IPCS INCHEM Home


    FAO Nutrition Meetings
    Report Series No. 40A,B,C
    WHO/Food Add./67.29




    TOXICOLOGICAL EVALUATION OF SOME
    ANTIMICROBIALS, ANTIOXIDANTS, EMULSIFIERS,
    STABILIZERS, FLOUR-TREATMENT AGENTS, ACIDS AND BASES





    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met at Rome,
    13-20 December, 19651 Geneva, 11-18 October, 19662




                   

    1 Ninth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1966 No. 40; 
    Wld Hlth Org. techn. Rep. Ser., 1966, 339

    2 Tenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, 1967, in press; 


    Food and Agriculture Organization of the United Nations
    World Health Organization
    1967


    POLYVINYLPYRROLIDONE

    Synonyms                      Polyvidone; PVP

    Empirical formula             (C6H9ON)n

    Structural formula

    MOLECULAR STRUCTURE 23

    Molecular weight              of unit: 111.1

                                  Average molecular weight range of the
                                  polymer between 11 500 and 25 000.

    Definition                    Polyvinylpyrrolidone contains not less
                                  than 95 per cent. (C6H9ON)n

    Description                   Fine white or light yellow powder,
                                  odourless, tasteless and slightly
                                  hygroscopic.

    Uses                          Clarifying agent.

    Biological Data

    Biochemical aspects

         Polyvinylpyrrolidone (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 upsilon 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 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).

    Acute toxicity

                                                                                               

    Animal         Route     Molecular weight     LD50              References
                                                  (mg/kg 
                                                  body-weight)
                                                                                           

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

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

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

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

    Guinea-pig     oral      40 000               100 000           Burnette, 1962
                                                                    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 body-weight for cats, and
    1-2 g/kg body-weight for dogs (Scheffner, 1955)

    Short-term studies

    PVP molecular weight up to 40 000

         Dog. Four groups of 4 beagle dogs were, fed 0, 2, 5, and 10 per
    cent. PVP (m.w. 38 000) for 2 years. There were no differences in
    weight gain, food consumption and results of the of blood and urine.
    At the end of the 2-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 per cent. level. No PVP was detected in
    the urine. No malignant tumours were detected (Burnette, 1962). In 2
    similar feeding experiments using a total of 32 dogs and lasting for 1
    year no adverse effects could be detected. The intestines, spleens and
    livers of all animals ware 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 220 000-1 500 000

         Dog. Two dogs were given oral doses of 5 g/kg body-weight PVP
    (m.w. 220 000 and 1 500 000) for 1-1/2 weeks and 2 weeks respectively
    without any abnormal findings (Scheffner, 1955).

    Long-term studies

         Rat. Groups of rats were fed diets containing 0, 1 and 10 per
    cent. PVP (m.w. 38 000) for 2 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 and Sodafabrik, 1958; Burnette,
    1962).

    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  small quantities that may enter
    the intestinal lymph nodes. Further feeding experiments in order to
    clarify the problem of possible storage or PVP intestinal lymph nodes
    and studies on the possible effects of PVP on the absorption of
    nutrients are required within the next 2 years.

    Evaluation

         The animal data provided do not allow the use of the normal
    procedure for arriving at an acceptable daily intake for man. The
    evaluation is based provisionally on the large clinical experience in
    man and the known metabolic inertness of this substance. No
    unconditional acceptance can be given because of probable accumulation
    in the lymph nodes.

    Estimate of acceptable daily intake for man

                                  mg/kg body-weight

       Conditional acceptance           0-1

    Further work required

         Further feeding experiments in order to clarify the problem of a
    possible storage of PVP in the intestinal lymph nodes. Studies on the
    possible effects of PVP on the absorption of nutrients.

    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. Wsch., 15, 

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

    Badische Anilin und 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

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

    Hübner, G. (1960) Virchows Arch. Path. Anat., 333, 29

    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
       POLYVINYLPYRROLIDONE (JECFA Evaluation)