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    VINYL CHLORIDE

    Explanation

         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.

                              H          Cl
                                \      /
                                  C = C
                                /      \
                              H          H

                      Vinyl Chloride

    BIOLOGICAL DATA

         Comprehensive monographs of the Biological Data relevant to the
    evaluation of carcinogenic risk to humans are available (IARC 1974 and
    1979).

    BIOCHEMICAL ASPECTS

    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)

    Biotransformation

         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
    Hathway, 1977)

    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.,
    1977)

         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
    al., 1979)

         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).

    TOXICOLOGICAL STUDIES

    Special Studies on Reproduction

         No studies are available on exposure by the oral route. One
    inhalation study in the rat has been reported.

    Rat

         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
    al., 1978)

    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
    al., 1981)

         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

         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.

                                                                                               

                                             Males                    Females
                                                                                           

    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).

    Prenatal Exposure

         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.

    Mice

         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.,
    1977).

    Rat

         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
    gestation.

         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).

    Rabbit

         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)

    Rat

         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)

    Acute Toxicity

         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)           "
                                                                

    Short-term Studies

         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).

    Comments

         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
    thiodiglycollic acid.

         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
    hematopoietic system.

    EVALUATION

    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
    established.

    Provisional Acceptance

         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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    See Also:
       Toxicological Abbreviations
       Vinyl Chloride (EHC 215, 1999)
       Vinyl Chloride (HSG 109, 1999)
       Vinyl chloride (ICSC)
       VINYL CHLORIDE (JECFA Evaluation)
       Vinyl chloride (PIM 558)
       Vinyl chloride (SIDS)
       Vinyl Chloride  (IARC Summary & Evaluation, Supplement7, 1987)
       Vinyl Chloride (IARC Summary & Evaluation, Volume 7, 1974)