Document Ne3KG00E7w59VRpB3Zr0eVGnV

Toxicological Profile for VINYL CHLORIDE rV / Agency for Toxic Substances and Disease Registry U.S. Ftiblic Health Service Comment Period Ends: APR 2 2 1988 CMA 009824 DRAFT TOXICOLOGICAL PROFILE FOR VINYL CHLORIDE Date Published -- January 1988 Prepared by: Technical Resources, Inc. under Contract No. 68-03-3268 Reviaed by: Syracuse Research Corporation under Contract No. 68-03-3521 for Agency for Toxic Substances and Disease Registry (ATSDR) U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA) Published by: OaJt Ridge National Laboratory under DOE Interagency Agreement No. 1423-1423-A1 CHA 009825 r DISCLAIMER Mention of company nama or product doat not constitute endorsement by tb* Apancy for Toxic Substances and Diiaaaa Rrjatry. I CMA 009826 foreword - The Superfund A--ndments and Reauthorlzatlon Act of 1986 (Public Law 99*499) extended and amended the Coaprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Suparfund). This public law (alao known aa SARA) diractad tha Agency for Toxic Substances and Dlaaaaa Registry (ATSDR) to prapara toxicological profilaa for hazardoua aubatancaa which ara neat comonly found at facilitlaa on tha CERCLA Rational Frioritiaa Liat and which poaa tha Boat significant potantial throat to huaan haalth, as datarminad by ATSOR and tha Enviromaantal Protaction Agancy (EPA). Tha liat of tha 100 aoat aignificanc hazardoua aubatancaa waa publiahad in tha Federal Rmgisemr on April 17, 1987. Saction 110 (3) of SARA diracta tha Administrator of ATSDR to prapara a toxicological profile for each aubacance on tha liat. Each profile auat include tha following content: % (A) An exABination, auaaary, and interpretation of available - toxicological inforaation and epldeaiologle avaluationa on tha hazardoua aubatance in order to arcertain the levels of significant huaan exposure for tha substance and tha associated acuta, subacute, and chronic haalth affects, (B) A detamination of whether adequate inforaation on tha health affects of each substance is available or in tha process of developaent to determine levels of exposure which present a aignificanc riak to huaan haalth of acuta, subacute, and chronic haalth affects, and (C) Where appropriate, an identification of toxicological testing needed to identify tha types or levels of exposure that nay present significant risk of adverse haalth affects in humans." This toxicological profile is prepared in accordance with guidelines developed by ATSDR and ERA. The guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary, but no less often than every three years, as required by SARA. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and health effects inforaation for the hazardoua substance being described. Each profile Identifies and reviews the key literature that describes a hazardous substance's toxicological properties. Other literature is presented but described In less detail then the key studies. The profile is not intended to be an exhaustive document; however, aore comprehensive sources of specialty information are referenced. iii CMA 009827 Each toxicological profile begins with e public health statement, which describes in nontechnical language a substance's relevant toxicological properties. Following the statement is material that presents levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Research gaps in toxicologic and haalth effaces Information are described in the profile. Research gaps that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program of the Public Health Service, and EPA. The focus f the profiles is on health and toxicological Information; therefore, wa have included this information in the front of the document. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public, tfe plan to revise these documents in response to public comments and as additional data become available; therefore, we encourage comment that will make the toxicological profile series of the greatest use. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, EPA, the Centers for Disease Control, end the National Toxicology Program. It has also been reviewed by a panel of nongovernment peer reviewers and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. 0 ' fajL+ifl*-' James 0. Nason, M.D., Dr. P.H. Assistant Surgeon General Atelnistrator, ATSDR contents FOREWORD .......................................................................................................... ill UST OF FICURES .......................................................................... '................. vii LIST OF TABLES ............................................................................................... ix 1. PUBLIC HEALTH STATEMENT ..................................................................... 1 1.1 WHAT IS VINYL CHLORIDE? ............................................................ 1 1.2 HOW MIGHT I BE EXPOSED TO VINYL CHLORIDE? .......................... 1 1.3 HOW DOES VINYL CHLORIDE GET INTO MY BODY? .......................... 2 1.4 HOW CAN VINYL CHLORIDE AFFECT MY HEALTH? ............................ 2 1.3 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO VINYL CHLORIDE? ................................... 2 1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS? .......................................................................... * 2 1.6.1 Toxic Effects Other Than Cancer ................................- * 4 1.6.2 Cancer .............................................................................. 4 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ............... .............................. . 4 2. HEALTH EFFECTS SUMMARY......... .................................................... 2.1 INTRODUCTION ............................................ 2.2 LEVELS OF SIGNIFICANT EXPOSURE .............................................. 2.2.1 Kay Studies and Graphical Presentations ................. 2.2.2 Biological Monitoring as a Measure of Exposure and Effects .................................................... 2.2.3 Environmental Levels as Indicators of Exposure and Effects .............. 2.3 ADEQUACY OF DATABASE................................................................. 2.3.1 Introduction ................................................................... 2.3.2 Adequacy of the Database for Health Effect End Points ...................................................................... 2.3.3 Adequacy of the Database for Other Information Needed for Risk Assessment ................... 7 7 8 8 16 16 19 19 19 23 3. CHEMICAL AND PHYSICAL INFORMATION.................................................. 3.1 CHEMICAL IDENTITY...................................................................... 3.2 PHYSICAL AND CHEMICAL PROPERTIES ........................................... 25 25 25 4. TOXICOLOGICAL DATA .............................................................................. 4.1 OVERVIEW ....................................................................................... 4.2 TOXICOKINETICS ............................................................................ 4.2.1 Absorption ...................................................................... 4.2.2 Distribution ................................................................... 4.2.3 Metabolism...................................................................... 4.2.4 Excretion........................................................................ 29 29 30 30 31 32 35 v CMA 009829 ty-h* 4.3 TOXICITY ....................................................................... 4.3.1 Lethality and Decreased Longevity ........... . 4.3.2 Systemic/Target Organ Toxicity ................. . 4.3.3 Developmental Toxicity ................................. 4.3.4 Reproductive Toxicity ............. ...................... 4.3.3 Genotoxicity .................................................... 4.3.6 Carcinogenicity ............................................. . 4.4 INTERACTIONS WITH OTHER CHEMICALS .......................... 3. MANUFACTURE, IMPORT, USX, AND DISPOSAL.......................... 5.1 OVERVIEW ........................................................................ 5.2 PRODUCTION ..................................................................... 5.3 IMPORT ............................................................................ 5.4 USES ............................................................................... 3.5 DISPOSAL........................................................................ 6. ENVIRONMENTAL FATE.............................................................. 6.1 OVERVIEW ....................................................................... 6.2 RELEASES TO THE ENVIRONMENT .................................... 6.3 ENVIRONMENTAL FATE .................................................... 6.3.1 Air ................................................................... 6.3.2 Water ................................................................ 6.3.3 Soil ................................................................. 7. POTENTIAL FOR HUMAN EXPOSURE ........................................... 7.1 OVERVIEW.......... .......................................................... 7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 7.2.1 Air ................................................................... 7.2.2 Water .......................................................... 7.2.3 Soil ................................................................. 7.2.4 Other ................................................................ 7.3 OCCUPATIONAL EXPOSURES ............................................. 7.4 POPULATIONS AT HIGH RISX ......................................... 8. ANALYTICAL METHODS .............................................................. 8.1 ENVIRONMENTAL MEDIA.................................................. 8.2 BIOMEDICAL SAMPLES .................................................... 9. REGULATORY AND ADVISORY STATUS ....................................... 9.1 INTERNATIONAL............................................................. 9.2 NATIONAL ....................................................................... 9.2.1 Regulations .................................................... 9.2.2 Advisory Guidance ........................................ 9.2.3 Data Analysis ............................................. 9.3 STATS ............................................................................. 10. REFERENCES ................. ........................................................ 11. GLOSSARY................................................................................ APPENDIXES A. PEER REVIEW ................................................................... B. FEDERAL REGISTER ANNOUNCEMENT.................................. 39 39 40 46 49 50 54 60 63 63 63 63 63 64 65 65 65 65 65 66 66 69 69 69 ' 70 ` 71 71 71 72 73 73 73 79 79 79 79 80 80 81 S3 101 107 109 vi CMA 009830 LIST or riOTXES l.X Health effect* froa breathing vinyl chloride ............................. 1.2 Health effects froa ingesting vinyl chloride ............................. 2.1 Effects of vinyl chloride*inhalation exposure .......................... 2.2 Effects of vinyl chloride*oral exposure ....... 2.3 Levels of significant exposure for vinyl chloride*- ................. inhalation............................................................................................... 2.4 Levels of significant exposure for vinyl chloride**oral ......... 2.3 Urinary output of thiodiglycolie acid froa volunteers 12 h after exposure to vinyl chloride in air for 12 h............... 2.6 Adequacy of the database on health effects of vinyl chloride (huaan data) ......................................................................................... 2.7 Adequacy of the database on health effects of vinyl chloride (aniaal data) ....................................................................................... 4.1 Proposed netabolle pathways for vinyl chloride ......................... 3 5 9 10 11 12 17 20 21 33 vii ft CMA 009831 Lin or TABLES 3.1 Chaaical Identity of vinyl chlorlda ............................................... 3.2 Physical and chaaical properties of vinyl chlorlda ................... 4.1 Excretion of radloaecivicy in rata exposed to 14C-vinyl chlorlda in air for 6 h .................................................................... 4.2 Pareant of adainlstsrad dosa of radioactivity axcratad 72 h following a singla oral dosa of -vinyl chlorlda in rats .................................................................................................. 4.3 Expariaantal protocol for anlaal axposura to vinyl chlorlda .. 4.4 Ganotoxleity of vinyl chlorlda in vivo ......................................... 4.3 Ganotoxleity of vinyl chlorlda in vitro ...................................... 4.6 Tunor ineidanca in aala and famala Spragua-Dawlay rats axposad by inhalation to vinyl chlorlda 4 h/day, 3 days/vaak for 32 vaaka .................................................. 4.7 Tunor ineidanca in tfistar rats orally axposad to vinyl chlorida ..................................................................................... 8.1 Analytical nethoda for tha quantification of vinyl chlorida .. 26 27 36 38 41 31 S3 56 58 74 ix * CMA 009832 1. FOBLIC HEALTH STATEMEMT 1.1 HHAT IS VIHTL CHLORIDE? . Vinyl chloride la a colorleaa fas with a alld, swaac odor. Host of cha vinyl chlorida produead in tha UniCad Statas la uaad to make -polyvinyl chlorida (PVC), a material uaad to aanufactura a variety f plastic and vinyl products ineludinf plpas, vira and cabla coatings, packaging natariala, fumitura and automobile upholatary, wall coverings, housawaras, and automotive parts. Much saallar amounts of vinyl chlorida ara usad as a refrigerant gas and in tha aanufactura of othar chlorinated coapounds. Tha aajor sources of release of vinyl chlorida to the environment are atmospheric emissions and wastewater discharges from tha plastics Industries (primarily vinyl chlorida and PVC manufacturers). Host of tha vinyl chlorida released to tha environment eventually ends up in air. > 1.2 HOV MIGHT I BE EXPOSED TO VXMTL CHLORIDE? Humans ara exposed to vinyl chlorida from environmental and occupational sources. Tha low levels of vinyl chlorida found in th environment (oftan called background levels) ara usually mors than a thousand times lower chan levels found in occupational locations. Background levels in the environment are usually expressed in terms of parts of vinyl chloride present in a billion parts of air or vater (ppb). Background levels found in the air we breathe result from the discharge of exhaust gasses from factories that manufacture or process vinyl chloride, or evaporation from areas where chemical wastes are stored. Highest background levels have been measured in air near vinyl chloride factories or over chemical waste storage areas. Air inside new ears may contain levels vinyl chloride higher than expected background levels, because vinyl chloride may seep into the air fr m the new plastic parts. Background levels in drinking water come from factories that release wastes Into rivers and lakes, from seepage Into vater in areas where chemical wastes are stored, or from contact with polyvinyl chloride pipes. In the past, concentrations exceeding expected background levels were present in foods packaged in plastic that contained vinyl chloride. Occupational sources, such as what night be experienced in vinyl chloride manufacturing or processing factories, may result in exposure to levels in the air much higher than those from environmental sources. Levels in the air in occupational locations are usually expressed in terms of parts of vinyl chloride per million parts of air (ppm). 1 CHA 009833 * 2 1.3 HOT DOCS VINYL CHLORIDE GET INTO MY BODY? The most Hkaly rout# for vinyl chi rlda to enter the body Is by braathlng contaminated air containing the vapor. This route of exposure nay ba important for parsons anployed in vinyl chlorlda manufacturing or processing, but nay also ba of concern for those living in a community where vinyl chloride plants are located, or those living near hazardous waste disposal sites. Vinyl chloride can also enter the body by eating food or drinking water containing the compound. Insignificant amounts of vinyl chloride can enter foods that are packaged in plastic made from polyvinyl chloride and insignificant amounts can enter drinking water transported in polyvinyl chloride pipes. In addition, vinyl chloride may be present in drinking water contaminated with hazardous waste. Levels of vinyl chloride present In drinking water and packaged foods and beverages are far below those expected to have an effect on health. Absorption of vinyl chloride through the skin is not likely to be important. 1.4 HOT CAM VIHYL CHLORIDE AFFECT MY HEALTH? Short-tern exposures to very high levels in contaminated air can cause dizziness, giddiness, stumbling and incoordination, headache, unconsciousness, and death. Long-term exposure to lower concentrations, for example, in factories where vinyl chloride was nada or processed, has caused "vinyl chloride disease," which Is characterized by severe damage to the liver, effects on the lungs, poor circulation in the fingers, changes in the bones at the end of the fingers, thickening of the skin, and changes in the blood. Increased risk of cancer of the liver, brain, lungs, and possibly other organs, and increased risk of miscarriage have been associated with breathing air in factories containing vinyl chloride. Health effects have not been associated with the very low levels of vinyl chloride measured in drinking water or foods. 1.3 IS THERE A MEDICAL TEST TO DETERXIHE WHITHER I HAVE SEEM EXPOSED TO VIHYL CHLORIDE? Vinyl chloride can be detected in urine and body tissues, but the tests are not a reliable indicator of exposure. Measuring the amount of the predominant breakdown product of vinyl chloride in the urine nay give seme indication of recent exposure; however, people differ in the quantity of excretion of this breakdown product. This method, therefore, is not a reliable indicator of either the level or the duration of exposure, particularly at low exposure levels. The laboratory tests cowndy used by doctors to evaluate liver damage end liver function generally are not reliable for monitoring liver damage from vinyl chloride exposure. l.g WHAT LEVELS OF EXPOSURE HAVE RESULTED HI HAIKFUL HEALTH EFFECTS? The graphs on the following pages show the relationship between exposure to vinyl chloride and known health effects. In the first sec of graphs labeled "Health effects from breathing vinyl chloride" (Fig. 1.1), exposure is expressed in parts of vinyl chloride per nillion parts CMA 009834 3 SHORT-TERM EXPOSURE (LESS THAN OH EQUAL TO H DAYS) EFFECTS IN ANIMALS CONC.M ah (ppm) EFFECTS M HUMANS 10,000 ---------------EFFECTS ON THE SRAM DEATH 1,000 LONG-TERM EXPOSURE (GREATER THAN 14 OAYS) EFFECTS M ANIMALS CONC.M m (ppm) EFFECTS IN HUMANS 10.000 KJONCY EFFECTS---------------- QUANTITATIVE DATA WERE NOT AVAILABLE EFFECTSON I THE UNBORN ] L 1.000 100 100 REDUCED UFESFAN-- TESTICULAR EFFECTS 10 LIVER EFFECTS 10 1J) LEVS. FOR EFFECTS OTHER THAN CANCER 1.0 01 0.1 Fig. 1.1. HmRS tffacts tnm ImiMn tayl cttarMt. CMA 009835 % 4 f air (ppm). In the second sot of graphs. the same relationship is shown for ths known "Health effects from ingesting vinyl chloride" (Fig. 1.2). Exposures ere expressed in milligrams of vinyl chloride per kilogram of body weight per day (mg/kg/day). In both graphs, effects in animals are shown on the left, effects in humans on the right. The first column, labeled "Short-term exposure," refers to effects associated with exposure durations of 14 days or lass. The column labeled "Long-term exposure" refers to exposures lasting longer than 14 days. The levels marked on the graphs as "Minimal risk for effects other than cancer" are estimates based on data obtained from laboratory animals, and hence are subject to the uncertainties involved in using animal data to predict effects in humans. This data extrapolation is necessary, however, because quantitative exposure data were not available for humans. 1.6.1 Toxic Effects Other Than Cancer For breathing vinyl chloride, animal data were sufficient to estimate that short-term exposure to 0.7 ppm would result in minimal risk from effects other than cancer. The data did not provide sufficient information to estimate with confidence a level that would be safe for long-term exposure. For ingesting vinyl chloride, minimal risk of effects other than cancer is expected for lifetime "doses" of 6.0013 mg/kg/day, based on data from laboratory animals. 1.6.2 Cancer From available data in animals, the Environmental Protection Agency (EFA) has estimated that breathing air containing 1 ppm vinyl chloride every day, all day, for 70 years, increases, at the most, risk of 1100 persons in a population of 10,000 (or 1,100,000 persons in a population of 10,000,000) developing cancer. Consuming 1.0 Mg/kg/day vinyl chloride from food and water every day for 70 years increases, at the most, risk of 23 persons in a population of 10,000 (or 23,000 persons in a population of 10,000,000) developing cancer. It should be noted that these risk values are plausible upper-limit estimates. Actual risk levels are unlikely to be higher and may be lower. 1.7 WHAT MCOHMEHDATIOH8 HAS THE FEDHAL OOVIUXZHT HADE TO FtOTECT HUMAB HEALTH? The Occupational Safety and Health Administration (OSHA) regulations state that a worker must not be exposed to a concentration of vtsgft chloride in air chat exceeds 1 ppm over any 8-hour work period, and that ths concentration must not exceed 5 ppm for more than 15 minutes. The national Institute for Occupational Safety and Health (M10SH) recommends that workers exposed to any measurable amount of vinyl chloride wear an air-supplied respirator. EFA has determined that factories must limit air emission of vinyl chloride to 10 ppm. Pursuant to the Safe Drinking Water Act, EFA established that community drinking water systems that regularly serve the same 25 persons for at least 8 months of the year must limit vinyl chloride in CMA 009836 * SHORT-TERM EXPOSURE (LESS THAN OR EQUAL TO 14 DAYS) EFFECTS IN ANIMALS OOSE (mgfto/Oay) EFFECTS IN HUMANS 1,000 DEATH QUANTITATIVE DATA WERE NOT AVAILABLE 100 LONG-TERM EXPOSURE (GREATER THAN 14 DAYS) EFFECTS IN ANIMALS DOSE (mqAp/dty) EFFECTS IN HUMANS 1.000 100 10 E(HFOFEOCPTS ON 10 1.0 1.0 DECREASED LiPE SPAN ANO LIVER EFFECTS 0.01 0.001 Fig. 1J. Health effect* froa 0.01 0.001 ttay! chtorMe. MNIMAL RISK LEVEL FOR EFFECTS OTHER THAN CANCER CMA 009837 6 cha drinking water to 0.002 ag/L, starting January 9, 1989. In ordar to limit ingastlon of vinyl chlorlda in fo d, tha Food and Drug Administration (FDA) raeantly amended its ragulations ragarding tha vinyl chlorlda contant of various plastics usad for food packaging. Limits ranga from 5 to SO ppm, dapandlng on cha nature of tha plastic and its usa. In ordar to exercise control ovar tha handling of vinyl chlorlda, EPA has designated tha chemical as a hazardous constituent of solid waste. If quantities graatar than 1 pound are released to cha environment, tha National Response Canter must be notified immediately. CMA 009838 % 2. HEALTH EFFECTS SUMMARY 2.1 nmODOCTIOH This sseclon sutmaarlzes and graphs data on eho health effects concoming exposure co vinyl chloride. Ths purposo of chla soeclon is Co -prosonc 1ovals of slpiifleant exposure for vinyl chloride bosod on koy toxicological studios, opldonlologleal Invoatigatlons, and environmental exposure data. The Information presented in this section is critically evaluated and discussed In Sect. 4, Toxicological Data, and Sect. 7, Potential for Human Exposure. This Health Effects Sunary section comprises two major parts. Levels of Significant Exposure (Sect. 2.2) presents brief narratives and graphics for key studies in a manner that provides public health officials, physicians, and ocher Interested individuals end groups vith (1) an overall perspective of the toxicology of vinyl chloride and (2) a summarized depiction of significant exposure levels associated withvarious adverse health effects. This section also includes information on Che levels of vinyl chloride that have been monitored in human fluids and tissues and information about levels of vinyl chloride found inenvironmental media and their association with human exposures. The significance of the exposure levels shown on the graph may differ depending on the user's perspective. For example, physicians concerned with the interpretation of overt clinical findings in exposed persona or with the identification of persons with the potential to develop such disease may be interested in levels of exposure associated with frank effects (Frank Effect Level, PEL). Public health officials and project managers concerned with response actions at Superfund sites may want information on levels of exposure associated with more subtle effects in htaans or animals (Lowest-Observed-Adverse-Effect Level, t/uet.) or exposure levels below which no adverse effects (No-ObservedAdverse-Effect Level, NQAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels) are of interest to health professionals and citizens alike, Adequacy of Database (Sect. 2.3) highlights the availability of key studies on exposure co vinyl chloride in the scientific literature and displays these data in three-dimensional graphs consistent with the format in Sect. 2.2. The purpose of this section Is to suggest where there might be Insufficient information to establish levels of significant human exposure. These areas will be considered by th Agency for Toxic Substances and Disease Registry (ATSDR), EPA, and the National Toxicology Program (NTP) of the U.S. Public Health Service in order co develop a research agenda co provide this information. 7 CMA 009939 8 2.2 LEVELS OF SIGNIFICANT EXPOSURE To holp public health professionals sddrsss ths needs of prs ns living or working near hazardous vasea sicas, cha toxicology dots summarized in this soccion ara organized first by routs of exposure** inhalation. Ingestion, and darnel*-and then by toxicological end points that are categorized into six general areas*-lethality, systenic/target organ toxicity, developmental toxicity, reproductive toxicity, genetic toxicity, and carcinogenicity. The data are discussed in terns of ehree exposure periods*-acute, lnternadiate, and chronic. Two kinds of graphs are used to depict the data. The first type is a "thermometer* graph. It provides a graphical siaaary of the human and aninal toxicological end points (end levels of exposure) for each exposure route for which data are available. The ordering of effects does not reflect the exposure duration or species of tested. The second kind of graph shows Levels of Significant Exposure (LSE) for each route and exposure duration. The points on the graph showing NOAELs and LOAELs reflect the actual doses (levels of exposure) used In the key studies. No adjustments for exposure duration or intermittent exposure protocol were nade. Adjustments refleeting the uncertainty of extrapolating aninal data to nan, intraspecies variations, and differences between experimental vs actual human exposure conditions were considered when estimates of levels posing nlnlnal risk to human health were nade for noncancer and points? These minimal risk levels were derived for the most sensitive noncancer end point for each exposure duration by applying uncertainty factors. These levels are shown on the graphs as a broken line starting from the aetual dose (level of exposure) and ending with a concave- curved line at Its terminus. Although methods have been established to derive these minimal risk levels (Barnes et el. 1987), shortcomings exist in the techniques that reduce confidence In the projected estimates. Also shewn on the graphs under the cancer end point are lowlevel risks (10*4 to 10*7) reported by EFA. Zn edditlon, the actual dose (level of exposure) associated with the tumor Incidence is plotted. 2.241 Key Studies and Graphical Presentations Dose-response-duration data for the toxicity end carcinogenicity of vinyl chloride are displayed In two types of graphs. These data ara derived from the key studies described In die following sections. The "thermometer* graphs la Figs. 2.1 and 2.2 plot exposure levels vs NOAELs and TftAvr- for various effects and'durations of Inhalation and oral exposures, respectively. The graphs of levels of significant exposure in Figs. and 2.4 plot end-point*specific NOAELs and LOAELs and minimal 1evolve? risk for acute (<1A days), intermediate (13-364 days), and chronic (k365 days) duration for inhalation and oral exposures, respectively. 2.2.1.1 Inhalation exposure Lethality and decreased longevity. Acute occupational exposure to high unspecified concentrations of vinyl chloride has caused death in hunans (ACCIH 1986a). Guinea pigs exposed to 100,000 ppm died vlthin 30 minutes as a result of central nervous system (CNS) depression (Patty CHA 00984 ft 9 i 1.000.000 i- Miarr. lc* jo ecwnwyou* OUMOAMO. AND MATH. M40 MN. MMIOMUO cm (w**naoeA'n.*h,cn*uouo OUMiAMtt.ATMaA.IMN 10.000 - NAT. TCTOGnY MM. UMONTHttMIMttOIIDII nat. 0MU0PanM.TrAaLaTaBTNvD. iiov.ouAovmAvMttn.MmiiaNnMunirsn' aAT.0e0MMOTWM. TBMC1TV. 7-0 QAVtt MTBOMTTWT U MOUOtt ACUTI LfTNM/TT. IMArOTOWOTY I OATtt, MIWMTT1NT 0 NAT. ACaoUrfitNUMTMMArUuToYM. M. Tt*WAMBTNTtIHNtronwonwr NAT. IMAlUfVAUUTi.AMOWTHO. MTIMATTMr 09 NAT. DMUMMITALiaNeiTV. MDAVtt. NAT, MJHMNM.A-13 MONTI NAT. ItMONTNtt MIMMII Ml NAT. I looooo A UOIIMITI MO f NIT. IMAW31QUOT7 OIOT1M. OiriMAHXr NAT. MMOMIM MimoTTINT O IOAOUAONMMAU Fig. 2.1. Effocta of vfcyl lU A CMA 009841 10 ANIMALS (m?ke/day) 1000 i-- RAT. LD, . rat, WATOxocrrr, 13 weeks 100 HUMANS QUANTITATIVE DATA WERE NOT AVAILABLE O RAT. HEPATOTOWaTY. 13 WEEKS RAT, HCMATOLOOC EFFECTS, LIFETIME O RAT, HEMATOLOOC EFFECTS. UPETIMS RAT, CANCER. UKETMC RAT, 0CCREASED SURVIVAL, HEPATOTONCITY, UflETME O RAT. DECREASO SURVIVAL, HEPATOTODOCITY, UKCTME LOAEL O NOAEL FI*. 12. Elftctt of tM cfcfariSt -ontf k*wi. CMA 009842 % ACUT1 (01AOAVOI OOVOO* UTHAUTY USUAL CMW (tMHIUya LtTMMjrv OMAN OUCTCN MOW OMOOAVOI MCISASSO TAMIT LONOOVTTY OAOAN CANCOO 1.000.000 r 100.000 10.000 1.000 100 10 MCN0 OM r 00 m(UW) rm r KtMNO tj* t'uvm 1.0 0.1 0.01 \i/ 0.001 10"* . 0.0001 N 0 0001 r HAT A LOAOL'AOR O--------- N1WMOI II VI/ V0SATMOAMMTC0 CNONKCSI 10* . L1VSL0 10-' . FI*. 13. Lorolo for Ttaji CMA 009843 12 acuti <*14 WS MTVMDWV <1*00* OAY* LKTH^TTV DUtSVffTcAOl* TOAMMOAKNT LffTMAUTY TONMOANT OWUWCTOO>N OLOONCMMVAMffVO TO4MWHN CANCH r100 10 |tW) roMm l 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 0r MT .MkOT*aM.MNOHNiOMk >4III / MMMM. MW L*Vt nX4. Lmb frrftayi (srauno 10-* hWuAmKLmIvuenLcSca to-'-I CMA O09Q44 13 c *1. 1930). Levels plotted as LQAELs n the graphs In Figs. 2.1 and 2.3 IneludA a 2-h LC50 of 230,800 ppa in rabbles (EFA 1985a), a lsvsl of 100,000 ppa ehae was lsehal in gulnsa pigs afesr 30 to 60 ain (Patty st al. 1930), a lavsl of 1000 ppa that dsersassd survival in mica sxpossd intsroittsntly for 5 days (Las at al. 1977a), and a laval of 50 ppa that daeraasad survival in rats and ales sxpossd intaraittantly for 6 to 12 nonths (Las at al. 1977a, Hong at al. 1981). Systemic/target organ toxicity, ftmans occupationally sxpossd to high lavsls of vinyl chloride bava suffered froa a syndroms called vinyl chlorlda dlsaasa, which displays aanifold signs of toxicity involving the liver, CHS, and peripheral circulation and nerves. Exposures have not been quantified, however, and thresholds for this syndrona have not been identified. Important target organs in animals are the liver and CHS. CHS effects generally follow acute exposure to high levels (see Figs. 2.1 and 2.3), such as 8000 ppm associated with CHS effects in humans (Lester et al. 1963), 70,000 ppm associated with anesthesia in dogs (Oster et al. 1947), and 50,000 ppm associated with intoxication in rats (Lester et al. 1963). CHS effects involving occupational exposure have been reported, but exposures have not been quantified (Dincava at al. 1985, Fertlconi at al. 1986, Halama at al. 1985). The liver appears to be the most sensitive orgsn in humans and animals. Acuta hepatotoxlcity was observed in mice dying after intermittent exposure to 1000 ppm for 5 to 9 days (Lee et al. 1977*% (see Figs. 2.1 and 2.3). In rats, exposures of intermediate (6 months) duration to 10 ppa were a LOAEL for liver effects (Bi et al. 1985) (see Figs. 2.1 and 2.3). A chronic LOAEL for liver effects in rats vas observed at 50 ppa in a chronic (12 months) experiment (Lae at al. 1977a) (see Figs. 2.1 and 2.3). However, since this was the lowest concentration tested, a chronic NAOEL could not be determined. After 12-month exposure, 100 ppa was a LOAEL and 10 ppa was a HOAEL for reduced terminal body weights in rats (Bi et al. 1985) (Fig. 2.1). Hininal risk levels are not estimated in Fig. 2.3 based on liver toxicity at the acuta level of 1000 ppm, because this level was a frank effect level, and a N0AEL or LOAEL was not Identified. A minimal risk level of O.00S ppm fox intermediate exposure is based on the LOAEL for liver effects observed in rats exposed intermittently to 10 ppa for 6 months (BI et al. 1985). Data were not sufficient to estimate a minimal risk level for chronic exposure. Developmental toxieity. In htaans, increased Incidence of fecal loss (Infante et al. 1976, ftacweller at al. 1977) has been associated with occupational exposure to vinyl chloride, but exposures have not bean quantified. Animal data identify a HOAEL for developmental toxicity in rabbits exposed intaraittantly to 2500 ppa on days 6 to 18 of gestation (John et al. 1977). The some study identifies intermittent exposure of mice at 50 ppm on days 6 to 15 of gestation as a HOAEL and similar exposure of rats at 2500 ppm as a LOAEL. A HOAEL for rats of 1500 ppm exposed intermittently on 10 days of gestation was identified from a study by Ongvary et al. (1978). The animal data are depicted in Figs. 2.1 and 2.3. A minimal risk leval of 0.7 ppa is estimated for acute exposure based on the HOAEL of 50 ppa for developmental toxicity in Sice (John CHA 009845 % 14 e *1. 1977). This NOAEL Is comfortably bolow tho NOAEL of 230 ppm for lotholity in mlco and bolow tho frank offact lovol of 1000 ppm for hepatotoxicity in tho acuto phaso of tho Loo ot al. (1977a) study. Two studios Indicating subtle offocts at unusually low exposure levels (Mirkova at al. 1978, Sal'nikova and Kitsovskaya 1980) wore insufficiently reported and judged to be inadequate for critical evaluation. Kaprodactlve toxicity. Two occupational studies associated effects on sexual and endocrinological function in nan sad woman and on gynecological health in women with exposure to vinyl chloride (Makarov 1984, Makarov at al. 1984). Although exposure levels were estimated, the reports were inadequately reported for critical evaluation, and the dace from these studies are not plotted on die graphs. data are limited to a 1-year study In rats in which intermittent exposure to 100 ppm was a LQAZL for testicular effects and 10 ppm was a NOAEL (see Figs. 2.1 and 2.3). Genotoxiclty. Several studies reviewed in Sect. 4.3.5.1 on genotoxiclty in humans demonstrate that vinyl chloride causes chromosomal aberrations in lymphocytes in occupationally exposed workers. The key study (Hansteen et al. 1978) identified a NOAEL of 1 ppm for this effect. Positive results were obtained in microorganisms in nonhuman systems, in the recessive lethal test in Drotophll* and in other mammalian test systems (see Section 4.3.3.2 on genotoxiclty in animals). Carcinogenicity. Several epidemiology studies, many of which have been reviewed by EFA (1985b), associated occupational exposure to vinyl chloride with cancers of the liver, brain, lung, and possibly other sites. Concentrations of vinyl chlotlde in the workroom air were not measured. In the key studies used by EFA (1985b) to derive an inhalation potency factor (Maltoni at al. 1980, 1981), rats were exposed intermittently to 1 to 30,000 ppm for 52 weeks, and mice and hamsters were exposed to 50 to 30,000 ppm for 30 weeks followed by an observation period. Estimation of carcinogenic potency was based on the Incidence f liver angiosareomas in rata. A statistically significant Incraase in tumor Incidence was observed in all three species at *50 ppm. Several other inhalation studies, reviewed in Sect. 4.3.8, Carcinogenicity, support the carcinogenicity of Inhalation exposure to vinyl chloride. Studies by Suxuki (1981, 1983) appear to define intermittent exposure of mice to 10 ppm as a low level associated with increased incidence of lung cancer, although statistical analyses were not performed. Mice were exposed for 4 weeks followed by a 41-week observation period. The concentration of 30 ppm associated with cancer in rats and hamsters end the eameantratlan of 10 ppm associated with lung cancer in mice are depleted in Figs. 2.1 and 2.3. From the incidence of liver angiosarcomas in rats of both sexes in the Maltoni et al. (1980, 1981) experiments, and based upon the absorbed doses of vinyl chloride, a q * of 2.95 x 10*1 (mg/kE/^y)*1 estimated by EFA (1985b). Asluming humans breathe 20 e3/day, absorb 30% of Inhaled vinyl chloride, and weigh 70 kg each, estimated concentrations associated with cancer risks of 10 , 10*5, 10*", and CMA 009846 t "i 15 10*7 are 9 x 10*, 9 x 10*, 9 x 10', and 9 x 10*7 ppm, respectively ( Flft. 2.3). 2.2.1.2 Oral exposure Lethality and decreased longevity. Oral lethality data are limited to an LD50 in rata of 500 mg/kg (Sax 1984), and an efface laval of 1.3 mg/kg/day and a NOAEL of 0.13 ag/kg/day in a lifatiaa dietary study in rats (Dow Chemical Company 1984, Til at *1. 1983) (sea Figs. 2.2 and 2.4). Systemic/target organ toxicity. Oral toxieicy data vara not located for humans. The liver appears to be the critical target organs for aalaals orally exposed to vinyl chloride. In a 13-week gavage study in rata, 300 mg/kg/day was a MAIL and 30 ag/kg/day was a NOAEL for hepatocoxlclty (Feron at al. 1975), (see Figs. 2.2 and 2.4). A minimal risk level of 0.30 mg/kg/day is estimated for intermittent oral exposure based on the NOAEL of 30 mg/kg/day (see Fig. 2.4). In a lifetime dietary seudy in rats (Dow-Chemical Company 1984, Til at al. 1983), a LOAEL of 1.3 mg/kg/day and a NOAEL of 0.13 mg/kg/day for hepatotoxiclty were identified (see Figs. 2.2 and 2.4). A minimal risk level for chronic oral exposure is estimated from the NOAEL of 0.13 mg/kg/day for hepatotoxiclty because this dose is also a NOAEL for decreased longevity. The minimal risk level is -0.0013 ag/kg/day (see Fig. 2.%). Other effects observed in a lifetime dietary study in rats by Feron; ec al. (1981) Include mild hematological changes at kl4.1 ag/kg/day, tot not at 5.0 mg/kg/day. These data are depleted in Fig. 2.2, but have ne bearing on critical evaluation. Developmental toxicity. Data were not located regarding developmental toxicity in orally exposed humans or animals. leproductive toxicity. Data were not located regarding reproductive toxicity in orally exposed humans or animals. Oenotoxlclty. See Sect. 2.2.1.1 on genotoxlclty associated with inhalation exposure. Carcinogenicity. Data were not located regarding cancer in orally exposed humans. In the key lifetime dietary study in rats (Feron et al. 1981) used by ETA (1985a, 1987a) to derive a potency estimate for oral exposure, rats vers fed diets that provided vinyl chloride at doses of 1.8, 5.8, or 17.0 ag/kg/day for lifetime. An increased Incidence of neoplastic nodules of the liyer end/or hepatocellular carcinoma, statistically significant, was observed at ml.8 ag/kg/day in females and at *5.6 ag/kg/day in males. The lover dose is depleted in Fig. 2.4 as toe lowest dose in animals associated with cancer. EPA (1985a, 1987a) estimated cancer potency at 2.3 (ag/kg/day)*^ based on the combined Incidence of liver and lung twois in both sexes of rats. Doses associated with excess cancer risks of 10*, 10*, 10*, and 10*7 are plotted In Fig. 2.4. 2.2.1.3 Dermal exposure Pertinent data regarding toxicity In humans or animals dermally exposed to vinyl chloride were not located in the available literature. CMA 009847 % 16 2.2.2 Biological Houle ring es Measure of Exposure and Iffacta 1 logical monitoring for axposura to vinyl chloride has had limited success. In an early study, Baretta at al. (1969) attempted to correlate postexposure concentrations of vinyl chloride in exhaled air with exposure levels. Although there was a very close relationship between exposure levels iSO ppm and levels In expired air, the method does not appear to be useful at exposure concentrations <30 ppm. Hath da have been devised to quantify vinyl chloride In urine (van Sittert and da Jong 1985) and tissue (Zuecato at al. 1979), but metabolism occurs s quickly that quantification of levels of unchanged compound in urine is not likely to reflect exposure levels, particularly at low concentrations. Mora recently, biological monitoring has focused on correlating urinary levels of thiodiglyeolic acid, the major urinary metabolite of vinyl chloride (Green and Hathway 1977), with exposure levels in the air (Hager at al. 1982). The results, presented in Pig. 2.3, suggest a reasonable correlation between exposure concentration and urinary output of thiodiglyeolic acid. In reviewing these data, however, Tarkovski (1984) noted that a great deal of individual variation occurred, and the correlation vas not strong enough to render this meehod reliable at exposure concentrations of <3 ppm. Tarkovski (1984) concluded that n reliable method exists for biological monitoring of exposure to vinyl chloride. As indicated in Sect. 4.3.2.1, Hepatotoxicity, liver disease is probably the most common adverse effect associated with exposure to vinyl chloride. Generally, routinely performed biochemical screening andllver function screening tests have not been useful in monitoring the presence, severity, or progress of vinyl chloride disease (Lee at al. 1977b, Lilia at al. 1973). More recently, Doss at al. (1984) measured total urinary porphyrins and secondary urinary eopfoporphyrln in several patients with liver disease resulting from exposure to vinyl chloride. These investigators observed a correlation between slightly to moderately elevated total urinary porphyrin and the early stages of toxic liver disease. Particularly noted was a marked elevation in urinary coproporphyrin. In cases of chronic liver disease, total urinary porphyrin vas markedly elevated to 3 to 6 times the upper normal limit, but coproporphyrin appeared to be elevated relatively less than was observed for acute toxicity. The investigators observed that elevated urinary coproporphyria la a common clinical pathological finding in vinyl-chloride*related liver disease and may be useful In monitoring chronic exposure sad progress of the clinical case. 2.2.3 Environmental Levels as Indicators of Kxposure and effects 2.2.9.1 Levels found in the environment Levels of vinyl chloride in environmental media are typically low and, generally, are not likely to result in significant human exposure. The most important medium for human exposure is air. Atmospheric levels in most places are usually below the level of detection (Stephens et al. 1986; Grimsrud and Rasmussen 1975a,b; Harkov et al. 1984; Uallace et al. 1984; EPA 1983b). Levels from trace to 105 Mg/m3 (0.4 ppm) have been CMA 009848 17 CONCENTRATION N AH (ppm) Flf. UL --tyt af uti tnm ntmmn 12 fc aftw *xpiwr* to fhyt cWarMa to air for 12 II S--rcr. Tarkawakl 1N4 CMA 009849 18 found near vinyl chloride production plant* (Gordon and Meeks 1977, Felllzzarl at al. 1979, 1ARC 1979, EPA 1985b), and lavals hava ranged froa undetectable to 23.4 pg/a^ (0.01 ppa) over landfills (Stephens at al. 1986, Baker and Mackay 1985). It Is unlikely that levels In ambient air would result In significant exposure. Several epldealologleal studies associated occupational exposure with adverse health effects. Including cancer; however, these studies (see Sect. 4, Toxicological Data) did not quantify exposure. A NIOSH survey of three vinyl chloride manufacturing plants reported a timeweighted average concentration of 0.18 to 69 ag/a^ (0.07 to 27 ppm) in workplace air (Flshbeln 1979). Concentrations in sons plants were as high as 100 to 800 ag/a-* (39 to 315 ppa) (Flshbeln 1979). There seems little doubt that occupational exposure reaaina the aost Important source of exposure to vinyl chloride. Levels In drinking water as high as 10 ag/L have been detected (Dyksen and Hess 1982, HSDB 1987), but aost aonitoring studies have reported no detectable vinyl chloride in drinking water (HSDB 1987, Conigllo et al. 1980). Data were not located regarding the aonitoring of vinyl chloride in soil, but exposure froa contact with eontsainated soil is likely to be negligible because dernal absorption is not considered significant (Hefner et al. 1973a). In the past, vinyl chloride had been detected in various foods, as. a result of migration from polyvinyl chloride food wrappings and containers (EFA 1985b). Currently, the FDA regulates the use of vinylchloridecontaining polymers to aalntain levels of vinyl chloride In food at S3 ppb. A recent report suggests that migration of vinyl chloride into food froa polymers containing very low levels would be negligible, and that intake froa food is expected to be negligible (Kontoainas et al. 1985). 2.2.3.2 Human exposure potential Monitoring data indicate that people living in the vicinity of vinyl chloride, PVC, or vinyl chloride copolymer manufacturers, or hazardous waste sites that contain vinyl chloride, would be exposed to this compound through Inhalation of eontsainated air, whereas people not living near these sources would bet exposed to negligible levels. Locations of large industrial sources include, but are not limited to: Flaqueaine, Louisiana; Houston, Texas; Lake Charles, Louisiana; Calvert City, Kentucky; Feint Coafort, Texas; Oklshoes City, Oklahoma; Baton Rouge, Louisiana; Delaware City, Delaware; Fansacola, Florida; and Aberdeen, Massachusetts (GMR 1986a,b). The greatest likelihood for human inhalation exposure to vinyl chloride is occupational. N10SH estimated that 17,000 workers are definitely exposed to vinyl chloride, and workava probably exposed aey be as many as 2.2 Billion (Sittig 1985). The level of vinyl chloride in drinking water is expected to be highest in areas where the raw water supplies are eontsainated with vinyl chloride. The aost probable source of surface water contamination is wastewater froa vinyl chloride, PVC, and vinyl chloride copolymer aanufecturers. The aost probable sources of groundwater contamination are landfills. It has been shown that use of PVC pipes aay resule in leaching of vinyl chloride monomer into drinking water supplies; CMA 009850 19 however, the concentrations In drinking water chat occur from these plpaa art balow chosa axpaccad Co causa advarsa haalch effects. 2.3 ADEQUACY OF DATABASE 2.3.1 Introduction Saction 110 (3) of SARA directs the Administrator of ATSDR to prepare a toxicological profile for each of the 100 most significant hazardous substances found at facilities on the CERCLA National Priorities List. Each profile must include the following content: "(A) An examination, summary, and interpretation of available toxicological information end epidemiologic evaluations on the hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acuta, subacute, and chronic health effects. (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans." This section identifies data gaps in current knowledge relevant to developing levels of significant exposure for vinyl chloride. Such gaps are identified for certain health effect end points (lethality, systemie/target organ toxicity, developmental toxicity, reproductive toxicity., and carcinogenicity) reviewed in Sect. 2.2 of this profile in developing levels of significant exposure for vinyl chloride, and for other areas, such as human biological monitoring and mechanisms of toxicity. The present section briefly summarizes the adequacy of existing human and animal data, identifies data gaps, and summarizes research in progress that nay fill such gaps. Specific research programs for obtaining data needed to develop levels of significant exposure for vinyl chloride will be developed by ATSDR. RTF, and EFA In the future. 2.3.2 Adequacy of the Database for Health Effect End Points 2.3.2.1 Introduction and graphic summary Tbs adequacy of the database for health effect end points in humans and animals is depicted in bar graphs in Figs. 2.6 and 2.7, respectively. The bera of full height indicate that there are "adequate" data to meet at least ona of the following conditions: 1. For noncancer health end points, one or more studies are available that meet current scientific standards and are sufficient to define a range of toxicity from no-effect levels (NOAELs) to levels chat cause effects (LOAELs or FELs). CMA 009851 e HUMAN DATA ADEQUATE DATA v SOME > DATA NO DATA No> IMMAlttV tiihc to menv MCtVMtNT*L J TOUC4TV Fig. 1*. Afcgaacy of the Atakuc m health etfecle ef tlayl chlwile (haaua data). CMA 009852 <S0o ,{ _ 0/ ng. 17. Adequacy U IIk database sa health effects a# riayl chlaride (aahaal data). 22 2. F r human carcinogenicity, a substance is classified as either a "known human carcinogen" or "probable human carcinogen" by both EPA and the International Agency for Research on Cancer (1ARC) (qualitative), and the data are sufficient to derive a cancer potency factor (quantitative). 3. For animal carcinogenicity, a substance causes a statistically significant number of tumors in at least one species, and the data are sufficient to derive a cancer potency factor. 4. There are studies that show that the chemical does not cause this health effect via this exposure routes Bars of half height indicate that "some" data for the end point exist but do not meet any of the criteria for "adequate" data. 2.3.2.2 Descriptions of highlights of graphs Figure 2.6 shows that human dose response data for oral and dermal exposure are lacking. Data are available that associate high inhalation levels of vinyl chloride with mortality in acute occupational exposure, but exposure levels were not quantified; therefore, the graphs indicate "some" but not "adequate" data. Data were not located for acute or intermediate inhalation exposure to vinyl chloride. Many epidemiological studies and case studies have characterized the syndrome known as vinyl chloride disease in occupationally exposed humans (see paragraph on vinyl chloride disease from inhalation exposure, human, in Sect. 4.3.2.3). There are also data iigplieating vinyl chloride as a cause of fetal loss (see Sect 4.3.3.1 on developmental toxicity from inhalation exposure, human). Because exposure levels were not quantified, the graphs for chronic toxicity and developmental toxicity indicate "some" data. Two studies suggest that occupational exposure Interferes with normal sexual activity and compromises gynecological health (Makarov 1984, Makarov at al. 1984). These data are inadequately reported for critical evaluation, and consequently, the graph for reproductive toxicity indicates "some* data. Although vinyl chloride is clearly a human carcinogen based on oceupetlonal data (see Sect. 4.3.6.1 on carcinogenicity from Inhalation exposure, huun), exposures were not quantified, and the data are classified as "some." The lack of dermal data Is not problematical since dermal absorption of vinyl chloride vapor is expected to be insignificant compared with inhalation absorption (Hefner et al. 1975a). Although there is a lack of oral data in humans, data in relevant animal models are sufficient to estimate significant levels of exposure for intermediate and chronic oral exposure. Deficiencies in the human inhalation toxicity data are somewhat more noteworthy because animal data ate sufficient for estimating a minimal risk level for intermediate duration but not for chronic inhalation exposure. From Fig. 2.7, it is apparent that the database for inhalation exposure in animals is more extensive than for humans. Inhalation data for acute lethality, intermediate duration toxicity, developmental toxicity, and carcinogenicity are sufficient for critical evaluation and are defined as "adequate." Inhalation data for chronic systemic toxicity CMA 009854 23 are Inadequate for defining a rang* of toxicity and, therefore, are graphically depicted aa 'some." The oral databaie is more nearly complete. Data 'adequate" for risk assaasmant are available for intermediate and chronic toxicity and carcinogenicity. However, acuta lethality data, limited to an LD50 in rata (Sax 198A), were judged to be *aoaa." Data ware lacking for acuta ayeteaic, developmental, and reproductive toxicity. Since oral expoaure la poaalble, the data gap regarding developmental and reproductive toxicity ahould be filled. 2.3.2.3 Summary of relevant ongoing reaeareh Peter Foilea at the American Health Foundation in Hew York City will conduct a atudy eponaored by the national Cancer Inatltute to develop monoclonal antlbodlaa that will aid in the decoction of cyclic DNA adducts in humane expoaed to environmental carcinogena. The study may contribute to our knowledge of adducts that are formed in humans from vinyl chloride exposure and the role these adducts play in human carclnogenaaia (NTIS 1987). Peter Guangerich at the Department of Biochemistry at Vanderbilt University in Nashville, Tennessee, will inveatigate the bioactivation and covalent binding of metabolites of vinyl halides, including vinyl chloride. This work, sponsored by the National Institute of Environmental Health Sciences, may contribute to our understanding of the impact of specific enzymes in Che liver and qther organa to the-i tonification and detoxification of vinyl chloride (NT1S 1987). D.P. Brown at NXOSH in Cincinnati, Ohio, la updating cohort mortality studios on several chemicals and mixtures, including vinyl chloride. It is hoped that the updated studies may provide sufficient statistical analyses to provide more definitive information regarding the association of vinyl chloride with various types of cancer (NTXS 1987). J.R. Glacin at Michigan State University has been investigating the migration of monomers in plastics into food stimulants. This project, sponsored by the U.S. Department of Agriculture, may allow more accurate estimation of the exposure of the population to vinyl chloride from foods packaged in plastic (NTXS 1987). 2.3.3 Adequacy of the Database for Other Information Needed for Bisk Assessment f.3.3.1 Pharmacokinetics and mechanisms of action V The pharmacokinetics of vinyl chloride in humans exposed by inhalation is relatively well understood, but little is known of oral and darnel pharmacokinetics. The gap in human pharmacokinetic knowledge is not a concern because the pharmacokinetics of oral vinyl chloride in relevant animal models Is well understood, and dermal exposure is not likely to be significant. Metabolism to an epoxide and an aldehyde provides reactive intermadlataa thought to be responsible for the carcinogenicity and probably the hepatotoxicity of the compound in CMA 009 55 ' 24 mintIs snd humans. Further understanding of the n*chanism of action on other systems, such as the CNS, could be gained. 2.3.3.2 Monitoring of human biological samples The most practical biological monitoring procedure appears to be quantification of urinary output of thiodiglycolic acid, the predominant urinary metabolite of vinyl chloride (Heger et al. 1982). Individual variation, however, renders this method unreliable at exposure concentrations <5 ppm (Tarkovski 1984). 2.3.3.3 environmental considerations Limited data are available regarding the vinyl chloride levels in foodstuffs. Monitoring data on levels of vinyl chloride in food contained in PVC packaging materials are needed. Intake of vinyl chloride by Ingestion of contsminated food was assumed to be negligible, based on strict FDA regulations and one laboratory study (Kontomlnas et al. 1985) that simulated actual food packaging and food storage conditions. This assumption should be verified with monitoring data. Data on the amount of leaching of vinyl chloride from rigid PVC water pipes into drinking water need to be obtained. Monitoring data alone cannot reveal the extent of the leaching problem, because monitoring data frequently reflect levels in drinking water supplies before transport through PVC distribution systems. T Limited data are available on the persistence of vinyl chloride in the environment, particularly in surface waters, soil, and groundwater. Although a half-life for vinyl chloride in surface water has been estimated, significant uncertainty exists.'Due to lack of data, it was not possible to estimate a half-life for vinyl chloride in soil or groundwater. ? CMA 009856 * 3. CHEMICAL AMD PHYSICAL IHFOEMATIOH 3.1 CHEMICAL IDENTITY Data pertaining to tho choaical identity of vinyl chloride are listed in Table 3.1. 3.2 PHYSICAL AMD CHEMICAL P10PSETIES The physical and cheaical properties of vinyl chloride ere presented in Table 3.2. 25 CNA 009857 26 Table 3.1. Cleuriral Identity af vinyl cMortde Parameter Value References Chemical name Synonym* and trade names Chemical formula Wigwemer line notation Chemical structure Chloraethene Vinyl chloride, chloroethyieae, ethylene mooochlaridc, monochloroethylenc, VC. VCM, inyl C monomer C:H)C1 G1UI SANSS 1987 SANSS 1987 HSDB 1987 HSDB 1987 H Cl \/ C=C /\ HH Identification numbers CAS Registry No. NIOSH RTECS No. EPA Hazardous Waste No. OHM-TADS No. DOT/UN/NA/IMCO Shipping No. STCCNo. Hazardous Substances Data Bank No. National Cancer Institute No. 75-01*4 KU962500Q U043 7216947 1086 49 057 92 169 None available HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 HSDB 1987 CMA 009858 27 Taka XI Pbytiral aad tkiWtai rrtf**m tt rityt tbhrtd. Froptfiy Vaioa Moiacalar wwgkt Color Phytical nail Odor Odor tbraafcaid Wator Air WWH| pw lafl{<>| poi|t Atttotfyiitioft tonpanan Salability Womt Orpaate aairaata Parity, g/oa1 Vapor droopy (or - I) Lop octnol*waur puuiifli osdlkiMis Vapor pawain Hoary*! Lawoaaauat SMtattivt Mb FMpote PI--aWtity Hma *13 Cotertea Oat MOd. iwoa 3.4 ppw (w/a)* 1000 ppa (a/a) -IJ3.I*C -13.4*C 472*C 27*1 atp/L a 23*C 1100 ap/L at 23*C Satobia ia hydrocarhoa*. oiL iloofedL MorinM latewta. aad noa iDi --pBi B_a_i a*** (-i4.ro in i.id 2PM aa Hp at 23*C 12 (amV)/aal a 10*C 1.3700 a 20*C -77.73 (opoo ap) 4-22 al* Kafeaoeaa Cowter aad Mapiara 1913 Cowter aad Mapiam 1913 Cawfar aad Mapiauo 1913 Vancbaataa 1913 Aaaon wd Haatala 1913 Aaoan aad Haatala 1913 Cowfa aad Mapiam 1913 Cowter aad Mapiam 1913 Cowter aad Mapiam 1913 EPA 1913b Cate aad Mapiam 1913 Cate aad MapWro 1913 Carter aad Magtore 1913 Vanchaana 1903 EPA 1907b Vwnbiina 1903 EPA 1903b EPA 1903b Cowter wd Mapiam 1903 Cowter aad Mapiam 1903 ppa (a/a) W ag/a1 a air p/a1 to PPM (a/a) teak MW (*/) to ap/L ppa (w/w) to ap/kp teMtfdaanfcaa ppa (a/a) - 1*0 ap/a1 p/a1 - as* ppa (a/a) ppa (w/a)-ap/l-pp/at ppa (w/w) - ap/kp - p/g ----1* CMA 009859 4. TOXICOLOGICAL DATA 4.1 OVERVIIV Much of the data suamarized in this section is reviewed In two recent SPA documents (SPA 1983a,b). Respiratory and gastrointestinal absorption of vinyl chlorida appears eo ba sapid. Humans retain -42% of vinyl chlorida inhalad ae concantrationa of 3 Co 24 ppm. Animal seudias suggest that gaaerointastinal absorption is nearly complete. Daraal absorption of vinyl chlorida vapors is not liksly to result in toxicity. Distribution of absorbed vinyl chlorida nay ba widespread, with highest levels of parent compound located in fat; but metabolism and excretion occur so rapidly that highest levels of excretory products are located in the liver and kidney, the priaary organs of aetabolisa and excretion. Regardless of the route of adainlstrstlon, inhalation or oral, aetabolisa proceeds via oxidation and subsequent conjugation with sulfhydryl groups. An important oxidative pathway involves mixedfunction oxidase and results in reactive electrophilic Intermediate^, 2-chloroethylene oxide and 2*chloroacataldehyda, which bind to liver ascroaolecules and aay be responsible for the toxicity and oncogenicity associated with vinyl chlorida. Excretion of polar aetabolltes is predominantly through the urine; when metabolic pathways ars saturated, substantial amounts of unmetabolized vinyl chlorida are exhaled. At sublethal doses, the liver is the primary target organ for carcinogenic and noncarcinogsnic effects of vinyl chloride in humans and animals. The significant feature of the toxicity of vinyl chloride is its carcinogenicity. In occupationally exposed humans and in animals exposed orally or by inhalation, an increased incidence of liver, lung, and brain tumors, and possibly other types of tumors, can be attributed to vinyl chloride. Other symptoms in occupationally exposed humans are collectively termed "vinyl chlorida disease,* end include acrooateolysia, circulatory disturbance in the extremities, Raynaud syndrome, scleroderma, hematological effects, and effects on the lungs, as well as effects on the liver. No counterpart of the human disease has been produced in experimental animals. Vivos of men occupationally exposed to vinyl chloride have suffered a greater number of miscarriages then wives of men otherwise employed. In occupationally exposed humans, vinyl chloride is genotoxic. This effect is associated with an increase In chromosomal aberrations in peripheral lymphocytes, end ic appears to be reversible when exp suras are reduced to si ppm. Vinyl chloride is mutagenic in a number f microbial and other test systems. Electrophilic metabolites of vinyl chloride, 2-chloroethylene oxide and 2-chloroecetaldehyde, have been shown to bind to naeromolecules. 2-Chloroethylene oxide forms adducts with DNA. These mechanisms may explain the toxicity and carcinogenicity of vinyl chloride. 29 CHA 0098A0 30 4.2 TOXXCOKXHXTXCS 4.2.1 Absorption 4.2.1.1 Inhalation Hunan. Krajswski at al. (1980) exposed young male volunteers to vinyl chloride nonoaer concentrations of 7.5 to 60 mg/m^ (3 to 24 ppm) by gas mask for 6 h. By measuring the difference between inhaled and exhaled concentrations, an average retention of 42t was estimated. Although the results varied among the individuals tested, the percentage retained appeared to be Independent of the concentration inhaled. Animal. Animal data, while demonstrating that inhalation absorption of vinyl chloride occurs readily and rapidly, are not sufficient to quantitatively determine the proportion of an Inhaled dose that is absorbed. Vlthey (1976) determined that peak blood levels occurred at 30 min in rats exposed head only to 7000 ppm. Bolt et al. (1977) placed rats that had been pretreated with 6-nitro-l,2,3benzothiadiazole to completely block the metabolism of vinyl chloride in a closed chamber containing 0.4 to 0.5 ppm ^C-vinyl chloride. Radioactivity in the chamber air declined only for the first 15 min of exposure. Indicating chat equilibrium between atmospheric and tissue levels of radioactivity had occurred, suggesting rapid uptake by the tissues of the rats. 4.2.1.2 Oral Human. Data regarding the oral absorption of vinyl chloride by humans were not located. Animal. Several studies In rats indicate that vinyl chloride is rapidly and probably completely absorbed from the gastrointestinal tract. Vlthey (1976) administered single 10 mL (44 to 92 mg/kg) oral doses of vinyl chloride in aqueous solution and observed that blood levels of vinyl chloride peaked in 10 to 20 min. Vatanabe et al. (1976a) administered single gavage doses of 0.05, 1, and 100 mg/kg 14C-vinyl chloride in corn oil and measured the amount of radioactivity excreted in expired air, urine, and feces, as well as the amount retained in the carcass, at 72 h. The fraction of the administered dose recovered in the feces, roughly indicative of the proportion unabsorbed, ranged from 0.47 to 2.39%, suggesting that absorption was nearly complete. Total recovery, howmvmr, ranged from 82.3 to 91.3%, suggesting substantial loss of radioactivity. Feron et al. (1981) provided rats with diets containing nominally 20, 60, or 200 ppm vinyl chloride monomer (from powdered polyvinyl chloride containing a high level of the monomer) for 4 h and manured the fecal excretion of vinyl chloride over 23 h from the start of the feeding period. Fecal excretion accounted for 8, 10, and 17% of the vinyl chloride present in the low, middle, and high diets, respectively. The investigators hypothesised that the vinyl chloride recovered from the feces was encapsulated by polyvinyl chloride and was not available to the rats for absorption, and that absorption of available vinyl chloride was virtually complete. CMA 009861 * 31 4.2.1.3 Dermal Human. Data regarding eh* denial absorption of vinyl chloride bv huaana were not located. Animal. Animal data suggest that dermal absorption of vinyl chloride gas is not likely to be significant. Hefner et al. (1973a) placed all but the heads of two anesthetized rhesus monkeys in chambers containing 800 or 7000 ppm *4C-vinyl chloride for 2.3 or 2 h, respectively, to measure the uptake of radioactivity. On the basis of vinyl chloride measured in expired air and radioactivity measured in selected tissues, the Investigators estimated dermal absorption of 0.031 and 0.023% of the available vinyl chloride at 800 and 7000 ppm, respectively. The investigators concluded that dermal absorption was far lass significant than inhalation absorption. 4.2.2 Distribution 4.2.2.1 Inhalation Homan. Data regarding the distribution of vinyl chloride in the tissues of humans exposed by inhalation were not located. Animal. Data from rat studies suggest that the distribution of inhaled vinyl chloride is rapid and widespread but depends on metabolism. Buchter et al. (1977) exposed rats to ^C-vinyl chloridst to determine tissue distribution of radioactivity. In rats precreated dlth 6-nitro-1,2,3-benzochiadiazole to block metabolism of vinyl chloridst, the highest levels of radioactivity were located in the fat, with lesser amounts in the blood, liver, kidney, muscle, and spleen. Vhsn mecab lism was not blocked, the highest levels of radioactive metabolites were located in the liver and kidney. At 10 min after a 5-min exposure of rats to 20,000 ppm **C-vinyl chloride, Duprat et al. (1977) detected radioactivity in the liver, bile duct, digestive tract, and kidney. Ac 3 h after the exposure described above, radioactivity was also detectsd in the urinary tract, salivary and lacrimal glanda, thymus, and skin. iMediately after a 3-h exposure to ^C-vlnyl chloride at 50 ppm, tissue levels of radioactivity, expressed as percent incorporated per gram of tissue, were highest in the kidney (2.13%) and liver (1.86%), with lover levels in Che spleen (0.73%) and brain (0.17%) (Bolt et al. 1976a). tfatanabe et al. (1976b) exposed rats to 10 ox 100 ppm ^C-vlnyl chloride for 6 h and measured radioactivity in tissues 72 h later. In order of decreasing concentration, radioactivity (present as nonvolatile metabolites) was detected in the liver, kidney, skin, lung, muscle, carcass, plasms, and fat. 4.2.2.2 Oral Human. Data regarding the tissue distribution of vinyl chloride in orally exposed humans were not located. Animal. Vatanabe et al. (1976a) measured the level of radioactivity present as nonvolatile metabolites in tissues of rats 72 h after single 0.03 to 100-mg/kg gavage doses of ^C-vinyl chloride in com oil. Highest levels occurred in the liver, -2 to 3 times higher than in the other tissues examined (skin, plasma, muscle, lung, fat, and carcass). CMA 009862 * 32 4.2.2.3 Derail Did regarding thi distribution of vinyl chloride following dermal exposure of huains or experimental animals were not located. 4.2.3 Metabolism 4.2.3.1 Inhalation human. In the only human data loeaead, Sabadie at al. (1980) examined the ability of aryl hydrocarbon hydroxylase in the S-9 fraction from surgically obtained liver specimens to metabolize vinyl chloride to electrophiles mudgenic to Salmonella cjphimirlum TA1330. The number of revertancs per plate were compared with that resulting from identically prepared S-9 fractions from female strain BD IV rad. Human S-9 fractions Induced mudtions (and presumably metabolism to a reactive electrophile) to an average 84 of the extent mediated by rat S-9, but a 9-fold individual variation was observed. Animal. Hefner et al. (1973b) exposed rats to vinyl chloride in a closed chamber at concentrations of -30 to 1000 ppm for 32.5 to 356.3 min. Additional rats pretraated with ethanol (to inhibit alcohol dehydrogenase activity) or SXF 525-A (to inhibit microsomal oxidase activity) were similarly exposed. Metabolism, estimated by measuring the rate of disappearance of vinyl chloride from the closed system, appeared to follow first-order kinetics with a half-life of 86 min at <100 ppm. At >220 ppm, metabolism was slowed to a half-life of 261 min, suggesting saturation of the pathway predominant at <100 ppm. Protreatment with ethanol depressed the rate of metabolism >83% at <100 ppm but <47% at >1000 ppm. Pretreatment with SKF 525-A, however, had no effect at <100 ppm but depressed metabolism 19% at >1000 ppm. The authors postulated three alternative pathways for metabolism, as depicted in Fig. 4.1. At low concentrations, sequential oxidation to 2-chloroethanol, 2chloroacetaldehyde, and 2-chloroacetlc acid involving alcohol dehydrogenase (inhibited by pretreatment with ethanol) appeared to be the predominant pathway. Little 2-chloroacetic acid was formed, however, probably because 2-chloroacetaldehyde conjugated rapidly with ubiquitous sulfhydryl groupa. When the alcohol dehydrogenase pathway became seturated, 2-chloroethanol say have been oxidized by catalase in the presence of hydrogen peroxide (H202) to a peroxide, which may have undergone subsequent dehydration to form 2-chloroacetaldehyde. An alternative pathway may have involved oxidation by mixed-function oxidase to form a highly raactive epoxide intermediate, 2-chloroethylene oxide, which spontaneously rearranged to form 2-chloroacetaldehyde. Hefner et al. (1975b) reported urinary excretion of polar metabolites and 2-chloroacetlc acid by rats exposed by inhalation. Other animal data expand the hypotheses of Hefner et al. (1975b). Hultmark et al. (1979) used an in vitro technique to determine that metabolism was HADPH-dependent, located in the microsomal fraction of the liver, and probably involved mixed-function oxidase. Bolt et al. (1977) reported that pratraatment with 6-nitro-l,2,3-benzothiadlazole waa sufficient to totally block metabolism of vinyl chloride in rats CHA 009863 33 CIHC - CH2 VMYt CHLOROE MIXED FUNCTION OXOASE o /\ H2C - CH cin2c - COOK 2-CHLOROACET1C AC FI*. 4.1. Pupn^ wafcrik pUhnyi far 4rl iMirlfc, *fe'_ - CMA 009864 % 34 exposed to *0.45 ppm In a closed system for 5 h. B It *e *1. (1977) and Bolt (1986) Intorprotod this observation to str ngly suggest that aetabolisa of vinyl chloride proceeds primarily through a nixed'function oxidase pathway with likely production of an epoxide internediate, because 6-nitrO'l,2,3-benzothiadiazole is known to inhibit some microsomal cytoehroae P-450 oxidation pathways. Bolt et al. (1977) and Fllser and Bolt (1979) exposed rats in a closed systea to 100 or 1000 ppa 14C-vinyl chloride. By aeasurlng the disappearance of radioactivity with tine, they determined 250 ppa to be the threshold at which saturation of aeCabolie pathways occurs. A aecabolic race (Vhi) of 110 jmol/h/kg was estimated for rats. In a similar experiment in rhesus monkeys, metabolic saturation was observed to occur at 200 ppa, with a V-m of 50 Mael/h/kg (Buchter et al. 1980). the of 50 jiaol/h/kg was suggested as a closer approximation of aetabollsa in huaans than Che value of 110 paol/h/kg estimated for rats by Fllser and Bolt (1979). Inhalation exposure has been associated with reduction in liver nonprotein sulfhydryl concentration in the rat (Hefner et al. 1975b, Bolt et al. 1976b), particularly at exposure concentrations >100 ppa (Vatanabe et al. 1978a, Jedrychowski et al. 1984). Urinary metabolites identified in rats exposed by inhalation include polar compounds resulting froa conjugation with sulfhydryl groups at low exposure concentrations (Vatanabe et al. 1976b, Hefner et al. 1975b) and 2- chloroacetlc acid at high exposure concentrations (Hefner et al. 1975b). Several investigators have observed the binding of nonvolatile f metabolites of -vinyl chloride to liver aacroaoleeules in vitro and * in rats exposed by inhalation (Kappus et al. 1976; Guengerlch and Vatanabe 1979; Guengerlch et al. 1979, 1981; Vatanabe et al. 1978a,b). In single'exposure experiments at different concentrations, the extent of aacroaolecular binding increased proportionately, to the amount of vinyl chloride metabolized and disproportionately to the exposure concentration (Vatanabe et al. 1978a). The extent of aacroaolecular binding was increased by repeated exposure to vinyl chloride (Vatanab et al. 1978b) and by pretreataent with phenobarbital (Guengerlch and Vatanabe 1979). Macroaolecular binding has been attributed to the reactive Intermediate 2-chloroethylene oxide, which may bind to DNA and SKA, and to its rearrangement product, 2-chloroacetaldehyde, which aay bind to protein molecules (Guengerlch et el. 1979, 1981; Guengerlch and Vatanabe 1979; Vatanabe et al. 1978a,b; Kappus et al. 1976; Bolt 1986). 4.2.3.2 Oral Human. Data regarding the aetabolism of vinyl chloride by orally exposed biwane were not located. Animal. Urinary metabolites Identified from rats orally exposed to -vinyl chloride are consistent with the aetabollc pathways postulated for inhalation exposure, in particular with the formation of 2chloroethylene oxide and 2-chloroacetaldehyde. Metabolites identified include H-acetyl-S'(2-hydroxyethyl)cysteine, N-aeetyl-S-(2chloroethyDcystelne, 2-chloroacetie acid, thiodiglyeollc acid, and glutamic acid (Vatanabe et al. 1976a; Vatanabe and Gehring 1976; Creen and Hathway 1975, 1977). Metabolic saturation appears to occur with a single gavage dose of >1 and <100 mg/kg/day (Vatanabe et al. 1976a). CM* 0098A5 % 35 4.2.3.3 Dermal Data regarding metabolism in humans or animals darmally exposed to vinyl chloride were not located. 4.2.4 Excretion 4.2.4.1 Inhalation Human. Human data suggest that exhalation of unmetabolized vinyl chloride is not an Important pathway of elimination at low exposure concentrations. Krajewski at al. (1980) exposed humans to air containing 7.5 to 80 mg/m* for 6 h and measured the mean concentration in expired air for 30 min at termination of exposure. Mean concentrations in expired air ranged from undetectable to 2.84 mg/m^, representing up to 3.60 to 6.73% of the inhaled concentration. In a study available as s brief abstract, Shu at al. (1986) reported that urinary concentration of thiodlglycolie acid increased with increasing air concentration of vinyl chloride in an occupational setting. Urinary concentrations of thiodlglycolie acid peaked within 20 h. The investigators suggested that dally urinary output of thiodlglycolie acid might be a satisfactory biological index of exposure to vinyl chloride. > Animal. The mods of excretion of vinyl chloride and its -? metabolites following inhalation exposure of animals to different concentrations reflects the saturation of metabolic pathways at low - concentrations discussed in Sect. 4.2.3.1, in the subsection on metabolism in animals after Inhalation exposure. The cumulative excretion of radioactivity over a 72-h postexposure period was measured in rats exposed to 10 or 1000 ppm (Vatanabe and Gehring 1976, Uatanabe at al. 1976b) or 5000 ppm (Uatanabe ec al. 1978b) ^C-vinyl chloride for 6 h. Radioactivity expired as C02 or vinyl chloride, excreted in the urine and feces, and retained in the carcass was expressed as a percentage of the total radioactivity recovered. The results presented in Table 4.1 suggest that metabolism was nearly complete at 10 ppm, because <2% of the recovered radioactivity occurred as unchanged parent compound. The predominant route for excretion of radioactive metabolites was through the urine, accounting for >70% of the recovered radioactivity. Metabolism appeared to be saturated at 1000 ppm, sine unchanged vinyl chloride increased to 12.3% and urinary radioactivity decreased Co 56.3%. At 5000 ppm, more than half the recovered radioactivity appeared as unchanged vinyl chloride, and urinary excretion accounted for -27% of the recovered activity. Generally, there wee little change in the proportion of recovered radioactivity excreted in the faces or exhaled as C02. The percentage of the radioactivity retained In the carcass and tissues appeared to be somewhat decreased at 5000 ppm compared with 10 and 1000 ppm, suggesting preferential retention of metabolites rather than unchanged vinyl chloride. Pulmonary excretion of unaltered vinyl chloride appeared to follow first-order kinetics regardless of exposure concentrations, with halflives of 20.4, 22.4, and 30 min at 10, 1000, and 5000 ppm. The urinary excretion of radioactivity was biphaslc, with the second or slow phase accounting for <3% of the total urinary excretion. Half-lives for the CMA 009864 * Table 4.1. Excretion of ladluattlilty to rata impend ta l4C-vlnyi chloride ia air for h Radioactivity expreaaed u percent of total recovered Expocure concentratioa (ppm) 10 1000 3000 Expirad vinyl chloride Expired CO: Urine Fecai Carcaaa and tisaucs 1.61 1109 67.97 4.43 13.84 1126 1130 36.29 4.21 14.48 54.5 8.0 27.1 3.2 7.3 Sourtt: Waunaba and Gehring 1976; Wataaaba et aL 1976b, 1978b. - - * CMA 009867 --~4 37 rapid (first-order) phase wars estimated ac 4.6, 4.1, and 4.5 h, respectively. Urinary metab litas included N-aeetyl- S* (2hydroxyethyl)cystains, thiodiglycolic acid, and possibly S-(2hydroxyachyl)cys tains. 4.2.4.2 Oral Human. Data regarding the excretion of vinyl chloride by orally exposed humans ware not located. Animal. In experiments in the United States (Vatanabe at al. 1976a, Vatanabe and Gahring 1976) and Great Britain (Green and Hathway 1975), which studied the similarities of pharmacokinetics following inhalation and oral exposure, single oral dosas of ^4C-vinyl chloride 'were administered to rats, and the excretion of radioactiviey was monitored over a 72-h period. Details are presented in Table 4.2. A striking Increase In exhalation of unchanged vinyl chloride end compensatory decreases in urinary and fecal excretion of radioactiviey and exhalation of C02 were observed at 220 mg/kg. suggesting that metabolic saturation had occurred at that dosage. At 51.0 mg/kg the predominant route of elimination was urinary excretion of polar metabolites. Exhalation of unchanged vinyl chloride was generally complete ' within 3 to 4 h, but excretion of metabolites continued for days (Green and Hathway 1975) Pulmonary excretion of vinyl chloride appeared to be monophasic at 5l.O mg/kg, with a half-life of >55 to 56 min (Vatanabe ec al. l$76e). At 100 mg/kg, pulmonary excretion of vinyl chloride was. biphasle, with half-lives of 14.4 and 40.8 min for the rapid and slower phases, respectively. Urinary excretion of radioactivity was biphasic, with the rapid phase accounting for >97% of total urinary radioactivity and having half-lives of 4.5 to 4.6 h for dosages of 0.05 to 100 mg/kg. Metabolites Identified in the urine of orally treated rats were consistent with the formation of 2-chloroethylene oxide and 2chloroacetaldehyde (Vatanabe et al. 1976a, Green and Hathway 1977), as postulated for metabolism following inhalation exposure. The major metabolite was identified as thlodiglycolic acid; nearly equivalent amounts of H-acetyl-S-(2-hydroxysthyl)cysteine were identified (Vatanabe et al. 1976a, Green and Hathway 1975). Smaller amounts of radiolabeled S-(2-chloroethyl)cysteine, urea, glutamic acid, and 2-ehloroacetic acid were also identified (Green and Hathway 1975). 4.2.4.3 Dermal Data regarding the metabolism of vinyl chloride following dermal exposure of humans or animals were not located. 4.2.4.4 Parenteral Human. Data regarding the metabolism of parenterally administered vinyl chloride in humans were not located. Animal. The elimination of radioactivity following intraperitoneal administration of 14C-vinyl chloride to rats resembles the pattern observed following inhalation and oral administration. Following an Intraperitoneal dose of 0.25 mg/kg, exhalation of unchanged vinyl CMlS 009848 * 38 Titliil Pereant of i^Minrii foot of radioactivity excratad 72 b fodowiag a dagfe oral 4m* of ,4C-*byl chloridr is ran Dooo (mg/kg) 0.05* 0.25* 1.0 20* 100* 430* Expired As vinyl chloride 1.43 3.7 113 41.6 66.64 91.9 As COi 8.96 13.5 13.26 4.8 152 0.7 Urine 68.34 73.1 39.30 216 10.84 5.4 Feces 139 4.6 120 1.0 0.47 0.7 Carcass 10.13 NR` 11.10 11.0 1.83 NR Total 91.23 96.9 88.83 81.0 8130 98.7 `Waunabe and Gohring 1976, Waunabo aL 1976a. *Groan and Hathaway 1973. `Not reported. CMA 009869 39 chloride, exhalation of C02, and urinary and faeal axeration of radioactivity accounted for 43.2, 11.0, 43.1, and 1.8% of tha administered dose, respectively (Green and Hathvay 1975). At 450 mg/kg, exhaled vinyl chloride increased to 96.2% of the administered dose, C02 decreased to 0.7%, urinary radioactivity decreased to 2.6%, and fecal radioactivity remained unchanged. Small doses administered intravenously were eliminated very rapidly and almost entirely by exhalation of unchanged vinyl chloride. Green and Hathvay (1975) administered a 0.25-ng/kg intravenous dose of ^4C-vinyl chloride intravenously to rats end recovered 80% of the dose within 2 min and 99% within 1 h as unchanged compound from expired air. 4.3 Torrcm 4.3.1 Lethality and Decreased Longevity 4.3.1.1 Inhalation Human. ACGXH (1986a) and EPA (1985a) reviewed early reports of acute toxicity at high levels resulting in lethality among occupationally exposed workers. Deaths appeared to be due to narcosis. Exposure levels were not reported, and an LClo cannot be identified. Animal. Patty et al. (1930) reported chat narcosis and death occurred within 30 to 60 min in guinea pigs exposed to 10% vinyl v chloride (100,000 ppm). EPA (1985a) reviewed a number of acute studies , in animals and reported 2-h LC30 values ranging from 117 to 500 ppm.for mice to 230 to 800 ppm for'rabbits. Mastromatteo et al. (1960) exposed rats, mice, and-guinea pigs (five per sex per group) to 10, 20, 30, or 40% (guinea pigs only) vinyl chloride in air (100,000, 200,000, 300,000. or 400,000 ppm) for 30 min. One guinea pig exposed to 40% died; all mice, rats, and one guinea pig exposed to 30% died; one mouse but no rats or guinea pigs exposed to 20% died. Long-term studies in rats and mice associate intermittent exposure to 50 ppm with decreased longevity. Lae et al. (1977a, 1978) exposed rats and mice (36 per sex per species) to 0. 30, 250, or 1000 ppm, 6 h/day, 3 days/week for up to 12 months. Acute lethality associated with toxic hepatitis and tubular naerosls of the renal cortex occurred in mice after 3 to 9 days at 1000 ppm. Shortened life span attributed to noncareinogenic effects of vinyl chloride occurred in all exposed groups of both species. In a subsequent study, Hong et al. (1981) exposed mice (t to 28 per sex per group) and rats (4 to 16 per sex per group) to 0, 30, 230, or 1000 ppm, 6 h/day, 3 days/week for up to 6 months (mice) or 10 mrnirtis (rata), followed by a 12-month observation period. A concentration- and duration of exposure-related decrease in longevity was observed in both species at all exposure concentrations, which was attributed to a combination of systemic toxicity and tumor development. 4.3.1.2 Oral Hunan. Data regarding reduced longevity in humans orally exposed to vinyl chloride were not located. 00970 et** 40 Animal. Sax (1984) reported an oral LDso in racs of 500 mg/kg. The kay lifetime oral acudy Is that submitted by Dow Chaaical Company (1984) and Til ac al. (1983), in which mala and famala Ulster racs wars fad diacs containing polyvinyl chlorida with a high laval of cha monomar. Diacary intakas of vinyl chlorida monomar vara asCioaCad ac 0, 0.014, 0.13, and 1.3 mg/kg/day. Groups eonslscad of 100 racs par sax axcapc for cha' high group, which concainad 30 rats par sax. Mortality was slightly but significantly incraasad in high-group rats, starting ac 68 waaks of craatmant. No affacts on longevity wara observed at sO.13 mg/kg/day, which is considered the NOAL for dacraasad survival. An earlier lifetime study in racs from this laboratory (Feron at al. 1981) supports the NOAH. for reduced survival of 0.13 mg/kg/day. In this experiment, diets containing polyvinyl chloride with high levels of vinyl chlorida monomer provided Intakes of 0, 1.7, 3.0, or 14.1 mg/kg/day. A marked and statistically significant increase in mortalicy occurred at X5.0 mg/kg/day. Females at 1.7 mg/kg/day had a slight but not statistically significant increase in mortality. 4.3.1.3 Dermal Data regarding lethality or reduced longevity in dermally exposed humans or animals were not located in the available literature. 4.3.2 Systemle/Target Organ Toxicity 4.3.2.1 Hepatotoxlclty Inhalation, human. Several epidemiologic studies have associated occupational exposure with Impaired liver function and/or biochemical or histological evidence of liver damage (Berk 1976, Buchancova ec al. 1983, Cedigk et al. 1973, Marsteller ec al. 1973, Popper and Thomas 1973, Doss et al. 1984, Lae et al. 1977b, Tamburro 1984, Tamburro et al. 1984). Several of these studies have been reviewed by EFA (1985a,b). Thresholds for hepatotoxlclty cannot be Identified, because data regarding exposure concentrations and duration were not available. Inhalation, animal. In the Lee et al. (1977a) study described in Sect. 4.3.1.1, in the subsection on lethality and decreased longevity in animals after inhalation exposure, acute hepatotoxicity was observed in mice dying after intermittent exposure to 1000 ppm vinyl chloride for 5 to 9 days. In an intermediate-length animal inhalation study (Torkelson et al. 1961), several species were exposed intermittently for up to 6 months, as detailed in Table 4.3. Air-exposed controls were maintained. Parameters of liver toxicity evaluated included gross and histopathologic examination, measurement of relative organ weights, and determination of serum levels of enzymes associated with liver damage. Biochemical parameters of liver status were within normal limits at all exposure concentrations, but histopathologic lesions occurred in rats exposed to 500 ppm and in rabbits exposed to 200 ppm. Elevated relative liver weights appeared to be the most sensitive indicator of hepatotoxicity and were observed in rats at 100 ppm, 7 h/day, but not ac 30 ppm by the same schedule. In a study designed primarily to evaluate effects on the testis (see Sect. 4.3.4.1, in the subsection on 009S71 * 41 MbU t*MiMMlpmacatfcraMaopnan to tpi ett Nmbartf T_ r - raVt^aMw <*nd vtpMji evphhMpfoa 1a Mala* FMaa (pa) (baan/Oay) ExpOMIV (OHMba) Ran 10 10 300 7 10-24 24 sa 100. or 200 7 30 100 or 200 03.1,2. or 4 10 0 30 1.2. or 4 4.3 4 OriMpip 10-12 S-12 3a 100. or 200 7 Rabbin 33 $a 100. or 200 7 t Dap 11 3a 10ar200 7 6 'Allaawbi^,npaaadldayi/wMk. Wee Torbatoa aL 19*1. 2*. f* V 009872 % 42 reproductive toxicity in animals after inhalation exposure), Bi et al. (1985) reported a concentration*related and significant elevation In relative liver weight in rats exposed to 10, 100, or 3000 ppm, 6 h/day, 6 days/week for 6 months. The 10-ppm concentration is considered a LOaEL for liver effects in intermediate*length exposures. The longer-term study by Lee et al. (1977a) in which rats and mice were exposed to 0, 50, 250, or 1000 ppm, 6 h/day, 5 days/week for up to 12 months (Sect. 4.3.1.1, in the subsection on lethality and decreased longevity in animals after inhalation exposure) failed to Identify a NOAEL for hepatotoxicity. Lae et al. (1977a) observed no adverse effects on biochemical parameters of rats or mice exposed to 5250 ppm. Several mitotic figures, indicating increased rate of call division, were observed in the livers of rats exposed to 50 or 1000 ppm at 8 to 9 months, and increased rate of DHA synthesis was observed at 50 ppm. Since the liver is a known target organ for the toxicity and oncogenicity of vinyl chloride, these effects are judged to be potentially adverse, and 50 ppm is considered an FEL in this study. Feron at al. (1979a) exposed rats to 0 or 5000 ppm, 7 h/day, 5 days/week for 4, 13, 26, or 52 weeks and observed histopathologic alteration of the liver after 13 weeks and ultrastructural alteration after only 4 veeks of exposure. Oval, human. Data were not located regarding hepatotoxicity in orally exposed humans. Oral, animal. A gavage study in rats Identifies 30 mg/kg as a NOAEL and 100 mg/kg as a LOAEL for liver effects in an intermediate* length study. Feron et al. (1975) administered vinyl chloride in soybean oil by gavage to groups of 15 rats per sex at 0, 30, 100, or 300 mg/kg. 6 days/week for 13 weeks. Parameters of liver toxicity evaluated included serum biochemistry, relative liver weight, and histopathologic and histochemical examination at all dosages and electron microscopy at 0 and 300 mg/kg. No effects were observed at 30 mg/kg, equivalent to 26 mg/kg/day. Reduced blood sugar and slightly altered hepatocytes were observed at 100 and 300 mg/kg. A dose-related increase in relative liver weight was observed and became statistically significant only at 300 mg/kg. Hypertrophic rough endoplasmic reticulum was observed at 300 mg/kg. The key long-term oral study chat defines thresholds for hepatotoxicity was reported by Dow Chemical Company (1984) and Til et al. (1983) and was described in Sect. 4.3.1.2, in the subsection on lethality and decreased longevity fn animals after inhalation exposure. Diets provided dally dosages of 0, 0.014, 0.13, or 1.3 mg/kg/day to rats for their lifetime. There were no effects on general appearance, behavior, food consumption, body weight, or limited hematologic and biochemical parameters. Relative organ weights were not evaluated. Noncarcinogenic adverse histopathologic effects were confined to the liver and consisted of hepatocellular alteration and hepatic cysts in both sexes at 1.3 mg/kg/day. An Increased Incidence of basophilic foci were observed in both sexes at 1.3 mg/kg/day and only in females in the two lower dosage groups. Lacking a dose-related Increase in the incidence of basophilic foci and histopathological evidence of adverse effects at 0.13 mg/kg/day, such as were observed at the higher dosage, CMA 009873 % basophilic foci in th* liver f rsts f on* itx any b* considered * nonadverse, although compound-related, affect. Th* dosage of 0.13 ng/kg/day, therefore, nay b* conaidarad a NQAEL, and 1.3 ng/kg/day may b* considered a LOAEL for hapatotoxicity. An earlier lifetime study fron this laboratory supports th* NOAEL for hepatotoxiclty of 0.13 ng/kg/day Feron *t al. (1981) fed diets containing polyvinyl chloride with high levels of vinyl chloride aonomer to rata that provided intakes of 0, 1.7, 3.0, or 14.1 ng/kg/day. An increased incidence of several histopathologic lesions, some of which were probably preneoplastic, were observed in die livers of. rats from all treated groups. Dezaal. Data regarding hapatotoxicity associated with darnel exposure of huaans or aniaals to vinyl" chloride were net located. Oeneral discussion. Symptoms sad signs of liver disease associated with occupational exposure to vinyl chloride include pain or discomfort In the right-hand upper quadrant of the abdoaan, hepatoaegaly, splenomegaly, portal hypertension, thrombocytopenia, esophageal varices, and evidence of fibrosis and cirrhosis; however, these observations are not pathognoaonic for vinyl chloride-induced liver disease (Lilis et al. 1973, Popper and Thomas 1973, Lee et al. 1977b). Severity of th* clinical picture appeared to correlate positively with duration of i exposure (Lilis et al. 1973). Biochemical screening and liver function tests generally have not been useful to monitor th* presence or pr fF*ss of th* disease (Lee et al. 1977b, Lilis et al. 1973), although recently, Doss et al,.(1984) noted that increased urinary porphyrin and coproporphyrin occurred conslatently"in cases of liver disease Induced by vinyl chloride and other industrial hepatotoxlns.. A number of investigators have noted that metabolites of vinyl chloride bind covalently to hepatocellular aacronoleeules and nay be Important in th* aechanlaa of carcinogenesis (Bolt et al. 1976b, Bolt 1986,. Kappus et al. 1976, Watinch* et al. 1978a, Vatanab* and Gehrlng 1976). A aechanlaa for nencarcinogenic liver effects has not been postulated; however, since aany of the lesions observed in the livers of vinyl chloride-exposed rats arc considered preneoplastic (Feron et al. 1981), it seems reasonable to suspect that aacroaolecular binding of reactive Intermediates asy be fnvolvwd is ooncarclnogenlc toxicity. ^derived from the die* oT Jaeger et 1. (19777, who observed tSdribexfc; Arodd* 1284 and phenoberbltal in rum# smpused ter vfiayl Chloride by with SHP * afiMf-fUaedett oxidase iced vinyl' chloride-Induced toxicity, noted that th* oral HQAKL for hapatotoxicity in a study (Dow Cheelcal Company 1984) was far below the NOAEL in a subchronis study (Faren at al. 1973). At laast for oral axpoaure, the duration of expeauro appears to ha of aajor Importance. 4.3.2.2 Nervous syatan offsets Inha1stion, hunsa. Vinyl ehlcrlda wss ones eonsidsrsd for use as an inhalation anesthetic (ACG1H 1986a). Acute exposures to 0.8 to 2.0% vinyl chloride (8,000 to 20,000 ppu) have been associated with CMA 009874 44 dizziness, giddiness, euph ris, ataxia, hsadaehs, and narcosis (Nicholson at al. 1975, Lester at al. 1963). Racant data from tha foreign literature suggest that subtle signs of neurotoxicity nay be associated with occupational exposure. Mild distal axonal neuropathy was reported In the legs of 45/64 exposed vinyl chloride workers, which was suggestive to the investigators of a dying-back syndroae (Perticoni at al. 1986). Helena at al. (1985) associated neurologic and psychiatric disease with occupational exposure. Dlnceva at al. (1985) reported eleetroencephalograa (EEC) changes that they thought were indicative of early evidence of neurotoxicity in workers exposed to vinyl chloride in combination with other organic solvents. Exposure levels were not reported by these authors. Inhalation, animal. Oster at al. (1947) anesthetized dogs with -7 to 50% (70,000 to 500,000 ppa) vinyl chloride and concluded that its' use as an anesthetic was unsuitable because of cardiac and auscular effects. Lester et al. (1963) exposed rats to concentrations ranging froa 5 to 15% (50,000 to 150,000 ppa) for up to 2 h to evaluate CNS effects. Moderate intoxication was observed at 5%, loss of reflexes was observed at 5 to 10%, and deep surgical anesthesia was reached at 15%. Patty et al. (1930) produced ataxia and narcosis in guinea pigs exposed to 2.5 to 5% (25,000 to 50,000 ppa) vinyl chloride for 2 to 5 ain. Oral. Neurologic effects in orally exposed huaans or animals have not been reported. Deraal. Neurologic effects in deraally exposed huaans or animals have not been reported. z General discussion. CNS effects appear to be a manifestation of acute inhalation exposure to high levels of vinyl chloride in humans.and animals (Nicholson et al. 1975, Lester et al. 1963) that may result in death, at least in animals (Lester et al. 1963, Mastromatteo et al. 1960). Recent data provide minimal evidence that chronic exposure to vinyl chloride may result in neurologic or psychiatric effects (Perticoni et al. 1986, Dlnceva et al. 1985, Halama at al. 1985). Further investigation Is needed. 4.3.2.3 Other systemic effects Vinyl chloride disease from Inhalation exposure, human. Vinyl chloride disease la the name given to tha total clinical syndrome associated with occupational exposure. It includes a syndrome known as aeroosteolysie or dissolution of the ends of the distal phalanges of the hands; circulatory disturbance in tha extremities; Raynaud syndrome; scleroderma; hematologic effects, and effects on the lungs; as well as the liver effects previously discussed (Halama at al. 1985, Sakabe 1975, Lilldtec al. 1973, Markowitz et al. 1972, Vllson et al. 1967, Dinman ec al. 1971, Preston et al. 1976). In addition, Mieu ec al. (1985) reported obscure effects of unknown toxicological significance on enzyme levels of leukocytes and thrombocytes of exposed workers. Other investigators have reported elevated levels of circulating IgG (Bogdanikowa and Zawilska 1984) or ijmsune complexes (Ward 1976) as part of the syndrome, but the biological significance of these effects is not clear. CMA 009875 ft 45 Vinyl chloride disease from inhalation exposure, animal. La c al. (1977a, 1978) exposed rats and mica to vinyl ehlorida at 0, 50, 250. or 1000 ppm 6 h/day, 5 days/week for up to 12 months, as dascrlbad In Sact. 4.3.2.1, In tha subsaetlon on hapatotoxicity In animals sftar inhalation axposura in this saction. Parsaacara of toxicity avaluatad included general appaaranca, faad consumption, body weight, hamatology, clinical chamistry, macrophaga counts of pulmonary washings, cytoganic axaainatien of bona marrow culturas, sonographic radiography of tha 1 ng bonas of tha limbs, gross nscropsy, salsetad organ vmights, and histopathologic axamination of a conprahanaiva sac of organs and tissuas. Abnormalitias obsarvad in tha mica ineludad body waight loss at 1000 ppm aftar 8 months of normal growth and alovacad pulmonary naerophaga count in mica from all axposura groups that had bronchioloalvaolar adanoms. Baeausa of its association with lung tumors, an alovacad pulmonary macrophaga count in mica in this study is not considered a noncareinogenic toxic efface. Kata exposed to 1000 ppm had reduced body weights compared with controls. Other noncareinoganic adverse affects ware not observed in rats. Bi at al. (1985) exposed rats to 10, 100, or 1000 ppm 6 h/day, 6 days/vaak for 12 months to evaluate effaces on tha testis (saa Sact. 4.3.4.1, in tha subseceion on reproductive toxicity in animals after inhalation axposura. At termination of exposure, a concentration'relaced decrease in body weights was evident and betas* statistically i significant at 100 ppm. '| In a series of studies on rats exposed to 0 or 5000 ppm 7 h/day, 5 days/week for 1 year, adverse affects not previously discussed included slightly reduced growth, hematologic evidence of anemia, decreased blood clotting time, and minor biochemical alterations of uncertain biological significance (Peron et'al. 1979a,b; Feren and Kroes 1979). Effects on tha kidney were noted and included elevated relative kidney weights, sllghely increased blood urea nitrogen (BOH), altered urinalysis parameters, and increased intensity of progressive nephrosis, all compared with controls. Other noncareinogenic lesions seen in treated rats included mild alterations of the Zynbal glands and lungs. Increased splenic hematopoiesis, degeneration of the myocardium and thickening of the walla of the arterlea, and hyperplasia of the olfactory epithelium. Vinyl chloride disease from, oral effects si vinyl chloride in orally Data regarding e not located. oral dxpopwtfe, animal. In a 13-week -_ ln Sect. A.'f.-J?.!:, In the, ttbkectinn on hepatotoxicity in oval exposure, Feron et al. '(1975)^treated rats with vinyl "as. 0, 30, 10C, or 300 ng/kg 8 days/week. Parameters of toxicity previously diseusssd Included general' appearance end behavior, body Ueigbt, food consumption, hamatology, soloeesd blood chemistry end urinalysis tests, gross appaaranca on necropsy, rslatlve weights f major organa, and histopathologic appearance of a vide range of orgens and tissues. Minor honatologic and biochenical changes vers observed but were not consldorod to bo adverse. Decreased relative adrenal weight was observed in nales et 300 mg/kg but wee not considered toxicologically significant. Mo adverse response was reported in other organa or tissuas. CHrt 00987$ * 46 In a lifetime study also described in Ssct. 4.3.2.1, in the subsection on hepatoxicity in animals after oral exposure, Feron et al. (1981) fed rats diets that provided 0, 1.7, 5.0, or 14.1 mg/kg/day vinyl chloride. An additional group was treated by gavage with 300 mg/kg 5' days/veek. Parameters of toxicity evaluated included general appearance and behavior, body weight, food consumption, hematology, blood chemistry, urinalysis, gross appearance at necropsy, and histopathologic examination of a wide range of tissues from controls and the two higher-dose groups, with a more limited histopathologic examination of low-dose rats. Lethargy and poor condition were reported at *5.0 ag/kg/day, apparently in rats that developed tumors. Noncarelnogenie effects included reduced blood clotting time and increased splenic hematopoiesis at *14.1 but not at 5.0 ag/kg/day. Vinyl chloride disease from dermal exposure. Data regarding toxic effects of vinyl chloride in dermally exposed humans or animals were not located. Vinyl chloride disease, general discussion. Vinyl chloride disease in humans appears to involve a large number of organ systems and tissues, including the liver, as discussed in Sect. 4.3.2.3, in the subsection on vinyl chloride disease in humans after Inhalation exposure (Halama at al. 1985, Sakabe 1975, Lilis et al. 1975, Markowitz at al. 1972, Wilson et al. 1967, Dinman et al. 1971, Preston et al. 1976). It is not possible to determine the critical affect in humans (the effect that occurs at the lowest exposure), because quantitative human exposure data were not provided. Animals exposed orally or by inhalation manifest cancerous and noncancerous liver effects similar to those seen in humans; but other effects seen in humans, such as acroosteolysis, Raynaud syndrome, and scleroderma, have not been reproduced in animals, even at very high exposures. Liver effects appear to be the critical end point in animals, and therefore animals are probably a satisfactory model for noncancerous end points of toxicity in humans. 4.3.3 Developmental Toxicity 4.3.3.1 Inhalation Human. Epidemiological data associate increased fetal loss with occupational exposure to vinyl chloride, although exposure data were not quantified. Using a questionnaire. Infante et al. (1876) and Vaxwailer et al. (1977) studied the outcome of pregnancies of wives of 95 vinyl chloride workers and a control group of 158 unexpoaed rubber workers and polyvinyl chloride fabricators exposed to 'very low* levels of vinyl chloride monomer. Data were obtained for the exposed cohort regarding pregnancies that occurred before and during employment in a vinylchloride-contaminated atmosphere. The most significant observation vas that "age adjusted" fetal loss occurred in 8.8% of the pregnancies of wives of controls and in 13.8% of the pregnancies of wives of exposed workers. The most significant difference occurred in wives of men under age 30, where fetal loss was 3.3% for controls and 20.0% for exposed workers. In a preliminary investigation of the potential for vinyl chloride exposure to increase the occurrence of congenital malformations, Infante CMrt 009877 % 47 (1976) compared eh* number of self rmations per 1000 live blrchs in three Ohio cities where polyvinyl chloride pr duetion plants were located (index cities) with the incidence in the state as a whole and with the Incidence in other parts of the counties in which the index cities were located. The incidence of malformations was greater in the three index cities by either comparison, and the difference was statistically significant. Greatest increases were noted in malformations of the CHS, upper alimentary tract, and genital organs, and in the incidence of clubfoot. An additional study of one of the Ohio cities revealed no association with parental occupation and no evidence chat parents of malformed Infants lived closer to the local polyvinyl chloride plant than did a randomly selected group of parents who delivered normal infants (Edmonds at al, 19737. Ifeonds et al. (1973) concluded that there was no association of birth defects with exposure to vinyl chloride. Theriault et al. (1983) investigated the incidence of birch defects in residents of a Canadian town where there is a vinyl chloride polymerization plant. The incidence of birth defects was significantly greater in the index town than in any or all of three matched towns with no potential exposure to vinyl chloride. The most commonly reported defects involved the musculoskeletal, cardiovascular, central nervous, and urogenital systems. The Incidence race peaked in March and vas lowest in September for the index town, but no seasonal effect was | observed in the comparison coMunitles. The lowest Incidence rate ^ followed the time of lowest estimated ambient atmospheric levels oft vinyl chloride by 8 months. In comparisons between parents of deformed Infants and control parents in the index town, no correlations were ' noted with proximity of residence to the vinyl chloride plant or with parental occupation. Furthermore, there were several industries in the index town that emitted pollutants into the anosphere. The investigators concluded that the available data did not substantiate an association between atmospheric vinyl chloride and an increased incidence of birth defects. Edmonds et al. (1978) compared the Incidence rates of CHS defects In a Vest Virginia county in which a polyvinyl chloride polymerization plant was located with those for other regions in the United States with no exposure to vinyl chloride. The incidence rates of the index county exceeded these of control aregf by fCIfefS? tp.2. by comparing data from:parents,of defggge^ipfthtt yi^rid^jtiy. ghpleh metchad controls living in'' the fiMex countyt no wtflmd'daa bated for d<[TeiifT`itfan|perl'Tn, for1 proximity to tha< po&yvtcpl ohiorlde plant, or gfejsitift of wind diroctlom and air pollution. Furthermore, ono major ^pP^saverat^ smaller chemical plants warm located in the area. Animal. Inhalation experiments in animals have not associated vinyl chloride with developmental toxicity at concentrations below those associated with maternal toxicity. John et al. (1977) exposed groups of 30 to 40 pregnant CF1 mica, 20 to 35 Sprague-Dcwlay rats, and 15 to 20 How Zealand white rabbits to vinyl chloride et 0 or 500 ppm 7 h/day on geetctlon days 6 to 15 for rats snd mice end 6 to 18 for rabbits. Additional groups of mico ware similarly exposed to 50 ppm, and additional groups of rats and rabbits were aimilsrly exposed to 2500 ppm. Parameters of maternal and developmental toxicity wore evaluated; CMA 009878 ft 48 b eh eh* fetus *nd litter were evaluated. In ale*. maternal effects were rescricced t 500 ppn end included increased a rtality, reduced body weight, end reduced absolute, but not relative, liver weight. Feeotoxicity, aanifeseed as increased fetal resorption, decreased fetal body weight, reduced litter size, and retarded cranial and sternebral ossification, was observed only at 500 ppm. There was no evidence of a teratogenic effect in ale* at either concentration. Maternal effects in rats at 500 ppa, but net at 2500 ppa, were were restricted to reduced body weight gain. Maternal effects in rats at 2500 ppa were death of one rat, elevated absolute and relative liver weights, and reduced food consunption. Reduced fetal body weight and an increase in the incidence of luabar spurs were observed at 500 but not 2500 ppa and are not considered signs of chemical-related fototoxicity. The incidence of dilated ureters, however, was increased at 2500 ppai and aay represent a chemical-Induced effect. Signs of asternal or developmental toxicity were not observed in rabbits at either 500 or 2500 ppa. For developmental toxicity the concentration of 2500 ppa represents a L0AEL in the rat and a N0AEL in the rabbit. Ungvary at al. (1978) exposed groups of pregnant CFY rats continuously to -1500 ppa on gestation days 8 to 14 or 14 to 21 in a study that Identified a NOAEL for developmental toxicity in rats. Controls consisted of groups of rats that were chamber exposed eo air only on gestation days 8 to 14 or 14 to 21. An additional control group consisted of unexposed rats that were not subjected to the chamber. Groups contained 14 to 28 litters, and the litter was a unit of coaparison for fetal effects. Maternal toxicity was aanifested by increased relative liver weight in daas exposed on gestation days 8 to 14 and slightly reduced body weight gain in daas exposed on days 14 to 21. There was no evidence of fetal toxicity or teratogenicity. In another part of this study, rats were exposed as described above on gestation days 1 to 9 and siaultaneously injected subcutaneously with physiologic saline. Coapared with air-exposed controls created with physiologic saline, these rats had significantly increased relative liver weights and fetal wastage, and a slight but not statistically -significant Increase in the percentage of fetuses with body weights <3.3 g. The investigators also observed one fetus with anophthalmia and on* with microphthalmia in rats exposed during days 1 to 9, as well as a tendency for increased fetal wastage In rats exposed on days 8 to 14. They suggested that the developmental toxicity of vinyl chloride should be tested by continuous exposure throughout the period of organogenesis. In a Bulgarian study, Mlrkowm et al. (1978) exposed pregnant rats to 0 ox 8.15 ag/a? (2.4 ppa) continuously throughout gestation. Fetotoxic effects included early poatinplantaclon fetal loss, reduced fetal body weights, retarded ossification, and fetal hematomas. Teratogenic effects included anoaalles of the brain. In offspring from rats allowed to deliver, liver function at 1 month of ago was compromised, as indicated by increased hexobarbltal sleeping time. In a Russian study, Sal'nikova and Kotsovskay* (1980) exposed pregnant rats to 0, 4.8, or 35.5 ag/a^ (0, 1.9, or 13.9 ppa) 4 h/day throughout gestation. Maternal effects included decreased RBC count and decreased urinary excretion of hippurle acid at 13.9 ppa. Fetal hemorrhages were reported at both exposure levels, and fetal edeaa was CHA 009879 49 reported at 35.5 mg/mi*. In offspring f rats allowed to deliver, bahavloral changes vara reported at 35.5 ag/a^, and liver effects, haaatologlc and blochaaical effects, and altered relative organ weights ware reported in both groups. 4.3.3.2 Oral Data regarding developaental toxicity in orally exposed huaans r aniaals were not located. 4.3.3.3 Deraal Data regarding developaental toxicity in dernally exposed huaans or .aniaals were not located. 4.3.3.4 General discussion Spldeaiologlc data suggest an association between paternal occupational exposure to vinyl chloride and fetal loss (Infante et el. 1976, Waxweller et al. 1977), but exposures were not quantified. In contrast, developaental toxicity was net reported in aniaals exposed to high levels for 7- to 12-day periods during organogenesis at levels below which asternal toxicity occurred (John at al. 1977, Ungvary et al. 1978). Ungvary at al. (1978), however, noted evidence of developaental toxicity in rats exposed In the first trinester coapared with rat* g exposed later in gestation and suggested that valid testing should ^ Involve exposure during the entire gestation period. A Bulgarian study reported both fetotoxlcity and teratogenicity in rats exposed continuously to a low concentration throughout gestation (Mirkova at al. 1978). The protocol and results were incoapletely reported; hence, Che study cannot be properly evaluated. Reporting probleas also preclude proper evaluation of a Russian study (Sal'nikov* and Kotsovskaya 1980) which reported developaental toxicity la rata, intermittently exposed to low level* throughout gestation. These studies^ however, underscore the need for further testing, using continuous exposure at low levels throughout geetation. 4.$.4 Rofsodeative Toxicity 4. 2. 4.4^cMalaaioau * ' . i. . r.J :'r * . ''.r ............ ,, &90 hSMtW da* MBMone levels Misridir aa'--|)m<iL logical health in ~ ter vSMgA chloride end evaluated by i, Itoraone levels war* eeasured, and women were given sldgfeal examinations. BXposures were reported as low. not aoedlng 1 allowable concentration (MAC) (30 mg/m* or -12 ppm); stags. In the range of 1 to 3 MAC (12 to 60 ppm); or significant, cascading 3 MAC (60 ppa). An exposura- and duration-related decline in sexual function was reported in exposed man and woman. Ovarian dysfunction, benign uterine growths, and prolapsed genital organs vara reported In 771 of exposed women. CMA 009880 * 50 Animal. Bi t *1. (1985) exposed *dulc aale Wistar rats to 0, 10, 100, r 3000 ppa, 6 h/day, 6 days/week for up to 12 a nths to evaluate offset* on th* tastas. Relativa tasticular weight, evaluated only after 6 months of exposure, was significantly raduced at 100 and 3000 ppm. Histopathological examination revealed a concentration*related increase in the incidence of testicular degeneration significant at 100 ppa. *.3.4.2 Oral Data regarding the reproductive effect* of vinyl chloride in orally exposed huaan* or aniaals were not found In th* literature . *.3.4.3 Dermal Data regarding th* reproductive effects of vinyl chloride in dareally exposed huaan* or aniaals were not found. 4.3.4.* General discussion Data regarding the reproductive effects of exposure to vinyl chloride are Halted. Huaan data associating occupational exposure with reduced sexual function in both sexes and iapaired gynecological health in uoaen (Makarov 1984, Makarov at al. 1984) are not adequately reported for proper evaluation; therefore, such data cannot be used to identify thresholds. Whereas aniaal data do associate exposure to vinyl chloride. with testicular effects, sexual perforaanc* and fertility were not testeda. 4.3.5 Genotoxicity 4.3.5.1 Huaan Genotoxicity studies of vinyl chloride in huaana include a large nuaber of chroaosoaal aberration tests in the peripheral lyaphocytes of occupationally exposed workers (Table 4.4). These tests have been consistently positive (Ducataan et al. 1975, Fbnes-Cravloto et al. 1975, Purchase et al. 1978, Hansteen et al. 1978, Kucerova et al. 1979, Katsova and Pavlenko 1985), with the exception of a less rigorously performed and reported Dow Cheaicsl Coapauy study (Killan et al. 1975). The key study in this group is Hansteen et al. (1978), in which blood froa 37 exposed workers and froa 16 to 32 unexposed controls was examined twice at intervals of 2 to 2.5 years. Exposure levels during the tine of first sampling were measured at 25 ppm, end there was a statistically significant increase in the percent of peripheral lymphocytes with chroaosoaal aberrations. When these workers were subsequently reexamined, exposure levels had dropped to 1 ppa, and there were me statistical differences between exposed and controls in the percentage of chroaosoaal aberrations. Anderson et al. (1980) observed an increase In lymphocytes with chroaosoaal aberrations in another cohort at exposure levels estimated at 50 ppa. Th* Incidence of aberrations was returning to normal, however, when th* cohort was resaapled after exposure levels had been reduced to <5 ppa. In a Russian paper (Katsova and Pavlenko 1985), 0.1 ag/a^ (-0.04 ppa) was suggested as a no-effect level for chromosomal aberrations. Th* study was insufficiently reported to allow critical CMA 009881 * 51 THU Cwinklly ef day! chloride is ffro Ead pout Spedas/test system Result References Recessive lethal DroaophUa mtlaaoputtr + Verburgt and Vogel 1977 Dominant lethal A imUmogum - Verburgt and Vogel 1977 Monas Purchase et at 1975. Anderson et al 1976 Sex chromosome lots A mtlmogamr - Verburgt and Vogel 1977 Chromosomal traaslocatioa A mtlanofoitrr Verburgt and Vogel 1977 Chronoaomal aberration Rat + Andenon and Richardson 1981 Mouse Welles and Hoimberg 19f4 Human lymphocyte + Hansteen et al 1978 | Sister chromatid exebaage Human lymphocyte - Haastosn et aL 1978 Human lymphocyte + Kucerova et at 1979 Chromosomal sberratioa Human lymphocyte Kucerovaet at 1979 Humaa lymphocyte + Purchase et al 1975, 1978 Human lymphocyte + Ducatman et aL 1975 Chromosomal aberratioo Human lymphocyte + Funes-Cravioto et al. 1975 Humaa lymphocyte + Katsov* aad Pavlenko 1985 Humaa lymphocyte - KiUaa et aL 1975 Micronecleus test Mouse + Jemma aad Ramel 1980 RNA alkylation* Rat + Left aad Bolt 1977 DNA alkylation Rat + LaibotaL 1985 DMA alkylation t .. Mouse Rat + Oaterman-Colkar et at 1977 + Green and Hathway 1978 - `Although RNA alkylation it not a genocoxic effect. th results of this tost are supportive evi dence that vinyl chloride metabolites interact with nucleic acids. CMA 009882 * 52 valuation, hovavar, and tha NOAEL from tha Hanstaan t al. (1978) study is accepted. 4.3.5.2 Nonhuman It is beyond tha scope of this document to evaluate all data regarding the mutagenicity of vinyl chloride in nonhuman systems. Representative data, largely taken from a recent EFA (1985b) review, are presented in Tables 4.4 and 4.5. Vinyl chloride is mutagenic in Salmonella ejphlmirlua (Rannug at al. 1974; Bartsch at al. 1975, 1976; Andrews at al. 1976; Simmon et al. 1977; Elmore et*al. 1976; Foneelet at el. 1980; de (feester at al. 1980), but only in strains reverted by base-pair substitution by alkylating agents'rather than by frameshift mutations (Bartsch et al. 1976). Metabolic activation may be necessary for any mutagenic activity in this system (Rannug et al. 1974) or for a maximal response (Simmon et al. 1977). Results in other microbial systems were mixed. Vinyl chloride was positive for recessive lethal effects but negative for dominant lethal effects, chromosomal translocation, and sex chromosome loss In DroMOphlla almogtsctr (Verburgt and Vogel 1977). The Investigators suggested chat the negative results in the dominant lethal test may indicate that metabolites capable of causing chromosomal damage did not reach the germ cells. Negative results were obtained for the dominant lethal test in mice (Purchase at al. 1975, Anderson et al. 1976). Positive results were obtained in mutation and cell transformation tests and in chromosomal aberration tests in in vivo and in vitro mammalian systems (Styles 1977, Orevon and Kuroki 1979, Janssen and Ramel 1980, Valles and Holmberg 1984, Imib and Bolt 1977, Lalb at al. 1985, Anderson and Richardson 1981). Positive results were also reported for DMA alkylation tests in rats (Green and Hathway 1978) and mice (Osterman-Golkar et al. 1977) and for SNA alkylation in rat liver microsomes (Laib and Bolt 1977). 4.3.5.3 General discussion Evidence strongly implicates the oxidation of vinyl chloride to the reactive intermediates 2-chloroethylene oxide and 2-chloroacetaldahyde as being responsible for mutagenicity in the systems discussed above. Reports indicate that 2-chloroethylene oxide and 2-chloroacetaldehyde are manyfold more active in S. cypbimurium than the parent compound or other oxidation products of vinyl chloride such as 2-chloroethanol or chloroeeetlc acid (Rannug et al. 1976, Bartsch 1976, McCann et al. 1975)..>.R-Chloroechylene oxide has also bean shown to be responsible for base substitutions in Escherichia coll (Barbin et al., 1985a), to be hi4tty> mutagenic in gene mutation and gene conversion tests in yeasts (Loprftno et al. 1977), and to induce mutations in Chinese hamster V79 cells (Huberman et al. 1975). In vitro testing has shown that 2-chloroethylene oxide Is capable of alkylating DMA to fora 7-(2-oxoethyl)guanine as the principal adduct (Barbin at al. 1985b). This adduct has not been shown to cause errors in DNA replication in an in vitro test with E. coIX DNA polymerase I, and the role of DNA alkylation in mutagenesis is unclear. CHA 009883 TaMa il Ceaetaaklty of vinyl iMiiMj la iHi Remit End point Speciea/leat ayalem Without With activation activation Reference! Reverse wilstkMi Sofmoarflo lypUmurtmm S. lypkimtuium S. lypkimtuium S. lypbimurtum SL lypbimurtum S. lyphimitrium Forward or reverie mtilioi Reverie mutation Forward mnletien Rec-repair Forward mutation CeH tranafbrmetion RNA alkylation' Etckerkkim coli S*cxkaromycei cerevisiae Sckizosmcckaromycti pomb* btcillut zubtlHs Ckineac bamaler ceN V79 Neonatal (mauler kidney cedi Rat liver aairroaomca + + + + -- + + + + RanangetaL 1974 + Rartachetal. 1975. 1976 + Andrew etaL 1976 + Simmon et al. 1977 NT* Elmore et aL 1976 + Poaceiet et al. I960, de Meeateret al. 1910 + Grehn et aL 197S NT Shahin 1976 + Lopriaaoet at. 1977 NT Ehnoraetal. 1976 NA* Dmvon and Karofci 1979 NA Stylet 1977 NA Laib and Boh 1977 vwo Not tailed. *Nol applicable. o `Although RNA alkylation ii not a genoloaic effect, the rcaulti of Ihia teat are mpportive evidence that S vinyl chloride mclabolilca inleracl with nockic acida. ' 54 4.3.6 Carcinogenicity 4.3.6.1 Inhalation Honan. Several report! (Tabershav and Gaffey 1974, Monson et al. 1975, Vaxweiler et al. 1976, Nicholson et al. 1975, Heath et el. 1975, Lilia et al. 1975, Popper and Thonas 1975, Bryen et al. 1976, Fox and Collier 1977, Heldaas et al. 1984, Ceryk and Zudova 1986) associate human cancer with occupational exposure to vinyl chloride. The sost. recent review of the huaan data Is that of EFA (1985b). Since none of the huaan studies quantify exposures sufficiently for quantitative risk assessaent, no single report is chosen as a key study. In a review of these data, XARC (1979) concluded that the huaan data constitute "sufficient" evidence for the carcinogenicity of the compound. EPA (1985b) classified vinyl chloride In XAlC Group 1; subsequently, EPA (1987b) placed this coapound in Carcinogen Assessaent Group A. Both classifications reflect the designation of vinyl chloride es a known huaan carcinogen. The Incidence of liver cancer, in particular angiosarcoma, provides the most convincing evidence for the carcinogenicity of vinyl chloride, because the expected background level (25 to 30 eases per year in the United States) is extreaely low (Heath at al. 1975). Host of the epidemiologic studies cited above reported a higher observed/expected ratio for liver cancer than for cancers of shy other site. Other cancers associated with vinyl chloride exposure Include tumors of the brain end CHS, the lung and respiratory tract, the digestive tract, and the lymphocytle/hematopoietic system, although statistical significance was not necessarily reached (Monson et al. 1975, Uaxveller et al. 1976, Bryen et al. 1976). Fox and Collier (1977), however, concluded that there is no evidence that cancers other than those of the liver are associated with exposure to vinyl chloride. Heldaas at al. (1984) also reported an unusual number of cases of malignant melanoma of the skin in exposed workers. The Heldaas et al. (1984) study, however, is based on incidence of cancer rather than on death due to cancer, which may explain why other studies have not reported an increase in malignant Generally, prolonged exposure (employment) increased the risk of cancer, particularly if intermittent high exposures have occurred (Bryen et al. 1976, Heath et al. 1975). Tabershav and Gaffey (1974) noted that an increased risk of malignancy correlated with an increased "exposure index," an Interplay of level and duration of exposure. Fox and Collier (1977), however, reported little correlation with duration of exposure. AmiPel. -The key animal inhalation studies of carcinogenicity are the sa^%m ef experiments by Maltoni et al. (1980, 1981) in SpragueDawley rats, Swiss mice, and golden hamseers. A report of interim results was published earlier (Maltoni and Lefemine 1975). All animals were chamber exposed; controls were chamber exposed to air only. The Cast material was. >99.9% pure. A complete gross and histopathological examination of every animal was performed. Mice and hamsters were exposed to vinyl chloride concentrations of SO to 10,000 ppm for 30 weeks, followed by an observation period of 51 weeks (mice) or 79 weeks (hamsters). Exposure levels and results from the most DMA 009885 55 comprehensive and longest-tsm experiments in rata ara praiancad in Table 4.6. Tha investigators nocad chat incraaaad incidanca of cunors occurred aC *50 ppm in all spaeiea caaead. All apacias ahovad an ineraaaa in tha incidanca of livar angiosarcoma. In addition to tha' tumor types praaantad in Tabla 4.6, tha authors aaaociatad axtra hapacic angiosarcomas, hapatomaa, Zymbal gland carcinomas, and neuroblastomas in rata with exposure to vinyl chloride. Other inhalation experiments support tha carcinogenicity of vinyl chlorlda. Rats, mica, and hamatars vara exposed to 50 to 2500 ppm vinyl chloride for 9 or 12 months (Kepllnger at al. 1975, MCA 1980). All apacias developed liver angiosarcomas in a concentration*related manner at *50 ppm, the lowest level tested. Metastases to lymph nodes or lung were common. Rats also developed Zymbal gland eumora at *50 ppa and brain tumors at *200 ppm, and mice developed lung tumors at *50 ppa. Viola at al. (1971) exposed rats to 3% vinyl chloride (30,000 ppa) for 12 months and observed primary tumors of the skin, lungs, and bones. Feron Kroes (1979) exposed rats to 0 or 5000 ppa for 52 weeks and observed primary tumors in treated rats in the brain, lung, Zymbal gland, and nasal cavity. Lee ec al. (1977a, 1978) exposed rats and mice to 0, 50, 250, or 1000 ppm, 6 h/day, 5 days/week for up to 12 months; subsequently, they observed an increasad incidence of hemangiosarcoma of the liver in rats at *250 ppm, as well as bronchioalveolar adenoma of the lung, mammary tumors, and hemangiosarcoma of the liver and others organs in mica at *50 ppm. In a latar study from the same laboratory^ Hong at al. (1981) exposed rats and nice to 0, 50. 250, or 1000 ppm,,,6 h/day, 5 days/week for up to 6 months, followed by a 12month observation period. Tumor types attributed to vinyl chloride exposure in rats were those observed by Lee et al. (1977a, 1978), in addition to bronchioalveolar lung tumors at *250 ppm and mammary tumors at all exposure concentrations. Suzuki (1978, 1981, 1983) also observed lung tumors as a primary carcinogenic response of mice to vinyl chloride. Lung tumors developed in 26 of 27 mice exposed to 2500 or 6000 ppa for 5 to 6 months (Suzuki 1978). Concentration*related increased incidences of lung tumors were observed in studies in which mice were exposed to 0 to 100 or 0 to 600 ppm for 4 weeks and then observed for up to 41 weeks postexposure (Suzuki 1981, 1983). Although in neither study was statistical analysis performed, it appeared that 10 ppa was a low level associated with an Increased incidence of lung tuM>rs in both studies. Hehlr ec al. (1981) reportad an increased incidence of lung eumora In mice given single 1-h exposures to 5000 or 50,000 ppm. Inhalation data In three species suggest that age at exposure has am effect on carcinogenic response. Drew et al. (1983) exposed rats, mice, and hamatars to 50 to 200 ppm for periods from 6 to 24 months or ftem 6 to 12 monehs during different portions of their lifespans. All three species had a maximal oncogenic response when exposed during the first 12 months of life. Exposures begun after a 12-month holding period did not produce a carcinogenic response. Maltoni et al. (1983) and Gotti et al. (1983) exposed rats in utero from gestation day 12 and after birth to 1 year of age to 2500 ppm and observed very high Incidences of liver and brain tumors. Liver angiosarcoma, with an average latency period of 50 weeks, developed in 32 of 56 males and in 38 of 55 females. CHA 009886 * 56 Tibia 4.6. Taaar iadOaaca h nk aid ftaala Spnpe-Dawlty raw npiiil by Mahrti to T<ayl cblertOa 4 fc/Oay, 5 4ay/waak far 52 Mk> Expoaura laval (PP) Dumb* of mdy (waaki) lachfcnca of kidney 0 I 5 10 25 50 100 150 200 250 500 2J00 6.000 10.000 30.000 135-147 147 147 147 147 135 143 143 143 135 135 135 135 135 6S 0/303 0/118 0/119 1/119 5/120 1/00 1/120 6/119 12/120 3/59 6/60 13/60 13/59 7/60 18/60 0/363 0/1 It 0/119 0/119 1/120 1/60 10/120 11/119 7/120 5/59 6/60 6/60 5/59 5/00 NR* 2A.^" y Nouaportad. Source Maboni at aL 1980,19U. a CMft 009887 57 Brain tuaors, with an average latency of 48 weeks, developed in 27 of 57 alas and in 28 f 57 faiaalas. Lover ineidancas of tumors davalopad in racs axpoaad for only 7 days in ucaro. Halconi ac al. <1980, 1981) exposed racs co 6000 or 10,000 ppm in utaro on days 12 Co 18 of gaacation and concinuad co obsarva chaa for 115 vaaks. In 54 high-dose progany, chara vara 3 vich Zyabal gland carcinoaa, 2 with angiosarcoaa, and 1 vich naphroblascoaa of cha brain. In-32 lov-dosa progany, 1 davalopad Zynbal gland carcinoaa and 2 had angiosarcoaa. 4.3.6.2 Oral Hasan. DaCa regarding cha carcinogenicity of vinyl chloride in orally axposad huaana vara not found. Anlaal. Cancer types observed in orally created racs resemble Chose observed froa inhalation exposure. In Che key oral study, Feron ac al. (1981) exposed groups of Vlscar rats co vinyl chloride in cha diet by incorporating polyvinyl chloride (FVC) povdar containing a high level of cha aonoaar. Diets vara fed 4 h/day, and food consumption and body weights vara aonicored. Volatilization of vinyl chloride froa the diet vas astlasted, and dosages of vinyl chloride available to cha rats vara also eseiaacad. In addicion, ona group received vinyl chloride by gavage 5 days/veek. Pertinent data era suanarized in Table 4.7. Exposure vas for Che llfeciae of che racs. Traacaanc of the 300*ag/kg gavage group vas ceralnated at 84 weeks because of high aortalicy. The liver cunor incidence data presented in Table 4.7 suggest Chat angiosarcomas pradoalnatad ac high dosages but thae hepatocellular carcinomas predominated ac low dosages. In addicion co cuaors of cha liver and. lung, cha investigators attributed exposure to the davalopaane of extra hepatic abdoalnal anglosareoaas and Zyabal gland Cuaors. They also noted soma evidence chae exposure enhanced the development of abdoainal aesothelioaas and adenocarcinomas of cha aaamary gland. Other oral studies indicate thac Che eype of Cuaor observed may depend on Che dosage given. Malconi (1977) ereacad rats by gavage ac 16.7 or 50 ag/kg/day for 52 weeks followed by an 84-week observation period. An increased incidence of liver angiosarcomas and kidney nephroblastomas vas accrlbuced co vinyl chloride. Zynbal gland carcinomas aay also have been Che resulc of exposure Co vinyl chloride. Dow Chemical Company (1984), in a lifetime study, administered vinyl chloride In the diet (from FVC containing a high level of of the aonomar) to racs ac dosages of 0.014 co 1.3 ag/kg/day. Males at 1.3 g/kg/day and females at all dosages had an increased Incidence of liver nodules and preneoplastic foci. Females at 1.3 ag/kg/day had Increased incidence of hepaeie neoplastic nodules, but no other carcinogenic response vas reported. 4.3.B.3 Dermal Data regarding the carcinogenicity of vinyl chloride in deraally exposed humans or aniaals were not found. CMA 009888 % Ta9fa4>7, It Dom* Sn (mtJtytoj) Vtkkto/i Ttpt atpa Ttnartyp* Tmmt iaddoct (frtlm) r 300 14 <d/ Uvw 2/34 0/34 F 17.0 143 FVC/dtat U*w 29/34 23/34 44/37 (F<M0l/ 29/37 (/< aooir F J.0 141 PVC/ditt Umt 9/37 (F < 0.00l/ 3/37 (/<aosr 39/39 (F < 0.001 / 19/39 (F< 0.0011* F 1.1 .14) FVC/dtat 2/39 3/39 20/31 <F<Ml/ 4/M F <L0 NA UammOObt Uw 0y 0/30 0/30 2/37 2/57 M 300 14 0/37 0/37 3/33 1/53 M 17.0 141 FVC/Ota 27/57 19/33 23/39 (F< 0.00l/ 0/39 (F< 0401 r U :- 143 FVC/Otat 27/39 <F< 0401 / 19/39 <F< Mir 7/34 <F <0.01/ 2/30 (F< Ml / 4/34 (F< 043/ 7/34 % 009889 CHA 59 TM*4.7 (iiiHwiI) Dwstfaaof Don* Ttrpi Sc* <a/k|/*y) (Wfei) VUdt/Mttod "t Tnwqpi nMjrrtriitmM M 1.1 143 PVC/dtat 1NWc aortala M ao NA iy 1 1 LMf Uw 1ftafMaaoMa Laag Iftautaa rf oady wm 143 m!k panty of cmpnod wMMtn *Nt Smm m *L lMt. I/M l/ 0/3* 0/M 0/33 0/33 0/33 0/35 CMA 009890 60 4.3.6.4 General discussion Ths dues reviewed indlcsts Chst chsrs is s similarity in esnesr cypss in experimentally txpossd animals and occupationally exposed humans. Th human data prssant ths strongest statistical cast for associating occupational exposure with liver angioser.coma (Monson et al. 1973, Waxveiler et al. 1976, Bryen et al. 1976, Fox and Collier 1977). The incidence of cancer of the brain, lung, and digestive tract, although not always statistically significant, is suggestive of a vinyl chloride etiology. The substantial amount of animal data also presents the strongest association for liver angiosarcoma (Maltonl et al. 1980, 1981; MCA 1980; Feron end Kroes 1979). Statistically significant increases have also been observed for lung cancer in mice (Lee et al. 1978; Hong et al. 1981; Suzuki 1978, 1981, 1983), and biologically significant increases have been reported for brain cancer in rats (Feron and Kroes 1979; MCA 1980; Kaltoni et al. 1980, 1981). Animal data suggest that both the young and the prenatal organism are susceptible to vinyl chloride'induced cancer (Kaltoni et al. 1980, 1981, 1983; Drew et al. 1983). It Is generally agreed that oxidation to 2-chloroethylene oxide, a highly electrophilic intermediate, is responsible for the mutagenicity of vinyl chloride (Gwinner et al. 1983, Valno 1978). In vitro testing has shown 2-chloroethylene oxide capable of alkylating DMA to form 7-(2-oxoethyl)guanine as the principal adduct (Barbin et al. 1985b). This adduct has not been shown to be involved in genetic miscoding, and the role of DMA alkylation in carcinogenesis is unclear. f 4.4 nrrSBACTIOHS KITH OTfflOt CHEMICALS A series of Investigations describes the Interactions of vinyl chloride with various ocher compounds, which clarifies the role of metabolism in the toxicity of this compound. In all studies, the acute toxicity to the liver of rats exposed by inhalation to high concentrations, as manifested by serum levels of enzymes indicative of liver damage and the histopathological appearance of the liver, was the end point evaluated. In the first study (Jaeger et al. 1974), pretreatment of rats with phenobarbltal resulted in liver damage as measured by biochemical and histopathological parameters. Liver damage was not detected in nonpretreated rats. The investigators suggested that phenobarbltal had induced the mixed*function oxidase (MFO) system to enhance metabolism of vinyl chloride to a toxic intermediate. In subsequent experiments (Reynolds et.al. 1975, Conolly et al. 1978), pretreatment with the polychlorinated biphenyl (FCB) mixture Aroclor 1234 wee also observed to cause acute exposure to vinyl chloride to result in hopatotoxlcity. The same mechanism. Induction of hepatic MFO, was suggested to result in oxidation of vinyl chloride to the epoxide, 2chlexeethylene oxide. Conolly and Jaeger (1978, 1979) investigated the effect of chemicals that regulate xenobiotle metabolism on vinyl chloride*Induced hepatotoxielty. Trlchloropropene oxide (TCF0), which depletes glutathione and inhibits epoxide hydrase conversion of an epoxide to its corresponding less-toxic alcohol, was found to enhance the toxicity of vinyl chloride in fasted FCB*protreated rats, but not in fed pretreated CMA 009891 % 61 rats. Sines nonprocsin sulfhydryl eoncantrstlons in chs llvtr in TCPOersstsd rats did n t differ fr a chess in control racs, chs Investigators suggested chac chs snhancsd coxicicy in TCPO-treated racs resulted froa inhibition of epoxide hydrass rachsr chan froa glucachions depletion. Ths lack of offset in fsd racs was judged co undsrseors chs laportanea of spoxids hydrass in chs detoxification of spoxids in glutathionedapIscad rats. In other parts of chess sane studies, cyscslns, chs racs-liaicing precursor of glutathione, was able to block depletion of nonproeein aulfhydryl in the liver and thus reduce ths Intensity of liver coxicicy in PCB-pretroaced, vinyl chloride-exposed rats. Trostaenc of fsd racs with dlschylaalsaee, another glutathione depleting agent, reduced liver nonprotein aulfhydryl to levels attained in fasted rats, but did not increase hepatotoxiclty. 4 CMA 009892 * S. MAMUFACTURI. IMPORT, UM, AMD DISPOSAL s.x omviiu Vinyl chloride is produced sc 10 locations in the United Stsces. During 1986, en estinaced 8.5 co 8.6 billion lb of this chemical wee produced in ehe United States. It is produced by thenaal cracking of ethylene diehloride. Vinyl chloride is used almost exclusively in the United States for the production of polyvinyl chloride (PVC) and several copolymers. These compounds yield a vide range of end-use products which are used by industries and consumers. 5.2 FRODUCTIOM Domestic production of vinyl chloride during 1986 was estimated to range between 8.5 and 8.6 billion lb. This was -94 to 98% of available production capacity in 1986. In 1985, 7.8 billion lb of vinyl chlorfde was produced in the United States (C&ER 1987). Manufacturers and sites of production are as follows (CMR 1986*): Borden Chemical in Geismar, Louisiana; Dow Chemical in Oyster Creek, Texas, and Plaquemine, Louisiana; Formosa Plastics in Baton Rouge, Louisiana, and Point Comfort, Texas; BF Goodrich in Calvert City, Kentucky, and La Porte, Texas; PPG Industries in Lake Charles, Louisiana; Shell Oil in Deer Park, Texas; and Vista Chemical in Lake Charles, Louisiana. Vinyl chloride is produced commercially by thermal cracking of ethylene diehloride (EDC). EDC used in this process is made by either direct chlorination of ethylene using liquid chlorine, or oxychlorlnation of ethylene using dry hydrochloric acid and oxygen (Cowfer and Maglstro 1985). Vinyl chloride is usually supplied as a liquid under pressure (IARC 1979). The technical grade product is available in 99.9% purity (Sax and Levis 1987). 5.3 IMPORT Imports of vinyl chloride were -200 million lb in 1987 (C&EN 1987). 5.4 USIS The use pattern for vinyl chloride is as follows (CMR 1986a): polyvinyl chloride (FVC), 85%; exports, 13%; end other, mostly copolymer use, 2. This use pattern indicates that vinyl chloride monomer is used almost exclusively in the United States by the plastics Industry. Very smell amounts are used as a refrigerant gas and as an Intermediate in the production of chlorinated compounds (Curry and Rich 1980, Gosselin ee al. 1984, LARC 1979). Limited quantities of vinyl chloride were used in the United States as an aerosol propellant, and as an ingredient of 63 CMA 009893 64 drug and cosmetic produces; howsvsr, these practices have been discontinued (EPA 1985b). Vinyl chloride is Industrially important because of its inherent flsae retardant properties, its wide variety of end-use products, and the low cost of producing polymers from vinyl chloride (Cowfer and Magiftro 1985). Principal end-use products include; PVC pipes, wire and cable coatings, packaging materials, furniture and automobile upholstery, wall coverings, housewares, and automotive parts and accessories; vinyl chloride-vinyl acetate copolymer floor coverings, phonographic records, and flexible film; vinyl chloride-acrylonitrile battery cell separators; and vinyl chloride-vlnylidine chloride copolymer food packaging film (Curry and Rich 1980, Salklnd and Pearlman 1978, Farkaa 1980). 5.5 DISPOSAL EPA requires that persons who generate, transport, treat, store, or dispose of this compound comply with regulations of the Federal Resource Conservation and Recovery Act (RCRA). The recommended method of disposal, reported by Slttig (1985), involves the incineration of this chemical after mixing it with another combustible fuel. Care should be taken to ensure that complete combustion has taken place in order to avoid formation of phosgene. An acid scrubber is required to remove HC1. ^ In addition to this method, other disposal techniques have been ' Ideveloped for the recovery of vinyl chloride from PVC latexes (Slttig 1985). i 3^6 CMA 009894 6. nvnomBHTAL fate 6.1 OVERVIEW Effluents and emissions from vinyl chlorlda and PVC aanufacturars ara responsible for the majority of vinyl chlorlda ralaaaad'to tha anvironaant. Whan ralaaaad to tha ataosphere, vinyl chlorlda ia expected to ba raaovad by raaetion with photochaalcally generated hydroxyl radlcala (half-life - 1.2 to 1.6 days). Raaetion products lncluda HC1, foraaldahyda, formyl chlorlda, acatylana, chloroacataldahyda, chloroaeatylchloranll, and chloroathylana. In photochaalcal saog situations, vinyl chlorlda has a half*Ufa of 3 to 7 h. When released to water, volatilization la axpactad to ba tha prlaary fata procass (half* Ufa -8.7 to 43.3 h). In waters containing photosansiclzers, such as huaic materials, sensitized photodegradatlon aay also ba important. When ralaaaad to soil, vinyl chloride will either volatilize rapidly fro* soil surfaces, or leach readily through soil, ultimately entering, groundwater. 6.2 RELEASES TO THE ERVHOHHENT Tha aajor source of release of vinyl chlorlda to the environment is believed to ba emissions and effluents froa plastic industries (primarily vinyl chloride and PVC aanufacturars). Vinyl chloride released in wastewater is expected to volatilize fairly rapidly (on the order of hours to days) into the ataosphere. Other sources of release include disposal of vinyl chlorlda wastes in landfills, lncoaplete combustion of PVC, tobacco saoka, spills, and biodegradation of erlchloroethyleno, tatrachloroethylane, and l,l,l*trichloroethane in groundwater (IARC 1979, H5DW 1967, Wakanan and Johnson 1978, Wilson and Wilson 1989, Smith and Dragon 1984). BPA estimated that prior to 1975, 110 aillion kg/yaar of vinyl chlorlda escaped into tha ataosphere froa PVC production facilities in the United States (IARC 1979). Worldwide emissions of vinyl chloride into tha ataosphere during 1982 vas -400 aillion lb (Hartasns at al. 1985). 6.3 HVH0MBAL PATE 6.3.1 Air Based on a vapor pressure of 2660 an Hg at 23*C, essentially all vinyl chloride in the ataosphere is axpactad to exist in vapor fora (Verschueren 1983, Elsenreleh at al. 1981). Consequently, removal from the ataosphere by dry deposition is not expected to ba an important face process. Vinyl chloride has a relatively high partition coefficient between air and water (R - 50), which suggests that significant amounts of vinyl chloride would not be raaovad froa the ataosphere by wet deposition (EPA 1985b). 65 CMA 009895 66 Reaction f vinyl chi rid* vapor with photochaaically generated hydroxyl radicals is predicted eo b* the primary degraded n mechanism for this compound in ch* atmosphere. Tha half-life for this reaction in the typical ataosphara has b*an -1.5 to l.S days (E?A 1985b). Products of this raaction ar* HC1, formaldehyde, formyl chloride, carbon monoxide, carbon dioxid*, chloroacetaldehyde, acetylene, chloroethylene, ehloroacetylchloranil, and H20 (EPA 1985b). In phocochcaical smog situations, the reaction half-life of vinyl ehlorid* is predicted to rang* between 3 and 7 h (HSOB 1987). Reaction with ozone (half-life 4.2 to 33 days), reaction with oxygen atoms [0(3P)] (half-life - 373 to 532 days), and direct photolysis ar* relatively insignificant degradation mechanisms in the atmosphere (EPA 1985b). 8.3.2 Veter The primary loss process for vinyl ehlorid* in natural water systems is volatilization Into the atmosphere. The half-life for vinyl chloride volatilization from a typical pond, river, and lake has been estimated to be 43.3, 8.7, and 34.7 h, respectively. These values ar* based on an experimentally determined reaeratlon rate ratio of -2 and assumed oxygen reaeratlon rata* of 0.008, 0.04, and 0.01 hour'^ for a typical pond, river, end lake, respectively (EPA 1985b). Predicted half-lives should be considered rough estimates since the presence of various salts in natural water systems aay affect the volatility of vinyl chloride significantly (EPA 1985b). In waters containing photosensltizers, such as huaic materials, photodegradation aay be fairly rapid. This suggests Chet in some waters sensitized photodegradation would also be a significant removal aachanism (HSDB 1987, EPA 1985b). Cheaicsl hydrolysis of vinyl chloride does not appear to be environmentally important. The hydrolytic half-life for vinyl chloride has been estimated to be <10 years (EPA 1985b). Vinyl chloride is not expected to oxidize chemically by reaction with photochaaically generated hydroxyl radicals, molecular oxygen, or alkyl peroxy radicals in natural water systems. limited available data on the biodegradation of vinyl ehlorid* indicate that this compound is resiseane to aicrobial degradation under aerobic conditions (EPA 1985b). Vinyl chloride is not expected to adsorb significantly to suspended solids and sediments in water or bloaceumulat* significantly in aquatic organisms (HSDB 1987). 8.3.3 Soil The relatively high vapor prassur* of vinyl chloride (2660 mm Hg at 25*C> indicates ehac this compound should volatilize quite rapidly from dry soil surface. The effecdv* helf-lif* (due to volatilization) of vinyl chloride placed 10 cm deep in dry soil is predicted to be 12 h (EPA 1985b). Evaporation from, aolat soil surfaces Is also expected to be significant since this compound does not adsorb strongly to soil and appears to volatilise fairly rapidly from water. Experimental data regarding adsorption of vinyl chloride to soil were not located. Based on the regression equations given by Lynan et al. (1982) and Sabljlc (1984), the soil adsorption coefficient (Koc) ?r vinyl chloride has been estimated to range between 17 and 131. These Koc CMA 009896 fc 67 values suggest chat this compound would ba highly mob11a in soil. Thus, vinyl chi rlda has cha p CenCial co leach into groundwater. Based on daca in aquatic media, chemical reaction of vinyl chloride in soil does not appear co be a significant fate process, and it appears that vinyl chloride would be resistant to biodegradation under aerobic conditions. CHA 009897 t 7. POTENTIAL FOE HUMAN EXFOSURE 7.1 OVERVIEW Anthropogenic sources iri responsible for all of the vinyl chloride found in the environment. Hose of the vinyl chloride released eo the environment will eventually locate in the atmosphere while much smaller amounts will eventually locate in groundwater. Vinyl chloride has been detected in the ambient air in the vicinity of vinyl chloride and PVC manufacturing plants and hazardous waste sites. Vinyl chloride is expected to leach into groundwater from spills, landfills, and industrial sources. Segments of the general population living in the vicinity of emission sources are exposed to vinyl chloride by inhalation of contaminated air. Average daily Intake of vinyl chloride by Inhalation for these people ranges from trace amounts to 2100 pg/day. The average daily intake of vinyl chloride by inhalation is expected to be essentially zero for the remainder of the population. However, short term inhalation exposure to relatively high levels may occur during use of new cars. This Is due to volatilization of vinyl chloride from vinyl polymers within the car interior. The majority of the general population is not expected to be exposed to vinyl chloride through ingestion of drinking water. However, people who have FVC water pipes chat have not been created adequately to remove vinyl chloride monomer may ingest -0.06 to 2.8 Mg/day of vinyl chloride from drinking water. The average daily intake of vinyl chloride through diet is predicted to be essentially zero. NIOSH estimated that 27,000 workers are definitely exposed to vinyl chloride and that workers probably exposed nay be as many as 2.2 million. Intake is expected to occur primarily through inhalation and less importantly by absorption through skin. Workplace air in some FVC manufacturing plants was found to contain 100 to 800 mg/m3 (39 to 312 ppm) vinyl chloride with,peak concentrations of up to 87,300 mg/m3 (34,000 ppm). A NIOSH survey of three vinyl chloride manufacturers reported a time-weighed-average exposure of 0.18 to 69 mg/m3 (0.07 to 27 ppm) vinyl chloride in workplace air. 7.2 IXVEXJ MONITORED OR ESTIMATED IN THE ENVIRONMENT 7.2.1 Air Air in rural/remote and urban/suburban areas of the United States typically contain no detectable amount of vinyl chloride (Stephens et al. 1986; Grimerud and Rasmussen 1975a,b; Harkov et al. 1984; Wallace ec al. 1984; EFA 1985b). Limited monitoring data indicate that in areas near vinyl chloride and polyvinyl chloride manufacturers, the 69 CMA 009898 70 e ncentrati n f vinyl chi rid* in air typically ranges from traee levels co -105 ag/m^ (Gordon and Meeks 1977, Pellizzari ec al. 1979, XARC 1979, BPA 1985b), buc may exceed 2600 ag/*^ (1 ppm) (Fishbein 1979). Elevated levels of vinyl chloride may also be found in the vicinity of hazardous waste landfills. Concentrations ranging from below detection limits to 5 to 8 pg/m^ (0.002 to 0.003 ppm) have been monitored In the air above some landfills (Stephens at al. 1986, Baker and Maekay 1985). Homes near a hazardous waste site in Southern California were found to contain levels as high as 1040 ag/n^ (0.4 ppm) (Stephens at al. 1986). Typical values for the average daily intake of vinyl chloride by inhalation in urban/suburban and rural/remote areas have been estimated co be essentially zero. Assuming chat the average intake of air is 20 mVday, the average daily Intake of vinyl chloride by people living in sourcedominated areas has been estimated to range from trace amounts to 2100 Mg/day. 7.2.2 Hater Vinyl chloride has been detected at varying concentrations in surface, ground, and drinking waters throughout the United States (EFA 1985b). Concentrations as high as 9.8 jig/L in surface water, 380 ag/L in groundwater, and 10 tig/L in drinking water have been reported (Dyksen and Hess 1982, HSDB 1987). There was no report in the literature of vinyl chloride being detected in sediment. The level of vinyl chloride Id groundwater in the United States was determined during the 1982 EFA Groundwater Supply Survey. Hater supplies , from 945 sites geographically located throughout the United States were studied. Results Indicate that vinyl chloride was positively identified in only 0.74% of groundwater supplies (detection limit 1 agA) The concentration detected was 8.4 pg/L (Vestrlck et al. 1984). Other studies have also reported the occurrence of vinyl chloride in groundwater throughout the United States at levels at or below 380 /ig/L (Cocruvo 1985, Coodankauf and Atkinson 1988, Page 1981, Coniglio et al. 1980, Stuart 1983). The concentration of vinyl chloride In finished drinking waters in the United States was studied during the 1976-1977 EFA National Organics Monitoring Survey (HOMS). Only 2 samples out of 113 contained detectable levels (>0.1 jig/L), and these averaged 0.14 agA (HSDB 1987). Results of other studies also indicate diet efts majority of drinking water supplies in the United States contain no detectable levels of vinyl chloride (HSDB 1987, Cenlglto et al. 1980). Based on these studies, it is assumed chat the average daily intake of vinyl chloride by ingestion of drinking water fdr most persona In the United States would be essentially zero. RstlmttOC provided in EPA (1985a) indicate that 0.9% of the United States population is exposed to levels of vlxtyl chloride in drinking water fel.O agA* and 0.3% of the population is exposed to levels >5 ag/L- --""1 CMA 009899 * 71 7.2.3 Soli Monitoring data for vinyl chloride in soil wars not located in the available literature. 7.2.* Other In the past, vinyl chloride had been detected in various foods as a result of migration from polyvinyl chloride food wrappings and containers (EPA 1983b). Vinyl chloride has been found in vinegar at levels up to 9.4 ppm, in edible oils at 0.13 to 14.8 ppm, and in butter at 0.05 ppa when these foods were packaged and stored in FVC containers (IARC 1979). At present, the Food and Drug Administration (FDA) regulates use of vinyl chloride polyaers available for use in production of articles Intended to contact food. These articles include food* packaging aaeerials, coatings, plastlsols, gaskets, and parts for food* processing (see Sect 9, Regulatory and Advisory Status). A recent study on the aigratlon of vinyl chloride froa FVC under conditions closely siaulatlng actual food packaging and storage revealed that at very low concentrations of vinyl chloride in FVC packaging aaterial, there was essentially zero migration of vinyl chloride (Kontoainas at al. 1985). It is reported that migration of vinyl chloride froa rigid FVC water pipes into drinking water occurs, and chat it is directly proportional to the residual level of vinyl chloride in the pipe itself. Under certain conditions, reaction with chlorine in the water may result in the complete removal of vinyl chloride from drinking water (Fist&ein 1979, Ando and Sayato 1984). During one study, it was found chat drinking water which ran through recently installed FVC pipes contained vinyl chloride at 1.4 ng/L, while water .which ran through a 9-year-old system contained 0.03 to 0.06 jig/L (HSDB 1987). This suggests that use of FVC pipe in water distribution systems contributes to intake of vinyl chloride through ingestion of contaminated drinking water. Assuming that the average daily intake of water is 2 L, the average intake of vinyl chloride from water contaminated with vinyl chloride from FVC pipes is expected to range from 0.06 to 2.8 pg/day. The interior air of two new cars was analyzed and the level of vinyl chloride was found to range from 824 to 3120 pg/m^ (0.3 to 1.2 ppm) (EPA 1983b). The source of vinyl chloride was believed to be volatilization from vinyl plastics found In the car Interiors. Levels of vinyl chloride in the air in new cars may exceed estimates of minimal risk levels for acute and Intermediate exposure. Vinyl chloride has been detected in tobacco smoke (EFA 1985b). Cigarettes and little cigars have been found to contain 5.6 to 28 ng vinyl chloride per cigarette (IARC 1979). 7.3 OCCUPATIONAL EXPOSURES NIOSH estimates definite worker exposure to vinyl chloride to be 27.000 persons and probable worker exposure to be 2.2 million (Sittig 1985). This includes >5000 workers employed in vinyl chloride synthesis, 5000 workers involved with polymerization processes, and as many as 350.000 workers associated with fabrication plants. Exposure is believed to occur primarily through inhalation and less frequently by absorption CMA 009900 * 72 through skin (Slttlg 1985). Zn the pest, concentration* of vinyl chi ride in workplace air in some plants producing PVC have been rep rted to range froa 100 to 800 mg/m3 (39 to 315 ppa) with peak concentrations up Co 87,300 mg/m3 (34,000 ppm) (lARC 1979). Currently, the Occupational Safety and Health Administration (OSHA) sets standards for occupational exposure to vinyl chloride (see Sect. 9, Regulatory and Advisory Status). A recent NI0SH survey of three vinyl chloride plants indicated that the timeweighted*average exposure to vinyl chloride varied between 0.2 to 70 ag/a3 (0.08 to 27 ppa) (XARC 1979). 7.4 FOFOLATIOHS AT HIGH RISK Data were not located specifically regarding subpopulations unusually sensitive to the effects of vinyl chloride. Individuals located near or downwind of production facilities, hazardous waste disposal sites, and landfills nay potentially be exposed to higher aabient atmospheric levels. Vorkers involved in the production or polymerization of vinyl chloride nay constitute a group at risk because of the potential for occupational exposure. Since the aid 1970s, however, atmospheric levels in the workplace have often been reduced to ml ppm (Fishbein 1979, Kllian et al. 1975, Hansteen at al. 1978). Occupationally exposed men may represent a sensitive subgroup because occupational exposure In aen has been associated with an Increased incidence of fetal loss in their wives (Infante et al. 1976, tfaxweiler et al. 1977). No threshold concentration has been deterained for this effect. Women (or couples) of child-bearing age may constitute a group at risk, because data suggest that aabient exposure to low (but not quantified) environmental levels is associated with an increase in the Incidence of malformations at birth (Infante 1976; Edmonds et al. 1975, 1978; Theriault et al. 1983). No threshold has been deterained for this effect. Inhalation studies.in animals demonstrated that exposure early in life resulted in greater risk of developing cancer than did exposure later in life (Drew et al. 1983). Although human studies that address the effect of age on cancer risk were not located,, the animal data suggest that exposure during the younger years may result in increased cancer risk. Other animal studies suggest that prenatal exposure may Increase cancer risk (Halton! et al. 1980, 1981). Although human data were not located, the animal data nay suggest chat the prenatal exposure of humans to vinyl chloride may increase risk of cancer. studies have demonstrated that pretreatment with xenobiotlcs or drugs that induce mixed-function oxidase (MFO) potentiates the hepatoPSxiclty of vinyl chloride (Jaeger et al. 1974, Reynolds ec al. 1975, ffeomlly et al. 1978). Although human data were not located, the animal^data suggest that human exposure to environmental pollutants or drugs that induce MFO nay result in Increased sensitivity to vinyl chloride. CMA 009901 I. AMALTTXCAL METHODS A variety of methods are available for the analysis of vinyl chlorlda In environmental and biological matrices. Ths methods of choice will dapsnd on Che nature of the sample aatrix, the required precision, accuracy and detection Halt, the cost of analysis, and the turnaround time of the Methodology. Pre-concentration of samples may not only increase the sensitivity but also, in certain Instances, decrease the time required for sample separation prior to quantification. The best sensitivity and specificity for vinyl chloride quantification are obtained with Hall detectors and photoionization detectors (Reding 1987). Mass spectrometry, although less sensitive than the most sensitive detectors, is often used as a confirmatory tool for vinyl chloride analysis. Details of analytical methodologies for vinyl chloride are given in LARC (1978). . 1 ENV110HMIHTAI. MEDIA Some of the more commonly used analytical methods for the quantification of vinyl chloride are given in Table 8.1. Other meth ds that are less sensitive (e.g., infrared analyzer and continuous monitoring instruments) and less commonly used (e.g., semiconductor devices) are given in XARC (1978). Details of sample collection, sample preservation, sample pretreatment, and quantification methods are provided in the cited references in Table 3.1. 8.2 BIOMEDICAL SAMPLES The concentrations of vinyl chloride measured in environmental samples may not reflect the concentration to which persons are exposed. Proper biological monitoring not only can be used to support environmental monitoring but also potentially may provide more accurate data on exposure levels. The two biological media that have been used moat extensively as promising Indicators of vinyl chloride exposure are breath and urine. A close agreement has been found between postexposure breath concentrations and the ambient vinyl chloride levels in both envlromental and Industrial conditions (Baretta at al. 1969, Tarkovski 1984). However, problems with quantification of low concentrations of vinyl chloride in exhaled air at ambient air levels of <30 ppm has led to limited application of this method (Tarkovski 1984). A reasonable correlation vas noted between urinary output of thlodlglycolic acid, the principal metabolite of vinyl chloride, and ambient levels to which persons were exposed (Hager at al. 1982). Measurement of urinary thlodlglycolic acid can be used as an indicator of vinyl chloride Intake only as long as Individual variability in metabolism due to such factors as liver disease, use of drugs, alcohol Intake, etc., can be accounted for. Therefore, it appears that there is 73 CMA 009902 CMA 0 0 9 9 0 3 TMU *M>yHral tm ** jiniMlfHim * <HmM T fllf Vla)-I rblirida I* air AnM la oc/fid QC/F1D 0ppb **> AccMtcy/ dial NtOSH ItM R4-M ppji NR* (ARC im, MiRcr aad Radar INS Air AdraiNlaa -- Twit PC; ibccawl HROC/MS RJlffb NR Kraal d al. IM2 Ak Or* MHfb **< to NmW- OC/MS M labaaablcal ROOSppk NR Grfcaared aad Raiararara l*75a,b Air Air fnfihMad by Na}8|0}* HROC/flD aad HROC/MS rorsh* NR Haifcaaaial INI, 1N4 ---- Air TmH h wM TuOC mu ib--i Air n ` *i \i Air Diukiaf **4 Fvrp aad trap la Taai OC; ibcraul HROC/FIO OC/FU) oc/eco OC/FID GC/HSD. OC/MS (CPA Method No Ml aad *24> H* NR NR N-IMat Hlilaaa d al im la* im Ml wb OK** NR NR 1*77. Hand) cl aL 1*19 McMarrjr cad Tarr 1471 aitprbCHSDl MKa RU 12 3 Ppk ETA INIs. APHA INI * <1 ' +'A.1 vK s* J Titbll Gfoaa4watcr, ligaii. PwpaM45*C aal In* iaTmuOC; GC/HSO (ETA McthM NMI0) Alt ppb Accuracy/ % ncrnn 101% at AK-J2.1 GPA 1412b e taf f* Taaaa OC Ibaratal lIRGC/HaR 4eUctor. IIROC/PID AM ppb (Hat) 104 I14 at e4iap 1411 (IffA Method 101.2, S24.2) AOIIHM S-Uffb MifraUaa af Aiatif water far &udl NctiM fii ! vstcr Is renter rial far a aaaibar of Ayi at W*C aolaliaa Gaautp iapacMl lata a OC GC/FID NR NR Aada aad SapRo I4M Water GC/FID <1 * NR IARC 1411 par iajartad lata a OC LaadRRpaa Oaa baa laaOM lAaa iia^t.4 by FTFE tshlsf IsUi wsa akmibad bi Taaaa GC tarbaat; trapped GC/MS 0 M Al Yota* aad Parker I4M ^MM MG^ MaaVi MAuMk M^^PRu^^ Sc^ImmI imI oyua Hearogeaeoaa aafk aiiaf vrilk nla aa4 Way! cbiocidt peeped iate a dab loop. |m ia dual loop iajaded iata a GC GC/ECO IN* (c4iswsi) NR Waaf al at 141} Faod (oraaga drtak. viac. alive ail) StMpIt mU Is iUi sri at 48*C for I b; Inbpait pu lejcctad iate GC GC/FID NR NR (My aa4 Creeby 1471 Foodatafla Rraalb Sample acakd ia riala aad eqeibbralcd at eO*C far a aUaiawao al 2 k kenhparr |M iajected taw GC Cryofcaic irappiap af capital air Ibatatal dcwtpiioa iaW GC GC/FID 1 5 ppb GC/FID. GC/ECD aa4 GC/MS NR NR IARC I4TI NR Caakk at al. 1415 O o -0 >0 o wwo LA TaUat.1 fM*M Qaaatifmliaa aaathad GC/MS Detadiae Had! 1 PN Accaracy/ % rwvan> Rdaraacca 71110 Uauaaat aL IMS Whale Moo*, gaa^la nNtratal laa wMvialat GC/BCD NR NR Kiairy Ml ytaaaa. aal lerwa }*C; haaWaw m WhN4 mu Fhaagaa IM2 m OC la Taaaa OC; GC/MS Sr-fwaiaa awthad NR Raid aad Leary 1*7* GC/MS a* HRGC/MS f*k NR luiaaqi delaag IMS, MMIaa at aL add) 1*7* Taw (h*, >a >i<aey. hrate) Hnai^aalta* laaiftaa alial ah crhaaoL Mratoii(riftiiiilb>inM vial at WC; Mpt fat Mjedatl iatoGC OC/FID Wb 7S-* 2vccm d aL 1*7* at*C; OC/BCD NR NR Raaaaayaatl Fla--agaa H "OC uauc IdMa; HSO "Not reported. HROC - n HP - kMS fomiMflnr. 6CP - eiectroa CMA 0 0 9 9 0 5 77 no suitable biological medium that can be used as a reliable Indicator for vinyl chloride exposure (Tarkovski 1984). The commonly used methods for Che quantification of vinyl chloride in biological media are given In Table 8.1. CMA 009904 9. REGULATOR! AND ADVISOR! STATUS 9.L INTERNATIONAL Advisory guidance issued by the World Health Organization (WHO) for vinyl chloride was not loeacsd in chs avsilsbls literature. 9.2 NATIONAL 9.2.1 Regulations 9.2.1.1 Air Tha Occupational Safety and Haalth Administration (OSHA 1983) regulations for vinyl chlorida stata that a worker must not ba exposad to a concentration of >1 ppm over any 8-h period and that a worker must not ba exposed to >3 ppm for any period of time exceeding 13 minutes. Direct contact with liquid vinyl chloride is prohibited. EPA (1982c) has established emission standards for vinyl chloride released to the atmosphere by vinyl chloride and polyvinyl chloride plants. Emissions are not to exceed 10 ppm. 9.2.1.2 Water Pursuant to the Safe Drinking Water Act, EPA (1987c) promulgated a maximum contaminant level (MCL) for vinyl chloride of 0.002 mg/L, equivalent to an estimated cancer risk of 10*3. xhis regulation is to become effective January 9, 1989 and is to apply to all community drinking water systems that regularly serve the same 23 persons for at least 8 months/year. 9.2.1.3 Pood The Food and Drug Administration (FDA 1988) recently proposed to amend its regulations regarding the vinyl chloride content of polymers used in packaging materials or processing equipment for foods. Depending on the nature of the polymer and its use, proposed vinyl chloride content may range from 5 to 30 ppm. *.2.1.* Other EPA (1982d) has designated vinyl chloride as a hazardous constituent of solid waste and requires that it be handled in accordance with tha regulations governing tha same. EPA (1987d) lists a reportable quantity (RQ) for vinyl chloride of 1 lb, but proposes that the RQ be changed to 10 lb. The RQ is the quantity that, if released to the environment, must be reported immediately to the National Response Center. 79 CilA 009907 80 9.2.2 Advisor? Guldsnes 9.2.2.1 Air The American Conference of Governmental Industrial Hygienists (ACGIH 1986b) recommends a Thrashold Limit Valua (TLV)-TWA for vinyl ehlorlda of 3 ppm and a Short-Tana Exposure Limit (STEL) of 10 ppm with tha notation that tha compound is a recognized human carcinogen. Tha National Institute of Occupational Safety and Health (NIOSH 1975) concluded that a TLV for vinyl chloride was inappropriate because of its carcinogenicity. NIOSH (1975) recommended that any workers exposed to vinyl chloride should wear an air*supplied respirator. 9.2.2.2 Vater EPA (1980), based on a human q-* of 1.76 x 10*2 (mg/kg/day) calculated from the incidence of tumors in a preliminary report of an Inhalation study in rats (Maltoni and Lafamine 1975), estimated levels in ambient water of 20, 2, and 0.2 pg/L associated with cancer risks of 10*3, io*6> 10*7, respectively, assuming daily consumption of 2 L water and 6.5 g fish and shellfish. For consumption of fish and shellfish alone, water concentrations of 5266, 525, and 52.5 pg/L correspond to cancer risk estimates of 10*3p io*6 l0*7, respectively. More recently, EPA (1985a, 1987b) estimated that cancer * risk levels of 10*4, 10*3, and 10** would result from daily consumption, of drinking water containing vinyl chloride at 1.5, 0.15, and 0.015 4 pg/L, respectively. EPA (1985a, 1987a) promulgated health advisories for vinyl chloride * in drinking watdr. A 10-day health advisory of 2.6 mg/L was based on-a NOAEL of 30 ag/kg/day in a 13-week gsvage study by Feron et al. (1975). Because data were not sufficient for derivation of a 1-day health advisory, the 10-day health advisory was adopted as a conservative 1-day health advisory. Longer-term health advisories of 0.013 mg/L for a 10 kg child and 0.066 mg/L for an adult were estimated from the NOAEL of 0.13 mg/kg/day in a lifetime dietary study in rats (Dow Chemical Company 1986, Til et al. 1983). 9.2.3 Data analysis 9.2.3.1 Inference doses (lDa> Reference doses for vinyl chloride have not been estimated by EPA. 9.2.3.2 Carcinogenic potency KPA (1985a) classified vinyl chloride in IARC Croup 1, and more recently, EPA (1987a) assigned the compound to Carcinogen Assessment Group (GA6) Class A. By either classification scheme, the designations have the same meaning, that evidence for carcinogenicity to humans is so convincing as to be considered "sufficient." EPA has derived several estimates of carcinogenic potency for vinyl chloride for both oral and Inhalation exposure. In an early estimate, EPA (1980) derived a q,* for human oral exposure of 1.76 x 10'2 (mg/kg/day)*1 based on preliminary reports of the incidence of total tumors in rats of both sexes exposed to vinyl chloride by inhalation at concentrations up to 10,000 ppm CHA 009900 81 (Maltoni and Lefamine 1975). A subsequent estimate of potancy for oral xpoaura Is 2.3 (mg/Vg/day)*l, which appears in E?A (1985a, 1987a) and represents ehe most recent analysis by CAG (EPa 1987a). This estimate was based on the incidence of lung and liver tumors in both sexes of rats exposed for lifetime to diets that contained vinyl chloride (Feron at al. 1981). The first estimate for carcinogenic potency by inhalation exposure, 2.5 x 10*2 (agAf/diy)derived in EPA (1984), was based on the same preliminary inhalation data (Maltonl and Lefemine 1975) that was used as the basis of the EPA (1980) oral estimate. A more recent estimate of 2.95 x 10*1 (ngAs/dey)*^ (EPA 1985b) was based on the final report of the incidence of liver angiosarcomas in male and female rats exposed for up to 1 year to concentrations up to 30,000 ppm (Maltoni at al. 1980, 1981). 9.3 STATE (Regulations and advisory guidance from the states were still being compiled at the time of printing.) 009909 CHh K 10. REFERZHCES ACGIH (American Conference of Governmental Industrial Hygienists). 1986a. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH: ACGIH; 623*626. ACGIH (American Conference of Governmental Industrial Hygienists). 1986b. Threshold Limit Values for Chemical Substances in the Work Environment Adopted by ACGIH with Intended Changes for 1986*87. Cincinnati, OH: ACGIH; 33. Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol; 3:272290. Anderson D, Richardson CR. 1981. Issues relevant to the assessment of chemically induced chromosome damage in vivo and their relationship to chemical mutagenesis. Hutat Res; 90:261*272. Anderson D, Hodge MCE, Purchase IFH. 1976. Vinyl chloride: dominant lethal studies in male CD-I mice. Hutat Res; 40:359*370. Anderson D, Richardson CR, Weight TM, Adams VC. 1980. Chromosomal analyses in vinyl chloride exposed workers. Results from analysis 18 and 42 months after an Initial sampling. Hutat Res; 79:151-162. Andrews AW, Zawlstowskl ES, Valentine CR. 1976. A comparison of the mutagenic properties of vinyl chloride and methyl chloride. Hutat Res; 40:273-275. Ando M, Sayato Y. 1984. Studies on vinyl chloride migration into drinking water from polyvinyl chloride pipe and reaction between vinyl chloride and chlorine. Water Res; 18(3):315-318. APHA (American Public Health Association). 1985. AWWA (American Water Works Association)/VPCF (Water Pollution Control Federation). Standard Methods for the Examination of Water and Wastewater, 16th ed. Washington, DC: APHA; pp. 591*602. Key study 83 CHA 009910 84 Baker LW, MacKay KP. 1985. Hazardous vast* management. Screening models for estimating toxic air pollution near a hazardous waste landfill. J Air Pollut C ntrol Assoc; 35(11):1190-1195. Balkon J, Leary JA. 1979. An initial report on a comprehensive, quantitative, screening procedure for volatile compounds of forensic and environmental Interest in human biofluids by CC/M5. J Anal Toxicol; 3:213*215. Barbin A, Besson F, Perrard MH, at al. 1985a. Induction of specific base*pair substitutions in E. cell trpA mutants by ehloroethylene oxide, a carcinogenic vinyl chloride metabolite. Mutat Res; 152:147*156. Barbin'A, Laib SJ, Bartsch H. 1985b. Lack of miscoding properties of 7(2-oxoethyl)guanine, the major vinyl ehlorlds-DRA adduct. Cancer Res; 45:2440*2444. Baretta El), Stewart RD, Hutchler JE. 1969. Monitoring exposures to vinyl chloride vapor; breath analysis and continuous air sampling. Am Ind Hyg Assoc J; 30:537. (Cited in Tarkovski 1984) Barnes 0, Beilin J, DeRosa C, et al. 1987. Reference Dose (RfD): Description and use in health risk assessments. Appendix A of the Integrated Risk Information System (IRIS). Washington, DC: Office of Health and Environmental Assessment, Office of Research and Development. SPA 600/8*86*0321. ' Bartsch H. 1976. Predictive value of mutagenicity tests in chemical carcinogenesis. Mutat Res; 38:177-190. Bartsch H, Malavaille C, Montesano R. 1975. Human, rat and mouse livermediated mutagenicity of vinyl chloride in 5. cyphimurlua strains. Inc J Cancer; 15:429*437. Bartsch H, Malavaille C, Montesano R. 1976. The predictive value of tissue-mediated mutagenicity assays to assess the carcinogenic risk of chemicals. IARC Scl Publ; 12:467*491. Berk P0. 1976. Vinyl chloride-associated liver disease. Ann Int Med; 84; 717*731. (Cited in EPA 1985a) *Bi V, Vang Y, Huang M, Meng 0. 1985. Effect of vinyl chloride on testis in rats. Ecotox Environ Safety; 10(2):281*289. Bogdasitowa B, Zawilska J. 1984. Immune complexes in the serum of patients occupationally exposed to vinyl chlorlda. Przeglad Lakarski; 41(3):253*257. Bolt HM. 1986. Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis. IARC Scl Publ; 70:261*268. "1 CMA 009911 as Bolt HM, Kappua H, Buchtar A, Bolt tf. 1976a. Dispositi n of (1,2^^C) vinyl chlorida in tho rat. Arch Toxicol; 35:153-162. (Cited in EFA 1985b) Bolt HM, Kappua H, Kaufnann R, at al. 1976b. Matabolisn of ^C-vinyl chlorida in vitro and in vivo. INSERM Symposia Sarios, IARC Selantific Publications N 13. INSERM 52: 151-164.j Bolt HM, Laib RJ, Kappua H, Buchtsr A. 1977. Pharmacokinatics of vinyl chlorida In tha rat. Toxicology; 7(2):179-188. Bryan 0, Engholm G, Englund A, Westerholm P. 1976. Mortality and cancer morbidity in a group of Svadish VCM and PCV production workers. Environ Health Parspact; 17:167-170. (Cited in EPA 1985b) Buchancova J, Reznak I, Horak V, Altmana P, Svehlova L, Suchova E, Sramkova E. 1985. Scintigraphic pictures of tha liver in workers after a long-term exposure to vinyl chlorida. Pracov Lek; 37(6):190-194. Buchtar A, Bolt HM, Kappus H, Bolt tf. 1977. Tissue distribution of 1,2-vinyl chlorida in the rat. Int Arch Oceup Environ Health; 39(1):27- 32. (German: English abstract) Buchtar A, Fllser JG, Pater H, Bolt HM. 1980. Pharmacokinatics of vinyl chloride in tha rhesus monkey. Toxicol. Lett; 6(l):33-36. * CMR (Chemical Marketing Reporter). 1986a. Chemical Profile: Vinyl Chloride. June 2, 1986. New York, MY: Schnell Pub. Co. CMR (Chemical Marketing Reporter). 1986b. Chemical Profile: Polyvinyl Chloride. June 9, 1986. Mew York, MY: Schnell Pub. Co. C&EN (Chemical and Engineering Mews). 1987. Key Chemicals: Vinyl Chlorida. 65(1):10. Chudy JC, Crosby MT. 1977. Some observations on the determination of monomer residues in foods. Food Cosmet Toxicol; 15:547-551. Conlgllo WA, Miller K, MacKaever D. 1980. The occurrence of volatile organics In drinking water. Criteria and Standards Division. Science and Technology Branch. Exposure Assessment Project. Cookie JP, Camp BJ, Welch BE. 1975. Trace composition of human respiratory gas. Arch Environ Health; 30:290-295. Conolly RB, Jaeger RJ. 1978. Effects of cysteine, dlethylmaleata and trlchloropropana oxide on acute vinyl chloride hepatotoxlelty. Toxicol Appl Pharmacol; 45(1):338. Conolly RB, Jaeger RJ. 1979. Acuta hepatotoxiclty of vinyl chloride and ethylene; modification by trlchloropropana oxide, diathylmaleate, and cysteine. Toxicol Appl Pharmacol; 50:523-531. CMA 009912 86 Conolly RB, Jaeger RJ, Szabo S. 1978. Acuta hapatot xiclty of ethylene, vinyl fluorlda, vinyl chloride, and vinyl bromide afcar Aroclor 1234 pretreatment. Expar Molac Pathol; 28:23*33. Cotruvo JA. 1985. Organic micropollutants In drinking vatar. Scl Total Environ; 47:7*26. Cottl G, Balgimlgll L, Mandrioli A, Naltonl C. 1983. Suitable aodala f r long*tan bioaaaays of therapeutic and toxic offacta of antiblaatic drugs: Brain tuaors of neuronal calls and prlaitive bipotential precursors produced in Spragua*Davlay rats by vinyl chloride. Dev Oncol; 13:376-378. Covfer JA, Magistro AJ. 19S3. Vinyl Chloride. Xn Klrk-Othmer Encyclopedia of Cheaical Technology. Vol. 23. New York, NY: Wiley Interscience; 865*883. Covfer JA, Magistro AJ. 1985. Vinyl polymers: vinyl chloride. Xn Kirk* Othmer Concise Encyclopedia of Chemical Technology. New York, NY: John tflley and Sons, Inc; 1229-1230. Curry S, Rich S. 1980. The Kline Guide to the Chemical Industry. 4th ed., Fairfield, NY: Charles H. Kline and Co. de Maestar C, Duverger-van Bogaert M, Laabotte-Vandepaer M, at al. 1980. Mutagenicity of vinyl chloride in the Ames test. Possible artifacts related to experimental conditions. Hutat Res; 77:173-179. Dinceva E, Kolev P, Dalbokova D. 1985. EEC changes in workers exposed to long-term combined effect of a mixture of organic solvents and vinyl chloride. Khig Zdraveopaz; 29(1):8-15. (Russian: English abstract) Dinaan BD, Cook UA, Whitehouae WM, Hagnuson HJ, Dltcheck T. 1971. Occupational acroosteolysls. X. An epidemiological study. Arch Environ Health; 22:61*73. Doss M, Lange CE, Veltman G. 198A. Vinyl chloride-induced hepatic coproporphyrinuria with transition to chronic hepatic porphyria. Klin Uochenschr; 62(4): 173-178-. Dow Chemical Company. 1984. Summary of Report on Lifespan Oral Carcinogenicity Study of Vinyl Chloride in Rats. FYI-0TS-1084-0353XN. FYI-AX-1084*033380. (Cited in EPA 1985b) Drevon C* Kuroki T. 1979. Mutagenicity of vinyl chloride, vlnylldene chloride end ehloropreae in V79 Chinese hamster cells. Mutat Res; 67:173-182. Drew RT, Boorman GA, Haseman JK, McConnell EE, Busey VM, Moore JA. 1983. The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters. Toxicol Appl Pharmacol; 68:120* 130. CMd 009913 * 87 Ducatman A, Hirschhom K, Selikoff IJ. 1975. Vinyl chloride exposure and human chromosome aberrations. Mutat Res; 31:163*168. Duprat P, Fabry JP, Gradiski D. Magadur JL. 1977. Metabolic approach to industrial poisoning: Blood kinetics and distribution of ^4C-vinyl chloride (VCM). Acta Pharmacol Toxicol Suppl (Kbh); 41(1):142-143. (Cited in EPA 1985b) Oyksen JE, Hess AF, III. 1982. Alternatives for-controlling organics in groundwater supplies. J Am Water Works Assoc; 74:394-403. Edmonds LD, Falk H, Niasin JE. 1975. Congenital malformations and vinyl chloride. Lancet; ii:1098. Edmonds LD, Anderson CE, Flynt JW, Jamas LM. 1978. Congenital central nervous system malformations and vinyl chloride monomer exposure: A commity study. Teratology; 17:137-142. Eisenreich SJ, Looney BB, Thornton JD. 1981. Airborne organic contaminants in the Great Lakes ecosystem. Environ Sci Technol; 15(1):30-38. Elmore JD, Wong JL, Laumbach AD, Streips UN. 1976. Vinyl chloride mutagenicity via the metabolites chlorooxirane and chloroacecaldehyde monomer hydrate. Biochem Biophys Acta; 442(3):405-419. (Cited in EPA 1985b) EPA. 1980. Ambient Water Quality Criteria Document for Vinyl Chloride. Cincinnati, OH: Environmental Criteria and Assessment Office. EPA 440/5-80-078. NTIS PB 81-117889. EPA. 1982a. Methods for organic chemical analysis of municipal and industrial wastewater. Test Method: Purgeable halocarbons - method 601 and Purgeable Method 624. EPA Report 600/4-82-057, Environmental Monitoring and Support Laboratory, EPA, Cincinnati, OH. pp. 601-1 to 601-10 and 624-1 to 624-12. EPA. 1982b. Test Methods for Evaluating Select Waste. Physical/Chemical Methods. Method 8010 Halogenated volatile organics. Office of Solid Waste and Emergency Response, EPA, Washington, DC. pp. 8010-1 to 8010- 12. EPA. 1982c. Emission standard for ethylene dlehloride, vinyl chloride, and polyvinyl choride. 40 CFR 61.65. SPA. 1982d. Identification and listing of hazardous waste. 40 CFR 261, Append VIII. EPA. 1984. Health Effects Assessment for Vinyl Chloride. Cincinnati, OH: Environmental Criteria and Assessment Office. EPA 540/1-86-036. EPA. 1985a. Drinking Water Criteria Document for Vinyl Chloride. Washington, DC: Office of Drinking Water, EPA. NTIS FB86-118320. CMA 009914 -Ak- iMipri 88 E?A. 1985b. Health and Environmental Effaces Prof11s for Chloroaehana. Cincinnati, OH: Environmental Crlearia and Assessment Offica. ECAO-CINP155. EPA. 1986. Tha Total Exposure Assassnant Methodology (TEAK) Study. Final report. Washington, DC: Offica of Research and Developaant, Environmental Monitoring Syseaas Division. RTI/2391/00-03 F. EPA. 1987a. Vinyl Chloride Health Advisory. Draft. Washington, DC: Offica of Drinking Water. EPA. 1987b. Graphical Exposure Modelling Systas (GEMS). C10GP. Online. Washington, DC: EPA, Offica of Toxic Substances, EPA. 1987e. National Primary Drinking Watar Regulations - Synthetic Organic Chemicals; Monitoring for Unregulated Contaminants; Final rule. Federal Register; 52(130):25690-25717. EPA. 1987d. Reportable Quantity Adjustments. Federal Register; 52(30):8140-8186. Farkas DF. 1980. Food Processing. In Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 11. New York, NY: John Wiley A Sons; pp. 180181. FDA (Food and Drug Administration). 1986. Proposed uses of vinyl chloride polymers. Federal Reglstar; 51(22):4177-4183. Faron VJ, Kroes R. 1979. One-year time-sequence Inhalation toxicity study of vinyl chloride in rats. II. Morphological changes in the respiratory tract, ceruminous glands, brain, kidneys, heart and spleen. Toxicology; 13(2):131-141. Feron VJ, Speak AJ, Willems Ml. Van Buttaum D, Groot AP. 1975. Observations on the oral administration and toxicity of vinyl chloride in rats. Food Cosset Toxicol; 13(6):633-638. Feron VJ, Spit BJ, Immel HR, Kroes ft. 1979*. One-year time-sequence inhalation toxicity study of viiqrl chloride in rats. III. Morphological chsnges in the liver. Toxicol; 13:143-154. Feron VJ, Kzuysse A, Til HP. 1979b. One-year time-sequence inhalation toxicity study of vinyl chloride in rats. 1. Growth, mortality, haematology, clinical chemistry, and organ mights. Toxicol; 13:25-35. *Ferem VJ, Hendrlksen CM, Speak AJ, Til HP, Spit BJ. 1981. Lifespan oral toxicity study of vinyl chloride in rats. Food Cosset Toxicol; 19(3):317-333. Filser JG, Bolt HM. 1979. Pharmacokinetics of halogenated ethylenes in rats. Arch Toxicol; 42(2):123-136. CMA 009915 89 Fishbeln L. 1979. P tential halogenatad industrial carcinogenic and mutagenic chaaicala. I. Haloganatad unsaturatad hydrocarbons. Sci Total Environ; 11:111-161. Fox AJ, Colliar FF. 1977. Mortality axparianca of workers exposed to vinyl chloride monomer in the manufacture of polyvinyl chloride in Great Britain. Br J Ind Med; 34:110. Funas-Cravioto F, Lambert B, Lindsten J, at al. 1975. Chromosome aberrations in workers exposed to vinyl chloride. Lancet; 1:459. Gedigk P. Muller R, Bechtelsheimer H. 1975. Morphology of liver damage among polyvinyl chloride production workers. A report on 51 cases. Ann MY Acad Sci; 246:279-285. Geryk E, Zudova Z. 1986, Vinyl chloride as occupational health hazard. Pracov Lek; 38(1):l-8. (Czech: English translation) Coodankauf 0, Atkinson JC. 1986. Occurrence of volatile organic chemicals in Nebraska groundwater. Ground Veter; 24(2):231-233. Gordon SJ, Meeks SA. 1977. A study of gaseous pollutants in the Houston, Texas area. AlCHE Symp Ser; 73:84-94. Goeselin RE, Smith RP, Hodge HC. 1984. Clinical Toxicology of Comtercial Products, 5th ed. Baltimore, MD: Williams and Wilkins; p. 11-166. Green T, Hathvay DE. 1975. The biological fate in rats of vinyl chloride in relation to-its oncogenicity. Cham Biol Interact; 11:545-562. Green T, Hathvay DE. 1977. The chemistry and biogenesis of the Scontaining metabolites of vinyl chloride in rats. Cham Biol Interact; 17:137-150. Green T, Hathway DE. 1978. Interactions of vinyl chloride with rat-liver DMA in vivo. Cham Biol Interact; 22:211-224. Greim H, Bonse G, Radvan Z, Reichert D, Henschler D. 1975. Mutagenicity in vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxirane formation. Biochem Pharmacol; 24:20132017. Crlmsrud EP, Rasmussen RA. 1975a. The analysis of chlorofluorocarbons in the troposphere by gas chromatography-mass spectrometry. Atmos Environ; 9:1010-1013. Crlmsrud EP, Rasmussen RA. 1975b. Survey and analysis of halocarbons in the a&osphere by gas chromatography-mass spectrometry. Atmos Environ; 9:1014-1017. Guengerich FP, Vctanabe PG. 1979. Metabolism of (^C)- and (^C1)labeled vinyl chloride in vivo and in vitro. Biochem Pharmacol; 28:589596. CMA 009916 90 Guangerich FP, Crawford UM, Jr, Vatanabe PG. 1979. Aetlvaci n of vinyl chlorlda Co covalantly bound aacabollcaa: Rolas of 2-chloroechyltne oxida and 2-chloroaeetaldehyde. Biochamlscry; 18:5177-3182. Guangerich FP, Mason PS, Stocc WJ, Fox TR, UaCanaba PC. 1981. Rolts of 2-haloethylsna oxida and 2-haloaeaCaldahydaa darlvad froa vinyl bromide and vinyl chlorlda In irravaraibla binding to proCaln and DNA. Cancar Raa; 41:4391-4398. Gwlnnar LM, Laib RJ, Filaar JG, Bole Hf. 1983. Kvldanca of chloroachylana oxida balng eha reactive metabolite of vinyl chlorlda eovarda DNA: comparative acudlaa vlch 2,2'-dlchlorodiachyl aehar. Carcinoganaais; 4:1483-1486. Halaaa J, Baekar-Stona S, Halaaa JM. 1983. Das haemangiosarkom dar bai arbalCars in dar PVC-industria and andara VC-badingca arkrankungan mie angiologlsh-dernstologlscher, hapcalogiachar, radiologiachar and naurologiachar symptomatik. Dar Radiolog; 25(l):22-29. (Garnan: English abaeract) *Hanstean IL, Hilloatad L, Thiis-Evansan E, Haldaas SS. 1978. Effaces of vinyl chlorlda in nan: A cytogenetic follow-up study. Ifueat Raa; 51:271-278. Harkov R, Kabbakua B, Bozzalli JW, Lioy PJ. 1983. Maaauraaanc of aalactad volatila organic compounds at ehraa locaeiona in Haw Jarway during tha summer season. J Air Pollut Control Aaaoc; 33:1177-1183. Harkov R,' Kabbakua B, Bozzalli JV, Lioy FJ, Dalaay J. 1984. Comparis n of aalactad volatile organic conpounds during tha summer and winter at urban altos in Haw Jaraay. Scl Total Environ; 38:259-274. Harsch DE, Croim DR, Slater UR. 1979. Expanded list of haloganated hydrocarbons measurable in aabient air. J Air Pollut Control Aaaoc; 29:975-976. Hartaana S, Bone JAM, Traapar J, Luyben KChAM. 1985. Bacterial dagradatlon of vinyl chlorlda. Biotech Letters; 7(6):383-386. Hanan E, Solnlnan V, Pyysalo H, Lsppaaaki E. 1979. On the occurrence of aliphatic chlorine and broaine compounds in autoaobile exhaust. Ataoa Environ; 13:1217-1219. Heath CV, Jr, Fable H, Craach JL, Jr. 1975. Characterlatics of cases of angloaarcoaa of tha livers aaong vinyl chloride workers in eha United State*. Ann SY Acad Scl; 246:231-236. Hefner RE, Jr, Vatanabe PG, Gahrlng PJ. 1975a. Percutaneous absorption of vinyl chlorlda: Toxicol Appl Pharmacol; 34:529-532. Hefner RE, Jr, Vatanabe PG, Gahrlng PJ. 1973b. Preliminary studies of the fata of inhaled vinyl chlorlda nonowar in rats. Ann NY Acad Sci; 246:135-148. 009917 CMA % 91 Hager M, Muller G, Norpath K. 1982. Untersuchungen zur Beziehung zvlachan Vlnylehlerld (VCH) - Aufnalsine und Metabolitenausschaidung bai 15 VCM-Exponierten. Inc Arch Occup Environ Haaleh; 50:187. (Clced in Tarkovski 1984) Hahlr RM, McNamara BP, McLaughlin J, Jr, tfllllgan 0A, Blarbovar G, Hardiacy JT. 1981. Cancar induction following alngla and multiple exposures co a conatane amount of vinyl ehlorida aononar. Environ Haaleh Parapacc; 41:63*72. Haldaaa SS, Langard SL, Andersen A. 1984. Incidence of cancer-among vinyl chloride and polyvinyl chloride workara. Br J Ind Mad; 41:25-30. Hong CB, Winston JM, Thornburg LP, Lee CC. 1981. Follow-up study on the eerelnoganeity of vinyl chloride and vinylidana chloride in rata and mica: Tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health; 7:909-924. HSDB (Hazardous Substances Data Bank). 1987. National Library of Medicine Report 169. Online: September 1987. Hubsnaan E, Bartsch H, Sacha I. 1975. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacecaldehyde. Int J Cancer; 16:639-644. Hultmark D, Sundh K, Johansson L, Arrhenius E. 1979. Ethanol inhibition of vinyl chloride metabolism in isolated rat hepatocytes. Cham Biol Interact; 25(1):1-6. IARC (International Agency for Research on Cancer). 1978. Methods for Che measurement of vinyl chloride in poly(vinyl chloride), air. water, and foodstuffs. In Environmental Carcinogens Selected Methods of Analysis. Egan H, Squireel DCM, Thain W, Davis W, ads. IARC Sci Pub No 22. IARC (International Agency for Research on Cancer). 1979. Monographs on Che Evaluation of the Carcinogenic Risk of Chemicals in Humans. Vinyl chloride, polyvinyl chloride and vinyl chloride-vinyl acetate polymers. Lyons, France: WHO, IARC; 19:377-401; 419-438. Infante. PF. 1976. Oncogenic and mutagenic risks in coammitles with polyvinyl chloride production'facilities. Ann NY Acad Sci; 271:49-57. Infanta PF, Wagoner JK, McMichael AJ, Waxweller RJ, Falk H. 1976. Genetic risks of vinyl chloride. Lancet (April 3); 734-735. Ives NF. 1975. Sensitive trapping and gas chromatographic method for vinyl chloride in air samples. J Assoc Off Anal Cham; 58:457-460. Jaeger RJ, Reynolds ES, Conolly RB, Moslem MT, Szabo S, Murphy SD. 1974. Acuta hepatic injury by vinyl chloride in rats procreated with phanobarbltal. Nature; 252(5485): 724-726. CMA 009918 92 Jaeger RJ, Murphy SD, Reynolds ES, Szabo S, M slan MT. 1977. Chemical modification f acuta hapatotoxlelcy of vinyl chlorida non mar In rats. Toxic 1 Appl Pharmac 1; 41:597-607. Jedrychowski RA, Sokal JA, Chmlalnicka J. 1984. Influence of axposura mod# on vinyl chlorida action. Arch Toxicol; 55(3):195*198. Jansaan D, Raaal C. 1980. Tha nicronuclaua taat aa pare of a short-tarn mutagenicity teat program for tha prediction of carcinogenicity evaluated by 143 aganta taatad. Mutae Has; 75:191-202. John JA, Smith FA, Leong BKJ, Schvetx BA. 1977. Tha effaces of .maternally inhaled vinyl chlorida on embryonal and fatal development in mice, rata, and rabbits. Toxicol Appl Phanweol; 39:497-513. Juhe VS, Lange CX, Stein G, Valtman G. 1974. Uber die sag. Vlnylehioridkrankheit. Barufa-Darmatoaen; 22:4-22. (German: English abstract) Kappus H, Bole HM, Buchtar A, Bole V. 1976. Liver microsomal uptake of [l*C] vinyl chloride and transformation to protein alkylaeing metabolites in vitro. Toxicol Appl Pharmacol; 37:461-471. Kataeva LD, Pavlenko GI. 1985. Cytogenaeie examination of the workers of chamical Industry. Mutae Rea; 147:301-302. Keplinger ML, Goode JV, Gordon DE, Calandra JC. 1975. Interim results of exposure of rats, hamsters, and mice to vinyl chlorida. Ann MY Acad Sci; 246:219-224. Kilian DJ, Piceiano DJ, Jacobson CB. 1975. Industrial monitoring: A cytoganic approach. Ann MY Acad Sci; 269:4-11. Kontomlnas MG, Gupta C, Gilbert SG. 1985. Interaction of vinyl chlorida with polyvinyl chloride in modal food systems by HFLC chromatography: Migration aspects'. Lebensm-Uiss u-Technol; 18(6):353-356. Krajavski J, Bobecki M. Gromiac J. 1980. Retention of vinyl chloride in the human lung. Br JInd Mad; 37(4):373-374. Krost KJ, Pellixxarl ED, Ualbuxn SG. Hubbard SA. 1982. Collection and analysis of hazardous organic emissions. Anal Cham; 54:810-817. Kuceronm M. Pellvkova 2, Batora J. 1979. Comparative evaluation of the freqnfftoy of rtirnmnsnmsl aberrations and the SCX numbers in peripheral lympbrntgrtes of workers occupationally exposed to vinyl chloride monomer. Mutat Res; 67:97-100. Laib RJ, Bolt HM. 1977. Alkylation of RNA by vinyl chloride metabolites in vitro and in vivo: Formation of l-M-6-ethenoadenosine. Toxicology; 8:185-195. CMA 00991? * 93 Lalb RJ, Barbin A, Bartsch H. 1984. Evidence that vinyl chloride alters tha fidelity of replication: Studios with chi roothylons oxide treated poly(dC-dC). Naunyn-Schmied Arch Pharmacol; 325(suppl): R17. Lalb RJ, Doaljer G, Bolt HM. 1985. Datactlon of N2, N-3-athenoguanine in lfver-DKA hydrolysates of young rats and after exposure of the animals to (1-4C) vinyl chloride. J Cancer Res Clin One; 109(2) :A7. Lee CC, Bhandarl JC, Winston JK, at al. 1977a. Inhalation toxicity of vinyl chloride and vlnylidene chloride. Environ Health Perspect; 21:23* 32. Lee FI, Harry DS, Adams WG, Litchfield M. 1977b. Screening for liver disease in vinyl chloride workers. r J Ind Med; 34:142-147. Lee CC, Bhandarl JC, Winston JM, House WB, Dixon RL, Woods JS. 1978. Carcinogenicity of vinyl chloride and vlnylidene chloride. J Toxicol Environ Health; 4:13-30. Lastar D, Greenberg LA, Adams WR, 1963. Effects of single and repeated exposures of humans and rats to vinyl chloride. Am Ind Hyg Assoc J; 24:265-275. Lilis R, Anderson H, Nicholson WJ, Daum S, Fischbein AS, Sellkoff IJ. 1973. Prevalence of disease among vinyl chloride and polyvinyl chi ride workers. Ann NY Acad Sci; 246:22-41. Loprleno N, Barale R, Baroncelli S, et al. 1977. Induction of gene nutaeions and gene conversions by vinyl chloride metabolites in yeast. Cancer Res; 46:233-237. Lyman WJ, Reehl WF, Rosenblatt DH. 1982. Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw Hill Book Co., New York, NY. pp. 4-9. Makarov IA. 1984. Sexual disorders In male workers occupationally exposed to methyl-methacrylate vinyl chloride. (Trans: 1-11) Gig Tr Prof Zabol; 6:19-23. Makarov IA, Solovyeva MS, Gnelltsky GI. 1984. On sexual disorders In women chronically exposed to methylmethacrylate and vinyl chloride. Gig Tr Prof Zabol; 3:22-27 (Trans.) Maltoni C, Lafamine G. 1973. Carcinogenicity bloassays of vinyl chloride. Current results. Ann NY Acad Sci; 246:193-218. Maltoni C. 1977. Recent findings on the carcinogenicity of chlorinated olefins. Environ Health Perspect; 21:13. CMA 009920 94 *Maltoni C, Lefemine 6, Cllibertl A, et al. 1980. Vinyl chloride carcinogenicity blossaays (BT project) as an experimental a del for risk Identification and aasessaent in environmental and ccupational carcinogenesis. Epidemiol Anlm Epidemiol Hum; Css Chlorure Vinyls Monoaere (Reun Club Cancerog Chia), 20th, Meeting Date 1979, pp. 11-112. Publ Essent, Paris, France. Melton! C, Lafamine C, Clllberti A, et al. 1981. Carcinogenicity bioassays' of vinyl chloride monomer: A model of risk assessment on an experimental basis. Environ Health Ferspect; 41:329. Maltonl G, Cotti, Valgiaigli L, Mandrloli A. 1983. Suitable models for long-term bioassays of the therapeutic and toxic effects of antiblastlc drugs: Liver angiosarcomas produced in Sprague-Davley rats by vinyl chlorida. Dev Oncol; 13:339-341. Markov!tx SS, McDonald CJ, Fethiere V, Kerzner MS. 1972. Occupational acroostaolysis. Arch Derm; 106:219-223. Marsteller HJ, Laibach WK, Muller R, Gedigk ?. 1973. Unusual splenomegallc liver disease as evidenced by peritoneoscopy and guided liver biopsy among polyvinyl chloride production workers. Ann NY Acad Sci; 93-134. Mastronatteo E, Fisher AM, Christie H, Danziger H. 1960. Acute Inhalation toxicity of vinyl chloride to laboratory animals. Am Ind Hyg Assoc J; pp. 394-398. MCA (Manufacturing Chemists Association). 1980.. Lettar regarding the study and report of effects of vinyl chloride. FYI-QTS-0480-0065. (Cited In EPA 1985b) McCann J, Simmon V, Streltwieser D, Ames BN. 1973. Mutagenicity of chloroacetaldehyde, a possible metabolic product of 1,2-dichloroethane (ethylene dichlorlda), chloroethanol (ethylene chlorohydrin), vinyl chlorida and cyclophosphamide. Froc Nat Acad Scl USA; 72(S):3190-3193. McMurry JR, Tarr J. 1978. Vinyl chloride in Texas' ambient air. Proc Ann Tech Meet Inst Environ Scl. pp. 149-155. Mlcu D. Mihallescu I. Vtlau C, Tarpa A. Chireu V, Zgoanta C. 1985. The value of some cytoenrymochemlcal investigations of the leukocytes and platelets in estimating the effects of occupational exposure to benzene, vinylvchloride, and carbon disulphide. Rev Row Med-Med Xnt; 23(2):115- 120. Miller JJ, Belxor MB. 1983. Air quality in residences adjacent to an active hazardous waste disposal site. AFCA Annual Meeting, June 16-21: pp. 2-17. Mlrkova E, Mihailova A, Nosko M. 1978. Embryotoxic and teratogenic effects in vinyl chloride. (Trans: 1-6) Khig Zdraveopaz; 21(5);440-443. (Bulgarian: English translation) CM* 009921 % 95 Monson RR, Peters JH, Johns n MN. 1975. Proportlonsl mortality among vinyl chi rids vorkars. Environ Haalth Psrspact; 11:75-77. Muller G, Norpoth K, Wickrama-Slnghe RH. 1979. An analytical method using GC-MS for the quantitative determination of urinary thiodiglyeolic acid. Int Arch Occup Environ Health; 44:185*191. Nicholson VJ, Hammond EC, Seidaan H, Sellkoff IJ. 1975. Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Ann NY Acad Scl; 246:225*230. N10SH (National Institute for Occupational Safety and Health). 1975. Recommended Standard.,.Occupational Exposure to Vinyl Chloride. NTIS PB-246*691. (Cited in EPA 1985b) NTOSH (National Institute of Occupational Safety and Health). 1984. N10SH Manual of Analytical Methods. 3rd ed. Vol. 2. Vinyl chloride in air. Method No. 1007, Washington, DC: U.S. Government Printing Office; pp. 1007-1 to 1007-4. NTIS (National Technical Information Service). 1987. Federal Research in Progress. Online: September 28, 1987. 0SHA (Occupational Safety and Health Administration). 1983. 0SHA Safety and Health Standards. 29 CFR 1910.1017. pp. 670*671. * Oster RH, Carr CJ, Krantz JC. 1947. Anesthesia XXVII. Narcosis with vinyl chloride. Anesthesiology; 8:359-361. Osterman-Golkar S, Jultmark D, Segerback D, et al. 1977. Alkylation of OKA and proteins in mice exposed to vinyl chloride. Bioehem Biophys Res Comm; 76:259*266. Page GW. 1981. Comparison of groundwater and surface water for patterns and levels of contamination by toxic substances. Environ Sci Technol; 15:1475-1481. Patty FA, Yapt WP, Waite CP. 1930. Acute response of guinea pigs to vapors of some new commercial organic compounds. V. Vinyl chloride. Pub Haalth Reports; 45:1963-1971. Pelllzzari ID, Erickson MD, Zoeidlnger RA. 1979. Formulation of preliminary assessment of halogenated organic compounds in man and environmental media. Research Triangle Park, NC: Environmental Protection Agency. EPA/560/13-79-006. Perticoni GF, Abbrltti G, Cantisani TA, Bond L, Mauro L. 1986. Pollneuropathy in workers with long exposure to vinyl chloride. Electro-physiological study. Electronyog Clin Neurophysiol; 26(l):41-47. Poncelet F, de Meester C, Duverger-van Bogaert M, et al. 1980. Influence of experimental factors on the mutagenicity of vinylic monomers. Arch Toxicol Suppl; 4:63-66. CHA 009922 % 96 Popper H, Th ui LB. 1975. Alterations llvor end epleen among workers expos d Co vinyl chloride. Ann NY Aced Sci; 246: 172*194. Preston BJ, Jones KL, Grainger RG. 1976. Clinicel especcs of vinyl chloride disease. Proe Soc Med; 69:284*306. Purchase IFH, Richardson CR, Anderson 0. 1975. Chromosomal and dominant lethal effects of vinyl chloride. Lancet; 410-411. Purchase IF, Richardson CR, Anderson D, at al. 1978. Chromosomal analysis in vinyl chloride exposed workers. Mutat Res; 57:325-334. (Cited In Anderson et al. 1980) Rsasey'JO, Flanagan RJ. 1982. Detection and identification of volatile organic compounds in blood by headspace gas chromatography as an aid to the dlagnoeis of solvent use. J Chronatogr; 240:423-444. Ranmig 0, Johansson A, Raael C, Wachtmeister CA. 1974. The mutagenicity of vinyl chloride after metabolic activation. Amblo; 3:194*197 aewwig o, Gotha R, Vaehaseister CA. 1976. The mutagenicity of chloroethylane oxide, chloroaeecaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride. Chem Biol Interact; 12:251-263. Rasmussen RA, Harsch DE, Sweeny PH. Krasnee JP, Crotm DR. 1977. Determination of atmospheric halocarbons by a temperature-programmed gas chromatographic freeze-out concentration method.. J Air Follut Control Assoc; 27:579-581. Reding R. 1987. Chromatographic monitoring methods for organic contaminants under the Safe Drinking Water Act. J Chromatogr Sci; 25:338-344. Reynolds ES, Moslem MX, Szabo S, et al. 1975. Hepatotoxicity of vinyl chloride and l,l*dichloroethylene. Am J Pathol; 81:219-231. Sabadla N, Malaveille C. Camus AH, Bartsch H. 1980. Comparison of the hydroxylacion of benzo(a)pyrene with the. metabolism of vinyl chloride, n-nltrosonorpholine, and n-nitroso-n'methylpiperaaine to mutagens by human and rat liver microsomal fractions. Cancer Res; 409(1):119-126. Sebljle A. 1984. Prediction of the nature and strength of soil sorption of organic pollutants by molecular topology. J Agric Food Chem; 32:243* 244, Sakabe H. 1973. Bene lesions among polyvinyl chloride production workers in Japan. Ann NY Acad Sci; 246:78. Sal'nikova LS. Kitaovskaya LA. 1980. Effect of vinyl chloride on embryogenesis of rats. (Trans: 1-7) Gig Tr Prof Zabol; (3):46-47. CMA 009923 % 97 Salkind AJ, Pearlman E. 1978. Batteries, secondary (alkaline calls). In Kirk-Othmer Encyclopedia Chemical Technology. VI. 3. New York, NY: John Viley & Sons; p. 605. SANSS (Structure and Nomenclature Search System). 1987, Chemical Information Systems. Online: September 1987. Sax HI, Ed. 1984. Dangerous Properties of Industrial Materials. 6th ed. New York: Van Nostrand Reinhold Co.; p. 2728. Sax Nl, Levis RJ, Eds. 1987. Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Rainhold Co.; p. 1223. Steahln MM. 1976. The nonmutagenicity and recomblnogenicity of vinyl chloride in the absence of metabolic activation. Mutat Res; 40:269-272. Simmon VF, Kauhanen K, Tardlff R6. 1977. Mutagenic activity of chemicals identified in drinking water. Proc Second Int Conf Environ Mutagens, Edinburgh, July 11-15, 1977. Progress in Genetic Toxicology. Elsevlar/North Holland Biomedical Press, Amsterdam, pp. 249-258. Shu P, et al. 1986. Study on exeretine regularity of thiodiglyeolie acid in urine of vinyl chloride-exposed workers. Chin J Prev Med; 20(2):8789. Slngley JE. 1984. Water (Municipal Treanant). In Kirk-Othmer Encyclopedia of Chemical Technology Vol. 24:387. Slttlg M. 1985. Handbook of Toxic and Hazardous Chemicals and Carcinogens. 2nd ed. Park Ridge, NJ: Noyes Publications; pp. 918-921. Smith LR, Dragun J. 1984. Degradation of volatile chlorinated aliphatic priority pollutants in groundwater. Environ Internet; 10(4):291-298. Stephens RD, Ball NB, Mar DM. 1986. A multimedia study of hazard us vasts landfill gas migration. In Pollutants in a Multimedia Environment. Y Cohen, ed. New York, NY: Plenum Press; pp. 265-287. Stuart JD. 1983. Organics transported thru selected geological media: Assessment of organics transported away from industrial waste disposal sites. Comm Univ Stores Inst of Waeer Resources. NTIS PB83-224246; pp. 1-10. Styles JA. 1977. A method for detecting carcinogenic organic chemicals using maaallan cells in culture. Br J Cancer; 36(5):558-S63. (Cited in EPA 198ba) Suzuki Y. 1978. Pulmonary tumors Induced in mice by vinyl chloride monomer. Environ Res; 16:285*301. Suzuki Y. 1981. Neoplastic and nonneoplastlc effects of vinyl chloride in mouse lung. Environ Health Perspect; 41:31-52. CMA 009924 98 Suzuki Y. 1983. Noimeoplastlc effect of vinyl chloride in mouse lung** lovor doses znd short-term exp sure. Environ Res; 32:91-103. Tsbershsv IR, Gsffey UR. 1974. Mortality study of workers in the manufacture of vinyl chloride and its polymers. J Oceup Med; 16(8):509318. Tsaburro CH. 1984. Relationship of vinyl monomers and liver cancers: angiosarcoma and hepatocellular carcinoma. Sem Liver Dis, May 1984. 4(2):158-169. Tsaburro CH, Kakk L, Popper H. 1984. Early hepatic histologic .alterations among chemical (vinyl monomer) workers. Hepatology; 4:413418. Tarkowski S. 1984. Preventive measure against occupational hazards in the PVC production industry. Prog Clin Biol Reg; 141:177-189. Theriault G, Xturra H, Gingras S. 1983. Evaluation of the association between birth defects and exposure to ambient vinyl chloride. Teratology; 27:339-370. *111 HP, Immel HR, Feron VJ. 1983. Lifespan oral carcinogenicity study of vinyl chloride in rats. Final report. Clvo Institutes, TNO. Report No. V 93.283/291099. (Cited In EPA 1983a, 1987b) - Torkelson TR, Oygen F, Rove VK. 1961. The toxicity of vinyl chloride as ... determined by repeated exposure of laboratory animals. Am Ind Hyg Assoc J; 22:354-361. Omana M, Warner M, Sheldon LS. 1983. Methods for sampling and analysis of breath. EPA/600/8-83/019 and NTI5 FB83-243277. Ungvary G, Hudak A, Tatrai E, Lorlncx M, Folly G. 1978. Effects of vinyl chloride exposure alone and in combination with trypan blue applied systematically during all thirds of pregnancy on the fetuses of CFY rats. Toxicology; ll(l):45-54. Valno H.,1978. Vinyl chloride and vinyl benzene (styrene) Metabolism, mutagenicity, and carcinogenicity. Chen Biol Interact; 22:117-124. van Slttert HJ. do Jong G. 1983. Blonsnitorlng of exposure to potential mutagems and carcinogens In industrial populations. Food Chen Toxic; 23(l)|f-U. Verburgt FO, Vogel B. 1977. Vinyl chloride mutagenesis in Drotophi1m nelenofascar. Mutat Res; 48:327-336. Versehuersn K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. New York, NY: Van Nostrsnd Reinhold Company; pp. 1183-1186. 009925 CM* % 99 Viola PL, Big tti A, Caputo A. 1971. Oneoganic raaponaa of rat akin, lungs, and bonas to vinyl chlorida. Cancar Ras; 31:316-522. (Cltad in EPA 1985b). Vakeham IB, Johnson HR. 1978. Vinyl chlorida formation from the tharmai dagradation of poly(vinyl chlorida). Polymar Eng Sci; 18(5):404*407. Wallaca LA, Pallizzari E, Harewall T, at al. 1984. Parsonal exposure to volacila organic confounds. Environ Ras; 35:293-319. Valias AA, Holmbarg B. 1984. Induction of slngla-strand bracks In DNA of mica aftar inhalation of vinyl chlorida. Cancar Latt; 25:13-18. Vang T, Lanahan R, Xanik M. 1985. Impact of trichloroethylenecontaminated groundwater discharged to the main canal and Indian River Lagoon, Varo Beach, Florida. Bull Environ Contam Toxicol; 34:578-586. Vard AM, Undoon S, Vetkins J, Valkar AE, Drake CS. 1976. Evidence of an immune complex disorder in vinyl chlorida workers. Proc Roy Soc Mad; 69:289-290. Vatanabe PC, Gehrlng PJ. 1976. Dose-dependant fata of vinyl chloride and its possible relationship to oncogenicity in rats. Environ Health Parspact; 17:145-152. Vatanabe PC, McGowan GR. Gehrlng PJ. 1976a. Fate of [l4C] vinyl chloride aftar single oral administration. Toxicol Appl Pharmacol; 36(2):339-352. Vatanabe PC, McGowan GR, Madrid EO, Gehrlng PJ. 1976b. Fata of [14C] vinyl chloride following inhalation exposure in rats. Toxicol Appl Pharmacol; 37:49-59. Vatanabe PG, Zempel JA, Pagg DC, Gehrlng PJ. 1978a. Hepatic macromoleeular binding following axposura to vinyl chlorida. Toxicol Appl Pharmacol; 44(3):571-379. Vatanabe PG, Zempel JA, Gebring PJ. 1978b. Comparison of the fata of vinyl chloride following single and repeated axposura in rats. Toxic Appl Pharmacol; 44:391-399. Vaxweller RJ, Stringer V, Vagner JK, Jones J, Falk H, Carter C. 1976. Neoplastic risk among workers exposed to vinyl chloride. Ann NY Acad Sci; 271:40-48. Vaxweller RJ, Falk H, McMlchael A, Mallov JS, Grivas AS. 1977. A crosssectional epidemiologic survey of vinyl chloride workers. NTIS PB274193. Vestrick JJ, Hello JV, Thomas RF. 1984. The groundwater supply survey. J Am Veter Vorks Assoc; 76:52-59. Vllson JT, Vilson BH. 1985. Biotransformation of trichloroethylene in soil. Appl Environ Microbio; 49:242-243. CM/s 009926 % 100 tfllson RH, McCormick UE, Tatum CF, Creech JL. 1967. Occupational aeroosteolysls raport f 31 casas. JAMA; 201:377*380. Withey JR. 1976. Pharmacodynamics and uptaka of vinyl chlorida monomer adainistarad by varioua routes to rats. J Toxicol Environ Health; 1:381*394. Young F, Parker A. 1984. Vapors and odors and toxic gases from landfills. In Hazardous and Industrial Vast# Management and Tasting: Third Symposium. ASTM STP 831. LP Jackson, AR Rohlik, PA Conway, ads. American Society for Testing and Materials, Philadelphia, PA. pp. 24-41. Zuccato S, Mancucci 7, Fanslll R and Mussini E. 1979. Head*space gaschromatographic analysis of vinyl chloride monomer in rat blood and tissues. Xenobiotiea; 9:27*31. CHA 009927 % 11. GLOSSARY Acute Exposure--Exposure to a cheaical for a duration of 14 days or lass, as spaeifisd In tha Toxicological Proflias. Bloconcantration factor (ICY)--The quotient of tha concantratlon of a ehaaical In aquatic organlsas at a spaclfic tlaa or during a discrata tine period of exposure divided by the concentration In tha surrounding vatar at tha sane tlaa or during the sens tlaa period. Carcinogen--A ehaaical capable of inducing cancar. Calling value (CL)--A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure--Exposure to a ehaaical for 365 days or more, as specified in the Toxicological Profiles. Developaental Toxicity--The occurrence of adverse effects on the developing organism that may result froa exposure to a ehaaical prior to conception (either parent), during prenatal development, or posenatally to the tlaa of sexual maturation. Adverse developaental effects may be detected at any point in the life span of the organiaa. Eabryotoxicity and Fetotoxieity--Any toxic effect on the conceptus as a result of prenatal exposure to a ehaaical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The taras, as used here, include aalforaationa and variations, altered growth, and in utero death. frank Effect Level (FEL)--That level of exposure which produces a statistically or biologically significant Increase In frequency or severity of unmistakable adverse effects, such as irreversible functional Impairment or mortality, in an exposed population when coapared with its appropriate control. SPA Health Advisory--An estimate of acceptable drinking water levels for a ehaaical substance based on health affects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Xanadlately Dangerous to Life or Health (IDLH) --The aaxiaua environmental concentration of a contaainant froa which one could escape within 30 aln without any escape-Impairing symptoms or irreversible health effects. 101 oo"28 % 102 Intermediate Exposure--Exposure to a ch mical fra duration of 15064 days, as spselfiad in tha Toxicological Fr filaa. Immunologic Toxicity*-Tha occurranca of advarsa affacts on tha immuna system that may rasult from axposura to anvironmantal agarics such as chemicals. la vitro--Isolated from tha living organism and artificially maintained, as in a cast tuba. In vivo*-Occurring within tha living organism. Kay Study**An animal or human toxicological study that bast illustrates tha natura of tha advarsa affects produced and tha doaas associated with thosa affacts. Lethal Conesntratlon(LO) (LClo)--The lowest concentration of a chemical in air which has bean reported to have caused death in humans or animals. Lethal Concentratlon(50) (LC)o)"A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 30t of a defined experimental animal population. Lethal Dose(LO) (LDLO)--Tha lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Sose(50) <U>SO)**The dose of a chemical which has bean calculated to cause death in 50% of a defined experimental animal population. Lowest-Observed*Adverse*Effeet Level (LQAKL)--The lowest dose of chemical in a study or group of studies which produces statistically or biologically significant increases In frequency or severity of adverse effects between the exposed population and its appropriate control. Lowest-Observed-Iffact Level (LOEL)**The lowest dose of chemical in a study or group of studies which produces statistically or biologically significant increases in frequency or severity of effects between the exposed population and Its appropriate control. Malformations-Permanent structural changes that may adversely affect survt^p., development, or function. Minimal' Kisk Level--An estimate of daily htman exposure to a chemical that is likely to be without an appreciable risk of deleeerlous effects (neneaneerous) over a specified duration of exposure. Mutagen--A substance that causes mutations. A nutation Is a change in tha genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. CMA 009929 * 103 Neurotoxicity--The occurrence of adverse offsets on ths nervous system following exposure to s chemical. So-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which there are no statistically or biologically significant increases In frequency or severity of adverse effects seen between the exposed population and Its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. So-Observed-Effect Level (SOIL)--That dose of chemical at which there are no statistically or biologically significant increases In frequency or severity of effects seen between the exposed population and its appropriate control. Permissible Exposure Limit (PEL)--An allowable exposure level in workplace air averaged over an 8-h shift. q.*--The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q.* can be used to calculate an estimate of carcinogenic potency, the Incremental excess cancer risk per unit of exposure (usually ag/L for water, mg/kg/day for food, and ag/m^ for air). Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an order of magnitude) of the dally exposure of the human population to a potential hazard chat is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from thp NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ)--The quantity of a hazardous substance chat is considered reportable under CERCLA. Reportable quantities are: (1) 1 lb or greater or (2) for selected substances, an amount established by regulation either under CERC1A or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-h period. Reproductive Toxicity--The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL)--The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TVA may not be exceeded. CMO 009930 104 Target Organ Toxicity*-This tarn covers s broad range of adverse effects on target organs or physiological systeas (e.g., renal, cardiovascular) extending from those arising through a single United exposure to those assuaed over a lifetiae of exposure to a cheaical. Teratogen*-A cheaical that causes structural defects that affect the development of an organise. Threshold Limit Value (TLV)--A concentration of a substance to which most workers can be exposed without adverse effect. The TLV aay be expressed as a TWA, as a STEL, or as a CL. .Time-weighted Average (TWA)--An allowable exposure concentration averaged over a normal 8-h workday or 40*h workweek. Uncertainty Factor (UT)--A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the ease of humans, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is sec equal to 10. CMA 009931 * APPENDIXES CM* 009932 Ammxx a; ran revhv A peer review pnl was assembled for vinyl chlorlda. Tha panal consIscad of cha following members: Dr. Richard Monson, Harvard University; and Dr. Anthony Guarlno, South Alabama Unlvarslty. Thasa axparts eollactivaly hava knowledge of vinyl chlorlda'a physical and chaalcal properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk t humans. All reviewers ware selected in conformity with the conditions for pear review specified in the Superfund Amendments and Reauthorizaclon Act of 1986, Section 110. A joint panal of scientists from ATSDR and ERA has reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' conents not incorporated into the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in this record. 107 CM* 009933 APPENDIX *: FEDERAL UOISTU ANNOUNCEMENT DEPARTMENT OP HEALTH AND HUMAN SERVICES AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY ENVIRONMENTAL PROTECTION AGENCY (ATSDR-2; FRL-3269-7) NOTICE OF AVAILABILITY OP TOXICOLOGICAL PROFILES AGENCIES: Department of Health and Hunan Services (DHHS): Agency for Toxic Subaeancaa and Dlaaaaa Raglscry (ATSDR); and Environmental ProcacClon Agancy (EPA). ACTION: Noclca. SUMMARY: Tha Suparfund Amendments and Reauthorization Act (SARA) (Public Lav 99*499) aaanda tha Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Suparfund) (42 U.S.C. 9601 at aaq.) by establishing certain requirements for tha Agancy for Toxic Subatancaa and Dlaaaaa Reglatry (ATSDR) of DHHS and EPA with regard to hazardoua subatancaa which ara moat cononly found at facilities on the CERCLA National Priorities List (NPL). Aaong these statutory raquiraaanta is a mandate for tha Administrator of ATSDR to prepare toxicological profiles for each substance previously Included on the first priority list of 100 chemicals. Tha list Identified the first 100 ehaaieals which both Agencies dataralnad posed tha most significant potential threat to human health. This Use was published In the Federal .Register on April 17th, 1987 (52 FR 12866) as required by SARA section 110 This notice announces the expected availability dates of the first 25 draft toxicological profiles for review and comment. 109 CMA 009934 110 AVAILABILITY: Tha following draft toxicological pr flits art txpacttd to bt publicly availablt by tht datt indicatad: Datt/Profllt CAS # Octobtr 17, 1987: Bsnzo(a)anthracana Banzo(a)pyrana Barylliua Chloroform Chroaiua Chrysana bibanco(a,h)anthractnt Haptachlor/Haptachlor tpoxidt Nlckal N-Nltrosodlphanylaaina 56*55-3 50-32-8 7440-41-7 67-66*3 7440-47-3 218-01-9 53-70-3 76-44-8 / 1024-57-3 7440-02-0 86-30-6 Octobtr 29, 1987: Aldrln/ditldrIn Aratnlc Banco(b)fluoranthant FCBa Aroclor 1260, 1234, 1248, 1242, 1232, 1221, 1016 2,3,7,8 - Tatrachlorodibanzo-p-dioxin 309-00-2 / 60-57-1 7440-38-2 205-99-2 11096-82-5, 11097-69-1. 12672-29-6^ 53469-21-9, 11141-16-5, 11104-28-2812674-11-2 1746-01-6 Novaabar 5, 1987 Bancana Bis(2-aehylhaxyl)phthalata Cadaiua 1,4-Dlchlorobanzana Mathylana chlorlda 71-43-2 117-81-7 7440-43-9 106-46-7 75-09-2 Novaabar 30, 1987 Cyanida Tat'f Tatrachloroatbylana Trichlacoathylana Vinyl ablorlda 57-12-5 7439-92-1 127-18*4 79-01-6 75-01-4 CMA 009935 ft Ill A full 90-day public comment pari d will ba providad for aach profila, starting from tha actual ralaasa data. The elosa of tha comment period for aach draft profila will ba indicated on tha fr nt of aach profila. Requests for draft toxicological profiles should ba sent to: Ns. Gaorgl Jonas Director, Office of External Affairs Agency for Toxic Substances and Disease Registry Chaablea 28 South 1600 Clifton Rd. Atlanta, GA 30333 Specify the profiles you wish to review. One copy of each profila requested will be forwarded, free of charge, as they bacons available. In the case of undue delays, requestors will be notified. Five copies of all eoassants should be sent to Ns. Jones at the above address by the end of the cosnent period. All written comments and tha draft profiles will be available for public inspection at the Agency for Toxic Substances and Disease Registry (ATSDR), Building 28 South, Room 1103, 4770 Buford Highway, NE, Chaablea, GA, from Sam to 4:30pm. Monday through Friday, except legal holidays, Written comments and other data submitted in response to this notice and the draft toxicological profiles should bear the docket control number ATSDR-2. CMA 00993d % 112 SUPPLEMENTARY INFORMATION: I. BACKGROUND On October 17, 1986, the President signed the Superfund Amendments end ReeuChorizetion Act of 1986 (Public Lev 99-499), which extends end emends the Comprehensive Environments! Response, CompenseCion, end Liability Act of 1980 (CERCLA or Superfund, 42 U.S.C. 9601 et seq.). Section 110 of SARA emends section 104(i) of CERCLA by establishing requirements for the preperetion of: (1) lists of hezerdous substances in order of priority, (2) toxicologicel profiles of those substences, end (3) e reseerch progren to fill date gaps associated with the substances. In compliance with section 104(1)(2)(A) of CERCLA, ATSDR end EFA published on April 17, 1987 (52 FR 12866) the first priority list of 100 hazardous substances. This priority list of 100 was further broken down into four groups of 23 chemicals. The first group of 25 was to be the subject of the second phase of the requirements, l.e., the development of the first set of toxicological profiles. Section 104(1)(3) of CERCLA spells out the content of these profiles end the timetable by which they must be developed. Profiles on at least 25 substences on Che first priority list were to be completed within one year of the enactment of SARA (by October 17, 1987). The remaining seventy-five ere to be completed et e rata of at least twenty-five per year with the total 100 completed within four years after the enactment of the SARA amendments. Revision and republication is mandated as necessary but no less often chan once every three years. Each profile is required to include an examination, summary end interpretation of available toxicological information and epidemiologic evaluations. This information and data are to be used to ascertain the levels of significant human exposure for the substance and the associated health effects. The profiles must also include a determination of whether adequate Information on the health effects of each substance is available or in the process of development. The Agencies' intention is that this information be used to identify the key toxicological testing needs that when filled will improve our ability to define significant human exposure levels. The toxicological profiles are to be provided to the States and made available to the public. The profiles are to be prepared in accordance with the guidelines developed by ATSDR and EPA. These guidelines were published along with the priority list of 100 in the April VI, 1987 Federal Register Notice (52 PR 12870). Ths current notice announces the projected availability dates of the first 25 draft toxicological profiles. The documents have undergone extensive internal review and have been subject to scientific and technical peer review by outside experts. Ve are now announcing their availability and encouraging public participation and comment on the further development of these profiles. Although the profiles will not be completed by the October 17, 1987 deadline, ve believe chat the extra time given to peer review and public review and consent is important to the development of quality profiles of scientific merit. ~1 CMA 009937 * 113 Although wo oro reasonably c nfident that tho key studios for each of tho 23 substances wore considered during tho pr fils development process, this Federal Raglatar notice solicits any significant studies, including unpublished data, which may aid the revision of these draft profiles. XX. LEVELS OF SIGNIFICANT HUMAN EXPOSURE The setting of specific levels of slgniflcsnt human exposure has presented a unique set of problems. The significance of a specific level of a hazardous substance depends on the context in which chat level is evaluated. For example, a low level chat may be insignificant with respect to esusing acute, iaedlately debilitating symptoms nay be highly significant with respect to causing gradual, chronic effects over a longer term. Since these profiles are intended for use by a diverse group of people who have different situations in which to interpret the significance of specific levels, it was considered appropriate at this tins to describe the range of exposures over which effects may occur (where data are available), and'to allow the user to make determinations as to which type of effect is significant in any particular instance. A format for graphically displaying the levels of significant human exposure has been developed and is used in the profiles to present the ranges over which effects may be observed. We encourage public comment and racoMsndations on this specific issue. * III. SOLICITATION OF PUBLIC COMMENT. We are soliciting public comment on all phases of the devel pment of the toxicological profiles. A previous Federal Register notice, published on April 17, 1987 (92 FR 12866) solicited comment on the first priority list of hazardous substances. We are currently reviewing those comments and are evaluating the impact that those comments nay have on the priority list and the methods used in its development. As the first 23 toxicological profiles become available in draft form, we are eager to provide them to the States, industry, public health professionals, scientists and the general public. We welcome cowsnt and feedback on the content of the profiles; the format and scope of the documents; the process used in the development of the levels of significant human exposure and the overall process used in the development of the profiles. __ There are specific Items that ve would like to drew to the attention of the reader and would strongly encourage as candidates f r close attention during tho comment period. A. PUBLIC HEALTH STATEMENT The draft profiles include a public health statement which is intended to provide the lay public with a concise statement of the general health risks associated with the chemical of concern. The suMary as originally planned should be able to stand alone. If removed from the rest of the document, it should still be capable of conveying CMA 009938 * 114 to tho public the substantive health concerns associated with tha substance. We aro also considering tha development f aora abbreviated versions, of tha public health statements and are evaluating a nuaber o different formatsThis notice specifically invites consents on the existing public health effects stateaents in the draft profiles and solicits raeoaaendations for alternative approaches. B. DATA/STUDIES USED IN THE DEVELOPMENT OF THE PROFILES In general, and for each cheaical-specific profile, have the appropriate studies been used in the development of these documents? Our concern here is that we capture the critical, or "key", studies but n t alss other data that aay be important in the valid evaluation of the toxicological profile cheaicala. C. FORMAT ADD CONTENT OF THE PROFILES The draft profiles represent our best effort to provide the information required by Section 104 (i)(3) of CERCLA in the aost useful foraat for the various identified users of the profiles, given the constraints of the tight tlaafraae. Every effort has been aade to define sections clearly and to foraat the documents in such a way that they can be used as resource documents by many different audiences. We specifically request coaaent on the foraat and concent of Che initial set of profiles, including how the format night be aodified for subsequent sets of profiles. D. LEVELS OF SIGNIFICANT HUMAN EXPOSURE What is the aost useful way of presenting this type of information? For this first generation of profiles we have selected a graphic presentation that reflects a 'range* of values that covers both upper and lower bounds of effect levels. Is this aore useful than a single nuaber? Are there ocher ways of presenting this type of information chat would be aore useful to the eventual user? E. IDENTIFICATION OF SIGNIFICANT DATA GAPS Tha process used to develop die draft profiles has resulted In the Identification of the full range of health effects data gaps associated with each cheaical. However, depending on Individual circumstances sons subset of the identified data gaps aay be essential in determining levels of significant exposure, while other data gaps aay be lass imediscs. ATSDR, EPA, and the National Toxicology Program (NT?) have been exploring ways to Identify the critical data eleaents that are needed to establish significant huaen exposure levels. This notice specifically requests eoHwnt and suggestions for approaching this phase of tha-toxicological profile process. CMA 009939 *