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POLYVINYL ALCOHOL

1. EXPLANATION
Polyvinyl alcohol is a synthetic resin that is prepared by polymerization of vinyl acetate,
followed by partial hydrolysis of the resulting ester in the presence of an alkaline catalyst. The
number of acetate groups in polyvinyl alcohol is determined by the degree of hydrolysis (86.5–
89.0% hydrolysis for this food additive specification). Polyvinyl alcohol is used as a coating,
binder, sealing and surface finishing agent in food products such as dairy-based desserts,
confectionery and cereal products and dietary supplement tablets, in the range of 0.2–1.8% by
weight.

Polyvinyl alcohol has not been evaluated previously by the Committee.

Polyvinyl alcohol (synonyms, vinyl alcohol polymer, PVA, ethenol homopolymer) is a water-
soluble synthetic resin, prepared by the polymerization of vinyl acetate, followed by partial or
complete catalysed hydrolysis. The primary raw material used in the manufacture of polyvinyl
alcohol is vinyl acetate monomer dissolved in methanol. The polymerization involves the
presence of two proprietary cataytic agents. After polymerization, the material undergoes
controlled hydrolysis with aqueous sodium hydroxide, during which the ester groups in the vinyl
acetate are replaced with hydroxyl groups. Polyvinyl alcohol is precipitated, washed and dried to
form an odourless, tasteless, white or cream-coloured granular powder.

The physical characteristics of polyvinyl alcohol vary depending on the degree of polymerization
and hydrolysis. Polyvinyl alcohol is classified into grades of partially and fully hydrolysed
polymers with different intended functional uses. Polyvinyl alcohol has a history of use in
cosmetic, food packaging materials, pharmaceutical and medical applications.

2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion

(a) Oral administration

Three male Fischer 344 rats received water containing 0.01 mg of 14C-labelled polyvinyl alcohol,
by oral gavage. More than 98% of the administered dose was excreted in the faeces within 48 h,
with trace amounts (0.18%) detected in the urine. No radioactivity derived from polyvinyl
alcohol was detected as expired carbon dioxide (CO2).

In a second study, three male Fischer 344 rats received 0.1 mg of 14C-labelled polyvinyl alcohol
by oral gavage, daily for 10 consecutive days. Twenty-four hours after the final dose, the
quantity of radioactivity recovered from the blood, liver, kidneys, skin, muscle and adipose
tissues accounted for 0.05% of the total administered dose. The principle route of excretion was
in the faeces, with <0.2% of the administered dose being detected in the urine (Sanders &
Mathews, 1990).

The 36th Report of the Cosmetic Ingredient Review Expert Panel reported a study attributed to
the Haskell Laboratory (1960; original source documents not provided) in which groups of six
Charles River rats received 100 mg (equivalent to a dose of 250 mg/kg bw) of polyvinyl alcohol
(commercial grade, non-radioactive) daily for 7 days, followed by 100 mg per day of: (a) high
viscosity, unhydrolysed polyvinyl alcohol labelled with 14C, average relative molecular mass,
148 000; or (b) high viscosity, polyvinyl alcohol, average relative molecular mass, 150 000; or
(c) low viscosity, polyvinyl alcohol, average relative molecular mass, 32 000. Three rats per
group were killed after receiving five doses of the test material, and three rats were killed after
receiving 10 doses. Urine and faeces were collected each day for analysis. A similar study was
carried out using groups of four male mongrel dogs that received 2 g of polyvinyl alcohol per
day (equivalent to 200 mg/kg bw per day). No radioactivity was detected in the urine of any
animals. For the high viscosity preparations (a) and (b), trace amounts (<1 ppm) of radiolabel
were detected in the brain, kidney and liver of both rats and dogs. For the low viscosity solution
of polyvinyl alcohol, (c), marginally larger quantities of radiolabel were detected in these organs
(brain, 0.60–1.29 ppm; kidney, 0.52–1.35 ppm; liver, 1.21–6.91 ppm) (Cosmetic Ingredient
Review Expert Panel, 1998).

(b) Intravenous administration

Groups of female BALB/cCrS1c mice aged 8–12 weeks received 125I-labelled polyvinyl alcohol
with relative molecular mass ranging from 14 800 to 434 000, by injection into the tail vein. The
half-life for excretion varied from 90 min for the polyvinyl alcohol of low relative molecular
mass, to 23 h for polyvinyl alcohol of highest molecular weight. The principal route of excretion
was in urine. Almost 80% of polyvinyl alcohol of low relative molecular mass (14 800) was
excreted by this route within 30 min of administration. The slower rate of excretion of the high-
molecular-weight polyvinyl alcohol appeared to be caused by lower permeability at the renal
glomeruli that was related to high relative molecular mass (Yamaoka et al., 1995).

Female Fischer 344 rats received a single intravenous injection of 14C-labelled polyvinyl alcohol
(0.1 mg/kg bw) in the tail vein. Sixty-four percent of the dose was excreted in the urine and 3%
in the faeces within 24 h. Seventeen percent of the dose was retained in the liver at 24 h,
decreasing to 12% by day 3 and 4% by day 10. A further 2% was excreted in the urine between
days 1 and 10. Faecal excretion accounted for 5% of the administered dose by day 3 and 13% by
day 10. There was no evidence for metabolism of polyvinyl alcohol (Sanders & Mathews, 1990).

(c) Intravaginal administration

Five female Fischer 344 rats received a single dose of 0.5 mg of 14C-labelled polyvinyl alcohol
(equivalent to 3 mg/kg bw) intravaginally. The animals were killed after 4 days and tissues were
examined. There were marked variations in the amount of residual radioactivity detected in the
vagina (from trace amounts to 19% of the administered dose). Most of the radioactivity derived
from polyvinyl alcohol was excreted in the urine or faeces. Although low (0.1–0.8% of the dose),
absorption of polyvinyl alcohol administered by this route was greater than that of polyvinyl
alcohol administered orally. The greatest quantity of radiolabel (0.8%) was reported in the liver.
In follow-up studies, groups of rats received 1, 3 or 10 daily doses of 14C-labelled polyvinyl
alcohol (3 mg/kg bw). Blood was collected from animals in each group for up to 30 days after
the last dose. Radioactivity derived from polyvinyl alcohol was very low but increasingly
concentrated in the liver over time and, to a lesser extent, in the kidneys, muscle, skin, adipose
tissue and spleen. The peak concentration in the liver, 24 h after the administration of 10
consecutive doses of 3 mg/kg, was <2 ppm. Concentrations of the polyvinyl alcohol only
decreased slowly after the cessation of dosing (Sanders & Mathews, 1990).

2.1.2 Biotransformation

No information was available.

2.1.3 Effects on enzymes and other biochemical parameters

No information was available.

2.2 Toxicological studies


2.2.1 Acute toxicity

The results of studies on the acute toxicity of polyvinyl alcohol are summarized in Table 1.

Table 1. Acute toxicity of polyvinyl alcohol

Species Sex Route LD50 (mg/kg bw) Reference

Subcutaneous
Mouse NA injection >300 JSCI (1968)a

NA Oral >1 500 JSCI (1968)a

Males and Intraperitoneal 2 000–4 000 Burford & Chappel


females (1968)b

Males and Burford & Chappel


Oral >4 000
females (1968)b

NA Oral 14 700 Zaitsev et al. (1986)c

Rat Males Oral >10 000 Hazleton Laboratories


(1959)d

NA Oral >20 000 Zaitsev et al. (1986)c


Males Oral >21 500 Hazleton Laboratories
(1959)d

NA Oral >5 000 CTFA (1980)d

NA Oral >15 000 CTFA (1980)d

Dog NA Oral >20 000 Hazleton Laboratories


(1959)d

NA, not available

The relative molecular mass or percentage hydrolysis of the polyvinyl alcohol used was not available for the studies
cited in Table 1

a Provided as results only, no original data provided for evaluation

b Groups of two male and two female albino mice received a single intraperitoneal injection of a 5% solution of
acacia gum in saline containing polyvinyl alcohol (no relative molecular mass specified) at a concentration of
250, 1000, 2000, 3000 or 4000 mg/kg, or orally at 250, 500, 1000, 1500, 2000, 3000 or 4000 mg/kg. After
intraperitoneal administration, one male mouse at 2000 mg/kg and two males and one female at 4000 mg/kg
died. After oral administration, two male mice at 1000 mg/kg and one male at 3000 mg/kg died. No other
deaths were reported in the study. The study is an unpublished research report and is not accompanied by GLP
or QA certification

c Provided as results only. The original reference was provided in Russian with no English translation and,
therefore, not subject to evaluation

d Studies reported by the Cosmetic Ingredient Review Expert Panel (1998). Original documents not available for
evaluation for this report

2.2.2 Short-term studies of toxicity

Mice

In a study undertaken by the Pharmacology Department of Osaka University and reported in the
Japanese Standards of Cosmetic Ingredients (JSCI), 10 mice received polyvinyl alcohol at a dose
of 500 mg/kg bw per day for 20 days. The route of administration was not specified. Other than
one death, no treatment-related adverse effects were observed. The report contains no original
data suitable for evaluation purposes and the relative molecular mass and percentage hydrolysis
of the polyvinyl alcohol used were not identified (Japanese Standards of Cosmetic Ingredients,
1968).

In another study by the same researchers, 30 mice received polyvinyl alcohol at a dose of 100,
500 or 1000 mg/kg bw per day for 26 weeks. No signs of toxicity were seen and no differences
were observed in either growth rate or body-weight gain, compared with controls. No
toxicologically significant histopathological changes in stomach, intestines, heart, lungs, liver,
kidneys, pancreas, thyroid and spleen were reported. The report contains no original data suitable
for evaluation purposes and the relative molecular mass and percentage hydrolysis of the
polyvinyl alcohol were not identified.

Two groups of 50 female B6C3F1 mice received 20 µl of a 25% aqueous solution of polyvinyl
alcohol by intravaginal administration, daily for 30 days. Animals in one group were returned to
their cages immediately after dosing. Animals in the other group were restrained in a vertical
nose-down position for several minutes after dosing. A control group of 50 mice received 20 µml
of deionized water only. No lesions related to treatment with the test material were observed
(National Toxicology Program, 1998).

Polyvinyl alcohol sponges were inserted subcutaneously into male Bar Harbor C57 mice.
Biopsies were taken at 1, 3, 5, 6, 9 and 18 weeks. The sponges became more resistant to cutting
at each biopsy. There was evidence that fibroblast capsules were extending into the sponges,
accompanied by considerable collagenous material. Vessels were observed extending into the
sponges at 6 weeks. No evidence of toxicity around the implant site was reported. This study was
a published report with no original data suitable for evaluation. The relative molecular mass and
percentage hydrolysis of the polyvinyl alcohol were not identified (Moore & Brown, 1952).

None of the available short-term studies in mice are relevant to the current evaluation of
polyvinyl alcohol.

Rats

Groups of 10 rats received one of two preparations of 0.5% polyvinyl alcohol in drinking-water
for 8 weeks (equivalent to 116 or 151 mg per day or an average of 500 or 700 mg/kg bw per
day). The relative molecular mass and degree of hydrolysis of the polyvinyl alcohol used were
not specified. Two animals at one dose died in the seventh and eight weeks respectively. All
animals in the other dose group lost condition and body weight during the study. No macroscopic
pathology related to treatment with the test material was observed in the surviving animals. The
absence of adequate controls prevented interpretation of sporadic lesions reported to occur in the
brains, lungs and kidney of individual animals. The study was provided as results only and was
not certified for GLP or quality assurance (QA). A NOEL was not identified in this study
(Haskell Laboratory, 1936).

Forty-six female Holtzman rats, divided into four groups received one of three grades of
polyvinyl alcohol (relative molecular mass, 37 000, 133 000 or 185 000) as a 5% solution in
physiological saline or saline by subcutaneous injection, daily for 4 weeks. Animals were given
distilled water containing 1% sodium chloride throughout the study. Animals were killed on days
29 or 30 and tissues were taken for weighing and for histological examination. All rats in the
group given polyvinyl alcohol of relative molecular mass 133 000 had polydipsia, progressive
severe hypertension and body-weight loss. By comparison, animals in the groups receiving
polyvinyl alcohol of relative molecular mass 37 000 or 185 000 showed a small increase in blood
pressure compared to the control group. At sacrifice, accumulation of ascitic fluid in the
abdominal cavity, enlarged, pale and granular kidneys with evidence of punctuate surface
haemorrhage, glomerulonephritis, and enlargement of the heart, liver and spleen were observed
in animals given polyvinyl alcohol of intermediate relative molecular mass. Less marked
hepatosplenomegaly and renal and cardiac enlargement were also reported in the group given
high-molecular-weight polyvinyl alcohol, but tissues from this group were not otherwise
reported to be grossly abnormal. No abnormalities were reported in the group given low-
molecular-weight polyvinyl alcohol. Histological examination indicated severe renal, cardiac and
splenic arterial lesions in the group given intermediate-molecular-weight polyvinyl alcohol,
consistent with hypertension. The authors suggested that the observed pathological effects were
dependent on the relative molecular mass of the polyvinyl alcohol rather than on its chemical
structure. The study was a published report with no original data suitable for evaluation (Hall &
Hall, 1963).

Four rats received 2 g of polyvinyl alcohol in 45 g diet (equivalent to 4400 mg/kg bw per day)
for 2 weeks, followed by 4 g of polyvinyl alcohol in 45 g diet (equivalent to 8800 mg/kg bw per
day) for 2 weeks. Two animals were killed after 4 weeks. The remaining two animals received
10 g of polyvinyl alcohol in 25 g diet (equivalent to 28 600 mg/kg bw per day) for a further 2
weeks and were killed after week 6. No toxicity related to treatment with polyvinyl alcohol was
reported in the two animals killed at week 4. Hepatic hydrophobic degeneration was noted in the
two animals killed at week 6. The study was a published report with no data suitable for
evaluation. A NOEL was not identified in this study (Hueper, 1939).

Groups of 20 male and 20 female outbred Sprague-Dawley rats were given diets containing
polyvinyl alcohol at a dose of 0, 2000, 3500 or 5000 mg/kg bw per day for at least 90 days. The
study was conducted in compliance with USDA regulations for GLP (Part 58 of 21 CFR), EEC
GLP regulation 99/11/EEC and OECD GLP principles. Ten animals of each sex per group were
examined for neurobiological effects before the start of treatment and between days 88–91.
Blood was obtained from up to 10 animals of each sex per group on days 28, 56 and at
termination (days 95 and 96). Unformed stools accompanied by anogenital staining, were
observed in males at 3500 and 5000 mg/kg bw per day. These effects were considered to be
related to the high content of unabsorbed test material in the diet and not to adverse toxicological
effects. No deaths related to treatment with the test material occurred during the study. All
animals were killed between days 92 and 99. No significant differences in body weight,
neurobehaviour, haematology, blood coagulation, clinical chemistry, urine analysis, organ
weight or macroscopic and microscopic pathology were observed. Food consumption in the
treated groups was comparable or slightly higher than that of controls throughout the study. The
NOEL was 5000 mg/kg bw per day (Huntingdon Life Sciences, 2000a).

Two groups of 10 rats received one of two preparations of polyvinyl alcohol at a dose of 500
mg/kg bw every second day for six doses (average dose, 250 mg/kg bw per day). The
preparations were stated to differ in relative molecular mass and degree of hydrolysis, but details
were not provided. One animal from one group died 24 h after the first injection and one animal
from the second group after the sixth injection, apparently from pre-existing conditions not
related to treatment. The remaining animals had oedema and necrosis at the injection site. A
number of animals showed abnormal lung pathology and a majority of animals exhibited
abnormal renal pathology. However, the absence of adequate controls for this study did not allow
a thorough evaluation of these findings to be made. The study was a research report that did not
appear to be certified for GLP or QA, and no raw data were suitable for evaluation (Haskell
Laboratory, 1936).
In a subsequent study, groups of 10 rats were given one of two preparations of polyvinyl alcohol,
or a mixture of equal concentration, at a dose of 500 mg/kg bw per day for up to 16 days. The
preparations were stated to differ in relative molecular mass and degree of hydrolysis, but details
were not provided. No deaths occurred during the study. Animals exhibited swelling of the
subcutaneous tissue at the injection site. Abnormal lung pathology and renal pathology was
observed in several animals (number not stated). Degenerative testicular changes were also seen
in a considerable number of animals. The absence of adequate controls for this study prevented a
thorough evaluation of these findings from being made. A NOEL was not identified in these
studies.

Groups of 10 rats, dehaired on the back, received one of two preparations of polyvinyl alcohol at
a dose of 120 mg per day, 5 days per week, for 8 weeks. The preparations were stated to differ in
relative molecular mass and degree of hydrolysis, but details were not provided. Animals lost
hair at the application site during treatment, possibly owing to the application of the test material
with adhesive tape. The lack of adequate controls, however, did not permit evaluation of this
effect. The report states that all animals were killed at the end of the treatment period, but also
states that 1 week after the last treatment, all animals showed even hair growth. No skin lesions
or inflammatory reactions were seen at the application site. Animals killed at an unspecified time
after completion of treatment showed no indications of abnormal pathology or histology. The
study was provided as results only and was not certified for GLP or QA. A NOEL was not
identified in this study (Haskell Laboratory, 1936).

Twelve albino rats aged 2 months received 1 ml of a 5% aqueous solution of polyvinyl alcohol
by subcutaneous injection, five times a week for 4 weeks. One rat died at the end of week 3. Six
rats were killed after the final injection and the remaining five were killed 2 weeks later. Organs
and tissues were removed for macroscopic and histological examination. Necrosis and
granulomatous inflammatory tissue was found to be associated with a large amount of polyvinyl
alcohol retained at the injection site. Polyvinyl alcohol was also found in the lumens of blood
vessels associated with a number of organs, occluding smaller vessels, in particular the
capillaries of the lungs associated with endothelial degeneration. Aggregates of polyvinyl alcohol
were found in the renal glomeruli. Spleens were moderately enlarged, dark red and firm. All
animals showed increased numbers and swelling of Kupffer cells. The absence of adequate
controls for this study prevented a thorough evaluation of these findings. The study was a
published report with no original data suitable for evaluation (Hueper, 1936).

Groups of 20 male and 20 female outbred Sprague-Dawley rats were given diets containing
polyvinyl alcohol at a dose of 0, 2000, 3500 or 5000 mg/kg bw per day for at least 90 days. The
study was conducted in accordance with USDA GLP regulations (Part 58 of 21 CFR), EEC GLP
regulation 99/11/EEC and OECD GLP principles. Ten animals of each sex per group were
examined for neurobiological effects before the test and between days 88 and 91. Blood was
taken from up to 10 animals of each sex per group on days 28 and 56 and at termination (days 95
and 96). Unformed stools accompanied by anogenital staining were observed in males at 3500
and 5000 mg/kg bw per day. These effects were considered to be related to the high content of
unabsorbed test material in the diet and not to adverse toxicological effects. No deaths related to
treatment with the test material occurred during the study. All animals were killed between days
92 and 99. No significant differences in body weight, neurobehaviour, haematology, blood
coagulation, clinical chemistry, urine analysis, organ weight or macroscopic pathology were
observed. Microscopic examination of an extensive range of organs and tissues from animals in
the control group and the group treated with a high dose, including the gastrointestinal tract and
Peyer’s patches, and all gross lesions indicated no evidence of treatment-related abnormal
pathology. Food consumption in the test groups was comparable to or slightly higher than that of
controls throughout the study. This was the only short-term study provided, in any species, that is
directly relevant to the safety evaluation of oral exposure to polyvinyl alcohol. The NOEL was
5000 mg/kg bw per day (Huntingdon Life Sciences, 2000a).

2.2.3 Long-term studies of toxicity and carcinogenicity

Groups of 100 female B6C3F1 mice received 20 µl of deionized water containing 0 or 25%
polyvinyl alcohol by intravaginal administration, 5 days per week for 104–105 weeks. A second
control group of 100 animals were not treated. The test material was reported to have a relative
molecular mass of 24 000 and to be 88% hydrolysed. No evidence of carcinogenic activity
related to treatment with the test material was observed during the study. The study was subject
to peer review by the National Toxicology Program Technical Reports Review Sub-Committee.
The relevance of this study to the current evaluation of oral exposure to polyvinyl alcohol is very
limited (National Toxicology Program, 1998).

2.2.4 Genotoxicity

Polyvinyl alcohol and preparations containing polyvinyl alcohol were not genotoxic in a range of
studies in vitro and in vivo (see Table 2).

Table 2. Studies of genotoxicity with polyvinyl alcohol

Endpoint Test system Test material Concentration Results Reference

In vitro

Reverse S. typhimurium PVAc 10 000 mg/ plate Negative Shibuya et al.


mutationa TA1537, TA98 (1985)d
TA100

Reverse S. typhimurium Dental adhesive 500 mg/plate Negative Schweikl et al.


mutationa TA97a TA98 containing PVA (1986)d
TA100 TA102

Reverse S. typhimurium PVA 5 000 mg/ plate Negative Huntingdon


mutationa TA1535, Life Sciences
TA1537, TA98 (2000b)
TA100

Reverse S. typhimurium PVA 7 500 mg/ plate Negative Huntingdon


mutationb TA 1537 Life Sciences
(2000b)e
Reverse E. coli WPA PVA 5 000 mg/ plate Negative Huntingdon
mutationa uvrA/ pKM101 Life Sciences
2000b)e

Chromosome Chinese hamster ST-Film 0.0075 mg/ml Negative Shibuya et al.


aberration V79 cells containing PVAc (1985)d

Cell mutationa Mouse PVA 5 000 mg/ml Negative Huntingdon


lymphoma Life Sciences
L5178Ycells, (2000c)e
Tk +/- locus

In vivo

Micronucleus Mouse bone ST-Film 156 mg/kg Negative Shibuya et al.


formation marrow containing PVAc (1985)d

Micronucleus Mouse bone PVA 2 000 mg/kg Negative Huntingdon


formation marrow Life Sciences
(2000d)e

PVA, polyvinyl alcohol

ST film, the trade name for a film containing PVA that is used as a vaginal contraceptive

S9, 9000 × g supernatant of rat liver homogenate

a In the absence and presence of metabolic activation from S9 liver microsomal preparations

b In presence of metabolic activation from S9 liver microsomal preparations

c Relative molecular mass and percentage hydrolysis unknown

d Published studies. Original data not available for evaluation

e Study conducted in accordance with USDA GLP regulations (Part 58 of 21 CFR), EEC GLP regulation
99/11/EEC and OECD GLP principles

2.2.5 Reproductive toxicity

(a) Multigeneration study of reproductive toxicity

In a two-generation study of reproductive toxicity, groups of 26 male and 26 female rats of both
the P0 and F1 generations received polyvinyl alcohol in the diet at concentrations of 0, 2000,
3500 and 5000 mg/kg bw per day. Mating started in the P0 generation at age 85 days and in the
F1 generation at age 99 days. Animals were treated from 70 days before mating, throughout the
14-day mating period, until they were killed. Females were killed on day 14 of lactation. The P0
and F1 males were killed after the P0 and F1 females.
F1 and F2 pups were given a macroscopic physical examination and body weights were recorded
on days 4, 7, 14 and 21. On day 21, F1 pups were randomly selected for reproductive assessment
(one pup of each sex per litter).

A macroscopic postmortem examination was carried out on all parental animals. The brain, liver
and kidneys were collected from five males and five females selected at random from each
group. The right epididymes from 10 males selected at random from each group for each
generation were collected and processed for assessment of sperm. Microscopic examination was
carried out on selected tissues and organs (reproductive tissues, liver, kidney and brain) from five
animals of each sex per group.

F1 and F2 pups underwent macroscopic postmortem examination and the brain and thymus were
taken from one pup of each sex per litter for determination of organ-weight ratios. Testes and
epididymides from one F2 male pup per litter from each group, and ovaries with oviducts and
uterus with vagina from one F2 female pup per litter from each group were weighed.

No adverse macroscopic effects related to treatment with polyvinyl alcohol were noted in the
parental animals. Unformed stools and anogenital staining were observed in males at 3500, 5000
and occasionally at 2000 mg/kg bw per day in both the P0 and F1 parental animals. These effects
were considered to be related to the high content of unabsorbed test material in the diet rather
than adverse toxicological effects and were consistent with the findings from a 90-day study
undertaken by the same researchers. Statistically significant decreases in body-weight gain were
observed in males of the P0 generation at a dose of 2000 or 5000 mg/kg bw per day, but not in
males of the P0 generation at 3500 mg/kg bw per day, nor in any of the females of the P0 or F1
generations. Except during lactation, food intake was increased in both generations at 3500 and
5000 mg/kg bw per day. The authors considered that this was consistent with maintenance of
normal calorific intake. No adverse effects on reproductive performance that were related to
treatment with the test material were noted in males (as assessed by mating and fertility indices
and sperm assessment) or females (as assessed by mating, fertility and pregnancy indices and
data on estrous cycling) of either the P0 or F1 generations. There were no treatment-related
effects on litter parameters or macroscopic and microscopic observations in either the F1 or F2
generations. This study was certified as having been conducted in accordance with USDA GLP
regulations (Part 58 of 21 CFR), EEC GLP regulation 99/11/EEC and OECD GLP principles.
The NOEL for this study was 5000 mg/kg bw per day (Huntingdon Life Sciences, 2000e).

2.3 Observations in humans


No information on oral exposure in humans was available.

3. DIETARY INTAKE
Polyvinyl alcohol is intended to be used as a moisture-barrier coating in food supplement tablets
or in traditional food products, for example, dried fruits to be included in breakfast cereals or
nuts to be included in yoghurt.
The quantity of polyvinyl alcohol in the final product depends on the surface area of the product
to be coated rather than on its weight. Maximum estimates of levels of use of polyvinyl alcohol
were derived by selecting products within each food category with the greatest proportion of
moisture-sensitive components, estimating the surface area of those components and assuming
that the entire surface area would be coated. In this way, the manufacturer established a common
denominator for use of polyvinyl alcohol of 2.3 mg/cm2 for all food products.

This additive is typically applied such that the overall weight of a product increases by a
maximum of 4%. In the dossier, the manufacturer assumes that 45% of this weight gain
represents polyvinyl alcohol, and thus a maximum of 1.8% of the weight of the final product
comprises polyvinyl alcohol.

For this monograph, calculations of dietary intake have been performed on the basis of quantities
of polyvinyl alcohol added for each food category to be considered, as described in Table 3. The
results will therefore be related to finished food products.

Table 3. Proposed use of polyvinyl alcohol in foods

Proposed food use Use level (%)

Ready-to-eat breakfast cereals with dried fruit or nuts 0.5

Multi-component chocolate bars 1.5

Ice cream and frozen yogurt with inclusions 0.2

Nut and fruit mixtures 1.5

3.1 Assessment based on the budget method


The budget method is used to estimate the theoretical maximum level of a food additive in the
proportion of the food and/or beverage supply likely to contain it that would not result in
exceedance of the acceptable daily intake (ADI) by the population (Hansen, 1979).

Maximum level of use of polyvinyl alcohol: 1.5 g/100 g or 15 000 mg/kg, intended to be used in
a limited number of food categories. Solid food only: 15 000/160 = 93.75 mg/kg bw per day,
corresponding to an intake of 5.6 g per day

3.2 Assessments based on household surveys


Calculations were made using data obtained from the French food safety agency (Agence
Française de Sécurité Sanitaire des Aliments, AFSSA) and using household data (SECODIP,
1993). The mean individual self-production consump
tion computed from the INSEE food consumption survey in 1991 and the mean individual
eatingout consumption (Centre de Recherche pour l’Etude et l’Observation des Conditions de
Vie, CREDOC) are added "by translation" to the home consumption (Table 4). The total mean
intake corresponds to the sum of the average consumptions. The "high consumer" intake
corresponds to the highest intake of polyvinyl alcohol at the 97.5th percentile (confectionery)
plus the average intake for other categories.

Table 4. Estimated intake of polyvinyl alcohol based on household surveys in France

Food category Use level Food intakea (g/day) Percentage Intake of polyvinyl
(g/100 g) of alcohol (g/person
consumers per day)

Mean 97.5th Mean 97.5th


percentile percentile

Breakfast cereals 0.5 2.8 17.7 59.7 0.01 0.09

Dairy-based desserts 0.2 24.1 77.5 91.3 0.05 0.15

Fruit and nut mix 1.5 2.2 9 84.9 0.03 0.13

Confectionery 1.5 3.2 25.9 — 0.07 0.39

Sum of means — — — — 0.016 —

High consumer — — — — 0.48 —

a Total population

3.3 Assessments based on model diets


The following results on the estimated daily intake of polyvinyl alcohol partially hydrolysed
from all proposed food categories in the United States by population group were provided by the
manufacturer and are based on data from the 1994–1996, 1998 United States Department of
Agriculture (USDA) continuing survey of food intakes by individuals (CSFII) (Table 5). The
manufacturer’s calculations are confirmed by the use of Market Research Corporation of
America (MRCA) mean frequency of eating and USDA data on mean portion size (Table 6).

Table 5. Estimated mean daily intakes of polyvinyl alcohol by the population of the United
States

Population group Mean intakea 90th percentilea


(g/person per day) (g/person per day)
Infants 0.101 0.216

Children 0.178 0.371

Female teenager 0.243 0.475

Male teenager 0.329 0.641

Female adult 0.210 0.424

Male adult 0.275 0.549

a Consumers only

Table 6. Mean intake of polyvinyl alcohol based on model diets in the United States

Food category Use level (g/100 g) Mean intake of food Mean intake of
(g/day) polyvinyl alcohol
(g/person per day)

Breakfast cereals 0.5 20 0.1

Dairy-based desserts 0.2 39.5 0.08

Mix of nuts and fruits 1.5 5.2 0.08

Confectionery 1.5 0.3 0.0045

Sum of means — — 0.26

To try to assess high levels of consumption, the approach to the monitoring of food additives
used by the United Kingdom was employed (Rees & Tennant, 1994). This approach consists of
the use of high levels of consumption for broad food categories based on the 97.5th percentile of
consumption observed in national dietary surveys in the United Kingdom (Table 7).

Table 7. Estimating high levels of consumption of polyvinyl alcohol, in the United Kingdom

Food category Use level (g/100 g) High-level Polyvinyl alcohol


consumptiona (g/day) intake (g/person per
day)

Breakfast cereals 0.5 130 0.65

Dairy-based desserts 0.2 125 0.25


Mix of nuts and fruits 1.5 54 0.81

Confectionery 1.5 64 0.96

a High level rates of consumption, from UK MAFF (1998), for the European Commission SCOOP report

3.4 Assessments based on individual data


In addition, estimation of dietary intake was done using data on food consumption from Food
Standards Australia New Zealand (FSANZ). These results are based on consumption by
consumers only and assume that the additive is used at its maximum level for all food products
in each food category considered (Table 8).

Table 8. Estimated dietary intake of polyvinyl alcohol based on individual data in Australia
and New Zealand

Country Food category Use level Mean food Food intake: consumers only Mean intake Polyvi
(g/100 g) intake: all (g/day) of polyvinyl consum
W respondents alcohol: all per day
(g/day) respondents
Mean 95th percentile (g/person per Mean
day)

Australia Breakfast cereals 0.5 5 46.3 115 0.025 0.23

Dairy-based desserts 0.2 5.2 162.9 346.8 0.01 0.33

Mix of nuts and fruits 1.5 3.9 39.9 100 0.06 0.6

Confectionery 1.5 10.3 39.9 120 0.15 0.6

Total consumption 0.7

New Zealand Breakfast cereals 0.5 2.5 35.1 87.5 0.01 0.17

Dairy-based desserts 0.2 4.5 175.3 502 0.009 0.35

Mix of nuts and fruits 1.5 4.6 52.9 151 0.07 0.79

Confectionery 1.5 8.2 43 130 0.12 0.64

Total consumption 0.9

The total consumptions are based on the sum of the category representing the highest intake of
polyvinyl alcohol for consumers only, plus the average intake for all respondents for the other
food categories.
These calculations overestimate exposure to polyvinyl alcohol by considering that, for the food
categories considered, all the food ingested contains the additive. Nevertheless, all the results
appear to be consistent with a mean consumption of around 0.5 g/person per day. For high-level
consumers, it is not possible to exclude some intakes of >1 g/person per day.

It should be noted that the previous calculations do not include the potential intake of polyvinyl
alcohol from food supplements. Assuming a daily ingestion of 10 tablets each weighing 1 g,
corresponding to 10 g of food supplement, the additional intake of polyvinyl alcohol would be
180 mg/day.

4. COMMENTS
The Committee examined a large database of studies of the toxicity of polyvinyl alcohol after
administration by various routes to a number of species. Much of the information was found to
be dated, not relevant to oral administration, or from studies that were not conducted in
compliance with GLP or that were conducted with material that did not comply with the
specification for polyvinyl alcohol as prepared at the current meeting. Nonetheless, the
Committee was able to conclude that polyvinyl alcohol was very poorly absorbed after oral
administration, that the acute oral toxicity was generally very low and that, taken as a whole, the
results were consistent with very low toxicity and showed no evidence for carcinogenicity.

The Committee also considered a number of recent studies, which had been performed with
preparations of polyvinyl alcohol complying with the food additive specification, and which met
appropriate standards for GLP. A 90-day study of toxicity in rats treated orally revealed no
toxicity with polyvinyl alcohol at doses of up to 5000 mg/kg bw per day. No significant
differences in body weight, neurobehaviour, haematology, blood coagulation, clinical chemistry,
urine analysis, organ weight or macroscopic pathology were observed. Microscopic examination
of an extensive range of organs and tissues, including the gastrointestinal tract, from the control
group and the groups given high doses showed no evidence for treatment-related pathology. This
was the only short-term study provided, in any species, that was considered to be directly
relevant to the safety evaluation of oral exposure to polyvinyl alcohol.

No toxicity was observed in a two-generation study of reproduction in rats in which the parental,
first and second generations received a maximum dose of polyvinyl alcohol of 5000 mg/kg bw
per day.

In both the 90-day and the two-generation studies, the most notable observations were loose or
unformed stools in the groups given higher doses of polyvinyl alcohol, this being attributed to
the high intestinal concentration of unabsorbed test material and increased food consumption in
these groups. The Committee considered that these observations did not represent adverse
effects.

There was no evidence for genotoxicity in a battery of tests undertaken with preparations of
polyvinyl alcohol complying with the food additive specification.
The Committee also noted a report that more polyvinyl alcohol was absorbed after intravaginal
than oral administration, and reviewed a study involving the intravaginal administration of
polyvinyl alcohol to mice, 5 days per week for 104–105 weeks, that provided no evidence for
local or systemic carcinogenic activity.

5. EVALUATION
The Committee identified a NOEL of 5000 mg/kg bw per day for polyvinyl alcohol on the basis
of the maximum dose tested from both the 90-day and the two-generation studies in rats. The
Committee noted the lack of reports of any apparent toxic or carcinogenic effects in studies
concerning polyvinyl alcohol as a whole, the very poor absorption of preparations of polyvinyl
alcohol complying with the specification after oral administration and the absence of any effects
on the gastrointestinal tract in the 90-day study in rats. Despite the absence of long-term studies
or studies in a second species, the Committee considered the data adequate for the establishment
of an ADI. The Committee therefore established an ADI for polyvinyl alcohol of 50 mg/kg bw
per day, on the basis of the NOEL of 5000 mg/kg bw per day from the 90-day and two-
generation studies in rats, with a safety factor of 100.

The intake estimate based on use levels provided by the sponsor and national food consumption
data (from the USA) shows a mean ingestion of around 0.5 g per day, equivalent to 8.3 mg/kg
bw per day for a 60 kg adult. Extreme intakes based on Australian and New Zealand
consumption data during one day were shown to reach 2–2.5 g per day at the 97.5th percentile,
corresponding to 33 and 42 mg/kg bw per day respectively.

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