POLYVINYLPYRROLIDONE (PVP)
Explanation
This substance was evaluated for acceptable daily intake for man
(ADI) by the Joint FAO/WHO Expert Committee on Food Additives in 1966
and 1973 (see Annex I, Refs. 12 and 32). Toxicological monographs were
issued in 1966 and 1973 (see Annex I, Refs. 13 and 33). Since the
previous evaluation, additional data have become available and are
summarized and discussed in the following monograph.
BIOLOGICAL DATA
Povidone is the generic name for polyvinylpyrrolidone (PVP). It
is the soluble homopolymer of N-vinyl-2-pyrrolidone. As a food
additive it appears as the form identified as K-30. To clarify the
discussion, the relationship of K-30 to other marketed forms is as
follows:
Form K-range* Average molecular weight
K-15 or 17 12-18 10 000
K-30 26-35 40 000
K-90 80-100 360 000
* Note: based on viscosity.
It should be noted that the data described in this evaluation
include some studies of povidone having molecular weights other than
that of K-30.
Another related product is crospovidone - chemically
identified as polyvinylpolypyrrolidone or cross-linked, insoluble
polyvinylpyrrolidone. It is the insoluble, cross-linked homopolymer of
N-vinyl-2-pyrrolidone. Crospovidone is not the subject of the present
evaluation.
BIOCHEMICAL ASPECTS
Absorption
Loehry et al. (1970) measured the permeability of the rabbit
small intestine to water soluble molecules over a range of molecular
weights from 60 to a molecular weight of 80 000. They reported a well
correlated inverse log/log linear relationship between absorption and
molecular weight. The amount of povidone (average molecular weight
33 000) that was cleared from the lumen by blood was 0.39% of the urea
cleared from the lumen by blood. If urea is completely absorbed from
the intestine, then povidone of this average molecular weight is 0.39%
absorbed.
Hanka (1971) detected povidone in the portal venous blood of
rabbits following intestinal perfusion with a solution containing
povidone (av. mw 40 000).
Other studies of the gastrointestinal absorption of povidone have
usually been associated with conventional toxicity studies that have
been conducted. Scheffner (1955) reported that povidone (av. mw
16 000) was not absorbed from the gastrointestinal tract of guinea-
pigs. It was reported that, following the oral administration of
isotopically labelled povidone (av. mw 40 000 and 70 000) to rats,
less than 0.5% of the activity was absorbed from the gastrointestinal
tract (Shelanski, 1953; Burnette, 1962). In a group of rats fed diets
containing 1% and 10% povidone (av. mw 38 000) for two years, no
evidence of absorption of povidone from the gastrointestinal tract was
observed (Shelanski, 1957; Burnette, 1962). Angervall & Berntsson
(1961) reported that povidone (av. mw 11 500) was not absorbed from
the gastrointestinal tract of man and rat. Burnette (1962) reported
that in a group of beagles fed 2.5% and 10% povidone (av. mw 38 000)
in the diet for one year, povidone was found in the mesenteric lymph
nodes indicating gastrointestinal absorption.
Distribution
Information on the distribution of povidone within the body comes
primarily from studies following its intravenous or intraperitoneal
administration. Ravin et al. (1952) administered intravenous infusions
of varying average molecular weights to rabbit, rat, dog and man.
Cells of the reticuloendothelial (RES) retained povidone; the higher
molecular weight molecules were retained the longest. Povidone with an
average molecular weight of less than 40 000 left the body within a
few days. Fresen & Weese (1952) reported on the presence of povidone
(av. mw 38 000) in the RES as did Jeckeln (1952) for povidone (av. mw
40 000). Others have also made similar reports (for example, Frommer,
1955; Heinrich et al., 1966). Povidone storage in the RES is as a
result of its incorporation into macrophages by pinocytosis (Pratten &
Lloyd, 1979). This incorporation gives rise to the vacuolated
appearance which has led to the description of "foam cells". The
earlier assumption that the molecules were stored in the mitochondria
(Traenckner, 1954) is incorrect (Wessel et al., 1974).
Povidone of varying molecular weights was reported not to pass
the blood-brain as well as the placental barriers (Ravin et al.,
1952).
Elimination
The elimination of povidone has been studied by a number of
investigators, again mostly following intravenous and intraperitoneal
administration. The elimination of varying molecular weights has been
tabulated from the world literature by Wessel et al. (1974). The T 1/2
for the elimination of povidone in the average molecular weight range
of 40 000 has been reported to be as low as 12 hours and as high as 72
hours. The glomerulus can clear povidone of a molecular weight of at
least 25 000 and perhaps as high as 40 000 and the peritubular
capillaries are permeable to even larger molecules of povidone
(Gartner et al., 1968).
TOXICOLOGICAL STUDIES
Carcinogenicity studies
Hueper (1957, 1959, 1961) reported on three studies involving
povidone of various molecular weights.
In the first study, Hueper (1957) utilized four forms of povidone
having average molecular weights of 20 000, 22 000, 50 000 and
300 000. In one series four povidones were implanted in powder form
subcutaneously into the nape of the neck in C57 black mice and
Bethesda black rats. In a second series the same four povidones were
implanted intraperitoneally in the same two species. In still another
series, rats were given 2.5 ml of a 7% solution intravenously once a
week for eight weeks. All animals from all studies were autopsied
either after dying on study or being sacrificed after 24 months.
Hueper used the descriptions lymphosarcoma, reticulum cell sarcoma and
Kupffer cell sarcoma. For purposes of this discussion all will be
considered as RES sarcomas. The results were as follows:
Povidone RES
Species Route (av. mw) sarcomas Carcinomas
Mouse Subcut. 20 000 0/50 0/50
(powder) 22 000 3/50 0/50
50 000 0/50 0/50
300 000 1/50 0/50
i.p. 20 000 0/50 0/50
(powder) 22 000 1/50 0/50
50 000 3/50 0/50
300 000 0/50 0/50
Rat Subcut. 20 000 7/50 0/50
(powder) 22 000 0/50 1/50
50 000 9/50 0/50
300 000 7/50 1/50
i.p. 20 000 7/50 4/50
(powder) 22 000 2/50 0/50
50 000 5/50 0/50
300 000 12/50 0/50
i.v. 20 000 2/50 1/50
22 000 0/50 1/50
50 000 6/50 1/50
300 000 2/50 1/50
The reported incidence of sarcomas among control mice was 0.4%.
Among the rats 1/23 of the studied, untreated controls had an RES
sarcoma. Other "control" rats had been exposed to various metal dusts
or to dextran and did not provide useful data.
A similar study was done by Hueper (1959) in which the incidence
of RES sarcomas was 11/200 in untreated rats. In this study,
additional samples of povidone within the same molecular weight range
used previously were studied. The data suggested the development of
RES sarcomas related to the parenteral administration of povidone as
well as other polymers including dextran. Again the studies were
controlled only to a limited extent. There were no manipulation
controls for any of the groups.
In the third study Hueper (1961) emphasized molecular size as a
study criterion. He used povidone "K-17" (molecular weight range
2000-38 000 with the major fraction being between 5000 and 15 000;
average mw 10 000) and povidone "K-25" (major fraction of molecular
weight between 15 000 and 30 000; average mw 18 000) (these averages
for K-17 and K-25 are somewhat lower than what has been reported since
then for these forms). He also used for comparison purposes in rats
two povidones having an average mw of 50 000. One made by GAF and one
made by BASF. The materials were administered intraperitoneally in
divided doses over a period from approximately six to 10 weeks.
Maximum survival was 24 months for rats and 28 months for rabbits (at
which times the experiments were terminated by sacrificing the
surviving animals). Results were as follows:
Povidone Total RES
Species type Administration sarcomas Carcinomas
Rat K-17 2 g 3/35 2/35
K-25 2 g 1/35 2/35
50 000 (GAF) 9 g 2/20 0/20
50 000 (BASF) 9 g 0/30 0/30
Control 2/30 3/30
Rabbit K-17 62.2 g 0/6 0/6
K-25 62.2 g 0/6 0/2
Control 0/2 0/2
Hueper concluded that the rabbit may have had less tumours
because of the ability to filter larger molecules at the glomerulus
than the rat can.
Teratogenicity studies
Povidone K-25 (av. mw less than 40 000) was tested for prenatal
toxicity in rats. The animals received 10% povidone K-25 added to
their feed. Substance-containing feed was available ad lib. on days
0-20 post-coitum. All foetuses were examined for externally
recognizable skeletal malformation, variations and retardations in the
case of two-thirds of the foetuses of a litter; the examination
covered organ malformations, variations and retardations. The pregnant
animals tolerated administration of substance-containing feed with no
clinically recognizable symptoms of poisoning. The only observed
effect was slightly loose faeces. With all other parameters examined,
no changes, and particularly no damage to the progeny, such as could
be attributed to administration of K-25 were found (BASF 1977c).
A similar study was conducted on povidone K-90. The animals
received 10% K-90 added to their feed. The results were qualitatively
and quantitatively similar to those observed with povidone K-25 (BASF
1977d).
In a special teratogenicity study, injection of povidone (av. mw
11 500) into the yolk sac of nine-day rabbit embryos (500 mg/embryo)
did not increase the number of resorptions or malfunctions compared to
the number of resorptions and malformations induced in saline injected
embryos (Claussen & Breuer, 1975).
Mutagenicity and transformation tests in vitro
Povidone K-30 was tested for mutagenic effects on the germ cells
of male mice (dominant lethal test) after one intraperitoneal
application. The animals received a single injection of 3 160 mg
povidone K-30 (dissolved in aquadest.) per kg body weight in a volume
of 10 ml/kg. No animals displayed any recognizable symptoms of
toxicity over the entire test period. The administration of povidone
K-30 had no effect on the conception rate, average number of
implantations, percentage of living foetuses or the mutagenicity index
(BASF 1977e).
Mutagenicity and transformation tests in vitro employing mouse
cells (lymphoma L5178Y, TK+/-BUDR and Balb/3T3, respectively)
demonstrated that PVP at concentrations of 0.5%, 1.0%, 5.0% and 10.0%
in the media did not cause significant mutagenic or transformation
effects when compared to non-treated cells (Carchman, 1978).
Quantification of RES storage
Frommer (1956) quantified storage of povidone "foam cells"
following the administration of povidone (av. mw 20 000, 40 000 and
125 000) in rats. He suggested a threshold existed for storage
equivalent to the system content of 0.1 g/kg.
Acute toxicity
Average LD50
Animal Route molecular weight (mg/kg bw) References
Rat Oral 10 000-30 000 40 000 Scheffner, 1955;
BASF, 1958
Mouse Oral 40 000 Scheffner, 1955;
BASF, 1958
i.p. 12 000-15 000 Angervall &
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 povidone (av. mw up to 40 000) in high doses caused
diarrhoea, the minimal effective dose being 0.5 g/kg bw for cats, and
1-2 g/kg for dogs (Scheffner, 1955).
Two dogs were given oral doses of 5 g/kg bw povidone (av mw
220 000 and 1 500 000) for one-and-a-half weeks and two weeks,
respectively, without any abnormal findings (Scheffner, 1955).
Four pure bred beagles of each sex were given 0, 25 000, 50 000
and 100 000 ppm povidone (K-90) in the feed for 28 days. Another group
of eight animals receiving 100 000 ppm cellulose in the feed were also
used as control. No toxic effects or pathological changes were noted
which could be related to the administered substance, except slightly
increased relative spleen weight was observed in the female animals of
the 100 000 ppm group (BASF, 1977).
Povidone K-90 was administered to Sprague-Dawley rats (10
rats/sex/group) in concentrations of 25 000 and 50 000 ppm in the feed
over a 28-day test period. No toxic effects or pathological-
histological changes were noted due to administration of K-90 (BASF,
1973).
Povidone was also evaluated for acute toxic effect by rapid
intravenous administration to beagle dogs (Hazleton Laboratories,
1970). One animal of each sex was given 0, 1, 3 or 10 g of povidone/kg
bw. The animals were observed for the subsequent 28 days. No deaths
occurred at any dose. Immediately following administration, the
animals showed tremors and/or subconvulsive movements, defaecation,
salivation, depression and ptosis. There were early sporadic changes
in transaminases and haematologic values which generally returned to
normal within 48 hours of the dose and remained essentially within
normal limits during the remainder of the 28-day observation period.
Gross and histopathological examinations of brain, spinal cord,
thyroid, adrenal, heart, lung, thymus, spleen, parathyroid, trachea,
oesophagus, salivary gland, liver, kidneys, stomach, pancreas, small
and large intestine, mesenteric lymph nodes, urinary bladder, prostate
and testes in males, uterus and ovaries in females, bone, peripheral
nerve, and skeletal muscle were conducted. No histopathological or
gross pathological changes were reported.
Four groups of animals, each group consisting of two males and
two females, were distributed as follows: control, 10% diet of Solka
Floc;* 2% povidone K-30 plus 8% Solka Floc; 5% povidone K-30 plus 5%
Solka Floc; 10% povidone K-30. The feeding period was two years. There
were no reported adverse effects at the end of this treatment.
Histopathological examination of thyroid, parathyroid, heart, lung,
rib bone and bone marrow, skin, stomach, small bowel, large bowel,
liver, gall bladder, spleen, kidneys, lymph nodes, urinary bladder,
uterus or prostate, left adrenal, pancreas and testes or ovaries were
conducted. Swollen RES cells in the lymph nodes of the high dose group
were reported. There was evidence of this in the middle and low dose
groups and the 10% Solka Floc control, but "less consistently and to a
lesser degree". No other histopathological findings were reported
(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 povidone, but povidone 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; Wolven & Levensten, 1957; Shelanski,
1958).
Chronic studies
Groups of rats (Wistar strain) were fed diets containing 0, 1 and
10% povidone (mw 38 000) for two years. No toxic effects or gross
histological changes were noted which could be attributed to the test
compound (BASF, 1958; Burnette, 1962).
* Solka Floc = cellulose.
In another two-year rat feeding test povidone (K-25) was added to
the feed in concentrations of 50 000 or 100 000 ppm. Groups each of
100 rats (Sprague-Dawley) equally divided by sex were used in this
study. The feed intake, body weight, clinical parameters tested (urea,
GPT, HB, Ery, HT, Leuco, differential blood count, urine status),
macroscopic organ findings and the absolute and relative organ weights
(heart, liver, kidneys) did not differ from those of the two control
groups. No differences were found between average life span of the
test and the control animals. In all control and test groups, the
appearance of benign and malignant tumours was within the normal
limits usually found in rats in long-term investigations in this
strain of rats. Histological examination of the tissue of the organs
revealed no changes that could be associated with the feeding test.
There was no evidence that povidone K-25 or its degradation products
were stored in either the mucous membrane of the duodenum or the
intestines or the mesenterial lymph nodes (BASF, 1978b).
OBSERVATIONS IN MAN
Daily subcutaneous injections of polyvinylpyrrolidonevasopressin
in a woman with diabetes insipidus for six years led to a papular
dermatosis. Polyvinylpyrrolidone was detected in biopsy material (La
Chapelle, 1966).
To date, the only chronic toxic effect noted in man upon
subcutaneous injection has been cutaneous thesaurismosis after
parenteral doses of 200-1000 g over 3-12 years (La Chapelle, 1966).
Injection of a povidone-containing medication (Depot-Impletol) in
a woman resulted in large foreign body granulations in the breast and
in the epigastric area (Gille & Brandau, 1975).
Comments
Only data on the soluble homopolymer of N-vinyl-2-pyrrolidone
i.e., povidone were evaluated.
No carcinogenicity has been reported for povidone as a
consequence of oral administration.
Studies involving parenteral administration, primarily
intravenous or intraperitoneal indicate that there may be some storage
of povidone in the reticuloendothelial system (RES) under certain
conditions.
The primary predictor of long-term storage relates to the
molecular size of povidone in the circulation. That is, if the
molecular size is such that filtration at the kidney occurs then the
likelihood of storage is less.
This leads to a question of povidone's absorption from the
gastrointestinal tract. It is difficult to determine the exact level
of povidone's absorption from the gastrointestinal tract. This
difficulty is due to the fact that the absorption of a compound like
povidone that is both hydrophilic and lipophobic is dependent on its
molecular size and weight, and the fact that polymer products such as
povidone consist of a range of molecular weights. It would appear that
any povidone absorbed from the gastrointestinal tract would be of the
size that would be cleared by the kidney thus reducing the likelihood
of accumulation in the RES. Data from studies of povidone's oral
absorption, distribution and elimination are needed to test this
hypothesis. These data could be obtained from studies using
radiolabelled povidone. Mathematical analyses of data available on
molecular sizes absorbed from the intestine and filtered at the
glomerulus may also provide the information sought.
Since the phenomenon of RES storage may be common to all high
molecular weight polymers, povidone should also be evaluated from the
viewpoint of comparing it to other polymers used as food additives.
The only reported biological effect attributed to oral
administration of povidone is stool softening or diarrhoea. In long-
term feeding studies in rats no evidence of carcinogenicity was noted
as well as no indication of storage in the RES.
EVALUATION
Establishment of an ADI is deferred pending a review and
evaluation of existing or new data relating to pharmacokinetics and
RES storage.
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See Also:
Toxicological Abbreviations