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    Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents



    WHO FOOD ADDITIVES SERIES NO. 5







    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization
    Geneva
    1974

              

    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.

    HYDROXYPROPYL DISTARCH GLYCEROL

    Explanation

         Modification is performed by the use of 0.1% epichlorhydrin and
    up to 10% propylene oxide. Cross-linkage would be no greater than
    expected on modification with 0.1% epichlorhydrin. Substitution by
    treatment with 10% propylene oxide would probably add no more than
    15-20 ether linkages per 100 glucopyranose units.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         The in vitro digestibility of a hydroxypropyl distarch glycerol
    (degree of substitution 0.04) by pancreatin and porcine intestinal
    mucose was found to be 86% of that of the native starch (Leegwater,
    1971).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

         Groups each of 10 male and 20 female rats were fed the modified
    starch at a level of 10% in their diet for a period of three
    generations. Rats were mated (P1, F1 and F2) at week 12 and 20
    after weaning. Each generation was mated twice and the litter from the
    second generation used to produce the next generation. No adverse
    effects were noted on fertility, number of pups per litter, body
    weight of young, mortality experience or resorption quotient that
    could be ascribed to treatment. The average relative caecum weight
    (filled) of females of the P and F2 generation was greater than
    controls, but empty caecum weight did not differ from controls. The
    relative caecum weight (filled and empty) of males of the F1
    generation did not differ from controls. Growth of the F3b generation
    maintained on test diet for three weeks was normal. Relative organ
    weights were comparable to control, with the exception of decreased
    thyroid weight and distinctly increased caecal weight (both filled and
    empty) in male pups, and increased empty caecal weight in female pups.
    Gross examination of organs at autopsy did not show any compound-
    related changes. Gross and microscopic examination of F3b rats did
    not show any compound-related changes (Til et al., 1971b).

    Short-term studies

    Rat

         Groups of 10 male and 10 female rats were fed for eight weeks on
    a diet containing 25 or 50% modified starch. Although the body weights
    of males at the higher level tested were slightly lower than those of
    the controls, the differences were not statistically significant. The
    faecal dry matter content was increased at both test levels in both
    sexes and there was considerable diarrhoea at the 50% level in both
    sexes. Slight diarrhoea occurred at the 25% level in both sexes.
    Caecal weights were increased in a dose-related manner at all levels
    in all test groups but no histological abnormalities could be detected
    in the caeca (de Groot & Spanjers, 1970).

         Groups of 25 male and 25 female rats were fed for 13 weeks on a
    diet containing 1 and 5% of modified starch or 5% of native starch.
    The general appearance and behaviour of test rats was comparable with
    the controls. One male and one female rat died at the lower test
    level. Growth, feed consumption, body weight, haematology at one and
    three months, urinalysis at one and three months, gross and
    histopathological findings were comparable in all groups (Knapp,
    1967a).

         In another experiment, groups of 10 male and 10 female rats were
    fed for 90 days diets containing 0, 5, 10 or 30% modified starch. No
    differences between test and control animals were noted with regard to
    appearance, behaviour, growth, food consumption, haematology, serum
    chemistry urinalysis. No definite diarrhoea occurred at any test
    level. The amounts of dry matter in the faeces did not vary
    significantly between controls and treated animals. Only at the 30%
    level were the caecal weights increased in both sexes. Gross and
    histopathology were otherwise unremarkable in all groups.
    Histopathology of the enlarged caeca showed no recognizable
    abnormality (de Knecht-van Eekelen et al., 1970).

    Dog

         Three groups of four male and four female beagle dogs were given
    in their diet 1 and 5% of modified starch or 5% of native starch for
    13 weeks. Haematological studies, blood sugar, blood urea, serum GPT
    and alkaline phosphatase as well as urinalysis were comparable for all
    groups. Appearance and behaviour were normal. Body weight changes were
    unrelated to the administration of the test substance. Gross and
    histopathology showed no consistent abnormalities. Organ weights of
    thyroid, heart, liver, spleen, kidneys, adrenals and testes showed no
    test-related changes (Knapp, 1967b).

    Pig

         Groups of eight Pitman-Moore miniature pigs were weaned at three
    days of age, and were fed formula diets containing 5.4% unmodified
    starch or 4.9% hydroxypropyl distarch glycerol for 25 days. Growth was
    normal during the test period. At termination of the study,
    biochemical analyses of blood (haemoglobin) and serum (cholesterol,
    triglyceride, calcium, phosphorus, alkaline phosphatase, urea
    nitrogen, total protein, albumin and globulin) were similar for test
    and control animals. Relative organ weight as well as carcass
    composition (water, fat, protein, ash, Ca, PO4, Na, Mg) and liver
    composition (water, fat, protein and ash), were similar for test and
    control animals (Anderson et al., 1973).

    Long-term studies

         Groups of 30 male and 30 female rats were fed for 104 weeks
    modified starch at 0, 5, 10 and 30% of their diet. No differences were
    noted between test and control animals with regard to appearance,
    behaviour, food consumption, haematology, serum chemistry and
    urinalysis. The mortality of females at the 30% level was slightly
    higher. The growth rate was slightly reduced for both sexes at the 30%
    level when compared with controls. Caecal weight was increased at 30%
    in males and at 10% and 30% in females. Microscopic examination
    revealed no noticeable changes in the caecal wall. Renal calcification
    accompanied by focal hyperplasia of the pelvic epithelium was more
    marked in males fed 30% of the test compound than in control males. No
    distinct compound-related gross or microscopic changes were
    encountered in any of the organs examined (Til et al., 1971a).

    OBSERVATIONS IN MAN

         Twelve volunteers consumed 60 g modified starch on each of four
    successive days. No adverse effects were noticed and no abnormalities
    occurred as regards frequency and amount of faeces or faecal water and
    lactic acid content (Pieters et al., 1971). 

    Comments:

         The feeding studies with rats, dogs and pigs show that the
    modified starch is well utilized. The studies with radio-labelled
    hydroxypropyl starch provide some information in the rat on the
    metabolic fate of the hydroxypropyl moiety. Several short-term studies
    in the rat and dog show no adverse effects even at high dietary
    levels. The available evidence for the group of modified starches
    considered indicates that caecal enlargement without associated
    histopathological changes is without toxicological significance. The
    long-term and reproduction studies in the rat indicate no significant
    adverse effects and may be used for evaluation.

    EVALUATION

    Estimate of acceptable daily intake for man

         Not limited.*

    REFERENCES

    Anderson, T. A. et al. (1973) Unpublished data submitted to Corn
         Refiners Ass., Inc.

    de Groot, A. P. & Spanjers, M. Th. (1970) Unpublished report
         No. R 3096 by Centraal Instituut voor Voedingsonderzoek

    Knapp, W. A. jr (1967a) Report of Hazleton Laboratories Inc.,
         submitted by the International Latex and Chemical Corporation

    Knapp, W. A. jr (1967b) Report of Hazleton Laboratories Inc.,
         28 February submitted by the International Latex and Chemical
         Corporation

    de Knecht-van Eekelen, A., Willems, M. & de Groot, A. P. (1970)
         Unpublished report No. R 3093 by Centraal Instituut voor
         Voedingsonderzoek

    Leegwater. D. C. (1971) Unpublished report No. R 3431 by Centraal
         Instituut voor Voedingsonderzoek

    Pieters, J. J. L., van Staveren, W. A. & Brinkhuis, B. G. A. M. (1971)
         Unpublished report No. R 3433 by Centraal Instituut voor
         Voedingsonderzoek

    Til, H. P. et al. (1971a) Unpublished report No. R 3363 by Centraal
         Instituut voor Voedingsonderzoek

    Til, H. P., Spanjers, M. Th. & de Groot, A. P. (1971b) Report No. 3403
         of Centraal Instituut voor Voedingsonderzoek, submitted to WHO

              

    *    See relevant paragraph in the seventeenth report, pages 10-11.


    See Also:
       Toxicological Abbreviations
       Hydroxypropyl distarch glycerol  (FAO Nutrition Meetings Report Series 46a)
       Hydroxypropyl distarch glycerol (WHO Food Additives Series 1)
       Hydroxypropyl distarch glycerol (WHO Food Additives Series 17)
       HYDROXYPROPYL DISTARCH GLYCEROL (JECFA Evaluation)