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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.

    POLYVINYL PYRROLIDONE

    Explanation

         This substance has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 13) in 1966.

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Polyvinyl pyrrolidone (PVP) is a macromolecular polymer of
    N-vinylpyrrolidone. It is metabolically inert in rat, dog and man as
    shown by experiments using 14C- or 131I-labelled PVP (Ravin et al.,
    1952). It has been widely used as plasma expander. The excretion of
    PVP is inversely related to increasing molecular weight. The
    glomerulus can excrete all PVP of molecular weight 40 000 or below
    within a few days (Ravin et al., 1952). Low molecular weight PVP
    adsorbs various substances, e.g. bacterial toxins, inorganic poisons,
    barbiturates, vitamins and hormones in the blood, either reducing
    their toxicity or prolonging their activity (Weese, 1944). In blood it
    is mainly attached to the gamma-globulins (Bennhold & Schubert, 1944). 
    The reticuloendothelial system retains PVP with a molecular weight in
    excess of about 100 000 for a long time (Ravin et al., 1952; Heinrich
    et al., 1966; Weese & Fresen, 1952). PVP is also accumulated in the
    mitochondria of the kidneys (Traenckner, 1954). In the PVP-storing
    cells it is surrounded by proteins, carbohydrates and lipids in a
    capsule-like manner, perhaps due to coacervation processes (Hübner,
    1960). The problem of whether the extremely long storage of PVP in the
    body produces toxic effects is open to discussion (Altemeir et al.,
    1954; Ammon & Miller, 1949).

         Transfer of intravenously injected PVP to the brain or through
    the placenta was not observed (Ravin et al., 1952). I.v. injection of
    131I-labelled PVP has been clinically used to detect gastrointestinal
    protein losses.

         PVP of m.w. 11 500 is not absorbed from the intestinal tract by
    man or by rat (Angerwall & Berntsson, 1961). PVP of m.w. 16 000 is not
    absorbed from the gastrointestinal tract by guinea-pigs (Scheffner,
    1955).

    TOXICOLOGICAL STUDIES

    Special studies

         In rats, weekly subcutaneous injections of 6% solution induced
    fibrosarcoma in 43% (Lusky & Nelson, 1957).

         Daily hypodermal injections in the guinea-pig lead to
    accumulation in liver, spleen and lungs (Cabanne et al., 1966).

         Six different samples were given to rats by subcutaneous and
    peritoneal implantation and by intravenous injection. After 18 months,
    127 of 295 rats treated with four of the samples were dead: of these,
    34 had generalized reticulum cell sarcomas, originating from lymph
    nodes, and four had sarcomas originating from Kupffer cells. No
    tumours were seen in rabbits or mice given comparable treatment
    (Hueper, 1956).

    Acute toxicity
                                                                         

    Animal      Route   Molecular       LD50           References
                        weight          (mg/kg bw)
                                                                         

                                                       Scheffner, 1955;
    Rat         oral    10 000-30 000   > 40 000       Badische Anilin &
                                                       Sodafabrik, 1958

                                                       Scheffner, 1955;
    Mouse       oral                    > 40 000       Badische Anilin &
                                                       Sodafabrik, 1958

                i.p.                    12 000-15 000  Angerwall &
                                                       Berntsson, 1961

                                                       Burnette, 1962;
    Rat         oral    40 000          100 000        Shelanski et al.,
                                                       1954

                                                       Burnette, 1962;
    Guinea-pig  oral    40 000          100 000        Shelanski et al.,
                                                       1954
                                                                         

         Oral PVP (m.w. up to 40 000) in higher doses causes diarrhoea,
    the minimal effective dose being 0.5 g/kg bw for cats, and 1 to 2 g/kg
    bw for dogs (Scheffner, 1955).

    Short-term studies

    PVP molecular weight up to 40 000

    Dog

         Four groups of four beagle dogs were fed 0, 2, 5 and 10% PVP
    (m.w. 38 000) for two years. There were no differences in weight gain,
    food consumption and results of the examinations of blood and urine.
    At the end of the two-year period all animals were in good health and
    histological examination disclosed no specific changes, except for
    swollen RES cells in the mesenteric and other lymph nodes of all test
    groups, especially at the 10% level. No PVP was detected in the urine.
    No malignant tumours were detected (Burnette, 1962). In two similar
    feeding experiments using a total of 32 dogs and lasting for one year
    no adverse effects could be detected. The intestines, spleens and
    livers of all animals were shown to be free of PVP, but PVP was
    demonstrated in the mesenteric lymph nodes of all animals, including
    the controls (Burnette, 1962).

         Several other short-term studies in rat, cat and dog showed no
    toxic effects (Scheffner, 1955).

    PVP molecular weight 220 000 to 1 500 000

    Dog

         Two dogs were given oral doses of 5 g/kg bw PVP (m.w 220 000 and
    1 500 000) for one and-a-half weeks and two weeks respectively without
    any abnormal findings (Scheffner, 1955).

    Long-term studies

    Rat

         Groups of rats were fed diets containing 0, 1 and 10% PVP
    (m.w. 38 000) for two years. No toxic effects or gross or histological
    changes were noted which could be attributed to the test compound.
    There was no evidence of absorption of PVP from the intestinal tract
    (Badische Anilin & Sodafabrik, 1958; Burnette, 1962).

    OBSERVATIONS IN MAN

         Daily subcutaneous injections of polyvinyl-pyrrolidone-
    vasopressin in a woman with diabetes insipidus for six years led
    to a papular dermatosis. Polyvinylpyrrolidone was detected in biopsy
    material (La Chapelle, 1966).

    Comments:

         There is a large amount of experience available on the parenteral
    administration of PVP to man. I.v. injected PVP having a molecular
    weight exceeding 40 000 is stored in the body for a long time, mainly
    in the RES. Orally administered PVP is not absorbed from the
    intestinal tract except perhaps in very small quantities that may
    enter the intestinal lymph nodes. Further feeding experiments in order
    to clarify the problem of possible body storage of PVP and studies on
    the possible effects of PVP on the absorption of nutrients are needed.
    The animal data provided do not allow the use of the normal procedure
    for arriving at an acceptable daily intake for man. Any evaluation
    would have to be based on the large clinical experience in man and the
    known metabolic inertness of this substance. However, recent data on
    the absorption of macromolecules and other accumulation and
    persistence in retriculoendothelial cells did not allow the setting of
    an ADI.

    EVALUATION

         Not possible with data provided.

    REFERENCES

    Altemeir, W. A., Schiff, L., Gall, E. A., Gluseffi, J., Freiman, D.,
         Mindrum, G. & Braunstein, H. (1954) Amer. Med. Assoc. Arch.
         Surg., 69, 300

    Ammon, R. & Müller, W. (1949) Dtsch. Med. Wschr., 15, 465

    Angerwall, L. & Berntsson, S. (1961) J. Inst. Brwnig. 67, 353

    Badische Anilin & Sodafabrik, A. G. (1958) Unpublished report
         submitted to WHO

    Bennhold, H. & Schubert, R. (1944) Klin. Wschr., 23, 30

    Burnette, L. W. (1962) Proc. Sci. Sect. Toilet Goods Assoc., 38, 1

    Cabanne, F., Chapnis, J. L., Duperrat, B. & Patelat, R. (1966)
         Ann. Anat. path., 11, 386

    Heinrich, H. C., Gabbe, E. E., Nass, W. P. & Becker, K. (1966)
         Klin. Wschr., 44, 488

    Hubner, G. (1960) Virchows Arch. path. Anat., 333, 29

    Hueper, W. C. (1956) Proc. Am. Ass. Cancer Res., 2, 120

    La Chapelle, J. M. (1966) Dermatologia (Basel), 132, 476

    Lusky, L. M. & Nelson, A. A. (1957) Fed. Proc., 16, 318

    Ravin, H. A., Seligman, A. M. & Fine, J. (1952) New England J. med.,
         247, 921

    Scheffner, D. (1955) Thesis, University of Heidelberg, summary
         submitted to WHO

    Shelanski, A. A., Shelanski, M. V. & Cantor, A. (1954) J. Soc. Cosm.
         Chem., 5, 129

    Traenckner, K. (1954) Z. ges. exp. Med., 123, 101

    Weese, H. (1944) Med. Z., 1, 19

    Weese, H. & Fresen, O. (1952) Zieglers Beitr., 112, 44


    See Also:
       Toxicological Abbreviations