These substances were evaluated for an Acceptable Daily Intake by
    the Committee in 1969, 1973, 1976 and 1980 (Annex 1, Refs 17, 32, 41,
    53) and toxicological monographs were prepared on each occasion.  In
    1980, a Group Acceptable Daily Intake of 0-10 mg/kg bw/day was

         The present Committee considered the consequences of changing the
    specifications to include the solvent residues dimethyl sulfoxide
    (DMSO), isobutanol and methyl ethyl ketone.  The Committee noted that
    no ADI had been established for these solvents.   (Isobutanol and
    methyl ethyl ketone were reviewed by the twenty-third meeting of the
    Committee in 1979; in both cases it was concluded that the data
    available were insufficient for evaluation of the compounds for an
    ADI.  Dimethyl sulfoxide has not previously been evaluated by the

         Additional toxicological data on sucrose esters of fatty acids
    were available and are summarized and discussed in the following
    monograph addenda.



    2.2  Toxicological studies

    2.2.2  Short-term studies  Dogs

         Groups of three male and three female beagle dogs received in
    their diet sucrose esters of mixed stearic and palmitic acids at
    concentrations of 0.3%, 1% or 3% daily for 26 weeks.  A separate
    control group of three male and three female dogs maintained on diet
    alone served as control.  During the entire study, the group mean
    daily intake of the esters was equal to 102, 345 and 1091 mg/kg bw/day
    in male dogs and 104, 367 and 1139 mg/kg bw/day in female dogs in the
    three corresponding treatment groups.  No animals died during the
    study.  Body weights, food and water consumption, clinical chemistry,
    hematology and urinalysis were essentially within normal ranges. 
    Gross and microscopic examinations of tissues and major organs
    revealed no significant changes that could be attributed to the
    ingestion of the esters (Chesterman  et al., 1979).

    2.2.3  Long-term/carcinogenicity studies  Mice

         Groups of 21 male and 21 female ddY mice were fed on a diet
    containing 0, 0.3 or 3% sucrose ester for 76 weeks.  No significant
    differences in average growth rate or food intake were found.  Organ
    weights and hematological indices of five animals of each sex of each
    group showed no significant differences between test and control
    animals.  Serum alkaline phosphatase activity was higher in males on
    the 3% diet and blood triglyceride levels were three times the control
    level in males on the 0.3% and 3% diets.  However, no such differences
    were found in females and the significance of the findings is
    uncertain in view of the small number of animals examined.  Mortality
    was said to be unaffected but data on this were not provided.  Gross
    and micro-pathological findings in three controls, three 0.3% and ten
    3.0% animals showed no evidence of abnormalities caused by exposure to
    the sucrose ester (Murata  et al., 1976).


    2.2.2  Short-term studies  Rats

         Groups of five male and five female CD rats were given diets
    containing 0, 10% or 20% sucroglyceride for 13 weeks.  The intakes
    were equal to 5.38 and 6.15 g/kg bw/day for males and females of the
    lower dose group, and 11.03 and 12.03 g/kg bw/day for males and
    females of the higher dose group, respectively.  In female, but not
    male, animals of both treatment groups, food intake was significantly
    lower than controls throughout the study.  Weight gains were reduced
    for rats of both sexes in the higher treatment group, and to a lesser
    extent in the lower group but the decrease in weight gain was only
    statistically significant in top dose group males.  Water intake of
    the high dose males during week 4 was significantly elevated relative
    to controls but no such differences were apparent in weeks 8 or 13. 
    There was a dose dependent reduction in liver weight in animals of
    both sexes.  There were no histopathological changes related to
    treatment (Hunter  et al., 1980).  Dogs

         A preliminary study was performed to establish suitable dietary
    levels for a 13-week study in beagle dogs.  Three pairs of one male
    and one female dog received diets containing 0, 10 or 20%
    sucroglyceride in their diets. Due to enforced variations in protocol
    during the course of the study, direct comparison between pairs was
    complicated by other variables but treatment with sucroglyceride in
    semi-synthetic diet at 10 or 20% levels resulted in reduced body
    weight gain or slight weight loss.  Animals in the higher dose group,
    whose treatment continued for a longer period, showed some signs of
    recovery.  Deterioration in coat condition was noted in both dogs in
    the higher dose group but a marked improvement was apparent following
    the addition of corn oil to the diet (Chesterman  et al., 1980a).

         Four groups of five male and five female beagle dogs received
    sucroglyceride in the diet at levels of 0, 5, 10 or 20% for 132 weeks;
    two animals of each sex were observed for a further 8 weeks after
    cessation of treatment.  At termination, a bone marrow smear was
    prepared from each animal and organs were weighed.  Comprehensive
    histopathological examinations were performed on all animals.

         Animals in the 20% dose group showed adverse effects on body
    weight and two males in the 10% group also showed adverse effects on
    body weight which were probably treatment-related.  During the post-
    treatment observation period some animals from the treated groups
    showed an increased body weight gain, most marked in the animals which
    had received 20% sucroglyceride.  No ophthalmological or hematological
    changes due to treatment were observed and no abnormalities were seen

    on urinalysis.  Elevated alkaline phosphatase activity was seen in a
    number of animals of the 20% dose group, returning to normal 4 weeks
    after treatment ceased.  SGPT levels were increased in the highest
    dose group but fell during the post-treatment period.  Cholesterol
    values for control animals were higher than usual but treatment with
    20% sucroglyceride led to lower cholesterol levels, and cholesterol
    values in previously treated animals tended to rise when treatment was
    discontinued.  No gross abnormalities due to treatment were seen at
    autopsy and all organ weights were within normal limits although, when
    adjusted for final body weight, the mean kidney weights for all groups
    receiving sucroglyceride were significantly greater than control
    values.  In addition, the mean heart weights of the 10% and 20% groups
    were also elevated after 13 weeks dosing but no significant
    differences remained in animals 8 weeks after treatment was
    discontinued.  The only histopathological effects noted were in the
    livers of female animals treated with 20% sucroglyceride.  After 13
    weeks marked numbers of vacuolated centrilobular hepatocytes were
    observed, all of which showed moderate to marked fat deposits.  The
    liver of one female killed 8 weeks after cessation of treatment with
    20% sucroglyceride showed a minimal number of vacuolated centrilobular
    hepatocytes with trace fat deposits (Chesterman  et al., 1980b).

    2.2.3  Long-term/carcinogenicity studies  Rats

         Four groups of 50 male and 50 female CD weanling rats were given
    diets containing 0, 5%, 10% or 20% sucroglyceride for 106 weeks
    (females) or 108 weeks (males).  The intakes averaged over the whole
    treatment period were equal to 1.59, 3.37 and 7.70 g/kg bw/day for
    males, and 1.86, 4.01 and 9.25 g/kg bw/day for females in the three
    respective dose groups.  Satellite groups of 15 animals of each sex
    were included for interim blood anlaysis; these animals were
    sacrificed after 78 weeks.

         All rats killed  in extremis or found dead during the course of
    the study were subjected to macrosocopic autopsy examination and,
    where possible, tissues were examined histologically.  At terminal
    autopsy, organ weights were recorded.  Complete histopathological
    examination was performed on each group.

         Food intake in rats receiving 20% sucroglyceride was greater than
    controls, particularly during the first 52 weeks but body weight gain
    of treated male, and to a lesser degree female, animals showed a dose-
    related decrement in the early part of the study and up to week 78 in
    the top dose group.  Food efficiency was significantly reduced in the
    20% dose group and in males of the 10% dose group.  Water intake in
    the highest dose group was elevated during weeks 5, 13, 26 and 40 and,
    for females only, during week 51; thereafter no treatment dependent
    difference was observed.  Clinical signs during the study included
    brown staining of the fur, pale fecal pellets and poor grooming in all

    treatment groups.  Mortality in the treated animals was lower than in
    controls, probably associated with the reduced body weight.  The only
    consistent difference in hematological parameters between control and
    high dose animals was a marginally elevated platelet count at weeks
    25, 51 and 77; subsequent (week 78) examination of all dose groups did
    not conclusively indicate any treatment-related effect and no changes
    were seen at week 102.  During weeks 6, 12 and 25, serum alkaline
    phosphatase and SGPT were higher in the top dose group than in
    controls but the levels were similar to controls at subsequent
    analyses.  A transient elevation of SGPT was observed in the
    intermediate dose group only during week 6.  Treatment-related
    elevated serum potassium concentrations were  observed at weeks 25 and
    51 in females of the top dose group and in both sexes at week 77, but
    the differences were small and were not noted in week 102.  Urinalysis
    did not reveal any treatment-related changes other than a decrease in
    urine volume, which was possibly related to treatment in female rats
    of the top dose group during weeks 51, 77 and 78.

         No treatment-related abnormalities were seen in the
    ophthalmoscopic examinations or at autopsy.  Small but statistically
    significant differences were seen in some organ weights but these were
    generally not dose dependent and histological examination did not
    reveal any abnormalities related to these differences.  A dose-
    dependent increase in the incidence of basophilic hepatocytes was
    observed in females only.  These changes are commonly observed in old
    rats of this strain.  There was no treatment-related effect on the
    incidence of any tumour type or on the total number of tumours per
    group (Hunter  et al., 1982).


         Modifying of the specifications was considered by the Committee
    for these substances manufactured by a process using the solvents
    DMSO, isobutanol and/or methyl ethyl ketone.  It was noted that an ADI
    (or provisional intake) had not been established for these solvents
    but that DMSO and isobutanol occur naturally in the diet and methyl
    ethyl ketone has been identified as a product of intermediary
    metabolism.  The levels of these solvents in foods as consumed arising
    from residues in sucrose esters of fatty acids which comply with the
    revised specifications are insignificant relative to naturally
    occurring levels in the diet, and there is no reason to suppose that
    they present a hazard.

         The Committee also reviewed new toxicological studies on a palm
    oil sucroglyceride, including a long-term carcinogenicity study in
    rats and short-term studies in rats and dogs.

         It was concluded that sucrose esters of fatty acids manufactured
    by a process using DMSO, isobutanol and/or methyl ethyl ketone as
    solvents, and the palm oil sucroglyceride, could be included in the
    previously established group ADI of 0-10 mg/kg bw/day for sucrose
    esters of fatty acids and sucroglycerides.


    CHESTERMAN, H., ANDREW, J.E. & HEYWOOD, R. (1980a). Celynol MSPO 11
    preliminary dietary toxicity study in beagle dogs. Unpublished Report
    No. 2307 from Huntingdon Research Centre submitted to WHO by Rhône
    Poulenc, Paris, France.

    PRENTICE, D.E., OFFER, J.M. & JOLLY, D.W. (1980b). Celynol MSPO 11
    oral toxicity study in beagle dogs. Unpublished Report No.
    RBNP/141/80255 from Huntingdon Research Centre submitted to WHO by
    Rhône Poulenc, Paris, France.

    GAPINATH, C. (1979). Sucrose ester of mixed stearic and palmitic acid
    dietary study in beagle dogs. Unpublished report from Huntingdon
    Research Centre submitted to Ryoto Company Ltd., Tokyo, Japan,
    submitted to WHO by Rhône Poulenc, Paris, France.

    (1982). Celynol MSPO 11 igenic and toxic effects in dietary
    administration to rats. Unpublished report No. RNP/139/82995 from
    Huntingdon Research Centre submitted to WHO by Rhône Poulenc, Paris,

    WOODHOUSE, R.N. (1980). Celynol MSPO 11: Preliminary assessment of
    toxicity to rats in dietary administration for 13 weeks. Unpublished
    Report No. RNP/138/79689 from Huntingdon Research Centre submitted to
    WHO by Rhône Poulenc, Paris, France.

    MURATA, T., KIMURA, R., AKIMOTO, T., SATO , M. & ITO, K. (1976). Study
    on chronic toxicity of a sucrose ester of fatty acids. Unpublished
    report of the Shizuoke College of Pharmacy and Hokkaido Institute of
    Pharmaceutical Sciences, Japan, submitted to WHO by Rhône Poulenc,
    Paris, France.

    See Also:
       Toxicological Abbreviations