This compound has not been previously evaluated by the Joint
Expert Committee on Food Additives.
Vinyl Chloride is a gas that is used in the production of vinyl
chloride homopolymer and mixed polymer resins. Low levels of the
monomer (up to 1 ppm) may be present in the polymer used in food
packaging. Migration of the monomer into the food may occur, and
result in vinyl chloride being present in the dietary.
C = C
Comprehensive monographs of the Biological Data relevant to the
evaluation of carcinogenic risk to humans are available (IARC 1974 and
Absorption, distribution and excretion
The metabolism of vinyl chloride is dose dependent and a
saturable process. Low doses of vinyl chloride administered by gavage
are metabolized and eliminated primarily in the urine. In contrast
higher doses are mainly excreted, unchanged via the lung. In one study
about 75% of the dose (250 ug/kg) administered to rats was excreted as
non-volatile urinary metabolites, and 12 to 15% was excreted as CO2
in the expired air. When rats were dosed with 450 mg/kg 14C labelled
vinyl chloride, 90% of the 14C was excreted via the pulmonary route,
as unchanged vinyl chloride and less than 1% as CO2. Excretion of the
monomer occurred within 5 hrs post dosing, whereas 14CO2, and the
14C labelled urinary metabolites were excreted up to 72 hr post
dosing. (Green & Hathway, 1975)
Similar results were observed in a study by Watanabe et al.
(1976a) in which male SD rats, were administered by gavage a single
dose of 0.05, or 1 or 100 mg/kg of 14C-vinyl chloride, and the routes
and rates of elimination of 14C followed for 72 hrs post dosing. At
the lower dose levels 59-68% of the 14C was excreted as non-volatile
compounds in the urine, and 9-13% as CO2, in the expired air. At the
high dose level (100 mg/kg), 67% of the dose was eliminated as
unchanged 14C vinyl chloride, and 11% as non-volatile urinary
metabolites, and 32% respired as 14C02. The percentage of the dose
remaining in the carcass at the end of the study was approximately 10%
at the lower doses, and 2% at the high dose. The metabolism of vinyl
chloride administered by other routes (inhalation or i.p. injection)
has also been shown to be dose dependent. (Watanabe et al., 1976b)
Vinyl chloride dissolved in either oil or water when administered
to rats by gavage, was absorbed extremely rapidly. Peak blood serum
concentrations of vinyl chloride were observed within 10 minutes of
dosing. (Withey, 1976)
The principal 14C urinary metabolites of orally administered 14C
vinyl chloride, in the male rat, are N-acetyl-S-(2 hydroxyethyl)
cysteine, N-acetyl-S-vinylcysteine and thiodiglycollic acid and lesser
amounts of urea, glutamic acid, chloracetic acid and traces of
methione and serine. The proportions of the three major urinary
metabolites in the rat appear to be unaffected by either the dose, or
the route of administration. (Green & Hathway, 1977)
In another study the formation of the various S-containing
urinary metabolites of vinyl chloride was determined. Male rats were
dosed by gavage according to the following system: (1) 14C-vinyl
chloride, 100 mg/kg, (2) chloracetaldyde, 50 mg/kg, (3)
S-(2-hydroxyethyl)L-cysteine (500 mg/kg) or (4) S-(carboxymethyl)-
L-cysteine (250 mg/kg), injections of L-(u-14C) cysteine
hydrochloride for 5 days, and then a single dose of 14C-vinyl
chloride (450 mg), 30 minutes after the final treatment, (5) and 24 hr
urine samples collected, and the vinyl chloride metabolites measured.
The results of the study indicated that chloroacetaldehyde and
S-(carboxy-methyl)-L-cysteine but not chloroacetic acid, were involved
in the biogenesis of thiodiglycollic acid from vinyl chloride. When
rats were given a single,dose of 14C-vinyl chloride, and sacrificed
after 45 minutes, the major 14C metabolite in the liver was N-acetyl-
S-(2 hydroxyethyl) cysteine. S-(carboxymethyl)-L-cysteine was
identified among the hydrolytic products from the hepatic extract of
vinyl chloride treated animals. It was concluded that in rats,
chloroethylene oxide was formed from vinyl chloride which was
converted to chloroacetaldehyde, and that either of these products
could react with glutathione in the presence of a glutathione
S-epoxide transferase to form S-(2-acetal)cysteine which subsequently
gave rise to S-(2-hydroxyethyl)cysteine its N-acetyl derivative,
S-(carboxymethyl)-L, cysteine and thiodiglycollic acid. (Green and
Effect Vinyl Chloride on Cytochrome P-450
The role of microsomal oxidases in the metabolism of vinyl
chloride was demonstrated in a study in which rats were exposed to
vinyl chloride in a closed system (50 ppm), and the uptake of
vinyl chloride measured. The uptake was decreased, following
administration of inhibitors of cytochrome P-450 dependent metabolism
(3)-bromophenyl-4(5)-imidazole or (nitro-l,2,3-benzathiadiazole), or
was increased by DDT pretreatment. (Bolt, et al., 1976)
When rats were exposed to vinyl chloride (5% Atmosphere) for
6 hrs, and microsomal liver preparations made 24 hr post exposure,
there was a decrease in the level of cytochrome P-450 and the total
activity of the microsomal enzymes. (Reynolds et al., 1975)
The metabolism of vinyl chloride by hepatic microsomes in vitro
was blocked by the addition of SKF-525A. Vinyl chloride metabolism
caused a loss of both cytochrome P-450 and microsomal haem, but not
cytochrome b5 or NADPH-cytochrome-c-reductase. (Ivanetich et al.,
In another study rats exposed to 5% vinyl chloride atmosphere for
18 hrs, showed a decrease in the level of hepatic microsomal P-450
(linear with time). The decrease was lower in rats treated with CoC12
or SKF 525-A, and was increased in rats treated with phenobarbital or
DDT. It was also noted that hepatic glutathione was rapidly depleted
during the first 6 hrs of exposure to vinyl chloride. (Pessayre et
Studies on the binding of 14C-vinyl chloride by hepatic
microsomes showed that the 14C became irreversible bound to the
microsomal proteins in the presence of NADPH generating systems. Only
negligible binding occurred in the absence of NADPH. Decreased binding
occurred in the system in the presence of CO, SKF 525A or glutathione,
and was increased by TCPO (1,1,1-trichloropropene-2,3-oxide).
(Pessayre et al., 1979)
Alkylation of DNA and RNA
Rats were exposed to 1,2-14C vinyl chloride and liver RNA
isolated. 14C was incorporated into the RNA, and hydrolysis of the
RNA indicated that all,the nucleosides were labeled. Labelling
occurred in the 1-N6-ethaooadenosine, suggesting that vinyl chloride
metabolites react with adenosine moieties (Laib and Bolt, 1977. Rat
liver microsomes were incubated with NADPH and 1,2-14C-vinyl chloride
and polyadenylic acid (PA) and,polycytidylic acid (PC), and the latter
compounds re-isolated I4C was irreversibly bound to the PA and PC,
and was present in 1-N6-ethenoadenosine and 3-N4-etheno-cytadine
(Laib and Bolt, 1977).
Special Studies on Reproduction
No studies are available on exposure by the oral route. One
inhalation study in the rat has been reported.
Groups of male and female Sprague-Dawley/Wistar rats (25 rats/
sex/dose) were exposed to 0, 50 ppm or 500 ppm of vinyl chloride one
hour per day, 5 days per week for 10 weeks (49 exposures) before they
were mated. The rats were evaluated for numbers of matiogs,
percentages of pregnancies, fertility and lactation indices. The F1,
F2 and F3, offspring were evaluated for litter size, percent of
stillborn pups, post-natal growth, viability, survivability and
reproduction anomalies. The various indices of reproduction
performance measured for each generation were similar for test and
control animals. (Hehir et al., 1981)
Special Studies on Mutagenicity
The mutagenicity of vinyl chloride has been reviewed by Bartsch
et al. (1976), Fishbein (1976) and, Hopkins (1979).
Using Salmonella tester strains, direct mutagenicity of vinyl
chloride was reported at 20% (v/v) in air (200,000 ppm) in the absence
of metabolic activation (McCann et al., 1975, Bartsch et al., 1976).
The mutagenic response was greatly increased by the addition of S9
fraction from PCB treated rat(McCann et al., 1975), or in the presence
of a NADPH generating systems, or, with combinations of microsomal and
soluble protein fractions from rat liver (Bartsch et al., 1975a). 20%
vinyl chloride (v/v in air) was inactive in systems employing
S. typhimurium strains TA 1536, TA 1537 and TA 1538. (Rannug et al.,
1974) Aqueous solutions of vinyl chloride (with an initial cone of
0.083M) (comparable to that derived from the 20% v/v in air) with and
without activation showed no evidence of mutagenicity with
S. typhimurium strains TA 1530, TA 1535 (Bartsch et al., 1975b) It
seems likely that the lack of activity in these systems was due to
rapid loss of the monomer from the solution into the atmosphere. The
possible role of non-enzymatic effects increasing the mutagenicity
of vinyl chloride was investigated by Garro et al., (1976) who
demonstrated an increase in the mutagenic response in the
S. typhimurium system, in the presence of free radical generating
systems (riboflavin + u.v. light).
Mutagenic activity of vinyl chloride was reported in yeast
(S. pombe and S. cerevisiae) in the presence of purified mouse
liver microsomal preparations (Loprieno et al., 1977)
Vinyl chloride was mutagenic to S. pombe in the "host mediated"
assay when mice were treated with an oral dose of 700 mg/kg of vinyl
chloride. (Loprieno et al., 1976)
Vinyl chloride was not active in a dominant lethal test in CD-1
mice. In this study mice were exposed to vinyl chloride via inhalation
at levels of 30,000, 10,000 and 3,000 ppm (6 hr/day for 5 days) and
then bred successively with unexposed mice over an 8 wk period. No
differences from controls were observed in the vinyl chloride treated
group as shown by preimplantation egg loss, early deaths/pregnancy,
early deaths/total implants/pregnancy and post implantation loss.
(Anderson et al., 1976)
Vinyl chloride produced a significant increase in the frequency
of recessive lethals in male Drosophila melangaster. The effect was
not dose related, since exposure to increasingly high doses (in excess
of 10,000 ppm) failed to cause a higher frequency of recessive lethals
(Verburgt and Vogel 1977, Magnusson and Ramel, 1978). When the
Drosophila were exposed to phenobarbital (dissolved in a 1% sucrose
solution) for 24 hr prior to exposure to vinyl chloride, phenobarbital
treatment enhanced the number of recessive lethals in test groups
compared to the groups not exposed to phenobarbital. This effect was
noted at 10,000 ppm exposure to vinyl chloride but not at higher
levels of vinyl chloride exposure. (Magnusson and Ramel, 1976).
Chloracetic acid and chloroacetaldehyde were toxic, while
chloroethanol was a weak mutagen to Salmonella typhimurium TA 1530
(Bartsch et al., 1976). Chloroethylene oxide and 2-
chloroacetaldehyde also showed some mutagenic activity to strain TA
1530 (Malaveille et al., 1975). In another study the mutagenic effect
of chloroethylene oxide, chloroacetal-dehyde, 2 chloroethanol and
chloroacetic acid, in Salmonella typhimurium TA 1535, was compared.
A mutagenic effect was only observed with chloroethylene oxide and
chloroacetal-dehyde, the oxide being approximately 20 times more
active than the aldehyde, on an equimolar bases. Increasing the
concentration of chloroethanol (from 0.1 to 1 M) resulted in a weak
mutagenic response, but chloracetic acid was inactive. (Rannug, et
al., 1976) Using a more sensitive bacterial tester strain
(S. typhimurium TA 100), chloroacetaldehyde was shown to be a
hundred times more effective in causing mutagenic changes, than
chloroethanol (McCann et al., 1975)
Vinyl chloride was mutagenic in the presence of microsomal
preparations (derived from phenobarbital treated rats) and other
co-factors in a system using V79 Chinese Hamster cells. (Drevon et
Special Studies on Carcinogenicity
Groups each of 80 Wistar rats sex (Cpb:WU; Wistar random)
(approx. 5 wks of age, males 71-115 g, females 61-106 g) for control
and high dose level groups and 60 rats/sex for the middle and lowest
dose groups, were fed PVC containing diets 4 hour/day, 7 days/week.
The polyvinyl chloride (PVC) diets contained 10% PVC, containing
varying amounts of vinyl chloride monimer (VCM), and the oral exposure
to VCM during the period of feeding was 0 (control), 1.7, 5.0 and
14.1 mg/kg body weight/day. The study was terminated when about 75% of
the control rats were dead (for males, week 135 and females, week
144). Another group of rats (80/sex) received VCM (10% solution in
soya-bean oil) by gavage, 5 days/week for 83 weeks. The dose was
approximately 300 mg/kg b.w. The rats were fed normal chow diet, ad
lib. Treatment was discontinued at week 84. Interim sacrifices were
carried out at week 26 and 52, in the control and two highest test
groups, (10 males, 10 females). The parameters studied included body
weight, food consumption, hematology, clinical chemistry, gross
pathology and a complete histological study of all tissues and organs
of all animals in the high dose groups and control, and limited
histopathology on all other groups as well at interim sacrifices.
In the low dose group (1.7 mg VCM/kg b.w.) mortality of males was
similar to control, and the death rate of females was only slightly
higher, but at the 5.0 and 14.1 mg VCM/kg b.w., a marked dose related
increase in mortality was observed, with females dying earlier than
males. Rats in the 14.1 and 300 mg/kg treatment group showed a
significant decrease in blood clotting time, slightly increased levels
of alpha-foetoprotein in the blood serum, liver enlargement and an
increased hematopoetic activity in the spleen. No other significant
changes were observed in any of the other hematological, biochemical,
urine analyses and organ function, parameters studied. Liver to body
weight ratios were higher in the 14.1 and 300 mg/kg group, than in
controls. Liver changes were most pronounced and occurred earliest and
most frequently in the 300 and 14.1 mg/kg groups, and there was a
clear dose response pattern at all levels of exposure.
The incidence of foci of cellular alteration was much higher in
each of the three test groups receiving VCM powder than in control
groups, and in the groups receiving VCM in oil. Similar differences
were observed for neoplastic nodules and hepatocellular carcinomas, it
was clearly dose related, and higher in females than males.
Angiosarcomas were observed in the 3 highest dose groups, but not in
the low dose group and control. In the 5 and 14.1 mg/kg group the
incidence of angiosarcomas in the males was 3 times higher than in the
females. This difference was not observed in the 300 mg/kg group,
where the incidence was about 50% in both sexes.
Tumors were also reported a number of sites other than the liver.
Angiosarcomas were present in the lungs in the two high dose groups
(0/55 controls, 0/58, 1.7 ppm, 4/56, 5 ppm, 19/59, 14.1 ppm and 19/55
at 300 ppm for males, and 0/57 controls, 0/58, 1.7 ppm, 1/59, 5 ppm
and 23/59 at 300 ppm for females). Abdominal mesotheliomas were also
observed in all groups including controls (3/55, 1/58, 7/56, 8/59 and
1/55 for males, and 1/57, 6/58, 3/59, 3/57 and 0.54 for females, in
the 0, 1.7, 5.0, 14.1 and 300 ppm groups respectively). In addition
although females in the 14.1 and 300 mg/kg had a relatively short
survival time compared to control, the incidence of adenomas of the
mammary glands was twice as high in the test group as control. A few
test animals developed tumors of the Zymbal gland. The high incidence
of liver-cell tumors in females in the low-dose group, demonstrates
the absence of a "no observed adverse effect in this study." (Feron et
In another study vinyl chloride monomer was tested in animals of
different species, strain, sex and age. The vinyl chloride was
administered by different routes, intra-peritoneal, injection,
inhalation and ingestion. For the long term ingestion studies, (a)
groups each of 80 Sprague Dawley rats, 13 weeks of age equally divided
by sex were dosed with vinyl chloride monomer in olive oil at dose
levels equivalent to 50, 16.65 or 3.33 mg/kg b.w. (b) Groups each of
150 SD rats (equally divided by sex) 10 weeks of age, were
administered vinyl chloride monomer in olive oil, at dose levels
equivalent to 1, 0.3, or 0.03 mg/kg b.w. Dosing was 5 times a week for
52 or 59 weeks. In each case, control and test animals received olive
oil alone 85 weeks after the final treatment. In study (a), 35, 39, 32
and 23 animals were still alive in the 50, 16.65, 3.33 mg/kg b.w. and
control groups respectively at the termination of the study (136
weeks). 16 liver angiosarcomas, 2 neproblastomas, 1 Zymbal gland
carcinoma and 1 thymic and 1 intra-abdominal angiosarcoma was found in
the 50 mg/kg dose group; 9 liver angiosarcomas, 2 Zymbal gland
carcinomas and 3 nephroblastomas occurred in rats in the 16.65 mg/kg
b.w. dose group; 1 intra-abdominal angiosarcoma was found in the
3.33 mg/kg dose group; and one zymbal gland tumor in the control
group. Study (b) was terminated at 136 weeks. 3 liver angiosarcoma,
1 extrahepatic angiosarcoma, one hepatoma, and 5 Zymbal gland
tumors were found in the 1.0 mg/kg group; 1 liver angiosarcoma,
1 extrahepatic angiosarcoma, and 1 hepatoma in the 0.3 mg/kg group.
None of these tumors were reported in the 0.03 mg/kg group. One Zymbal
gland tumors was reported in the control groups of 150 rats. (Maltoni
et al., 1981)
Groups each of 108 (Wister-derived strain) rats equally divided
by sex were administered vinyl chloride in drinking water, at
concentration of 0, 2.5 or 250 ppm (equivalent to daily intake of
approximately 12, 1.2 or 0.12 mg/kg for males, and 22, 2.2 at
0.22 mg/kg for females) for 152 weeks, for doses of 0-25 mg/kg, and
115 weeks for males in the 250 ppm group, and 101 weeks for females in
the 250 ppm group. Spratt's Laboratory Diet No. 1, in powdered form
was provided ad lib. Observations of appearance and behavior were
made daily. Body weights were recorded weekly up to week 135. Food
intake was measured over a 24 hr preceding each body weight
determination, and water consumption was measured daily. Post mortem
examination was carried out on animals dying during the course of the
study, and at termination of the study. Microscopic examination was
limited to livers from all animals, and other tissues where the
presence of tumors was suspected from macroscopic examination.
Mortality was similar for males in all groups, but in the case of
females there was a significant dose related trend (females week 100,
Cumulative deaths 20, 12, 19, 43, in the 0, 2.5, 25 and 250 ppm groups
respectively). Body weight of test animals compared to control were
variable during the course of the study, with the exception of test
animals in the 250 ppm group which had lower body weights than
control. Food intake of test and control males were similar during the
first 60-80 weeks, when all treated groups showed decreased food
intake. Females did not show this trend. Water intake of all groups
was lower than controls from weeks 60-70 of the study.
The total incidence of benign tumors in treated male and female
groups was similar to the respective controls, except for females in
the 250 ppm group, in which the incidence was lower. Malignant tumors
occurred with greater frequency in the highest dose groups, the
increase being most marked in the females.
In addition to angiosarcoma in the liver, five males in the
250 ppm vinyl chloride group had angiosarcoma in the spleen, and a
single subcutaoeous angiosarcoma was present in male in the 25 ppm
vinyl chloride group. (Evans et al., 1980)
Inhalation studies have been carried out in which the following
species were exposed to vinyl chloride; rat (Sprague Dawley and
Wistar), mouse (Swiss), hamster (Golden). In Sprague Dawley rats
exposed to concentrations of vinyl chloride ranging from 50 ppm -
10,000 ppm 4 hrs/day/5 days/week for 52 weeks, and surviving up to 130
weeks. The tumors most frequently reported were, Zymbal gland,
nephroblastomas, angiosarcomas of the liver, angiosarcomas at other
sites, and brain neuroblastomas (Maltoni, 1974). In a study in mice
(11 week old Swiss) exposed to concentration of 50-10,000 ppm vinyl
chloride 4 hr/day/5 day/week for 30 weeks and then maintained another
51 weeks, 176/364 animals had adenomas/or adenocarcinomas of the lung,
60/344 had mammary carcinomas, and 47/344 had angiosarcinomas of the
liver. There was a significant increase in the incidence of tumors in
all the treated groups with the exception of lung tumors in the 50 ppm
group. In contrast to the rat, no tumors of the brain, hepatomas,
nephroblastomas or subcutaneous carcinomas were reported.
Dose (ppm in drinking water) 0 2.5 25 250 0 2.5 25 250
Approx. daily intake
(mg/kg b.w.) 0 0.12 1.2 12 0 0.22 2.2 22
Total benign tumors 15 19 25 21 59 58 58 21
Total malignant tumors 10 7 9 15 6 14 6 32
Mammary gland adenocarcinomas 0 0 0 0 2 3 3 15
Lung (metastases) 0 0 0 3 0 0 0 3
Hepatocellular carcinomas 1/50 0/50 0/47 3/50* 0/52 1/52 0/45 3/45*
Angisosarcomas 0 0 0 4 0 0 0 6
Undifferentiated tumors 0 0 1 4 0 0 0 2
* No of livers examined histologically
In a study with golden hamsters, exposured by inhalation to vinyl
chloride at 50-10,000 ppm, 4 hr/day/5 day/wk for 30 weeks. After 109
weeks liver angiosarcomas were reported in the 6000 ppm group (1/30)
and 500 ppm group (2/30), liver adenomas, in the 10,000 ppm group
(1/30), 6000 ppm group (1/30) and (2/30) 500 ppm group, cholangioma
carcinomas in the 10,000 ppm group (2/30), and 600 ppm (2/30).
Melanomas (total of 6), lymphomas (6) and for stomach papillomas (35)
were present in the treated groups, and 0, 2 and 2 respectively in
controls (Maltoni, 1977).
Groups each of 30 pregnant rats (SD) were exposed to vinyl
chloride in air at 10,000 or 6000 ppm 4 hr/day/wk on 12 to 18 days of
pregnancy, and the parents and offsprings were maintained for 143
weeks without further exposure. 1/30 breeders had a Zymbal gland
carcinomas, whereas 5/51 and 3/32 of the offsprings had Zymbal gland
carcinomas. In addition in the offsprings, 3/51 nephroblastoma (at the
10,000 ppm level), 1/51, and 1/32, stomach papillomas, and 1/51 and
2/32, mammary gland malignant tumors, were reported in the 10,000 and
1,000 ppm groups respectively (Maltoni et al., 1981).
Breeders and their offsprings (1 day old) were exposed to VCM at
10,000 or 6000 ppm, 5 day/week for 5 weeks (from day 1 to 5 weeks of
age for offspring). After 124 weeks, the incidence of tumors was as
follows: Hepatomas (20/44) and (20/42), Zymbol gland carcinomas.
(1/44) and (2/42) liver angiosarcomas (15/44) and (17/42) were
reported at the 10,000 and 6000 ppm groups respectively, for the
offspring. None of these tumors were reported for the breeders
(Maltoni et al., 1981).
Special Studies on Teratogenicity
No studies are available for administration of vinyl chloride by
the oral route. In the following studies, exposure was by inhalation.
Groups of 30 to 40 bred female CF-1 mice were exposed to vinyl
chloride (500 or 50 ppm) for 7 hr daily on day 6-15 of gestation. Some
of the mice in each group, were also given 15% ethanol in their
drinking water. The mice were sacrificed on day 18 of gestation and
the fetuses examined for visceral and skeletal malformation. The dams
were examined for corporu lutea, implantations and intrauterine
deaths. At the 500 ppm level there was significant maternal toxicity.
The incidence of resorption was higher than current controls, but not
that of historical controls in the laboratory. Fetal body measurement
were lower in litter of mice receiving ethanol and vinyl chloride,
compared to vinyl chloride alone. Examination of the skeletons
revealed only minor skeletal variations, and no major skeletal
malformations at an incidence greater than controls. (John et al.,
Groups each of 25-35 bred Sprague Dawley rats were exposed to
vinyl chloride (500 and 2,500 ppm) for 7 hrs daily on days 6-15 of
Some of the mice in the high dose group were given ethanol (15%)
in their drinking water on day 6-15 of gestation. The rats were
sacrificed on day 21 of gestation and the fetuses examined for
visceral and skeletal abnormalities. The dams were examined for
corpora lutea, implantations and intrauterine deaths. At the highest
dose levels there was significant increase in absolute and relative
liver weight. The effect was more pronounced in the group also exposed
to ethanol. There was no significant effect on litter size, the number
of implantation sites/dam or incidence of absorption in any of the
exposed animals. Fetal body weight and crown-rump length were
significantly reduced in the 2,500 ppm group in combination with
ethanol, but not in the 2500 ppm vinyl chloride alone group. However
decreased fetal body weight was observed in rats exposed to 500 ppm
vinyl chloride. Unilateral and bilateral dilated uterers were observed
in litters of rats exposed to 2500 ppm vinyl chloride. No increase in
the incidence of skeletal anomalies were observed in litters of rats
exposed to 2500 ppm vinyl chloride. However, rats exposed to both
2500 ppm vinyl chloride and ethanol, showed a significant increase in
incidence of spurs, and missing centra of the cervical vertabrae.
(John et al., 1977).
Groups each of 15 to 20 bred rabbits (New Zealand) were exposed
to 500, or 2500 ppm VC for 7 hrs daily on days 6-18 of gestation. Some
of the rabbits in the higher dose groups were also exposed to 15%
ethanol in their drinking water (days 6-18). On day 29 of gestation
the pregnant rabbits were sacrificed, and the fetuses examined for
visceral and skeletal abnormalities. The dams were examined for
corpora lutea, implantations, and intrauterine deaths. There was no
effect on maternal weight gain or liver weight or food consumption in
rabbits exposed to 2500 ppm vinyl chloride alone, but those exposed to
a combination of vinyl chloride and alcohol showed a significant
decrease in weight gain and food consumption.
Exposure to vinyl chloride alone did not cause any change in the
incidence of reabsorptions, but exposure to vinyl chloride plus
ethanol caused a marked increase in the number of resorption. There
were no differences in fetal body weight or crown-rump length in the
exposed group. Delayed ossification was observed at all dose levels.
(John et al., 1977)
Pregnant CFY rats were exposed continuously to 4000 mg/m3 vinyl
chloride during the first, second or third trimester. Vinyl Chloride
had no teratogenic or embryotoxic effect when exposure was during the
second and third trimester. Exposure to vinyl chloride during the
first trimester resulted in increased fetal mortality and embryotoxic
effect. (Ungvary et al., 1978)
LD50 - None available
Available data are limited to LC50.
Species 2 hr LC50 Reference
mice 294 g/m3 (113,000 ppm) Prodan et al., 1975
rats 390 g/m3 (150,000 ppm) "
rabbits 295 g/m3 (113,000 ppm) "
guinea pigs 595 g/m3 (230,000 ppm) "
Groups each of 30 rats (equally divided by sex) were administered
by gavage vinyl chloride in soya-bean oil at dose levels equivalent to
0, 30, 100 or 300 mg/kg body weight for 6 days/week for 13 weeks.
There was no significant change in appearance, body weight gain or
food intake, between test and control animals. Hematologic parameters
were similar for test and control animals with the exception of the
total number of white blood cells and sugar content of the blood in
the 100 and 300 mg/kg groups. Biochemical indices, were similar for
test and control animals with the exception of decreased serum GOT and
GPT and urinary GOT, in males in the 300 mg/kg group.
The relative weight of the liver increased with increasing doses
of VCM. A dose related increase in weight with significance at the
highest dose level was also noted for the adrenal glands in males.
Histological changes in the liver and other organs were minimal.
Electron microscopy of the liver, showed hypertrophy of the
endoplasmic reticulum in hepatocytes of animals in the 300 mg/kg
group. No differences were demonstrated in concentration or
distribution of liver enzymes in test and control animals. (Feron
et al., 1975)
OBSERVATIONS IN MAN
Information on toxic effects associated with vinyl chloride
exposure in man has been developed from industrial exposure
situations. Epidemiologic studies of workers exposed to vinyl chloride
showed an association between exposure to vinyl chloride and increased
risk of cancer at multiple organ sites, including the liver, brain,
lung and lymphatic and hematopoietic system. (Tabershaw/Cooper, 1974;
Ott et al., 1975; Monson et al., 1974; DeLorme and Theriault 1978;
Spirtas and Kaminski, 1978)
The carcinogenic responses are associated with very high
occupational exposures, and a long latent period (15 to 20 years)
following the onset of exposure. Other toxic effects reported in
workers exposed to vinyl chloride include acro-osteolysis,
thrombocytopenia and liver damage, (consisting of fibrosis of the
liver capsule, periportal fibrosis associated with hepatomegaly)
splenomegaly, and disorders of the nervous system. (IARC, 1979)
Chromosomal aberrations have also been reported, and in most
cases consisted of fragments, dicentrices and rings and breaks and
gaps. An excess of fetal deaths was reported in women whose husbands
were exposed to vinyl chloride (Infante, 1976a). An excess of
deformities (central nervous system, upper alimentary and genital
tracts, and of clubfoot) in stillborn and live children, was reported
in cities where vinyl chloride plants were located (Infante et al.,
1976b; Infante, 1981).
Orally administered vinyl chloride is rapidly absorbed. The
metabolism is dose dependent and a saturable process. Low oral doses
are metabolized and excreted primarily in the urine. In contrast
higher doses are mainly excreted, unchanged via the lung. The
principal urinary metabolites are derived from the oxidative
metabolism of vinyl chloride, involving the cytochrome P-450 system.
Chloroacetaldehyde and chloroethylene oxide are considered to be the
major metabolites, which react with glutathione in the presence of
glutathione-S-epoxide transferase to form S-(2 acetal) cystene which
subsequently give rise to the metabolites identified in urine, namely,
N-acetyl-S-(2 hydroxyethyl) cysteine, N-acetyl-g-vinyl cysteine and
Vinyl chloride was not teratogenic in studies with mice, rats and
rabbits and had no effect on reproductive performance of rats.
High concentrations of vinyl chloride have shown some mutagenic
activity to strains of Salmonella typhimurium. However, the
mutagenic activity of vinyl chloride in this system is considerably
increased in the presence of microsomal and other oxygenase enriched
systems. Vinyl chloride was also mutagenic in a number of other
systems, including host mediated assay in the mouse, and recessive
lethals in Drosophila melangaster. Vinyl chloride was not active in
a dominant lethal test. Chloroethylene oxide and 2-chloro-acetaldehyde
metabolites of vinyl chloride were active in the Salmonella system
whereas chloracetic acid was not.
Vinyl chloride was carcinogenic to rats, mice and hamsters when
administratered by oral inhalation or i.p. injection routes. The liver
was one of the principal site for occurrence of tumors. Other tumors
reported included pulmonary angiosarcomas, extrahepatic abdominal
angiosarcomas, and tumors of the Zymbal gland. None of the available
studies have established a "no effect" level.
Epidemiology studies of industrially exposed individuals have
shown that exposure to high levels of vinyl chloride is associated
with significant increases in the incidence of cancer at multiple
organ sites, including the liver, brain, lung and lymphatic and
Level causing no toxicological effect
Vinyl Chloride is a carcinogen in experimental animals and man.
A "no effect" level in experimental animals has not been
Human exposure to vinyl chloride in food as a result of its
migration from food contact material should be reduced to the lowest
levels which are technologically achievable.
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