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ftvyiuvj^y' , iJCL IAFC Monographs on the Evaluation of the Carcinogenic Risk 377 of Chemicals to Bmans (1979), 7oUme 19 2cidLA^a4t^( VINYL CHLORIDE, POLYVINYL OSLOtXDl end VINYL CHLORIDE-VINYL iCNTATN CCMLSHIU Vinyl chloride This substance was considered by a previous LARC Working Group, In June 1974 (IARC, 1974). Since that time new data have become available, and these have been Incorporated Into the monograph and taken into account In the present evaluation. A literature compilation (Warren et al.t 1978) and a review (Mllby, 1977) are available. 1. Chemical and Physical Data 1.1 Synonyms and trade names Cham. Abstr. Services Reg. No.: 75-01-4 Chem. Abstr. Name: Chloroethene Chloroethylene; monochloroethylene; VC; VCM; Vinyl C monomer 1.2 Structural and molecular formulae and molecular weight C2H3C1 H >c=c<Cl H Mol. wt: 62.5 1.3 Chemical and physical properties of the pure substance From Weast (1976), unless otherwise specified (a) Description: Colourless gas (Wlndholz, 1976) (b) Boiling-point: -13.37C (c) Melting-point: -153.8C (d) Density: d^20 0.9106; vapour density, 2.2 (air = 1) (Anon., 1972) 378 IARC MONOGRAPHS VOLUME 19 (e) Refractive index: n^ 1.3700 (_f) Spectrosocpy data: Infra-red, nuclear magnetic resonance and mass spectral data have been tabulated (Grasselli & Ritchey, 1975). Solubility; Slightly soluble in water (0.11 g/100 g at 25C) (Hardie, 1964); soluble in ethanol; very soluble in ether, carbon tetrachloride and benzene (h) Volatility: Vapour pressure is 2530 mm at 20C (Hardie, 1964) (i) Stability: Flash-point, -78C (closed cup) (Hardie, 1964); polymerizes in light or in the presence of a catalyst (Windholz, 1976); on combustion it degrades to hydrogen chloride, carbon monoxide, carbon dioxide and traces of phosgene (O'Hara et at., 1971) (i) Reactivity: On treatment with strong alkalis at high tempera tures it loses hydrogen chloride (Miller, 1969). (k) Conversion factor: 1 ppm in air = 2.6 mg/m23 1.4 Technical products and impurities Vinyl chloride is generally supplied as a liquid under pressure. Usually no inhibitor is added when it is to be shipped within the US. A typical analysis of a commercial US grade is as follows: water, 50 mg/kg (ppm); nonvolatile residue, 5 mg/kg (ppm); acetaldehyde, <1 mg/kg (ppm); acetylene, <1 mg/kg (ppm); iron, 0.1 mg/kg (ppm); hydrogen chloride, <0.1 mg/kg (ppm); and hydrogen peroxide, 0.01 mg/kg (ppm). In Japan, commercial vinyl chloride meets the following specifications: purity, 99.9% min; water, 200 mg/kg (ppm) max; hydrogen chloride, 1 mg/kg (ppm) max; iron, 1 mg/kg (ppm) max; and evaporation residue, 50 mg/kg (ppm) max. Chlorinated hydrocarbons may be present as impurities. 2. Production. Use, Occurrence and Analysis 2.1 Production and use (a) Production, The first synthesis of vinyl chloride appears to have been made in 1835 (Regnault, 1835). Addition of hydrogen chloride to acetylene, former1} halogens in the l ethylene dichlori hydrogen Vin years (U1 products US imporr 1976 (US 150 millCanada (< Tole in the fc Republic (690), Tt and the l kg- In J In 1976, chloride; (b) Ab u was for tl The remail duction o: in the prc vinylidenc Th 1 plastic pi In consume For detail chloride-v Hard! gerant, as production phonamides being used Llmlti propellant (US Enviror honance and [' Ritchey, 3 at 25C) |in ether, [die, 1964) 1964); |c (Windholz, ie, carbon ira et al.. |sure. US. - 50 mg/kg |kg (ppm); pride. |ifications: i g/kg g/kg |e in VINYL CHLORIDE AND POLYMERS 379 formerly the most important route of synthesis, has been displaced by the halogenation of ethylene; over 95% of the vinyl chloride monomer produced in the US and Japan in 1976 was made from ethylene. In this process, ethylene is reacted with hydrogen chloride and oxygen to give ethylene dichloride, which is subsequently cracked to produce vinyl chloride and hydrogen chloride. Vinyl chloride has been produced commercially in the US for over fifty years (US Tariff Consoission, 1928). In 1976, nine companies reported the production of 2580 million kg (US International Trade Commission, 1977). US imports have been negligible; exports amounted to 291 million kg in 1976 (US Department of Commerce, 1977), and in 1977, exports were about 150 million kg to the following countries (% of total): Brazil (28), Canada (8), Colombia (11), Mexico (14), Norway (12) and Yugoslavia (14). Total western European production in 1976 amounted to 3925 million kg, in the following countries (millions of kg): Belgium (490) , the Federal Republic of Germany (990), Finland (25), France (620), Greece (25), Italy (690), The Netherlands (340), Spain (190), Sweden (95), Switzerland (30) and the UK (430). Exports from western Europe in that year were 44 million kg. In Japan, commercial production of vinyl chloride began prior to 1946. In 1976, eighteen companies produced a total of 1281 million kg vinyl chloride; 115 million kg were exported. (b) Use About 96% of the 2274 million kg vinyl chloride used in the US in 1976 was for the production of vinyl chloride homopolymer and copolymer resins. The remainder was used (essentially by one company internally) in the pro duction of methyl chloroform and as a comonomer with vinylidene chloride in the production of resins. For a detailed description of the uses of vinylidene chloride-vinyl chloride copolymers, see p. 450. The largest use for polyvinyl chloride resins is in the production of plastic piping and conduit. Other Important uses are in floor coverings, in consumer goods, in electrical applications and in transport applications. For detailed descriptions of the uses of polyvinyl chloride and vinyl chloride-vinyl acetate copolymers, see pp. 406 and 414. Hardie (1964) reported that vinyl chloride has been used as a refri gerant, as an extraction solvent for heat-sensitive materials and in the production of chloroacetaldehyde (an intermediate in the synthesis of sulphonamides); however no evidence was found that vinyl chloride is presently being used for these purposes. Limited quantities of vinyl chloride were used in the US as an aerosol propellant, but in 1974 it was banned from use in pesticide aerosol products (US Environmental Protection Agency, 1974a), in self-pressurized household ucc 060468 380 IARC MONOGRAPHS VOLUME 19 containers, and as an Ingredient of drug and cosmetic products (US Consumer Product Safety Commission, 1974a,b). Vinyl chloride was used in western Europe in 1977 in the production of polyvinyl chloride (95%) and for other uses, including the production of methyl chloroform (5%). In Japan in 1976, vinyl chloride was used in the production of poly vinyl chloride (92-94%) and for other uses, such as in copolymers (6-8%). The US Occupational Safety and Health Administration's health standards for exposure to air contaminants require that an employees's exposure to vinyl chloride not exceed an eight-hour time-weighted average of 2.6 mg/m3 (1 ppm) in the workplace air in any eight-hour work shift of a forty-hour work week. During any work shift an employee's exposure may not exceed a celling concentration limit of 13 mg/m3 (5 ppm), averaged over any period of 15 minutes or less (US Occupational Safety and Health Admini stration, 1974). The work environment hygiene standards for exposure to vinyl chloride in various countries, in terms of time-weighted averages (8-hr) and ceiling concentrations (10- or 15-min), were as follows in 1977: Canada, 10 ppm (8-hr) and 25 ppm (15-min); Finland, 5 ppm (8-hr) and 10 ppm (10min); Italy, 50 ppm (8-hr), although this is expected to change to 25 ppm (8-hr); Japan, expected to be 10 ppm; The Netherlands, 10 ppm (8-hr); Norway, 1 ppm (8-hr) and 5 ppm (15-min); Sweden, 1 ppm (8-hr) and 5 ppm (15-min); USSR, 12 ppm (Bertram, 1977). In France, the standards were reported to be 5 ppm for 1 week, with a ceiling concentration of 15 ppm, in already existing factories, and 1 ppm and 5 ppm, respectively, for new factories; in Spain, no limits; in Denmark, 1 ppm (8-hr); in Belgium, 5 ppm (1 week), ceiling 15 ppm; in the Federal Republic of Germany, the same as for France in existing factories, and 2 ppm (1 year) and ceiling 15 ppm (1-hr) for new factories; in the UK, 10 ppm (8-hr), ceiling 30 ppm max; and in Switzerland, 10 ppm (1 week, 8-hr day for 5 days) (Thomas, 1977). In August 1977, the proposed European value was 3 ppm over one year for existing and future plants, with an 'alarm-value' of 15 ppm (Commission of the European Communities, 1977a), The US Environmental Protection Agency has proposed new rules to reduce the national emission standard for vinyl chloride from 10 ppm to 5 ppm in order to reduce vinyl chloride emissions by one-half within 3 years of the actual rulemaking. This would result in hourly emissions (based on new average-sized plants) of 5.1 kg from an ethylene dichloridevinyl chloride plant (Instead of 10.3 kg); 9 kg from a dispersion process polyvinyl chloride plant (instead of 17.5 kg); and 13.5 kg from a sus pension process polyvinyl chloride resin plant (instead of 16 kg) (US Environmental Protection Agency, 1977). In Is limi 0.3 mg/ Th 1 mg/kg packagi (Commis level o Republi (Thomas 2.2 Vi: Th and pol (US Env (a Tht prior u scrapin; hands di Between found i: Air cone chloride 100-800 (Filato-'. et al., 1976). (Bol ' she 0.35 ppn mated tl chloride On mer to v (50-250 the US t chloride vinyl ch Barnhart mg/m3 (C ride pla VINYL CHLORIDE AND POLYMERS 381 Im Che Federal Republic of Germany, Che emission In the environment is limited to 3 kg/hr/source or 150 mg/m3/source, with a ground level of 0.3 mg/m3 (992 confidence) in Inhabited areas (Thomas, 1977). The Commission of the European Communities has adopted a level of 1 mg/kg; (1 ppm) as the amount of vinyl chloride wh^ch can be present in packaging and 0.01 mg/kg (ppm) in foodstuffs packed In polyvinyl chloride (Commission of the European Communities, 1977b, 1978). A maximum migration level of 0.05 mg/kg has been adopted in Belgium, Denmark, the Federal Republic of Germany, France, Italy, The Netherlands, Spain and Sweden (Thoma^, 1977). icurrence Vinyl chloride is not known to occur as a natural product. The occurrence of vinyl chloride in ambient air near vinyl chloride and polyvinyl chloride plants, in water, and in food has been reviewed (US Environmental Protection Agency, 1975a,b). (a) Occupational exposure The air concentration of vinyl chloride in a polymerization reactor prior to ventilation is of the order of 7800 mg/m3 (3000 ppm); during the scraping procedure, 130-260 mg/m3 (50-100 ppm); and that close to the hands during scraping, 1560-2600 mg/m3 (600-1000 ppm) (Cook et al., 1971). Between 1950 and 1959, concentrations up to 10.4 g/m3 (4000 ppm) were found in one factory near the polymerization reactors (Ott et al., 1975). Air concentrations of vinyl chloride in working places in polyvinyl chloride-producing factories have been reported variously to range from 100-800 mg/m3 (40-312 ppm), with peaks up to 87.3 g/m3 (33 500 ppm) (Filatova & Gronsberg, 1957); from 112-556 mg/m3 (43-214 ppm) (Anghelescu et al. 1969); and >195 mg/m3 (>75 ppm) in a Yugoslav plant (Orusev et al.. 1976). In a Russian synthetic leather plant, <113.6 mg/m3 (44 ppm) (Bol's kov, 1969) and in three UK cable factories, 0-4-0.9 mg/m3 (0.150.35 p ) (Murdoch 4 Hammond, 1977) were detected. In 1974, it was estimated t t 20 000 US workers, past and present, had been exposed to vinyl chlorid in manufacturing plants (Heath et al., 1975). On |a time-weighted average, the concentration of vinyl chloride mono mer to yhlch coagulator operators are exposed ranges from 130-650 mg/m3 (50--250|ppm) (Baretta et al., 1969). However, in a more recent survey for the US National Institute for Occupational Safety and Health of three vinyl chloride plants it was reported that the time-weighted average exposure to vinyl chloride ranged from 0.2-70 mg/m3 (0.07-27 ppm) (Milby, 1977). Barnhart et al. (1975) found <0.03-15 mg/m* (<0.01-5.89 ppm), 0.03-220 mg/m3 (Q.01-84.77 ppm) and 0.05-57 mg/m3 (0.02-21.8 ppm) in 3 vinyl chlo ride pl4nts in the US. 382 I ARC MONOGRAPHS VOLUME 19 In 1974, it was reported that polyvinyl chloride leaving certain manufacturing plants may have contained 200-400 mg/kg (ppm) vinyl chloride monomer; on delivery to che customer, this level was about 250 mg/kg (ppm); and after processing, levels of 0.5-20 mg/kg (ppm) were reached, depending oil the method of fabrication (Anon., 1974). Wilkinson et al. (1964) found 100 mg/kg (ppm)1 residual vinyl chloride monomer in polyvinyl chloride dis persions. However, new processing methods leave as little as 1-2 mg/kg (ppm) residual vinyl chloride in vinyl chloride resins (US Food and Drug Administration, 1975). Residual vinyl chloride in commercial food grade resins has been reduced by processing and stripping techniques to 115 ug/kg (ppb) for resin, less chan 0.048 ug/kg (ppb) for compound and less than 0.043 Ug/kg (ppb) for sheet polyvinyl chloride (Saggese et al., 1976). Industrial grade) polyvinyl chloride-coated films used for food packaging were found to cohtaln 5-71 Ug/kg (ppb) of monomer (Gilbert et al., 1975) and plastic bottj.es up to 7.9 mg/kg (ppm) (Breder et al., 1975). (b) Air | It has been estimated that prior to 1975 vinyl chloride emissions from US polyvinyl chloride plants amounted to 110 million kg/year (US Environmental Pro! tection Agency, 1975b) and that the average concentration of vinyl chloride) in air around these plants was 44 ug/m3 (17 ppb) (US Environmental Protection Agency, 1976). Vinyl chloride has been determined in the air in the Houston, Texas, area (where an estimated 40Z of the US production capaci ;y is located) in concentrations of 8 Ug/m -3.2 mg/m3 (3.1-1250 ppb) (Gordon A Meeks, 1977) and in the ambient air near two vinyl chloride plants in the Long Beach, California, area in concentrations of 0.26-8.8 mg/m3 (ojl-3.4 ppm) (National Field Investigations Center, 1974). It has also been detected in the air in Delaware City, Delaware, In maximum concentrations of 3.9 mg/m3 (1.5 ppm) with a mean of 2 mg/m3 (0.8 ppm) (Lillian et al., ^975). (c) Water j Vinyl chloride has been detected in effluent discharged by chemical and latex manufacturing plants and in raw water in the US (Shackelford A Keith, 1976). The highest concentration of vinyl chloride detected In finished drinking-water in the US was 10.0 Ug/1 (Safe Drinking Water Committee, 1977; US Environmental Protection Agency, 1975a). I In 1974, it was estimated that about 12.3 kg/day vinyl chloride were discharged in the waste-water effluent from 2 vinyl chloride plants in the Long Beach, California, area (National Field Investigations Center, 1974). (d) Food In May 1973, aI branch of the US Treasury Department banned the use of polyvinyl chloride for the packaging of alcoholic beverages (Anon., 1973a), as a result of studies reported by the US Food and Drug Administration indi cating that up to 2(j, mg/kg (ppm) vinyl chloride monomer were present in alcohol chloric mg/kg < levels It (ppm) ( in butt et al., chlorid (e Vii cone end another 16 new c Vir. and litt marijuat 2.3 Ana Ac methods sphere, is avail vinyl ch. 1975b). water, at A gi National chloride 5-litre e 1977). A ga mission o foodstuff into cont An o of German- is bast by gas chi tion and . Normen Au; 3 certain vinyl chloride -50 mg/kg (ppm); :ed, depending (1964) found chloride dis: 1-2 mg/kg d and Drug - food grade s to 115 ug/kg leas than . 1976). 1 Packaging -- , 1975) '). missions -ar (US ^ncenccation CD' A in c vKined of the US 2 mg/m3 at two vinyl acions of =ar, 1974). in maximum o ppm) chemical elford & ted in ter ide were -s in the 1974). a use of 1973a), :lon Indi ct in VINYL CHLORIDE 4ND POLYMERS 383 alcoholic beverages packaged in this material (Anon., 1973b). Vinyl chloride has been found in a variety of alcoholic drinks at levels of 0-2.1 mg/kg (PP-m) (Williams, 1976a,b; Williams & Miles,*1975) and in vinegars at levels o f up to 9.4 mg/kg (ppm) (Williams & Miles, 1975). It pas been found in edible oils, in concentrations of 0.05-14.8 mg/kg (ppm) (Rbesli et al., 1975; Williams, 1976a; Williams & Miles, 1975), and in butter and margarine, in concentrations of 0.05 mg/kg (ppm) (Fuchs et al., L975), when these products were packaged and stored in polyvinyl chloride containers. (e) Other Vin;yl chloride has been found in 2/7 new automobile interiors in coneentr ations of 1-3 mg/m3 (0.4-1.2 ppm) (Hedley et al., 1976). In another study (Going, 1976), no concentrations above 10 ppb were found in 16 new o used automobiles or In 4 new or old mobile homes. Vinyl chloride has been detected in domestic and foreign cigarettes and little cigars, in concentrations of 5.6-27 ng/cigarette, and in a marijuana cigarette at a level of 5.4 ng/cigarette (Hoffmann et al., 1976). 2.3 Ana. .ysis A &omprehensive critical review, containing over 100 references, of methods sampling and analysis of vinyl chloride in the workplace atmo- sphere, ambient air, water, food, cigarette smoke and polyvinyl chloride is avail;,ble (Egan et al., 1979). Methods of collection and analysis of vinyl ch4'oride have also been reviewed (US Environmental Protection Agency, 1975b). A review of methods used to determine vinyl chloride in air, water, anid water piping is available (Laramy, 1977). A gas chromatographic method of analysis has been accepted by the US National Institute for Occupational Safety and Health for determining vinyl chloride in the workplace atmosphere, in the range of 0.008-5.2 mg/m* in a 5-litre air sample (National Institute for Occupational Safety and Health, 1977). A ga, chromatographic analytical method has been proposed by the Commission o the European Communities for determining vinyl chloride in foodstuffs and in vinyl chloride polymers and copolymers intended to come into cont act with food (Commission of the European Communities, 1977b). An o fficial analytical method has been drafted in the Federal Republic of Germany for determining residual vinyl chloride in polyvinyl chloride, It is bas ed on treatment of the polymer with N, iV-dlmethylacetamide, followed by gas chiromatographlc analysis of the solution with flame-ionization detection and has a limit of detection of 0.5 mg/kg (ppm) (Deutsche Industrie Normen k\us schuss, 1977). ucc 060472 384 IARC MONOGRAPHS VOLUME 19 3.) Biological Data Relevanc to the Evaluation of Carcinogenic Risk Co Humana (a) Oral a<[ministration Rat: Groups of 40 male and 40 female 13-week-old Sprague-Dawley rats received gastric|intubations of 0, 3.33, 16.65 or 50 mg/kg bw vinyl chloride dissolv d in olive oil 4-5 times/week for 52 weeks. After 85 weeks from the itlal treatment, 35, 39, 32 and 23 animals were still alive. At 120 eks, 9 liver angiosarcomas, 2 Zymbal gland carcinomas and 3 nephroblastoma occurred in rats administered the 16.65 mg/kg bw dose; and 16 liver angiosarcomas, 2 nephroblastomas, 1 Zymbal gland carcinoma, and 1 thymic and 1 intra-abdominal angiosarcoma were found in the 50 mg/kg bw group. One intra-abdominal angiosarcoma was seen in the low-dose group, and 1 Zymbal gland tumour occurred in the control group (Maltoni, 1977a; Maltoni et al.t 1975). (b) Inhalatllion and/or intratracheal administration Mouse: Grou is of 30 male and 30 female 11-week-old Swiss mice were exposed to concen :rations of 130-26 000 mg/m3 (50, 250, 500, 2500, 6000, or 10 000 ppm) vi| tyl chloride in air for 4 hours/day on 5 days/week for 30 weeks. A tota of 344 mice (176 males and 168 females) died within 61 weeks. At 81 wee] (end of experiment), 176 animals (3.5, 57, 66, 57, 70 and 70Z in the dlJ 'ferent groups, respectively) had adenomas and/or adenocarcinomas of the lung, 60 animals (33, 32, 24, 30, 28 and 47Z, respectively) had mamma: adenocarclnomas and 47 animals (2, 19, 19, 20, 5 and 16Z, respectively] had angiosarcomas of the liver. Except for lung tumours, which were not ini creased in the group treated with 50 ppm, a significantly higher number of leoplasms occurred in all treated groups. In 80 male and 70 female untreati :d controls, 8 pulmonary tumours and 3 lymphomas were observed (Maltoni 1977; Maltoni et al., 1974). 'The Working [Group was aware of studies in progress to assess the carcinogenicity ofl vinyl chloride in rats by administration in the drinklngwater and by admin lstratlon in the diet, and of complete but unpublished studies by iahalat ion in rats (IARC, 1978a). In all his experiments, Maltoni used vinyl chloride that contained the following impufltles (mg/kg): water, 100; acetic aldehyde, 5; acetylene, 2; allene , 5; butane, 8; 1,3-butadiene, 10; chloroprene (see also, p. 131), 10; ' diacetylene, 4; vinyl acetylene, 10; propine, 3; methyl chloride, 100. Gt were e> in air were ot treatec liver ^ (hi3tol A doseno tumo study w 1975). albino chlorii expos ei ppm gr minate ding p' and a i for 26 had an had an angios adenoc reticu ucc 060473 T ue-Dawley rats v vinyl After 85 vere still '.arcinomas and kg bw dose; i carcinoma, a the 50 mg/kg -ow-dose group, =>ni, 1977a; 3/week for d within 61 66, 57, 70 d/or adeno, respec- 20, 5 and lung tumours, ignificantly 80 male and as were as the the drinkingublished ontained 5; ace- ene (see m, 3; VINYL CHLORIDE AND POLYMERS 385 - Groups of 100 male and 100 female CDI Swiss/ChR mice (age unspecified) were exposed to 130, 520 or 6500 mg/m3 (50, 200 or 2500 ppm) vinyl chloride in air (purity unspecified) for 7 hours/day on 5 days/week for 9 months and were observed for an additional 9 months. After 8 months' exposure, 49 treated animals died with tumours. A total of 42 pulmonary adenomas, 41 liver angiosarcomas and 11 mammary gland adenocarcinomas were observed f (histological evaluation was carried out on grossly visible tumours only). A dose-related carcinogenic effect was evident (see Table I). At 8 months, no tumours were observed in 200 controls (100 females and 100 males). The study was still in progress at the time of reporting (Keplinger et at., 1975). Table I Incidence of tumours in mice exposed to vinyl chloride (purity unspecified) for 8 months1 Exposed groups 50 ppm 200 ppm 2500 ppm Control No. of mice with tumours at death Male Female Total 1 34 3 12 15 6 24 30 0 00 Type and location of tumour Adenomas Angiosar comas Adenocar cinomas lung liver mammary gland 22 12 11 28 28 00 2 3 6 0 lFrom Keplinger et at. (1975), preliminary results Two groups each of 12 male and 12 female 3-month-old NMRI outbred albino mice were exposed to either 130 or 1300 mg/m3 (50 or 500 ppm) vinyl chloride in air for 6 hours/day on 5 days/week. The 500 ppm group was exposed for 26 weeks only (due to the poor condition of the mice); the 50 ppm group was exposed for 52 weeks, at which time the experiment was ter minated. In the low-dose group, 18/24 animals had developed tumours, including pulmonary adenomas in 13/24, angiosarcomas at various sites in 15/24 and a mammary carcinoma in 1 mouse. Inhalation of 500 ppm vinyl chloride for 26 weeks induced pulmonary adenomas in all mice; in addition, 8 mice had angiosarcomas, mammary adenocarcinomas were found in 4 animals, 1 mouse had an angiosarcoma of the liver, 1 an adenoma of the kidney and 1 an angiosarcoma of brown fat. In the control group, 3/48 had tumours: 1 adenocarcinoma of the mammary gland, 1 dysgermlnoma of the ovary and 1 reticulum-cell sarcoma of the spleen (Holmberg et at., 1976). UCC 060474 386 IARC MONOGRAPHS VOLUME 19 Groups of 36 male and 36 female 2-month-old albino CD mice were exposed to 130, 650 and 2600 mg/m3 (50, 250 and 1000 ppm) vinyl chloride (99.8Z pure) In air for 6 hours/day on 5 days/week for 52 weeks; at that time, 70, 52, 46 and 38 animals were still alive, respectively. A total of 12, 22 and 48 mice developed lung adenomas In the exposed groups, res pectively; 1 lung adenoma was found In untreated control animals. In addition, angiosarcomas of the liver developed In 3, 23 and 31 treated mice, respectively, and angiosarcomas In other organs in 7, 5 and 9 mice. Mammary gland tumours were found in 9, 3 and 13 mice, respectively; most of these tumours metastasized to the lungs (Lee et al., 1977, 1978). Rat: A group of 26 male 3-month-old Ar/IRE Wistar rats were exposed to an atmospheric concentration of 3Z v/v (equivalent to 78 g/m3 or 30 000 ppm) commercial grade vinyl chloride (99Z pure) for 4 hours/day on 5 days/ week for 12 months; the experiment was terminated at 54 weeks. Skin tumours developed in the submaxillary parotid region in all 17 surviving rats (14 epidermoid carcinomas, 2 mucoepidermoid carcinomas, 1 papilloma); in addition, lung tumours developed in 7 rats and osteochondromas in 5. No tumours were observed in 25 untreated controls killed at an unstated time (Viola et al., 1971) [Maltoni i Lefamine (1974) examined slides from this experiment and concluded that the skin tumours were Zymbal gland tumours and that the lung tumours were metastases from these]. Groups of 30 male and 30 female 21-week-old Sprague-Dawley rats were exposed by inhalation to 130-26 000 mg/m3 (50, 250, 500, 2500, 6000 or 10 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 17 weeks. At 86 weeks, 18, 15, 37, 33, 16 and 9 animals were still alive In the 6 groups. At 155 weeks (end of experiment), carcinomas of the Zymbal gland were found in 0, 1, 1, 3, 6 and 7 animals, respectively (1 in un treated controls), nephroblastomas in 1, 2, 0, 2, 1 and 1 animals, liver angiosarcomas inO, 0, 1, 1, 1 and 0 animals and angiosarcomas at other sites in 2, 0, 1, 2, 1 and 1 (1 in controls). Brain neuroblastomas were seen in 0, 0, 0, 2, 2 and 6 animals, respectively (Maltoni, 1977a; Maltoni et al., 1974). Groups of 64-96 13-week-old Sprague-Dawley rats were also created for 52 weeks with the above concentrations of vinyl chloride in air. The following tumours developed in various organs by the end of the experiment, at 135 weeks: carcinomas of the Zymbal gland in 29/239 rats at the 4 highest dose levels, and nephroblastomas (26/257 rats) and angiosarcomas of the liver (47/357 rats) in all the treated groups (the numbers of rats given were those alive at 26 weeks); a total of 14 angiosarcomas was observed in organs other than the liver. The tumours of the liver and kidney metastasized to ocher organs. No such tumours were observed in 58 untreated controls alive at 26 weeks (see Table II). In a group of 60 17week-old Sprague-Dawley rats treated with 78 g/m3 (30 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 43 weeks, 30 (50Z) developed Zymbal gland carcinomas, 13, liver angiosarcomas and 1, a lung angiosarcoma within the 61 weeks of observation (Maltoni et al., 1974). S>U)93 5O *t".Sslrr-a" n )-j n^> wC sei*;* * "P ?S 5* f 3 0 ft *f^t4 C0fOtft $& drOHt* f1t ft ft O rt j- an>r <k *i it * M ar HH* ft qc*'< ff1 W Hie D g0^1 Mf*tMtrj H<fHtH O1 *s-i C oti h *-* p 3 H* ft "* tHC--U`- PCft f(At *xfr)tj 0 fftt rftt hp. u VINYL CHLORIDE AND POLYMERS Table II Incidence of tumours In Sprague-Dawley rats exposed to vinyl chloride for 4 hours/day on 5 daya/week for 52 weeks and surviving up to 130 weeks Concentration of vinyl chloride (ppm) Total no. of animals at start No. of animals alive at 26 weeks No. of Zymbal gland tumours No. of nephro blastomas No. of angio sarcomas of the liver No. of angio sarcomas at other sites No. of brain neuro blastomas No. of other tumours 10 000 6000 2500 500 250 50 Controls 69 72 74 67 67 64 68 61 16 5 9 3 7 11 60 7 4 13 3 3 10 59 2 6 13 3 5 7 59 4 4 720 8 59 0 6 420 7 59 0 1 1 1 0 10 58 0 0 0 0 0 10 lFrom Maltoni et al. (1974) O O 387 060476 388 I ARC MONOGRAPHS VOLUME 19 "f Wiatar rats were also exposed by Inhalation to 130-26 000 mg/m3 (50, 250, 500, 2500, 6000 and 10 000 ppm) vinyl chloride In air for 52 weeks. After 136 weeks of observation, 1 Zymbal gland carcinoma was found, whereas at a comparable time the Sprague-Dawley rats had developed 29 such tumours. In the Wistar rats, 1 nephroblastoma, 8 liver angiosarcomas and 1 brain neuroblastoma were found in the 10 000 ppm group; 3 nephroblastomas, 2 liver angiosarcomas and 1 brain neuroblastoma in the 6000 ppm group; 3 liver angiosarcomas in the 2500 ppm group; and 1 nephroblastoma and 4 liver angiosarcomas in the 500 ppm group (Maltoni, 1977a; Haltoni et at., 1974). The effect of length of treatment by inhalation of vinyl chloride on the incidence of liver angiosarcomas was investigated. Groups of 60-120 Sprague-Dawley rats were given either 15.6 or 26 g/m3 (6000 or 10 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 5, 17 or 52 weeks. The experiment was terminated at 155 weeks. Liver angiosarcomas developed in 13 (22%) and 9 (15%) of the 6000 and 10 000 ppm groups exposed for 52 weeks; 1 (0.6%) liver angiosarcoma was found in a rat exposed to 6000 ppm for 17 weeks and none in the 10 000 ppm group. No such tumours were induced in rats treated for 5 weeks (Maltoni, 1977b) (No information was given about tumours occurring at ocher sites]. The influence of age on the incidence of liver tumours was examined in Sprague-Dawley rats exposed to 15.6 or 26 g/m3 (6000 or 10 000 ppm) vinyl chloride in air for 4 hours/day on 5 days/week for 5 weeks, starting at the age of 13 weeks (120 rats/group) or 1 day (43 and 46 rats). The animals were observed for 135 weeks. One hepatoma was reported in the older rats created with 10 000 ppm. In the newborn rats, 10 angiosarcomas and 13 hepatomas were observed in the 6000 ppm group, and 10 angiosarcomas and 15 hepatomas were found in rats treated with 10 000 ppm. No liver tumours were reported in the 249 uncreated rats (Maltoni, 1977b). Groups of 36 male and 36 female 2-month-old CD rats were exposed to 0, 130, 650 and 2600 mg/m3 (0, 50, 250 and 1000 ppm) vinyl chloride In air (99.8% pure) for 6 hours/day on 5 days/week for 12 months, at which time the surviving animals (72, 70, 58 and 51) were killed. In rats treated with 250 and 1000 ppm, liver angiosarcomas occurred in 12 and 22 and lung angiosarcomas developed in 3 and 13 (Lee et at., 1977). In a report of a study in progress, 4 groups of 80 Sprague-Dawley male rats received either 5% ethanol in the drinking-water or drinking-water only for 4 weeks prior to beginning inhalation of 1560 mg/m3 (600 ppm) vinyl chloride for 4 hours/day on 5 days/week for 12 months or air; ethanol-water was given until death or sacrifice. After 60 weeks from the first exposure to vinyl chloride, 55 rats had died or had been sacrificed; liver tumours were found in 21/28 (75%) in the vinyl chloride-ethanol group and 5/13 (38%) in the vinyl chloride only group (Radike et at., 1977). Hamster; Groups of 32-35 male 11-week-old golden hamsters were exposed by inhalation to 130-26 000 mg/m3 (50, 250, 500, 2500, 6000 and 10 000 ppm) vinyl ch weeks fr At 109 w treated epitheli in 2/70 with 50, and 35 fi and 2 anc 1974). Kabt week for Between 9 cinomas w months of inadequac (c) A gr given sin oil. One (The Work: not given d) Group received s oil, 2, 3 coma were times and Prena. given 15.6day by inJu 17/32 and ; (end of exf offspring; cinoma; nr and 1, a ne a Zymbal gl 000 mg/m5 (50, for 52 weeks. 3 found, whereas 29 such tumours, and 1 brain blastomas, 2 am group; 3 itoaa and 4 laltoni et al., I chloride on ps of 60-120 sr 10 000 ppm) ',7 or 52 weeks. ;mas developed osed for 52 -d to 6000 ppm :rs were induced was given about | | f I t t t f I VINYL CHLORIDE AND POLYMERS 389 vinyl chloride in air for 4 hours/day on 5 days/week for 30 weeks. At 48 weeks from the initial treatment, 60/198 treated animals were still alive. At 109 weeks (end of treatment), 2 liver angiosarcomas were seen in hamsters treated with 500 ppm and 1 in those created with 6000 ppm. Skin tricho epitheliomas developed in 22 treated hamsters (in 1-6 animals/group) and in 2/70 controls. Two animals treated with 6000 ppm and 1 each treated with 50, 2500 and 10 000 ppm developed melanomas. In addition, 6 lymphomas and 35 forestomach papillomas and acanthomas were found in treated animals, and 2 and 2, respectively, in controls (Maltoni, 1977a; Maltoni et al,, 1974). Rabbit: A group of 40 rabbits were exposed for 4 hours/day on 5 days/ week for 12 months to air containing 26 g/nr (10 000 ppm) vinyl chloride. Between 9-15 months of exposure, 12 skin acanthomas and 6 lung adenocar cinomas were seen. No similar tumours occurred in 20 controls after 15 months of observation (Caputo et al., 1974) [The Working Group noted the inadequacy of reporting]. (c) Subcutaneous and/or intramuscular administration A group of 75 male and female 21-week-old Sprague-Dawley rats were given single s.c. injections of 4.25 mg/anlmal vinyl chloride in 1 ml olive oil. One nephroblastoma occurred in the treated animals (Maltoni, 1977a) [The Working Group noted that survival times and period of observation were not given]. (d) Intraperitoneal administration Groups of 30 male and 30 female 13-week-old Sprague-Dawley rats received single injections of 4.25 mg/animal vinyl chloride In 1 ml olive oil, 2, 3 or 4 times in 2 months. One nephroblastoma and 1 s.c. angiosar coma were found (Maltoni, 1977a) [The Working Group noted that survival times and period of observation were not given]. (e) Other experimental systems Prenatal exposure: Two groups of 30 female Sprague-Dawley rats were given 15.-26 g/mJ (6000 or 10 000 ppm) vinyl chloride in air for 4 hours/ day by inhalation from the 12-18th day of pregnancy. Of the offspring, 17/32 and 23/54 had died by the 95th week after birth. After 143 weeks (end of experiment), 1 s.c. angiosarcoma was observed in each group of offspring; 1 animal exposed in utero to 6000 ppm had a Zymbal gland car cinoma; and 3 animals exposed to 10 000 ppm had Zymbal gland carcinomas, and 1, a nephroblastoma. One female rat treated with 10 000 ppm developed a Zymbal gland carcinoma (Maltoni, 1974; Maltoni, 1977a). *re exposed 3 000 ppm) ucc 060478 1 1 ) 390 IARC MONOGRAPHS VOLUME 19 3.2 Other relevant biological data (a) Experimental systema Toxic effects The 2-hour LC50 of vinyl chloride for mice was 294 g/m3 (113 000 ppm); for rats, 390 g/m5 (150 000 ppm); for guinea-pigs, 595 g/m3 (230 000 ppm); and for rabbits, 295 g/m5 (113 000 ppm). Vinyl chloride gas had a narcotic effect on experimental animals, the most sensitive species being mice, followed by rats, guinea-pigs and rabbits. The death of animals was prece ded by excitement, contractions and convulsions, accelerated respiration, followed by respiratory failure. Rabbits and guinea-pigs had more accen tuated muscular contractions and convulsions than mice and rats. Micro scopically, congestion of the internal organs with more intense damage to the lungs, liver and kidneys were found (Prodan et al., 1975a). The hepatotoxicity of vinyl chloride has been shown to be increased after administration of cytochrome P-450 inducers such as phenobarbital, Aroclor 1254 and hexachlorobenzene (Ivanetich et at., 1977; Reynolds et at., 1975a,b). The extent of liver damage has been measured by the release of alanine a-ketoglutarate, glutamic oxalacetlc and glutamic pyruvic transaminases (Reynolds et al., 1975b, 1976) and of sorbitol dehydrogenase (Conolly & Jaeger, 1977) into the serum. A single 6-hour inhalation exposure to 130 g/m5 vinyl chloride (50 000 ppm) produced acute liver injury in male Sprague-Davley rats pretreated with phenobarbital or Aroclor 1254. The degree of injury, as indicated by elevation of serum levels of enzymes derived from the liver, correlated with the magnitude of Induction of cytochrome P-450 and morphological changes in the endoplasmic reticulum (Reynolds et al., 1975a,b, 1976). Similar find ings were reported in phenobarbltal-pretreated male Holtzman rats (Jaeger et al., 1974) and in phenobarbital-treated male Charles River CD-I rats that received 10 daily exposures for 6 hours/day to 35 g/m5 (13 500 ppm) vinyl chloride in air (Drew et al., 1975). Cytochrome P-450 concentration decreased during in vivo exposure or during in vitro incubation of liver homogenate from phenobarbital ot 3- methylcholanthrene-induced rats (Ivanetich et at., 1977; Reynolds et al., 1975c). In an abstract, it was reported that male rats pretreated by gavage with Aroclor 1254 for 3 consecutive days and exposed on day 4 by inhalation to 62.5 g/m5 (24 000 ppm) vinyl chloride for 4 hours showed significant elevations of serum alanine-a-ketoglutarate transaminase and severe degener ation and necrosis of the liver (Conolly et al., 1977). Overnight fasting, which depletes hepatic glutathione, of Aroclor-pretreated male Holtzman rats before exposure to 26 g/m5 (10 000 ppm) for 4 hours significantly increased the hepatotoxic effects, as measured by sorbitol dehydrogenase levels in the serum (Conolly & Jaeger, 1977). S Inn Ppm viny. Injury tr vinyl ch; cantly er In fed n Expc 2 hours/c histopath and lungs denoting large qua by vinyl Mice vlnyl chi some acur renel cor lost weig for 12 mor The r exposed ti a function 1976a). Vinyj oxide and (Border A Embrt Pregn (30 and 5C rats to 13 and New Ze 6-18 of ge to 152 etb of several received v 1975). Absor: The i> and review* Henschler, 1975; Mala 1976; Plug 1976b,c). (113 000 ppm); (230 000 ppm); had a narcotic ing mice, ,ils was precerespiration, more accen ts. Micro be damage to increased obarb^al, >yr i b, W Jtamic "bitol ride (50 000 etreated ndicated by rrelated with 1 changes in '.ilar find-s (Jaeger j-1 Tats 500 ppm) ^>sure or i ob 33 et al., gavage inhalation iicant [ j 1 1 I VINYL CHLORIDE AND POLYMERS 391 Simultaneous exposure to 1.75 g/m3 (671 ppm) vinyl chloride with 200 ppm vinylidene chloride prevented vinylidene chloride-induced hepatic injury in fasted male rats. However, pre-exposure to concentrations of vinyl chloride which depleted hepatic glutathione concentrations signifi cantly enhanced early acute hepatotoxic response to vinylidene chloride in fed rats (Jaeger et al., 1975a,b). Exposure of guinea-pigs to 260 g/m3 (100 000 ppm) vinyl chloride for 2 hours/day for 3 months resulted in marked growth disturbances and intense histopathological and histochemical lesions in the liver, kidneys, spleen and lungs. Interruption of the exposure resulted in a regenerative effect, denoting a certain degree of reversibility of the hepatorenal lesions. Large quantities of vitamin C reduced the gravity of the lesions caused by vinyl chloride (Frodan et al., 1975b). Mice were exposed to 130, 650 or 2600 mg/m3 (50, 250 or 1000 ppm) vinyl chloride for 6 hours/day on 5 days/week. The highest dose caused some acute deaths with toxic hepatitis and marked tubular necrosis in the renal cortex. From the 6th month of treatment, all mice became lethargic, lost weight quickly and died. Only a few mice exposed to 50 ppm survived for 12 months (Lee et al., 1977). The non-protein, free SH-groups of the liver are depleted in rats exposed to 390-5200 mg/m3 (150-2000 ppm) vinyl chloride for 1-7 hours, as a function both of concentration and duration of exposure (Watanabe et al., 1976a). Vinyl chloride and two of its presumed metabolites, chloroethylene oxide and chloroacetaldehyde, depressed DMA. synthesis in rat liver in vivo (Border & Webster, 1977). Embtyotoxicity and teratogenicity Pregnant CF-1 mice were exposed by inhalation to 130 and 1300 mg/m3 (50 and 500 ppm) vinyl chloride on days 6-15 of gestation, Sprague-Davley ratB to 1300 and 6500 mg/m3 (500 and 2500 ppm) on days 6-15 of gestation, and New Zealand rabbits to 1300 and 6500 mg/m3 (500 and 2500 ppm) on days 6-18 of gestation, for 7 hours/day, with or without simultaneous exposure to 15% ethanol in the drinking-water. A significantly increased incidence of several skeletal anomalies was observed in offspring of mice that received vinyl chloride plus ethanol (John et al., 1977; Schwetz et al., 1975). Absorption, distribution, excretion and metabolism The in vivo and in vitro metabolism of vinyl chloride has been studied and reviewed (Antweiler, 1976; Bartsch & Montesano, 1975; Bonse 4 Henschler, 1976; Green & Hathway, 1975, 1977; Haley, 1975; Hefner et al., 1975; Malaveille et al., 1975; MUller 4 Norpoth, 1975; Mllller et al., 1976; Plugge 4 Safe, 1977; Watanabe 4 Gehring, 1976; Watanabe et al., 1976b,c). UCC 060480 392 IARC MONOGRAPHS VOLUME 19 Low concentrations (L30 mg/m3, 50 ppm, for 65 min) of vinyl chloride are readily metabolized in rats exposed by inhalation and are converted into polar metabolites, which are predominantly excreted in the urine; a very small amount is expired in air as unchanged vinyl chloride (Hefner et al., 1975). Following exposure of male rats by inhalation to 26 mg/m3 (10 ppm) 14C-vinyl chloride for 6 hours, urinary l4C-activity and expired vinyl chloride comprised 68 and 2Z, respectively, of the recovered radioactivity; after exposure to 2600 mg/m3 (1000 ppm) 14C-vinyl chloride, the proportion of the radioactivity in the urine was lower and that expired as vinyl chloride higher, representing 56 and 12Z, respectively. The pattern of pulmonary elimination of 10 and 1000 ppm vinyl chloride per se was descri bed by apparently similar first-order kinetics, with half-lives of 20.4 and 22.4 min, respectively; the half-lives for the initial phase of excretion of 14C-radioactivity in the urine were 4.6 and 4.1 hours, respectively. 14C-Radioactivity recovered from the carcass after 72 hours was 14 and 15Z, respectively; no vinyl chloride per se was found in tissues. The propor tions of 3 urinary metabolites, /V-acetyl-S-(2-hydroxyethyl)cysteine, thiodiglycolic acid (thiodiacetic acid) and an unidentified metabolite, were not markedly influenced by the level of exposure (Watanabe et al., 1976b). Following single oral administration of 0.05, 1 or 100 mg/kg bw 14Cvinyl chloride to male rats, excretion in the urine was 59, 68 and 11Z, respectively; the l4CC>2 in expired air accounted for 9, 13 and 3Z, respec tively; pulmonary elimination of unchanged vinyl chloride represented only 1-3Z of the lower dose levels and 67Z of the higher level. The pulmonary clearance of 0.05 and 1 mg/kg bw doses of vinyl chloride was monophasic, with half-lives of 53.3 and 57.8 min, respectively; it was biphasic after administration of 100 mg/kg bw, with half-lives of 14.4 and 40.8 min for the fast and slow phases, respectively. The percentages of the doses left in the carcass after 72 hours were 10, 11 and 2Z of the 0.05, 1 and 100 mg/kg doses, respectively. Two of 3 urinary metabolites were Identified as /17-acetyl-S-(2-hydroxyethy1)cysteine and thiodiglycolic acid; their propor tions were not influenced by dose (Watanabe et al., 1976c). It has been suggested that the metabolism of vinyl chloride in rats following oral and inhalation exposure is a saturable process (Watanabe et al., 1976b,c). The kinetic parameters and half-lives for the elimination of vinyl chloride from rats after inhalation and i.v. administration have also been reported by Withey (1976). When rats were exposed to initial concentrations of less than 260 mg/m3 (100 ppm) (1,2-34C]-vinyl chloride, about 40Z of that inspired was absorbed by the lung. Highest radioactivity levels were observed in the liver and kidney immediately after exposure. Most of the radioactive metabolites were excreted rapidly, largely by the kidneys: the radioactivity in the urine amounted to 70Z within 24 hours. Some metabolites, however, remained in tissues (mostly in spleen, liver, kidneys) even 48 hours after exposure (Bolt et al., 1976).t Metabolites that were not excreted in urine were partly excretet Green & vk to chloi dehyde in vivo. chloride, homogena internet et al., of the 1 formed w et al., of vinyl acetalde Met chrome P Salmon, 3-bromop. vinyl ch. oxide, w: (Barbin t 1975). t thione 5which is 1977) (Fi which is methyl gl thiodigly Chlo bolites, N-Acetyl197 7; Wa vinylcyst after ora ethyl)cysethyl)cys chloride obtained ; taldehyde. tion of th animals gl or chloroa Hathway, 1 Folio Hathway, 1 acid were VINYL CHLORIDE AND POLYMERS 393 excreted via faeces and partly via expiration of 1HC02 (Bolt et at., 1976; Green & Hathway, 1975). , Vinyl chloride is metabolized by microsomal mixed-function oxidases to chloroethylene oxide, which can rearrange spontaneously to chloroacetaldehyde (Fig. 1). Although there is no direct evidence for this pathway in vivo, the following data are consistent with this hypothesis. Vinyl chloride in the presence of a mouse liver microsomal fraction, rat liver homogenate, an NADPH generating system and oxygen yielded an alkylating intermediate which reacted with either 3,4-dichlorobenzenethiol (GMthe et al*y 1974) or with 4-(4-nitrobenzyl)pyridine. The absorption spectra of the latter adduct was identical to those obtained with the product formed with synthetic chloroethylene oxide (Barbin et at., 1975; Bartsch et at., 1976). These studies indicate that the primary in vitro metabolite of vinyl chloride is chloroethylene oxide, which can rearrange to chloroacetaldehyde. Metabolism of vinyl chloride occurs predominantly through the cyto chrome P-450 system (Ivanetich et at., 1977; Reynolds et at., 1975c; Salmon, 1976). Inhibitors of microsomal mixed-function oxidases, such as 3-bromophenyl-4(5)-imidazole or 6-nitro-l,2,3-benzothiadiazole, reduced vinyl chloride metabolism in vivo (Bolt et at., 1976). Chloroethylene oxide, with a half-life of 1.6 min in aqueous solution at neutrality (Barbin et at., 1975), rearranges to chloroacetaldehyde (Bonse et at., 1975). Chloroacetaldehyde combines directly or enzymatically via gluta thione 5-transferase with glutathione to form 5-formylmethylglutathione, which is excreted as ^-acetyl-5-(2-hydroxyethyl)cysteine (Green 4 Hathway, 1977) (Fig. 1). Chloroacetaldehyde can be oxidized to chloroacetic acid, which is either excreted as such or bound to glutathione to form 5-carboxymethyl glutathione, which upon further enzymic degradation is excreted as thiodiglycolic acid (thiodiacetic acid) (Plugge 4 Safe, 1977). Chloroacetic acid was metabolized in rats to two major urinary meta bolites, 5-carboxymethylcysteine and thiodiacetic acid (Yllner, 1971). JV-Acetyl-5-(2-hydroxyethyl)cysteine (a major metabolite) (Green & Hathway, 1977; Watanabe et at., 1976b,c), 5-(carboxymethyl)cysteine and N-acetyl-Svinylcysteine have been shown to be metabolites of vinyl chloride in rats after oral administration (Green A Hathway, 1977) and ^-acetyl-5-(2-hydroxyethyl) cysteine after inhalation (Watanabe et at., 1976b); 5-(2-chloroethyl)cysteine was also identified after oral administration of vinyl chloride to rats (Green & Hathway, 1975). As thiodiglycolic acid was obtained as a common metabolite in rats dosed separately with chloroace taldehyde, chloroacetic acid or S-(carboxymethyl)cysteine, the identifica tion of the same 5-containlng metabolite from vinyl chloride-treated animals gives further support to the hypothesis that chloroethylene oxide or chloroacetaldehyde are formed and react with glutathione (Green & Hathway, 1977). Following oral administration of 14C-vlnyl chloride, (Green & Hathway, 1975; Watanabe et at., 1976c), 1'*C-labelled urea and glutamic acid were identified as minor metabolites (Green & Hathway, 1975). Figure la CU2 = CHC1 ixed-function ^ h2c- oxidftfe* CUCI _Q_ C1CH2-CHQ vinyl chloride chloroethylene oxide" chloroacetaldehyde" aldehyde dehydrogenase C1CU2-C00U nonochloracetlc + CSH G-S-CH2-CHO S-f ormylmethyl' glutathione cya-S-CRi-CHjOH -*------------------------------------- cys-S-CH2-CHO S-(2-hydroxye thyl)cystelue" 1 if -Ac-cye-S-CHj-CHjOH il-acetyl-S- (2-hydroxyetbyl)cysteine" S-foraylne thy1cysteine a Adapted from Plugge & Safe (1977) b Detected in vivo o Detected in vitro d GSH = glutathione aldehyde oxidase xanthine oxldaae * GSH^ I g-s-ck2-cooh -carboxymethylglutathlone cys-S-O^-COOH S-carb0xynethy1cyatelne^ *--NHj (transamination) (oxidative decarboxylation) i HOOC-CH2-S-CH2-COOa thlodlglycollc acld^ (thlodlacetlc acid) [ARC MONOGRAPHS VOLUME 19 V-H -P Ban m or 1 OC| r, Off. Hft) XriI ji < CL aO to ET BC 'UtHvoti'OfGt HfOt 0H< P << <0 n ft 3 ,,SnS ^ jftrpft vO O g p *)--0* OH* cWCr '* 3frtt* Hrtot t0 < B- & c* 8? K ft ft) < PB. OHCfHfiL -*O1 ft Hp. ^1 HXmT man HO rt H ft c4* H ft koH 3*033 3 W fL rt *x4 J M H ft) H> v| ft N O CM rorrp-'--'P* ^ i t4. ff H Ui H H1 1 o ft P rt 3 * SJ* ft) Octft ft M *9 H r4* rr H ft p* rt vO *si 3 3ft* c ft h- vv ft 'fOtft fXtT ^* ct*+*1*0 p< N* flP- srtr H TJ u ** 0m r0**4 0u 0n Wa * X4*hO0UJH0 WJT-*4<wW=455 0 0) Jj C c ^0 *r -H 4J A *t^ *4 L t3 p3-* 1y-4 4<Ju 00 J V It p 0) P^ X y W5 pa u 0^ v VINYL CHLORIDE AND POLYMERS 395 ft In vitro binding of 14C-vinyl chloride was shown to be dependent on ft the thiol content of proteins (Bolt & Filser, 1977), and binding was ft dependent on the presence of NADPH, oxygen and micrbsomal enzymes (Kappus I et al., 1976). It has been suggested that an epoxide of vinyl chloride I is involved in the covalent binding reaction (Kappus et al., 1975). In 1 the presence of a rat liver microsomal system, vinyl chloride binds to RNA ft in vitro (Kappus et al., 1975) and to RNA and DNA in vivo (Laib & Bolt, I 1977). Chloroacetaldehyde reacts with adenosine to give l,JV6-ethenoadenosine E (Barrio et al., 1972). Chloroethylene oxide and vinyl chloride, incubated 1 in the presence of a mouse liver-microsomal preparation with adenosine I in vitro, produced the same product (Barbin et al., 1975). Reaction of I chloroacetaldehyde with cytidine gives 3,tf4-ethenocytidine (Barrio et al., I 1972). l,iV6-Ethenoadenosine was isolated after hydrolysis of polyadenosine 1 that had been incubated with rat liver microsomes and * 4C-vinyl chloride I or with liver RNA of rats treated with 1"C-vinyl chloride (Laib & Bolt, 1 1977). The corresponding etheno-derivatives of deoxyadenosine and deoxy1 cytidine were identified in hydrolysis products obtained from calf thymus 1 DNA treated with chloroacetaldehyde in vitro and from liver DNA of rats I fed 250 mg/1 vinyl chloride in their drinking-water (Green 4 Hathway, 1978). 1 The 2-hydroxyethyl derivatives of guanine, cysteine and histidine I were identified after chemical reduction of the hydrolysis products of DNA 1 and proteins isolated from the livers of mice treated with ^4C-vinyl ft chloride (Osterman-Golkar et al., 1977). 1 Mutagenicity and other short-term tests I The mutagenicity of vinyl chloride has been reviewed by Bartsch & 1 Montesano (1975), Bartsch et al. (1976) and Fishbein (1976). [ Vinyl chloride vapour induced reverse mutations of the base-pair | substitution type in Salmonella typhimuriitm G46, TA1530, TA1535 and TA100 I In the presence of a 9000 x g supernatant from rat liver (Andrews et al., 1 1976; Bartsch et al., 1975; Garro et al., 1976; Malaveille et al., 1975; 1 McCann et al., 1975; Rannug et al., 1974), mouse liver (Bartsch et al., I 1975; Garro et al., 1976; Malaveille et al., 1975) and human liver biopsy I specimens (Bartsch et al., 1975, 1979; Malaveille et al., 1975). Although I vinyl chloride also induced mutations in the absence of a metabolic activaI tion system, a much higher mutagenic response was observed when a 9000 x g I supernatant from liver was added (Andrews et al., 1976; Bartsch et al., 1 1975; McCann et al., 1975). 1 Vinyl chloride in aqueous or methanollc solution was not mutagenic I in the Salmonella test system (Bartsch et dl., 1975; Rannug et al., 1974) I but produced reverse mutations in Escherichia aoli K12 (Greim et al., 1975), 1 forward mutations in Schizosaccharotnyces pombe and mitotic gene conversions 1 in Saccharomyces cerevisiae in the presence of a 9000 x g supernatant from 1 mouse liver. Forward mutations in S. pombe were also induced in the hostI mediated assay in mice (Loprleno et al., 1976, 1977). I IQC 060484 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ft 1 ft 1 396 IARC MONOGRAPHS VOLUME 19 Vinyl chloride as vapour or as ethanol solution was not mutagenic in Neuroapora craasa in the presence or absence of a metabolic activation system (Drozdowicz 4 Huang, 1977). In inhalation experiments in Drosophila melanogaster, vinyl chloride was mutagenic in the recessive lethal test (Magnusson & Ramel, 1976; Verburgt 4 Vogel, 1977) but not mutagenic in tests for dominant lethals, translocations and sex-chromosome loss (Verburgt 4 Vogel, 1977). No dominant lethals were observed in male CD-I mice after exposure by inhalation to 7.8, 26, or 78 g/m3 (3000, 10 000 or 30 000 ppm) vinyl chlo ride in air for 6 hour3/day for 5 days (Anderson et at., 1976, 1977). Exposure Co vinyl chloride vapour in the presence of a 15 000 x g supernatant from phenobarbital-pretreated rat liver induced forward muta tions in V79 Chinese hamster cells in terms of 8-azaguanine and ouabain resistance (Drevon st al., 1977). The mutagenicity of several possible metabolites of vinyl chloride has also been examined. Chloroethylene oxide was the strongest mutagen among those tested in 5. typhimurium TA1530 and TA1535 (Bartsch et al., 1975; Malaveille et al., 1975; Rannug et al., 1976), E. aoli (Hussain 4 Osterman-Golkar, 1976), S. pombe (Loprieno et al., 1977), S. aereviaiae (Loprieno et al., 1977) and V79 Chinese hamster cells (Huberman et al., 1975). Chloroacetaldehyde was mutagenic in S. typhimurium TA1535, TA1530 and TA100 (Bartsch et al., 1975; Malaveille et al., 1975; McCann et al., 1975; Rannug et al., 1976) and V79 Chinese hamster cells (Huberman et al., 1975). Chloroethanol was a weak mutagen in S. typhimurium TA153Q, TA1535 and TA100 (Bartsch et al., 1976; Malaveille et al., 1975; McCann et al., 1975; Rannug et al., 1976; Rosenkranz et al., 1974). Chloroacetic acid was not mutagenic in S. typhimurium TA1530, TA100 or TA1535 (Bartsch et al., 1975; Malaveille et al., 1975; McCann et at., 1975; Rannug et al., 1976). 1,2-Dichloroethane, a possible by-product of vinyl chloride production and a main component of waste products from vinyl chloride industries (EDC-tar), was mutagenic in S. typhimurium TA1535 (Rannug 4 Ramel, 1977) and in S. typhimurium TA100 (McCann et al., 1975) in the presence or absence of a liver microsomal metabolic activation system. (b) Humans Toxic effects Exposure to vinyl chloride is associated with multiple systemic dis orders, including a sclerotic syndrome, acro-osteolysis (sometimes associa ted with a Raynaud-like symptomatology), thrombocytopenia and liver damage, consisting of parenchymal damage, fibrosis of the liver capsule, periportal fibrosis associated with hepatomegaly, and splenomegaly (Lange et al., 1974a; Thomas et al., 1975). Ex. factory disease removed after t, Not found it chloridt but fibi premalij Of present: due to p (William Exp and live vision f Ele 200 poly populati was f oun symptoms immunolo in 2/30 order (W Ag were exa. of dlsor and sple; anaemia syndrome spontanet incidenc! levels d: spastic snggestir Hal syst Redt vinyl chi lence of ting that (Miller ucc 060485 t mutagenic ln activation /inyl chloride 1976; '-ant lethals, 77). -r exposure by t) vinyl chlo- 1977). 5 000 x a orward muta-- nd ouabain VINYL CHLORIDE AND POLYMERS 397 Examination of 70 workers from a single polyvinyl chloride-producing factory showed a high frequency of signs and symptoms of vinyl chloride disease. Although skin and bone changes may disappear when the patient is removed from contact with vinyl chloride, the thrombocytopenia persists after termination of exposure (Veltman et al., 1975). Non-cirrhotic portal fibrosis with associated portal hypertension was found in 7 patients who had been involved in the production of vinyl chloride monomer for 4-15 years. An angiosarcoma developed in one patient, but fibrosis was a more common lesion and was considered to be probably not premalignant (Smith et al., 1976a). Of 487 workers involved in polyvinyl chloride production, two cases presenting with thrombocytopenia were found to have portal hypertension due to periportal fibrosis, with oesophageal varices and splenomegaly ! (Williams et al., 1975, 1976). 1 chloride '5t mutagen -h et al., (Hussain & w .n t 535, TA1530 Cann et al,. erman et al. 530, TA1535 -ann et al., cetic acid rtsch et al., ' al., 1976). 2 production tries 1. 1977) e or absence aie dis- s associa-- -r damage, 'eriportal Exposure to vinyl chloride was not only associated with circulatory and liver dysfunction and skin and bone disorders, but also deafness, vision failure and giddiness (Jtihe & Lange, 1972). Elevated carcino-embryonic antigen levels have been found in 48Z of 200 polyvinyl chloride workers, as compared with 9% of a normal healthy population (Page et al., 1976). No evidence of an auto-immune disorder was found in 13 patients employed in polyvinyl chloride production who had symptoms of 'vinyl chloride disease' (Lange et al., 1974a); however. Immunological data from 19/28 patients with vinyl chloride disease and in 2/30 workers exposed to vinyl chloride suggested an Immune complex dis order (Ward et al., 1976). A group of 168 workers (114 from one factory and 54 from another) were examined medically at various times during 1962-1969. Manifestations of disorders of the nervous system were recorded commonly; hepatomegaly and splenomegaly occurred in 30Z and 6% of workers; and some cases of anaemia and leucopenia were also observed. The incidence of Raynaud's syndrome fell from 6Z in 1962 to 2.9% in 1966; this phenomenon cleared spontaneously upon removal of the subjects from exposure: these different incidence figures were associated with a 22-fold decrease in vinyl chloride levels during the period of the study. A much higher percentage of vaso spastic changes was found In the two groups (66 and 55Z, respectively), suggesting that vinyl chloride acts as an irritant in the reticuloendotheHal system to produce reactive splenic enlargement (Suciu et al., 1975). Reduced pulmonary function has been observed ln workers exposed to vinyl chloride (Gamble et al., 1976; Miller et al., 1975). The preva lence of this impairment was similar in smokers and nonsmokers, sugges ting that occupational or other environmental factors were operative (Miller et al., 1975). ucc 060486 398 IARC MONOGRAPHS VOLUME 19 Embryotoxicity and teratogenicity A significant excess of foetal deaths was reported in women whose husbands were exposed to vinyl chloride: 15.8Z, or 23, foetal deaths in 139 pregnancies, as compared with 8.8Z (24/273) in the age-adjusted control group. This excess of foetal deaths was shown not to be a function of chronic abortions, l.e., the association was maintained after excluding pregnancies of women who had had more than 2 abortions (Infante et at., 1976a). The significance of this study was questioned because data col lection methods were not specified and there was no statistical treatment of the data (Paddle, 1976). Subsequently, the data collection methods were described, showing that there had been no interviewer-respondent bias, and details of statistical analyses were specified (Infante et at., 1976b). In a registry-based study, Infante (1976) reported that an excess of central nervous system defects, of deformities of the upper alimentary and genital tracts, and of clubfoot has been observed in stillborn and live children in 3 cities in Ohio in which vinyl chloride polymerization plants are located. In hospital-based studies in newborns in Painesville (Ohio), where there are two polyvinyl chloride plants, and in Kanawha county (West Virginia), where there is one plant, excesses of anencephaly and spina bifidawere reported, but no association was made with vinyl chloride (Edmonds, 1977; Edmonds et at., 1975, 1978), Mutagenicity and other short-term tests Chromosome aberrations were found in workers occupationally exposed to vinyl chloride in the US (Ducatman et at., 1975; Heath et at., 1977), Sweden (Funes-Cravioto et at., 1975), the UK (Purchase et at., 1975), Belgium (Leonard et at., 1977), Hungary (Szentesi et at., 1976) and Norway (Hansteen et at., 1976). These aberrations were in most cases fragments, dicentrics and rings, and breaks and gaps. 3.3 Case reports and epidemiological studies1 In 1974, more than 40 years after the introduction of vinyl chloride into industry, Creech 4 Johnson (1974) first reported an association of exposure to this chemical with cancer in man. Three cases of liver angio sarcoma were reported in men who were employed in the manufacture of poly vinyl chloride resins (one had cleaned reactor vessels) in a single vinyl chloride polymerization plant in the US. 'The Working Croup was aware of a study in progress on the occupational and conmwnity carcinogenic risk of vinyl chloride (IARC, 1978b). E matic and an countr Czecho et at. Roche Romani Harry, 1974a; of 64 (Spirt: Nc toxic r review zation of live eluded detectc organs Tl one yea compare system, of the those m vinyl c for 15Z of expo In plants due to were li 1974). grounds related failed to reti: The each of 5 years seniorit a 2.3-fc 3 were c jomen whose :al deaths in ldjusted control unction of r excluding nte et al,, se data col;:al treatment an methods aspondent bias, a al,, 1976b). an excess of alimentary Iborn and live .zation plants -hloride ly exposed 'Z-. 1977), 1975), and : cases 1 chloride ation of iver angiore of polygle vinyl occupational VINYL CHLORIDE AND POLYMERS 399 By reviewing medical records and pathological material and by syste matic medical screening, the association between exposure to vinyl chloride and angiosarcoma of the liver has been reported frcto a number of other countries*. Canada (Delorme & Theriault, 1978; Noria et al., 1976); Czechoslovakia (Lloyd, 1975); the Federal Republic of Germany (Lange et al., 1974b, 1975); France (Couderc et al., 1976; Ravier et al., 1975; Roche et al., 1978); Italy (Maltoni, 1974); Norway (Lloyd, 1975); Romania (Lloyd, 1975); Sweden (Byren & Holmberg, 1975); the UK (Lee 4 Harry, 1974; Smith et al., 1976b); the US (Block, 1974; Falk et al., 1974a; liakk et al., 1974); and Yugoslavia (SariX et al., 1976). A review of 64 reported cases in various countries as of October 1977 is available (Spirtas 4 Kaminski, 1978). No history of acro-osteolysis and no evidence of exposure to hepatotoxic materials other than vinyl chloride was reported in a clinical review of 7 cases of liver angiosarcoma among US vinyl chloride polymeri zation workers (Heath et al., 1975). In a pathological evaluation of cases of liver angiosarcoma among exposed US vinyl chloride workers, it was con cluded that these tumours were often multicentric: angiosarcomas were also detected in the wall of the duodenum, in the heart and kidney, and in other organs (Thomas 4 Popper, 1975). The cancer risk among a cohort of males in the US who had at least one year of occupational exposure to vinyl chloride was studied. When compared with the US male population, an excess of cancer of the digestive system, of the liver (primarily angiosarcoma), of the respiratory system, of the brain and of unknown sites, as well as lymphomas was observed in those members of the study cohort with the greatest estimated exposure to vinyl chloride (Tabershaw 4 Gaffey, 1974) [Vital status was undetermined for 15% of the study cohort, and only 50Z had 15 or more years since onset of exposure to vinyl chloride]. In a proportional-mortality analysis of 161 deceased workers in two US plants producing and polymerizing vinyl chloride, a 50% excess of deaths due to all cancers was reported. Sites of cancer with the greatest excess were liver and biliary tract, brain, digestive tract and lung (Monson et al., 1974). Falk et al. (1974b) questioned the authors' conclusion, on the grounds that not all deaths studied were among workers in activities directly related to vinyl chloride production or polymerization and that the study failed to include deaths among workers who had terminated employment prior to retirement or death. The cancer mortality experience of 257 US workers (255 were traced), each of whom had been occupationally exposed to vinyl chloride for at least 5 years and observed after 10 years from onset was studied using union seniority and company employment records. Among 24 deaths from all causes, a 2.3-fold excess was observed in deaths from cancer; of the 24 deaths, 3 were due to haemanglosarcoma of the liver (Nicholson et al., 1975). ucc 060488 400 IARC MONOGRAPHS VOLUME 19 No excess of total or cause-specific mortality was reported in a study of 2100 male workers in the UK exposed to vinyl chloride for periods of up to 27 years; in addition, the authors reported a decreasing risk of morta lity with increasing duration of exposure to vinyl chloride (Duck et al., 1975). Wagoner et al. (1976) challenged the conclusions of the study on the grounds of analytical shortcomings. After reanaly3ing the data, the authors (Duck 4 Carter, 1976) reported an increased risk of cancer of the digestive system 15 years after initial exposure to vinyl chloride. The cancer mortality of 594 US workers exposed occupationally to vinyl chloride and to lesser amounts of vinylidene chloride (see p. 439) and other compounds (such as methyl methacrylate, see p. 187, and acrylonitrile, see p. 73) was studied. Although no angiosarcomas were found (no deaths due to any liver cancer), an excess of ail malignancies combined was reported among those workers classified as having been highly exposed to vinyl chloride when compared with all other exposure categories. However, the number of workers in the lower exposure categories who were exposed for more than 10 years was small, resulting in part from the fact chat workers first took jobs in the dry end of the polymerization process where exposures to vinyl chloride were low; many employees who remained with the units and established seniority would subsequently have moved to the higher exposure areas (Ott et al., 1975). The incidence of abnormal sputum cytology among workers in the vinyl chloride-polyvinyl chloride industry in Italy was much higher than expected, even when compared with a population of heavy smokers who did not work in chemical industries (Maltoni, 1976). Waxweiller et al. (1976) studied the cancer mortality experience of 1294 individuals with 5 or more years of employment and 10 years since onset of employment in departments or jobs with direct exposure to vinyl chloride at 1 of 4 vinyl chloride-polyvinyl chloride production plants in the US. When compared with the US white male population, an excess of cancer was found in four organ systems: brain and central nervous system, respiratory system, hepatic system, and lymphatic and haematopoietic systems. This excess of organ-specific cancer was restricted to chose workers with 15 or more years since onset of vinyl chloride exposure. For all malignant neoplasms combined, the standard mortality ratio was 184; for the brain and central nervous system, 498; for the respiratory system, 194; for the hepatic system, 1606; and for the lymphatic and haematopoietic system, 176. Of 14 histologically confirmed cases of biliary and liver cancer among workers from these 4 plants, 11 were angiosarcoma of the liver. Of 10 cases of brain cancer, 9 were classified histologically as glioblastoma multiforme, a cell type of brain cancer reported to be unusual in the US. Of the 14 cases of primary lung cancer, 5 were large-cell undifferentiated and 3 were adenocarcinoma. In 771 workers employed in a Swedish vinyl chloride-polyvinyl chloride plant since its start' in the early 1940's, a 4- to 5-fold excess of cancer of the liver and pancreas was found. Although the risks of cancer of the brain an signific. Whei currently sure to v those inc initial e (Fox S Co Fox males who chloride from livei was thougt evidence i Relativel> even in c follow-up effect of A stu in the pro Republic o an excess phatlc org. with durat: The r of age and facilities, was higher leukaemia a 1976) . The in period in a polymerized were includ was found b< et al., 197< VINYL CHLORIDE AND POLYMERS 401 brain and of the lung were also increased, they were not statistically significant (Byren et al., 1976). Whereas no excess mortality from lung cancer was demonstrated among currently employed individuals 15 years after initial occupational expo sure to vinyl chloride, a 56% excess of lung cancer was observed among those individuals who had terminated employment less than 15 years since initial exposure; this excess was found for each duration of exposure (Fox S Collier, 1976). Fox & Collier (1977) investigated the cancer mortality among 7561 males who were exposed to vinyl chloride in the manufacture of polyvinyl chloride in the UK at some time between 1940 and 1974. An excess mortality from liver cancer was reported for each group of workers, whether exposure was thought to be high, medium or low; however, the authors reported no evidence of an excess mortality from cancers other than of the liver. Relatively few subjects had long-term exposure to vinyl chloride, and even in cases in which men had completed 20 years of employment, the follow-up period was judged to be too short to evaluate the carcinogenic effect of vinyl chloride. A study was reported of cancer mortality among 7021 males employed in the production and polymerization of vinyl chloride in the Federal Republic of Germany. When compared with the national male population, an excess of cancers was found for 4 organs; liver, brain, lung and lym phatic organs. This excess of organ-specific cancer was shown to increase with duration of exposure (von Reinl et al., 1977). The risk of cancer mortality was investigated among residents 45-years of age and older in three US communities with vinyl chloride polymerization facilities. Among males, the death rate from central nervous system cancer was higher than that for the state as a whole. No excess mortality from leukaemia and aleukaemic leukaemia or from lymphoma was found (Infante, 1976). The incidence of liver and lung cancer was studied for a 4-year period in a city in Yugoslavia with a factory in which vinyl chloride was polymerized and polyvinyl chloride processed. Polyvinyl chloride workers were included in the study. Except for liver angiosarcoma, no association was found between cancer incidence and place of work or residence ($ari et al., 1976). ucc 060490 -f 402 IARC MONOGRAPHS VOLUME 19 Polyvinyl chloride 1. Chemical and Physical Data 1.1 Synonyma and trade namea Chem. Abstr. Services Reg. No.: 9002-86-2 Chem. Abstr. Name: Chloroechene homopolymer Atactic poly(vinyl chloride); chloroethylene polymer; poly(chloroethylene); poly(vinyl chloride); poly(vinylchloride); polyvinyl chloride; PVC; vinyl chloride homopolymer; vinyl chloride polymer Airex; AL 30; AL 31; Armodour; Aron compound HW; Astralon; Bakelite OYNV; Bakelite QSAH 7; Bakelite QYAC 10; Bakelite QYJV 1; Bakelite QYOH-1; Bakelite QYSJ; Bakelite QYSL 7; Bakelite QYT0 7; Bakelite UCA 3310; Benvic; Blacar 1716; Bolatron 6200; Bonloid; Breon; Breon 107; Breon 113; Breon 121; Breon 125/10; Breon 151; Breon 4121; Breon 111EF; Breon 112EP; Breon P 130/1; Breon S 110/10; Breon S 125/12; C 65; Caliplast; Carina S 70-01; Carina S 70-71; Chemosol; Chloroscop; Cobex (polymer); Contizell; Corvic 55/9; Corvic 65/50; Corvic 206573; Corvic 20560600; Corvic 20650600; Corvic C 65/02; Corvic D 55/9; Corvic D 57/15; Corvic D 57/17; Corvic D 60/11; Corvic D 65; Corvic D 65/02; Corvic D 65/8; Corvic D 75/10; Corvic D 6518; Corvic H 55/34; Corvic P 65/50; Corvic P 65/54; Corvic P 65/55;Corvic R 65/81;Corvic S 46/70; Dacovin; Dacovin 2082; Danuvil 70; Darvic 110; Darvis Clear 025; Daycell; Decelith H; Denka Vinyl SS 30; Denka Vinyl SS-Y; Diamond Shamrock 40; Diamond Shamrock 71; Diamond Shamrock 450; Diamond Shamrock 7602; DN 4; DN 5; Dorlyl; Durofol P; Dynadur; E 62; E 66; Ekavyl SD 2; Ekavyl SDF 58; Ekavyl SK64; Ekavyl SK66; E 66P; 103EP8; E-PVC; Escambia 2160; Escambia 2200; Europhan; Exon 605; Exon 640; Exon 654; Exon 965; Exon 9269; Exon 9290; Exon 9269A; FC 4648; Flocor; Genotherm; Genotherm N; Genotherm UG 200; Geon 51; Geon 59; Geon 72; Geon 101; Geon 103; Geon 110X233; Geon 120X241; Geon 121; Geon 124; Geon 126; Geon 128; Geon 131; Geon 151; Geon 85542; Ceon 101EP; Geon 102EP; Geon i < J j I 081; Norv Norv Opal` 650; Pant: Pevi; Pevi; D 101 S 50: Poroc PVKhQYSA; (poly 540; Solvi Solvi Sumil VINYL CHLORIDE AND POLYMERS 403 Geon 103EP; Geon 103EP8; Geon 103EPF7; Geon 135J; Geon 121L; Geon Latex 151; Guttagena; Halvic 223; Halvijc 229; HC 325; Hl-S Film No. 111L; Hishirex 502; Hishirex 502Z; Hispavic 229; Hostalit; Hostalit E; Hostalit P 7078; Hostalit PVP 3475; Hostalit PVP 5470; Hostalit S; Hostalit S 4070; HX-M; Igellte F; Igellte P; Improved Wilt Pruf; Kanevinyl PSH 10; Kanevinyl PSL 81; Kanevinyl S 1001; Kanevinyl 5 1007; KhS 010; KhSE 3; Klegecell; Kohiner R 687; KR 800; Kureha S 901; L 5; Lak Kh SL; Lonza 380 ES; Lonza G; Lucoflex; Lucovyl BB 800; Lucovyl BB 8010; Lucovyl GB 1150; Lucovyl GB 9550; Lucovyl GS 1200; Lucovyl GS 8001; Lucovyl PB 1302; Lucovyl PE; Lucovyl PE 1100; Lucovyl PE 1290; Lucovyl PE 1311; Lucovyl PE 1355; Lucovyl KB 8010; Lutofan; Marvinal; Marvinol; Marvinol 14; Itarvinol 53; Marvinol 57; Marvinol 7000; Marvinol VR 50; Marvinol VR 53; Mirrex MCFD 1025; Movinyl 100; Mowilith F; Myraform; NIKA-TEMP; Nikavinyl SG 700; Nipeon A 21; Nipol 576; Nipolit CM 081; Nipolit SK; Nipolit SK 081; Nipolit SL 082; Nipolit SM 092; Nipolit SV 13081; Norvinyl; Norvinyl P 2; Norvinyl P10; Norvinyl S 1-70; Norvinyl S 1-80; Norvinyl S 3-68; Novon 712; Ongrovil S 165; Ongrovil S 470; Opalon; Opalon 410; Opalon 440; Opalon 610; Opalon 630; Opalon 650; Opalon 660; Opalon R 7611; Ortodur; P 400 (vinyl polymer); Pantasote R 873; Fattina V 82; Fevikon D 61; Pevikon KL 2; Pevikon PE 709; Pevikon PE 712; Pevikon PS 690; Pevikon R 23; Pevikon R 25; Pevikon R 45; Pevikon R 341; Pevikon S 602; Pliovic D 100X; Pliovic DB 80V; Pliovic K 906; Pliovic K 90E; Pliovic S 50; POK 60; Polivinit; Polwinit; Polyco 2622; Polytherm; Porodur; Prototype III Soft; PVKhL 4; PVKhS 60; PVKh-S 60; PVKh-S 65; PVKh-S 63Zh; OSAH 7; QSAN 7; Quirvil; Quirvil 278; QYSA; Ravinil R 100/65D; Rucon B 20; Ryurene S 800B; S 61; S 65 (polymer); S 70; S 901; Scon 5300; Sicron; Sicron 530; Sicron 540; Sicron 548; Sicron 548FM; SKhV 71; S-Lon; SM 200; Solvic; Solvic 223; Solvic 229; Solvic 239; Solvic 334; Solvic 340; Solvic 406; SP 60; SP 60 (chlorocarbon); SR11; Sumilit EXA 13; Sumilit PXA 13; Sumilit PX-A; Sumilit PX-N; Sumilit FXNH; ucc 060492 404 IARC MONOGRAPHS VOLUME 19 Sumllit FX-NL; Sumllit SX 11; Sumllit SX 13; Sumllit S x~D; Sumillt SX 7G; Sumllit VS 9200; Sumitomo PX 11; SV 55; SX 11; SX 7G; SX 8T; Takilon; Technopor; Tenneco 1742; TK 1000; Tocryl C 440; Trovidur; Trovldur N; Trovithern HTL; TS 1100; U 1; U 1 (polymer); Ultron; VA 15; VC 100; VC 410; Veron P 130/1; Veatolit B 7021; Veatollt GH; Veatolit S 60; Veatolit S 6554; Veatolit S 6857; Veatolit S 7054; Veatolit S 7554; Veatolit S 8054; Vinika KR 600; Vinika KR 800; Vinika 37M; Vinika 35R; VInikulon; Viniplaat; Viniplen P 73; Viniplen P 74; Viniplen P 73E; Viniplen P 73EM; Vinnol E 75; Vinnol H 100/65; Vinnol H 100/70; Vinnol H 60d; Vinnol H 700; Vinnol H 100/70d; Vinnol H 75F; Vinnol P 70; Vinnol P 70E; Vinnol P 100/70e; Vinnol Y; Vinoflex; Vinoflex P 313; Vinylchlon 4000LL; Vlnylite QYJV; Viplast RA/F; Volgovinyl E 62; Volgovlnyl E 62P; Volgovinyl E 66P; VSKh-S; Vygen 85; Vygen 110; Vygen 120; Vygen 313; Welvic G 2/5; Welvic PRIO 953; Welvic PRO 686; Welvic R 7/622; Welvic RI 7/316; Welvic RIO 715; Wilt Pruf; Winidur; X-AB; Yugovinyl 1*2 Structural and molecular formulae and molecular weight 'H H II -c--c- II H Cl n (CjHjCl)^ Mol. wt: 60 000-150 000 (average) 1*3 Chemical and physical properties of the polymer From Windholz (1976), unless otherwise specified Description: White or colourless granules (Hawley, 1971) Density: 1.406 <> Refractive index: n 1.54 < (e 1.4 te A with va the ape PV' tially ' mer made the come Mb: at a le* us d are material also use PVf (PVC ret PVC are form is For samples, 'V S X-D; p; SX 11; 1000; TS 1100; I Veron P r/estolit S 54; 37M; tplen P 74; 1: 100/65; |100/70d; I'Oe; I Vinylite I Vol Mtayl 131. w 1 7/622; |-AB; |rage) Id VINYL CHLORIDE AM) POLYMERS 405 I (d) Solubility: Solvents for unmodified polyvinyl chloride (PVC) 1 of high molecular weight are: cyclohexanone, methyl cycloI hexanone, dimethyl formamide, nitrobenzene, tetrahydrofuran, 1 isophorone and mesityl oxide. Solvents for lower polymers are: I di-n-propyl ketone, methyl amyl ketone, methyl isobutyl ketone. I acetonylacetone, methyl ethyl ketone, dioxane and methylene 1 chloride. | (e) Stability: PVC is unstable to heat and light in the absence of 1 added stabilizers. Thermal decomposition products can include I ethylene, benzene, toluene (Eckardt & Hindin, 1973), 1,3,5- I trlchlorobenzene (Tsuge, 1969) and naphthalene (Dyer & Esch, I 1976). 1 1.4 Technical products and impurities I A wide variety of vinyl chloride homo- and copolymers are available. I with varying properties designed for specific applications. Consequently, I the specifications vary widely. 1 PVC resins for the production of rigid plastics are processed essen[ tially without plasticizer: the polymer may be a homopolymer or a copoly1 mer made with low levels of comonomer such as vinyl acetate or ethylene. | The comonomers are used to aid in Che processing of the resulting polymer. ; Most of the flexible and semirigid PVC plastics contain plasticizers | at a level of 10-100Z of the resin weight. The plasticizers most commonly used are dialkyl phthalates (e.g., dloctyl phthalate). Other compounding | materials (such as pigments, fillers and light- and heat-stabilizers) are also used. 1 PVC dispersion or paste resins are used in the form of plastisols (PVC resin dispersed in plasticizer). In Europe, significant amounts of PVC are used in the form of latexes; in the US very little of the latex form is used. I For concentrations of unreacted vinyl chloride monomer in various PVC samples, see p. 382. ucc Q60494 406 IARC MONOGRAPHS VOLUME 19 2. Production, Use, Occurrence and Analysis 2.1 Production and use (a) Production A method for the synthesis of PVC was reported in 1872 (Baumann, 1872). Commercial homopolymers of vinyl chloride were introduced in 1933 (Darby 4 Sears, 1968). Vinyl chloride polymer is currently produced by one of four processes: suspension, emulsion, bulk or solution polymerization. In the US in 1976, over 80% of homopolymers and copolymers were produced by the suspension polymerization process. In 1976, 22 US companies reported production of 2065 million kg PVC resins of all types (US International Trade Commission, 1977); approxi mately 230 million kg of the total were copolymers. US exports of uncom pounded PVC resins in 1977 were about 72 million kg, and exports of com pounded PVC (excluding any additives in compounded products) were approxi mately 39 million kg. These exports went primarily to Belgium (13%), Brazil (12%), Canada (21%), Iran (6%), New Zealand (7%) and Venezuela (13%). US imports of PVC resins are negligible (approximately 1% of domestic production). Total western Europe production in 1976 amounted to 3745 million kg. The major producers were the following countries (production in millions of kg): Austria (40), Belgium (200), the Federal Republic of Germany (1020), Finland (35), France (615), Greece (25), Italy (675), The Netherlands (290)Norway (55), Portugal (15), Spain (215), Switzerland (30), Sweden (110) and the UK (415). Exports from western Europe in that year were 1050 million kg and imports 690 million kg. PVC was first produced commercially in Japan prior to 1946. In 1976, nineteen companies produced a total of 1044 million kg; 121 million kg were exported, and 15 million kg Imported. (b) Use Use of PVC resins in the US in 1976 was as follows: building and con struction industries (49%), consumer goods (15%), electrical applications (8%), packaging (9%) and transportation (7%), with miscellaneous uses accounting for the remainder. Since 1968, the major uses have been in the building and construction industries, in consumer goods, packaging and electrical wire insulation. In building and construction, PVC resins are used in piping and con duits (Including water pipes), in flooring, in windows and other rigid structures, in pipe fittings, in sidings and as swimming-pool liners. They are used in such consumer products as upholstery, wall coverings, garden hoses and appliances and also in gramophone records, stationery supplies, footwear,.' toys, outerwear and sporting goods. Electrical appllcat: uses of } liners ar beverages into the covers, : In 1 the US in tubing ar blood stc parenterc The and fitti (10%), ar and other In ^ sheet (14 other, it The component contact v (3) paper rigid and may not e effect (U An e tion of F 2.2 Occu PVC It h PVC may h occurred effluents Agency, 1 productlo The and by in 1974b,c). ucc 060495 i / VINYL CHLORIDE AND POLYMERS 407 applications consist primarily of wire and cable insulation. The major uses of PVC in packaging are in plasticized film, bottles and bottle-cap liners and gaskets; however, in the US, its use for packaging of alcoholic beverages has been banned because of migration of viqyl chloride monomer into the alcohol. Major uses in transport include upholstery and seat covers, automotive tops and automotive floor mats. In 1975, 27 million kg PVC were used in Europe and 14 million kg in the US in plastic materials for medical applications, including external tubing and catheters; in sheet form for splints; and in shunts, balloons, blood storage bags, cannulae, surgical drapes and packaging containers for parenteral substances (Halpern 4 Karo, 1977). The 1977 western Europe use pattern for PVC was as follows: piping and fittings (24%), rigid and flexible films (20%), profiles (12%), cable (10%), artifical leather cloth (8%), bottles (7%), gramophone records (3%) and other uses (16%). In Japan in 1976, It was used as follows: piping (31%), film (17%), sheet (14%), extrusions and artifical leather (12%), wire/cable (11%) and other, including flooring (15%). The US Food and Drug Administration permits the use of PVC as a component of the following products when they are intended for use in contact with food: (1) adhesives; (2) resinous and polymeric coatings; (3) paper and paperboard (in contact with dry food only); and (4) semi rigid and rigid acrylic and modified acrylic plastics. The amount present may not exceed that which is reasonably required to produce the Intended effect (US Food and Drug Administration, 1977). An estimated 700 000 to 2 million workers are employed in the produc tion of PVC in the USA (Infante, 1977). 2.2 Occurrence PVC is not known to occur as a natural product. It has been estimated that prior to 1975 more than 22.7 million kg PVC may have been discharged into the environment in the US. These losses occurred as particulates in air emissions, suspended solids in water effluents, and components of solid wastes (US Environmental Protection Agency, 1974b). Workers in the USSR have been exposed to PVC dust In the production of block polymer (Filatova et al., 1974). The disposal of PVC by ocean dumping, as solid waste, as landfilling and by incineration has been reviewed (US Environmental Protection Agency, 1974b,c). UCC 060496 408 IARC MONOGRAPHS VOLUME 19 i 2.3 Analysis Mo information was available to the Working Group on methods for determining PVC residues in foods or other parts of the environment. A rapid and simple way of identifying fifteen packaging films, includ ing PVC, has been described in which the films were treated with ten dif ferent solvents and the solubility and physical appearance of the film at room temperature and at the boiling-points of the solvents were noted (Van Gieson, 1969). Plastics, including PVC, have been identified by measurement of the pH of an aqueous solution of the pyrolysis products, followed by thin-layer chromatography, and by reaction of PVC with pyridine (Braun & Nixdorf, 1972). PVC has been separated from plasticizers, stabilizers, modifiers, fillers, pigments and other inorganic additives by gel permeation chroma tography or sequential solvent extraction. The resulting additive-free fraction has been analysed by chlorine analysis, infra-red spectroscopy, molecular-weight determination by viscosity measurements and thermal gravimetry and differential thermal analysis (Brookman, 1974). Pyrolysis-gas chromatography has been proposed to identify PVC in polymers used in medical applications (Nematollahi et al.% 1970), in three commercial polymers (in this case, pyrolysis-gas chromatography was used in combination with thermogravimetric analysis and differential thermal analysis) (Boettner et al.t 1969), and among some chlorine-containing polymers (Tsuge et at., 1969). Pyrolysis-gas chromatography has also been used to identify polymers, including PVC, among 37 commercial polymers (Okumoto & Takeuchi, 1972), in plastics and rubbers (Fischer, 1967) and in adhesives used in building (in this case, pyrolysis-gas chromatography was used in combination with thermogravimetry, differential thermogravi metry and differential thermal analysis) (Rona, 1971). Thin-layer chromatography of pyrolysis products has been used to iden tify high polymers, including PVC (Pastuska, 1969). Thermogravimetry and infra-red spectral analysis have been used to determine PVC in floor tiles (Powell, 1974). 3.1 Card Subcu Rat: abdominal some addlt appearance (38.6Z) ma. che site oi similar but risk. No J implant of of 0.03 mm a similar g the reporti were never Groups into the at* received an animals were rats were k; were found i developed ir A group (of unstated animals were after the lm fibrosarcoma In rats films or per (Kogan & Tug; *The Wor carcinogenic! administration ucc 060497 methods for vironment. >S films, includ! wth ten diff the film ac were noted emenc of the by thin-lay Nixdorf, modifiers, tion chromaitive-free ^ctroscopyf therrpja] y PVC in In three y was used 1 thermal taining is also been 'lymers 967) and Geography tnogravi- ed to iden- ised to VINYL CHLORIDE WD POLYMERS 409 3. Biological Data Relevant to the Evaluation of Carcinogenic Risk to Hitmans * 3.1 Carcinogenicity studies In animals1 Subcutaneous or lntraperitoneal administration Bat: A group of 45 adult Wlstar rats were given s.c, implants in the abdominal wall of squares or discs of a commercial FVC known to contain some additives; the Implants were 0.04 nan thick and 15 mm vide. At the appearance of the first tumour, 44 animals were still alive. Seventeen (38.62) malignant tumours (fibrosarcomas and 1 llposarcoma) developed at the site of film Implantation, with a latent period of 189-727 days; a similar but perforated film did not produce local tumours in 27 rats at risk. No local tumours were found in a group of 50 rats given a s.c. implant of cotton (Oppenheimer et al., 1952, 1955). With a pure PVC film of 0.03 mm thickness, 4 malignant tumours were obtained after 533 days in a similar group (Oppenheimer et al., 1955) [The Working Group noted that the reporting of this experiment was preliminary and that final results were never forthcoming]. Groups of 35 (male and female) Wlstar rats were given a s.c. implant into the abdomen of FVC film 4 x 5 x 0.16 mm. A group of 25 control rats received an Implant of glass of similar size. After 300 days, 30 and 20 animals were still alive in the two groups, respectively; all surviving rats were killed 800 days after implantation. One sarcoma and one fibroma were found after 580 days in the PVC-treated rats, whereas no local tumours developed in the control group (Russell et al., 1959). A group of 80 outbred albino rats (sex unspecified) received implants (of unstated size) of FVC film by laparotomy to surround the kidney. The animals were sacrificed at 3, 10, 15, 30, 90, 195, 285, 300 and 380 days after the implantation. Of rats that survived 285-375 days, 6/16 developed fibrosarcomas at the site of Implantation (Raikhlln & Kogan, 1961). In rats implanted in the kidney with either FVC capsules, whole PVC films or perforated PVC films, 5/16, 2/5 and 1/5 sarcomas were observed (Kogan 4 Tugarinova, 1959). IThe Working Group was aware of a study in progress to assess the carcinogenicity of PVC powder by inhalation exposure and intrapleural administration to rats (1ARC, 1978a). ucc 060498 410 I ARC MONOGRAPHS VOLUME 19 3.2 Other relevant biological data (a) Experimental systems Rats and guinea-pigs exposed cc day for periods varying from 2-7 mot damage (Frongia et at., 1974). the anterior abdominal wall. < - In tries', mixed wi for 24 hours/ extensive lung reportec bromosul in 1, si Raynaud' implanted into 1968). Severe id dogs (Harrison i.c. tissue of of abnor of 37 PV abnormal transami abnormal Ingested and rectally absorbed PVC particles (5-110 urn) were found to be transported by both the lymphatic and the portal system from the intes tinal wall of rats, guinea-pigs, rabbits, chickens, dogs and pigs (Volkheimer, 1975). Cas wrappers sealed a has not Polakoff In rats, inhalation of fumes from heated PVC produced interstitial oedema, as well as focal bronchial and intra-alveolar haemorrhage in the lungs of some animals (Cornish 4 Abar, 1969). No data on the embryotoxicity, teratogenicity, metabolism or muta genicity of this compound were available to the Working Group. (b) Humans Workers exposed to PVC dust during the manufacture of articles made from PVC showed alterations in the respiratory organs (e.g., changed bronchovascular pattern, increased pulmonary ventilation at rest) (Vertkin 4 Mamontov, 1970). Dur distress combusti chloric been rep' tance, a. thermal . The be causes 1953). 3.3 Case Pneumoconiosis due to inhalation of PVC dust was suggested following pulmonary biopsies in a male patient who had inhaled PVC dust for 1 year and exhibited granulomatous lesions due to foreign bodies. The severity of the disease was shown by the observed dyspnoea, secondary polyglobulia and reduced respiratory function (Szende et at., 1970). Fibrotic lung changes and altered pulmonary function tests have been reported in 96 workers exposed to PVC dust; the changes were more pro nounced in those with long exposure (Lilis et at., 1976; Waxweiler et at., 1976). A pT cates frt cutting, eating). was fount [The stuc by the f; vities d: Reduced pulmonary function and an enhancement of pulmonary function defects associated with an increased risk of respiratory impairment were noted in a number of nonsmoking workers exposed to an occupational environ ment contaminated with vinyl chloride fumes and PVC dust (Miller, 1975; Miller et at., 1975). 1The exposed t ucc 060499 VINYL CHLORIDE WD POLYMERS All In 15 polyvinyl production workers employed in 'PVC-processing indus tries', where stabilizers, colours and bulk materials were added to and mixed with the basic FVC powder, the following pathological findings were reported: in 7, slight to moderate thrombocytopenia; in 7, increased bromosulphaleln retention; In 6, reticulocytosis; in 1, leucopenia; and in 1, slight splenomegaly. Neither scleroderma-lik& skin changes nor Raynaud's syndrome were observed (Lange et al., 1975). A large proportion of abnormal liver function tests and platelet counts were found in a group of 37 FVC process workers: 20% had abnormal alkaline phosphatase, 60% abnormal lactic dehydrogenase, 30% abnormal serum glutamic-oxaloacetic transaminase, 10% abnormal serum glutamic-pyruvic transaminase, and 35% abnormal platelets (Wegman, 1975). Cases of 'meat-wrappers' asthma' have been reported, in which meat wrappers developed respiratory symptoms when exposed to fumes of PVC film sealed and cut with a hot wire. The identity of the causative agent(s) has not been established (Brooks 4 Vandervort, 1977; Falk & Portnoy, 1976; Polakoff et al., 1975; Sokol et al., 1973). During the period 1970-1975, 175 fire-fighters experienced respiratory distress due to the toxicity of hydrogen chloride gas released from the combustion of PVC plastics (Dyer 4 Esch, 1976). Carbon monoxide, hydro chloric acid and phosgene (Cornish 4 Abar, 1969; Dyer 4 Esch, 1976) have been reported as the major PVC pyrolysis products of toxicological impor tance, although more chan 75 components have been identified following the thermal degradation of PVC (Dyer 4 Esch, 1976). The few cases of dermatitis that have been reported are believed to be caused by sensitivity to plasticizers in polyvinyl plastics (Morris, 1953). 3.3 Case reports and epidemiological studies1 A proportional mortality study was carried out using death certifi cates from 1970-1972 of 707 male plastic workers (extruding, moulding, cutting, turning or otherwise machining plastics, and including PVC fabri cating) . A statistically significant excess of stomach cancer mortality was found (24 observed versus 16.4 expected, P<0.05) (Baxter 4 Fox, 1976) [The study is limited by the use of proportionate mortality methodology and by the fact that not all deaths studied were among workers engaged in acti vities directly involving PVC]. 'The Working Group was aware of a study in progress on workers exposed to PVC (IARC, 1978c). ucc 060500 -( 412 IARC MONOGRAPHS VOLUME 19 In a cross-sectional mortality study of 4341 deaths during 1964-1973 among current and former employees of 17 PVC fabricators, an excess in total cancer mortality, particularly that of the digestive system, was reported among both white males and white females. The risk of cancer of the breast and urinary organs was also reported to be in excess among white females (Chiazze et at., 1977) [The study is limited by the use of proportionate mortality methodology and by the fact that not all deaths were among workers engaged in activities directly involving PVC]. Casterline et at (1977) reported a case of a 22-year-old male who developed a squamous-cell carcinoma of the buccal mucosa as a result of a habit, acquired at the age of 8 years, of chewing plastic materials con taining PVC. No prior history of mouth or lip lesions, of smoking tobacco or drinking alcohol, or of occupational exposure to vinyl chloride was noted. Vinyl chloride-vinyl acetate copolymers 1. Chemical and Physical Data 1.1 Synonyms and trade names Chem. Abstr. Services Reg. No.: 9003-22-9 Chem. Abstr. Name: Acetic acid ethenyl ester polymer with chloroethene Acetic acid vinyl ester polymer with chloroethylene; chloroethylenevinyl acetate polymer; polyvinyl chloride-polyvinyl acetate; vinyl acetate-vinyl chloride copolymer; vinyl acetate-vinyl chloride polymer; vinyl chloride-vinyl acetate polymer A 15; A 15 (polymer); A 15-0; A 15S; Bakelite LP 70; Bakelite VLFV; Bakelite VMCC; Bakelite VSJI> 10; Bakelite VYHD; Bakelite VYHH; Bakelite VYNS; Bakelite VYNW; Breon 351; Breon 425; Breon AS 60/41; Corvic 51/83; Corvic 236581; Corvic R 46/88; Denkalac 41M; Denka Vinyl MM 90; Diamond Shamrock 744; Diamond Shamrock 7401; Exon 450; Exon 454; Exon 470; Exon 481; Exon 760; Flovic; Geon 100x150; Geon 130x10; Geon 135; Geon 351; Geon 400x47; Geon 421; Geon 427; Geon 434; Geon 103EP-J; Geon 440L2; Geon 450xl50PN; Geon 150XML; Geon 103ZX; Hostalit PVP; Leucovyl PA 1302; Lucovyl GA 8502; Lucoyyl I1A 6028; Lucovyl PA 1208; Marvinol VP 56; SOME; Nor PVC AX PA VAC H 4< VTF: via: 1.2 Sen 1.3 Chem (a) (b) 1.4 Tech Low to obtain vinyl ace described ves are u No d in the co I luring 1964-1973 I in excess In system, was sk of cancer of r'cess among by the use of |zt all deaths PVC]. l-oId male who a result of a iterials con Ivoking tobacco .lorlde was |:h loroethylene|ite; vinyl jride |iakelite ^akelite jj.5; Breon benkalac |imrock 7401; c; Geon -eon 421; :0PN; '.ucovyl 50ME; VINYL CHLORIDE AND POLYMERS 413 Norvinyl P 6; Opalon 400; Pevlkon C 870; Pllovac AO; Pliovic AO; PVC Cordo; Resin 4301; Rhodopas 6000; Rhodopas AX; Rhodopas AX 30/10; Rhodopas AX 85/15; Sarpifan HP 1; Solvic 523KC; Solvic PA 513; Solvic 513PB; Sumilit PCX; Tennus 0565; VA 3 (copolymer); VAGD; VH 10/60; Vilit 40; Vinnol H 10/60; Vinnol H 15/45; Vinnol H 40/60; Vinylite VGHH; Vinylite VTDR; Vinylite VYDR 21; Vinylite VYFS; Vinylite VYHD; Vinylite VYHH; Vinylite VYNS; Vinylite VYNW; Vinyon; VLVF; VIICC; VYHH; VYNS; VYNW 1.2 Structural and molecular formulae and molecular weight in combination with HH Jy Mol. wc: .100 000 1.3 Chemical and physical properties of the copolymers (a) Description: White powder (b) Stability: Sensitive to excessive exposure to heat and light in the absence of added stabilizers. Hydrogen chloride gas Is a decomposition product of degradation. 1.4 Technical products and impurities Low levels of vinyl acetate are copolymerized with vinyl chloride to obtain resins with specific properties. Depending upon the use, the vinyl acetate level may vary from 2-20%, with an average of 11-12%. As described in the monograph on polyvinyl chloride, p. 405, various additi ves are used to aid in processing the resins. No detailed information on the possible presence of unreacted monomers in the copolymers was available to the Working Group. IJCC 060502