Document 5kOJbokZB3R5pwKGy6MZq7njV

EPA/600/X-B5/374 * September 1985 HEALTH AND ENVIRONMENTAL EFFECTS PROFILE FOR CHLOROETHENE * WFirpn?uA.tu'Jin1/ m ASSESSHENT OFFICE ,fnCnecF,rrEArTH^D E"*ETAl ASSESSMENT ..FIrL?LRISEARCH Wl DEVELOPMENT U.S. ENVIRONMENTAL PROTECTION A6ENCV CINCINNATI. OH 4S268 # DUPLICATE COPY VAB.OOOl129390 DISCLAIMER A This report Is an external draft for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. VAB.0001129391 PREFACE A The first draft of this document was prepared by Syracuse Research Corporation under Contract No. 68-03-3112. This document was subsequently reviewed and revised by ECAO-Clnclnnatl and the Carcinogen Assessment Group, the Exposure Assessment Group and the Reproductive Effects Assessment Group of the Office of Health and Environmental Assessment. * VAB.0001129392 TABLE OF CONTENTS INTRODUCTION 1 1.1. STRUCTURE AND CAS NUMBER.................................................................. 1 1.2. PHYSICAL AND CHEMICAL PROPERTIES ............................................... 1 1.3. PRODUCTION DATA................................................................. 1.4. USE OATA..................................................................................................... 2 ENVIRONMENTAL FATE AND TRANSPORT PROCESSES................................................... 5 2.1. WATER............................................................................................................. 5 2.1.1. 2.1.2. 2.1.3. 2.1.4. 2.1.5. 2.1.6. Hydrolysis................................................................................ Oxidation ................................................................................ Photolysis................................................................................ Microbial Degradation ....................................................... Other Reactions .................................................................... Transport ................................................................................ 5 5 6 6 7 7 2.2. AIR.................................................................................................................. 9 2.2.1. 2.2.2. Chemical Decomposition....................................................... Physical Removal................................................................... 9 n 2.3. SOIL.............................................................................................................. 2.4. SUMMARY...................................... 11 12 EXPOSURE.......................................................................................................................... 13 3.1. 3.2. 3.3. 3.4. WATER...................................................................................................... FOOO...................................................................................................... [ INHALATION.............................................................................................. OERMAL.......................................................................................................... 13 14 15 1$ PHARMACOKINETICS. ............................................................................. ..... 17 4.1. 4.2. 4.3. 4.4. ABSORPTION . DISTRIBUTION METABOLISM . EXCRETION. . EFFECTS 17 18 19 22 5.1. 5.2. 5.3. 5.4. 5.5. 5.6. CARCINOGENICITY.......................................................................................... MUTAGENICITY.............................................................................................. TERATOGENICITY.......................................................................................... OTHER REPRODUCTIVE EFFECTS ................................................................ CHRONIC TOXICITY ..... ................................................................ OTHER RELEVANT INFORMATION ................................................................ 27 62 67 70 71 78 2 * VAB.OOOl129393 TABLE OF CONTENTS (cont.) 6. AQUATIC TOXICITY............................................................................................. 6.1. 6.2. 6.3. ACUTE TOXICITY ...................................................... CHRONIC STUDIES................................................. OTHER RELEVANT INFORMATION .............................. [ 7. EXISTING GUIDELINES AND STANDARDS ................................................. 7.1. 7.2. HUMAN........................................................... AQUATIC................................................................ !.*!!!!! 8. RISK ASSESSMENT ............................................................................................. 9. REPORTABLE QUANTITIES ..... ...................................................... 9.1. 9.2. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY ..................................................................... WEIGHT OF EVIOENCE AND POTENCY FACTOR (Fl/Eoin> FOR CARCINOGENICITY.................................................. ,u 10. REFERENCES APPENOIX: LITERATURE SEARCHED A Page 80 80 80 80 81 81 81 82 90 90 98 v VAB.OOOl129394 LIST OF TABLES Mi 1-1 2-1 4-1 4-2 5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8 5-9 5-10 5-11 5-12 Title Page United States Manufacturers of Chloroethene....................................... 3 Chloroethene Reaction Rates Constants for Gas-Phase Reactions......................................... 10 Percent of 14C-Chloroethene Recovered During 72 Hours Following Single Oral Doses........................................................................ 24 Percent of 14C-Chloroethene Recovered During 72 Hours Following Inhalation Exposure......................... 25 Bioassay Data for Male Wlstar Rats (Ar/IRE) Exposed to Chloroethene by Inhalation ........................................................................ 28 Bioassay Data for Sprague-Dawley Rats Exposed to Chloroethene for 52 weeks............................................................................ 29 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 32 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 35 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 30 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 42 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 44 Animal Bioassay Data for Inhalation Exposure to Chloroethene ....................................................................................................... 47 Bioassay Data for Wlstar Rats Exposed to Chloroethene. .... 51 Bioassay Data for Humans Occupationally Exposed to Chloroethene................................................................................................... ` A Bioassay Data for Humans Occupationally Exposed to Chloroethene ....................................................................................................... 54 55 Bioassay Oata for Humans Occupationally Exposed to Chloroethene ....................................................................................................... 57 * vl * VAB.0001129395 LIST OF TABLES (cont.) No^ mie _pia 5-13 Bioassay Data for Humans Occupationally Exposed to Chloroethene.................................................................................... .... 58 5-14 Bioassay Data for Humans Occupationally Exposed to Chloroethene.................................. ................................................................... $0 5-15 Bioassay Data for Humans Occupationally Exposed to Chloroethene ..................................................................................................... 5-16 8-1 Summary of Mutagenicity Data on Chloroethene ................................... Cancer Data Sheet for Derivation of ............................................... 63 87 8-2 Cancer Data Sheet for Derivation of q-j*.............................................. 88 9-1 Toxicity Summary for Chloroethene............................................................. 94 9-2 Composite Scores for the Chronic Toxicity ofChloroethene. . . 96 9-3 Minimum Effective Dose (MEO) and ReportableQuantity (RQ). . . 99 9-4 Bioassay Data for Male Wlstar Rats (Ar/IRE) Exposed to Chloroethene byInhalation for 12 months ............................................. 100 9-5 Bioassay Data for Sprague-Dawley Rats Exposed to Chloroethene for 52 weeks................................................................................... 9-6 Animal Bioassay Data for Inhalation Exposure to Chloroethene ...................................................................................................... 102 9-7 Animal Bioassay Data for Inhalation Exposure to Chloroethene for 12 months .......................................................................... 105 9-8 Animal Bioassay Data for Inhalation Exposure to Chloroethene ....................................................................................................... ...... 9-9 Animal Bioassay Data for Inhalation Exposure to Chloroethene ....................................................................................................... m 9-10 Animal Bioassay Data for Inhalation Exposure to Chloroethene....................................................................................................... ........ 9-11 Animal Bioassay Data for Inhalation Exposure to Chloroethene....................................................................................................... ........ 9-12 Bioassay Data for Male and Female Mlstar Rats Exposed to Chloroethene......................................................................................................... A vl 1 VAB.0001129396 LIST OF TABLES (cont.) No. 9-13 9-14 9-15 9-16 9-17 9-18 9-19 9-20 Title Bioassay Data for Humans Occupationally Exposed to Chloroethene ................................................................................................. Bioassay Data for Humans Occupationally Exposed to Chloroethene ................................................... Bioassay Data for Humans Occupationally Exposed to Chloroethene ................................................................................................. Bioassay Data for Humans Exposed to Chloroethene ..................... Bioassay Data for Humans Occupationally Exposed to Chloroethene ................................................................................................. Bioassay Data for Humans Occupationally Exposed to Chloroethene ................................................................................................. Derivation of Potency Factor (F), Agent: Chloroethene. . . . Derivation of Potency Factor (F), Agent: Chloroethene. . . . Page 119 120 121 122 123 124 127 128 A vlll VAB.0001129397 BCF bw CAS CNS CS Koc *oW MED MVC ppb ppm PPt PVC RQ RVd RVg TLV VCM US LIST OF ABBREVIATIONS Bioconcentration factor Body weight Chemical Abstract Service Central nervous system Composite score Soil sorption coefficient Octanol/water partition coefficient Minimum effective dose Monovinyl chloride Parts per billion Parts per million Parts per trillion Polyvinyl chloride Reportable Quantity Dose-rating value h Effect-rating value i Threshold limit value Vinyl chloride monomer Uater solubility * VAB.OOOl 129398 1.1. 1. INTRODUCTION STRUCTURE AND CAS NUNBER Chloroethene may be more commonly known by the chemical name vinyl chloride. Other synonyms for chloroethene Include chloroethylene. vinyl chloride monomer (VCH). monovinyl chloride (HVC), and ethylene monochlorlde (Verschueren. 1983). The structure for chloroethene Is: The molecular weight for chloroethene Is 62.50 and the empirical formula ^2^3^' Registry number Is 75-01-4. 1.2. PHYSICAL AND CHEMICAL PROPERTIES Chloroethene Is a colorless gas at normal temperatures and pressures with a mild, sweetish odor (Verschueren, 1983). It Is soluble In hydro carbons, oil, alcohol, chlorinated solvents, and most coamon organic solvents (Cowfer and Haglstro. 1983). Selected physical properties of chloroethene are listed below: Melting point: Bolling point (1 atm): Specific gravity: Refractive Index: Vapor pressure: at 25*C at 20*C at 0*C -153.8*C -13.4*C 0.9121 (15/4*C) 1.3700 (20*C) 2660 mm Hg 2320 mm Hg 1230 mm Hg Cowfer and Maglstro, 1983 Cowfer and Maglstro, 1983 Verschueren, 1983 IARC, 1979 Verschueren, 1983 Carassltl et al., 1978 Cowfer and Maglstro, 1983 0707p 10/17/85 VAB. Log octanol/water partition coefficient: Water solubility at 25C: Conversion factors (air) 0.6 (calculated) 1.2 (calculated) Callahan et al., 1979 Habey et al., 1981 2763 reg/i * 1 mg/cm,*0.39 ppm 1 ppm*2.60 mg/cm* Horvath, 1982 Verschueren, 1983 h Horvath (1982) has reviewed the available literature data regarding the solubility of chloroethene In water. The experimental results have been shown to vary considerably. The recommended value has been given above. Chloroethene polymerizes In light or in the presence of a catalyst (IARC, 1979). 1.3. PRODUCTION DATA The current domestic Industrial manufacturers of chloroethene are listed in Table 1-1 along with their respective locations and annual capacities. In 1982 and 1983, U.S. production of chloroethene was reported to be 5.97 and 6.88 billion pounds (USITC, 1984). Chloroethene Is Industrially produced by the pyrolysis of ethylene dlchlorlde (Cowfer and Maglstro, 1983) as shown: 2C1CH2CH2C1 - 2CH2 * CHC1 2HC1 The ethylene dlchlorlde Is formed by either the direct chlorination of ethylene or by the oxychlorlnatlon of ethylene (Cowfer and Naglstro, 1983). 1.4. USE DATA Chloroethene has the following use pattern (CNR, 1983): Polyvinyl chloride (PVC) Miscellaneous (mostly copolmer use) Export 85% 1.5% 13.5% 0707p 0 09/17/85 VAB.0001129400 TABLE 1-1 United States Manufacturers of Chloroethene* Manufacturer Borden Chem. Dow OuPont (Conoco) Formosa Plastics Georgia-Pacific BF Goodrich PPG Industries Shell Chem. *Sourct: SRI, 1984 Location Gelsmar, LA Oyster Creek, TX Plaquemlne, LA Lake Charles, LA Baton Rouge, LA Point Comfort, TX Plaquemlne, LA Calvert City, KY La Porte, TX Lake Charles, LA Oeer Park, TX Norco, LA TOTAL Annual Capacity (millions of pounds) 610 750 1250 700 300 530 1000 1000 1000 900 840 700 9580 0707p 09/17/85 VAB.OOOl129401 Limited quantities of chlorethene were used In the United States as an * aerosol propellant In pesticide aerosol products and In self-pressurized household containers and as an Ingredient of drug and cosmetic products {I ARC 1979). However, these uses are no longer In practice. .Nearly all of the chloroethene consumed In the United States Is used for the production of polyvinyl chloride or other polymers. 0707p I 09/17/85 VAB.0001129402 2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES * The individual fate processes, pertaining to chloroethene, are discussed below with respect to water, air and soil. Evaporation from water and photooxidation in the atmosphere appear to be the major chloroethene fate processes In aquatic and atmospheric media, respectively. 2.1. WATER 2.1.1. Hydrolysis. Based on results obtained from studies of chloro- ethene levels In samples of darlfer effluent from a chloroethene plant stored at 50 C for 57 hours at pH 4.3, 8.0 and 9.4 In sealed septum vials, Callahan et al. (1979) reported that chloroethene hydrolysis over a pH range of 4.3-9.4 does not appear to be environmentally Important. Mabey et al. (1981) also reported that chloroethene hydrolysis Isnot environmentally significant. The hydrolytic half-life of chloroethene has been estimated to be <10 years at 25*C (Hill et al.. 1976). 2.1.2. Oxidation. Experimental results show that chloroethene will not be significantly degraded by molecular oxygen at temperatures and oxygen concentrations present In natural waters (Hill et al., 1976); however, experiments at 85*C have shown that chloroethene Is degraded by hydroxyl radicals (Hill et al., 1976). The rate constant for the reaction between chloroethene and hydroxyl radicals In aqueous solution at room temperature Is about 7.3x10* IT* sec` (Guesten et al.. 1981); assuming an average OH concentration of 10"* H in natural water, a half-life of -no days is calculated. An estimated rate constant of 3 IT* hr`* for oxidation of chloro- e ethene by RO^ (peroxy radical) (Habey et al., 1981) suggests that this * reaction has no environmental significance. The Importance of reaction with a singlet oxygen cannot be evaluated because of the lack of rate constant data. 0707p -5- 10/10/85 VAB.0001129403 2.1.3. Photolysis. Chloroethene In water does not absorb ultraviolet radiation above 218 nm (Hill et al.f 1976), therefore, direct photolysis In the aquatic environment Is not expected to occur. As an experimental confirmation. Hill et al. (1976) exposed solutions of 10 ppm chloroethene In water to filtered light >300 nm from a mercury lamp^ no photolysis occurred over a 90 hour period. Hill et al. (1976) also experimentally studied the photosensitized photolysis of chloroethene In water. Chloroethene decomposed rapidly when Irradiated with ultraviolet light In the presence of acetone (a high energy triplet sensitizer) or hydrogen peroxide (a free radical source). Since a high-energy sensitizer Is required for effective photolysis, the ability of chloroethene to undergo photosensitized photolysis In natural waters Is not certain. Various humic substances may be effective photosensltlzers. Polyvinyl chloride plants are likely to use small amounts of peroxides In their polymerization processes. As a result, aqueous effluents containing v both chloroethene and peroxides may be susceptible to sunlight-induced decomposition (Hill et al., 1976). 2.1.4. Microbial Degradation. The limited amount of existing data Indicates that chloroethene Is resistant to microbial degradation. Hill et al. (1976) found that an Isolated bacterial culture containing two species of bacteria and three mixed fungal populations was unable to biodegrade chloroethene over a 5-week period at concentrations of 20-120 mg/i. Helfgott et al. (1977) observed no degradation of chloroethene at 20*C over * a 5-50 day period using an acclimated sewage seed as a microbial Inoculum. 0707p 10/10/85 VAB.0001129404 2.1.5. Other Reactions. It Is possible, though not proven experimentally, that In an environment such as a municipal water chlorination, chloroethene may be converted to more highly chlorinated compounds based on the reactivity of carbon-carbon double bonds with chlorine and hypohalous acid (Hill et al., 1976). Many salts have the ability to form complexes with chloroethene and can Increase Its water solubility. Therefore, the presence of salts In natural waters may significantly Influence the amount of chloroethene remaining In the water (Callahan et al., 1979). 2.1.6. Transport. 2.1.6.1. VOLATILIZATION -- The available data Indicates that chloro ethene will evaporate rapidly from the aquatic environment. Scherb (1978) measured the evaporation half-life of chloroethene from a flowing channel and found It to be -1-4 hours with a slight dependence on weather condi tions. Turbulent flow Increased the evaporation rate. f Dllllng et al. (1975) experimentally measured the evaporation rate of chloroethene (1 ppm) from an open container containing 200 m solution (65 mm depth) at 25*C while being stirred at 200 rpm. An Initial half-life of 26 minutes was determined with 90X evaporation In 96 minutes. In a subse quent study (Dllllng. 1977), a half-life of 27.6 minutes was obtained for 0.89 ppm chloroethene. In water under the same experimental conditions. While the results of these experiments cannot be extrapolated directly to the aquatic environment, they do demonstrate the volatility of chloroethene In dilute aqueous solution. McConnell et al. (1975) have experimentally determined the unitless Henry's Law Constant for chloroethene at 10*C to be 50; this converts to a * Henry's Law Constant of 1.2 atm-m*/mo1e. This value of Henry's Law * 0707p 10/10/85 VAB.0001129405 Constant Indicates that volatilization Is both significant and rapid from all bodies of water (Lyman et al.t 1982). In addition, Lyman et al. (1982) have calculated the Henry's Law Constant for chloroethene at 20*C to be 2.4 atm-mVmole which the authors used to calculate an evaporation half-life of 2.5 hours from a stream 1 m deep, moving 1 m/sec with a wind current of 3 m/sec. knlle Habey et al. (1981) have theoretically calculated the reaeration rate ratio of chloroethene to be 0.675 at 25*C, Hill et al. (1976) have experimentally measured the ratio to be -2. Assuming the oxygen reaeration rates from a typical pond, river and lake are 0.008, 0.04 and 0.01 hr*1 (Mabey et al., 1981), respectively, and a reaeration ratio of 2, the follow ing chloroethene evaporation half-lives are calculated: pond river lake 43.3 hours 8.7 hours 34.7 hours 2.1.6.2. ADSORPTION -- No experimental data were found In the avail able literature as cited In the Appendix regarding sorption of chloroethene to particulate matter and sediment In water. The calculated octanol/water partition coefficients for chloroethene (Section 1.2.) suggest adsorption may not be significant. Hill et al. (1976) have suggested that aquatic sediments could exhibit long-term storage of low levels of chloroethene If extreme environmental conditions, such as continual high levels of chloroethene Input, were present. 2.1.6.3. BIOACCUNULATION et al. (1977) examined the bloaccumu- latlon of *C-chloroethene In a closed model aquatic ecosystem during a 3-day period. The high volatility of chloroethene minimized any potential bloaccumulatlon; however, relatively low tissue concentrations found In fish suggested that chloroethene Is not blomagnlfled to any substantial degree. 0707p 10/17/85 VAB.0001129406 The BCF of an organic chemical can be estl- mated from the K ow or US by use of the following regression equations: Log BCF * 0.76 Log KOW-0.23 Log BCF * 2.791-0.564 Log US (In ppm) Velth et al., 1980 , Kenaga and Goring, 1978 (2-1) (2-2) Assuming, from Section 1.2., that Log K Is -0.9 and that US Is 2763 ppm, the BCFs calculated from Equations 2-1 and 2-2 are 2.8 and -7, respec tively, Indicating little Importance of bloaccumulatlon In aquatic organisms. 2.2. AIR 2.2.1. Chemical Decomposition. The atmospheric chemical removal pro cesses Include reaction with hydroxyl radicals, reaction with other radi cals, reaction with ozone and photolytlc transformations (Cupltt, 1980). Table 2-1 contains available rate constants for the reaction of chloroethene with hydroxyl radicals, oxygen atoms [0(*P)], and ozone along with calcu lated half-lives. Reaction with hydroxyl radicals appears to be the major removal mechanism for chloroethene In the atmosphere. The products of OH reaction with chloroethene are HC1, formaldehyde, formyl chloride, CO, C0p, chloroacetaldehyde, acetylene, chloroethylene epoxide, chloroacetyl- chloranll, and H-0 (Uoldbaek and Klaboe, 1978; Kaglya et al., 1975; Muller and Korte, 1977). A relatively high reactivity of chloroethene has also been demonstrated In smog chamber studies In which chloroethene and nitrogen oxides were Irradiated with sunlamps and black lights (Carassltl et al., 1978; Dllllng et al;, 1976; Gay et al., 1976; Kanno et al., 1977; Cox et al., 1974). Chloroethene In vapor-phase does not absorb light of wavelengths >220 nm (Fujlmoto et al., 1970; Hill et al., 1976); therefore, direct photolysis will not occur In the atmosphere. 0707p 10/17/85 VAB.0001129407 I 0707p - 10- 09/17/85 TABLE 2-1 Chloroethene Reaction Rates Constants for Gas-Phase Reactions Chloroethene Reaction with Rate Constant Temperature CC) Calculated Half-life* (days) Reference OH OH OH 0 <p) 0 (p> 03 O3 4.5x10"** cm*/molecule-sec 6.6x10"** cm*/molecule-sec 5.6x10"** cm*/molecu1e-sec 5.98x10*** cm*/molecule-sec 8.6x10*** cm*/mo1ecule-sec 2.45x10*** cm*/molecu1e-sec 1.2x10* cm*/mo1e-sec 23 26.2 27 25 25 25 27 1.8 1.2 1.4 532 373 33 4.2 Howard, 1976 Perry et al., 1977 Cox et al., 1974 Atkinson and Pitts, 1977 Sanhueza and Helcklen, 1975 Zhang et al.v 1983 Lyman et al., 1982 *Assumlng average atmospheric concentrations of 10* molecules/cm* for OH; 2.5x10* molecules/cm* for 0 (P); 1x10** molecules/cm* or 1.6x10*** moles/cm* for O3 VAB.0001129408 k 2.2.2. Physical Removal. The physical atmospheric removal mechanisms Include dissolution (wet deposition), adsorption on aerosol particulates and dry deposition (Cupltt, 1980). These physical removal processes are not expected to be significant compared with the chemical removal processes. 2.3. SOIL No experimental data could be found concerning the microbial or chemical degradation of chloroethene In soil as cited In the Appendix. Experimental data were also not located concerning the adsorption of vinyl chloride to soil. The Kqc of an organic chemical can be estimated from Its US or Kqw by use of the following regression equations developed by Kenaga and Goring (1978): Log Koc 3.64-0.55 Log US (In ppm) Log Koc 0.544 Log Kow + 1.377 (2-3) (2-4) Assuming, from Section 1.2., that US Is about 2763 ppm and Log K Is ow -0.9, the Koc values calculated from Equations 2-3 and 2-4 are 56 and 74, respectively. Indicating a high soil mobility. Prediction of K from the oc molecular topology and quantitative structure-activity relationship analysis method of Sabljlc (1984) yields a Kftc value of 17, again Indicating high soil mobility. The high vapor pressure of chloroethene suggests that evaporation from soil will occur rapidly. Jury et al. (1984) predicted that the effective half-life (due to volatilization) of chloroethene placed 10 cm deep In dry soil will be only 12 hours. The presence of water, which may result In transporting chloroethene deeper In soil, may lengthen the half-life. 0707p -11- 10/17/85 2.4. SUMMARY The primary loss process for chloroethene released Into^water Is evapo ration Into the atmosphere. For a variety of natural waters the half-life for this process would be expected to take hours to days. In waters con taining appropriate photosensitizers, which may Include humic substances, photodegradation may occur fairly rapidly. Chemical hydrolysis and oxida tion of chloroethene In water are not expected to be environmentally Impor tant. Limited microbial data suggests that chloroethene Is resistant to microbial degradation. Chloroethene Vs not expected to bloaccumulate significantly In aquatic organisms. Chloroethene reacts In the troposphere with photochemically produced hydroxyl radicals with a half-life of 1.2-1.8 days under average conditions. In photochemical smog situations, the half-life would be reduced to a few hours. Chloroethene can be expected to volatilize quite rapidly from soil. rm Some leaching of choloroethene from soil Into groundwater Is expected to occur. 0707p 09/17/85 VAB.0001129410 3. EXPOSURE 3.1. WATER Exposure of chloroethene to the aquatic environment can result from wastewater releases generated by manufacturing of the chemical and use of the chemical to produce polyvinyl chloride and other products. The source of chloroethene In potable water Is the leaching of unreacted monomer from polyvinyl chloride transmission pipes (Flshbeln, 1979; Ando and Sayato, 1984; Banzer, 1979; Nakamura and Mlmura, 1977). Westrlck et al. (1984) reported the results of the U.S. EPA's Groundwater Supply Survey conducted by the Office of Drinking Water In which 945 water supplies throughout the United States were measured for volatile organic compounds. Chloroethene was detected In 7 of the 945 waters anal yzed at a maximum concentration of 8.4 pg/i and a median concentration (In positive samples) of *2.6 pg/L. Cole et al. (1984) have reported the preliminary findings from the U.S. EPA's Nationwide Urban Runoff Program (NURP) In which priority pollutants were monitored In urban stormwater run off; chloroethene was not detected In any samples from 15 reporting cities. Chloroethene has been detected In drinking water In Miami, FL and Philadelphia, PA at approximate concentrations of 5.6 and 0.27 pg/l, respectively (U.S. EPA, 1975). A level of 50 ppb chloroethene were detected in drinking water wells In Long Island, NY (8urma$ter, 1982). Data from nine states In the United States Indicated that chloroethene was detected In 7% of wells end surface waters tested with a maximum groundwater concentra tion of 380 iig/l (Oyksen and Hess, 1982). Conlgllo et al. (1980) has summarized available chloroethene monitoring data from over 100 United States cities' surface and groundwaters which were analyzed; chloroethene was found In raw surface water (7.6% positive), finished surface water 0707p -13- 10/17/85 (2.3% positive), raw groundwater (15.4% positive) and finished groundwater (4.0% positive) at levels of 0.1-9.8 yg/t. The gross analysis available from the U.S. EPA STORET Data Base reports the following data regarding chloroethene: Water No. observations Max. concentration Min. concentration Median concentration Sediment 5553 202,662 vg/l 0 107 yg/1 Fish Tissue 649 580 yg/kg 0 23 yg/kg 530 250 mg/kg 0 6 mg/kg - Chloroethene has been detected In wells from a speciality product plant In Sanborn, NY that manufactures graphite cloths (Pfaudler Co., 1984). The source of chloroethene Is evidently the trichloroethylene used as a solvent In the plant. Two active wells In this area showed chloroethene concentra tions of 7 and 28 ppb. Groundwater obtained as a result of several soil borings In this area contained chloroethene at concentrations varying from none detected to 79 ppb. 3.2. FOOD Small quantities of chloroethene can be exposed to food by migration of chloroethene monomer present In polyvinyl chloride food wraplngs and con tainers (Gilbert et aT., 1980). The U.S. Food and Drug Administration has found that up to 20 mg/kg (ppm) chloroethene may be present In alcoholic beverages packaged In polyvinyl chloride containers (IARC, 1979). In 1973, the United States Treasury Department banned the use of chloroethene polymers for packaging alcoholic beverages (IARC, 1979). In addition to alcoholic beverages, chloroethene has been detected In vinegar packaged In these containers at levels up to 9.4 mg/kg (IARC, 1979). 0707p * -14- 10/17/85 3.3. INHALATION Chloroethene Is emitted to the atmosphere at both chloroethene produc tion facilities and polyvinyl chloride production plants (Graedel, 1978; Flshbeln, 1979; Bertram, 1977). In addition, chloroethene Is emitted to air In gases released from sanitary landfills (Bruckman and Muelder, 1982; Graedel, 1978), In emissions resulting from the thermal degradation of poly vinyl chloride (Wakeman and Johnson, 1978), and In tobacco smoke (Graedel, 1978). The U.S. EPA estimated that prior to 1975, In excess of 100 million kg/year of chloroethene escaped to the atmosphere In the United States from polyvinyl chloride production facilities and that the average chloroethene concentration In the air around these plants was 17 ppb (IARC, 1979; Flshbeln, 1979). Harkov et al. (1983) detected only trace amounts of chloroethene In 3/113 samples of general urban air analyzed from Newark, Elizabeth, and Camden, NJ during July-August 1981. Subsequent monitoring of 105 air samples from the same cities during January-February 1982 detected no chloroethene (Harkov et al., 1984). Bozzelll and Kebbekus (1979) found an average chloroethene concentration of 3.4 ppb In 11 positive samples taken In East Rutherford, NJ In 1978 that showed detectable levels of chloro ethene; Bozzelll et al. (1980) found an average concentration of 0.4 ppb In six air samples that showed detectable levels of chloroethene (73 total samples). The samples were collected from six urban New Jersey areas. NcMurry and Tarr (1978) detected chloroethene In 29% of 62 air samples taken In the vicinity of production and use facilities near Channelvlew, TX; maximum concentration detected was 13 ppb. Gordon and Meeks (1977) found chloroethene levels of 3.1-1250 ppb In Houston, TX air during June-July, 0707p * -15- 10/17/85 1974; large production and use facilities are located In the area. Chloroethene has been detected In the air of Delaware City. DE at an average concentration of 790 ppb {Lillian et al., 1975). Pelllzzarl {1977) found chloroethene concentrations of 400-120,000 ng/cm* In a few- air samples from New Jersey; Pelllzzarl {1978) and Pelllzzarl et al. {1979) have also detected chloroethene In air samples from various Industrialized United States locations. Gay and Noonan (1975) detected chloroethene concentra tions of 40 ppb In a residential Niagara Falls area near a chloroethene plant, 28 ppb downwind from the plant and 0 ppb upwind from the plant. Grlmsrud and Rasmussen (1975) analyzed the air In the rural Northwest U.S.A. and did not detect chloroethene above the detection limit of 5 ppt. The air Inside two new automobiles was found to contain 0.4-1.2 ppm chloroethene (Hedley et al., 1976); the chemical was thought to have volati lized from plastics In the automobile Interiors. 3.4. DERMAL t Pertinent monitoring data were not located In the available literature as cited In the Appendix. 0707p -16- 10/10/85 *. PHARMACOKINETICS The pharmacokinetics on chloroethene have been reviewed by the U.S. EPA * (1980, 1984a), Valnlo (1978), Dietz et al. (1983) and Bolt et aT. (1981). 4.1. ABSORPTION Gastrointestinal absorption of chloroethene In rats occurs rapidly following Ingestion of aqueous or vegetable oil treatment solutions (Wlthey, 1976). Maximum blood levels were reached within 10-20 minutes of dosing with aqueous (22.6 or 28.2 mg/rat) or vegetable oil (12.53 or 25.1 mg/rat) chloroethene solutions. Quantitatively, absorption of chloroethene (In PVC powder) from the gastrointestinal tract of rats was -83-92% based on fecal recovery (Feron et al., 1981). Absorption of chloroethene from the lungs following Inhalation exposure occurs rapidly with blood levels equilibrating to atmospheric levels within a short period (Watanabe et al.t 1976b; Wlthey, 1976; Ouprat et al., 1977; Bolt et al., 1977). Wlthey (1976) reported that equilibrium blood levels In rats were reached within 30 minutes of exposure at levels up to 7000 ppm. Similarly, Bolt et al. (1977) reported that blood levels reached an equi librium within -15 minutes following Inhalation of chloroethene. In human volunteers, 42% of Inhaled chloroethene was retained by the lungs (Krajewskl et al., 1980). Absorption efficiency did not appear to be affected by expo sure at 7.5-60 mg/m*. Individual variation, however, was high with mean retention values after 6 hours exposure at 30 mg chloroethene/m* ranging from 30-71% among five volunteers. Hefner et al. (1975a) reported that percutaneous absorption of chloro ethene was 0.031 and 0.023% of the available compound In rhesus monkeys exposed (excluding head) at 800 and 7000 ppm (2045 and 17,894 mg/m*) for 2.5 and 2.0 hours, respectively. 0707p + -17- 10/17/85 4.2. DISTRIBUTION The distribution of chloroethene and/or Its metabolites following oral exposure was studied by Watanabe et al. (1976a). Rats were given single oral doses of X4C-chloroethene by gavage at 0.05, 1.0 or 100.0 mg/kg and the amount remaining In the body was determined after 72 hours. The liver contained the most radioactivity at all dose levels (up to 3 times that In other tissues) while the skin, lung, plasma, fat, carcass and muscle contained less In decreasing concentration. The distribution of 14C-chloroethene was determined In rats exposed by Inhalation at 20,000 ppm (51,125 mg/m) for 5 minutes (Duprat et al., 1977). At 10 minutes after the exposure period radioactivity was detected In the liver, bile duct, digestive tract and kidneys. At 3 hours after exposure radioactivity was also detected In the urinary tract, salivary and lacrimal glands, thymus and skin. Watanabe et al. (1976b) determined tissue levels of radioactivity In rats exposed by Inhalation to 10 or 1000 ppm (26 or 2556 mg/m*) X4C-chloroethene for 6 hours. At 72 hours after expo sure, radioactivity was detected In the liver, kidney, skin, lung, muscle, carcass, plasma and fat In decreasing concentration. Immediately after a 5-hour Inhalation exposure at 50 ppm (128 mg/m*) X4C-chloroethene, tissue levels of radioactivity, expressed as % Incorporated/g tissue, were highest In the kidney (2.13%) and liver (1.86%) with lower levels In the spleen (0.73%) and brain (0.17%) (Bolt et al., 1976). Radiolabeled com pounds (probably as metabolites) were still detectable In these tissues 48 hours after exposure was started. In a German study (Buchter et al. 1977), radioactivity from labeled chloroethene was concentrated In the adipose tissue with lesser amounts In blood, liver, kidney, muscle and spleen when 0707p -18- 10/17/85 Its metabolism was blocked using 6-nltro-1,2,3-benzothladlazole. When metabolism was not blocked, highest levels of radiolabeled metabolites were detected In the liver and kidney. 4.3. METABOLISM Metabolism of chloroethene occurs primarily by oxidation by hepatic microsomal enzymes. The toxicity and mutagenicity of chloroethene are regarded as attributable to its oxidized metabolites (U.S. EPA, 1984a). Two metabolism schemes have been suggested, one Involving alcohol dehydrogenase, the other a mixed function oxidase system (Figure 4-1) (Bartsch and Montesano, 1975). Henschler and Bonse (1977) reported that chloroethene Is oxidized to an epoxide and further to the aldehyde. The unsymmetrlcal and unstable epoxide Intermediate, chloroethylene oxide. Is thought to be responsible for the mutagenic potential of chloroethene (Section 5.2.) (Gwlnner et al., 1983). Unmetabollzed chloroethene does not appear to be mutagenic (Section 5.2.). In human liver specimens chloroethene was metabolized by aryl hydro carbon hydrolylase enzymes at a rate -84% that of rat liver preparations 4 (Sabadle et al., 1980). In vitro metabolism of chloroethene with human liver preparations resulted In electrophilic metabolites which were muta genic to Salmonella tvphlmurlum (TA1530 and TA100). Jaeger et al. (1974) reported that pretreatment of rats with phenobarbltal enhanced hepatic metabolism of chloroethene; Hultmark et al. (1979) reported no effect of phenobarbltal, but pyrazole (alcohol dehydrogenase Inhibitor) and ethanol treatment Inhibited metabolism of chloroethene. Metabolic activity was localized In hepatic mlcrosomes and was NAOPH-dependent, suggesting that the metabolizing enzyme Is a cytochrome p450 (Hultmark et al., 1979). These data suggest that both pathways of metabolism occur. Hefner et al. (1975a) 0707p -19- 10/17/85 _ <>i i jn t,n Cl t*r*r*ft*M* CHa- CH, II Cl OH * CHa-CH I Cl 0 CM**McUl4t>y4t HC - CHa I Cl cMrttUtytoftt mnt* CHa-C-OH IH Cl 0 cMwiciU act CtvloroactiJiaatiy4t 4 CH,-C-OH IN Cl 0 CfkltrMCtllC K4 6-5-- DV-CHO %,ygrn*i 0707p FIGURE 4-1 Metabolic Pathways of Chloroethane 09/17/85 VAB.0001129418 suggested that the alcohol dehydrogenase pathway predominated at low exposure levels (saturable at 105-220 ppm or 268-562 mg/m*) and others predominate at higher levels. Metabolites of chloroethene, chloroethylene oxide and chloroacetaldehyde can react with glutathione or other cellular macromolecules (Watanabe and Gehrlng, 1976). Kappus et al. (1976) reported that a metabolite of chloroethene, probably chlorethylene oxide* bound Irreversibly to liver proteins. Hepatic glutathione content was decreased In rats exposed to chloroethene at >100 ppm (256 mg/m*) (Watanabe et al., 1976a). Irreversible binding to proteins In the kidney, small Intestine, lung, spleen, muscle and albumin occurs to a lesser extent than In liver (Bolt and Fllser, 1977). Guengerlch and Watanabe (1979) and Guengerlch et al. (1981) reported covalent binding of radioactive metabolites of 14C-chloroethene to proteins and nucleic acids following U\ vivo and In vitro treatment in rats. Gwlnner et al. (1983) reported that chloroethylene oxide was responsible for alkylation of ONA, causing mutagenic and carcinogenic effects; chloroacetaldehyde appar ently has little or no similar activity. Hathway (1977), however, reported that chloroacetaldehyde caused depurlnatlon of calf thymus ONA suggesting that this metabolite could also alter ONA and elicit oncogenic effects. Metabolism of Inhaled chloroethene appears to be saturable at -220-250 ppm (562-639 mg/m*) with a metabolic rate (VIMXI of 110 pmol/hour/kg bw In rats (Bolt et al., 1977; Fllser and Bolt, 1979; Hefner et al., 1975b). During the Initial phase of metabolism, when alcohol dehydrogenase metabo lism may predominate, a t^of 86 minutes was determined, while a slower rate, t^ .. * 261 minutes occurred during the second, saturated stage of metabolism (Hefner et al., 1975b,c). The amount of chloroethene metabolized followed MichaelIs-Menten kinetics (Gehrlng et al., 1978). Chloroethene 0707p -21- 10/17/85 metabolism In rhesus monkeys was also a dose-dependent, saturable process with first order kinetics below the saturation point of 200-300 ppm (511-767 mg/m*) {Buchter et al., 1980). A ymd x of ~50 mmol/hour/kg bw In the rhesus monkey was suggested as a closer approximation of metabolism in man than that In rodents (10-fold higher rate than primates). Watanabe et al. (1978b) conducted single-exposure and 7-week Inhalation studies of chloroethene (5000 ppm or 12,781 mg/m*, 6 hours/day, 5 days/ week) In rats to compare Its metabolism after acute and repeated exposure. Based on the time course and routes of excretion, metabolism of chloroethene appeared to be the same following acute and repeated exposures. There was no evidence that chloroethene Induced Its own metabolism or Increased the activity of several other hepatic enzymes. Binding of chloroethene or Its metabolites to hepatic macromolecules was Increased 20-25% In rats exposed repeatedly compared to rats treated for one exposure. Comparing continuous and Intermittent acute exposure, Jedrychowskl et al. (1984) reported that h hepatic nonprotein sulfhydryl content was decreased In a dose-related manner over the exposure range of 15-15,000 mg chloroethene/m* (time-weighted average concentrations) regardless of exposure schedule. Intermittent exposure at 500 or 15,000 mg/m* (TWA) did result In less urinary thlodl- glycollc acid excretion than continuous exposure. 4.4. EXCRETION * Elimination of chloroethene and its metabolites following oral Ingestion has been studied In rats by Green and Hathway (1975), Watanabe and Gehrlng (1976) and Watanabe et al. (1976a). x*C-ch1orethene was administered In corn oil by gavage In both studies at dose levels of 0.25 and 450 mg/kg or 0.05, 1.0, and mg/kg, respectively. Elimination of radioactivity was monitored in the exhaled air (as chloroethene or carbon dioxide), urine and 0707p -22- 09/17/85 A TABLE 4-1 Percent of i4C-Chloroethene Recovered During 72 Hours Following Single Oral Doses 0.05a Expired: as Chloroethene as Carbon Dioxide Urine Feces Carcass Cage wash Totalc 1.43 8.96 68.34 2.39 10.13 0 91.25 aUatanabe and Gehrlng, 1976 bGreen and Hathway# 1975 * cPercent of dose administered NR Not reported 0.25** 3.7 13.5 75.1 4.6 NR NR 96.9 Dose 1.0a 2.13 13.26 59.30 2.20 11.10 0.84 88.83 20a 41.6 4.8 22.6 1.0 11.0 NR 81.0 100a 66.64 2.52 10.84 0.47 1.83 0 82.30 *S0*> 91.9 0.7 5.4 0.7 NR NR 98.7 0707p -24- 09/17/85 VAB.0001129421 A TABLE 4-2 Percent3 of 14C-Ch1oroethene Recovered During 72 Hours Following Inhalation Exposure Concentration ( 1000b 5000c 5000c`d Expired: as Chloroethene as Carbon Dioxide Urine Feces Carcass Cage wash Total recovered, yg 1.61 12.09 67.97 4.45 13.84 0.15 248 12.26 12.30 56.29 4.21 14.48 0.23 6642 54.5 8.0 27.1 3.2 7.3 NR 25,670 53.7 9.6 25.7 1.4 9.7 NR 24,070 aPercent of total recovered bWatanabe and Gehrlng, 1976 cWatanabe et al., 1978a treatment following repeated exposure to unlabeled chloroethene (6 hours/ day, 5 days/week for 7 weeks) 0707p 09/17/85 VAB.0001129422 Exhalation of unchanged chloroethene following Inhalation exposure in human volunteers represented 3.6-4.7% of the Inhaled concentration (3, 6, 12 or 24 ppm (7.7# 15, 31 or 61 mg/m*). Elimination by this route repre sented a minor portion of the absorbed dose and decreased to- undetectable levels within -30 minutes after exposure was terminated (Krajewskl et al., 1980). Green and Hathway (1975) have examined the elimination of radioactivity from l4C-chloroethene following Intraperltoneal and Intravenous Injection at 0.25 or 450 mg/kg. Following Intraperl toneal Injection at 0.25 mg/kg exhalation of unchanged chloroethene and CO. and urinary and fecal radio activity accounted for 43.2, 11.0, 43.1 and 1.8% of the administered dose, respectively. At 450 mg/kg by Intraperltoneal Injection exhaled chloro ethene, CO^, urinary and fecal radioactivity accounted for 96.2, 0.7, 2.6 and 0.1% of the dose, respectively. Intravenous dosing at 0.25 mg/kg resulted In 99.0, 0.1, 0.5 and 0.1% of the dose recovered as unchanged exhaled chloroethene, CO*, urinary and fecal compounds, respectively. 0707p -26- 10/17/85 5.1. CARCIN06ENICITY 5. EFFECTS The carcinogenicity of chloroethene In animals has been well established ft by the numerous available studies. Several reviews of the available data on the carcinogenicity of chloroethene have been reported (Maltonl, 1977a; Valnlo, 1978; IARC, 1979; Maltonl et al.. 1982; U.S. EPA, 1983a; Tamburro. 1984; Kalmaz and Kalmaz, 1984; U.S. EPA, 1984a,b). Maltonl et al. (1980) prepared an extensive summary document of a series of carcinogenicity bioassays conducted on chloroethene between 1971-1977. Due to the abundance of data and the recent review documents on the carcinogenicity of chloro ethene, this summary will emphasize recently reported bioassays and those studies useful for quantitative carcinogenic risk estimation. In 1971. Viola et al. (1971) reported that chloroethene was carcino genic, Inducing skin carcinoma, lung carcinoma and osteochondroma, in Wlstar rats exposed by Inhalation at 30.000 ppm (76,687 mg/m), 4 hours/day. 5 days/week for 12 months (Table S-l). Maltonl and coworkers (Maltonl and Lefemlne, 1974, 1975; Maltonl, 1977b; Maltonl et al.. 1980) reported liver angiosarcoma and renal nephroblastoma In Sprague-Oawley rats given chloro ethene by gavage at 16.65 and 50 mg/kg (Table 5-2). in rats treated by inhalation an Increased Incidence of liver angiosarcoma occurred among groups treated at >10& ppm (256 mg/m*) chloroethene and kidney nephroblas tomas occurred among rats treated at 6000 and 10,000 ppm (15,337 and 25,562 mg/m) (see Table 5-2). Maltonl et al. (1980, 1981) exposed Sprague- Oawley rats, Swiss mice and golden hamsters to chloroethene by Inhalation at levels of 1-30,000, 50-10,000 and 50-10,000 ppm (2.6-76,687, 128-25,562 and 128-25,562 mg/m*), respectively, 4 hours/day, 5 days/week for 1 year (rats) or 30 weeks. Liver angiosarcoma and nephroblastoma occurred In rats 0707p 10/17/85 VAB.0001129424 0707p Male TABLE 5-1 -28- 10/17/85 Dose or Exposure*1 (PPM) Duration of Treatment 30,000 12 months 0 HA Duration of Study >12 monthsc >12 monthsc Purity of Compound Vehicle or Physical State Target Organ Tumor Type 99% vapor/air skin epidermoid carcinoma lung carcinoma bone osteochondroma NA air only skin epidermoid carcinoma lung carcinoma bone osteochondroma Tumor Incidence 15/26 6/26 5/26 0/25 0/25 0/25 QUALITY OF EVIDENCE Strengths of Study: Weakness of Study: An appropriate route of administration was used. The chloroethene was relatively pure. Appropriate controls were Included for comparison. i Only male mice were tested. The duration of the study could have been longer. No statistics were compiled on Incidences between treated and untreated animals. Overa11 Adequacy: Adequa te aSource: Viola et al.. 1971 ^Exposure was for 4 hours/day, 5 days/week for 12 months. cSurv1v1ng animals were killed at 20-day Intervals following treatment. NA * Not applicable VAB.0001129425 0707p TABLE 5-2 Bioassay Data for Sprague-Dawley Rats Exposed to Chloroethene for 52 weeks3 Exposure Route Sex Dose or Exposure* Inhalation IU|Will P|Mi * 6,000 ppm 200 ppm 150 ppm 100 ppm 0 ppm Oral (gavage) 50 mg/kg 16.65 mg/kg Duration of Study (weeks) Vehicle or Physical State Target Organ Tumor Type IM 155 143 143 143 143-155 vapor/air vapor/air vapor/alr vapor/air vapor/alr air only liver kidney liver kidney liver liver liver liver kidney angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma angiosarcoma angiosarcoma angiosarcoma nephroblastoma 136 olive oil liver angiosarcoma kidney nephroblastoma 136 olive oil liver angiosarcoma kidney nephroblastoma Tumor Incidence 9/60 5/60 13/60 4/60 12/120 5/120 1/120 0/500 0/120 16/80 2/80 9/80 3/80 1 -29- 10/10/85 VAB.0001129426 V &LOLO 58/01/01 ~0" TABLE 5-2 (coni.) Exposure Route Sex Oral (gavage) (coni.) N.F Dose or ixposurec 0.0 Mg/kg * Duration of Study (weeks) Vehicle or Physical State olive oil only Target Organ Tumor Type liver kidney angiosarcoma nephroblastoma Tumor Incidence 0/150 0/150 QUALITY Of EVIDENCE Strengths of Study: A broad range of dose levels were tested. Carcinogenic response was shown by two routes of administration. Duration of study was long In all cases. Weakness of Study: Overall Adequacy: No statistics were reported. The sex of test animals Is not reported. Data for the control group for the gavage studies Is reported In Haltonl et al.# 1981. Animals treated by gavage. The purity of the chloroethene Is not reported. Adequate Comments: _______ ____________ __________ ____ ___________ _________ _____ __________________ _ This study focused on different factors affecting the carcinogenic effect (animal species, strain and age, treatment duration, and exposure levels). * ^Source: Haltonl, 1977b ^Purity of compound not reported cExposure to chloroethene by Inhalation was for 4 hours/day, 5 days/week for 52 weeks; by gavage once dally In olive oil 4-5 days/week. NR - Not reported VAB.0001129427 TASK 5.3 AiiImI Bloessey Biti for Inin lit loo Exposure to Chloroethene* 0707p -3 2 - 10/ 10/ 8$ Species/ Strife Bit/ Sprifoe Biwley Sex Bose or E xpesure* written of Treetoent {weeks) 10. *. 2,500 52 52 52 s 52 Borittoe of Study {weeks) Vehicle or Phystcel Stite 58 ilr/viper 135 iir/vipor 135 iir/vipor 135 iir/vipor 135 iir/vipor / 135 itr/vipor 143 iir/vipor 143 iir/vipor 143 iir/vipor 135 itr/vipor 147 itr/vipor 147 itr/vipor 147 itr/vopor Tirget Orpin Tuoor Type Tuoor Incidence liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney ingtosircooi nephroblestooi ingtosircooi nephroblistool ingtosircooi nephroblestooi inglosercooi nephroblestooi ingtosircooi nephroblestooi ingtosircooi nephroblestooi ingtosircooi nephroblestooi ingtosircooi nephroblestooi ingtosircooi nephroblist001 ingtosircooi nephroblestooi ingtosircooi nephroblistool ingtosircooi nephroblestooi ingtosircooi nephroblistooi , 18/50 m 7/60 S/50 13/55 5/55 13/50 5/50 6/50 6/50 3/S5 5/55 12/120 7/120 6/115 11/115 1/120 10/120 1/50 1/50 5/120 1/120 1/115 0/115 0/115 0/115 VAB.0001129428 -33- 10/10/8 S 0707p Species/ Strain Sax at/ Spragwelawley N,f Rouse/ Swiss R.f Naas tor/ Syrian Seldeu R.f Dos* ir t *posurec (PP>) 1 1lt 2.500 .10 Bara!ton of Treatnent (weeks) 5? M Duration of Study (nooks | U7 135-147 1 II II 1 109 119 119 109 109 air/vapor air only air/vapor air/vapor air/vapor air/vapor air/vapor air/vapor air only air/vapor air/vapor air/vapor air/vapor air/vapor llvor kidney liver kidney liver lung liver long liver long liver lung liver lung liver lung liver lung forestonacb forestoMck forestonacb fores tonach forestonacb anglosarcona nephroblasIona anglosarcona nephroblastoon anglosarcona tunor anglosarcona tunor anglosarcona tunor anglosarcona tunor anglosarcona tunor anglosarcona tunor anglosarcona tunor paplllona/ acanthona paplllona/ acanthona paplllona/ acanthona paplllona/ acanthona paptlloan/ acanthona 0/11B 0/118 0/363 0/363 10/56 45/56 13/60 47/60 16/59 40/59 14/60 50/60 10/60 41/60 1/60 6/60 0/150 15/150 10/30 10/30 17/30 9/30 4/30 0707P 1 TADLE 5-3 (coni.) Species/ Strain Nam tor/ Syrian Gotten $01 Ouse or Exposure* M SuralIon of Treetaunt (wks) Duration of Study (nooks) Vehicle or Physical State air/vapor air only Target Organ Timor Type forest forestoaach paptlloM/ acanthoma papilloma/ acantdoM Timor Inc tdence 3/30 3/60 Strengtks of Study Overall Adeguacy C ts: Chteroetbooo was atelnlstored by Inhalation to rats. alee and hamsters at a broad of antaats wore performed. Duration of studies was Inna. Adeguato Extensive examinations This report was extensive and h of the data was not reported bore due to the scope of this project ^Source: HalionI et al.. 1001 tfurlty of compound was >99.00 cExposure was for 4 hours/day. 5 days/week NA Net applicable -34- 10/17/BS t n ^B.0001129430 0707P TABLE 5-4 Animal Bioassay Data for Inhalation Exposure to Chloroetheneab*c Species/ Strain Rat/CD H F n F N F N F Dose or Exposure** (PP) 50 * 50 250 250 1000 1000 4 0 + 0 Vehicle or Physical State vapor/air vapor/air vapor/air vapor/air vapor/air vapor/air air only air only Target Organ liver lung liver lung liver lung liver lung liver lung liver lung liver lung liver lung Tu*r Type hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemangl osar coma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma Timor Incidence (p value) 0/36 0/36 0/36 0/36 2/36 0/36 10/34 (p<0.05)* 3/34 6/34 4/34 15/36 (p<0.05)e 9/36 0/35 ' 0/35 0/35 0/35 -35- _ 10/10/85 DrAB.0001129431 0707P TABLE 5-4 Species/ Strain Dose or Vehicle or Sex Ixposure^ Physical (PP) State Mouse/CD-1 N F N F N F 0 0 50 50 250 250 air only air only vapor/air vapor/air vapor/air vapor/air respiratory tract liver respiratory tract liver respiratory tract liver respiratory tract liver respiratory tract liver respiratory tract liver bronchioloalveolar adenoma hemang 1 o s a r c oma bronchioloalveolar adenoma hemangtosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma 1/26 0/26 0/36 0/36 8/29 3/29 4/34 0/34 10/29 7/29 (p<0.05) 12/34 16/34 (p<0.05) -36- 09/17/85 ^^B.0001129432 TABLE 5-4 (cont.) 0707p . -37- Species/ Strain Dose or Vehicle or Sex Exposure*1 Physical Target Organ (PP) State Tumor Type Tumor Incidence (p value) House/CD-1 H 1000 4 1000 vapor/air vapor/air respiratory tract liver respiratory tract liver bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma 12/33 13/33 (p<0.05) 26/36 18/36 (p<0.05) QUALITY OF EVIDENCE Strengths of Study: Three different dose levels of chloroethene were tested by Inhalation In two species of animals. Some statistics were reported. Chloroethene was quite pure. An exten sive examination of organs and tissues was performed. Heakness of Study: Overa11 Adequac y: The significance of bronchioloalveolar adenoma In mice Is not reported. of study was short (due to mortality). # Adequa te The duration a Source: Lee et a1. 1978 ^Duration of treatment and duration of study 12 months cPur1ty of compound 99.8% "Exposure was for 6 hours/day, 5 days/week eS1gnlfIcantly different from controls by Elscher Exact Probability Test VAB.0001129433 10/10/85 tolail lloattaif lata Spec Us/ Strati lat/CI Bos* or Buratlon of Buratlon Sax iaposoro* Treatnent of Study <BPi) (Moths) (Booths) M SO B or 10c IB or 22 2S0 0 or 10 10 or 22 90.80 i 99.80 1000 S or 10 10 or 22 99.80 0 Mouse/CB-1 M 2S0 1000 I 0 10 or 22 HA 1 13 99.80 1 13 99.00 1 13 99.80 13 99.80 air/vapor air/vapor air/vapor air ooly air/vapor air/vapor air/vapor atr only liver lung liver lung liver lung lung lung liver lung liver lung liver lung liver hepatocellular carclnona henanglosarcona bronchioloalveolar tunor henangl osarcom hepatocellular carclnona henanglosarcona bronchioloalveolar tunor henanglosarcona hepatocellular carclnona henanglosarcona bronch1o1oa1veolar tunor henanglosarcona henanglosarcona henanglosarcona henanglosarcona henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona 0/66 0/66 0/66 0/66 2/68 5/68 (p<0.05) 2/68 y 2/68 7/72 (p<0.05) ) 14/72 lp<0.05) ; / \r\Tsy 7/72 y 1/72 0/72 0/72 0/72 3/32 1/32- 19/32 0/32- 20/32 0/32 - 3/32 0/32 VAB.0001129434 > Species/ Strain Sh Nie or Exposure* Suratloo of Treatment Sura Mon of Study (PP) (months) (Booths) Nouse/CS-1 1 2 I ISM 99.SK air/vapor lung bronchioloalveolar tumor 12/32 liver hemang 1 osar coma 0/32 3 IS 99.OX air/vapor lung bronchioloalveolar 21/32 tumor liver hemanglosarcoma 4/32 3 IS 99.OX air/vapor lung bronchioloalveolar S/20 tumor liver hemanglosarcoma lb/20 IS HA air only lung bronchioloalveolar 2/32 tumor liver hemang 1 osar coma 0/32 IS 99.OX air/vapor lung bronchioloalveolar 3/16 tumor 4 - liver hemanglosarcoma 1/16 99.OX air/vapor lung liver bronchioloalveolar tumor hemanglosarcoma 16/20 9/20 . 1000 I 99.OX air/vapor lung liver bronchioloalveolar tumor hemanglosarcoma 14/24 13/24 10 99.OX air/vapor lung bronchioloalveolar 11/56 tumor liver hemanglosarcoma 1/56 09/17/85 0707p /"N TABLE 5-5 (cont.) ShcW Strain Sex Base or E xpesere* Bora!Ion of Treatnent Bora!Ion of Study <PP) (Months) (onths) Purity of Conpound Vehicle or Physical State Target Organ Tenor Type lenor Incidence (p value) Strengths of Stody Weakness of Stody Overall Adegeacy: C ts: Two aolnal splocles w Incidence with respect QUALITY Of EVlPflCt Bose and repor ted. exposure levels were varied to show a dose-response. Statistics of tenor deration of troatweet was too short Adogoate * This stody was condocted enhance that reported ^Source: Hong ot al.t 1001 hours/day, I days/week c0oratlon of exposure was for 0 or 10 Months* followed hy a 12-nonth deration group. HA - Hot applicable The results presented are for the conblned treatnent -40- 10/ 10/ 8S t VAB.0001129436 tiQ iO i SpNltt/ Strain Neuse/ICt n.r lat/fSM Swu/A/J V *.f 8at/f344 *.f IMli 5-6 tolatl IlMtt*], utt fat InfcaliMM (p,r, to CklorootlwM* Ouse or Exposure* (PP) 8 0, 50, $08, 5808, 58,808 588 8 58 8 588 58 0 Ourat Ion f Treataent 1 lay Cl hour) 1 Say (I hour) 1 Say Cl hour) 1 Say Cl hoar) IM H. 1 Say Cl hour) 18 1 hour exposures M 188 1 hour exposures M 18 1-hour exposures 100 1-hour exposures M Duration of Study 18 NKMlthS 18 Months 18 Months 18 Months 18 Months llfettae 20 Months 20 Months 20 Months 20 Months llfettae llfettae llfettae Vehicle or Physical State air/vapor air/vapor air/vapor air/vapor alr/vaper air/vapor air/vapor atr only atr/vapor air only air/vapor atr/vapor air only Target Organ lung lung lung lung lung lung liver lung lung lung lung lung liver lung liver lung liver Tuaor Type adenoaa carclnoaa adenoua carclnoaa adenoaa carclnoaa adenoaa carclnoaa adenoaa carclnoaa Malignant adenoaa carclnoaa adenoaa carclnoaa adenoaa carclnoaa adenoaa carclnoaa Malignant Malignant Malignant Malignant Malignant Malignant Tuaor Incidence 45/131 3/131 24/143 1/143 18/139 1/139 14/139 0/139 12/120 0/120 0/178-190 per dose # 124/146 22/166 31/90 3/90 65/158 7/158 29/84 2/84 0/180 0/180 0/180 0/180 0/100 0/100 $8/01/01 VAB.0001129437 > 0707P TAilE 5-6 (coni.) Species/ Soso or Strain Sox t xposure tPPti oration of Treatment oration of Study Vehicle or Physical State Target Organ Tumor Type QUALITY Of EV1BEIICI Strengths of Stody: Exposeros wore condocted al exposure levels using rats and nice of both sexes. Weakness of Stody Overall Adequacy Exposures, except for 100 Incidence of corctnonas wot 1 United treatments at 50 ppm, were very brief. Lung adenomas are useally c nd statistics were not performed. No carcinogenic affect was shown C ts: Pulmonary spontaneoosly In A/J - mice and may not he a valid test for carcinogenicity ^Source: Mehlr et al., 1901 ^Purity of compound not reported NA Not applicable Tumor IncIdence The ' -43- 10/17/85 i VAB.0001129438 iABLE 5 AnlMl Blussay Data for Inhalation Species/ Strain Rat/COBS I II I House/CDl Swiss Sex R.F N.F Dose or Exposure*) <P*) Duration of Treatment (onths) Vehicle or Physical State 2500 * 200 50 0 2500 12 air/vapor liver Zymbal glande 12 air/vapor liver ZyiRbal g1ande 12 air/vapor liver Zymbal glande 12 air only liver * Zymbal g1ande 9 air/vapor liver lung 200 50 9 * 9 i air/vapor liver lung air/vapor liver lung 0 NA air only liver lung angiosarcoma tumor angiosarcoma tumor angiosarcoma tumor anglosarcoRia tumor anglosarcoiRa alveolar adenoma alveolar carcinoma angiosarcoma alveolar adenoma alveolar carcinoma angiosarcoma alveolar adenoma alveolar carcinoma angiosarcoma alveolar adenoma alveolar carcinoma 114/147 12/13 82/141 2/23 28/139 3/14 0/143 0/25 101/101 101/101 18/101 130/134 119/134 4/134 46/121 , 92/120 10/120 0/97 10/96 1/96 VAB.0001129439 10/10/85 TABLE 5-7 (cont.) 0707p . 45. 10/17/85 Species/ Strain Dose or Duration Vehicle or Sex Exposure*! of Physical Target Organ ipm) Treatment State (months) Tumor Type Tumor Incidence Hamster/ Golden Syrian H,F 2S00 200 50 0 12 air/vapor liver 12 air/vapor liver 12 air/vapor liver 12 air only liver angiosarcoma angiosarcoma angiosarcoma angiosarcoma 56/66 12/88 7/74 0/83 QUALITY OF EVIDENCE Strengths of Study: Three species of animals, both sexes of each were exposed at three levels. Exposure was for 12 months and a long latency was allowed. Appropriate controls were maintained. Histological examination of major organs was conducted. Overall Adequacy: Adequate Tumors were reported as total number of tumors, therefore, tumor Incidence reported here (tumor bearing animals/total animals examined) aSource: MCA, 1980 ^Duration of study was for lifetime cPur1ty of compound was not reported ^Exposure was for 7 hours/day, 5 days/week eNot all rats were examined for Zymbal gland tumors NA Hot applicable VAB.0001129440 > / 0707p -47- 1A8LE 5-8 i BiU for likMliUoft Ixposure lo Chloroftht^ SpKW Dos* or Duration of DuralIon Vehicle or Strain San Exposure* TroitaMt of Study Physical laryet Organ (MtlK) (Months) state Timor Type Timor Incidence 0at/f344 f TOO TOO 6 12 10 air/vapor air/vapor air/vapor liver naamary gland liver ry gland liver ry gland hemangl osarcoma hepatocellular carcinoma flbroademma hemanglosarcoma hepatocellular carcinoma fibroadenoma hemanglosarcoma hepatocellular carcinoma fibroadenoma 4/76* 3/7$ 28/76* 11/55* 4/56* 28/56* 13/55* 8/54* 24/55* TOO 24 air vapor liver ry gland heoungtosarcoou hepatocellular carcinoma f tbroadenoma 19/55* 9/55* 26/55* air only liver ry gland heounglosarcoma hepatocellular carcinoma fibroadenoma 1/112 1/112 24/112 Hamster/ Golden Syrian f 200 0 alr/vapor all sites mammary gland stomach hcounglosarcoou carcinoma adenoma 13/88* 28/87* 23/88* 200 12 200 10 air/vapor alr/vapor all sites mammary gland stomach all sites amonary gland stomach hemanglosarcoma carcinoma adenoma hemanglosarcoma carclnoou adenoau 4/52* 31/52* 3/50e I 2/103 47/102* 20/101* l0 HA air only all sites mammary gland stomach heounglosarcoma carclnoou adenoma 0/143 0/143 5/138 VAB.0001129441 10/17/85 TAB!I 5*8 (coot.) P 0707p Spelts/ Strain Sex Dos* or I ipserec (PP*) leritlen of Treatment (months) Bur*lton of Study (Months| Vehicle or Physical Stale Target Organ Tumor Type Tunor Incidence Hns*/ B5C3M Mouse/ 08C3F1 Rnsi/ Swiss F F F 18 air/vapor all sites ry gland heamnglosarcoma carcinoma 45/57* 29/57** 12 16 air/vapor all sites hemanglosarc manmary gland carcinoma 49/90** 37/90** 24 air only all sites hemanglosarc mammary gland carcinoma 4/49 3/49 IB atr/vapor all sites hemanglosarc ***** gland carcinoma lung carcinoma 29/57** 33/57** 1B/55** 12 air/vapor all sites hemanglosarc 30/47** mammary gland lung carcinoma carcinoma 22/47** 15/47** air only all sites maunary gland lung hemanglosarcoma carcinoma carcinoma 1/71* 2/71* 9/71* -48- 10/10/85 Strengths of Stody Meekness of Study Overall Adequacy: ts: The chloroetheno teas adnlnlstered at a maximum tolerated dese. Several species of rodents blstepathelegtcal examlnot lens mere performed. Statistics were performed. Complete Only female animals ware tested. Adequate o Additional tests By these authors showed 11 was started after 12 months of non-exposure no carcinogenic effect In rats and hamsters If chloroethene *Soorce: Brew et al., 1903 ^Purity of compound not reported hours/day, 5 days/week *P<0.01 (life table analysis) *p<0.05 (life table analysis) HA - Hot applicable VAB.0001129442 h response occurred. In rats exposed for 6 months during the Interval 12-18 months or 18-24 months, no carcinogenic effect was evident. Rats exposed for 12 months during months 0-12 developed Increased Incidences of liver and mammary tumors while those treated during months 12-24 showed no carcino genic effect. In hamsters, hemanglosarcomas, mammary gland carcinomas and stomach adenomas were Increased among animals treated early In their lifetime (see Table 5-8). Hamsters treated for 6 or 12 months during the Interval 12-24 months showed little evidence of a carcinogenic effect. In mice, hemangl osar coma, primarily of the peritoneum or dermis, and mammary gland carcinoma developed In both strains during all treatment Intervals and durations, but the highest Incidences occurred when treatment was during the Initial 12 months of the study (see Table 5-8). Swiss mice also developed an Increased Incidence of lung carcinoma following chloroethene Inhalation exposure. This study (Drew et al., 1983) provides strong evidence that exposure to chloroethene early In life leads to a greater carcinogenic risk. Walton1 et al. (1983) and Cottl et al. (1983) treated rats with chloro ethene by Inhalation at 2500 ppm (6391 mg/m*) 4-7 hours/day, 5 days/week from day 12 of gestation and after birth until offspring were 1 year of age. Liver angiosarcoma developed In 32/56 males and 38/55 females, having an average latency period of -50 weeks. Lung metastases .occurred In -40% of the rats with liver angiosarcoma. Brain tumors (medulloeplthelloma, medulloblastoma and neuroblastoma) developed In 27/57 males and 26/57 females with an average latency of -48 weeks. An oral carcinogenicity study of chloroethene was conducted by Feron et al. (1981) using male and female Wlstar rats (n60-80/sex). Chloroethene exposure resulted from the addition of PVC powder with a high chloroethene A 0707p 10/17/85 VAB.0001129443 content In the diet or by gastric Intubation of chloroethene In soybean oil. Doses from PVC-contalnlng diets were 0, 1.8, 5.6, and 17.0 mg chloroethene/kg/day; Intubation at 300 mg/kg/day was given on 5 days/week. Rats were treated for their lifetime. Mortality of rats treated at "300 mg/kg/day reached -40% by 18 months; most rats that died had severe lesions of the lungs and liver, so that treatment was discontinued at 84 weeks. A doserelated Increase In nonneoplastic hepatic lesions and neoplastic changes In the liver and lungs were reported (Table 5-9). These data suggest that w hepatic angiosarcomas develop at high dose levels while hepatocellular car cinoma occurs at doses as low as 1.8 mg/kg/day. The Dow Chemical Company (1984) conducted a long-term carcinogenicity study of chloroethene administered as PVC In the diet of Wlstar rats. Dietary levels were established to give doses of 0.0, 0.014, 0.13 and 1.3 mg chloroethene/kg bw/day and were administered for up to 149 weeks (lifespan). The high-dose group consisted of 50 rats of each sex while all other groups contained 100 animals of each sex. Additional groups of 10 animals of each sex were maintained on the treated diets for interim sacrifices at 9 and 18 months. General health, body weights and food consumption were not affected by chloroethene treatment while mortality In the high-dose group was slightly Increased. Clinical chemistry parameters were not affected. ft Hlstopathologlcal examination of the liver showed an Increased Incidence of liver nodules and preneoplastic foci among males and females Ingesting 1.3 mg chloroethene/kg/day and among female rats treated at 0.13 and 0.014 mg/kg/day (Section 5.5.). Female rats exposed at 1.3 mg/kg/day had an Increased Incidence (9/49) of hepatic neoplastic nodule compared to controls (0/98). No other carcinogenic effects were reported. 0707p # -50- 10/17/85 -51- 10/10/85 0707p I KpOSWrC RmU Oral (gavage) Sex F Oral WotI F Oral (gavage) Oral (diet) R R test ir iipoturo^ (ag/kg/day) 11.0 S.I 1.0 O.B 300* 17.0 Deration of IrNtamt (weeks! B4 143 143 143 04 143 TABLE 5-9 Chloroetheoe* Vehicle or Physical Slate soybean oil PVC PVC PVC untreated diet only soybean oil PVC Target Organ liver long liver long liver long liver long liver long liver long liver long Tuaor Type neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa neoplastic nodule hepatocellular carclnoaa anglosarcoaa anglosarcoaa Tuaor Incidence (p value! 2/54 0/S4 29/54 23/54 44/57 (1X0.001 ) 29/57 (p<0.001) 9/57 (p<0.001|* 5/57 (p<0.05)e 39/59 (p<0.001) 19/59 (p<0.001)* 2/59 3/59 26/50 (p<0.01)* 4/58 0/50 0/58 2/57 2/57 0/57 0/57 3/55 1/55 21/ii 19/55 23/59 (p<0.001>* 8/59 (p<0.001)* 27/59 <p<0.001)* 19/59 (p<0.01)* VAB.0001129445 1 TABU 5-1 (coni.) 0707p -5 2 - 10/10/85 Iipotwi Root* SOK Bos* or txpesure* (ag/kg/day) duration of Treatment (nooks) Vehicle or Physical State Target Organ Tuoor Type Tunor Incidence (p value) Oral Idiot) (coot.) H 5.0 153 153 4 PVC PVC untreated diet only < liver Tung liver lung liver lung neoplastic nodule hepatocellular carclnoM angl osar com angl osarcom neoplastic nodule hepatocellular carclnoM anglosarcoM angl osarcom neoplastic nodule hepatocellular carclnoM anglosarcoM anglosarcoM 7/55 (p<0.01)e 2/55 (p<0.01J* 5/55 (p<0.05)e 7/55 1/58 1/58 0/58 0/58 0/55 0/55 0/55 0/55 QUALITY Of EVIPfBCI Strengths of Study: The dose of cbloroetheee uas dotorntnod following gastrointestinal digestion of PVC- containing diet. Treatnent was for the IlfotlM of the rats. Several dose levels wore adnlnlstorod. A largo nunher of rats of both sexes were used in each Noakness of Study: Overall Adeguacy: Ho control group for rats treated By gavage was Included Adequate ^Source: Foron ot al., 1901 duration of study was 153 weeks cPurity of conpeund was not reported *Qesage given 5 days/woek *Cunpared with controls using chi-square HA Hot applicable VAB.0001129446 Mai ton1 et al. (1980, 1981) and Rice (1981) reported that rats exposed In utero to chloroethene on days 12-18 of development had an Increased Incidence of Zymbal gland carcinoma, nephroblastoma and subcutaneous angio sarcoma than expected. Pregnant Sprague-Dawley rats (n-19) were exposed at 6000 and 10,000 ppm (15,337 and 25,562 mg/m*) for 4 hours/day on days 12-18 of gestation and the progeny were observed for 115 weeks. A total of 86 p> ogeny resulted, 54 exposed at 10,000 ppm and 32 at 6000 ppm. Three Zymbal gland carcinomas, 1 nephroblastoma and 2 angiosarcomas occurred among the high-dose progeny, while 1 Zymbal gland carcinoma and 2 angiosarcomas developed among the low dose rats. In humans, the carcinogenicity of chloroethene has been demonstrated in several reports, causing angiosarcoma of the liver and some evidence of Increased brain, lung and circulatory system cancers among occupationally exposed workers. According to the International Agency for Research on Cancer (IARC, 1982) the epidemiological data provide "sufficient" evidence to classify chloroethene as a Group 1 (human carcinogen) chemical. Reviews of the epidemiological evidence on chloroethene have been conducted by IARC (1979), Wagoner et al. (1980), U.S. EPA (1980, 1983a), Tamburro (1984) and Kalmaz and Kalmaz (1984). Oue to the number of epidemiological reports summarized In these reviews and the number of case reports (Creech and Johnson, 1974; Evans et al. 1983; Dow Chemical Company, 1983) of angio sarcoma and carcinoma of the liver, this document presents select data which provide sufficient data for the assessment of human cancer risk. In a retrospective study of 161 deaths among chloroethene workers, Monson et al. (1974) reported 8 cases of hepatic and biliary cancer (8 angiosarcomas) while only 0.7 were expected (relative risk * 11.4) (Table 5-10). In addition, 5 cases of brain cancer, 13 cases of lung cancer, 13 digestive tract cancers and 5 hematopoietic system cancers were Identified, 0707p -53- 10/17/85 0707p TABLE 5-10 Bioassay Data for Humans Occupationally Exposed to Ch1oroethenea*b -5 4 - 10/17/85 Size of Exposed Population 161 Size of Control Population Sex 161 H 4 Target Organ liver and biliary tract brain lung digestive lymphatic and hematopoietic system Tumor Type cancer cancer cancer cancer cancer Number of Cases Observed Number of Cases Expected 8 0.7 5 1.2 13 7.9 13 8.3 5 3.4 Relative Risk 11.4 4.2 1.6 1.6 1.5 QUALITY Of EV10ENCE Strengths of Study: Deaths In a chloroethene-exposed population were compared with a comparable age/time/ cause-specific reference population. The Incidence of several causes of death were examined. Weakness of Study: The levels of exposure and duration of exposure are not reported. No statistics are reported. Overall Adequacy: Adequate i ^Source: Nonson et al., 1974 ^Level and duration of exposure not reported NR - Not reported VA^OOOl129448 * /--v 0707p -5 6 - 10/17/85 TABU 5-11 Bioassay Data for Huaans Occupationally Exposed to Chloroethenea>b Size of Size of Duration E xposed Control Sex of Target Organ Population Population Exposure Tumor Type Number of Cases Observed*) Number of Cases Expected Relative Risk (p value) 1287 U.S. death H,F >5 years liver and cancer rates " biliary tract brain and CNS cancer lymphatic and hematopoietic respiratory system . cancer cancer 7 3 3 11 0.4 17.5 (p<0.01) 0.6 5.0 (p<0.05) 1.7 1.8 (NS) 5.7 1.9 (p<0.05) QUALITY Of EVIDENCE Strengths of Study: Tumor Incidences were analyzed on the basis of latency period. Statistical analyses of different types of cancer compared to expected values were performed. The study was of workers with >5 years exposure. Meekness of Study: Levels of exposure were not available. Overall Adequacy: Adequate ^Source: Maxweller et a1. 1976 ^Level of exposure not reported incidence of tumors after 15-year latency NS > Not significant j VAB.0001129449 > * 07O7p -57- Size of Expose* Population 750 Size of Control Popeletloo 1888 Sne*tsb population IABLE 5-12 Oleassay Bata for Munans Occupationally Expose* to Chloroethene* Level of Exposure porto*1ca11y up to 15.000 BuratIon of Exposure >10 years <1 to >10 years <1 to >10 years Target Organ liver/ pancreas brain lung Tenor Type cancer cancer cancer Hunter of Cases Observe* 4 2 3 Hunter of Cases E xpec ted 0.88 0.33 1.70 Relative Risk (p value) 5.8 (p-0.005) 8.1 (p-0.043) 1.7 (p0.28) Strengths of Study Meekness of Stu*y Overall Adegoacy: The expose* population was cenpare* to the Swedish population lengths of exposure. Statistics were couplie* to show slonlflcai o Specific levels of exposure are not reporte*. A relatively snail Adeguate `Source: Byron ot al.. 1878 Incidence of liver tuners ases In tenor incidences. was reported based on r of cancer deaths was exawtned I 10/17/85 I VAB.0001129450 lAtll 5-13 Itoassay isU for Hunans Occupationally Exposed to Chloroethene* Site of IipuM Population Slit tf Control Population level of Exposure (ppa) duration of Exposure Torfet Orpen Timor Type Nwbcr of Coses Observed Umber of Cases Expected Relative Risk 7409 death rates for Itfland and Moles <25 lo >200 0-20 years liver cancer 4 1.04 2.44 i OI D ITT Of IVIREMCE Strenftbs of Study Levels er exposure of workers were est lusted frou alr-sauple ueterlnf. Ourat ton of exposure was reported population was coopered to death rates {based on age groups) of Infland and Males. The exposed Meekness of Study few deaths were reported. He statistics were reported Overall Adequacy: l tutted `Source: fox and Collier, 197? M /1 7/85 VAB.0001129451 a1 Nakamura (1983) conducted a retrospective mortality study of Japanese workers from 25 plants producing chloroethene and/or PVC between 1950-1975. A group of 4524 males having at least 1 year exposure before December 31. 1964 were Identified. A total of 209 deaths were confirmed and all death certificates obtained while the fate of 29 workers was unknown. The cohort was separated into "PVC workers" and "other workers". Among the PVC workers the number of deaths due to malignant neoplasms was significantly Increased (37 observed vs 26.9 expected; p<0.05). Deaths due to liver cancer were also significantly Increased (6 cases vs 2.54 expected; p<0.05) while deaths due to other cancers were not significantly different from expected (Table 5-14). There was no Increase In deaths due to cancer In general or specific sites among the "other workers" group. A retrospective mortality study of 454 male workers exposed to chloro ethene during Its production and polymerization to PVC was conducted by Heldaas et al. (1984). The cohort consisted of men working for at least 1 year during 1950-1969 and the group was followed during 1953-1979. A total of 23 cancer deaths were observed (20.2 expected) with 1 case of liver angiosarcoma. 5 lung cancers (2.8 expected). 3 colon cancers (1.4 expected). 2 thyroid cancers (0.16 expected) and 4 malignant melanomas of the skin (0.8 expected) (Table 5-15). In addition, two cases of malignant melanoma were diagnosed after the termination date and were not Included. The authors (Heldaas et al.t 1984) noted that "the Increased Incidence of cancer Is accounted for almost entirely by the high exposure group" when workers were grouped by exposure depending on job classification. The authors also noted that this study Is consistent with others In that It shows an increased risk of cancer at several sites among chloroethene exposed workers. The high level of malignant melanoma among this group of workers Is unique and warrants further attention. A 0707p 10/17/85 VAB.0001129452 Btoassay Data for Huwns TABLE 5-14 Size of Site of Duration Exposed Control Sex of Population Population Exposure Target Organ Tunor Type Number of Cases Observed Number of Cases Expected Relative Risk (p value) 4524 Japanese Mortality rates >1 year all sites liver llgnant neoplasm cancer 37 6 26.94 2.54 1.37 (p<0.05) 2.36 (p<0.05) 0I4 I ALITY Of EVIDENCE Strengths of Study A large group of workers having at least 1 year of exposure and 10 years latency was studied. Death certificates were obtained for a majority of deceased employees. Weakness of Study Exposure levels were not determined, limited data on diagnosis and cause of death available from death certificate* nr*wnt*i --------- Overall Adequacy: Adequate C nts: were for PVC-workers workers showed aSource: Nakamara, 1983 blevel of exposure not significant F -i a VAB.0001129453 0707p . -61- V TASli 5-15 Oloassay Rata for Humus Occupationally Exposed to Chloroethene* Slit of Exposed Population siio r Control Nfililtm level of duration Son Exposure of Exposora Target Organ Tunor Typo Noobor of Cases Observed Nuuber of Cases ixpected Relative Risk Norway Cancer Mortality Records M varies over years* > >1 year all sites liver lung colon tbyrold skin cancer anglosarcowa cancer cancer cancer nelaneea 20.2 NR ?.o 1.4 0.16 0.8 1.1 NA 1.8 2.1 12.5 5.0 QUALITY Of iviomci ( Stroogtbs of Stody: The cobort consisted of workers exposed for at least 1 year Having a win lows of 10 years latency estlaated. Meekness of Stody: Ike sal11 wanker of cancer deetks prevents a definitive conclusion. Overall Adeguacy: Adeguate Exposure levels were * HA Mot applicable; MR Mot reported i 10/17/85 1 VAB.0001129454 ) 077P Assay Reverse eolation TAIL! 5-14 SMry of Mutagenicity Data on Chloroemono Indicator/ Organism tvnhlmurlum Application ConeenlratIon or Oose eery M# vapor 111x75 alnutes very high 11fold nodIon 4 very Mft vapor M.M vapor HR 200 for 90 Inotes 0. 0.2, 2.0. 201 In air fl.W Ml Ml llfold medium 0.003 R vapor 11fold medium 0. O.a. 1.2, 4.0, 9.4, 115.4ft In air 0.0105 N Ml >99.9K >99.90 >99.9)1 vapor plate Incorporation 11fold medium 200 vapor Ml OR vapor 20x15 hours Activating Sysl Response C nt Reference f /- /- - p / * /- * Oo mutagenic activity with Raneug et al., out metabolic activation; 1974 OADP necessary; tested In 1A1535 i k - Negative In IA153S Rannug et al., 1974 - negative In TA1535, TA1537, Rannug et al.. TA1530 (frameshlft) 1974 Mutagenic In TA1530, TA1535, artsch et al., 6-45 with or without meta 1975, 1979; bolic activation from rat, artsch and noose or human liver Hontesano, i960 - Oo mutagenic effect In 1A1530, TA153S or 6-45 artsch et al., 1975, 1979 t Tested In strain TA1535 for Andrews et al., base-pair substitutions 1974 - Chloroethene was negative Elmore et al., in TA100 while several 1974 netabolltes were positive Positive In TA100 Simmon, 1975 - Tested In strain TA1530 Poncelet et al.. 1980 - Tested In strain TA1530 Poncelet 1 et al., 1980 Positive In strain TA1530 Poncelet with and without metabolic et al., 19B0; activation DeUeester et al.. 1900 -63- 09/17/85 VAB.0001129455 98/U/Ol -fr9- ALQLQ Assay Indicator/ Orfiatsa Rec-repair laclllos Sum Coapowd md/or Portly Application plate-disc 0.010A N forward tatIon Rever so tall Rover so tattoo forward tattoo Escherichia 2l........ l- iSll SptcA*rooB>cf| Schlzo- iKtHruRtH >n.n >99.9x H.m It40Id nodi 10.a m I looId Medina 10.A ON liquid aodtoo 0.275 and 0.S5X lloold aodtoo 1A. 32, 40 rtt ln forward Mutation Recessive lethal Recessive lethal MGPRT Meurosnora crassa 9iem*\ H Melanooaster h 1* tlanonastor 99.9X >99.HX 4 99.995X vapor and ethanol solution vapor vapor CNO MR vapor ?S and SOX 30-50,000 ppo >2-1? days 1-20% In air for 3 Hours MR Cell trans ferMat ton Cell trans ferMat ton forward nutation neonatal hauster kidney cells neonatal haMSter kidney cells Chinese banster cells - V79 NR NR 99.9X Itguld MOdtUM 0.025-250 wg/nk vapor 10-SOX vapor S-30X mm Mo growth Inhibition with repair-deftclent strains 1A8M, Her-5, fR-13, HC-1. Metabolites of chloroethene were autogenic flMore et al., 197b Strain K-12, Metabolic GrelM et al., activation necessary; HTR 1975 resistance Strain K-12 for gal*, arg*, nad* OrelM et al., 1975 No autagenlc effect In strain 05 Shahtn, 1976 Mutagenic only with Loprleno, 1977 Metabolic activation; Metabolites active with or without activation Conldla were exposed for 3.5 or 24 hours: strain nlc-1 Drozdowtcz and Huang, 1977 Increased recesstve-lethals Verburgt and after 850 ppM for 2 days or Vogel, 1977 30 ppM for 17 days Increased recessive lethal Magnusson and Mutations following treat- Ranel, 1978 Ment at all levels Mutagenic only with Metabolic activation Krahn, 1979; Krahn et al., 1982 No Increase In transforned cells Styles, 1977 5-fold Increase In trans- Styles, 1977 forMed cells 8-araguenlne and ouabain Orevon and resistance Induced Kurofcl, 19^AB.0001129456 absence of metabolic activation (see Table 5-16). Hetabolltes of chloroethene, chloroethylene oxide and chloroacetaldehyde, were very active In the absence of metabolic activation. Grelm et al. (1975) reported that chloroethene was positive In a forward mutation assay (resistance to 5-methyl-DLtryptophane) and In reverse mutation systems (gal*, arg , nad ) using Escherichia coll strain K-12 only when a metabolic activation system was provided. In the yeasts, Schlzosaccharomvces pombe and Saccharomvces cerevlslae. forward mutations and mitotic gene conversions, respectively, were Induced by chloroethene exposure only when a metabolic activation system was provided (loprleno, 1977). In a mutagenicity assay for forward mutations In Neurosoora crasso, exposure to chloroethene by vapor or In ethanol 1c liquid medium was not positive with or without metabolic activa tion (Drozdowlcz and Huong, 1977). Chloroethene vapors caused an Increased frequency of recessive lethal mutations In Drosophila melanogaster. but no increase In dominant lethal mutations, translocations or sex-chromosome loss (Verburgt and Vogel, 1977; Magnusson and Ramel, 1978). Chloroethene vapors were mutagenic and effec tive In transforming mammalian cells In, vitro with metabolic activation (Krahn, 1979; Krahn et al., 1982; Sytles, 1977; Drevon and Kurokl, 1979). In liquid medium, however, chloroethene did not Increase the transformation of neonatal hamster kidney cells In culture (Styles, 1977). The dominant-lethal assay using male CD-I mice has been used to test the mutagenic potential of chloroethene In vivo. Two studies (Anderson et al., 1977; Hlmeno et al., 1983) have reported no Increase In post-lmplantatlonal fetal deaths after adult male mice were exposed by Inhalation prior to mating (see Table 5-16). In the In vivo exposure assay for mlcronuclel In erythrocytes, two studies (Jenssen and Ramel, 1980; Richardson et al., 1983) 07Q7p -66- 10/17/85 VAB.0001129457 have reported positive effects In mice exposed by Inhalation at 50,000 ppm (127,812 mg/m*) for 4-6 hours. An Increase In chromosomal and chromatid damage In bone marrow cells has been. reported In male rats (Anderson and Richardson, 1981) and Chinese hamsters (Basler and Roehrborn, 1980) exposed to chloroethene by Inhalation. Evidence of mutagenicity In humans occupationally exposed to chloro ethene has been reviewed by Hopkins (1980). A number of the available studies reported that chloroethene caused lymphocyte chromosomal aberrations among exposed workers; Flelg and Thless, 1978; Kucerova et al., 1979; Hansteen et al., 1978) (see Table 5-16). Although some of the positive studies are limited by small sample sizes, taken collectively they support the conclusion that chloroethene Is mutagenic to humans following occupa tional exposure. 5.3. TERATOGENICITY The effects of chloroethene on embryonal and fetal development following maternal Inhalation were determined by John et al. (1977, 1981). Groups of 30-40 female CF-1 mice were exposed to 0, 50 and 500 ppm (0, 126 and 1278 A mg/m*), 7 hours/day on days 6-15 of gestation. Pregnant Sprague-Dawley rats (n*20-35/group) and New Zealand rabbits (n-15-20/group) were exposed at 0, 500 and 2500 ppm (0, 1278 and 6391 mg/m*) chloroethene for 7 hours/day on days 6-15 (rats) or 6-18 of gestation (rabbits). Females were observed for signs of maternal toxicity and body weights monitored during the study. Animals were sacrificed on days 18 (mice), 21 (rats) or 29 (rabbits) of gestation and uteri examined for live, dead and resorbed fetuses. Fetuses were weighed, measured and examined for external. Internal and skeletal anomalies. Female mice exposed at 500 ppm had decreased weight gain and food consumption; mortality was 5/29. No toxic effects were observed in the 0707p 10/17/85 VAB.0001129458 A rat or rabbit dams. Among mice exposed at 500 ppm (1278 mg/m3), fetal resorptions were Increased, litter size was decreased and fetal body weights were reduced. Fetal crown-rump length was greater among mice exposed at 50 ppm (128 mg/m) than among controls. In rats, one death (1-/17) occurred among dams exposed at 2500 ppm (6391 mg/m*). There was no effect on litter size. Implantations or resorptions among rats exposed at either level. Fetal body weight was decreased among rats exposed at 500 ppm but not among those exposed at 2500 ppm. In rabbits a decreased number of live fetuses/litter was observed among those exposed at 500 ppm but not among the 2500 ppm exposure group. No effects on fetal body weight or length among exposed rabbits was observed. Examination for anomalies revealed only delayed ossification of the skull among mice exposed at 500 ppm with no Increase In skeletal or soft tissue anomalies among fetuses of either dose group. Similarly, In rats there was no Increase In skeletal or soft tissue anomalies, but delayed ossification of the skull was evident among fetuses exposed at 2500 ppm. Among rabbits, no treatment-related anomalies were observed. Oelayed ossification of sternebrae occurred more frequently among fetuses exposed at 500 ppm compared to controls, but this trend was not , evident among fetuses exposed at 2500 ppm. The teratogenicity and embryotoxlc effects of chloroethene vapor were determined In CFY rats exposed on days 1-9. 8-14, or 14-21 of gestation (Ungvary et al., 1978). Exposure was at 1565 ppm (4000 mg/m*) continu ously during the treatment period. The group exposed to chloroethene during days 1-9 of gestation was also given physiological saline by subcutaneous Injection on days 7 and 8 as part of another test. On the 21st day of gestation dams were sacrificed and uteri examined for live, dead and resorbed fetuses. Increased fetal loss (p<0.05) was reported among the 19 * 0707p -68- 10/10/85 VAB.0001129459 Utters exposed on days 1-9 of gestation. There was a tendency for Increased fetal loss and resorption among rats exposed on days 8-14 but no similar effect among fetuses exposed during the last week of development. Based on a gross and Internal examination (about half of the live fetuses were dissected) there was no Increase In gross. Internal or skeletal malfor mations among any group of chloroethene-exposed fetuses. These data demon stratematernal toxicity and embryotoxlc effects occurring concomitantly when exposure was during early gestation, but no evidence of a teratogenic effect was demonstrated (Ungvary et al., 1978). In a Bulgarian study available as an English abstract (Mlrkova et al., 1978), continuous Inhalation exposure to chloroethene at 2.4 ppm (6.15 mg/m*) In rats for 21 days of pregnancy resulted In early postlmplantatlonal resorptions. Delayed skeletal ossification, decreased fetal weight, frequent hematomas, hydrocephaly (54.4% of fetuses) and encephalocoele (2.53% of fetuses) were also reported. Among neonates, signs of toxic hepatopathy were reported. In a Russian study available as an English Pr abstract (Sal'nikova and Kltsovskaya, 1980), rats were exposed to chloro ethene at 1.9 ppm (4.8 mg/m*) or 14 ppm (35.5 mg/m*) for 4 hours/day during the entire gestational period. Hemorrhages occurred among 49 and 51% of the fetuses exposed at the two dose levels and organ weight changes and hematological changes were reported. No malformations were reported. A study conducted by the National Institute for Occupational Safety and Health examined the rate of fetal loss and other health effects among workers exposed to chloroethene during the production of PVC (Uaxweller et al., 1977). The results of a questionnaire as to outcomes of pregnancies * were analyzed by age of father at the time of conception, and before or after exposure at the plant. A total of 148 pregnancies occurred prior to 0707p 10/17/85 VAB. * exposure and 139 occurred after exposure to chloroethene. In comparison 159 and 273 pregnancies occurred among the reference control group (rubber workers not exposed to chloroethene) before and after their employment. The percent of fetal loss was 6.1 and 6.9% for chloroethene-exposed and control groups, respectively before exposure. After exposure, however, there was a significant (p<0.05) Increase In fetal loss among women whose husbands were exposed to chloroethene. Fetal loss was 15.8% and 8.8%, respectively among exposed and control groups with the age group, 25-29 years showing a larger m Increase (22.9% vs. 3.4% In controls). The Incidence of anencephaly, spina bifida and hydrocephalus among Infants born to parents residing In the area of a PVC plant led Edmonds et al. (1978) to conduct a case-control study to examine the possible correla tion between chloroethene exposure and the malformations. Based on an analysis of parental occupation and residence with respect to the plant, no relationship could be established between the cases of CNS malformations and exposure to chloroethene. Th'erlault et al. (1983) examined the possible association between a high Incidence of birth defects among Infants born to residents of a town that had a potential exposure to chloroethene due to the presence of a vinyl chloride polymerization plant. The occurrence of defects appeared to fluctuate seasonally as did environmental chloroethene levels. Mothers of children with birth defects appeared to be younger than those In comparable communities. An analysis of occupation and residence of the parents did not show an association between birth defects and exposure to chloroethene. 5.4. OTHER REPRODUCTIVE EFFECTS Anderson et al. (1977) conducted a dominant lethal assay of chloroethene using CD-I male mice and examined their fertility after exposure. Exposure 0707p 10/17/85 VAB.0001129461 was at 3000, 10,000 and 30,000 ppm (7669, 25,562 and 76,687 mg/m*) on 6 hours/day for 5 days. Males were mated for 8 weeks after treatment. The number of mated females that became pregnant was comparable between all dose groups and controls throughout the 8-week mating period. 5.5. CHRONIC TOXICITY A 12-month Inhalation toxicity study of chloroethene was conducted by Lee ?t al. (1977a) using C0-1 mice and CD rats. Groups of 36 animals of each sex and species were exposed at 0, 50, 250 or 1000 ppm (0, 128, 639 or 2556 mg/m*) for 6 hours/day, 5 days/week. Interim sacrifices of 4 animals per sex, species and exposure level were scheduled at 1, 2, 3, 6 and 9 months with the remaining survivors sacrificed at 12 months. Food consump tion, body weight, hematological and clinical chemistry determinations were made throughout the study. When moribund or at scheduled sacrifice intervals, animals were killed and necropsled for examination of all major organs. Tumors, abnormal growths and other lesions were prepared and examined microscopically. Tumors developed at an Increased Incidence among male and female mice exposed to all levels of chloroethene compared to controls (see Table 5-4, Section 5.1.). Mice exposed to 50 ppm also showed some toxic effects (rough hair coat, weight loss, lethargy, anorexia) and unscheduled deaths (occurring between the 6th and 12th month), which may or may not have been tumor-induced. Other toxic effects (non-neoplastlc) among mice exposed to 50 ppm were not reported. In rats, an Increased Incidence of tumors occurred only In groups exposed to 250 and 1000 ppm (see Table 5-4). Two females exposed to 50 ppm died during the study (due to apparent toxic effects (lethargy, weight loss, lost muscular tone). No other toxic effects or changes In clinical chemistry or hematology occurred among the rats exposed at 50 ppm chloroethene. A 0707p 10/10/85 VAB.0001129462 In a three-part chronic Inhalation toxicity study of chloroethene, Feron and coworkers (Feron et al., 1979a,b; Feron and Kroes, 1979) exposed Wlstar rats to 5000 ppm (12,781 mg/m) 7 hours/day, 5 days/week for 52 weeks. Toxic effects observed during the exposure period Included slightly reduced growth rate, Increased serum potassium levels. Increased blood urea nitro gen, slight anemia, slightly shortened blood clotting time and Increased mortality. At necropsy, kidney, heart and spleen weights were Increased. Hepatic changes, tubular nephrosis, focal degeneration of the heart and Increased hematopoietic activity of the spleen were observed histologically. Hepatic morphological changes Included degenerative, hyperplastic and neoplastic (hepatocellular carcinoma and angiosarcoma) lesions. Viola (1970) conducted a 12-month Inhalation study of chloroethene at 0 or 30,000 ppm (76,687 mg/m*) In male Wlstar rats. Groups of 25 animals were exposed for 4 hours/day on 5 days/week for the 12-month period. Histo logical examinations after sacrifice were performed on the brain, liver, kidneys, thyroid and paws of the rats. Diffuse degeneration of the grey and white matter of the cerebrum and cerebellum atrophy were observed In the h exposed rats. Hepatic changes Included diffuse Interstitial Inflammation, proliferation (hypertrophy) of Kupffer's cells and partial necrosis. Tubulonephrosls and chronic Interstitial nephritis were characterized In the kidneys. The thyroid had an Increase In parafollicular cells. Effects noted upon examination of the paws Included metaplasia of the metatarsal bones, chondrold metaplasia, epidermal hyperkeratosis, basal layer vacuoli zation and degeneration, and general epidermal edema. No similar abnormali ties were observed In the visceral organs, skeletal elements or skin In control group animals. 0707p -72- 10/17/85 Chronic Inhalation toxicity studies of chloroethene at levels of 50-500 ppm (128-1278 mg/m*) have been conducted by Torkelson et al. (1961) In rats, rabbits, guinea pigs and dogs. In the first experiment a group of 10 rats of each sex were exposed to 500 ppm chloroethene (1278 mg/m) for 7 hours/day on 5 days/week for 4.5 months. Controls consisted of five rats of each sex. Exposure at 500 ppm (1278 mg/m*) resulted In Increased average liver weights In both sexes (significant, p*0.001, only In males), centrllobular granular degeneration In the liver and tubular and Interstitial changes In the kidney of treated rats. A second experiment was conducted using rats (20-24 of each sex/group), guinea pigs (10 males, 8 females/ group), rabbits (3/sex/group),guinea pigs (10 males, 8 females/group), rabbits (3/sex/group) and dogs (1/sex/group) exposed at 100 or 200 ppm chloroethene (256 or 511 mg/m*) for 7 hours/day, 5 days/week for 6 months. Unexposed and air exposed controls were Included. In rats, significantly (p<0.005) Increased liver weights occurred In males and females exposed at both chloroethene levels. In rabbits exposed at 200 ppm (511 mg/m) hepatotoxlc effects were observed with centrllobular granular degeneration in both sexes, necrosis with foamy vacuolization In males and necrosis with periportal cellular Infiltration In females. In a third experiment, rats (24/sex), guinea pigs (12/sex), rabbits (3/sex) and. dogs (1/sex) were exposed to 50 ppm (128 mg/rn*) for 7 hours/day, 5 days/week for 6 months. Additional groups of male rats (nl0/group) were exposed at 50 ppm for 1, 2 or 4 hours/day, 5 days/week for 6 months. Exposure at 50 ppm had no appar ent toxic effects on any species In regard to mortality, growth and gross or microscopic organ examination compared to unexposed or air exposed controls. Lee et al. (1978) and Hong et al. (1981) conducted a bioassay of chloro ethene In C0-1 mice and CO rats exposed by Inhalation at 0, 50, 250 or 1000 0707p -73- 10/17/85 ppm (0, 128, 639 or 2556 mg/m*) for 6 hours/day, 5 days/week for 1, 3 or 6 months (mice) or 1, 3, 6 or 10 months (rats). Following exposure all groups were subsequently maintained for a 12-month observation period. Groups consisted of 8-28 mice of each sex, and 4-16 rats of each sex per duration and exposure level. In mice the mortality rate was Increased for all duration and exposure level groups. Mortality among mice exposed at 250 and 1000 ppm (639 and 2556 mg/m*) was correlated with the cumulative tumor Incidence (see Table 5-5) while no Increased Incidence of tumors occurred among mice exposed at 50 ppm (128 mg/m*). Mortality among the low-dose group (15/16 for those exposed for 6 months vs. 11/56 In controls) was therefore regarded as a toxic effect. The mortality rate for males and females combined In the control group and the 50 ppm group exposed for 10 months was 13/32 and 17/26, respectively. The chronic toxicity of chloroethene Inhaled at 0, SO, 500 and 20,000 ppm (0, 128, 1278 and 51,125 mg/m*), 5 hours/day, 5 days/week for 10 months was studied by Sokal et al. (1980) using male Ulstar rats (85/group). Exposure at all chloroethene levels resulted In toxic effects which Included decreased body weight. Increased relative organ weights (heart, spleen, kidney, and liver), slight changes In blood chemistry and morphological changes In the liver and testes. Specifically among rats exposed at 50 ppm, heart and spleen weights were Increased and nuclear polymorphism of hepatocytes was slightly Increased. The toxic effects of chronic chloroethene Inhalation on the liver were examined by Ulsnlewska-ICnypl et al. (1980) using male Ulstar rats. Groups of 35-40 animals were exposed at 0, 50, 500 or 20,000 ppm (0, 128, 1278 or 51,125 mg/m*) chloroethene for 5 hours/day, 5 days/week for up to 10 months. Interim kills of 7-10 animals/exposure group were conducted at 1, 3 and 6 months. In rats exposed at 500 and 20,000 ppm, liver enlargement was 0707p -74- 10/17/85 evident with decreased microsomal cytochrome p-450 content within 3 months * of exposure. Electron microscopic examination revealed concurrent hepato cellular changes ranging from smooth endoplasmic reticular proliferation In rats exposed at 50 ppm (128 mg/m*) to hypertrophic smooth endoplasmic s reticulum, swelled mitochondria. Increased lipid droplets and cytoplasmic degradation following exposure at 20,000 ppm (51,125 mg/m*). The nonneoplastic effects of chronic chloroethene Inhalation on the lung were examined In mice exposed at 2500 and 6000 ppm (6391 and 15,337 mg/m), 5 hours/day, 5 days/week for 5 and 6 months (Suzuki, 1980). Toxic effects seen In both dose groups Included bronchlolar epithelial prolifera tion and hypertrophy and hyperplastic alveolar epithelium (which also developed Into alveologenlc tumors; Section 5.1.). The chronic toxicity of chloroethene following oral administration was studied by Feron et al. (1975) In male and female Ulstar rats. Chloroethene was dissolved In soybean oil and administered by gavage to groups of 15 males and 15 females at approximate doses of 0, 30, 100 and 300 mg/kg bw on 6 days/week for 13 weeks. 8ehav1or, body weights and food Intake were not affected by chloroethene Ingestion at any dose level. Liver weights showed a dose-related Increasing trend In males and females but were significantly elevated (p<0.05) only In the high-dose group. Adrenal weight In males showed a dose-related decreasing trend. Hyperbasophllla of hepatocytes with ultrastructural changes were seen In the livers of rats exposed at the highdose level. There was, however, no clinical evidence of hepatic damage as determined by liver enzyme assays. The Dow Chemical Company (1984) conducted a 149-week study In which chloroethene was administered to Ulstar rats as dietary powdered PVC forti fied with the monomer. Gastrointestinal digestion apparently liberated 0707p -75- 10/17/85 almost all of the available chloroethene. Dietary levels were established to give doses of 0.0, 0.014, 0.13 and 1.3 mg chloroethene/kg bw/day. In addition, a group of unexposed controls were housed separately from the other test groups. Groups consisted of 100 males and 100 females, except for the high-dose group which contained 50 rats of each sex. Additional groups of 10 rats/sex/dose level were maintained for Interim sacrifices at 9 and 18 months. General health, behavior, body weight and food Intake were not affected by chloroethene exposure at any dose level tested. Mortality was slightly Increased In the high-dose group. No changes In clinical chem istry parameters were reported. Hepatotoxlc effects occurred among males and females exposed at 1.3 mg/kg/day. Liver changes Included hepatocellular polymorphism, hepatic cysts, cellular alterations Including clear cell foci (38/98 In males and females combined vs. 16/197 In controls) and basophilic foci (29/98 vs. 13/197 In controls). Neoplastic nodules (females) and hepatocellular carcinoma (males) were also Increased among high-dose rats. In females, treated at 0.014 and 0.13 mg/kg/day there was also an increased Incidence of basophilic foci of the liver (21/100 and 26/96, respectively, vs. 9/98 In controls). In humans exposed occupationally to chloroethene a number of chronic toxic effects have been reported In addition to the carcinogenic effects (see Section 5.1.). In 1975, Lllls et al. (1975) reviewed some of the toxic effects In human workers exposed to chloroethene during the production of PVC. This review Identified acroosteolysls and scleroderma (bone and skin changes of the phalanges), hepatotoxlclty (hepatomegaly, tenderness and abnormal liver-function tests) and some pulmonary effects that were asso ciated with exposure to chloroethene. Several recent studies (Oestouet and Murphy, 1983; Black et al., 1983) have Indicated that schleroderma and acroosteolysls are recognized toxic effects of chloroethene exposure. 0707p -76- 10/17/85 r-i.1 s Lllls et al. (1975) found that Raynaud's syndrome occurred In -10% of workers with >20 years of exposure. Abnormal peripheral circulation (deter mined by the Allen test) was also found to be associated with length of exposure to chloroethene. Bone changes In the fingers and toes and hepatotoxlc effects were confirmed among a group of 354 PVC workers (Lllls et al.f 1975). Sakabe (1975) reviewed a number of reports on chloroethene-related symptoms among Japanese chloroethene production and PVC-productlon plants. This study confirmed the occurrence of acroosteolysls and Raynaud's syndrome among the Japanese companies. The National Institute of Occupational Safety and Health (Uaxweller et al., 1977) conducted a survey of health effects among chloroethene-exposed workers from a PVC and rubber tire production plant. Based on exposurelevel groupings there was an association between chloroethene exposure and the prevalence of hepatomegaly, CNS abnormalities, high blood pressure and fetal loss by spouses. There was no excess In acroosteolysls, Raynaud's syndrome, respiratory effects or chromosomal aberrations In exposed workers compared to a reference group of Industrial workers. Lee et al. (1977b) detected no Increased Incidence of liver toxic effects or impaired liver function among a group of 422 PVC-productlon workers. Liver biopsies of 15 exposed workers revealed slightly Increased fibrosis compared to 5 control m workers. Tamburro et . al. (1984) conducted a study of liver biopsies among 48 chloroethene workers and 30 nonchemical workers. Twenty-three of the exposed workers had.hepatic lesions, which Included focal hepatocyte hyper plasia (n17), and more advanced mixed hyperplasias (n*6). In comparison, 5 of the reference group had hepatic lesions (4 focal hepatocyte hyperplasia, one mixed hyperplasia with sinusoid dilation). Doss et al. (1984) reported that porphyrinuria occurred among 36 workers exposed to chloroethene; this 0707p -77- 09/17/85 VAB.0001129468 effect may be useful In clinical diagnosis of hepatic damage. Among a group of 200 chloroethene-productlon workers* Langauer-Lewowlcka et al. (1983) reported that 54 had an astheno-autonomlc syndrome and 88 showed the astheno-autonomlc syndrome In addition to other neurological symptoms (pyramidal syndrome, cerebellum dlstrubances and trigeminal neuropathy). Scleroderma and Raynaud's syndrome were also prevalent among the chloroethene production workers. Neurological effects may have been due to direct toxic effects or as a result of vascular deficiency. Lloyd et al. (1984) conducted a case-control study of 265 workers exposed to chloroethene In the production of PVC and found an association between exposure and Impaired lung function. 5.6. OTHER RELEVANT INFORMATION There is a large body of data on the toxic effects of chloroethene following single or short-term exposures, primarily by Inhalation (U.S. EPA, 1980). Many of the studies have been conducted to study the hepatotoxlc effects and Its progression to hepatic carcinogenicity (Drew et al., 1975; Reynolds et al., 1975; Jaeger et al., 1974, 1975; Conolly and Jaeger, 1977; Du et al., 1979; Bolt et al., 1979). In addition, a number of studies have examined the effects of hepatic enzyme Inducers or simultaneous exposure to other toxicants on the acute toxicity of chloroethene (Drew et al., 1975; Reynolds et al., 1975; Jaeger et al., 1974, 1977; Conolly et al., 1978; Pessayre et al., 1979b). Pretreatment with phenobarbltal or ODT appears to Increase the formation of chloroethylene oxide by cytochrome p450 and also Induces epoxide hydrase which Inactivates the formed epoxide. Toxic effects appear to result when epoxide formation rates exceed the glutathione * Inactivation rate and the epoxide binds to liver cell components (proteins, nucleic acids) Including cytochrome p450 (Conolly and Jaeger, 1979; Pessayre 0707p -78- 10/17/85 et al., 1979a). Pessayre et al. (1980) reported that 3-day exposures to chloroethene resulted In decreased cytochrome p450 concentrations and Increased metabolites Irreversibly bound to liver proteins. In addition to the hepatotoxlc effects associated with acute chloro ethene exposure. Inhalation exposure to 10,000-20,000 ppm (25,562-51,125 mg/ms) caused decreased circulation and depressed contractlblllty with pulmonary resistance or bronchoconstrlctlon (Avlado and Smith, 1975; Tatral and Ungvary, 1981). A 0707p 0 10/17/85 VAB.0001129470 6. AQUATIC TOXICITY 6.1. ACUTE TOXICITY Few data on the responses of freshwater and marine organisms to chloroethene exposure were available for a comprehensive evaluation of aquatic toxicity. Brown et al. (1977) reported complete mortality of northern pike (Esox luclus) after a 10 day exposure to 388 ppm chloroethene. However, the descriptions of test methods and handling procedures for control and test organisms were Incomplete. No difference could be detected between bacte rial cultures of five bacterial populations and test cultures containing up to 900 mg/ft. Indicating that chloroethene was not toxic to bacteria at these concentrations (Hill et al., 1976). 6.2. CHRONIC STUDIES Samolloff et al. (1980) Investigated the effects of chloroethene on developmental stages of a nematode (Panaorellus redlvlvus) exposed at log concentrations of 0.000625-62.5 ppm. A 96-hour growth cycle was required to complete the development of the four life stages. Successful completion of each experimental growth stage at Individual concentrations of chloroethene was compared to the control population by a 2x4 contingency analysis (Xs test). Over the range of concentrations, the test organisms displayed little variation from the control group (p<0.001), indicating that chloro ethene had little effect on the develomental success of P. redlvlvus at the concentrations tested. 6.3. OTHER RELEVANT INFORMATION Additional Information pertinent to the aquatic toxicity of chloroethene could not be located In the available literature as cited In the Appendix. 0707p t * -80- 10/17/85 7.1. HUNAN 7. EXISTING GUIDELINES AND STANDARDS Chloroethene Is recognized as having carcinogenic potential In humans and has an assigned TLV at 5 ppm (~10 mg/m) (ACGIH, 1985)." The Occupa tional Safety and Health Administration (Code of Federal Regulations, 1981) has reported that no worker may be exposed to chloroethene at >1 ppm over an 8-hour period. A level of 5 ppm was the maximum level for a 15-minute exposure. Direct contact with liquid chloroethene Is prohibited. There are standards for monitoring chloroethene and establishing regulated areas where exposure Is expected. Various respiratory protection apparatus are required for exposures greater than the permissible exposure limits. The NIOSH (1975) reported that the concept of establishing a TLV for chloroethene gas was Inappropriate based on Its carcinogenic effects. The NIOSH, therefore, recommended that workers exposed to any measureable chloroethene should wear an air-supplied respirator. 7.2. AQUATIC Guidelines and standards for the protection of aquatic organisms from the toxic effects of vinyl chloride could not be located In the available literature as cited In the Appendix. 0707p * -81- 10/17/85 8. RISK ASSESSMENT Chloroethene has been recognized as a human and animal carcinogen by the IARC (1974, 1979, 1982) (IARC group 1) and the U.S. EPA (1980. 1984a,b). Unit risk estimates (q,*) for the carcinogenicity of chloroethene have been determined based on the available animal carcinogenesis data following oral and Inhalation exposure (U.S. EPA, 1980, 1984a,b). Epidemiological evidence shows an Increased risk of cancer development among chloroethene* exposed workers but does not provide sufficient exposure and Incidence data to quantify risk based solely on human data. Viola et al. (1971) reported the development of skin carcinoma, lung carcinoma and osteochondroma In rats exposed to chloroethene by Inhalation to 30,000 ppm (76,687 mg/m), 4 hours/day, 5 days/week for 12 months (see Table 5*1). Mai ton1 et al. (1980) conducted a battery of carcinogenicity tests on chloroethene administered by. Inhalation to rats, mice and hamsters. Inhalation exposure at 10 and 25 ppm (26 and 64 mg/m*), 4 hours/day, 5 days/week for 1 year produced liver angiosarcoma (1/119 and 5/120) and renal nephroblastoma (1/120) (spontaneously rare tumors) In rats, while mice developed liver and lung tumors at 250 ppm (639 mg/m*) (see Table 5-3). Hamsters developed forestomach tumors after Inhaling chloroethene. Lee et al. (1977a, 1978) reported liver hemanglosarcomas and lung adenomas In mice exposed to chloroethene at 50, 250 and 1000 ppm (128, 639 or 2556 mg/m*), 6 hours/day, 5 days/week for 12 months (see Table 5-4). Rats treated on the same regimen developed liver and lung hemangl osar comas at 250 and 1000 ppm (639 and 2556 mg/m*), while no tumors developed after treatment at 50 ppm (128 mg/m*). Hong et al. (1981) reported a low Incidence of liver and lung tumors among mice treated at 50 ppm (128 mg/m*), 6 hours/day, 5 0707p e -82- 10/17/85 days/week for only 1 month. Greater tumor Incidences occurred with longer exposure duration and/or higher exposure levels (see Table 5-5). In rats, liver and lung tumors developed as a result of treatment at 250 and 1000 ppm (639 and 2556 mg/m*), while 50 ppm (128 mg/m*) did not produce hepatic or pulmonary tumors. The Manufacturing Chemists Association (MCA, 1980) sponsored a carcinogenicity bioassay of chloroethene by Inhalation at 50, 200 and 2500 ppm (128, 511 and 6391 mg/m*), 6 hours/day, 5 days/week In rats and mice. In rats exposed for 12 months and observed for their life time, liver angiosarcoma and Zymbal gland tumors developed following treat ment at all levels (see Table 5-7). Mice were exposed for 9 months and observed for their lifetime. Mice developed an Increased Incidence of liver angiosarcoma and lung alveolar adenomas and carcinomas following treatment at all dose levels compared to controls (see Table 5-7). Studies by Hehlr et al. (1981) and Suzuki (1981, 1983) have shown that even brief Inhalation exposures to chloroethene cause the development of liver and lung tumors. Hehlr et al. (1981) reported a dose-related Increase In lung adenomas In mice exposed for a single 1-hour exposure at 50-50,000 ppm (128-127,812 mg/m*) or ten 1-hour exposures at 500 ppm (1278 mg/m*) (see Table 5-6). Suzuki (1981, 1983) reported a dose-related Increase In pulmonary tumors among mice exposed at 1, 10 or 100 ppm (2.6, 26 or 256 rag/m*), 5 hours/day, 5 days/week for 4 weeks. Data reported by Drew et al. (1983) suggest that the carcinogenic effect of chloroethene Is diminished If animals are exposed after aging 12 months coa^ared to young animals (see Table 5-8). This may be an artifact of the latency of tumor development. In addition to the previously noted gavage study of chloroethene conducted by Maltonl (1977b) (see Table 5-2), Feron et al. (1981) and the 0707p -83- 10/17/85 Dow Chemical Company (1984) have conducted oral carcinogenicity studies of chloroethene In which the compound was administered as PVC-contalnlng diets or by gavage. Haltonl (1977b) reported that rats treated with chloroethene In olive oil by gavage at 16.65 or 50 mg/kg/day (5 days/week) for 1 year developed Increased Incidences of liver angiosarcoma and renal nephro blastoma (see Table 5-2). Liver hepatocellular carcinoma and angiosarcoma of the liver and lungs were reported In rats treated at 300 mg/kg/day by gavage or at 17.0, 5.6, or 1.8 mg/kg/day as PVC-contalnlng diet (see Table 5-9) (Feron et al., 1981). The Dow Chemical Company (1984) administered PVC-contalnlng diets to rats so that dose levels were 0.014, 0.13 and 1.3 mg chloroethene/kg/day. Rats treated at the highest dose level developed Increased hepatic neoplastic nodules and preneoplastic foci while most effects were noncarclnogenlc. Monson et al. (1974) reported an 11-fold Increase In hepatic or biliary cancer or both among chloroethene workers compared to expected numbers. In addition, brain cancer, lung cancer, digestive tract cancer and hemato poietic system cancers were Increased among the chloroethene workers (see Table 5-10). Waxweller et al. (1976) reported similar results among another group of chloroethene workers with Increased llver/blllary, brain, respira tory tract and hematopoietic system cancers (see Table 5-11). Byren et al. (1976; see Table 5-1?) reported Increased liver, brain and lung cancer deaths among Swedish chloroethene and PVC-productlon workers. Fox and Collier (1977) reported an Increased Incidence of liver cancer deaths among PVC-productlon workers (see Table 5-13). Among Japanese chloroethene and PVC-productlon workers the total number of cancer deaths and liver cancer deaths were increased (Nakamura, 1983; see Table 5-14). Recently, Heldaas et al. (1984) reported Increases In total cancer deaths, malignant melanoma. 0707p -84- 10/17/85 lung cancer, thyroid cancer and colon cancer among chloroethene and PVC pro duction workers (see Table 5-15). The small number of cancer deaths (n*23) limited a clear exposure-related conclusion, but the authors noted that most cancers occurred among workers categorized as having high exposure. In summary, chloroethene has been shown to be a carcinogen In several species of laboratory rodents producing a high Incidence of liver, kidney, lung, brain and Zymbal gland tumors. A dose-related carcinogenic response has been shown following Inhalation and oral exposure. A similar carcino genic effect has been shown In humans with Increased deaths due to liver, brain, lung and hematopoietic systems among chloroethene-exposed workers. The carcinogenicity unit risk estimate (q.*) for humans exposed to chloro ethene by Ingestion of contaminated water was determined to be 1.74x10'* (mg/kg/day)'1 (U.S. EPA, 1980). This slope parameter was calculated based on the Incidence of total tumors among rats exposed by Inhalation at 50-10,000 ppm (128-25,562 mg/m*) {Maltonl and Lefemlne, 1975). A correction was made for the relationship between Inhalation (ppm) and oral (mg/kg/day) dose levels. The q.* was also corrected by the cube root of the ratio of the body weight of humans to the body weight of rats. The U.S. EPA (1984b) calculated a carcinogenic potency factor (q *) for humans based on the oral Intubation study by Maltonl (1977b). The Incidence of liver angiosarcoma was 0/150, 9/80 and 16/80 among rats treated at 0, 16.5 and 50 mg/kg/day (5 day/week) for 52 weeks (equivalent doses 0, 4.6 and 13.9 mg/kg/day). The q.* was determined to be 1.4096x10~* (mg/kg/day)'1 after the cube root body weight ratio correction was made (U.S. EPA, 1984b). More recent data reviewed In this document have shown carcinogenic effects at dose levels below those previously used for risk estimation and, therefore, would result In more conservative potency estimates of chloro ethene carcinogenicity. Additional studies by Maltonl et al. (1980, 1981) 0707p -85- 10/17/85 tested the carcinogenicity of chloroethene In rats by Inhalation exposure to 1-30,000 ppm (2.6-76,687 mg/m*) for 4 hours/day, 5 days/week for 52 weeks (see Table 5-3). No carcinogenic effects were evident at chloroethene levels of <5 ppm (12.8 mg/m*). At 10 ppm (26 mg/m*) liver angiosarcoma occurred In 1/119 rats and liver angiosarcoma (5/120) and renal nephro blastoma (1/120) occurred at 25 ppm (64 mg/m). The dose-response data for liver angiosarcoma or kidney nephroblastoma could be used for the determination of a value for carcinogenic risk following Inhalation exposure of chloroethene. Since the first liver angiosarcoma appeared at 10 ppm (26 mg/m*), these data result In the highest (most conservative) estimate of carcinogenic risk of chloroethene (Table 8-1). The carcinogenic potency factor, q^, following Inhalation exposure to chloroethene was determined to be 2.95x10** (mg/kg/tfay)`* using the GLOBAL computeriza tion of the multistage model of carcinogenic risk (Howe and Crump, 1982). The unadjusted value was corrected by the cube root of the body weight ratio to give the human q *. A carcinogenicity risk estimate for oral exposure to chloroethene can be calculated from dose-response data for lung and liver tumors reported by Feron et al. (1981) among rats exposed by dietary treatment. The U.S. EPA (1984a) calculated a carcinogenicity risk estimate for lifetime exposure to chloroethene through the drinking water. The estimated total Incidence of lung and liver tumors In female rats treated with diets containing chloro- ethene-fortlfled PVC (Feron et al., 1981) were used to calculate a q * value for oral exposure to chloroethene (Table 8-2). The q * was deter mined to be 1.9 (mg/kg/day)*1 using the GLOBAL computerization of the multistage model. 0707p -86- 10/17/85 TABLE 8-1 Cancer Data Sheet for Derivation of q-j* Compound: Chloroethene Reference: Maltonl et al., 1980, 1981 Species, Strain, Sex: Rat, Sprague-Dawley, M,F combined Body weight: 0.35 kg (assumed) Length of exposure (1e) - 365 days Length of experiment (Le) * up to 1029 days Lifespan of animal (L) * 1029 days Tumor site and type: Liver angiosarcoma Route, vehicle: Inhalation, air Experimental Doses or Exposures ppm mg/m* Transformed Dose* (mg/kg/day) Incidence No. Responding/No. Tested or Examined 10 25 50 100 150 200 250 500 2500 6000 10,000 30,000 25.6 63.9 127.8 255.6 383.4 511.2 639.0 1278.1 6390.5 15337.4 25562.3 76687.1 Controls 0.344 0.860 1.719 3.438 5.158 6.878 8.596 17.19 86.97 206.3 343.9 1031.6 0.0 1/119 5/120 1/60 1/120 6/119 12/120 3/59 6/60 13/60 13/59 7/60 18/60 0/363 Unadjusted qi* from study - 5.0381387x10"* (mg/kg/day)~lb Human q<j* - 2.95x10*1 (mg/kg/day)"* *D0.223 mVday x 4/24 x 5/7 x (C]x0.5+0.35 x 365/1029 bThe unadjusted qj* was derived from the dose-response data up to doses of 1.719 mg/kg/day. The goodness of fit hypothesis was rejected for the data at >3.438 mg/kg/day. 0707p -07- 09/17/85 TABLE 8-2 Cancer Data Sheet for Derivation of q*j* Compound: Chloroethene Reference: Feron et al., 1981 Species, Strain, Sex: Rat, Wlstar, F Body weight: 0.25 kg (assumed) Length of exposure (1e} * 1001 days Length of experiment (Le) * 1001 days Lifespan of animal (L) - 1001 days Tumor site and type: Liver neoplastic nodules, hepatocellular carcinoma and angiosarcoma; lung angiosarcoma Route, vehicle: oral, diet or soybean oil by gavage (high dose) A Experimental Doses or Exposures (mg/kg/day) Transformed Dose (mg/kg/day) 17.0 (dietary, 7 days/week) 5.6 (dietary, 7 days/week) 1.8 (dietary, 7 days/week) 0.0 (dietary, 7 days/week) PVC powder only no chloroethene 17.0 5.6 1.8 0.0 Unadjusted qi* from study - 0.294 (mg/kg/day)*1 Human q-j* 1.9 (mg/kg/day)'1 Incidence No. Responding/No. Tested or Examined 56/57 42/59 26/58 2/57 0707p 10/17/85 VAB.0001129479 The two q-j* values determined here, 2.95x10"* (mg/kg/day)"* for Inhalation exposure and 1.9 (mg/kg/day)"* for oral Ingestion of chloro- ethene differ by a factor of -0. This suggests that the oral route may be slightly more effective. These differences are relatively small considering that the data were generated by different research groups using different protocols. These q^ values are >10-fold higher than that calculated by U.S. EPA (1980) based on the tumor Incidences In rats exposed by Inhalation to 120-25,562 mg/m* (Maltonl and Lefemlne, 1975) and also higher than the d] calculated by U.S. EPA (1984b) based on the Incidence of tumors In rats treated by gavage at 0-50 mg/kg/day (Maltonl, 1977b). Since chloro- ethene Is activated through a saturable pathway It Is Important to limit the use of tumor response data for risk assessment to dose levels well below the saturation level of 200-250 ppm ymol/kg/ha) (Bolt et aT.# 1977; Fllser and Bolt, 1979; Hefner et al., 1975b). At higher doses the Increase In concentration of active metabolite will not be linear, thus limiting the tumorogenlc response. The dose levels used to derive the most recent q^* values are below the saturable dose and therefore more likely to be In the linear dose response range than the previously developed q * values. Therefore, the higher q^ values of 2.95x10"* and 1.9 (mg/kg/ day) 1 are recommended for estimating the Increased lifetime risk of cancer for human Inhalation and oral exposure to chloroethene, respectively. 0707p -89- 10/17/85 9. REPORTABLE QUANTITIES 9.1. REPORTABLE QUANTITY (RQ) RANKING BASEO ON CHRONIC TOXICITY The toxic effects of chronic exposure to chloroethene In animals and humans have been summarized In Section 5.5. of this document.' A reportable quantity based on chronic toxicity of chloroethene has been previously determined by the U.S. EPA (1983b). Animals exposed by Inhalation had toxic effects Involving the liver, spleen, and kidneys with Increased early mortality. Lee et al. (1977a) exposed rats and mice at 50, 250 and 1000 ppm (128, 639 and 2556 mg/m) chloroethene 6 hours/day, 5 days/week for 12 months. Tumors developed In both species exposed at the two higher dose groups with toxic effects In mice (weight loss, lethargy, anorexia and increased mortality) exposed at 50 ppm. Feron et al. (1979a.b) and Feron and Kroes (1979) exposed rats at 5000 ppm (12.780 mg/m*) for 7 hours/day. 5 days/week for 52 weeks and reported toxic effects which Included: slight growth retardation, hematological and blood chemistry changes. Increased kidney spleen and heart weight, and Increased mortality. Nonneoplastic histological changes were seen In the kidney, heart, spleen and liver with neoplastic effects In the liver. Inhalation exposure at 30,000 ppm (76,687 ig/m) for 4 hours/day. 5 days/week for 12 months In rats resulted In hepatic hlstopathologles. Including Interstitial Inflannatlon. Kupffer-cell hypertrophy and partial necrosis, and tubulonephrosls and nephritis of the kidneys (Viola. 1970). Cerebral and cerebellar atrophy was also noted among exposed rats. Examination of the paws of these rats revealed metatarsal bone metaplasia, chondrold metaplasia, basal cell degeneration and vacuoli zation, epidermal hyperkerltosls and edema. Torkelson et al. (1961) con ducted several experiments exposing rats at 500 ppm (1278 mg/m*) and rats, guinea pigs, rabbits and dogs at 50. 100 and 200 ppm (128, 256 and 512 mg/m*) chloroethene 7 hours/day, 5 days/week for 4.5-6 months. No toxic 0708p -90- 10/17/85 effects were detected In any species following 6 months exposure at 50 ppm A (128 mg/m). Rats showed hepatotoxlc effects at 100, 200 and 500 ppm (256, 511 and 1278 mg/m) exposures while rabbits developed hepatotoxlc effects (centrllobular granular degeneration, vacuolar degeneration and necrosis) at 200 ppm chloroethene. Lee et al. (1978) and Hong et al. (1981) exposed mice and rats to chloroethene at 50, 250 and 1000 ppm (128, 639 and 2556 mg/m') for 6 hours/day, 5 days/week for up to 6 months (mice) or 10 months (rats) and allowed a 12-month observation period after exposure. The 4 development of tumors among animals of both species exposed at 250 and 1000 ppm caused Increased mortalities. Increased early mortality among mice and rats exposed at 50 ppm was regarded as a toxic effect since no tumor response occurred at this dose level. Sokal et al. (1980) reported Increased heart and spleen weights and nuclear polymorphism of hepatocytes among rats exposed at SO ppm (128 mg/m) chloroethene (5 hours/day. 5 days/week) for 10 months. Suzuki (1980) reported toxic effects on the lungs, Including bronchlolar and alveolar epithelial proliferation among mice exposed at 2500 and 6000 ppm (6391 and 15,337 mg/m) for 5 hours/day, 5 days/week for 5 and 6 months. Chronic toxic effects following oral exposure to chloroethene are seen primarily in the liver. Chloroethene was administered by gavage to rats at * 30, 100 and 300 mg/kg.on 6 days/week for 13 weeks causing Increased liver weights and hyperbasophlllc hepatocytes with ultrastructural changes at the high dose level (Feron et al.. 1975). In the l9-week dietary administra tion study of chloroethene conducted by the Dow Chemical Company (1984), rats Ingested chloroethene at 0.014, 0.13 and 1.3 mg/kg bw/day. Hepatotoxlc effects developed In females exposed at all three levels (basophilic foci of the liver at low doses and more severe effects at the high dose group) while only males exposed at 1.3 mg/kg/day showed an Increased Incidence of liver 0708p * 10/10/85 VAB.0001129482 hlstopathologles. Mortality was slightly Increased among rats of the high dose group. Neoplastic nodules among females and hepatocellular carcinoma In males occurred In some rats of the high dose group. In the available teratogenicity studies of chloroethene (John et al.t 1977. 1981; Ungvary et al.f 1978; Mlrkova et al.# 1978; Sal'nikova and Kltsovskaya. 1980) In mice, rats and rabbits, maternotoxlc effects (reduced weight gain, mortality) and delayed fetal development occurred at similar exposure levels. Among mice exposed at 500 ppm (1278 mg/m*) for 7 hours/ day on days 6-15 of gestation fetal resorptions were Increased, Utter size decreased and fetal body weights reduced. Oelayed ossification was reported In mice (500 ppm), rats (2500 ppm) and rabbits (500 ppm) exposed utero to chloroethene 7 hours/day but no developmental anomalies occurred (John et al., 1977, 1981). Ungvary et al. (1978) also reported Increased fetal loss and resorptions among rats exposed (1500 ppm) during early gestation (days 1-9) but no malformations occurred after exposure during any trimester of gestation. In humans, toxic effects associated with chronic occupational exposure to chloroethene Include hepatotoxlclty, acroosteolysls and schleroderma, Raynaud's syndrome and occasionally pulmonary effects. Several studies (tills al., 1975; Sakabe, 1975; Destouet and Murphy,. 1983; Black et al., 1983) have reported changes In the bones and skin of the phalanges possibly as a result of abnormal peripheral circulation among chloroethene-exposed workers. Waxweller et al. (1977) reported a prevalence of hepatomegaly, high blood pressure and abnormalities of the CNS function among a cohort of chloroethene-exposed workers. Tamburro et al. (1984) also reported an Increase In hepatic lesions (primarily focal hepatocyte hyperplasia) among liver biopsy specimens of chloroethene workers. Langauer-Lewowlcka et al. (1983) reported freguent cases of astheno-autonomlc syndrome and other 0708p * -92- 10/17/85 neurological symptoms in addition to scleroderma and Raynaud's syndrome among a group of 200 chloroethene-productlon workers. These chronic toxic effects In humans are useful In qualitatively assessing the toxicity of chloroethene but due to the lack of sufficient exposure data, are Inadequate for quantification of a dose-response relationship. Therefore they are Inadequate for the derivation of a reportable quantity. A summary of chronic toxicity studies of chloroethene In animals deemed adequate for quantitation of toxic effects. Is presented In Table 9-1. The dose In mg/kg/day were calculated by expanding the Inhalation exposure over a 24-hour day and a 7-day week, by multiplying by the animal Inhalation rate and by dividing by the animal body weight. The values for Inhalation rates used In the calculation were 0.039 m*/day for mice, 0.223 mVday for rats (Federal Register, 1980) and 2.0 mVday for rabbits (U.S. EPA, 1985). The animal body weights were 0.03 kg for mice, 0.35 kg for rats (Federal Register, 1980) and 3.8 kg for rabWts (U.S. EPA, 1985). Studies of ade quate experimental design and containing sufficient dose-response data for the determination of CSs and RQs are summarized In Table 9-2. The human HEDs were calculated by multiplying the animal dose by the cube root of the ratio of the animal body weight to the human body weight (70 kg) and by 70 kg to express the NED In mg/day. For short-term studies, the doses were divided by a factor of 10, as Indicated on Table 9-2. The studies conducted by Lee and cowOrkers (Lee et al., 1977a; Lee et al., 1978; Hong at al., 1981) result In the highest CS and lowest RQ. In these studies mice and rats exposed to chloroethene at 50 ppm (128 mg/m*) 6 hours/day, 5 days/ ^ months (Lee et al., 1977a) or $ months followed by a 12-month latency had a higher rate of early mortality. Since tumor response at the exposure level was low, deaths were regarded as toxic effects. The exposure 0708p -93- 10/17/85 10/17/85 .94. 0708p RmU Spec Us/ Strain Inhale!tea lce/CS-1 1 Sex it. el Start M 1! Vehicle/ Physical State alr/vaper rat/CS M.F alr/vaeer rat/Mtstar M.f 124 alr/vaper rat/MIstar II 2$ alr/vaeer n.ot n.n HR SO ppe (128 Mg/a") S hours/day, S days/week for 12 Months SO PPM (120 Mg/M") S hours/day, S days/week for 12 Months S000 ppM (12,781 Mg/M") 7 hours/day, S days/week for 52 weeks 99X 20,000 ppM (78,887 Mg/a") 4 heurs/day, 5 days/week for 12 Months rat/NR M.f 40-48/ alr/vaper rahhtt/08 M.f 4/freep alr/vaper 1 tce/CD-l M.f IS alr/vaper NR 99.OX 50-500 ppM (128-1278 Mg/a") 7 hours/day, 5 days/week for 4.5-8 Months 200 ppM (511 Mg/M") 7 hours/day, 5 days/week for 8 Months 50 ppM (128 ng/M") 8 hours/day, 5 days/week for 8 Months 29.7 14.8 1897 5017 17.0-170 58.0 29.7 Mortality 20/72 vs. 2/72 In controls (May he tunor Induced deaths) Lee et al., 1977a Mortality In feMales 2/38 vs. 0/38 in controls Lee et al., 1977a Reduced growth rate. Increased blood urea nitrogen, slight anoMta, shortened blood clot ting tlMt, increased Mortality, Increased organ weights and hlsteleflcal hepatic changes Cerebral degeneration; cere bellar atrophy. Hepatic hyper trophy, InflaMnatlon and partial necrosis. Tubulonephrosls and nephritis, proliferative changes of the bones, cartilage and epIderMls of the paws Increased liver weight with centrelobular degeneration at all levels except 50 ppm; No toxic effects at 50 ppM 1 Hepatotoxlclty with centrolobular degeneration and necrosis at 200 ppn Feron et al., 1979a,b; Feron and Kroes, 1979 Viola, 1970 Torkelson et al.. 1981 Torkelson et al., 1981 Mortality 15/18 vs. 11/50 In controls Lee et al., 1978; Hong et al.. 1981 VAB.0001129485 10/17/8S ' -95- 0708p SpecIts/ Strain Inhalation rat/CB Sex He. at Start N#f ft rat/HIstar H rat/Hlstar 7 Mtce/CB-1 17 ral rat/MIstar M.f SB 100 Vehicle/ Physical State Purity air/vapor soybean ell/ saintInn PVC powder/ diet M.K 99.7* M.ttX Hi 99.97* SO pp (128 ng/n) t hours/day, S days/week for 10 Months SO pfMR (128 ng/) S hours/day, 5 days/week for 10 Months S00 ppM (1278 ng/n*) S hours/day, S days/week for 10 Months 2500 ppM (4391 Mg/M*) S hours/day, S days/week for 5-4 Months 300 ag/kg 4 days/week for 13 weeks 1.3 Mg/kg/day for 149 weeks Inhalation Mlce/CF-1 f 19 4am air/vapor HO rat/CFV f 19 1 litters 500 ppM (1278 Mg/M*) 7 hours/day on days 4-15 of gestation 4000 eg/M* continuously on days 1-9 of gestation 14.4 12.1 121 1234 Mortality 17/24 vs. 13/32 In controls lee et al., 1978; Hong et al., 1981 Increased heart and spleen weight and nuclear polynorphtsM of liver cells Sokal et al., 1980 Increased liver weight; ultrastructural hepatocyte changes MtsntewskaKnypl et al., 1980 Brenchlolar and alveolar proliferative changes Suzuki, 1980 257 1.3 4B5 2549 Increased liver weight, hyperbasophilia of hepatocytes with ultrastructural changes Clear cell foci, basophilic foci, hepatocellular polyMorphlsM of the liver, hepatic cysts Increased fetal resorptions,, decreased Utter size, decreased fetal body weight, delayed ossification feron et al., 1975 Bow Cheolcal Coopany, 1984 John et al., 1977, 1981 Increased fetal loss due to resorptions Ungvary et al., 1978 0001129486 TABIC 9-? Composite Scores for Iho Chronic Toxicity of Chloroothene tool* Inhalation Inhalation Inhalation Spec Us mice 1 rat 1 rat Animal ioso/lxpesore |0|Mai) 29.1 for 12 months 14.B for 12 months 1H1 for 12 months Human MB <M|/day) 1S7 US 20,313 Inhalation rat h SOU for 12 months 40,029 a i Inhalation Inhalation Inhalation rats rats 1 rabbit 170 for 4.S months 33.9 for 4 months 54.0 mg/m* for 4 months 203* 40.S* 140* RVd Effect ^e CS 2.2 Increased early Mortality 10 2 Slight Increase In Mortality In foMales 10 1.0 Slight growth retardation; slightly short 7 ened blood clotting tlMe; Increased potas- sIom contents of the blood seruM; Increased kidney, heart and spleen weights; slight signs of anenla; tubular nephrosis; Mild focal degeneration of the nyocardlun; In creased heMitopoletlc activity In the spleen; degenerative, hyperplastic and neoplastic changes In liver parenchyma 1.0 Metatarsal bone Metaplasia; chondrotd Meta plasia; epIderMal hyperkeratosis, hasal B layer vacuolliatlon and degeneration, dis appearance of the cutaneous adnexa and epIderMil edena of the skin of the paw; diffuse degenerative lesions of the grey and white Matter of the brain; atrophy of the granular layer of the cerebellum; livers were marked by an Increased volume, diffused Interstitial hepatitis, abnormal prolifera tion of Kupffer's cells and partial necrosis; kidney marked by tubulonephrosts sometimes accompanied by chronic Interstitial nephritis; colloid goiter and Increase In parafollicular cells of the thyroid 2.0 Central lobular granular degeneration In the 4 liver; Interstitial and tubular changes In the kidneys; Increased mean liver weight 3.1 Increased mean liver weight 4 2.2 Central lobular granular degeneration In the 7 liver; necrosis with foamy vacuolliatlon In males and necrosis with periportal cellular Infiltration In females 22 21 7 B 12 12.4 15.4 RQ Reference 100 tee et al.. 1977a 100 Lee et al., 1977a 1000 feron et al.. 1979a,b; feron and Kroes, 1979 1000 Viola, 1970 1000 Torkelson et al., 1961 1000 Torkelson et al.. 1961 1000 Torkelson et al.. 1961 VAB.0001129487 10/17/85 IM 0708p -97- 7A8LE i-2 (cent.) Rout* S|mcI*s Inhalation MlSt lobelotloo rats Inhalation Mouse Dose/E xpoivrc 29.7 4 12 Mtbsi,nMt vs observable* 14.0 for lb Months, plus 12 Months observation 1290 for S or 0 Months Hunan HI 8 (Mg/day) 4 552* Inhalation Inhalation Oral Oral Inhalation Inhalation rat 12.1 for 10 Months rat 121 for 10 Months rat 257 for 19 weeks rat 1.9 for 149 weeks Mice 405 on * days b.15 of gestation rats 2549 on days 1-9 of gestation 145 1,440 900* 15.4 2,550 * 90,511 Effect Increased Mortality or rlbondlty during observation period 10 Slightly Increased Mortality or axirlbuadlty during exposure and observation period 10 1.9 OrelIforation and hypertrophy of the teralnal bronchtolar cells, hyperplasia of alve olar epIthelluM, degeneration of alveolar septa cells, occasional Inflannatton 2.9 Increased heart and spleen weights, hepatocyte nuclear polyworphlsM t 1.0 Increased liver weight, oltrastroctoral hepatocyte changes 7 * 2 4 1.0 Increased liver weight, hyperbasephtlla of hepatocytes with oltrastroctoral changes 4 9.7 Clear cell foci, basophilic foci In liver, 5 hepatocellular polyworphtsM, and hepatic cyst 1.0 Increased fetal resorptions, decreased litter slxe, decreased fetal body weight, delayed ossification 0 1.0 Significantly Increased fetal Mortality and fetotoxlc effects S An uncertainty factor of 10 was applied to convert frow a subchronic anlnal exposure to a chronic hunan HE0. Reference 22 100 Lee et al., 1970; Hong et al., 1901 21 100 Lee et al., 1970; Hong et al., 1901 9.1 1000 Suzuki, 1980 4.4 5000 Sofcal et al., 1980 4 5000 UtsnlewsfcaKnypl et al., 1980 7 1000 feron et al., 1975 18.5 1000 Dow Chentcal Conpany, 1984 8 1000 John et al., 1977, 1981 8 1000 Ungvary et al., 1978 1 10/10/8S VAB.0001129488 58/01/01 -86* 9 taaLO M*C96l) Vd3 *S*n q* Aq AtsnovAajd auop uaaq spq (jo;opj~j) jo;opj Aoua;od a jo uov;pavjp pup (apvjoiqa iAuva) auaq;aojotqo jo iPv;ua;od DvuaBouvojpo jo uov;pniPAa am *81*6 J >-6 saiqpi ui pazvjpuwns ajp savpn;s am pup ;uawn3op svq; jo *l*S uov;aa$ uv paAaiAaj ajp auaq;aojoiqo uo p;pp A;vavua6ouv3Jf 19*U*A* am A1I3IN330NI38V3 803 (0lQ3/l-4) 80A3VJ A3N3iQd ONV 33N3QIA3 JO 1H9I3A *2*6 ov;pj ;q6vA Apoq * aq; jo ;ooj aqno aq; Aq pa;oajjoo ajp qatqit `sasop (.ppivup o; pa;jaAuoo ajp sajnsodxa ipwvup * A6oi opoq;aui ;uajjno aq; ui *%0S jo Aouavovjja uov;dJOsqp pup 6uvuin$sp pup a;pj uov;PLPquv upuinq aq; Aq 6uvA|dvuntu Aq q;u upuinq p o; Auaajip pa;jaAuoo spa ajnsodxa uov;PLPquv aq; *ajojajaq; tsapads Buouip paiPApba aq o; pajapvsuoo ajan sajnsodxa uov;pt.pquv *;uattinaop snovAajd aq; ui *03H aq; 6uvAVJap jo poq;au aq; uv saouajajjvp J asnpoaq pa;tnsaj 00L jo 08 dAv;PAjasuoa ajotu aq; *uov;puvwja;ap ;uasajd aq; ui *0001 J 08 up o; spuodsajjoa qovqA *02 J S3 JaAOt p aouaq pup *PA8 Jaoi p uv Buv -;tnsaj *ja6jpi spa Q3u aq; `JdAaAoq !08 aq; J ^vspq aq; sp pasn spa Apn;s auips aq; *(QC861 *Vd3 *S*ft) 08 aq; jo uov;Puvuwa;ap snopajd aq; ui *(C*6 iqPl) auaq;aojoiqo o; ajnsodxa ovuojqo jo A;pvxo; aq; jo uov;p;uasajdaj aAv;PAjasuoo ;sotu aq; sp uasoqa ajaA *(1861) `l? ;a 6uoh pup (8Z.61 **LLSi) *1? ;a aa; Aq pa;jodaj aovui uv p;pp AnVX03 uiojj paAVJap asoq; *08 ;saAoi pup S3 ;saq6vq aqj. '(2*6 IQP1 aas) AtaAv;3->dsaj *001 pup 12 ajp 08 pup S3 ;up;tnsaj aq; pup 0L J a8 * sjupjjpa ajpj A;VP3Joui uv aspajauv ;qBvi$ aqi *PA8 auips aq; Aupnuassa ;nq Q3H upuinq jaqBvq P uv -s;insaj vAal ajnsodxa aApoajja auips aq; *s;pj ui *oot $V % 08 a;pvJdojddp aq; pup ZZ aq PinoA { A8xPA8) S3 Buvunsaj aqi *pasn sv 01 J 3 A8 up pajja dvxo; aq; sp * Aui?3->ui paspajouv uo paspq pup *zmZ aq PinoA ^A8 aqi 'App/Bui isl jo Q3w upuinq p o; sppai aovui uv vaAat ajnsodxa V VAB.0001129489 TABLE 9-4 Bioassay Data for Hale Wlstar Rats (Ar/IRE) Exposed to Chloroethene by Inhalation for 12 months2 Dose or Exposure0 (PP) Duration of Study Purity of Compound Vehicle or Physical State Target Organ Tumor Type Tumor Incidence 30,000 >12 monthsc 0 >12 monthsc NA vapor/air air only < skin lung bone skin lung bone epidermoid carcinoma carcinoma osteochondroma epidermoid carcinoma carcinoma osteochondroma 15/26 6/26 5/26 0/25 0/25 0/25 QUALITY Of EVIDENCE Strengths of Study: An appropriate route of administration was used. The chloroethene was relatively pure. Appropriate controls were Included for comparison. Weakness of Study: Only male mice were tested. The duration of the study could have been longer. No statistics were compiled on Incidences between treated and untreated animals. Overall Adequacy: Adequate ^Source: Viola et al., 1971 ^Exposure was for 4 hours/day, 5 days/week for 12 months. Surviving animals were killed at 20-day Intervals following treatment. NA * Not applicable .0001129490 TAIL* 9.5 Bioassay Bata for Sprague-Dawley Rats exposed to Chloroethene for 52 weeks1'* 0708p -101- (xposore Booto Iokalatloo Sox Oral (gavage) V Bose or f xposurec IB. B.BBO ppx ISO 100 0 5B M/kf 1I.IS ng/kg 0.0 xy/ka BurntIon of Study (weeks) 1SS 155 143 143 143 143-155 130 130 130 Vehicle or Physical State vapor/air vapor/air vapor/air vapor/air vapor/air air only ollvo oil ollvo oil olive oil only Target Organ liver kidney liver kidney liver liver liver liver kidney liver kidney liver kidney liver kidney Tumor Type angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma angiosarcoma 1 angiosarcoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma Tumor Incidence 9/50 5/50 13/50 4/50 12/120 5/120 1/120 0/500 0/120 15/00 2/80 9/00 3/00 0/150 0/150 QUALITT Of IVIBIIICI Strengths of Study: A Broad range of dost levels were tested. Carcinogenic response was shown by two routes of administration. Duration of study was long in all cases. Meekness of Study No statistics were reported. The sox of test animals Is not reported. Bata for the control group for the gavage studies Is reported In Naltont ot al., 1901. Animals treated by gavage. The purity of the chloroethene Is not reported. Overall Adoguicy: Adequate This study focused on different factors affecting the carcinogenic effect (animal species, strain and age, treatment duration, and exposure levels). ^Source: Haltonl, 19?Tb ^Purity of compound not reported Exposure to chloroethene by Inhalation was for 4 hours/day, 5 days/week for 52 weeks; by gavage once dally in olive oil 4-5 days/week. HO Hot reported VAB.0001129491 > 10/10/85 UBLK 1-6 AaImI Imssay Bata for Inhalation Eifosuri to Ch1oroethene*b r SpocIts/ Strain Bat/ SpragueBanloy - Boso or Buratlon of Sox iKpesure* Treatment tPP) {nooks) R.f 38.088 52 4 18.000 52 * 6.000 S2 2,500 52 soo 52 250 S2 200 52 ISO $2 100 52 < SO S2 B 2S 52 10 S2 s 52 Buratlon of Study (nooks) 68 135 135 13S 135 135 143 143 143 135 14? 14? 14? Vohlclo or Physical Stato air/vapor air/vapor g> air/vapor air/vapor air/vapor 'air/vapor air/vapor air/vapor air/vapor air/vapor air/vapor air/vapor air/vapor Target Organ liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney liver kidney Tumor Typo angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma angiosarcoma nephroblastoma Tumor Incidence 18/60 NR ?/60 5/60 13/55 5/59 13/60 6/60 6/60 6/60 3/59 5/59 12/120 7/120 6/119 11/119 1/120 10/120 1/60 1/60 5/120 1/120 | 1/119 0/119 0/119 0/119 VAB.0001129492 0708p TABLi 9 SfKitt/ Strain lot/ SprageeBawley Sir H.f Rnm/ Swiss H#f - Haas ter/ Syrian Bolden H.f i Bote or t xposurec (MM) Aeration of Treatment (weeks) 1 52 0 HA 1 1 lB.BBf A. BOB SB SB 2,500 SB SOB SB 25 SB SB SB B HA 10.000 B.OBB 2.500 SOB 250 SB SO A so so so Buret loo of Stedy (weeks) 147 135-1 01 SI 01 01 01 01 81 109 109 109 109 109 alr/vayor air only air/vapor air/vapor air/vapor a1r/vapor air/vapor air/vapor air only air/vapor air/vapor air/vapor air/vapor air/vapor liver kidney liver kidney liver long liver long liver long liver long liver long liver long liver long fores tomch fores teauch fores tomch foresteauch fores tomch eng lot or com nephrohlestom angl osarcom nephrohlestom anglosarcom tumor anglosarcom tenor o anglosarcom tenor anglosarcom tenor anglosarcom tumor anglosarcom tenor anglosarcom tumor papl 1 lom/ecenthom papl11one/acanthorn papl 1 lona/acanthona papl 11oM/acanthona papl 1 lom/acanthom 0/110 0/110 0/363 0/363 10/56 45/56 13/60 47/60 16/59 40/59 14/60 50/60 . 10/60 41/60 1/60 6/60 0/150 15/150 10/30 10/30 17/30 9/30 1a 4/30 -103- 10/10/85 VAB.0001129493 > OlOBp ; IABLE 9-S (coni.) Species/ Strata Haas ter/ Syr Ian Golden Sox Doso or E xposurec CPP*I Burnt ton of Treataent (weeks) BuratIon of Study (weeks) Vehicle or Physical State alr/vapor air only forest fores taMch Timor Type papl 1 loaa/acanthoaa papl 1 loaa/acanthoaa Tuaor Incidence 3/30 3/SO Strengths of Study Overall Adequacy WWIHY Ofe f Chler tlens of antails adalnlstored By "f* nor*nra, Inhalation to rats, alee, and duration of studies was long. haasters at a broad ranee Adequate Extensive exaatna- Ifcti ra^rl m mlwntra M auck ,f tlM MU ms Mt nmM htr, 4m U Um scop. *Source: Ha HonI et al., 1901 ^Purity of c was >99.90 c!xpesere was for 4 hour s/day. S days/week HA Net applicable . -104- 10/17/85 VAB.0001129494 > 0708p TABLE 9-7 Affinal Bioassay Data for Inhalation Exposure to Chloroethene for 12 months* -105- Species/ Strain Rat/CO Dose or Sex Exposure0 (PP) 4 N 50 F 50 n 250 F 250 n 1000 F 1000 II 0 F0 Vehicle or Physical State vapor/air vapor/air vapor/air vapor/air vapor/air vapor/air air only air only Target Organ liver lung liver lung liver lung liver lung liver lung liver lung liver lung liver lung Tumor Type hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma hemanglosarcoma Tumor Incidence (p value) 0/36 0/36 0/36 0/36 2/36 0/36 10/34 (p<0.05) 3/34 6/34 4/34 15/36 (p<0.05) 9/36 0/35 * 0/35 0/35 0/35 VAB.0001129495 3^ 09/17/85 0708p TABLE 9-7 Species/ Strain House/CD-1 Dose or Vehicle or Sex ixposurec Physical (pp) State h 0 air only respiratory tract liver F 0 air only respiratory tract liver N SO vapor/air respiratory tract liver F SO vapor/air respiratory tract liver n 250 vapor/air respiratory tract liver F 2S0 vapor/air respiratory tract liver bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma bronchioloalveolar adenoma hemanglosarcoma # bronchioloalveolar adenoma hemanglosarcoma 1/26 0/?6 0/36 0/36 8/29 3/29 4/34 0/34 10/29 7/29 (p<0.05) 12/34 1 16/34 (p<0 05) . -106- 09/17/85 VAB.0001129496 f / TABLE 9-7 (coni.) 0708p .107- Species/ Strain Dose or Vehicle or Sex lxposurec Physical Target Organ (Pf*> State Tumor Type Tumor Incidence (p value) Nouse/CD-1 91 * 1000 vapor/air respiratory tract liver bronchioloalveolar adenoma hemangl osar coma 12/33 13/33 (p<0.05) f 1000 vapor/alr respiratory bronchioloalveolar 26/36 tract adenoma liver hemanglosarcoma 18/36 (p<0.05) QUALITY OF EVIDENCE Strengths of Study: Three different dose levels of chloroethene were tested by Inhalation In two species of animals. Some statistics were reported. Chloroethene was quite pure. An extensive examination of organs and tissues was performed.. Weakness of Study: h- Overa11 Adequac y: The significance of bronchioloalveolar adenoma In mice Is not reported. The duration of study was short (due to morality). Adequate ^Source: Lee et al.f 1978 ^Purity of compound was 99.8X cExposure was for 6 hours/day, 5 days/week for 12 months VAt^.0001129497 09/17/85 I1 TABLE 9-8 AntaaT IlNtuy liti for Inhalation Exposure to Chloroethene*b Species/ Strolii Bil/CO 1 M Beuse/CB-1 n.f i 4 Bose or Exposure* SB * BurstIon of Treatoent (oontbs) S or 10* * 0 250 S or 10* Duration of Study (oonths) 18 or 22* 18 or 22* Vehicle or Physical State air/vapor air/vapor 1006 S or TO* * 0 BA SB 2S0 1000 0 1 * 1 w 1 BA 18 or 22* , air/vapor 18 or 22* air only 13 air/vapor 13 air/vapor 13 air/vapor 13 air only Target Organ Tuoor Type liver lung liver lung liver lung lung lung liver lung liver lung liver lung liver mm hepatocellular carclnooa heoanglosarcooa bronchioloalveolar tuoor heoanglosarcona hepatocellular carclnooa heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa hepatocellular carclnooa heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa heoanglosarcooa heoanglosarcooa heoanglosarcooa heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa bronchioloalveolar tuoor heoanglosarcooa Tuoor Incidence 0/66 0/66 0/66 0/66 2/68 S/68 2/68 2/68 7/72 14/72 4/72 7/72 1/72 0/72 0/72 0/72 3/32 1/32 19/32 0/32 20/32 0/32 3/32 0/3? VAB.0001129498 O7O0p m*1 / ISK. \ I TAliE Specie*/ Strain Nst nr Duration of Duration Sex I xposurt* Treatnent of Study (P) (Mtltl) (Months) Reose/CD-1 M 250 6 1000 0 0 D ID 10 10 atr/vapor air/vapor * air/vapor air only air/vapor air/vapor air/vapor air/vapor IlNtf liver lung liver lung liver lung liver lung liver lung liver lung liver lung liver bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona bronchioloalveolar tunor henanglosarcona 12/32 0/32 21/32 4/32 S/20 16/20 2/32 0/32 3/16 1/16 16/20 0/20 14/24 13/24 11/56 1/56 I -109- 10/10/85 VAB.0001129499 0708p TABLE S-B (cont.) $9Klti/ Strain Sax Bast ar E xposurec Baratton of Treatmnt Surat ton of Study <PPi) (Months) (maths) Vehicle or Physical State Taryet Organ Strengths of Study Weakness of Study Overall Adequacy: C ts: IAL1TV Of EtflOEIOCE JSSt, r,r,KiUr* ,e,, "r* "' 10 5N~ * The duration of treatmnt was tee short In all cases. Adequate study uos conducted In enhance that reported ^Source: Hong at al.. 1001 fcfurtty of c was W.n Exposure was fur 0 hours/day, S days/Week duration of exposure was for 0 or 10 ths, followed hy a IB duration group. NA Not applicable latency ported Turor Type Tumr Incidence Statistics of tumr caublned -110- 10/10/85 VAB.0001129500 >) 10/10/8$ -111- 0708p AhImI IlNttiy lata SpKln/ Strain Noese/ICR Sex M Dost or txpesere (PP) S. 0 Rat/f344 M 0. SO. S00. . SO. Hwso/A/J M 0 SO 0 Rlt/TSM M so 0 Dwattoo of Irtatamt 1 toy (I dour) I toy |1 Door) 1 toy (1 tour) 1 toy |1 Door) 1 toy (1 deer) ten 1-deer exposeres 100 1-deer exposeres ten 1-deer exposeres 100 1-doer exposeres 10 Months 10 nontds 10 Months 10 Months 10 Months lifeline 20 Months 20 Months 20 Months 20 Months lifeline lifeline lifeline air/vapor air/vapor * air/vapor air/vapor air/vapor alr/vapor atr/vapor air only alr/vapor air only a1r/vapor alr/vapor air only a limy leny leny leny leny leny liver leny leny leny leny leny liver leny liver leny liver adenona caretnone adenona carctnona adenona care Inona adenona care Inona adenona careInona naltynant adenona careInona adenona careInona adenona careInona adenona careInona naltynant naltynant naltynant naltgnant naltynant naltynant 5/137 3/137 24/143 1/143 10/139 1/139 14/139 0/139 12/120 0/120 0/170-190 per dose 124/166 22/166 31/90 3/90 6S/1S8 7/158 29/84 2/84 0/180 0/180 ' 0/180 0/180 0/100 0/100 VAB.0001129501 070P TABLE 9-9 (coni.) Speclet/ Strain Sex Dote nr Exposure <ppa) SuratIon of Treatment Duration of Study Vehicle or Physical State Target Organ lixaor Type Strengths of Study: Exposures conducted at several exposure Weakness of .Study Exposures, except for TOO 1-Sour ISo Incidence of carcinoses was 1 Overall adequacy Ltslted C ts: Pulsonary spontaneously ^Source: HeSIr et al., 1901 ^Purity of c not reported HA > Hot appIlcaSlo ppm, were very Srlef. Lung adenosis are usually co mre not perforsed. Ho carcinogenic effect was shown Timor Incidence ' -112- 10/17/85 I VAB.0001129502 >} * 10/10/85 -113- 0708ft Species/ Strain 4 fet/COOS Sex M Nonse/Ctl Swiss R, f Haas ter/ telden Syrian R,F TAKE 9.10 AmImI ItMKiy feta for Inhalation Exposure to Chloroethene9***9 fese or Exposure* (PPa) isto * aw w asw 2W so 0 asw aw so 0 feraltoo of Treatawnt la aonths 12 aonths ia aonths U aonths 9 aonths 9 aonths 9 aonths HA 12 aonths 12 aonths 12 aonths 12 aonths Vehicle or Physical State air/vapor a1r/vapor air/vapor air only air/vapor i air/vapor air/vapor air only air/vapor a1r/vapor air/vapor air only Target Organ liver Zynhal gland9 liver Zyabal gland9 liver Zyahal gland9 liver Zyahal gland9 liver long liver long liver long liver long liver liver liver liver Tunor Type Tunor Incidence anglosarcoaa tunor anglosarcoaa tunor anglosarcoaa tunor anglosarcoaa tunor anglosarcoaa alveolar adenoaa alveolar carclnoaa anglosarcoaa alveolar adenoaa alveolar carclnoaa anglosarcoaa alveolar adenoaa alveolar carclnoaa anglosarcoaa alveolar adenoaa alveolar carclnoaa anglosarcoaa anglosarcoaa anglosarcoaa anglosarcoaa i 114/147 12/13 82/141 2/23 28/139 3/14 0/143 0/25 101/101 101/101 18/101 130/134 119/134 4/134 46/121 92/120 10/120 0/97 10/96 1/96 S6/66 12/88 7/74 0/83 .0001129503 0?08p i TABLE 9-10 (coot.) Sptcltf/ Strain lost nr Exposure" IPP> Duration of Treatment Vehicle or Physical State Target Organ Tuner Type Tumor Incidence QUALITY Of EVIDEMCE Strengths off Study: Throe speclet of antails, Beth sexes of each were exposed at three levels. Exposure was for 1? Months and a long latency teat aliened. Appropriate controls were Maintained. Histological examination of najor organs was conducted. 4 Overall Adequacy: Adequate . Coemnts: Tuners were reported at total mater of turnrs, therefore, tuner Incidence reported here (tunor hearing animals/total culmis exanlned) "Source: NCA, IBM duration of study was for Itfettne cPurtty of cenpound was not reported ^Exposure was for 1 hours/day, S dayt/Weok "Net all rats were exanlned for Zynhal gland tuners HA - Hot applicable -114- 10/17/85 ) VAB.0001129504 fll TABLE 9-11 i AiiImI IlMssiy Bata for Inhalation Exposure to Ch1oroethene**b ShcW Strain Sox Boso or Exposure* tPP) Boratlon of TroaUwnt |Moths) Boratlon of Study (onths) Vehicle or Physical State Target Organ Ttwor Type Tunor Incidence Bat/f344 i tir Haas ter/ Bolden Syrian F I atr/vapor liver heMnglosarcoM hepatocellular 4/76* ry gland carctnoM f tbroadenima 3/75 28/761* 12 24 atr/vapor liver heMnglosarcoM 11/55*) hepatocellular ry gland carctnoM f IbroadenoM 4/56*) 28/56** 24 atr/vapor liver heMnglosarcoM hepatocellular 13/55*) ry gland carctnoM f IbroadenoM 8/54*) 24/55<* 24 24 air only liver heMnglosarcoM 19/55*) hepatocellular ry gland carctnoM f IbroadenoM 9/54* 26/55* 24 air only liver heMnglosarcoM hepatocellular 1/112 ry gland carctnoM f IbroadenoM 1/112 24/112 4 24 atr/vapor all sites heMnglosarc BMory gland carctnoM StOMCh adenoM 13/88* 28/87* 23/88* 12 24 a1r/vapor all sites aannary gland steach heMnglosarcoM carctnoM adenoM 4/52* 31/52* 3/50* 24 atr/vapor all sites MOMry gland steMch heMnglosarcoM carctnoM adenoM 2/103 47/102* 20/101* 24 air only all sites heMnglosarc Mnury gland carctnoM StOMCh adenoM 0/143 0/143 5/138 VABXOOl129505 * /"Ts TABLE 9-11 (coni.) - 116- SpNtM/ Strain Sex Bott nr E xposerec <PP*I BurntInn of Treatment (MtllS ) Duration of Study (Months) Vehicle or Physical State Target Organ Tumor Type Tunor Incidence House/ B6C3f 1 House/ Swiss f f f r 90 SO 0 so so 0 6 12 HA * 6 12 HA 18 air/vapor all sites ry gland henanglosarcona carclnona 46/67* 29/67* 18 alr/vaper all sites henanglosarconi 69/90* ry gland carclnona 37/90* 24 air only all sites henanglosarconn 4/69 ry gland carclnona 3/69 IB air/vapor all sites heManglosarcona 29/67* nauMiry gland carclnona 33/67* lung xarclnona 18/65* IB air/vapor all sites henanglosarcona 30/47* MMMary gland carclnona 22/47* lung carclnona 11/45* 18 air only all sites henanglosarcoMi 1/71* Mannar y gland carclnona 2/71* lung carclnona 9/71* Strengths of Study Meekness of Study Overall Adeuuacy: C ts: ODAUTt Of EVIDENCE The chloroethene was adnlnlstered at a nailnun tolerated dose. Several species hlstepathologlcal exaMlnatlons were perfumed. Statistics were perfumed. Conplete Only fenele entasis were tested. Adeguate * Additional tests By these aethers shewed little or no carcinogenic effect In rats and haesters If chloroethene exposure was started after IB Months of non-exposure. Heerce: Bew et al.. 1903 ^Purity of c not reported Exposure was for 6 heurs/day, S days/weefc Vb.oi p<O.OS HA - Hot applicable; HR - not reported VAB.OftQl129506 ) > /10 10/85 0708p TABLE 9-1? Bioassay Oata for Nate and Female Mis tar Rats Exposed to Chloroethene* !><: * -117- Exposure Route Oral (gavage) Oral (diet) Dose or E xposurt (mg/kg/day) 300* 17.0 5.6 1.8 0.0 Duration of Treatment (weeks) 143 143 143 Vehicle or Physical State soybean oil PVC PVC PVC untreated diet only Target Organ liver lung liver lung liver lung liver lung liver lung Tumor Type hepatocellular carcinoma angiosarcoma angiosarcoma hepatocellular carcinoma angiosarcoma angiosarcoma hepatocellular carcinoma angiosarcoma angiosarcoma hepatocellular carcinoma angiosarcoma angiosarcoma hepatocellular carcinoma angiosarcoma angiosarcoma Tumor Incidence (p value) 1/109 56/109 42/109 37/117 (p<0.001> 36/117 (p<0.001) 24/116 21/115 8/115 5/115 5/116 0/116 0/116 0/112 0/112 0/112 VAB.OOOl129507 >) 0708p i TABLE 9-12 (cont.) Exposure Route Dose or Exposure*! (mg/kg/day) Duration of Treatment (weeks) Vehicle or Physical State Target Organ Timor Type Tumor Incidence (p value) QUALITY OF EVIDENCE Strengths of Study: The dose of chloroethene was determined following gastrointestinal digestion of PVCcontalnlng diet. Treatment was for the lifetime of the rats. Several dose levels were administered. A large number of rats of both sexes were used In each group. Weakness of Study: No control group for rats treated by gavage was Included Overa11 Adequac y: Adequate ^Source: Feron et al.. 1981 ^Duration of study was for 143 weeks cPur1ty of compound was not reported ^Dosage given 5 days/week NA - Not applicable -118- 09/17/85 VAB.0Q01129508 >f I TABLE 9-13 Btoassay Data for Huaans Occupationally Exposed to Chloroethene8>b OlOBp . -Ill- * Size of Size ef Exposed Control Sex Target Organ Population Population 161 161 N liver and biliary tract brain lung digestive lymphatic and hematopoietic system Tunor Type cancer cancer cancer cancer cancer Nunber of Cases Observed 8 5 13 13 5 Number of Cases Expected 0.7 1.2 7.9 8.3 3.4 Relative Risk 11.4 4.2 1.6 1.6 1.5 QUALITY OF EVIDENCE Strengths of Study: Deaths In a chloroethene-exposed population were compared with a comparable age/time/ cause-specific reference population. The Incidence of several causes of death were examl ned. Weakness of Study: The levels of exposure and duration of exposure are not reported. No statistics are reported. Overall Adequacy: Adequate ^Source: Nonson et al., 1974 *Leve1 and duration of exposure not reported 10/17/85 VAB.0001129509 Bioassay Data for Humans TABLE 9-14 Size of Exposed Population Size of Control Population Sex Duration of Exposure Target Organ Tumor Type Number of Cases Observedc Number of Cases Expected Relative Risk (p value) U.$. death rates M >5 years liver and biliary tract cancer brain and CNS cancer 7 3 0.4 17.5 (p<0.01) 0.6 5.0 i lymphatic and hematopoietic respiratory system cancer cancer 3 11 (p<0.05) 1.7 1.6 (NS) 5.7 1.9 (p<0.05) i tiALITY OF EVIDENCE Strengths of Study a Tumor Incidences were analyzed on the basis of latency period. of different types of cancer compared to expected values were was of workers with >5 years exposure. Statistical analyses performed. The study Weakness of Study t Overall Adequacy: Levels of exposure were not available. * Adequa te aSource: Waxwe Her et al., 1976 ^Level of exposure not reported incidence of tumors after 15-year latency Not significant VAB.0001129510 ) > 0708p TABLE 9-15 Bleassay Bata for Munans Occupationally Exposed to Chloroethene* Stxo of Ixpesed Nfslatloi Site of Cootrol Population Sox level* of Exposor* 750 1909 N periodically Swedish up to 19,000 population ppn oration of ixposoro >10 years <1 to >10 years <1 to >10 years Taryet Oryan liver/pancreas brain Tuny Tunor Typo cancer cancer cancer uuher of Cases Observed Nunber of Cases Expected 4 0.00 2 0.33 3 1.70 Relat Wo Risk (p value) 5.8 (p<0.005) 0.1 (p<0.043) 1.7 (p<0.?6) QUALITY Of EVIBEIICE Strenytbs of Study: The exposed popelalion was coopered to the Swedish population. The Incidence of liver tenors was reported based on looytbs of exposure. Statistics were compiled to show stynlftcant Increases In tuner Incidences. Meekness of Study: Specific Towels of exposure are not reported. Oft relatively snail nuuber of cancer deaths ties exantned. Overall Adoyoacy: Adeyuato `Source: Byron et.al., 1970 -121- 09/17/85 VAB.0001129511 > 0708p * -122- I TASK 9-16 Bleassay Bata for Munans Exposed to Chloroethene* Exposor Site of Site of level of Root# E xposed Control Sox Exposoro NpsIlttM Popolattoo (PRO) Duration of Exposure Target Organ Tuner Type Hunker of Cases Observed Hunker of Cases Observed Relative Risk Bernal plot 7409 death rates N <75 to >700 6-70 years liver cancer for England 1okalat Ion and Males plot oral 4 1.64 7.44 0UlITT Of EVIBEMCE Streogtks of Stody: levels of exposoro of Markers Mere estimated fron air-sample neterlng. Ourat Ion of exposure Mas reported. The exposed population Mas cenpared to death rates (based on age groups) of England and Males. Meekness of Stody: feu deaths Mere reported, ho statistics Mere reported. Overall Adequacy: Halted `Source: Fox and Collier. 197? M /1 7/85 VAB.QD01129512 ) TABLE 9-17 Bioassay Bata for Humans Occupationally Exposed to Ch1oroethenea*b Size of Exposed Population Size of Control Population Sex 4524 Japanese mortality rates H Duration of Exposure Target Organ Tumor Type >1 year all sites liver malignant neoplasm cancer Number of Cases Observed Number of Cases Expected Relative Risk (p value) 37 26.94 1.37 (p<0.0S) 6 2.54 2.36 (p<0.05) Strengths of Study: QUALITY OE EVIDENCE * A large group of workers having at least 1 year of exposure and 10 years latency was studied. Death certificates were obtained for a majority of deceased employees. Weakness of Study: * Overall Adequacy: Exposure levels were not determined. Limited data on diagnosis and cause of death available from death certificates prevented specific classification of cancer types. Adequate Data were for PVC-workers. Non PVC-workers showed no Increase In cancer deaths. I aSource: Nakamara, 1983 *M.evel of exposure not significant VAB.0001129513 1 070*P -124- 1ABLI 9-18 Oleassay data for Huaans Occupationally EiposH it Ch1orMlliene< Site of Exposed Popelalion Site of Control Npolatton Level of Attrition . Target Sox Exposure of Organ Exposure Tuner Type Huaber of Cases Observed Munber of Cases Expected Rclit%lvWc Risk 454 Nimiy CMMr H varies >1 year all sites cancer NarUIUf over liver anglosarcooa Records years* lung cancer colon cancer thyroid cancer skin aelanoai X 20.2 HR 2.0 1.4 0.16 0.0 1.1 HA 1.0 2.1 12.5 5.0 QM41ITY Of E910t8Ct Strengths if Study: Id* codert coosIttod of werkert exposed for at least 1 year davlof a alntaua of 10 years latency. Exposure levels were estlolled. HNkMii if Study: Ike saaII nuaber of cancer deaths prevents a definitive coocleslon. mail Adequacy; Adoguate ^Source: Meldaat et al.t 1984 o *ESt looted 2000 ppo In 1950.1954; 1000 ppo In 1955.1959; 500 ppa In 1960-1947; 100 ppo In 1958.1974 04 Hot applicable; Hi - Hot reported rnmmmmm l t;-| ! f mm VAB.0001129514 10/17/8S Chloroethene has been shown to be carcinogenic In rats, mice and ham sters and Is regarded as a human carcinogen according to the IARC criteria (IARC, 1974, 1979, 1902). Under U.S. ERA'S proposed risk assessment guide lines for carcinogenicity (Federal Register, 1984) chloroethene Is classi fied In Group A. This classification Indicates that there Is sufficient epidemiological evidence to support a causal association between exposure and human cancer. In a battery of carcinogenicity tests of chloroethene Maltonl et al. (1980, 1981, 1982) have reported an Increased Incidence of liver angiosarcoma, kidney nephroblastoma, lung and brain tumors among rats and mice treated by Inhalation or orally and forestomach tumors In hamsters exposed by Inhalation. Numerous other studies (Lee et al., 1978; Hong et al., 1981, MCA, 1980; Hehlr et al., 1981; Suzuki, 1981, 1983; Drew et al., 1983) have confirmed the development of liver angiosarcoma following Inhala tion exposure to chloroethene. In addition to the gavage study by Maltonl (1977a), Feron et al. (1981) and Dow. Chemical Company (1983) have reported a carcinogenic effect on the liver and lungs following oral Ingestion of chloroethene. The predisposition of chloroethene and PVC workers to angiosarcoma of the liver has been reported In several case reports and numerous epidemio logical studies (IARC, 1974, 1979; Monson et al., 1974; Waxweller et al., 1976; Byren et al., 19*76; Fox and Collier, 1977; Nakamura, 1983; Heldaas et al., 1984). These data are sufficient to regard chloroethene as a human carcinogen (IARC group 1). In addition to liver cancer, exposure to chloro ethene has been associated with an Increased risk of lung, brain, hemato poietic and digestive tract cancers. The potency factor (F-factor) for the carcinogenicity of chloroethene will be determined from the available animal studies since exposure data for 0708p w -125- 10/17/85 humans are lacking. Data on the development of liver angiosarcoma among rats exposed by Inhalation (see Table 9-6; Maltonl et al., 1981) could be used to determine a potency factor for exposure by this route (Table 9-19). The unadjusted 1/ED10 was calculated using the computerized multistage model, GLOBAL 82 (Howe and Crump. 1982). The corrected 1/ED10 (F factor) was calculated by multiplying the unadjusted value by the cube root of the ratio of the human body weight (70 kg) to the rat weight (0.35 kg). The F-factor for chloroethene based on the development of liver angiosarcoma was determined to be 1.6 (mg/kg/day)*1. The U.S. EPA (1984a) recently Indicated that the Carcinogen Assessment Group estimated the risk of carcinogenicity of chloroethene following oral Ingestion based on dose-response data reported by Feron et al. (1981) (Table 9-20). The total combined Incidence of liver and lung tumors among female rats exposed through the diet was used to estimate risk. Using the combined Incidence for estimating carcinogenic risk a potency factor of 15.0 was determined. This F-factor Is greater than that derived from the Inhalation exposure study, and Is, therefore, a more conservative estimate of the car cinogenic potency of chloroethene but has been determined using the combined Incidence of liver and lung tumors. Combining tumor Incidences may over estimate carcinogenic potency If tumor Incidence does not represent primary tumors only. According to the Hazard Ranking Scheme for Reportable Quantities for Carcinogenic Potency (U.S. EPA, 1984c) a chemical with an F factor of 10-100 Is placed In Potency Group 2; the IARC classification as a Group 1 compound and the classification of chloroethene In Potency Group 2 ranks chloroethene as being a high hazard for carcinogenicity. 0708p -126- 10/17/85 TAIL! 9.19 Berlvatlon of Potency factor (f) s N*t: Chloroethene oforonce: txposore root* Species: Strain: Sea: Veittele or physical state: * My wetplit:* oration of treataent: oration ef stePy: lifespan ef antaal:* Tarpet orpan: I Tmht type: Caperteental Peses/eapesore (ap/a*):c TransferM Pesos (ap/kp/Pay): Tenor IncIPence: IlnaPJesteP 1/1 ip (f factor): N 1/ftyp |f factor): Naltont ot 1M 1981 Inhalation rat Sprapee>8awley .f air/vapor 0.35 kp SIS Pays op to 1029 Pays op to 1029 Pays liver anplosarceaa 0.0 0.0 0/98) 0.2777771 |ap/kp/Pay)~* V.4 |ap/kp/Pay)~* t liver anplosarceaa 25.4 0.344 1/119 OfstlaateP Neper toP, OaseP on Perat Ion of lonpest stoPy C4L08AL 82 reJecteP tie peoPness ef fit fcypothesls for eapeseres >128 ap/a* > t liver anplosarceaa 43.9 0.840 5/120 liver anplosarceaa 28 1.719 1/40 VAB\001129517 10. 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