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