slightly lower than concurrent control
    weights from weeks 13 and 60, respectively, through termination of the
    study (with the exception of week 108 in the 5% group). These
    differences were generally small (less than 9%), and the majority were
    not statistically significant. No consistent dose relationship was
    evident. Evaluation of mortality, general health and behaviour, food
    consumption, urinary chemistry and volume, terminal organ and
    body-weights, and subcutaneous tissue masses observed in-life did not
    indicate any effects which could be attributed to the administration
    of mannitol at levels of 1, 5, and 10% of the diet (Gongwer et al.,
    1978).

    Observations in man

         mannitol has a slow rate of absorption from the intestinal tract
    and exerts laxative properties. The laxative threshold for man was
    found to lie between 10 and 20 g of mannitol per single dose (Ellis &
    Krantz, 1941).

         In man, i.v. administration of mannitol is practiced for
    induction of diuresis in oliguria, for forced diuresis in poisoning
    cases, or to measure the extracellular fluid compartment. There is an
    extensive literature available on these aspects (Milde, 1965;
    Widdowson & Dickerson, 1964).

         Following the i.v. injection of 10 g mannitol into man, 81% of
    the dose was excreted unchanged in the urine and up to 80 g produced
    no toxic effect (Smith et al., 1940).

         Administration of 25 g mannitol on 3 subsequent days did not
    significantly influence either the blood-sugar level or the
    respiratory quotient (Ellis & Krantz, 1941).

         When 100 g mannitol was fed, the maximum increase in blood sugar
    level was 10 mg/dl (Field, 1919).

         The i.v. injection of 10 g of mannitol daily over a period of 1
    month produced no significant changes in non-protein nitrogen,
    CO2-combining power of blood, red cell count, or renal function
    (Ellis & Krantz, 1941).

         Ten patients fasted overnight were administered 28 to 100 g of
    (U-14C)-mannitol orally as a 5% aqueous solution. Within this dose
    range, about 20% of the mannitol ingested was excreted unchanged in
    the urine, indicating appreciable absorption. The level of
    radioactivity in the blood rose for the first 2 hours and remained at
    a plateau for 2 to 4 hours; the radioactive compounds present in blood
    were not identified and data on blood glucose levels were not
    reported. Expired 14CO2 increased for 8 hours after mannitol
    ingestion; however, (U-14C)-mannitol administered i.v. produced very
    little radioactive CO2. Oral doses of 40 g or more generally caused
    frequent bowel movements, diarrhoea, and excretion in the stool of a
    higher percentage of the dose. Only traces of radioactivity occurred
    in the urine and stools after 48 hours. It was concluded that within
    an oral dose range of 40 to 100 g, approximately 65% of ingested
    mannitol was absorbed; about one-third of the absorbed mannitol was
    excreted in the urine, the remainder being metabolized presumably in
    the liver (Nasrallah & Iber, 1969).

         Based on the above study, the caloric value of dietary mannitol
    was considered to be about 2 kcal per g (Dwivedi, 1977).

    Comments

         Mannitol is dehydrogenated to fructose and then metabolized
    through the mammalian glycolytic pathway; it occurs endogenously in
    humans.

         No mutagenic or cytotoxic effect was found when mannitol was
    tested in vitro and in vivo. Teratogenic studies in several
    species did not reveal any compound-related adverse effects.

         Mannitol, when fed to rats and mice at up to 5% of the diet, was
    not carcinogenic. Retinopathy and cataract formation occurred at
    increased incidences in male rats in the earliest carcinogenicity
    study, but these effects were not seen in four subsequent studies. An
    increase in the number of benign thymomas was noted in female Wistar
    rats, observed in a lifetime feeding study, and this was not
    reproduced in three other studies designed to evaluate the species
    specificity of this finding. One of the species tested (female Fischer
    rats) had an increased incidence of adrenal medullary hyperplasia plus
    pheochromocytoma (for a discussion of adrenal medullary lesions
    produced by polyols, see Annex 1, reference 62, section 2.5).

         Clinical experience with this substance as a therapeutic agent in
    man has indicated no adverse effects. Mannitol is poorly absorbed and
    exerts a laxative effect on man and animals, a common feature of all
    polyols.

    EVALUATION

    Estimate of acceptable daily intake for man

         ADI "not specified". The fact that high doses of mannitol exert a
    laxative effect in man, which is common feature of all polyols, should
    be taken into account when considering appropriate levels of use of
    polyols, alone and in combination.

    REFERENCES

    Abdo, K.M., Haseman, J.K., Boorman, G., Farnell, D.R., & Kovatch R.
         (1983). Absence of carcinogenic response in F344 rats and
         B6C3F1 mice given D-mannitol in the diet two years.
         Fd. Chem. Toxicol., 21, 259-262.

    Ariyama, T. & Takahasi, K. (1929). J. Agric. Chem. Soc. Japan,
         5, 674.

    Beck, F.F., Carr, C.J., & Krantz, J.C. Jr. (1936). Acute toxicity of
         certain sugar alcohols and their anhydrides. Proc. Soc. Exp.
         Biol. Med. 35, 98-99.

    Carr, C.J., Musser, R., Schmidt, J.E., & Krantz, J.C. Jr. (1933). Fate
         of mannitol and mannitan in animal body. J. Biol. Chem,
         102, 721-732.

    Carr, C.J. & Krantz, J.C. Jr. (1938). Sugar alcohols; fate of
         polygalitol and mannitol in animal body. J. Biol. Chem.,
         124, 221-227.

    Dwivedi, B.K. (1977). Absorption, metabolism and application of
         polyols. In: Hood, L.F., Wardrip, E.K., Bollenback, G.N. (eds).
         Carbohydrates and health, Westport, CN, USA: the AVI Publishing
         Company, Inc., pp. 27-28.

    Ellis, F.W. & Krantz, J.C. Jr. (1941). Sugar alcohols; metabolism and
         toxicity studies with mannitol and sorbitol in man and animals.
         J. Biol. Chem., 141, 147-154.

    Field, C.W. (1919). Blood sugar curves with glucose, lactose, maltose,
         mannite, and cane sugar. Proc. Soc. Exp. Biol. Med., 17, 29.

    FDRL (1972. Teratological evaluation of FDA 71-32 (mannitol) in mice,
         rats and hamsters. Food and Drug Research Laboratories Inc.,
         Maspeth, NY, USA. Submitted to WHO by ICI Americas Inc.,
         Wilmington, DE, USA.

    Gongwer, L.E. (1960). Unpublished report submitted to WHO by Atlas
         Chemical Industries, Ltd. Available from ICI Americas Inc.,
         Wilmington, DE, USA.

    Gongwer, L.E. (1961). Unpublished report submitted to WHO by Atlas
         Chemical Industries, Ltd. Available from ICI Americas Inc.,
         Wilmington, DE, USA.

    Gongwer, L.E. (1963). Unpublished report submitted to WHO by Atlas
         Chemical Industries, Ltd. Available from ICI Americas Inc.,
         Wilmington, DE, USA.

    Gongwer, L.E., Auletta, C.S., Rinehart, W.E., Brown, W.R., & Killeen,
         J.C. (1978). Mannitol II: lifetime feeding study of A-132-01320
         in three strains of female rats. Unpublished report BMRD No. 218
         from ICI Americas Inc., Wilmington, DE, USA. Submitted to WHO by
         ICI Americas Inc.

    Green, S. (1977). Present and future uses of mutagenicity tests for
         assessment of the safety of food additives. J. Environ. Pathol.
         Toxicol., 1, 49.

    Milde, M.D. (1965). Ann. Rev. Pharmac., 5, 125.

    Nasrallah, S.M. & Iber, F.L. (1969). Mannitol absorption and
         metabolism in man. Am. J. Med. Sci., 258(2), 80-55.

    NTP (1981). Mutagenesis testing results. Results from the Salmonella
         typhimurium assay. National Toxicology Program, Technical
         Bulletin No. 4, April 1981.

    NTP (1982). Carcinogenesis bioassay of D-mannitol (CAS No. 69-65-8) in
         F344/N rats and B6C3F1 mice (feed study).  National Toxicology
         Program, Technical Report Series No. 236.

    Pitkänen, E. & Pitkänen, A. (1964). Polyhydric alcohols in human
         urine. II. Ann. Med. Exp. Fenn., 42, 113-116.

    Robb, B.J. (1964). Unpublished report submitted to WHO by Atlas
         Chemical Industries, Ltd. Available from ICI Americas Inc.,
         Wilmington, DE, USA.

    Saatman, R.A., DeBaeck, P.J., Straett, C.S., Malya, P.A.G., Hubben,
         F., Yah, C., Enold, G.L., & McCurdy, D.H. (1978). Mannitol: a
         lifetime feeding study in rats. Part I. Unpublished report No.
         BMRD 220 from ICI Americas Inc., Wilmington, DE, USA. Submitted
         to WHO by ICI Americas Inc.

    Silberman, A.K. & Lewis, H.B. (1933). Glycogen formation after oral
         administration of mannitol to white rats. Proc. Soc. Exp.
         Biol. Med., 31, 253-255.

    Smith, W.W., Finkelstein, N., & Smith, H.W. (1940). Renal excretion of
         hexitols (sorbitol, mannitol, and dulcitol) and their derivatives
         (sorbitan, isomannide, and sorbide) and of endogenous
         creatinine-like chromogen in dog and man. J. Biol. Chem.,
         135, 231-250.

    Sonnenberg, H. (1975). Effects of furosemide, acetazolamide, and
         mannitol on medullary collecting-duct function in the rat kidney.
         Pfluegers Arch., 373, 113-123.

    Todd, W.R., Myers, J., & West, E.S. (1939). On metabolism of sorbitol
         and mannitol. J. Biol. Chem., 127, 275-284.

    U.S. FDA. (1974) Mutagenic evaluation of compound FDA 71-32, mannitol,
         U.S.P. Litton Bionetics, Inc. U.S. NTIS Report (PB-245-449).

    Wick, A.N., Morita, T.N., & Joseph L. (1954). The oxidation of
         mannitol Proc. Soc. Exp. Biol. Med. 85, 188-190.

    Widdowson E.M. & Dickerson, J.W.T. (1964). In; Comar L.C. & Brommer,
         F. (ed.), Mineral Metabolism. New York-London, Vol. IIA, p. 13.
    


    See Also:
       Toxicological Abbreviations
       Mannitol (FAO Nutrition Meetings Report Series 40abc)
       MANNITOL (JECFA Evaluation)