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    GLUCOSE ISOMERASE (non-immobilized and immobilized)
           from STREPTOMYCES RUBIGINOSIS

    EXPLANATION

         These enzymes preparations have not been previously reviewed by
    the Joint FAO/WHO Expert Committee on Food Additives.

    BIOLOGICAL DATA

    Biochemical aspects

         No information available.

    Toxicological studies

    Special studies on reproduction

    Rats

         Groups of 10-12 male Wistar-derived rats were fed diets for
    60 days containing 0, 0.4, or 1.6% of an enzyme preparation
    (non-immobilized), in use prior to 1973 (designated HFE), or 0.125 or
    1.25% of an enzyme preparation immobilized to DEAE-cellulose
    (designated DCI), which has been used since 1973. Females kept on the
    same diets for 14 days were mated on a one-to-one basis with the dosed
    males. After one week the first set of females were replaced with a
    new set and mated with the males. One set of females was allowed to
    cast their litters normally and nurse the young until weaning at 21
    days. The second set of females was sacrificed on day 13 of pregnancy
    and the uterine contents examined. The fertility was slightly
    depressed in all dosed groups as compared to the control values and
    the response was characterised as not unusual in animals fed semi-
    purified diets. Resorptions were increased as compared to controls in
    the high-dose HFE and DCI groups, but the magnitude of the effect was
    not regarded as significant. There were no compound-related effects on
    gestation, viability, or lactation indices, nor on corpora lutea,
    total implants, or live fetuses (Cox et al., 1973).

         Groups of 24-29 pregnant Wistar rats were fed diets which
    provided 0, 200, or 800 mg/kg b.w./day of HFE, or 62.5 or 625 mg/kg
    b.w./day of DCI. The test compounds were fed beginning at day 14 of
    pregnancy and continued through parturition and lactation until
    weaning at day 21. No compound-related changes were observed on
    fertility, gestation, viability, or lactation indices (Cox et al.,
    1973).

    Special studies on teratology

    Rats

         Groups of 22 pregnant female Wistar-derived rats were given doses
    of 0, 200, or 800 mg/kg b.w. of HFE, or doses of 62.5 or 625 mg/kg
    b.w. of DCI by gavage daily from days 6 through 15 of pregnancy. The
    animals were sacrificed and their uterine contents examined 1 day
    prior to the full term of pregnancy. One-third of the foetuses were
    subjected to visceral examination and two-thirds were processed for
    skeletal examination. No compound-related effects were observed on
    soft tissue or skeletal abnormalities, nor on number of implant sites,
    resorption sites, or live and dead foetuses (Cox et al., 1973).

    Rabbits

         Groups of 13-17 female Dutch-belted rabbits were artificially
    inseminated and dosed daily with 0, 200, or 800 mg/kg b.w. HFE or with
    62.5 or 625 mg/kg b.w. DCI by gavage on days 6-18 of pregnancy. On day
    28 the animals were subjected to Ceasarean section and the uterine
    contents examined. The pups were placed in an incubator for 24 hours
    for evaluation of neonatal survival, then examined for visceral
    abnormalities and processed for skeletal examination. There was a
    small increase in number of resorptions and/or foetal deaths in the
    high-dose HFE groups. There were no compound-related effects on
    corpora lutea, implant sites, live foetuses, or soft tissue or
    skeletal anomalies (Cox, et al., 1973).

    Acute toxicity

         No information available.

    Short-term studies

    Rats

         Groups of 20 weanling rats/sex/dose were fed diets containing 0,
    3, 6, or 12% of an enzyme "cake" of a glucose isomerase preparation
    for 90 days. Pathology studies were conducted on 10 animals of each
    sex in the high-dose and control groups. No adverse effects were found
    with respect to body-weight gain, clinical chemistry, haematology,
    relative and absolute organ weights, or gross and microscopic
    pathology (Oser, 1969).

         A 33-week feeding study was carried out in Wistar rats. Groups of
    30 males and 30 females were fed diets containing 0.4 or 4.0% HFE or
    0.125 or 1.25% DCI. The animals in the high-dose HFE group showed a
    marked decrease in food intake and began losing weight by the ninth
    week. Four animals/sex in the high-dose HFE group were sacrificed and
    necropsied at 10 weeks. The remaining animals in the high-dose group
    were removed from the 4% diet and separated into 2 equal groups. One

    group received a basal (control) diet and one received 2% of the HFE
    preparation. An immediate resumption of food intake and growth ensued,
    and after a 2-week period all of the original animals on the high-dose
    diet were recombined and put on the 2% diet. An interim sacrifice of 5
    animals/sex/group was conducted at week 16 for pathological
    examination. Laboratory analyses for haematology, clinical chemistry,
    and urinalysis were conducted on 10 animals/sex/group at 6, 12, and 26
    weeks. The results of these analyses indicated no compound-related
    effects. Gross and microscopic pathology studies and studies on organ
    weights at 16 and 33 weeks showed no compound-related effects of
    either enzyme preparation.

         An additional study was conducted to determine if palatability
    was the cause of the weight loss exhibited in the high-dose (4%) HFE
    animals. Groups of 10 rats/sex were given 0 or 2000 mg/kg b.w. of the
    HFE preparation daily by gavage in a water vehicle (both groups
    received a control diet). Decreased weight gain was observed in the
    treated rats, more markedly in the males. However, the magnitude of
    the effect was much less than seen in the dietary study, indicating
    that palatability was likely a factor in that study (Cox et al.,
    1973).

    Dogs

         Groups of 5 dogs/sex were given diets containing 0.4 or 4.0% HFE,
    or 0.125 or 1.25% DCI, for 30 weeks. An interim sacrifice of 1
    animal/group/sex was carried out at 11 weeks in the high-dose group
    and 14 weeks in the remaining groups. There were palatability problems
    in dogs at the 4% level of the HFE preparation. After 2 weeks, 0.1%
    dried garlic was added to their diet in an attempt to mask the odor of
    HFE. At 12 weeks, because of reduced-weight gain and palatability
    difficulties, the high-dose HFE diet was reduced to 2.0%. Other than
    reduced-weight gain in the high-dose HFE dogs there were no compound-
    related effects on weight gain, haematology, clinical chemistry,
    urinalysis, organ weights, or gross or microscopic pathology
    (Cox et al., 1973).

    Long-term studies

         No information available.

    Observations in man

         No information available.

    Comments

         Decreased weight gain, due in part at least to reduced dietary
    palatability, was seen when high doses of the non-immobilized (HFE)
    form of the enzyme was fed to rats and dogs. A suggestion of a
    possible foetotoxic response was also seen when high doses of the
    enzyme were given to rats and rabbits. No gross or microscopic
    pathology was associated with this form of the enzyme.

         The immobilized form of the enzyme showed no adverse effects in
    short-term feeding studies in rats and dogs, teratology studies in
    rats, dogs, and rabbits, or in reproduction studies in rats except for
    a small increase in resorptions, which was of uncertain significance,
    in animals given high doses of the substance.

    EVALUATION

    Level causing no toxicological effect

    Non-immobilized enzyme

    Rats:     2% (20,000 ppm) in the diet, equivalent to 2000 mg/kg
              b.w./day.

    Immobilized enzyme

    Rats:     1.25% (12,500 ppm) in the diet, equivalent to 1250 mg/kg
              b.w./day.

    Estimate of acceptable daily intake for man

    Non-immobilized enzyme

    No ADI allocated, because no information was available on the food use
    of the non-immobilized enzyme.

    Immobilized enzyme

    Acceptable for use in food processing when used as a component in an
    immobilized system.

    REFERENCES

    Cox, G.E., Bailey, D.E., & Morareidge, K. (1973). Sub-acute feeding
         studies in rats and dogs with glucose isomerase enzyme
         preparations. Unpublished report of Food and Drug Research
         Laboratories, Inc., Waverly, NY, USA. Submitted to WHO by Nabisco
         Brands, Inc.

    Oser, B.L. (1969). Subacute (90 day) feeding studies with enzyme cake
         and isomerase 100 (converted starch). Unpublished report of Food
         and Drug Research Laboratories, Inc., Waverly, NY, USA. Submitted
         to WHO by Nabisco Brands, Inc.
    


    See Also:
       Toxicological Abbreviations