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    WORLD HEALTH ORGANIZATION

    WHO Food Additives Series 1972, No. 1




    TOXICOLOGICAL EVALUATION OF SOME 
    ENZYMES, MODIFIED STARCHES AND 
    CERTAIN OTHER SUBSTANCES




    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    16-24 June 19711





    World Health Organization

    Geneva

    1972





                   

    1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
    Nutrition Meetings Report Series, 1972, No. 50.

    The monographs contained in the present volume are also issued by the
    Food and Agriculture Organization of the United Nations, Rome, as FAO
    Nutrition Meetings Report Series, No. 50A

    (c) FAO and WHO 1972



    ACETYLATED DISTARCH PHOSPHATE

    Modification is usually performed by the use of up to 0.1 per cent. of
    phosphorus oxychloride and 5 per cent. acetic anhydride.  Vinyl
    acetate may be used as an alternative acetylating agent.  Maximum
    acetylation amounts usually to 2.5 per cent. acetyl groups.

    Biological data

    Biochemical aspects

    The digestibilities in vitro by pancreatin and porcine mucosal
    enzymes of acetylated distarch phosphates, modified to 1.6 per cent.
    and 2.3 per cent. acetyl content, were found to be 93 per cent. and 81
    per cent. respectively of that of unmodified starch (Leegwater, 1971).

    Short-term studies

    Rat

    Groups of 10 male and 10 female rats were fed 0, 25 and 50 per cent.
    of two different modified starches (acetic anhydride and vinylacetate
    modified) in their diet for 8 weeks.  Body-weights of animals on the
    higher test level were somewhat lower than at the 25 per cent. level
    and also lower than controls in both sexes.  However, the differences
    were not statistically significant.  The faecal water content was
    variable and could not be related to dietary dosage levels. 
    Production of faecal dry matter was increased in both sexes at the
    higher level tested and slightly so at the 25 per cent. dietary level.
    The incidence of diarrhoea was insignificant.  A dose-related increase
    in caecal weight occurred in both sexes.  No histological abnormality
    of the enlarged caeca was noted (de Groot & Spanjers, 1970).

    Pig

    Groups of 4 male and 4 female pigs were given 0, 35 or 70 per cent. of
    modified starch in their diet over 14-1/2 weeks.  Growth rate and food
    consumption were satisfactory.  Haematology, blood chemistry and
    urinalysis revealed no treatment-related abnormalities. 
    Ophthalmoscopy showed no abnormalities associated with the test
    substance.  Organ weight, gross and histopathology revealed no
    abnormalities in test or control groups.  Three pigs in the higher
    test group died suddenly at various intervals during the test without
    any evidence pointing to the cause of their death.  One pig in the
    higher test group and another in the 35 per cent. group showed
    evidence of neurological malfunction. The animal on 70 per cent. test
    substance died, that on the lower dietary level recovered.  No
    histological evidence of nervous system involvement was noted in these
    two nor in any other animal (Shillam et al., 1971).

    Man

    Twelve volunteers consumed on each of 4 successive days, 60 g
    acetylated distarch phosphates of either 1.6 per cent. or 2.33 per
    cent. acetyl content.  No abnormalities were observed as regards
    frequency and amount of faeces as well as faecal water and lactic acid
    content.  No other adverse effects were noticed (Pieters et al.,
    1971).

    Long-term studies

    Rat

    Groups of 30 male and 30 female rats were fed two different modified
    starches (acetic anhydride and vinylacetate modified) at levels of 0,
    5, 10 and 30 per cent. in their diet for 104 weeks.  Appearance,
    behaviour, food consumption and mortality were not adversely affected
    nor was diarrhoea observed at any level.  Growth was slightly
    depressed at the highest dietary level with both modified starches.
    Haematology, serum chemistry and urinalysis revealed no effects
    related to treatment in any group.  There was a dose-related increase
    in the caecal weight in both sexes at the 30 per cent. level but in
    males only at the 10 per cent. level.  All other organ weights showed
    no treatment-related changes. No gross or microscopic pathological
    abnormalities were noted which could be related to the test substances
    or which would point to any carcinogenic effects or to any compound
    related effects.  The caeca appeared remarkably normal (Til et al.,
    1971a).

    Reproduction studies

    Rat

    A three generation study was performed using 5 males and 10 females
    for the P generation and 10 males and 20 females of the F1b and F2b
    to produce successive generations by mating at week 12 and 20 after
    weaning.  The F3b generation was kept for 3 weeks after weaning and
    then sacrificed for histopathological study.  The P, F1b and F2b
    parents were used for determination of implantation sites.  The test
    material, fed at 10 per cent. of the diet consisted of a starch
    modified with 5 per cent. acetic anhydride and 0.02 per cent.
    phosphorus oxychloride (D.S. of 0.093) and another starch modified
    with 4.5 per cent. vinylacetate and 1.2 per cent. phosphorus
    oxychloride (degree of substitution of 0.064, 0.04 per cent, P
    introduced).  No adverse effects were noted in respect of health,
    behaviour, mortality, growth, fertility, litter size, resorption
    quotient, weaning weight of pups or mortality of young.  Caecal
    weights were only increased in tests using starch modified with acetic
    anhydrides.  Gross pathology of the F3b generation revealed a
    significant difference in the average thyroid weights.  Gross
    examination at autopsy did not reveal any pathological changes
    attributable to the ingestion of the starch but histopathology is
    still outstanding (Til et al., 1971b).

    Special studies

    Groups of 10 male and 10 female rats were fed 0, 25 or 50 per cent. of
    two different modified starches (acetic anhydride and vinylacetate
    modified) in a low residue diet for 7 days followed by the additional
    feeding of 4 per cent. cellulose for 3 days.  The body-weights of all
    animals fed 50 per cent. modified starch were somewhat lower than
    those of the controls.  Production of faecal dry matter was increased
    in the higher groups and less so at the 25 per cent. level.  Diarrhoea
    occurred at the higher level with both modified starches.  The
    addition of 4 per cent. cellulose had no effect on the severity or
    frequency of the diarrhoea.  At the higher level there was also some
    loss of hair in both sexes (de Groot and Spanjers, 1970).

    Comments

    The feeding studies with rat and pig show that these modified starches
    are well utilized.  The long-term and reproduction studies in rats
    indicate no unusual adverse effects apart from caecal enlargement. 
    The suddenness of the death of some of the animals in the pig study
    indicates an aberrant effect not related to the feeding of modified
    starches.  This is reinforced by the absence of any pointer to a
    target organ.  The available evidence for the group of modified
    starches considered suggests that this finding, when not associated
    with any histopathological changes, is of little toxicological
    significance.  It is thus appropriate to use the long-term and
    reproduction studies for evaluation.

    EVALUATION

    Temporarily not limited.*

    Further work required by 1973

    Histological report to complete the reproduction study in the rat.

    REFERENCES

    de Groot, A. P. & Spanjers, M. Th. (1970) Unpublished report No. R
    3096 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

                   

    * Except for good manufacturing practice.

    Shillam  K. W. G., Medd, R. K., Loveridge, G. G., Street, A. E.,
    Hagne, P. & Spicer, E. J. F. (1971) Unpublished report No. 3978/71/136
    by Huntingdon Research Centre

    Til, H. P., Spanjers, M. Th., van der Meulen, H. C. & de Groot, A. P.
    (1971a) Unpublished report No. R 3351 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 Also:
       Toxicological Abbreviations
       Acetylated distarch phosphate  (FAO Nutrition Meetings Report Series 46a)
       Acetylated distarch phosphate (WHO Food Additives Series 5)
       Acetylated distarch phosphate (WHO Food Additives Series 17)
       ACETYLATED DISTARCH PHOSPHATE (JECFA Evaluation)