Document brJKZyn6467rB1pxQ51j7J6g

VTTCL3SE CTL33SE and VINVT.TOE C3DDRSH-VDKL C77.TRIDF: GQPCEflOS Virvlidene chloride 1. Clerical and ?hvsisal Data 1.1 Synonyms arel trade names i Cam. Abstr. Services Reg. No.: 75935-4 i Car.. Abstr. Name: 1.1-Dichicroethene 1 , l-Piehloroeshylene; aaym-rtinhl croechylene Sccnatex V. J>U. w 1.2 Strucraal and molecular fiT-nuSas and weiaht r2n'2n . 2 Msl. wt: 97.0 1.3 Qi--wirai and physical properties of fee cure substance Fran Wsast (1976), unless otherwise spiciflwd (a) Description: dear liquid with a sweet odour (Hardie, 1964; Wadtolz, 1976) (b) Rni1 ino-point: 37C (c) Melting-coint; -122.1C (d) Density: d20 1.218; vapour density ^c--3^--C. 3.4 (air = 1) (Ann., 1972) (e) Refractive Index: n^ 1.4249 () SpecLiueuspy data: X vapour <200 m; infra-red, nuclear magnetic resonance, and mass spectral data haw been tabulated (Genets! 11 & Ritchey, 1975) () Solubility: Insoluble in water (0.04% wt/vol. at 20O; miscible with most organic solvents (Bardie, 1964) CM* 014064 BFG6H89 (h) Volatility: Vapour pressure is 400 sra at 14.33C (Perry & Chilton, 1973) (i) Stab^irv: (closed cs), -17C (Aran., 1972) ; easily polymerised at taiperattres above CC in the presence of oxygen or other catalysts Gfirdfcclz, 1976) ) Conversion factor: 1 pen in air is aporracrately 4 mgymJ 1.4 Technical products and iscurities Vinylidene chloride is cosnercially available in the CS with the following epical yerif1rations; vinylidene chloride, 99.6 vt %; acetylene, 25 mg/fcg max.; other chlorinated hydrocarbons, none exceeding 0.25 wt %; aridity (as hydrogen diloride), 10 mg/kg max.; peroxide (as hydrogen peroxide), 10 wq/kg wax.; water, 50 ag/kg sax.; and inhibitor (ncnarethyl ether of hydroauinme), 180 ee 220 mg/kg (PPG Industries, 1975). Typical p--1far vinylidene chloride produced in Japan are as follows: specific gravity M?). 1.2129; melting-point, -122.1C; boiling-point, 33.4C; and refractive index (n*), 1.4249. 2. Production, Use, OasurrenoB and Analysis 2.1 Piudaction and use (a) Productiai Vinylidene chloride was first prepared by Begnault in 1838 by the reaction of trichloroethane and alcoholic potassiaa hydroxide (Bernhardt, 1943). Although vinylidene diloride way be prepared by several methods, it is , <fm,, iaiiy in the OS and Japan by the dehydrochlorinaticn (using aodiim hydroxide or lime) of 1,1,2-trichloroethane, derived fraa ethylene diehloride. The resulting cruds vinylidene chloride is pirifled by washing, drying, and frecticnal distil laricn. Inhibitors are normally added at this point (Hassling t Biwards, 1971). 7 25018034 CMd 014065 BFG6119Q Ihe csRinersial production of vinylidene chloride was dependent on the development and cmmestialication of vinylidene chloride ccpolyrers, and was first resorted in the US in 1940 (US Tariff emission, 1941). It is estirsted that two US ccnparies produced a combined total of 70 million leg vinylidene chloride in 1376 and that one of these cocpanies manufactured an adrtfrinnal 50 million leg for captive use as an inisolaced intermediate in the production of 1.1, l-trimlcroethane. US imports and everts of vinylidene chloride are negligible. Vinylidene chloride has been produced eenaereialiy in Japan since 1951. Zn 1976, three rrnpwnies produced a combined total of 2S.1 million kg. Japanese imports and eparts of vinylidene chloride are negligible. (b) Pee deluding the amount used as an isolated interaediate in the production of 1,1,1-trichlcsoethane, more than 90% of the vinylidene in the PS and Japan is used in the production of copolymers of hici viiylidene chloride content, the ocher major nunaner usually being vinyl chloride. Bor a discussion cn the uses of vinylidene chloride-vinyl r*'i*~** copolyraers and other vinylidene chloride-based polymers, see p. Ihe rraining 10% or less of the vinylidene chloride pmtiumnrt is used in the manufacture of aodacrylic fibres, which are largely based cn acrylonitrile with small irouits of vinylidsae chloride and other monaaers. Bor a discussion on the uses of these fibres, see "toylie and aodacrylic fibres", p. lbs flmsriffsn Qcnfersncs of Govessaental Industrial Bygienists UtfSTH) -.....that an splcyee's exposure to vamylidane dilnride does not exsaad an eight-hour time weighted average of 40 ag/m* (10 ppm) in the workplace air in any eight-hour work shift of a forty-hour work week. During any fifteen period, the A32B fittirosaj an absolute ceiling cenoBicration limit of 80 ng/m* (20 ppn) provided the daily threshold limit value (in teste of eight-hour time wei^xted values) is not exceeded (MSB, 1976). 25018035 CMA 014066 1 BFG61191 2.2 Occurrence Vinylidene chloride is net taewn to occur as a naenrai product, (a) Air Workers involved in manufacturing facilities using vinyl chloride in polymerization processes (e.g., polyvinyl chloride) have been resorted to be ocpcsed to vinylidme chloride concentrations (Jaeger, 1576; Ott et cl., 1575) in amounts of less than 20 wq/mi (5 pan) and most frequently to trace amounts (Kramer i bitchier, 1572). Vinylidene chloride at levels of 8 mgtfa* (2 pan) has also been rescued to be a contaminant of sulanerine and at levels of 0-2 ppm of spacecraft sosspheres (Altman & Dituner, 1966). Brciaaims ef vinylidene chloride in the US in 1974 have ban estimated at 1.52 million kg fran nermer synthesis operations (reduced to 277 thousand kg by new control technology in late 1975), 308 thousand kg frxa polymer synthesis operations, and 13.8 thousand kg frem polyner fabrication opera tions (Busfaon & Rosareich, 1976). (b) tttc Vinylidsne chloride has been detected in effluent discharged from chwnioal aamufacaaaag plants in S Netherlands at a of 32 vg/1 (Buroaop-Qost, 1976) and in effluent discharged by <-Krni-y ard latex manufacturing plants in the OS. It has also been vSt***^-* in toll, river, and raw water in the US (Shackelford & Keith, 1976). Cm highest reported ccncensation ef vinylidom chloride in the US finished drinking water was 0.1 ug/1 (US Ehviuamental gmirmLim Agercy, 1975). (e) Other Vijylidose chloride has been found as as irpurity in trichloroethylene (reranticn Uliana; 0.192) fljfc^sov 6 Bodyagin, 1970), in vinyl chloride inaiiaf (limit of defection, 5 mg/kg) (Kissel t al., 1975; Sassu it al., 1968), and at a level of 0.011% in ixrrcnetrial chlorcpcene (Raginyan & Shirinyan, 1969). Aw Oamarcial household and IndustrA saran films have been analyzed for vinylidene chloride monomer. Six rolls of household film had 25018C36 CMA 014067 BFG61192 rrf-gmeg concantraticns ranging frm 6.S to 10.4 mg/kg, with an average of 3.3 mg/kg. There were no significant differences ir. sarnies taken frtn the beginning (outside) or the end (inside) of each roll. The industrial V* showed levels ranging from 10.3 to 26.2 ac/kg with levels increasing fran the beginning to the end of the roll (Birkel er si., 1577). 2.3 Analysis Vinyiidene chloride has been identified in air by trapping in pyridine and colorimetric determination of the cyanine obtained by reaction with barbituric acid or aniline. The limit of detaotioi was 10 ag/rn1 (2.5 ppm) (Grcnsberg, 1975). Gas chronstography has been used to determine vinyiidene dHoride as an iapdty (1) in trichloroethylene (Vlasov Bodyagin, 1970) and (2) in vinyl chloride (Sassu re al., 1968) with a lisdt of detection of 5 mg/kg (RLezel ct al., 1975). The sane thed has been applied to the detection of free viiyteriene chloride in latex (Ballini rt al., 1974). rv Sanpling tenhniqiiss using activated carbon as adsorbed with subsequent solvent or thernal desorption and gas chituetog:aphie analysis have been evaluated to determine vinyiidene chloride in industrial atmospheres (Severs 6 Story, 1975). A sarplang technique for of air pollutants including vinyiidene chloride cn different gas chionatogranhy has besn evaluated. The irrngraunis were tbeanally fla sorted and analyzed by gas chreratography using flare ionizaticn detecticn; the limit of detection is 4 ug/aJ (1 ppb) (Bussell, 1975). Vinyiidene chloride has been detected in saran films by gas chictracography with electron capture detection and ness spectrometry cocfiataticn. The limit of detection of the method is 5 mg/kg (ftirkel rt al., 1977). 5018037 CMA 014068 BFG61193 *0 3. aioloeieal Data As!event tc the Evaluation of Cagsanooenic Risk to Harass 3.1 Carsinaegurlty arid related studies ir. arigals1 (a) Crai administration Hat: In a preliminary report, of an ongoing study, grass of 30 sale and 30 female Sprague-Dewley rats were acSrdnistered 5, 10 or 20 mg/kghw vinylidene riilnrirtw in olive ail by starach tube onse daily, 4-5 days/week, for 32 weeks; 1 casranrma of the Zymbal gland was observed in a rat treated with the 10 mgAg bv dose. A control group of 100 tale and 100 female rats wee given olive oil alone. At the that of reporting, the rats had been observed for 93 weeks after the start of treatment (Maitoni at fiZ., 19775 (b) Inhalation exposure Meuse: In an esqwhsent; still in progress at the time of reporting,. groins of Swiss miee, 9 or IS weeks of age, were exceed 4 hours/day, 4-5 days/week, to vinylidene chloride vapours in air at raromrealigns of 800 , 400 , 200, 100, or 40 mg/n* (200, 100, SO, 25 or 10 ppB). Due to toxicity, mice treated with 200 (60 males and 60 fsales) or 100 ppm (30 sales aid 30 fsralss) were eagioeed for only 2 days and these treated with 50 ppm (30 males sod 30 fumeLas) for one week only . At the 25 ppm level, 30 sales sid 30 fasales were initially eapoead and a further group of 120 sale and 120 fscale same was started at the sase exposure level and tteaetaac of both grays continued for 52 weeks; at the tine of reporting, 98 weeks, 24/150 sales and 1/150 females had developed adeno carcinoma of tbe kidney, ofleu bilateral. Gee sale had a kidney arienocardnona in the gray treated with 50 ppm for one week. No such turmirs had omirrad in mice eayaaed to 10 ppm for 52 weeks or in 380 controls (both grays oheervad \sxtil 98 weeks of age) (Maltani, 1977; Maltani it cl., 1977). lThe working Gray wes auere of ongoing studies to assess the carcino genicity of vinylidane chInrtrie in sdoe by akin application! and in some and rats fay oral adanistraticn (SMC, 1978). The working Gray wes also a&sse of ongoing oral (drinking-water) and inhalation studies using rats in which the data analysis was not aaoplete (Raspy at cl., 1977). Further inhalation studies an tun strains of rats were also inoocplete (Viola i Caputs, 1977). CMA 014069 BFG61194 25018038 A group of 36 male and 36 female CD-I mica, 2 souths of age, ware exposed co 220 mg/m3 (53 ppm) vinylidene chloride in air 6 hours/day, 5 days a veeic for 12 months, ae which else the experiment was terminated. Two males died early in the experiment and were replaced by healthy mice; 2 males were killed in the 9th month of treatment and one female during the 10th month of treatment. Bronchiolo-alveolar adenomas occurred in 6 mice and angiosarcomas of the liver occurred in 3 mice treated with vinylldene chloride; no such tumours occurred in controls, three hepatomas and 2 skin keratoacanthomas were also reported to occur in treated mice (Lee at al., 1977, 1978) [The Working Group noted the short duration of the experiment]. Bat: A group of 36 male and 36 female CD rats were exposed to viaylidene chloride in air at a concentration of 220 mg/m1 (55 ppm) 6 hours/day, 5 days a week for up to 12 months, at which time the experiment was terminiated and all survivors killed. Two rats developed angiosareomas, one in the meaenterie lymph node and one in the subcutaneous tissue. Such tumours' did not occur in controls (Lee at al., 1977, 1978) [The Working Group noted the short duration of the experiment]. One group of 60 male and 60 female Sprague-Dewley rats were exposed to 800 reduced to 600 mg/m1 (200 reduced to ISO ppm), and 6 groups of 30 female and 30 male Sprague-Dswley rats were exposed to 40, 100 , 200 or 400 mg/m3 (10, 25, 50 or 100 ppm) vinylidene chloride in air for 4 hours/day, 4-5 days a week for 52 weeks aad observed for up co 82 weeks (time of reporting). The -*--i were 16. weeks old ae the start of treatment. An increased incidence of mammary fibroadenomas and carcinomas (40-60Z) was reported when compared with 100 male and 100 female controls (32Z). Ho dose-response relation was found. Zn addition, one Zymbal gland carcinoma was seen in one rat eraaeed with the 100 ppm dose (Halted at al., 1977). Hamster: In a study still la progress, no tiaours had occurred at 74 weeks among a group of 30 mala aad 30 female Chinese hamsters, 28 weeks of age, exposed co 25 ppm vinylidene chloride in air 4 hours/day, 4-5 days a week for 52 weeks (Malted at al., 1977). r CHA 014070 BFG61195 25018039 3.2 Other relevant biological data The adverse biological effects of viaylideae chloride have been reviewed (SPA, 1976; Haley, 1975; Warren & Ricci, 1978). (z) Experimental svsteas Toxic effects Results reported for acuta toxicity studies on viaylideae chloride have been highly variable, the lethal concentrations are dependent on the dietary paraaecers (fed or fasted animals) and on the hepatic glutathione content which exhibited significant variations in diurnal rhythm (Jaeger et cl., 1973a, 1974). The LC| by inhalation for a 4 hour exposure was 40-60 ag/1 (10,000-15,000 ppm) in fed rats and 2-10 mg/1 (500-2500 ppm) in fasted rats (Jaeger et cl., 1973b); the minimum lethal concentration was 10,000 ppm for a 24 hour exposure for fed rats (Jaeger et cl., 1974). The LCjo of viaylidene chloride for rats following exposure for 4 hours and observation for 2 weeks was 25.4 mg/l (6350 ppm) (Siegel et d., 1971). The oral IDs* in nice was 200 mg/kg bw (Jones 6 Rathway, 1978a). The oral LD$t was 1500 mg/kg bw in normal rats and 80 mg/kg bw in adrenalecsomized rats (Jenkins et cl., 1972). Zn deg, the oral minimal lethal dose was 5750 mg/kg bw and the i.v. minimal lethal dose was 225 mg/kg bw. The s.e. minimal lethal dose in rabbits was 3900 mg/kg bw (Barsoum & Saad, 1934). Death was due to vascular collapse and shock (Jaeger et cl., 1973b). Inhalation studies using rats, guinea-pigs, dogs, rabbits and monkeys with exposures at mean level of 189 mg/m} (48 ppm) for 90 days produced significant mortality snd liver damage but so changes in haeaacologieal parameters (Prendergast et d., 1967). Inhalation of vinylidene chloride for 20 6-hour exposures at 2 mg/l (500 ppm) caused nose irritation, reduced weight gain sad hepade histopathologleal changes in rats (Gage, 1970). In fasted rats exposed to 0.8 mg/l (200 ppm) for 4 hours, liver parenchymal cell injury was observed (Reynolds et cl., 1975). Minima) liver changes characterised by an increase in cytoplasmic vacuolization of occasional individual hspecocycss were noted is SpragueDawley rats created with 6-8 mg/kg bw/dsy for 90 days vinylidene ehloride CMA 014071 BFG61196 25018040 given at a concentration cf 200 ag/1 in their drinking-water. In a status report an a two-year study with rale and female Scrague-Qswley rats receiving 16-40 mg/kg iw/day (200-230 ag/1), 8-20 sg/kg iw/day (100-120 ag/1) and 5-12 ag/kg iw/day (60-70 ag/1) in their drinking-water, no --effects were noted except far a ncn-dose related decrease in survival of male rats only at 18 and' 24 amths. Rats esgxased far 30 or 90 days to doses cf 0.1-0-3 ag/1 (25-75 ppm) in air showed minimal tradcoicgical effects in the Liims (Norris, 1977). Vinyiidene chloride affects the activity of several liver enzymes, notably it decreases hepatic glucose C phoinharsse and increases serum alanine a-ketsglutarate transaminase (SMC). It increases the liver con tent of triglycerides and demmsee that of glutathione. Decreased hepatic glutathione cogenerations increase the lethality and hepatotcxicity at vinyiidene chloride (Jaeger at cl., 1973a,c). The aacroaanal enzyme inducers, r**^^^*1 and 3-metfaylofaolanthsens, increased the lethality . of vinyiidene chloride inhalation (Carlson & Puller, 1972). Vinyl chloride, when acfadnistered simultaneously with vinyiidene chloride, prevented the injury associated with vinyiidene chloride inha lation in fasted rats (Jaeger, 1975). Various errsddes (l,l,l-radtdi)oxcpropa-2,3-fflddr;n 2,3-epcxycrtcanl-cl; styrene adds; tuirartisne monoxide; and cyclohesane oxide) echanoed the hepataaddty of virylidsne chloride in male rats and decreased the acuta oral ZD (Andersen & Jenkins, 1977). a attarvotoxicity and teratatenicity Rats were given vizylidans chloride either as 200 og/1 in the drinking- water or as 20-160 ppa (80-640 ag/as) 7 hcurs/day by inhalation on cays 6-15 of gestation. Rabbits were given the saa dose by inhalation on days 6-18 of gestation. No effect was seen both in rats or rabbits. Seme evidence at esbryoteodcity as fioetetrsdcLty was observed in both rats and rabbits exceed to vinyiidene chloride by inhalation; these effects were associated with maternally trade levels of exposure (Norris, 1977). *''"t"T7's'W'pT4Ti 25018041 CMi*> 014072 BFG61197 Absorption, distribution, excretion and aatabollsa Is rats, as the dose level of radioactive vinyiidene chloride is increased froa 1-50 ag/kg bv oral, or froa 0.04-0.3 ag/1 (10-200 ppm) inhalation, the aeeabolie pathway becoaes saturated so that percentage wise, less of the dose administered is aetabolized and acre is eliaisated via the luags as vinylldcae chloride. At the 1 mg/kg bv oral dose and the 10 ppa inhalation dose, there was so difference in elimination by fed versus fasted rats. At 50 mg/kg bv oral or 200 ppa inhalation, there was a significant increase in the excretion of viaylldcse chloride via the lungs and decrease in urinary excretion of radioactivity in fed versus faseed rats (Morris, 1977). The aaln eliminative route for 1*C-vinyiidene chloride after iacragescrlc, i.v. or l.p. administration to rats is pul monary; both unchanged vlsylidene chloride and related COt are exereted by that route and other vlsylidene chloride metabolites via the kidneys. Biotrassformation of vlsylidene ehlorida gives thiodihydroxyacetic acid and an .7-acetyl-S-cystainylacecyl derivative as major urinary metabolites * together with substantial smouses of ehloroacatie acid, dlchlohydroxyacetie add and thiohydroxyacetie acid (Jones & Hathvey, 1978b). Mice metabolise a greater proportion of as oral dose of 50 mg/kg bv vinylldcae chloride thas rata. Mice (but not rats) exerete a small amount of tf-acetyl-S-(2-carboxymethyl)cysteine and they excrete more V-acecyl-Scystelnylacetyl derivative thas do rats (Jones & Bathwey, 1978a). Metabolic conversion of visylideae ehlorida into an epoxide which can rearrange to the correspondent acyl ehlorida has been proposed (Heaschler, 1978; Jonas & Bathwey, 1978a,b). Mutasenidtv end other short-eerm easts Vlsylidene ehlorida at concentrations.of 21 and 20Z (20,000-200,000 ppm) in air prodncad reverse mutations is Salmonslla typkimurim XA100 and IA 1530 in the presence of 9000 g supernatant froa liver, lusg end kidneys of mice and rats (Bareach ft cl., 1975) asd is one human liver specimen (Bartsch ft at., 1976). At a concentration of 31 (50000 ppm) in air, it is mutagenic in 5. typnisurim TA1535 in the presence of a S-9 mix of liver or kidney from mice and rats protracted with Aroelor 1254. It was weakly sueagcale in the presence of a S-9 mix of liver froa a human subject who had been receiving long-term phcnobarbltal medication (Jones 6 Bathwey, 1978e). Reverse mutations were induced in Eseharickia eoli Z. 12 by vlsylidene ehlorida solution in the presence of liver alcrosomes froa urine precreated with phanobarbital (Grain St cl., 1----- CMA 014073 BFG61198 25018042 Vinylidene chloride was rcz mutagenic in the dominant lethal test in ! 0-1 *^0* exposed by inhalation to 40, 120 and 200 cg/h3 (10, 30 anf 50 pen) for 6 hours/day fer 5 days (Anderson zt zl., 1979). (b) Hoaans Acute expestee to high concentrations of vinylidsse chloride in air results in central nerrous system^ degression and narcosis. Beseated exposures to lev concentrations is associated with liver and renal dysfaticn. Skin contact with vinylidene chloride causes irritation which say be pertly due to the hydroquinene racnanethyl ether inhibitor. Contact with the aye conjunctivitis and transient mntal injury (Irish, 193). 3.3 resorts and epidemiological studies Ott at si. (1976) investigated the cancer risk among a cohort of 138 workers econd to vinylidene chloride where vinyl chloride was not used as a osaolyner. The authors reported that there were no findings statistically related or individually attributed to vinylidene chloride escosure in this [The Marking Group noted that because 27 workers were lost to follow-ip but considered alive in the analyses, and that because 55 people had less than 15 years since first eaoosure and cnly 5 deaths were observed, these factors preclude any judgment on the findings]. Vinylidene chloride-vinyl chloride cooolvers 1* ch*""1-*'1 and Shysical Data 1.1 Synonyms and trade names Gem. teetr. Services Beg. Mo.: 9011-06-7 Cham. Abetr. time: 1,1-Trtdiloeoethene polymer with chloroethane Qjlcroatbylan^l,1-dichloroetfaylane polymer; 1,l-dichlaznethylene- uoncMdiloroethylene polymer; 1,1-dichlnroethylane polymer with chlaroethylsne; vinyl chloride copolymer with vinylidene chloride; vinyl ghl rrr-i rU_1 f 1 nrrv^yl >r copolymer; vii^l cfalaride- vinylidene rhlnrids copolymer; vinyl cbleride-vinylidme chloride polymer; vinylidene chloride-vinyl chloride polymer ! 25C18C43 CMA 014074 BFG61199 Arson 202; Breon CS 100/30; Daran; Saras O. 6795H; Sow 874; Dev Lacax 874; SI 67; Geos 222; Geon 652; 33iS 1; KhS 596; Kurehalon AO; Laplen; latex SVTQi; Polyeo 2611; QX 2168; Saraa 633; Saras 746; Saras Reals 683; S? 489 SVSh 1; SVXfa 40; V? 925; Velea; VUa* 65; Viniden 60; VEhVD 40; Viniden 60 1.2 Structural and molecular formulae and aolecular weight in combination with CCjSjCIj)^ (C2I3Cl)y Mol. vt: 10,000 to 100,000 1.3 Chemical and physical properties e< the copolymer (a) Description: Crystalline or amorphous powder depending upon che eoaeeat of vinyliden* chloride (Anon., 1973) (b) Msltlnt-ooint: 183-195C (Wessling 6 Edvards, 1971) (c) Solubility: Soluble is tecrahydrofursn, 1,4-dioxase, cyclohexanone, cyclopentaaoae, chlorohenseaa, and dichloro benzene (Wessling 4 Edvards, 1971). (d) Steh^i'tcy: Resistant eo suslighc and weathering; y-rays cause eross and chain scission (Wessling 4 Edvards, 1971) 1.4 Technical products and lapuricies Vinylidene chloride-vinyl chloride copolymers are eonmereially available In the US la several forma: resins, latexes, films, and fibres. The identity aad amount of Impurities in these produets are not available. Zn general, products obcalaed by emulsion polymerisation (i.e., latexes) have vacyiag amounts of additives used in the polymerisation process, such as initiators, activators, snd surface-eerivs agents. 25018044 CMA 014075 BFG61200 ar' 51/ virr/Licene chloride-vinyl chloride copolymers oraasrcially available in Japan are believed to be based or. 80-90% vinylidene -U1--units. 2. Production, Use, Occunetaje and Analysis 2.1 Production and use (a) Production The polymerization of vinylidene chloride was first observed by Regnault in 1838. During the 1930's in the US, the caroerical development of the polymer begin. She pure honopolymer is difficult to fabricate hunniee its softening point is very close to its deccnyuaition point. Oje discovery that inclusion of lenwll amounts of oeher nmaners lowered the softening point led to the gjinen-ial introduction in 1940 in the US of the family of vinylidene ddoride copolymers now taown as sazan (Gabbett & ardth, 1964). The copolynmxs presently of asnnereial interest in the US ` are: vinylidene chloride-vinyl chloride (Saran B), vinylirfime chlcridealkyi acrylate (Saran C), and vinylidene chloride-asyloBitrile (Saran D. Because saran has now ocme to be a generic term in the US for copolymers of high vinylidene chloride content, and because these copolyners are also often referred to as sisply 'polyvinylidene chloride', the curposition, of the copolymers described in the literature is not always known. Vinylidene chloride-vinyl chloride copolymers axe presently produced in the US by free radical processes emilsim or suspension. In Japan, they are 4 by m wulsim process. The oaulsicn process produces a polymer latex vfcieh on be toad directly (usually with additional stabilizing ingredients) or the polymer can be recovered, usually by cnegulatim with sa electrolyte, followed by washing and drying. Hm mniTrirm tgocess has the advantage of producing a higher molecular weight polymer then the auapansion process and the disadvantage of the relatively high concentration of additives idiieh may affect same of the properties of the polymer. Suspension polymerization is usually used far copolymers ' used as moulding and extruding resins. 25018045 CMA 014076 BFG61201 Four US manufacturers now produce vinylidane chloride-vinyl chloride copolymer resins, lateses, and files, and one manufacturer produces vinyiidere chloride-vinyl chloride fibre. US psoduccicr. ci vinylidene chloric copolymers ir. 1977 has been estimated at 68 million kg (Anon., 1977). Vinylidene chloride-vinyl chloride copolyners vesre first produced acceercially in Japan in 1951. Zn 1976, four Japanese esepanies produced an estimated 31.9 million kg vinylidane chloride-vinyl chloride copolyners, 2.7 million kg of whit: was fibre and the remainder, latex and fils. (b) Use Vinylidene chloride-vinyl chloride copolymers have gained wide use due to their barrier properties to water and gases, their resistance to oil, grease, chemicals, and sunlight, their flexibility, and their heat sealability. Zn addition, the high chlorine content inparts fire retardaney to the product. Vinylidene chloride-vinyl chloride copolyners are used in the font of films for food packaging (the largest use); coatings for cellophane, paper and other surfaces; fibres; and tubes and pipes. Applications fee vinylidane chlfg-iA--viryl chloride copolyners in food packaging include: household food wrap; industrial food wrap for drum liners, cheese, lundaon meat, and sausage; shrink, fils for beef, poultry, and cheese; and in laminations for cap liners, cosaetics, and Incheon neat. A relatively new use is in a aoextrudsd sulti-layered film of polyethylene on a vinylidane chloride-vinyl chloride copolymer core (Both, 1976). Vijylidane chloride-vinyl chloride copolymers are used as coatings in many applications, and as such ace used in taoo fonts: solvent-soluble resins, and water dispersions or latexes. lbs solvent-soluble resins are used to cost other polymer films such as cellophane (the largest single application), piper drinking cups and platss, and cartons. Other uses include interior coatings far ship tanks, railroad tank cars, and fuel storage tanks, coatings for steel piles and structures, binders in coatings for magnetic tapes, audio tapes, video tapes, and cceputer tapes (Both, 1976; Hassling 6 Edwards, 1971). *0 5018046 7 CMA 014077 BFG61202 The latexes are used fcr coating paper fcr use in packaging potato chips, pretzels, cereal, and cake nixes, f=r crating polypropylene and ocl*r plastics fear packaging and for single serving containers; and fer erre^^g paperboard for packaging candy, naked goods, and frozen and refri gerated iterrs. Other applications include use as binders for paints and mwoven fabrics and as an additive to cement to make high-strength mortars and ccneretes (Rath, 1976; Wessling & Edwards, 1971). Extruded fibres made from vinylidene chloride-vinyl chloride oopelyner resins are used in a wide variety of applications where resistance to sunlight and diasicals is required (e.g., autarocive scat covers, outdoor furniture, agricultural shade cloth, and filter fabrics) (Wessling & Edwards, 1971). Vinylidene chloride-vinyl chloride copolyser resins are also extnaderi into tubes, rods, pipes, and pipe liners for use in oontaet with and other ccrrosiTO media (Wessling & Edwards, 1971). The nulti-layered film of polyethylene an a core of vinylidene ehloridevinyl chloride copolymer reportedly has found use in osteny devises (Roth, 1976). In Japan, approximately 8% of the vinylidene chloride-vinyl chloride copolymers produced are in the form of fibres used for ness, interior furnishings, and construction appliances. Appradmetely 75% are used in film applications, 13% in latex applications, and 4% in other inspedfied applications. The GS Rood and Drug Affadnistrstian permits the um of vinylidene chloride copolymers (including the copolymers with vinyl chloride) as oceponants of the products then they are intended for use in contact with food; (1) adhesives; (2) resinous and polymer castings; (3) paper and paperboard; (4) rigid and semirigid acrylic and notified acrylic plastics; (5) polyethylene phthalata polymers; and (6) packag ing material for use during the irradiating of prepackaged foods (GS Rood and Drug Administration, 1977). K Zli 4 l'08TO2 CHA 014078 ' BFG61203 2.2 Occurrence Vinylidene chicride-viryi chloride copolymers are not Known to occur as natural products. 2.3 Analysis The analytical chemistry of viryi polymers, including vinylidene chloride-vinyl chloride copolymers has heer. reviewed (Cdbler et zl., 1363). Methods of detecting surface finishing agents, such as vinylidene chloride polyners, on paper have been reviewed (Proksch, 1969). Methods of identifying polymer films, including vinylidene chloride copolymers, based an physical and chenical properties have been -4---- (Sriseon, 1974; van Giesan, 1969). 3. Biological Data Relevant to the Svaluamm of Carcitixienic Risk to Hunans 3.1 pw*-^rtenicity and related ststdi^s in ar"'> No data were available to the Working Grom. 3.2 Other relevant biological data Rats fed a diet mnraining 5% {vinyl chlorid^f^^A-v '-hleridef aopolyner for two years showed no bade effects. Two dogs fed a diet containing 54 of tbe aopolyner were also without evidence of tone effects (Wilson & McCosmdc, 1954). " T k Rabbits treated for three aenths i.v. with 1 ml/kg bw it solution of vinylidene chloride-vinyl rhlnride copolymer exhibited hypertrophy of the refimin endcrhaliil calls of tbe spleen, bone marrow, liver, lynphatic tissue and lings Q&yaaaki, 1959). (b) Smarts One case of contact destetitis, limited to tbe area of its application, has been reported front tbe use of Saran Wrap (a vinylidene chloride-vinyl chloride copolymer). A positive patch test to the aopolyner was also obtained (Osbourn, 1964). 25018048 CMA 014079 BFG61204 Two workers developed ptrjiitm: cranial nerve disorders after cleaning-out tank ears in which an aqueous dispersion of vinylideae chloride copolymers had been transported. These were attributed to trace reaction products found in the copolymer (l.e., aonochloroacecylene and/or dichlcroacetylene). The trigeainal nerve was principally involved, and to a lesser degree the occipital auricular sad eervleal cutaneous nerves as well as the muscles of mastication, the eye muscles and the hypoglossus (Henschier rr si., 1970). 3.3 Case reports and epidemiological studies No data were available to the Working Group. 4. Summary of Pete Reported end Evaluation 4.1 Experimental data Vinylideae chloride has been tested by oral administration is rats and by inhalation exposure in mice^ rats and hamsters. When given by ' inhalation in rats and mice, it induced malignant tumours, including angio sarcomas. The preliminary results of another Inhalation study in rats and mice indicate the induction of malignant tumours of tha kidney in mice, mostly males, and of an increased incidence of mammary tumours in rats. No carcinogenic effect was obsarvad in an on-going study in hamsters exposed to vinylideae chloride by inhalation. Tha oral study in rats is still uadsrvay and cannot be evaluated. Vinylideae chloride la mutagenic. No data on tha carcinogenicity of vinylideae chloride-vinyl chloride copolymer were available to the Working Group. 4.2 BaBaa_data Tha production volume of vinylideae chloride is high, sad the material is utilised almost entirely la the production of the eopolyaers. This suggests that occupationally exposed groups might be identified for epidemiological lavasdgaeloa. Production of tha vinylideae chloridevinyl chloride copolymer is extensive, sad its use in coastaer produets (including food packaging) iadicaees tha possibility of widespread human exposura. CMA 014080 BFG61205 25018049 The only epidemiological study available ta the Working Group reported no tumours associated vith exposure to vinylidene chloride, hut Che data were not adequate to persit an assessaenc of carcinogenicity. So case reports or epideaialogical studies relevant to the carcino genicity of vinylidene chloride-vinyl chloride copolymers were available to the Working Group. 4.3 Evaluation The single epidemiological study on vinylidene chloride available to Che Working Group was not adequate to permit an assessment of human careinogenieiey. In view of the substantial volume of vinylidene chloride manufactured, the use of this compound in eopolymers, the identification of the material la industrial amissions and in drinking water, and its presence in some trichloroethylene, some ehloroprene, and la household materials, the lack of human epidemiological studies is serious. The available experimental evidence of eareiaogeaielty of vinylidene chloride indicates chat it produces malignant tumours in miee and rats and that some of the tumours are similar to chose produced by vinyl chloride. This evidence is, however, limited by the fact chat it is partly based on studies whieh were still in progress. An evaluation of the carcinogenicity of vinylidene chloride will be made upon eosplaclon of studies known to be underway. ChA 014081 BFG61206 25018050 5. References jC3 (1976) TLVs Threshold limit Values for Cheg-ig*t Substances in Wbrkrccrr. Air Accctad by ACGIH, Chip. American Ccnrarence or Goverrsaer.tal Industrial Hygienists, p. 30 Altman, ?.D. 6 Dirser, D.S. (1966) Brvir3Rner.tal Biclocv, aethesda, Maryland, Federation of American Societies for aytrornental Biology, to. 326, 328 Anon. (1972) Fire Protection Onlrff cn Hazardous Mater^1 = - 4th ed., Boston, -National Fire Protection Association,o. 42-229 , ii ? _ \i _____ > 7 *'''**--*** 3", , i* / Anon. (1977) Vinylidene ralffride linked to cancer. Chen. 2r.a. News, February 28, tp. 6-7 Andersen, M.. & Jenkins, L.J., Jr (1977) Bihanosoent of 1,1-diehloroethylene heparctaddcy by prstreasnent with lew nolacular weight encnriries (Abstract Ho. 41). leaded. appl. Phamaccl., 41, 148 ? Anderson, 0., Hodge, M.C.S. s Purchase, I.F.B. (1978) Qcminant lethal studies with the halogenated olfins vinyl chloride and vinylidene di chloride in sale 0-1 mice. Bwiron. Health Perspect., 21, 71-78 w Bartsch,^., Malaveille, C., Mantesano, R. Tematis, L. (1975) Tissuemediated nucagenicity of vinylidene chloride and 2-chlorobutadiene in Salaontlla typhimtriisn. Harare (lend.), 255 , 641-643 Bartsch, H., Malaveille, C. & Mantesano, R. (1976) The tredictive value of tissue-mediami irneecmiciry assay to assess tna~ carcanocenZc stsk of chwnicals. Ia:~ Mantesano, R., Bartsch, H. k IttnatisTL., ads, Sqeemnc Tests in Qaerical Carcinooenesis, Lyon, XARC Scientific Publications No. 11, pp. 467-491 Birkel, T.J., Roach, J.A.G. & Sphon, JJU (1977) Oetessinaticn of vinyli dene chloride in saran films by electron capture gas-solid chranato- graphy and confirsBticn by mass seaetrcBstry. J. assoc, off. anal. Cmp., 60, 1210-1213 ----------------------------- Bollini, M., Saves, A. & Fochar, B. (1974) Oetessinaticn of free snarers in werer enialsims of synthetic polymers and copolymers. 2nd. Carta, 12, 234-240 (Qmp. Abstr., 81, 121672b] --------------- Bristcn, J.H. (1974) JVxmdix 3. Idenrifiration of film se^H*1*. In: Piaster* Filas, Nsw ycodc, Joan Wiley and Sens, Fp. 287-293 Carlson, G.P. & Fuller, G.C. (1972) Interaction of modifiers of hepatic miooscnal drug metabolism and tbe inhalation toxicity of 1,1-dicbloro- eehylene. Res. Cans. Qrm. Pathol. Phazmaool., A, 553-559 *^) * 1S L ,, Z -- `-i. n'' -hrtnnlegy ' Vdl. VI, New York, Barnes k Noble books, " Fp. 540-543 j / 25C18051 CMA 014082 BFG61207 Cobler, J.G., Lang, M.W. s, S.C. (1963) Analytical chsmistrv cf vinyl fors-fossing polymers. Sci. 3echnol. Pslvn. Films, 1, 703-312 fQien. Abstr., 70 , 73537m] ~ SPA (1376) Health and Srvicsnrgr.tal Incacts. Task l. viry'1 Chlor^-. _ EA-550/6-76-023, Washington DC, is awirurxemtal Protection Agency SKCOCP-Oaffr (1976)u A Canprehansive T-i s- 0f gqllusinc Substances Jfr-ich Wave Been Identified m Various Fresh waters, r*~~"'-,rc ^ 5<-nrees7 Suatic Animals, and Planes, and Bottom Sediments, lnt ec., FLO/TCC/ 73/76, Caamssicn of tae Sgqaean can*--^ 41 / "*/ I , .* - i ` *vl_ (/ Gabbett, J.F. Smith, W.M. (1964)- Chapter X. Coaolvw-itar,*"ns grolcyinc vinyl chloride or vinylidene chloride as pr^^l"poi tents. `in.":""** Ham, d.S., ad., Cocolymenzation. New York.. .rn gf p. 609 Gage, J.C. (1970) The subacute inhalation toxicity of 109 industrial cbenie&ls. Brit. J. ind. Mad., 27, 1-18 Grasselli, J.G. & Ritchey, W.M. (1975) OC Atlas of Soeetsal Data and Physical Constants for Qrcanie Cntuounes, Snc ed., Vol. Ill, ciev*!*"*, Ohio, Chemical RuCoer Co., p. 2ai Greim, H., Bonae, G., Radwn, Z., Reichert, D. & Heisailer, 0. (1975) ttjtegenicitty in vitro and q* chlorinated ethylenes as a function of metabolic r^1 formation. Biochem. Pharmacol., 24, 2013*2017 Gccnsbarg, E.S. (1975) Determination of vinylidene chloride in the *(Russ.). Gic. i Sanit., 7, 77-79 Haley, T.J. (1975) Vinylidene diloride: A review of the literature. din. Ttadool., S, 633-643 Bardie, D.W.F. (1964) Qdnrocarbms and ^ifTTphydr"^-trip<. Dich11"11^ ethvlenes. 2n: Kish, iU. otaraer, D.V., eds, aacyclooedia of Qwmnwl Technology, 2nd ed., \fal. 5, New Xdrk, John Wiley and Sans, pp. 178-180 Henschler, D.,. Broeer, F. Hcpf, H.C. (1970) "Polyneuritis cranialis" durdi Ve^giftung mit chlorierten Aoetylenen beia mit Vinyli- denchlorid-Oopolyneren ("Polyneuritis cranialis" following poisoning with chlorinated acetylenes handling visylidane copolymers). Arch, `Badtol., 26 , 62-75 Bensehler, D. (1978) Metabolism and mutagenicity of halogenated olefins. A caparison of structure and activity. Environ. Health Persoect., 21, 61-64 -------------------------------------- Busbcn, J. 6 Kornreich, M. (1976) Air Pollution Assessment of Vinylidene Qtloride, Springfield, Virginia r IS Twctti,-*! TnOirrwnrm Service, PB 256 738, p. 40 CMA 014083 BFG61208 IMG (1978) Information Bulletin on the Survey of Clericals 3eirg Tested fgr Carcinogenic:,ty, Mo. 7, Lyon. incarnationa.-, Agency zzr Jtesearcr. cn Cancer, gp. "6,^23/, 2/2, 278 <L L I-ish, 0.0. (1963) Aliphatic Saloaenatad Hydrocarbons. Ir.: Patty, F.A., ed., z?A!*~rial Hvciane and Ibxicsiocy, Vcl. II, 2nd revised ed., Mew Ycrx, lr.tsrscier.ee, gp. 1305-i36/~ Jaeger, R.J. (1975) Vinyl chloride sracner: caanents on its hspatotoxicioy and interaction with 1,1-dishloroetiylane. Ann. M.Y. Acad. Sd., 246, 150-151 Jaeger, R.J., Qsnolly, R.S. & Murphy, S.O. (1973a) Diurnal variation cf hepatic glutathione concentration and its correlation with 1,1dichloroetbylane inhalation toxicity in rats. Res. Cotm. shea. Pathol. Pharmacol.. 6, 465-471 Jaeger, R.J., Trabulus, M.J. & Mapfey, S.O. (1973b) The interaction of adrsralactcny, partial adrenal replacement therapy, and starvation with hepaeotoxieity and lethality of l.l-dxchloroethylene intoxication (Abstract Ns. 133). Toxicol, aopl. ftasmcol., 25, 491 Jaeger, R.J., Trabulus, M.J. & ttsphy, S.O. (1972) Biochemical effects * of 1,1-dichlorwthylene in cats: oanparisen with carbon tetra chloride and 1,2-dichicaoethyleas. Tbxieol. acol. Phamsool., 4, S>-46T So-i-Sia " Jaeger, R.J., Osnolly, R.S. & Murphy, S.O. (1974) Effect of 18 hr fast and glutathione depletion of 1,1-dich.lcroethylcne-induced bepatotoxicity end lethality in rats. Sxo. tool. Pathol., 20, 187-198 Jenkins, L.J., Trabulus, M.J. & Mirphy, S.O. (1972) Biochemical effects cf 1,1-diehloroethylane in rats: conparison with carbon tetra chloride and 1,2-diehloroethylena. Taxiecl. asol. Pharmeol., 23, 501-510 Jones, B.X. & Hathwsy, D.E. (1978a) Differences in metabolism of vinylidene chloride ben earn sdoe and rata. Br. J. Cancer, 37, 411-417 Jonee, S.JL & Hatiwey, D.E. (1978b) The biological fata of vinylidene chloride in rats. Chem.-biol. Interact., 20 , 27-41 Kiezel, ., Tlsrka, M. 6 Ruttowski, M. (1975) Gas dutwitagrighic determjnation of trace inptnities in distillates of vinyl chloride flcncmer (PCI.). Gaea. Anal. (Warsaw), 20 , 555-562 TChem. Abstr., 83, 212233S] Xrassr, C.G. & Mutchler, J.E. (1972) The oarselation of cUniml and environmental measurements fee workers exposed to vinyl chloride. Am. iad. Hyq. Assoc. J., 33, 19-30 j 25018053 A^rJLt^ j H . T. * ^1^1%.;".^ fZ , C `Ar\ . J) ft-' -- O^J. IW*i V \ it ?" .1 *1 J!Sj ^ * . "T * wi$ . tH i >\ A.u. - /.> *-- -'-t.* i.< > 'Cauh' V . \I . if ir CMA 014084 BFG6I209 Rurginyan, K.A. & Shiriryan, V.T. (1969) Identification and quantitative determination of sare irpurities in chlcrccrerie. Am. Run.. Ih.. 22, 61-65 [Qmb. Abstr., 71, 29974x] Lee, C.C., Shandari, J.C., Winston. J.M., House, W.3., Peters, P.J., Dixon, R.L. & Woods, J.S. (1977) initiation toxicity of vinyl chloride and vinylidene micside. Bntrcn. Health Persoeeu., 21, 25-32 " Maltcni, C. (1977) Recent findings on the carcinogenicity of chlorinated olefins, awircn. Health Perspeet., 21, 1-5 Maltani, C., Cotti, G., Merisi, L. & Ciieco, P. (1977) Carcinogenicity bioassays of vinylidene chloride. Research plan and early results. Mad. Iatvoro, 68, 241-262 Miyasaki, K. (1959) Bperiaimtal studies cn the retieulo-endochelial systeo by intravenous injeccicn of high molecular synthetic vinyl compounds in rabbits. Acta Pathol. Jtan., 9, 109-131 Harris. J.M. (1977) Tfaecicolocical and oharaacckinetic studies cn inhaled and invested vinvlider* nrAmr* lanpracory PIB&ghttfl at the 1977 `SiFPl Parser Synthetics Conference in fiuSago, Illinois, Septenber 26, 1977 Osbourn, R-A. (1964) Contact desrwtitis caused by Sasan Wrap. J. Abu trad. Assoc., 188, 1159 Ott, M.G., Langner, R.R. & Holder, B.B. (1975) Vinyl chloride espesure in a industrial ervirarment. A lang-eem mortality e^erience in 594 enployees. Arch, environ. Health, 30, 333-339 Ott, M.G., Fishbeek, W.A., Tbwisand, J.C. & Schneider, E.J. (1976) A health study of enployees exceed to vinylidene chloride. J. occup. Med., 18, 735-738 Persy, R.H. & Qiiltan, C.H. (1973) Qesnieal aioineers1 Handbook, 5th ed., cNew yack, McGraw-Hill Back Co., p. 3-61 PPG Industries (1975) Vinylidene chloride, Bulletin 12QA, Pittsburgh, Philadelphia Ptendergest, J.A., Jonas, R-A., Jenkins, L.J., Jr & Siegel, J. (1967) Effects cn espariaantal **" of long-test inhalation of trichloroethylene, l,ltl-tgichloreethane, dichlorndiflucL'methane, and t agol. Phanwcnl., 10, 270-289 Psoksch, A. (1969) Deearoination of chenical auxiliary and finishing agents [for caper] by rapid (Ger.). Allc. Pap.-ftodsch., 35, 1207-1208 [Can. Abetr., 72 , 4461k] 25018054 CMA 014085 BFG61210 Ranpy, L.W., Quest, J.F., fiacistsr., C.G., 3alrer, M.7. & Schwetz, 3.A. (1977) Interim results cf two-year toxicological studies in rats cf vinylidene chloride incorporated In the drinking water cr aoninisrered by repeated inhalation. Srvtrtn. Health Persaect., 21, 33-43 Reinhardt, R.C. (1943) Vinylidene chloride polvtsers. Zxd. Sha. Chet., 35, 442-448 * ----------------------- Reynolds, S.S., Moslen, M.T., Szabo, S., Jaeger, R.J. t Jtephy, S.O. (1975) Hepatotoodrity of vinyl chloride and 1,1-diehlcroethylane. Am. J. Pathol., 81, 219-236 --------- Roth, S.F. (1976) Saran coatines - latex or laecuer? In: Qianical Marketing and Soonenacs Reprints, Staten Island, New Yorter Marketing and Soonenacs Division a the Acerican Chemical Society, pp. 29-36 * Russell, J.w. (1975) Analysis of air pollutants using saspling tubes gas chranatography. Bnyiim. Sd. Techno1., 9_, 1175-1178 Sassu, G.M., Zilio-Grandi, F. 6 Conte, A. (1968) Gas-chromatographic determination of iirpurities in vinyl chloride. J. Crramatoor., 34, 394-398 [Qmau Abetr., 69, 8297x] -- Severs, L.w. & Story, L.K. (1975) Monitoring personnel exposure to vinyl chloride, vinylidene chloride and methyl chloride in an industrial work environment. An. ind. aye. Assoc. J.. 39 , 669-676 Siegel, J., Jones, R.A., Coon, AA. 6 Lyon, J.P. (1971) Sffects on experimental animals of acute, repeated and continuous inhalation closure?to dichloroaoeeylere mixtures. Ttodcol. anal. Pharmacol., 18, 168-174 " Shackelford, W.M. & Keith, L.S. (1976) Frequency of ccaanie Oaeounds Identified in tfctar. PAr-600/4-76-Q62, Athens, Georgf, C5 mviroi- manual grorertira Agency, pp. 130, 133-ffl jo. GS tovixcmmantal Protection Agency (1975) Prelinanarv Assessuem. of Suspected Carcinogens in Drinking Water, Washington DC, p. H-3 CS Food and Drug Adninistraticn (1977) ^ tUOB Lfclqi ./iitlft 21roasts 175.105, 175.300, 175.320, 175.360, 1757353,' I7?!l7b, 176.180, 177.1010, 177.1630, 178.3790, 179.45, pp. 438, 446, 452, 455, 465, 467-469t 471, 482, 486, 489, 496, 530, 596, 607-608 CS Tariff Oarndssion (1941) Synthetic Organic Oerdcals, 05 Production and Sain, 1940, Report No. 148, Second Series, Washington PCT (is Government Printing Office, p. 58 S209T0S2 CMA 014086 BFG61211 Van Giescn, P. (1969) Here's a quick, easy way to identify files. Packace &c., 14, 76-77 [Can. Afcstr., 71, 71274u] Viola, P.L. 6 Caputo, A. (1977) Carcinogenicity studies or. virylidene chloride. Environ. Health Persoecc., 21, 45-47 Vlasov, S.M. & Bcdyagin, G.N. (1970) Gas chianaLographlc analysis of trichloroethylene (Russ.). Tr. Ran. Raa. Tekhnol., 1, 1S1-162 (Oven. Abstr., 75, 71124c] ~ Weast, R.C., ed. (1976) QC Handbook of OMaastry and Physics, 57th ed., Cleveland, Chio, Qianum! aihher Co., p. C-2^8 Hassling, R.A. & Edwards, F.G. (1971) Virylidene chloride polymers. In: Bikalas, N.M., ed., Encyclopedia of Polymer Science and SffrnvOngy, plastics, Resins, Runners Fioess. Vol. 14, New tork, John Wiley and Seas, pp. 540-579 I Wilson, R.H. 6 MeOosnieJc, W.E. (1954) Toxicology of plasticsi. Plastaaers and sonaoers. Ind. Mad. Sure., 23, 479-486 '*> \ windtolr, M., ed. (1976) The Merck Index, 9th ed., Rahwey, N.J., Merck 6 Co., p. 1283 25018056 CMA 014087 BFG61212 | _ ** c Page 2 LR.4F? 1. Introduction The present report deals primarily with the results of a project of integrated research designed to study the long*term effects (toxic and carcinogenic) of vinylidene chloride (VDC). The project included several experiments, in which the monomer was administered by different routes (inhalation and ingestion) at different concentrations, on three animal species (Sprague-Dawley rats, Swiss mice and Chine hamsters). To our knowledge, this project, sponsored by several European producers of vinylidene choride --European Study Group for VDC Toxicity (BASF AG, Dow Chemical Europe SA, I.C.I. Ltd, and Solvay et Cie) -represents the most comprehensive study available in this area. Moreover, in this report available studies on long-term carcinogenicity bioassays, as well as on ocher biological parameters concerning the behaviour and effects of VDC, performed in other laboratories and in ours, are reviewed for a better understanding of the biological action of the monomer. 2. Vinylidene ehloride Vinylidene ehloride (VDC), or 1,1-dichloroethylene, CH2sC&2 ia produced in the 17.S.A., Japan, and several Vestesn European countries. Vinylidene ehloride is mainly employed for the production of poly(vinylidene chloride) (PVDC) resins and disper sions. Examples are Diofan* (BASF), Ixan (Solvay), Saran* (Dow), and Viclan* (ICI). The most important property of PVDC is its low permeability to oxygen and moisture. 25018037 CHA 014088 BFG61213 Page 3 ^*r The aajor use of PVDC is in the manufacture of flexible packaging for food. The following population groups may be potentially expos ed to VDC: (1) workers engaged in the production of VDC monomers; (2) workers manufacturing and processing VDC polymers on an industrial scale; (3) residents around factories producing VDC and VDC polymers; and, to a much lesser extent, (4) poeple undergoing contact with resins made with VDC and with materials containing these resins and (5) consumers of food preserved in packaging materials coated with VDC resins. 3. History Up to 1974 no data were available on long-term effects of VDC. In October 1974, at the XIth International Cancer Congress, held in Florence, Viola reported that he had observed cases of abdominal reciculosarcomas in a group of Viscar rats exposed to VDC by inhalation 4 hours daily, S days weekly, at 200 ppm for 5 months and subsequently at 100 ppm for 7 months. At the "Conference on Comparative Metabolism and Toxicity of Vinyl Chloride Related ComQ pounds" held at the National Cancer Institute in Sethesda in May 1977. Viola and Caputo (1977) reported in detail the results of this experiment and moreover the results of a further experiment in which VDC was tested on SpragueDawley rats, at 100 ppm and 75 ppm, under the same experimental conditions. The authors concluded: "A final statement of the pathological results must await the completion of the microscopic examination of the tissues and organs of all animals. Never theless*, it seems clear that there is no grossly observable correlation between tumour formation and VDC inhalation." 8S08T0SZ CMA 014089 BFG61214 Page 4 On the basis of Viola's communication in 1974 The Eu ropean producers of vinylidene chloride asked our In stitute and Tumour Centre to undertake the present pro ject of long-term carcinogenicity bioassays on VDC, which was started in the spring of 1975. From the start of the experiment it was immediately apparent that mice were more sensitive to the acute effects of VDC than rats, and i male more than female mice (Haltoni et al., 1975). At the beginning of 1977, in a series of reports (at the Aeeademia dei Lincei, Rome; at the International PVDC Seminar of TAPPI, Hamburg; at the Americn Cancer Society, Hew York; and at International Agency for Research on Cancer, Lyons), we reported chat under our experimental conditions VDC produced kidney adenocarcinomas in male Swiss mice. These early results were then published in full (Haltoni et al., 1977 a, b). In 1977 the interim results of a two-year toxicological study on the effects on rats of vinylidene chloride incorporated in their drinking water or administered by repeated inhalation, performec at the Toxicology Research Laboratory of Dow Chemical (Midland, USA), were given (Morris, 1977; Ramply et al., 1977). The research plan and results of the Dow studies were summarized as follows: "Male and female Sprague-Dawley rats were exposed to vinylidene chloride (VDC) orally or by inhalation in two-year toxicological studies. VDC was given in the drinking water at mean - S.D. concentrations of zero, 68 - 13 ppm, 106 - 22 ppm, and 220 - 35 ppm, which produced mean - S.D. dosage levels of zero, 5.9 - 0.6 mg/kg, 10.0 1.2 mg/kg, and 19.3 - 2.7 mg/kg for male rats and zero, 7.5 - 0.4 mg/kg CMA 014090 Xcan) % 8 BFG61215 i ii I t c Page 5 12.6 - 1.1 mg/kg, and 25.6 - 2.4 mg/kg for female rats. Forty-eight rats/sex/VDC level and 80 rats/sex in the control group were used in the two year study with an interim kill of an additional 10 rats/sex/ level at 90 days. In the inhalation study, rats were exposed to 0, 10 or 40 ppm of VDC vapour 6 h/day, 5 days/week for 5 weeks, after which the exposure levels were changed to 0, 25, and 75 ppm of VDC. Exposure continued for a total of 18 months and the rats held for observation and additional 6 months. Interim kills occurred at 1, 6 and 12 months. A separate 90-day study using 20 rats/sex/level was conducted at 0, 25, and 75 ppm of VDC vapor. There were 86 rats/sex/level in the two-year portion of the sutdy. The parameters monitored were: body weight, food and water consumption (drinking water study only), haematology, clinical chemistries, cytogeneeics of bone marrow cells (inhalation study only), mortality, terminal organ weights, and gross and histopathology. Based.on. interim .kills and.gross pathologic observations, the main conclusions are: increased dytoplasmic vacuolation of hepatocytes was seen in the livers of rats given 200 ppm VDC in drinking water or 25 or 75 ppm VDC vapor by inhala tion; based on gross tumor count, tumour incidence in VDC-exposed rats was not greater than controls." In 1977, in two similar articles, Lee et al. (1977 a, b) reported the results of a study, supported by the Natio nal Institute of Environmental Health Sciences (USA), on the carcinogenicity of vinyl ehloride and VDC in Albino CD-I mice and CD rats. In this project, mice and rats of both sexes were exposed by inhalation to 55 ppm of VDC, 6 hours daily, 5 days weekly. Similar groups of animals were kept as controls. The study lasted 12 months. In this experiment the authors reported that they had ob- 25018P60 CMA 014091 BFG61216  J> Toxicity and carcinogenicity bioassays of vinylidene chloride. II. Chronic toxicity and carcinogenicity. by C. Maiconi, G. Cocci, L. Morisi, and P. Chieco Institute of Oncology and Tuaor Centre, Bologna, Italy C CHA 0140,2 BFG61217 25C18061 i I v Page 6 served 6 lung adenomas among 35 created male mice versus 1 among 26 controls, 3 liver angiosarcomas (2 in males and 1 in females) and 3 hepatomas (2 in males and 1 in females) from 70 treated mice, versus none from 62 con trols. Two haemangiosareomas (1 of the mesenteric nodes, and 1 in subcutaneous tissue) were found in two of 71 treated rats versus none of the 70 controls. Concerning the bronehiolar adenomas and the hepatomas in mice, the authors concluded chat their significance is questionable, since the tumours may aecur also in untreated animals (and probably in consideration of the small number of tested animals). As far as angiosarcomas are concerned, on the basis of our experience with long-term effects of VDC, this result was unexpected by us (Maltoni et al., 1977 a, b). The possibility of unwanted exposure to vinyl chloride used in parallel experiments was discussed at Bethesda "Conference on Comparative Metabolism and Toxieiry of Vinyl Chloride Related Compounds" (1977). The compatibility of a prolonged inhalatory exposure of mice to 55 ppm of VDC with a long survival does not parallel our experience on the acute toxicity in several strains of mice (Swiss, Balb/C, C3H, C57 Black), and on the chronic toxicity in Swiss mice, which appeared to bw much more sensitive to toxic effects of the monomer. 4. Planning, materials, and methods The chambers for inhalation exposure were basically built of stainless steel and glass. The determination of VDC concentrations was carried out by gas chromatography. For the ingestion experiments VDC was administered in olive oil by gavage with a stainless steel stomach tube. 25C18CSS CMA 014093 BFG61218 Pig- 7 VDC was supplied and analyzed by the Central Laboratory of Solvay (Brussels). The iapurities and their levels in the VDC employed were as follows: 1.1- dichloroethyiene (VDC) 1.2- trans-dichloroethylene acetone methylene chloride mono and dichloroacetylene 999.5 g/kg 0.4 0.1 0.05 " 0.02 " As stabilizer -methoxyphenol at 200 ppm was used. The experiments utilized Sprague-Dawley rats, Swiss mice and Chinese hamsters. All the animals, except the ham sters, had been bred in our Institute for years, and, whatever their use, were all examined at death by complete autopsy, giving us extensive information concerning their current pathology. The animals were weaned and classified by sex when 4*5 weeks old, at which time they were numbered by ear punch and divided inco groups by litter distribution. After weaning, Che animals were given drinking water ad libitum and an adequate commercial diet. The animals were kept in groups of five in *Makrolon* cages with tops made of stainless steel wire, but during the period of inhalatory treatment they were housed in groups of ten in stainless steel wire cages with a solid bottom of the same metal. A shallow layer of white-wood shavings served as bedding. The animals were kept in a temperature-controlled labora tory at 19-20 *C. Five experiments were started around the same period. The plan of the experiments is given in tables 1 to 5. Polycarbonate 25018083 CMA 014094 BFG61219 Page 3 V Experiment 1 (3T401) studied the effects on rats of inhalation exposure to 200 (then reduced, after two exposures, to 150 because of the strong toxic effects), 100, 50, 25, and 10 ppm of VDC, 4 hours daily, 4-5 days weekly, for 12 months. One group of animals served as control. 150 ppm was the highest tolerable dose by Sprague-Dawley rats for long-term exposure. From time to time the treatment was reduced from 5 to 4 times weekly because of early toxic effects in animals exposed to 150 ppm. Experiment 2 (BT402) started with groups I, II, III, IV, V, and VI, and it was planned to study the effects on mice of inhalation exposure to the same range of VDCdoses as BT401. 25 ppm was found to be the highest tolerable dose by Swiss mice for long-term exposure. Doses of 200 and 100 ppm for 2 days, and of 50 ppm for 4 days (4 hours daily) caused death of a proportion of animals. When it appeared that exposure to 200, 100, and SO ppm had to be withdrawn because of high mortality and severe toxic effects, the number of animals exposed to 25 ppm was enlarged by adding a supplementary group (IV/2), with its proper controls (group VII). In conclusion only two dose levels (10 and 25 ppm) were selected for this long-term study. Experiment 3 (BT403) was designed to evaluate the effects of VDC on Sprague-Dawley rats by ingestion, at three dose levels: 20, 10, and 5 mg/kg body weight, once daily, 4-5 days weekly, for 52 weeks. Experiment 4 (BT 404) was started to complement experiment BT403 with a lower dose (0.5 mg/kg body weight) once daily, 4-5 days weekly, for 52 weeks. 25015084 CMA 014095 BFG61220 Pate 9 Experiment 5 (BOT405) was included to study the effects of VBC in Chinese hamsters at 25 ppm, which is the highest possible concentration for long*term exposure of mice and also one of the exposure levels of rats. The animals were examined weekly, and weighed every 2 weeks during the period of treatment and monthly after the treatment was over. All the detectable gross patho logical changes were recorded during the examination. All the animals were kept under observation until spontaneous death. Moribund animals were isolated, in order to avoid cannibalism. A complete autopsy was carried out on each animal. Histo logical examinations were performed on the Zymbal glands, interscapular brown fat, salivary glands, tongue, lungs, liver, kidneys, spleen, stomach, different segments of the intestine, bladder, brain, bone marrow (sternum) and any ocher organs with pathological lesions. Furthermore, cynological examinations were carried out on the bone marrow of the femur. Histological' sections were stained routinely with hematoxylin and eosin and, in particular eases, with Papanicolaou, Van Gieson, Mallory, and Gomory stains, silver stain, and Congo red. Cynological smears were stained with Giemsa and Papanicolaou stains. V Part of the results have been evaluated by statistical analysis (see Appendix). 5. Results 5.1. Chronic toxicity The toxie effect was studied by histological examination of tissues and organs in animals that had died spontaneous ly. Therefore the observed changes had to be considered Z5018CS5 CMA 014096 Page 13 -- j as partly due to the treatment and partly due to spon taneous pathology and to Immediate causes of death. 5.1.1. Rats Regressive changes, such as hepatocytes vacuolisation, cloudy swelling, fatty degeneration (Fig. 1), necro biosis , and necrosis were found in some animals, in treated as well as in control groups. rhese changes were observed more frequently in rats exposed to 200-150 ppm by inhalation (57.6 %) than in controls (20.5 %). 5.1.2. Mice Pathological changes were found in the liver and in the kidneys, both of control and treated animals. The most frequent findings were regressive changes (hepatocytes and vacuolisation, eloudy swelling, fatty degene ration, necrobiosis and necrosis) and amyloidosis in the liver, and regressive changes (eloudy swelling and necro sis of tubular cells), amyloidosis of glomeruli, and chronic nephritis in the kidneys. The incidence of these lesions in the groups of animals treated with doses compatible with long survival (25 and 10 ppm) and con trols is given in Tables 6 and 7. From these results no correlation emerges between the abovementioned changes and exposure to VDC. A higher incidence of more pronounced regressive or phlogistic changes was found in residual parenchyma of kidneys with renal adenocarcinoma. In this situation it is not clear if these changes were due to treatment or to the presence of the tumor. ZSG 18056 CMA 014097 BFG61222 Page II Areas of fibrosis, with or without calcium deposits (Fig. 2), were found in the liver of some of the few animals which survided treatment at the high doses of VDC. Such lesions were not noted in control animals. They should be interpreted as reparative scars, following severe necrosis of hepatic cells. 5.1.3. Hamsters Ho particular changes were found in hamsters, neither in treated nor in control groups. 5.2. Carcinogenicity 5.2.1. Rats Different kinds of tumours were observed in rats treated by inhalation and ingestion and in the control groups, the mammary ones being the most frequent. The incidence of the different types of neoplasias, and the distribution of the different histotypes of mammary tumours and of some biological parameters related to them, are given in Tables 8-22. In rats exposed to VDC by inhalation (Tables 8 & 11), and increase in the incidence of mammary tumours in general, but not of carcinomas, was observed among treated animals when compared with the control. Vithin the treated groups no dose/response relationship effect was found. No in* crease of mammary tumours was observed among rats to which VDC has been given by-stomach tube (Tables 13, 16, 18, and 21) (see statistical evaluation appendix). This phenomenon has been noted in other experiments studying compounds chemically related and also related to CMA 014098 p C3 O Q) BFG61223 Page 12 <* ^ ^ VDC, suggesting that this increase of mammary tumours may be due to some "non-specific factors" connected to inhala tion (such as olfactory stimulation with consequent stimulation of pituitary gland). No other relevant findings have been recorded. 5.2.2. Mice Because of the high early mortality in the groups treated with 200, 100 and 50 ppm, the results are mainly based on the groups treated at 25 and 10 ppm and on controls. 4*S* Various types of tumours were observed in mice, the most frequent ones being kidney adenocarcinomas, mammary tumours, pulmonary adenomas and leukemias. The incidence of these different types of tumours, and data on the histotypes of mammary neoplasias are given in Tables 23-25. 5.2.2.1. Kidney adenocarcinomas The most important finding was the onset of kidney adenocarcinomas in mice exposed to 25 ppm of VDC. This kind of tumour was also observed in one^of the surfivors of the 50 ppm group. Such tumours wer?''r?bundCn*icher'in the 10 ppm groupC**=a^che control groups, and they have >*' been noecd in untreated Swiss mice of our breeding. VJj^- Jst '7*^ The tumours of the kidneys were almost exclusively in males (29 of the 30). The kidney adenocarcinomas were found in left and right kidneys. In some cases they were bilateral (Fig. 3). Often in the same kidney they appeared to be multi- Z5G180S8 CMA 014099 BFG61224 Page 13 centric. At the autopsy the tumours were often quickly detected as nodules of different sizes. Often they were observed in uniformly enlarged kidneys, and also in kidneys without any peculiar gross change. Following different histological parameters, these tomours could present all the patterns occurring in current human pathology. The three different basis classical histotypes were observed, i.e. clear, granular and dark cell carcinomas; in dark cell carcinomas, the dytoplasa could be basophilic or strongly eosinophilic (Fig. 4-12). While some tumours were rather monomorphic, others presented pleomorphism of ^ different degree: large cells with very voluminous nuclei were frequently found (Figs. 13-15). The adenocarcinomas were found to show tubular, papillary, cystopapillary, solid, and uniform arrangements (Figs. 16-18). Several'of these different patterns in different combinations could be found in the same tumour. Two of these tumours were found with metastases, one in the lung, and one in the liver. Hyperplasia and dyspiasia of tubuli were found in the kidneys of some treated male mice (Fig. 19 & 20). 5.2.2.2. Mammary tumours and lung adenomas o Mammary tumours, almost exclusively carcinomas, were found both in treated and in control groups. They were of the type usually observed in the untreated animals of our breed of mice. A higher incidence of these tumours was observed in the treated groups, without a dose/response relationship (Tables 23 & 25). Pulmonary adenomas, some with cellular atypias, were found in treated and in control animals, with a higher incidence in the treated ones, without dose/ response relationship (Table 23). CMA 014100 BFG61225 25018059 Page 1& Statistical analysis was performed to assess the signi ficance of the differences in the incidence of mammary tumours and pulmonary adenomas in mice exposed to 25 and 10 ppm and in controls, also in relation to sex and age. The important of analyzing these factors emerged from the following considerations: (1) the spontaneous incidence of these tumours varied in the two sexes; (2) these tumours were age-correlated, as are many other spontaneous tumours; (3) in experiment BT402 the survival of mice exposed to 25 and 10 ppm was higher than survival of the con trol groups. The data on mortality rates and the results of statisti cal analysis are fully reported in the Appendix. They show: (1) There were some significant higher rates of mammary and pulmonary tumours in VDC-exposed groups when compared to the controls. O (2) Vhen the incidence of these tumours was adjusted for survival race, the significance of the difference between treated and control groups was reduced. (3) No dose/response relationship could be calculated, either during the total time of the experiment or in different time intervals. (4) Overall there was a clear fluctuation and imbalance of this trend in the different groups. BF(j61226 CMA 014101 25018070 Page 15 In conclusion the direct relation of this effect to VDC treatment remains open. 5.2.2.3. Leukemias No correlation between leukemias and VDC treatment was found. 5.2.3. Hamsters Tumours (mainly uterine carcinomas) were found in treated as well as in the control groups. Their incidence was not increased by VDC treatment. 6 6.1. Related research in our and other laboratories Acute toxicity In acute experiments, when VDC was administered at rela tively high doses to rats, it caused changes in the liver and plasma enzymes (Jenkins et al., 1972; JBger et al., 1972 and 1973). In rats exposed by inhalation to 200 ppm of VDC, Jgger et al. (1975) observed a massive mid-zonal hepatic necrosis with hepatic thrombosis and ehromatolysis within 2 h after a A-h exposure. Serum transaminase and sorbitol dehydrogenase were greatly elevated at 6 h. This effect in unfed rats was associated with glutathione (GSH) depletion. An extensive study of acute toxicity was performed in our Institute (Maltoni et al., 1975, in press), on SpragueDawley rats and 4 strains of mice (Swiss, Balb/C, C3H, C57 Black). From this study it emerged that mice are more sensitive than rats, and that Swiss and Balb/C mice are CMA 014102 1c0/1 o H* GO O BFG61227 Page 16 more sensitive than C3H and C57 Black mice. Apart from C3H mice, females appeared to be more resistant than males. Among the various effects observed the most pro* minent was necrosis, with eariorexis, in liver and in kidney. Such lesions appeared very marked and extensive in Swiss and Balb/C male mice. 6.2. Mutagenic effects Greim et al. (1975) and Bartsch et al. (1975) obtained positive results with the Ames test. These authors point ed out some species-specific differences. VDC given alone showed no mutagenic effects on Salmonella strains. In adding a metabolic system of rat liver enzymes, small mutagenic effects could be seen. Using mouse-liver microsomes, the effects were several times greater. These results parallel certain metabolic differences in the animal species. The ability of monoxygenases to form epoxides is twice as high in mice as in rats. In one of the further metabolic steps the epoxides can be trans formed by means of epoxide hydratases to diols or other compounds: this enzyme system is seven times more reac tive in rats than in mice (Oesch and Glatt, 1976); there fore, mice seem to produce much higher concentrations of *) reactive epoxides or their subsequent products of meta bolism, which are postulated to be the possible direct active toxic components. 6.3. Cytogenetic effects Balmer et al. Dow/MCA, 1975) could not detect any cyto genetic effects in rats exposed 6 weeks by inhalation to VDC in air at concentrations of 25 and 75 ppm. This was confirmed by BASF (1977), where in Chinese hamsters, exposed 5 days by inhalation to 100 ppm VDC, no increase 25018072 CMA 014103 BFG61228 Page 17 S'-' of chromosome aberracions in che bone marrow test could be found. After long-term exposure of 12 months to a concentration of 55 ppm Lee et al. (1978) could not find changes in the cytgenetic analysis of bone marrow test on rats as well as mice. After a single oral dose of 217 mg/kg b.w. of VDC no statistically significant increase of the chromosome aberration rate was found (BASF, 1976). On the basis of these results no cytogenetic effect of VDC could be found, either by long-term or by acute application of a high dose, in inhalation and oral stu dies with rodents. 6.4. Pharmacokinetic and metabolic studies Jaeger et al. (1974) reported that the hepatotoxic effect of VDC is much higher in unfed rats than in fed rats, and that there is an inverse correlation between hepatotoxieity and the concentration of glutathione. These findings led to che hypothesis that the detoxification of VDC is primarily dependent upon che glutathione concentration. Jaeger et al. (1977) pointed out that in unfed rats and fed raes exposed by inhalation to high doses of ^C-VDC, 14C radioactivity was found in various organs, particular ly in kidney and in liver. The largest amount of total radioactivity was detected in the kidney of unfed rats. 14C activity in liver cells was detected in mitochondrial, microsomal, and cytoplasmacie fractions. Significantly more radioactivity was found in all liver fractions of unfed rats. The administration of trichloropropane epoxide, an epoxide hydrase inhibitor, seemed to increase the toxicity of VDC significantly in unfed rats, the enhance- 25018073 CMA 014104 BFG61229 Page 18 'r' Bene of eoxicicy being proportional to the concentration of the inhibitor. This last result supports the hypothe sis of the role of epoxide derivatives in toxicity of VDC. McKenna et al. (1977) showed that in rats and mice expo sed to ^4C-VDC, 14C was covalently bound to macromolecules in liver and kidney of both species. The *4C acti vity was higher in liver and in kidney of nice, in coaparlson to rats. The authors concluded that these data indicate an enhanced production of reactive aetabolites of VDC in aice. The data of Jaeger et al. and McKenna et al. bring further evidence that VDC toxicity does not correlate directly with the exposure per se, but is reflected in the balance of the aaount of toxic aetabolites and detoxification processes, which in turn are dependent upon nany biologi cal factors. 6.5. Epidemiological studies In a recent study, published in November 1976, Ott et al. examined the mortality and the health control findings among 138 employees exposed to measured levels of VDC, } ranging from 5 ppm to 75 ppm TVA (time weighted average), where vinyl chloride was not used as a second monomer. There were no findings in that study significantly rela ted to VDC. Hepatic damage was observed in 2 individuals with a positive history of ethanol consumption. The authors recommended "that additional epidemiologic data should be developed where exposure has taken place, with careful consideration given to obtaining an accurate history of alcohol consumption". 25018074 n 137 CMA 014105 BFG61230 Page 19 In a similar study Thiess et al. (1977) reported mortali ty rates and health control findings of 629 employees exposed to VDC as well as to vinyl chloride and acrylo nitrile. The VDC working-area concentrations were about 50 ppm (1955-1965), about 10 ppm (1965-1975), and 5-10 ppm after 1975. No significant increases in mortality or tumour incidence were found. Two lung carcinomas occurred at a very young age but with an exposure period of 14 and 25 months only (smoking habits unknown). 7 Conclusions (1) Kidney adenocarcinomas were observed in Swiss (almost exclusively male) mice exposed by inhalation to VDC ae SO and 2S ppm. Under our experimental conditions, 50 ppm VDC was already a near lethal dose, and 25 . ppm was the highest dose compatible with long survival of the treated animals. No renal tumours were observed in mice exposed to 10 ppm VDC or in controls. (2) Kidney adenocarcinomas were not observed in rats exposed to VDC by inhalation at doses from 150 to 10 ppm, or by ingestion (gavage) at doses from 20 mg to 0.5 mg/kg b.w., or in hamsters exposed by inhalation to 25 ppm. (3) The increase of mammary tumours in rats exposed to VDC by inhalation was not dose-related, and there fore it is difficult to evaluate its specific rela tion to the administration of the monomer. This phenomen has been observed in other long-term inha lation bioassays. CMA 014106 BFG61231 25018075 Page 20 (4) The dependence of che increase of mammary tumours and lung adenomas in mice on VDC treatment still remains open and needs further clarification. (5) In our experiments we did not observe liver angiosarcomas, either in treated rats or in mice. The animals used were of the same breed chat is highly susceptible to induction of angiosarcomas by vinyl chloride. (6) Our results have failed to confirm Viola's preliminary findings, which suggested chat VDC was causing recieulosarcomas in rats. $ (7) Under our experimental conditions, adenocarcinoma of kidney in mice was the only tumour specifically linked to VDC exposure. (8) As far as this effect was concerned, there was a ___ ~___ _ __ _ strong host influence: mice were more susceptible than rats and hamsters, and male mice much more than female mice. (9) There was a clear cut direct relationship between the degree of susceptibility to acute toxid and Q carcinogenic effects in the different animals speeies and sexes studied. (10) As a result of in vivo and in vitro studies it is probable that VDC is metabolised into more reactive compounds responsible for the toxic, mutagenic and carcinogenic effects of the monomer. The rate at whieh the actice metabolic compounds are formed and meeabolized depends on che concentration of administered VDC and on the metabolic pathways in the tested' animals, whieh appear to be strongly influenced by species and sex, as well as by other factors. CHA 014107 BFG61232 25018076 Page 21 ^ r^ (11) The nice used had the appropriate metabolic condi tions for indicating the oncogenic potentiality of VDC. (12) From a scientific point of view, the results of the studies on toxic, mutagenic, and carcinogenic effects of VDC and on its metabolism represent an exceptional integration of experimental multidisciplinary infornation. (12) Ve think that further investigations are needed in biological, biochemical, epidemiological, and medi- _ cal fields, in order to w (a) further investigate the roles of species, strain, and sex on the pathological effects of VDC; (b) learn more about the metabolism, with particular regard to active mecabolie compounds, and the bio* logical factors influencing the metabolic pathways; (c) collect all possible epidemiological and medical data on occupationally exposed groups, which to* gather with experimental results will provide the background for risk assessment. c 8 Summary The present report deals with the results of a wide array of correlated and integrated experiments aimed at the study of the long-term effects of VDC, with particular regard to carcinogenicity. The monomer is employed in the production of polymers whose major use is in the manu facturing of flexible packaging for food. CMA 014108 "BFG612.33 5018C77 ro Page 22 The monomer was tested by inhalation, in Sprague-Dawley rats (200-150, 100, SO, 25, 10 ppa), Swiss mice (200, 100, 50, 25, 10 ppo), and Chinese haasters (25 ppa), and by ingestion in rats (at the doses of 20, 10, 5, 0.5 ag/kg body weight, in olive oil, by stoaach tube). The treatment was carried out 4-5 tiaes weekly, for 1 year, with the exception of the groups of mice, treated by inhalation, at 200, 100 and 50 ppa, in which it was withdrawn after a few days, because of the excessive acute toxicity. 25 ppa is therefore the highest tested dose, compatible with a long-term treatment, by inhala^ tion in mice. The aost important result was onset of kidney adenocar cinomas in mice exposed by inhalation at 50 and 25 ppm. Male mice appeared to be more susceptible than females. This tumour was not observed in aiee exposed by inhala tion at 10 ppa VDC or in the other treated animal species. Increase of mammary tumours in rats and mammary tumours and lung adenomas in mice were found following inhalatory exposure to VDC. The lack of dose/ response relationship, the results of statistical analysis, and biological information from these as well as from other correlated Q experiments leave the problem of the correlation between these tumours and inhalation exposure to VDC or other monomers still open. The available data based upon the studies performed in our and other laboratories show good correlation among the results of studies on carcinogenicity, toxicity, mutagenicity, and metabolism of VDC. On the basis of our present knowledge on VDC toxicity and carcinogenicity, the need for further experimental and CMA 014109 BFG61234 25C18078 epidemiological investigations for risk assessment has been suggested. 9 References Balmer, M.F., Ramply, L.V., & Quast, J.F. (197S). Dow Chemical Co., unpublished data. Bartsch, H., Malaveille, C., Mcntesano, R., & Tomatis L. (197 Tissue-mediated mutagenicity in vinylideae chloride and 2-chlorobutadiene in Salmonella throhiaurium. Nature. 225, 641-643. BASF (1976). Unpublished results. Greim, H., Bonse, G., Radvaa, Z., Reichert, D., & Hens'chier, D. (1975). Mutagenicity in vitro and potential carcinogeni city of chlorinated ethylenes as a function of metabolic oxirane formation. Biochemical Pharmacology. 24, 2013-2017. Jaeger, R.J., Conolly, R.B., & Murphy, S.D. (1974). Effect of 18th fast and glutathione depletion on 1,1-dichloroethylene-induced hepatoxicity and lethality in rats. Experimental Molecular Pathology. 20, 187-198. Jaeger, &.J., Conolly, R.B., Reynolds, E.S., & Sheldon D.(197 Biochemical toxicology of unsaturated halogenated monomers. Environmental Health Perspectives. 11, 121-128. Jaeger. R.J., Shoner, L.G., & Coffman, L. (1977). 1,1-Dichloroethylene hepatoxicity: proposed mechanism of action and distribution and binding of 14C radio activity following inhalation exposure in rats. Environmental Health Perspectives, 21, 113-119. CMA 014110 BFG61235 25018079 Page 24 Jaeger, R.J., Trabulus, M.J., & Murphy, S.D. (1972). Vinylidene chloride hepacoxicicy and dissociation from a liperoxidative mechanism. Toxicology and Applied Pharmacology. 22, 310. Jaeger, F.J., Trabulus, M.J., & Murphy, S.D. (1973). Biochemical effects of 1,1-dichloroethylene in rats: dissociation of ies hepacoxicicy from a lipoperoxidative mechanism. Toxicology and Applied Pharmacology. 24, 457-467. Jenkins, L.H., Trabulus, M.J., & Murphy, S.D. (1972). Biochemical effects of 1,1-dichloroechylene in rats: comparison with carbon tetrachloride and l,d-diehloroechylene Toxicology and Applied Pharmacology. 23, 501-510. Lee, C.C., Bhandari, J.C., Vinston, J.M., House, V.B., Dixon, R.L., & Voods, J.S. (1978). Carcinogenicity of vinyl chloride and vinylidene chloride. Journal of Toxicology and Environmental Health. 4, 15-30. Lee, C.C., Bhandari, J.C., Vinston, J.M., House, V.B., Peters, P.J., Dixon, R.L., & Voods, J.S. (1977). Inhalation toxicity of vinyl chloride and vinylidene chloride. Environmental Health Perspectives. 21, 25-32. o Malconif C. (1977 b). Recent findings on the carcinogenicity of chlorinated olefins. Environmental Health Perspectives. 21, 1-5. Halconi, C., Cocci, G., & Chieco, P. (1975). Tossicicl acuta da eloruro di vinilidene: l'effetto della specie e del sesso. Cli Osoedali della Vita. 2/6, 105-106. n 37 CMA BFG61236 25C18CS0 Page 25 Maiconi, C., Cocci, G., Morisi, L. & Chieco, P. (1977 a). Carcinogenicity bioassays of vinylidene chloride (research plan and early resulcs). La Medicina del Lavoro, 68, 241-262. Maltoni, G., Patella, V., & Maioli, P. (In press). Toxicity and carcinogenicity bioassays of vinylidene chloride: acute toxicity. McKenna, K.J., Watanabe, P.G., & Gehring, P.J. (1977). Pharmacokinetics of vinylidene chloride in rats. Environmental Health Perspectives. 21, 99-105. Morris, J.M. (1977). Investigation of the potential toxicologieal effects and pharmacokinetics of inhaled and ingested vinylidene chloride in laboratory animals (MCA-Toxicology Programs for vinylidene chloride). Paper presented at European TAPPI Meeting, Hamburg. Oesch, F., & Glatt, H.R. (1976). Screening tests in cheaieal carcinogenesis. IARC Scientific Publications. 12, 255-274. Ott, M.G., Fishbeek, V.A., Townsend, J.C., & Scheider, E.J. (1976). A health study of employees exposed to vinylidene chloride. Journal of Occupation Medicine. 18, 735-738. Raspy, L.V., Quest, J.F., Huaiston, C.G., Balaer, M.F., & Schvett, B.A. (1977). Interim resulcs of two-year toxicological studies in rats of vinylidene chloride incorporated in Che drinking waeer or administered by repeated inhalation. Environmental Health Perspectives. 21, 33-43. Viola, P.L. (1974). Communication at the XI International Cancer Congress, Florence. Unpublished data. CHrt 014112 BFG61237 Page 26 ^ -- s' Viola, P.L., & Caputo, A. (1977). Carcinogenicity studies on vinylidene chloride. Environmental Health Perspectives. 21, 45-47. c CHA 014113 BFG61238 w W o (