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--'^:^f .- '*- ,. -. ,* ,;*. j.,^* 'U : ". . iv :.;:J.-C-' .\(-\\v . V V' ,'A&~ --^fvjit'v'v ' ,,: <*>: v;. - rvo -w-f' DANGEROUS'{ ' 'vfiv -. I' Z* V ' ''--it . j : PROPERTIES .V ; .. , ............................ -U> <!V ' '`tv .i *r "f. x c </> o to Jlfc o> -Nl CO . , .T.iiYvf '*a<j' -v-.: t^^:v.;-/av''a ---r-'-wtaf- ' .a July/Aug 1986 VdLS Nc^./ >V:'`V' ' ,,/ ' VNR INFORMATION SERVICES /i #'* V- "V1?.' ." v *4^5- j ^1: *. *-M ''- -`^a'; ' 1 j ^^Wf- 'a ,- . aa ' ^ ,' * 1 v' ' J '7 ... .' -'* . " - J :^v;, "I R&S 024674 CHEMICAL REVIEW K-nn- (ido) CHEMICAL REVIEW: VINYL CHLORIDE CAS RN 75-01-4 NIOSH # KU 9625000 SIC Code 2813 See N.I. Sax. 1984. Dangerous Properties of Industrial Materials. 6th ed. New York: Van Nostrand Roinhold, p. 2728. SYNS Chloroethene (9CI); chloroethylene (SCI); chlorethene; chlorethylene; chloroethene; chlorethylene; chlcmre de vinyle (French); cloruro di vinile (Italian); ethylene monochloride; EXON 470; monochloroethene; monochloroethylene; trovidur; vinyl chloride monomer; vinyl chloride, inhibited; vinyl C monomer; vinylchlorid (German); VC; VCM; winylu chlorek (Polish). STRUCTURAL FORMULA C1CH = CH, mi CjHiCl mw E2.S0 SPECIES IH MIXTURE 99.42% pure. COMMON USES Approximately 96% is used in pi iduction of vinyl chloride homopolymer and coploymer resins. It is also used in production of methyl chloroform and as a comonomer with vinylidene chloride in the production of resiins. Polyvinyl chloride resins are used in production of plastic piping and conduit. Other uses are in floor covering, consumer goods, electrical applications, and transport applications. Vinyl chloride has been used as a refrigerant, extraction solvent, and aerosol propellant. (R-63) STORAGE AND HANDLING INFORMATION TRANSPORT. RAIL (%) 90.0 TRANSPORT. BARGE (%> 2.0. TRANSPORT. PIPE (%) 8.0 CONTAINERS Pressure cylinders, t;ink cars, tank barges. GENERAL STORAGE PROCEDURE Protect against physical damage. Outside or detached storage is pref erable. Inside storage should be in a fire resistive stor age room, provided with adequate ventilation and free of sources of ignition 3nd heat. GENERAL HANDLING PROCEDURE Guard against all sources of ignition. ADDITIVE (%> Phenol. STANDARD CODES NFPA, 2.4T.1; ICC, flamma ble gas, red gas label, 300 lbs in an outside container; CSCG, liquefied flammable gas; IATA (inhibited) flammable gas, red label, not acceptable passenger, 140 kg cargo, (inhibited) flammable gas, not accept able. a PRODUCTION Manufacturer Location YeartVijlume *'/ Nina companies Dow Chemical Co. The B. F. Goodrich Co. PPG Industries, Inc. Allied Chemical Corp. American Chemical Corp. Cumberland Chemical Corp. Dow Chemical Corp. Ethyl Corp. U.S. Tire and Rubber Co. U.S. Rubber Co. Goodyear Tire and Rubber Co. Monchem, Inc. Monsanto Co. Tenneco Chemical Co. Union Carbide Corp., Chemicals Div. Goodrich Chemical Co. U.S. Midland. MI Clevelands OH 1377/2.530 mill kg Guayanilla. PR Maundsville, WV Watson. CA Calvert City. KY Charleston, WV Freeport, TX Plaquemine, LA Baton Rouge, LA Houston. TX Ashtabula. OH Painesville. OH Niagara Falls, NY Geisman. LA Texas City. TX Houston, TX Texas City. TX Louisville. KY Calvert City. KY Niagara Falls, NY measured by U.S. Taiili Comm. 1363/ 3.735.342 lb (sales 2.358,741 lb) R-63 R-63 R-63 R-63 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-47 R-70 JULY.'AUG 1906 13 FEATURES R&S 024675 HAZARDS Flammable gas. (R-l),Severe explosion risk @ 30,000 ppm, (R-7) When heated to decomp, it emits highly tox fumes of phosgene; can react vig orously with oxidizing materials. (R-9) WATER: AGENCY RESTRICTIONS, STANDARDS. OR CRITERIA EPA recommends an ambient water cone of zero for maximum protection of human health from potential carcinogenic effects due to exposure to vinyl chloride through ingestion ofcontaminated water and contaminated aquatic organisms. The levels that may result in incremental increase of cancer risk over the lifetime are estimated at IE-5. IE-6, and IE-7. The corresponding recommended criteria are 20 /ig/L, 2.0 Mg/L. and 0.2 fig/L. (R-l 1). AIR: AGENCY RESTRICTIONS. STANDARDS OR CRI TERIA M.E.C. equals 150 mg/nr1 if emission > 3 kg/H. (R-6) Clean Air Act designates that cones of vinyl chlo ride in all exhaust gases discharged to the atmosphere during ethylene dichloride purification shall not ex ceed 10 ppm except as provided for in 40 CFR 61.65(a). (R-l07) Clean Air Act emission standards for vinyl chloride-producing plants are specified. (R-108) FOOD: AGENCY RESTRICTIONS, STANDARDS. OR CRITERIA U.S. Treasury Dept, has banned the use of vinyl chloride polymers in packaging of alcoholic bev erages. (R-63) TRANSPORTATION: AGENCY RESTRICTIONS. STAN DARDS. OR CRITERIA HMTA designates vinyl chloride as a hazardous material for the purpose of transpor tation in commerce. Hazard class is flammable gas. A flammable gas label is required. Material is forbidden for transport on passenger-carrying aircraft or railcar. Maximum net quantity permitted in one package is 300 lb for cargo-only aircraft and package must bear a cargo aircraft only label. Material may be stowed on or below deck and away from living quarters on cargo vessels. For passenger vessels, the material is limited to quantities specified in 49 CFR 173.304 (charging of cylinders with liquefied compressed gas), 49 CFR 173.314 (requirements for compressed gases in tank cars), and 49 CFR 173.315 (compressed gases in cargo tanks and portable tank containers) and is also subject to the same stowage requirements as for a cargo vessel for the same material. (R-101) CERCLA designates vinyl chloride waste and heavy ends from the distil lation of vinyl chloride in vinyl chloride monomer production as hazardous materials under HMTA. (R101) WA sections 307(a) and 112 designate vinyl chlo ride as a hazardous material under HMTA. (R-101) HMTA also designates inhibited vinyl chloride as an optional hazardous material for international ship ment. IMCO code is flammable gases and DOT class is flammable gas. A flammable gas label is required. Material may he stowed on or below deck and away from living quarters on cargo vessels but must be stowed on deck and away from living quarters for passenger vessels. (R-l02) OCCUPATIONAL EXPOSURE: AGENCY RESTRIC TIONS. STANDARDS, OR CRITERIA OSHA standard for vinyl chloride is 1 ppm averaged over an 8-H period with a short-term ceiling exposure level of 5 ppm averaged over any period of time not to exceed 15 M. No employees may Ijc exposed to vinyl chloride by direct contact with liquid vinyl chloride. (R-109) ACGIH recommends a TLV of 5 ppm. fR-106) The NIOSH recommendation for occupational health standard environmental exposure limit is the mini mum detectable level averaged over a 10-H work pe riod with a short-term ceiling exposure of 1 ppm av eraged over any period of time not to exceed 15 M. (R-l 10) Regulated by OSHA as a recognized carcin ogen, Appendix Ala. (R-l 11) DISPOSAL; AGENCY RESTRICTIONS, STANDARDS. OR CRITERIA RCRA 3001-3004; subjects the heavy ends from the distillation of vinyl dichloride in vinyl chlo ride monomer production to handling and report/rccordkeepiug requirements. (R-l03) The Act also subjects the waste product, off-specification hatches, and spill residues in excess of 1.000 kg to handling and repon/recordkeeping requirements. (R-l04) The Act also designates vine I chloride as an Appendix VIII chemical. (R-105) OTHER AGENCY RESTRICTIONS. STANDARDS. OR CRITERIA OSHA prohibits the use of vinyl chloride in aerosol sprays. (R-7) STATE Gas. (R-63) COLOR Colorless. (R-6) ODOR Mild, sweetish. (R-6) AUTOIGNITION POINT (C) 472.22. EXPLOSIVENESS Reactive at high temp or pres sure. Polymerizes with evolution of heat, in presence of air, oxygen, sunlight, or heat. EXPLOSION LIMITS (%) Lower, 4; upper, 22. (R-47) MELTING CHARACTERISTICS - 153.8 C (caution, flash p -78 C). (MERCK* 83/YVIN) u DANGEROUS ?RC?EHTE3 OF INDUSTRIAL MATERIALS REPORT 1 AQUEOUS SOLUBILITY Snlubi 'fly lppm) Temp (C) 60 10 TEST CONDITIONS No method or test conditions reported. 1.1 25 TEST CONDITIONS No method or test conditions reported. Mr/n/h\t CHEMICAL REVIEW Mniu,,l ><'! R-118 R-119 BOILING POINT (C) - 13.37 (ignites). SOLUBILITY CHARACTERISTICS Slightly soluble. DENSITY 20/4 C = 0.9100. (R-03) 250/25 C = 0.908. (R-71) SOLUBILITY: OTHER SOLVENTS Soluble in ethanol; very soluble in ether, carbon tetrachloride, and ben zene. (R-63) N-OCTANOL/WATER COEFFICIENT l.og/kow 1.38. est, substituent constant estimation. (R-l I) ODOR THRESHOLD-AIR Air = 25.000 ppm; slight odor (re 4,000 ppm. Odor index (u 20, C = 100. (R-b) OTHER PHYSICAL/CHEMICAL PROPERTIES Polymer izes in light or in presence of catalyst: on combustion it degrades to HC1, CO, CCX. with traces of phosgene: on treatment with strong alkalis at high temps it loses HCI. (R-03) Vapor density = 2.2 (air = I) (R-03) Vinyl chloride is a nonreactive gas that has no ten dency to escape. When it escapes, high cones may tion of' ethylene to form ethylene dichloride (KDC) and subsequent purification. Vinyl chloride is produced by thermal cracking of EDC. (R-70) Vinyl chloride gas 3J S <fi io A ^1 Qi  ANIMAL TOXICITY TEXT Value 20 ppm 500 Time Specie* Hmn Rat Param TCLo LD50 Houle Inh Orl lUf 1WPFA5 0017 TXAPA90031 and vapor is produced during the production of poly vinyl chloride. (R-l 13) TOXIC COMBUSTION PRODUCT HC1, phosgene, CO; hazardous, employ self-contained breathing ap paratus. EXTINGUISHING METHOD Stop flow of gas. Usewater to keep containers cool. Do not extinguish un less necessary to effect an immediate shutoff of flow. Dry chemical and CO- can be used to extinguish vinyl chloride fires. PERSISTENCY Polymerizes in presence of air, ox ygen, sunlight, or heat. Volatilizes and will leave water quite soon. TOXICITY CARCINOGENICITY Studies indicate positive de velopment from occupational exposure. INHALATION LIMIT (Text) Regulations: OS HA car cinogen. (29CFR* 1910) OSHA PEL (TWA) 1 ppm. {`J9CFR* 1910) OSHA peak 5 pptn/15 M. (29CFR* 1910) Recommendations: NIOSH ceiling 2.55 ing/m* 15 ACUTE TOXICITY: TERRESTRIAL LIFE--INHALATION LC50 Species LC50 (rtiglm') Mus 305,500 Mas 68,550 TEST CONDITIONS A total of 536 white mice were tested in Pravdin-type gas chambers. Ton cones were used. Durnhon (II) K'J 2 R-ll 2 R-lH RESULTS The LC50 was found, using the Behrens method, to be 27,419 ppm (1 ppm = 2.5 mg/m3 under test condi tions). The LC10 was equal to 139.975 ppm. Rat 119,100 TEST CONDITIONS A total of 70 rats were tested @ 5 cones of VC in a Pravdin-type gas chamber. 2 R-l14 RESULTS The LC50 was determined, using Behren's method, to be 47.640 ppm (1 ppm = 2.5 mg/m3 under test conditions). The LC100 was equal to 208,425 ppm. Gpg 590,000 TEST CONDITIONS A total of 30 guinea pigs were tested @ 5 cones of VC in a Pravdin-type gas chamber. 2 R-U4 RESULTS The LCSO was determined, using Behren's method, to be 236.215 ppm (l ppm = 2.5 mg/m3 under test conditions). The LC100 was equal to 277,900 ppm. Rbt 590,000 TEST CONDITIONS A total of 20 rabbits were tested @ 5 cones of vinyl chloride in Pravdin-type gas chambers. 2 R-l14 RESULTS The LCSO was determined, using Behren's method, to be 236.215 ppm (1 ppm = 2.5 mg/m3 under test conditions). The LC10 was equal to 277,900 ppm. Mus 293,750 Rat 330,000 Gpg 535.000 Rbt 535,000 TEST CONDITIONS The experiments were carried out in a 580-L chamber of the Pravdin type. The animals were exposed to various cones of vinyl chloride for 2 H. After the animals were placed in the chamber, the gas was introduced at the beginning at the lower part of the cham ber without any ventilation. The gas was measured volumetrically. A total of 53$ mice, 70 rats, 30 guinea pigs, and 20 rabbits were used. LD5Q values were calculated according to the Behrens method. 2 2 2 2 R-l 17 R-l 17 R-i 17 R-117 f J3 So 0 fo u o> -J -J DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW M: 1 ppm/15 Nl. (CRSOE* PB-2-J6619/MOSH) ACC1H human carcinogen. (TLVADM 83/ACGIH) ACGIH TLV (TWA) 10 mg/m1' 5 ppm. (TLVADM 83/ACGIH) DIRECT CONTACT Acts as refrigerant under pro longed contact and as such can cause skin burns. GENERAL SENSATION Sweet-smelling gas. Pro posed limits will be I ppm for 8-H working day, 5 ppm for 15-M average; may be anesthetic above 500 ppm. Handling of uninhibited material has caused circulatory and bone changes. (30ZNA5 0001) PERSONAL SAFETY PRECAUTIONS Gas-tight gog gles and breathing apparatus is required in fire areas or where closed environment or poor ventilation causes high vapor cone. Eye goggles and impervious outer wear are recommended for areas where liquid vinyl chloride may be encountered. ACUTE HAZARD LEVEL Irritant. Moderately mx when inhaled. Should cause no problem in water. Emits tox vapors when heated to decomp. CHRONIC HAZARD LEVEL Chronic exposure has shown liver injury in rats and rabbits. Chronic irritant. DEGREE OF HAZARD TO PUBLIC HEALTH Irritant. Moderately tox with inhalation. Emits highly tox va pors when heated to decomp. ACUTE TOXICITY: TERRESTRIAL LIFE-STUDIES * For mice, the smallest cone that is fatal in 10 M is 10--12 mmol/L (about 25-30% volume). The smallest nar cotic cone is about 3.5 to 5 mmol/L (8-12% volume). Death occurs due to respiratory paralysis with result ant heart arrest. At a cone of 7 mmoi in air, it anes thetizes rabbits and dogs within a minute. Recovery is rapid with no apparent adverse effects even after prolonged anesthetization. (R-l 15) Single exposure of guinea pigs to vinyl chloride gas @ 10 (250 mg/L) in air resulted in narcosis and death within 30--60 Nl. Lower cones resulted in ataxia and narcosis. Patho logical examination revealed congestion and edema of the lungs and hvperima of the kidneys and liver. (R-l l) Vinyl chloride was considered for use as an anesthetic because of its narcotic properties and low acute ihl tox, however studies with dogs found vinyl chloride caused cardiac irregularities at anesthetic cones. (R-l06) * EEGs in rats were altered following oral administration of vinyl chloride and the altera tion varied with sex. Vinyl chloride @ 45 and 135 mg/kg altered learning ability. The compound @ 12 mg/kg had immunosuppressant activity in rabbits. (R- 36) Guinea pigs exposed to 5--7% cone of vinvi chloride lived only I H following exposure; exposure to 2.5% resulted m an 8-H survival time following exposure. Exposure to 1.5% for 1 H or to 0.5% for 8 H had no effect. (R-l 14) Five mice. 5 rats, and 5 guinea pigs were exposed to cones (iy 10%., 20%. and 30% for 30 M. At 10% cones, die animals became agitated, then bad unconscious movements, and some fell, in a state of narcosis. At 20%. the animals' symp toms were salivary secretion, narcosis, and respiratory failure. At 30%. all these symptoms occurred faster. Dead animals showed lung, hepatic, and renal conges tion. lung edema, and hepatic degeneration. * (R-l 14) Mice, rats, guinea pigs, and rabbits were tested to determine acute tox levels, symptoms of tox, and the pathological effect on the organs. Exposure was for 2 H in a gas chamber. Animals exposed to vinyl chlo ride gas without homogenization (no ventilation) died at cones 3 times lower than when the gas was stirred up continuously. The most common symptom in all animals was a state of narcosis, usually attained during the first hour. Narcosis proceeded from excitement to tranquility to falling down. These symptoms in cluded muscular contractions, tanico-clonic convul sions, respiratory disturbances, bradvpnea, ChcyneSrokes type respiration, and finally death by respi ratory failure. Circulatory disturbances were also noted. Animals that survived the 2-H exposure rapidly re gained a normal appearance. Autopsy revealed congestion of the lungs, liver, kidneys, brain, and spleen. Some animals also showed pulmonary edema, marmorated liter, and slight tumefaction of the kid neys. (R-114) ACUTE TOXICITY: HUMAN STUDIES Two Cana dian workers died following acute exposure to vinyl chloride gas; autopsies discovered congestion of the liver, spleen, and kidneys. (R-l 1) Workers exposed to vinyl chloride reported symptoms of euphoria and intoxication. Irritation of the respiratory tract, chronic bronchitis, headache, irritability, poor memory, and weight loss were also noted. (R-11) A 3-M exposure to 2.5% vinyl chloride produced dizziness and dis orientation in humans. (R-l 13) CARCINOGENICITY: IARC DETERMINATION VC is a human carcinogen. VC is carcinogenic in mice, rats, and hamsters by oral and inhalation exposure. (R-63) CARCINOGENICITY: POSITIVE KEFERENCE5 R-l2. R31. R-l 1. R-63. R-S5. R-86. R-89. R-90. R-93. R-97. CARCINOGENICITY: OTHER STUDIES This Study investigated the possibility that changes in nuclear size of HeLa S3 cells, exposed in vitro, might be used as (Continued on page 29) R&S 024678 IULY/AUG 1986 17 T' ';-: ~-'. vfi'x;^v.t:n* :;*r FEATURES ACUTE TOXICITY: AQUATIC LIFE--FRESHWATER STUDIES Sprctri Northern pike (Esox hicius) Durntum (Hi 240 E//rc( Lrvrl (mizll.l Hr/ 388 R-67 RESULTS The 10-D LD1Q0 to Northern ike (Esox lucius) was 388 ppm. Fifteen fish were exposed to 388 ppm in 15-20 gal tanks. Within 10 D all had died. First indication of tox was loss of scales. This phenomenon was followed by the appearance of a gray-white ulcerated area sur rounded by indurated borders. A lack of neutrophilic re sponse was also noted. Twenty fish from uncontaminated Illinois Benedictine Lake were used as controls. After 120 D. 1 fish died due to mechanical injury. (R-S7) SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE 1 Sftrars Roulr 8 Rot Ihl 30,000 ppm Dosing Srht'dulf 4 H/D, 5 D/W lor 12 mos Hr/ R-12 TEST CONDITIONS Twenty-five rats were sacrificed in lots at 20-D intervals after 12 mos of exposure. RESULTS After 10 mos. some animals showed a decrease in weight and aggressiveness to outside stimuli and dis turbed equilibrium. Thirteen animals died from cardi orespiratory complications. Two animals died from hematoperitoneum. Most of the animals showed pathological degeneration of the brain, liver, kidneys, and thyroid. Six rats showed histopathological alterations of the skeleton. Degeneration of the skeleton and connective tissue was similar to that observed in human acroosteolysis of the hands. Rbt Ihl 9-10 mg/L 4 H/D for S.5 mos R-17 RESULTS After 5 1/2 mos of exposure to vinyl chloride, alteied beta-waves (frequency > 80 Hi) appeared on the electroencephalogram from the anterior hypothalmic nu clei. and the potentials of the anterior and posterior nuclei increased by 18-30% and 70-85%. respectively, over con trol values. Concommitant changes in the cardiovascular system (bradycardia, arrhythmia, decreased voltage of electrocardiogram peaks or whole complexes, decreased duration of systole, increased arterial pressure, and re tarded blood flow) also occurred. The functional changes in the anterior and posterior hypothalmic nuclei may have a role in the pathogenesis of tox angioneurosis due to vinyl chloride. Rat Ihl 0.03-5 mos 0.04 mg/L 5 mos R-18 RESULTS Chronic exposure of rats to vinyl chloride dis rupted cardicc work rhythm, induced bradycardia and arrhythmia, and reduced the relative duration of I-1I and T-II sound intervals. The relative duration of the Q-T com plex did not change significantly. Within 15 D after ter mination of exposure, the rat cardiac activity rhythm re turned to normal, but the duration of I-H and T-II sound intervals remained below the initial levels for another 15 D. Authors concluded that the maximal permissible cone of vinyl chloride is significantly less than 0.03 mg/L. Rat Ihl 5.000 ppm 7 H/D. 5 D/W for 52 W R-23 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT _ W*.-,' R&S 024680 CHEMICAL REVIEW SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE (ConiinurH) Sprftr* Rvutf I)o\rs TEST CONDITIONS 80 male and female Wistar rats were used. A control group was also used. Posing SfhrduU K'l RESULTS After 4. 13. 26, and 52 W. 10 rats/sex/group were sacrificed and subjected to extensive examinations as to growth, mortality, hematology, clinical chemistry, and organ weights. Slight growth retardation throughout the experimental period and high mortality i ri the second half of the study were observed in the vinyl chloride-exposed animals. Some of the hematological parameters and bio chemical blood parameters were influenced by vinyl chlo ride after an experimental period of 52 W only. Blood clotting time was shorter in rats exposed to vinyl chloride monomer (YCM) than in the controls. There were minor indications of increased potassium contents of the blood serum in VCM-exposed animals during the first half of the experimental period. The kidneys were adversely af fected by VCM as indicated by increased blood urea ni trogen levels and relative kidney weights. After 52 W, increased weights of heart and spleen and slight signs of anemia were noticed in VCM-exposed rats. Mus NG NG Up to 6 mos R-24 RESULTS Electron microscopic studies of liver of mice exposed to vinyl chloride monomer for up to 6 mos re vealed changes mainly in and around sinusoids and in sinusoidal lining cells, particularly with only mild alter ations of hopatocytes. The angiosarcomas that developed in some mice arose from the sinusoidal lining cells. Rat Ihl 5.000 ppm TEST CONDITIONS After exposure to 0 ppm (control) or 5.000 ppm vinyl chloride. 62 male and 62 female Wistar rats were sacrificed (at 4, 13. 26. and 52 W) and subjected to extensive examinations. A description of the morpho logical changes observed in respiratory tract, ceruminous glands, brain, kidney, heart, and spleen were noted. 7 H/D. 5 DW for 52 W R-31 RESULTS The vinyl chloride effects included increased degree of tubular nephrosis, mild focal degeneration of the myocardia. and increased hemopoietic activity in the spleen. Ihl 50. 250, or 1,000 ppm 6 H/D. 5 D/W `or up to 1 Y R-41 hat Ihl 50, 500, and 20.000 ppm TEST CONDITIONS The activity of microsomal cyto chrome P-450 onooxygenase and ultrastructure of the liver were studied in rats exposed dynamically to 50. 500, and 2G,0OQ ppm VC over 10 mos. RESULTS Exposure of 2-mo-old albino CD-I mice (36 of each sex) to 1,000 ppm of vinyl chloride (VC) caused some acute deaths with tax hepatitis and marked tubular ne crosis of the renal cortex. Starting with the 6th mo, mice exposed to 50 or 250 ppm VC became lethargic, lost weight quickly, and died. Only a lew mice exposed to 50 ppm survived for 12 mos. Pulmonary macrophage count was elevated in some mice. In rats (groups of 36 male and 36 female CD) exposure to 1,000 ppm VC sightly depressed body weight of the females. Exposures cA 250 or 1.000 ppm caused a number of deaths. 10 mos R-45 RESULTS After 1 and 3 mos of exposure to 500 and 20,000 ppm VC. the level of cytochrome P-450 was slightly lower than in the control animals. Upon continuation of expo sure. it was restored to the original level accompanied by a slight increase of activity of aniline-p-hydrorylase. Liver enlargement, developed in the course of exposure, was accompanied by ultrastructural alterations begin- JULY/AUG 1986 R&S 024681 FEA HIRES SUBACUTE-CHRONIC EFFECTS: TERRESTRIAL LIFE (CWiW/) Spates Route Doses Dining Sihedule K'l rung in the 3rd mo of exposure to oil cones of VC. De velopment of hepatic alterations (hypertrophy of smooth and rough endoplasmic reticulum, swelling of mitochon dria. accumulation of lipid droplets, focal cytoplasmic degradation) also occurred. Rat Ihl 50. 500, and 20.000 ppm TEST CONDITIONS 340 male Wistar rats. 180-220 g, were exposed to vinyl chloride (VC) at the cones of 50, 500, and 20,000 ppm. 5 H/D. 5 D/W for 10 mos. 5 H/D, 5 D/W for 10 mos R-<8 RESULTS Morphological lesions in the liver and testes detected by light and electron microscope intensified with the duration of exposure. After 10 mos of treatment, the difference from the controls was statistically signlicant (p < 0.05) at all levels of vinyl chloride exposure. At that time, the relative weights of spleen, liver, kidneys, heart, and testes were significantly elevated in some groups of the exposed animals, the difference being most pro nounced for the spleen and dose-related lor the liver and kidneys. The no-tox-effect level of VC could not be es tablished. The lowest cone of VC (50 ppm) still caused some tox effects in rats, including slight hematological and biochemical changes and fluctuations, and also ultrastructural changes in hepatocytes and a tendency for an increased incidence of histological liver alterations. Statistical analysis involved the Students > test. Dog Ihl 10%. 20% volume in air 7 times/3 W, for 3 H each exposure R-l 12 RESULTS At 10% volume dogs showed no considerable changes in liver and kidneys. At 20% volume, respiratory paralysis, strong flow of saliva, and, alter narcosis, vom iting occurred. SUBACUTE-CHRONIC EFFECTS: HUMAN STUDIES Route Dn\es NG NG TEST CONDITIONS An epidemiological study was per formed covering 5.011 employees with 21,510 man-years experience in various phases of VC and PVC manufac turing in 32 plants throughout the U.S. and Canada. Duong Seheitule Ref Occupational R-87 RESULTS The total number of definitive cases of acroosteolysis (AOL) was 25: 16 other individuals were under suspicion. This condition is clearly associated with the hand cleaning of polymerizers. Workers engaged in other phases of VC or PVC manufacturing do not appear to be at risk of developing AOL. AOL appears to be a systemic rather than local disease. Currently neither the etiolog ical agent nor its portal of entry is known. NG NG Occupational R-88 RESULTS Two cases of acroosteolysis (AOL) occurring in men engaged in the polymerisation of VC are described. The bones affected were the terminal phalanges of the fingers and the sacroiliac joints, but in one case the pa tella and in the other the phalanges of the feet were in volved. The condition was accompanied by Raynaud's phenomenon and skin lesions. NG NG Occupational R-91 20 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW SUBACUTE-CHRONIC EFFECTS: HUMAN STUDIES {Conimurd) Routr D/>u>i Sfhrdlltf Rff TEST CONDITIONS The cohort of workers employed in a Swedish VC/PVC plant since its start in the early 1340s has been followed for mortality and cancer morbidity pat terns. Only 21 of the 771 persons could not be traced. Difficulties in establishing exposure levels at different work areas in the past makes an evaluation of dose-effect relationships impossible. RESULTS A four- to five-fold excess of pancreas/liver tu mors was found, including two cases latei clastifiod as angiosarcomas of the liver. The number of brain tumors and suicide do not deviate significantly from the ex pected. Cardiovascular and cerebrovascular diseases, on the other hand, d.ffer significantly from the expected. Ihl, dermal NG NG R*8 RESULTS VC is a skin irritant, and contact with liquid may cause frostbite upon evaporation. VC gas depresses the CNS. Lightheadedness, some nausea, and dulling of visual and auditory responses may develop in acute ex posures. Chronic exposure of workers may result in acroosteolysis. Raynaud's phenomenon, and sclerodermatus skin changes. Chronic exposure may also cause hepatic damage. NG NG Occupational R-ll RESULTS There are numerous clinical indications that chronic exposure to VC is tox to humans. Hepatitis-like liver changes, angioneurosis of a spastic character, Ray naud's syndrome, scleroderma-like skin changes, lytic lesions ot the terminal phalanges in hand and feet, and pseudoclubbing of the Ungers have been reported in many workers in the U.S. and Europe. The latter conditions had been termed occupational acroosteolysis. Other long-term effects include functional disturbances o( the CNS with adrenergic sensory polyneuritis, thrombocytopenia, splenomegaly, liver malfunction with marked iibrosis in the portal areas, and pulmonary insufficiency with re strictive changes in the lungs. NG NG Occupational for 1 Y R-ll RESULTS Workers exposed to VC for 1 Y showed a de crease ot peroxidase, indophenotoxidase, and glutathi one levels. Serum levels of gammaglutamic transpepti dase in exposed workers appear to be the best clinical pxncmeter for detecting abnormalities. Alkaline phos phatase. serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, lactic dehydrogen ase. and bilirubin levels were also increased in many cases. Other data are also available that suggest that VC disease is an immune-complex disorder. Immunolog ical and immuno-chemical investigations of workers with the syndrome showed the presence of circulating immune complexes in 19 of 28 pxrtients- Ihl NG NG R-43 RESULTS Liver function tests showed no diiierence be tween exposed workers and controls not exposed to VC and no cases of angiosarcoma or florid-VC induced liver disease. However, ot 422 exposed workers, 4 had en larged spleens, compxrred with none tor 202 controls. Liver biopsies ot selected cases showed no significant p>athological changes, although there was a minimal increase in portal tract and sinusoidal iibrosis in exposed workers. IULY/AUG 1906 :i r 33 99 </> o ro -u o> 00 ro ! ,b r; Occupational RESULTS Capillary microscopy study Showed that 10% or more ot workers exposed to VC have capillary abnor* malrhes that were not found in workers without exposure to VC. RESULTS A -ytologicul examination ol the sputa of nearly 4,COO hauan workers in lhe VC/PVC industry has shown a high incidence oi changes in bronchial epithelia, among which squamous dysplasia and atypical adenomatious proliieration were observed. R&S 024683 CARCINOGENICITY: ANIMAL STUDIES Sfjcem Houle I)om'\ Rat Ihl 0 or 5,000 ppm TEST CONDITIONS Alter exposure to 0 ppm (control) or 5,000 ppm vinyl chloride, 2 male and 62 female Wistar rats were sacrificed (at 4, 13. 26, and 52 W) and subjected to extensive examinations. A description of the n orphological changes observed in respiratory tract, ceruminous glands, brain, kidney, heart, and spleen were noted. Mus Ihl 50,250. or 1,000 ppm TEST CONDITIONS 2-mo-old albino CD-I mice were di vided into 4 groups, each consisting of 36 males and 36 females. Each group received 0, 50, 250, or 1,000 ppm VC. Four animals of each sex and exposure level were ter minated for various laboratory tests and gross and his topathologic examinations at the end of 1, 2, 3. 6. and 9 most the surviving animals were terminated at the end of 12 mos. Rat Ihl 0. 50, 250. or 1,000 ppm TEST CONDITIONS 2-mo-old CD rats were divided into 4 groups each consisting of 36 males and 36 females. Each group received 0, 50. 250, or 1.000 ppm VC, Four animals of each sex and exposure level were terminated at the end of 1, 2, 3. 6. and 9 mos; the surviving animals were terminated at the end of 12 mos. Srhrdtile Hej 7 H/D, 5 D/W for 52 W R-31 RESULTS Primary tumors were found in the brain (ependymona), lungs (papillary adenoma and mesenchymal types of tumors), ceruminous glands (mainly keratinized squamous cell tumors), and nasal cavity (carcinomas of the olfactory epithelium, carcino sarcoma, esthesioneuroepithelioma). 6 H/D, 5 D/W R-41. R-66 RESULTS Exposure to VC caused a high incidence of bronchioalveolar adenomas, liver hemangiosarcomas, and mammary gland tumors. The incidence of bronchiolar adenomas was: control group. 1/26 males and 0/36 fe males; 50 ppm group, 8/20 males and 4/34 females; 250 ppm group, 10/29 mates and 12/34 females; 1,000 ppm group. 22/33 males and 26/36 females. The incidence of liver hemangiosarcomas was: control group, 0/26 males and 0/36 females; 50 ppm group, 3/29 males and 0/34 fe males; 250 ppm group. 7/29 males (p < 0.05) and 16/34 females (p < 0.05); 1.000 ppm group. 13/33 males (p < 0.05) and 18/36 females (p < 0.05). Mammary gland tumors con sisted of adenocarcinomas and squamous and anaplastic cell carcinomas. There was a total of 0/36, 9/34, 3/34, and 13/36 mammary gland tumors in females exposed to 0. 50, 250, and 1.000 ppm. respectively. Metastases in the lung occurred in 0/36, 2/34, 2/34, and 8/36 females *n the 0, 50. 250, and 1,000 ppm groups, respectively. 6 H/D. 5 D/W for 1.2.3,6. or 12 mos R-41. R-86 RESULTS The Incidence of liver and lung hemangiosar comas was significantly increased in female rats. An in creased incidence ol these tumors was also seen in male rats, hut this was not significantly (p < 0.05) increased. None of the male (0/35) or temale (0/35) controls, and none of the 50 ppm dose group (0/36 males. 0/36 females) de veloped either liver or lung hemangiosarcomas. The in cidence of these tumors in the medium and high dose DANGE.OUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT *44 CHEMICAL REVIEW R&S 024684 CARCINOGENICITY; ANIMAL STUDIES (Cuntiit uni) A/Wl/l ttnUlf Rat Ihl 30,000 ppm TEST CONDITIONS 30 male and 30 female 17-W-old Sprague-Dawley rats were exposed to 30,000 ppm VC for J Y. The animals were then kept under observation until jpontaneous death. Rat lhl 50 ppm TEST CONDITIONS A total of 300 male and female Spra gue-Dawley rats (11 W old) were exposed to 50 ppm VC for 1 Y (4 H/D, 5 D/W}. A control group consisted of 100 untreated rats. The animals were then kept under obser vation until spontaneous death. Rat Ihl 1, 5. 10. and 25 ppm TEST CONDITIONS 13-week-old Sprague-Dawley rats in groups of 120 (males and females combined) were ex posed to 0, 1, 5, 10, or 25 ppm VC for 4 H/D. 5 D/W for 1 Y. The animals were then observed until spontaneous death. Rat Ihl 6.000 or 10,000 ppm TEST CONDITIONS 110 pregnant Sprague-Dawley rats were exoosed to 6,000 or 10,000 ppm VC for 4 H/D for 7 D, from the 12th to the 18th D of pregnancy. Offspring were examined for tumors to see it VC was transported transplacentally. The animals were examined 143 W post treatment. Four groups were used: Group 1 consisted of 30 dams who received 10,000 ppm VC; Group II consisted of 30 dams who received 6,000 ppm VC; Group HI con sisted of 54 offspring whose mothers received 10,000 ppm VC; Group IV consisted of 32 offspring whose mothers received 6.000 ppm VC. No controls were used. l)tinn StiirtfuU Kef groups were as iollows: 2/36 males and 10/36 females (p 0.05) from the 250 ppm group developed'hemangios- arcomas in the livers; 0/36 males and 3/34 females from the same group developed hemangiosarcomas in the lungs. A total of 6/34 males and 15/36 females (p < 0-05) from the 1,000 ppm group developed hemangiosarcomas in the liver; 4/34 males and 9/36 females (p < 0.0S) developed hemangiosarcomas in the lungs. VC did not cause any other type of tumor :n rats. 4 H/D, 5 D/W for 52 W R-89 RESULTS A total of 31/60 animals had Zymbal gland car cinomas and 17/60 had liver angiosarcomas. No mention of control animals was made. 4 HT). 5 D/W for 1 Y R-89 RESULTS After 100 W there were 55 survivors in the treated group and 28 in the control group. At this time the fol lowing results were observed: Of the animals in the treat ment group, 6/300 had Zymbal gland carcinomas (0/100 controls), 1/100 had a nephroblastoma (U100 control), 6/300 had liver angiosarcomas (0/100 controls), 7/300 had an giosarcomas at other sites (0/100 controls). 43/300 had mammary carcinomas (3/100 controls), 2/300 had mam mary carcinosarcomas (2/100 controls), 45/300 had mam mary ibroadenomas (3/100 controls), and 28/300 had other types of tumors (and/or sites) (7/100 controls). 4 H/D, 5 D/W lor 1 Y R-89 RESULTS After 87 W there were 49. 49. 62. 51. and 45 survivor* for the 0. 1. 5. 10. and 25 ppm dose groups, respectively. The number of animals with tumors (ex cluding survivors) at this time follows: within the 25 ppm group. 3 rats had Zymbal gland carcinomas. 3 had liver angiosarcomas, 10 had mammary carcinomas, and 7 had other type and/or site tumors; within the 10 ppm group. 1 had Zymbal gland carcinoma, 11 had mammary car cinomas, and 5 had other type and/or site tumors; within the 1 ppm group, 8 had mammary carcinomas and 4 had other type and/or site tumors; in the control group. 2 had mammary carcinomas and 4 had other type and/or site tumors. 4 H/D, 7 D R-89 RESULTS Group I: 1 animal had a Zymbal gland carci noma, 1 had an intraabdominal angiosarcoma, 1 had a liver fibroangioma, and 1 had a liver angioma. Group II: no tumors were found. Group III: 3 animals had Zymbal gland carcinomas. 1 had a nephroblastoma, I had a liver fibroangioma. 1 had a liver angioma, 1 had a Zymbal gland fibrosarcoma, and 1 had an ovarian leiomyosar coma. Group IV: 1 animal had a Zymbal gland carcinoma, 1 had a subcutaneous angiosarcoma, 1 had an intraabdominal angiosarcoma, 1 had a Zymbal gland adenoma, 1 had a skin carcinoma, 1 had a subcutaneous fibroan gioma. and 1 had a mammary carcinoma. JULY/AUG 1986 23 vSy's.', R&S 024685 FEATURES CARCINOGENICITY: ANIMAL STUDIES {Cmtmufti) Species Route Doses Rat Ihl 6,000 or 10,000 ppm TEST CONDITIONS 45 female and 44 male SpragueDawley rati began treatment at 1 D of age. Animals re ceived 6.000 or 10.000 ppm VC 4 H/D. 5 D/W for 5 W. The animals were then observed until spontaneous death. Dostuji Schedule Ref 4 H/D. 5 DAW for 5 W R-89 ? RESULTS Of the 46 animals receiving 10.000 ppm VC, there were 10 cases of angiosarcomas and 15 of hepato mas (total of 13 rats with tumors). Of the 43 rats exposed to 6.000 ppm VC. there were 10 cases of angiosarcomas and 13 of hepatomas (total of 17 .rats with liver tumors). At W 104 (from start of treatment) there were 5 and 8 survivors in the $.000 and 10.000 ppm exposure groups, respectively. Rat Ihl 6,000 or 10,000 ppm TEST CONDITIONS Groups of 120 (male and female com bined) Spraguo-Dawley rats 13 W ol age were exposed to 6.000 or 10.000 ppm VC lor 5 W. Controls consisted of 249 rats that were untreated. Alter treatment the animals were observed until spontaneous death. 4 H/D, SD/W for 5 W R-89 RESULTS Alter 104 W there were 55. 15, and 16 animals still alive in the 0. 6,000. and 10.000 ppm dose groups, respectively. The only tumor reported at this time was 1 hepatoma in the high dose groups. The results reported in another reference (R-65) after 135 W were identical to those at 104 W. This study showed that the age of the animals is an important factor in determining the inci dence of tumors and their relative distribution. The older rats (13 W) were much less susceptible to tumor incidence than the newborn rats (1 D). In addition, the authors con cluded that the shorter exposure period (5 W compared to 17 W) resulted in a sharp reduction in the onset of several types of tumors, especially liver angiosarcomas. Ham Ihl 50. 250. 500. 2.500. 6.000. or 10.000 ppm 4 H/D. 5 D/W for 30 W R-89 TEST CONDITIONS A total of 268 male Golden hamsters were exposed to 0. 50, 250. 500, 2,500. 6.000. or 10,000 ppm VC. 4 H/D. 5 D/W for 30 W. After treatment animals were observed until spontaneous death. Surviving animals were examined after 109 W of treatment. RESULTS Group I (10.000 ppm): 6/35 had skin trichoepi theliomas and basaliomas. 4/35 had forestomach epithe lial tumors, 1 subcutaneous angioma, and 1 gall bladder adenocarcinoma. Group II (6.000 ppm): 1/32 had a liver angiosarcoma. 2/32 had skin trichoepitheliomas and bas aliomas, 2/32 had melanomas. 7/32 had forestomach ep ithelial tumors. 2/32 had hepatomas, 2/32 had liver fibroangiomas. 2/32 had liver angiomas, and 1/32 had a biliducts adenocarcinoma. Group IQ (2.500 ppm); out of 33 hamsters. 1 had skin trichoepitheliomas and basa liomas, 1 had melanomas. 1 had lymphomas. 11 had forestomach epithelial tumors. 1 had hepatoma. 1 had a liver fibroangioma. and 1 had a liver angioma. Group IV (500 ppm): out of 33 hamsters. 2 had liver angiosarcomas, 4 had skin trichoepitheliomas and basaliomas. 1 had lym phomas. 7 had forestomach epithelial tumors, 1 had a subcutaneous angioma, and 1 had a bronchial carci noma. Group V (250 ppm): out of 32 hamsters. 3 had skin trichoepitheliomas and basaliomas. 1 had lymphomas, and 2 had forestomach epithelial tumors. Group VI (50 ppm): out of 33 hamsters. 6 had skin trichoepitheliomas and basaliomas, 1 had melanomas, 1 had lymphomas, and 4 had forestomach epithelial tumors. Group VII (0 ppm): out of 70 animals. 2 had skin trichoepitheliomas and basaliomas. 2 had lymphomas, and 2 had forestom ach epithelial tumors. Rat Ihl SO. 250. 500. 2.500. 6.000, or 10.000 ppm 4 H/D. 5 D.W for 52 W R-89 TEST CONDITIONS Groups of 64-74 Sprague-Dawley rats (male and female combined), age 13 W, were exposed to the above VC cones for 52 W. Controls consisted of 68 RESULTS After 135 W (end of experiment) increased in cidences of liver angiosarcomas, Zymbal gland carci nomas. and nephroblastomas were observed in the treated 24 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT e v-- j*,; i -fWTO1 I-"-* R&S 024686 CHEMICAL REVir^ CARCINOGENICITY: ANIMAL STUDIES {Continued* Specist Route Doset untreated rat*. Aiter exposure the animal* were observed until spontaneous death. Dmmg Schedule Rrf rats. The following incidences of these tumors were ob served in rats that survived until at least 26'W, when the first tumor was observed: for the controls. 50. 250. 500, 2,500, 6.000. and 10.000 ppm dose groups, respectively, liver angiosarcoma occurred in 0(58. 1(59. 4/59.7/59. 13/59. 13/60. and 9/61.' Zymbal gland carcinoma in 0/58. (V59, 0(59, 4/59, 2/59, 7/60. and 16/61; nephroblastoma in 0/58, 1/59, 6/59; 4/59. 6/59. 4/60, and 5/61. Rat Ihl 100, 150, and 200 ppm TEST CONDITIONS Groups ol 120 (male and female com bined) Sprague-Dawley rats, age 13 W, were exposed to the above VC cones for 52 V/. Controls consisted of 185 untreated rats. After exposure the animals were observed until spontaneous death. 4 H/D. 5 DAV for 52 W R-89 RESULTS The results after 143 W (end of experiment) were given. Liver angiosarcomas and nephroblastomas were observed in the treated but not control animals. The fol lowing are the number of animals observed with these tumors for the control, low. medium, and high dose groups, respectively; liver angiosarcomas, 0, 1. 5. and 12: ne phroblastomas, 0, 10, 7, and 3. Rat Ihl 50. 250. 500. 2.500, 6,000, and 10.000 ppm 4 H/D, 5 D/W for 17 W R-89 TEST CONDITIONS Groups of 60 (male and female com bined) Sprague-Dawley rats, age 17 W. were exposed to the above cones of VC. Controls consisted of 190 untreated rats. Aiter exposure the animals were observed until spontaneous death. RESULTS The results after 155 W (end of experiment) were given. The incidence of Zymbal gland carcinomas and brain euroblastomas were increased in the treated rats. The number of animals with these tumors for the control. 50, 250, 500, 2,500. 6.000, and 10,000 ppm dose groups, respectively, were as follows: Zymbal gland carcinoma, 1. 0. 1. 3. 6. and 7; brain neuroblastoma, 0, 0, 0, 0, 2. 2. and 6. Nephroblastomas and liver angiosarcomas were observed in 0-2 animals per each exposed group, but none were seen tn the control animals. Mus Ihl 50. 250, 500. 2.500, 6,000. and 10.000 ppm TEST CONDITIONS Groups of 30 male and 30 female Swiss mice, age 11 W, were exposed to the above VC cones for 30 W. Controls consisted of 80 untreated males and 70 untreated females. Alter exposure the animals were observed until their spontaneous death. 4 H/D. 5 D/W for 30 W R-89 RESULTS The experiment was terminated after 81 W. Lung tumors, mammary carcinomas, liver angiosarcomas, and epithelial tumors of the skin were increased in the treated mice. The following incidences (males and females com bined) of these tumors were noted in animals alive alter 16 W when the first tumor was observed; (for the control group followed by lowest through highest dose group were observed) lung tumors: 8/141, 2/57, 33/58. 38/58. 30/53. 8/54 and 35/50; mammary carcinomas: 0(141, 12/57, 11/58. 7/58. 9/53, 8/54 and 13/50; liver angiosarcoma: 0/141, 1/57, 11/58. 1/58. 11/53, 5(54 and 8(50; and skin epithelial tumors: 0/141. 0/57, 2'58, 1/58, 3/53, 6/54 and 3/50. Rat Ihl 50. 250, S00, 2,500, 6,000. and 10,000 ppm TEST CONDITIONS Groups o( 30 Wistar rats (males and females combined) were exposed to VC by inhalation for 52 W. Controls consisted of 40 untreated rats. After treat ment the animals were observed until spontaneous death. 4 H/D, 5 D/W for 52 W R-89 RESULTS After 136 W there were 3 animals still alive in the control group and none in the treated groups. Treat ment with VC caused an increased incidence of liver an giosarcomas. The number of rats with this tumor was. 0. 0, 1, 4, 3, 2. and 8 for the controls, and 50. 250, 500, 2,500. 6,000. and 10,000 ppm dose groups, respectively. Rat Orl 3.33, 16.65, and 50 mg/kg 4-5 D/W for 52 W R-89 IULY/AUG 1986 25 j .. f.- , iTe*!. . . . . TEST CONDITIONS Groups of 158-163 5prague-Dawley rats were to be given VC by gavage for 104 W. This ex periment was still underway at the time of the report. The control group received the olive oil vehicle only. 50 and 500 ppm TEST CONDITIONS Albino NMR1 mice. 12 W old. were used. Twelve male and 12 females were exposed lo 50 ppm VC for 6 H/D, 5 D/W for 52 W. The same number of rats were exposed at the same schedule for 26 W to 500 ppm VC. Each experimental group had a control series run parallel to it. Four animals of each sex from all groups were sacrificed and pathologically examined 26 W after start of exposure. Additionally, 4 control animals were sacrificed 1 Y after the start of the experiment. The re maining animals were allowed to live until spontaneous death, or were sacrificed when moribund. Mus Ihl 50. 200, or 2,500 ppm TEST CONDITIONS Groups of 100 male and 100 female CDI Swiss ChR mice (age NG) were exposed to 50, 200. or 2.500 ppm VC in air for 7 H/D, 5 D/W for 3 mos and were observed for an additional 9 mos. Rat Ihl 30.000 ppm TEST CONDITIONS Three-month-old male Wistar rats were exposed to 30.000 ppm VC (93% purity) vapors for 4 H/D, 5 D/W for 12 mos. Twenty-five rats served as a control group. At the end of treatment surviving animals were sacrificed at 20-D intervals. RESULTS After 120 W there were 4, 4. 2. and 2 animals still alive in the control, low. medium, and high dose groups, respectively. Treatment with VC was associated with an increased incidence of liver angiosarcomas. The numbers of animals with this tumor at 120 W were 0, 0. 3, and 16 for the control, low, medium, and high dose groups, respectively. 4-S DAV for 104 W RESULTS Since this experiment was still underway, con clusions were not made; however, the tumors found in animals that died at the time of the report (57 W] are given in the report. 6 H/D. 5 DAV for 52 W 6 H/D, 5 DAV for 26 W RESULTS The results of the control animals were pooled since no difference between the two groups was found. Out of a total of 48 control animals, 3 were found with tumors (1 mammary adenocarcinoma, 1 ovarian disgerminoma, and 1 reticulum cell sarcoma). In the 50 ppm group. 18/24 animals developed tumors. Alveologenic ad enomas were observed in 13/24 animals. Subperitoneal hemangiosarcomas were found in 14/24 animals, and subcutaneous hemangtosarcomas in 5/24 animals. In the 500 ppm group exposure was stopped at 26 W due to the bad condition of most of the animals. All (24/24) exposed animals in this group developed alveologenic adenomas. Subperitoneal hemangiosarcomas were found in 8/24 an imals. and mammary carcinomas were observed in 4/24 animals. The primary subcutaneous and subperitoneal hemangiosarcomas found in both the 50 and 500 ppm groups were all located in fat tissue. 7 H/D. 5 D/W for 9 mos R-63 RESULTS After 8 mos exposure, 49 treated animals died with tumors. A total of 42 pulmonary adenomas, 41 liver angiosarcomas, and 11 mammary gland adenocarcino mas were observed. Distribution of these tumors were as follows. Pulmonary adenomas: 2 in the 50 ppm group. 12 in the 200 ppm group, 28 in the 2.500 ppm group, and 0 in the control group. Liver angiosarcomas: 3 in the 50 ppm group, 11 in the 200 ppm group. 28 in the high dose group, and 0 in the controls. Mammary adenocarcinomas; 2 in the low dose group, o in the mid dose group, 6 in the high dose group, and 0 in the controls. 4 H/D. 5 D/W for 12 mos R-12.R-85 RESULTS Of 26 treated rats, 17 developed skin carcino mas (predominately epidermoid carcinomas). No tumors were found in the control animals. Treated animals with lesions of the lungs: 1 adenocanthoma, 3 adenocarcino mas. 1 squamous cell carcinoma, and 1 mucous-produc ing adenocarcinoma. Treated animals with lesions of the bone: 5 osteochondromas. 26 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT R&S 024687 f CHEMICAL REVIEV/ CARCINOGENICITY; ANIMAL STUDIES (CunUnutd) Sprdfi Houlr l>u\e\ i)n\lng Sili'diilr Rat Ihl 600 ppm or 600 ppm plus 5% ethanol 4 HD. S D/W for 1 Y in drinking water TE^T' <CONDITIONS Groups of 80 Sprague-Dawley male rats were used. One group was exposed to 600 ppm VC vapors; a second group received 5% ethanol in the drinking water (ad libitum) 4 W before the beginning of VC inhalation and continued to receive ethanol-water until death; the control group received only the ethanol-treated drinking water: and a fourth group received no treatment. RESULTS At the time of this preliminary report, 17% of the animals had been autopsied. Histological eviaence showed the latent period for angiosarcoma of the liver to appear was S3 W in rats exposed fo VC alone and in 38 W in rats exposed to VC and 5% ethanol. Preliminary results of this long-term study indicated synergism be tween inhaled VC and ingested ethanol in the induction of tumors. Rat Ihl SO. 500. 2.000. 5.000. 10.000. and 20,000 4 H/D. 5 D/W for 12 mos ppm TEST CONDITIONS Groups of 150-200 male and female Wlstar Ar/IRE rats, 3 mos old. were exposed to the above VC cones for 12 mos. Controls consisted of 200 rats not exposed to VC and kept under the same conditions for 13 mos. RESULTS Exposure to VC was associated with an in creased incidence of liver angiosarcomas, skin squamous cell carcinomas, and lung adenocarcinomas. The follow ing incidence oi these tumors were observed in the control group, followed by lowest to highest dose groups, re spectively. Liver angiosarcoma: 0/200. 0/200. 4/150, 10/200. 12/200, 16/200, and 18/150. Skin squamous cell carcinoma: 0/200. 0/200, 3/150. 0/200 (6/200 skin cecanlhomas, however (a*1 2,000 ppm), 20/200, 34/200, and 67/150. Lung adenocar cinomas; 0/200. 0/200,0/150. 8/200, 4/200, 14/200, and 21/150. Rbt Ihl 10,000 ppm TEST CONDITIONS Forty rabbits were exposed to 10,000 ppm vinyl chloride. Controls consisted of 20 rabbits not exposed to VC and kept under similar conditions for 15 NG RESULTS Skin acanthomas were observed in 12/40 ex posed rabbits and 020 controls. Lung adenocarcinomas were observed in 6 40 exposed rabbits and 0/20 controls. R&S 024688 m CARCINOGENICITY: HUMANS. Route Dose NG NG TEST CONDITIONS A retrospective cohort study oi work ers at iour VC facilities (that had been engaged in the polymerization of VC for at least 15 Y and had a sizable work force) was conducted. Employment records were ini tially obtained oi every individual who had ever worked at any of the 4 VC plants. Then individuals lor the study were selected from the records; those individuals having achieved 5 or more Y of employment and 10 Y since onset oi initial employment. A modified life-table technique was used to obtain the 12,720 person-years at risk ot dying, according to 5-Y age group, 5-Y calendar period, years oi work experience, and time since onset of exposure to VC. Comparison was made between the observed number of deaths among the study cohort members and that ex pected on the basis of the U.S. white male death rates specific for age and calendar year and cause. Dosing Schedule Occupational exposure R-93 RESULTS A iotal of 136 deaths occuried among workers exposed to VC as contrasted with 126.3 deaths expected. Only two causes of death were in excess among workers exposed to VC; nonmalignant respiratory disease, and all malignant neoplasms (6 observed vs 3.4 expected, and 35 observed vs 23.5 expected, respectively). The latter excess was statistically significant @ p <0.05. When can cer mortality was analyzed by site, excesses were found for 4 organ systems; brain and CNS (3 observed vs 0.9 expected), respiratory system (12 vs 7.7 expected), hepatic system (7 vs 0.6 expected, p <0.01), and lymphatic and hematoparitic systems (4 vs 2.5 expected). Of the 14 his tologically confirmed cases of biliary and liver cancer. 11 cases of angiosarcoma of the liver were diagnosed (this includes 4 cases still alive at the time of the report). JULY/AUG 1986 27 fc'v*-?*./\?v 'vr'' tn-.-rwA 1 FEATURES CARCINOGENICITY: HUMANS (Continued) Route Dene NG NG TEST CONDITIONS Identification particulars were ob tained lor over 7.000 men who were at some time between 1940 and 1974 exposed to VC monomer in the manufacture of PVC in Great Britain. Approximately 99% of these men have been traced and their mortality experience studred. The number of deaths observed was compared to that expected, using sex and age standardized death rates for England and Wales. NG 5-240 ppm TWA TEST CONDITIONS A retrospective cohort study of the mortality experience of indivtduals occupationally ex posed to VC between 1942 and 1960 was conducted. Em ployees were grouped into 4 exposure categories accord ing to the highest levels of VC exposure experiences for at least 1 mo. Departmental census lists were reviewed over the specified years (1942 and 1960) for 5 production units, Unit 1: copolymer plant. 1942-1960, Unit U; PVC and copolymer plant, 1953-1960, Unit III: VC monomer plant, 1947-1954, Unit IV: copolymer semiplant, 1946-1955, Unit V: vinyl latexes and polymer plant, 1946-1960. Exposure measurements were available of units I and 11 but not for the 3 smaller unit9. To investigate dose-response rela tionships with respect to VC, industrial hygiene data were reviewed for each job classification and each job was assayed on exposure level of low, intermediate, or high. The three categories were primarily based on estimated TWA cones for an 8-H D. The low level was defined as TWA cones below 25 ppm VC: the intermediate level was defined as 25-200 ppm; and the high level was defined as 200 plus ppm VC. A subjective evaluation of the other 3 units by industrial hygienists indicated that exposures were in the low to intermediate range, with occasional excursions to high levels. The observed mortality of the study population was compared to that of the U.S. white male population. NG NG TEST CONDITIONS A retrospective mortality study ol 8.384 men from 33 plants who had worked for at least 1 Y in a job involving exposure to VC before 31 December 1972 was conducted. The observed mortality was compared to that of the U.S. male population. Vital status could not be determined for 15% of the study population. Analysis was restricted to the 7,128 workers on whom follow-up was complete. Dnung Schedule Ref Occupational exposure R-S3 1 RESULTS The overall standardized mortality ratio. 75.4. shows a significant reduction compared with the national rates. Four cases of liver cancer were iound. Two of these have been confirmed by a panel oi liver pathologists as cngiosarcoma and 2 as not angiosarcoma. There is no evidence to support the hypothesis that cancers other than those of the liver are associated with exposure to VC monomer. The 2 cases ot angiosarcoma were iound in men who had been exposed to high cones ol the monomer although the second man died only 8 Y after first expo sure. Occupational exposure R-97 RESULTS The distribution of the malignant neoplasms with respect to exposure category suggests a possible dose-response relationship. Although the numbers of deaths were small. 9 ol the 13 malignancies were ob served in the high-exposure group. An approximate sta tistical evaluation of the difference between observed and expected malignancy deaths in the high-exposure group compared with all other exposure groups combined was periormed, based on the conditional distribution of in dependent Poisson random variables. A Chi-square value ol 6.1 ip <0.025) was obtained alter adjusting the total expected deaths to the observed number of deaths (high exposure 9 vs 4.64 expected; all other groups 5 vs 9.36 expected). The mortality experience 15 plus Y after initial exposure was examined. Eight ot the 9 malignancies ocuried in the high exposure groups. Again, the Chi-square comparison ol the distribution oi malignancy deaths be tween the high and all other exposure groups was sig nificant ip < 0.01). A comparison within the high exposure group between those individuals with < 1 Y of high ex posure versus those with 1 plus Y of high exposure was not significant. Occupational exposure R-96 RESULTS No specific cause oi death (cancer or otherwise) was statistically significantly greater than expected in the total gioup. When the group was analyzed according to duration or level ot exposure, again no significant in creases in cancer mortality was observed. However, some cancer mortality was increased although not signifi cantly. and may have been related to exposure. Accord ing to the authors, mortality from digestive cancer, res piratory cancer, cancer ol other unspecified sites, and lymphomas appeared to be related to exposure. R&S 024689 28 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT CHEMICAL REVIEW an index of the carcinogenicity of compounds. VC, along with other tested carcinogens, caused an in creased nuclear size in exposed cells. These effects were not seen with noncarcinogens. (R-4) 1,047 workers exposed to VC monomer from 3 different VC/PVC plants, and 289 workers from a polyvinyl chloride (PVC) extrusion plant manufacturing a PVC textile product (exposed to much lower cones of VC) were examined. Results: The carcinoembryonic anti gen (CEA) liters were determined. The investigation demonstrated that occupational exposure in VC/PVC plants can cause elevations in the CEA titers of oth erwise healthy individuals. (R-35) MUTAGENICITY: GENE MUTATION--POSITIVE REFER ENCES H-2. R-20, R-22. R-27. R-S8. R-59. ' MUTAGENICITY: GENE MUTATION--NEGATIVE REF ERENCES R-56. MUTAGENICITY: CHROMOSOMAL EFFECTS--POSI TIVE REFERENCES R-3. R-28. R-t9, R-60, R-64. MUTAGENICITY: GENE MUTATION STUDIES Assay Type Species-Cell Type Bacterial mutation assay Escherichia coh K12 TEST CONDITIONS Mutagenicity oi VC was evaluated in E. co/i K12 at 4 different loci, consisting of three back mutation systems (gal + , arg + , and nad + ) and one for ward mutation (MTR). The test was performed using liver microsomes from male mice pretreated for 10 D with 0.1% phenobarbital in the drinking water. VC gas (>99.9% pu rity) was bubbled thiough the liquid medium to give a cone of 10.6 mM. Iluule Dnses Ref 10.6 mmol R-100 RESULTS Mutagenicity was expressed as number oi col ony forming untis (ciu) on selective media per number of' efu on complete media. VC was mutagenic in the pres ence of a metabolic activation system. The % of sponta neous mutation rate at the different loci was as follows: gal+ 231%: arg+ 663%; MTR 172%; and nad-t- 148%. Yeast mutation assay Schizosaccharomyces pombe 16 or 48 mmol R-20 TEST CONDITIONS This haploid strain of S. pombe contains a missense mutation in the ade6 locus. Treatment with a mutagen causes forward mutation at 5 genetic loci for the biosynthesis of adenine. These mutations produce a change in the phenotype of the colonies, which can then be scored. VC.was bubbled through liquid cell suspensions, producing cones of 16 and 48 mM. RESULTS Mutagenic activity was found in S. pombe only when microsomal preparations (105.000 g) from mouse liver were included with the treatment solution. A doseeffect relationship was linear with mmol cones in treatments of 30 M. The VCM treatment did not produce any detectable decrease in the survival of cells, Host mediated microbial mutation mus. Schizosaccharomyces pombe Orl 700 mg/kg R-20 TEST CONDITIONS Swiss albino mice weighing 25 g each were treated orally with 1.85% VCM in 1 mL of olive oil (700 mg/kg body weight). Yeast cells of S. pombe (P. strain) were injectod into the peritoneum and incubated for various times to measure the forward mutation frequency. RESULTS VCM was found active at a dose of 700 mg/kg during 12 H of treatment. Data from regression analysis were significant at the 1% level. This demonstrated VCM was genetically active, in vivo, Ames assay Salmonella typhimurium TA1530, TA1535. G46 0.2, 2. or 20% RESULTS Exposure of S. typhimurium strains to VC in creased the number of His-t- revertants/plate. 16, 12. or 5 times over the spontaneous mutation rate. After 6 H of exposure to 20% VCM in air. the mutagenic response for TA153C strain was enhanced 7. 4, or S-fold when fortified postmitochondrial liver extractions from humans, rats, or mice were added. VC enzyme-mediated mutagenicity was dependent on an NADPH generating system. Highest mu tagenic response was seen with TA1530. Exposure of this strain to 20% VC in air, in the absence of any metabolic activation system, caused a linear increasing mutagenic response as a function of incubation time, which was 20 times the spontaneous rate. <> 48 H. Phenobarbitone pro- : 4 rw.`."Vv FEATURES MUTAGENICITY: GENE MUTATION STUDIES (Cwitmunl) Awtly [\l>r Sjin ir\-Cril `I\fir Itnul/' littH's Hr/ treatment of rats and mice increased the mutagenic re sponse by up to 15--40% as compared to untreated con trols. Sex-linked recessive lethal Drosophila me'onogaster Ihl 10.000. 100.000, R-27 200,000 ppm TEST CONDITIONS Male D. malanogaster, wild type strain Karsnas 60, 0-2 D old, were used lor treatment with VC. Males were mated individually with 2-3 Muller 5 females for D 6-12 after treatment without any brooding. Heterozygous daughters were individually mated to 2-3 Muller 5 males and the progeny tested lor recessive lethals. In induction experiments, males were treated with sodium phenobarbiturate and/or VC (1% solution sodium phenobarbiturate dissolved in sucrose water for 24 H). RESULTS VC increased the mutagenicity at the lowest exposure tested. There was no indication of an increased effect with higher cones. The experiments with sodium phenobarbiturate (one with 1% VC ar.d one with 10% VC) produced a pronounced effect. The total number ol re cessive lethals (when 1% VC was used) with sodium phen obarbiturate pretreatment was different from control at 0.1% significance level (using Chi-square and Yates Cor rection). Mammalian spot test Mus TEST CONDITIONS Female mice of inbred C57BL/6J Han (ct/a; wild type) were mated to Han rotated-bred males of T-stock strain. On the 10th D of gestation females were exposed to 12,000 mg/m3 (4,600 ppm) of VCM in air for 5 H. FI offspring were examined at 3-5 weeks of age for mosaic coat colors. An experiment using cyclophospha mide to test the ability to induce colored spots in the FI hybrids served as a positive control. Statistical evalua tions of the data were done by Chi-square test. Ihl 4,600 ppm R-56 RESULTS The mammalian spat test did not provide evi dence that VC induces somatic gene mutations in mam mals in vivo. No offspring with abnormal morphology were found in the VCM exposure group. Treatment with 10 mg (scu) CP/kg produced significant differences in the number of white and colored spots in the offspring in comparison with the control or VCM-treated group. Ames assay Salmonella typhimurium TA1S30 20% R-58 TEST CONDITIONS Liver S-9 tractions from adult female BD-V1 rats and from human patients were used as met abolic activation systems. RESULTS VC was mutagenic in the presence of both rat and human liver S-9 fractions. The number of his- revertants in S. typhimurium mediated by human and ro dent liver S-9 exposed to 20% VC (v/v) in air for 4 H and incubated for 48 H (a 37 C was 85 and 100 revertants/plate, respectively. The number of revertants/plate after expo sure to VC in the absence of cofactors (NADP-, G 6-P) was subtracted. Na/K ATPase assay Chinese ham-V79 TEST CONDITIONS The mutagenicity of VC was tested in V79 Chinese hamster cells in the presence and absence of a S-15 liver fraction from phenobarbitone-pretreated rats. The cells were exposed to a vapor cone of 5-30% (v/v) for 5 H. Mutagenicity was measured by the induction of 8-azaguanine and oubain resistance. 5, 10. 20, and 30% R-2 RESULTS Vinyl chloride induced both 8-azaguanine and oubain resistant dose-related mutants @ 5-30% VC in air in the presence of the S-15 fraction. At a cone of 30%, mutation frequencies were 10-20 times that of sponta neous reversions. At this cone there were 51 azaguanine and 4 oubain resistant colonies per 100.000 survivors. Nei ther toxicity nor mutation was induced in the absence of the metabolic activation system. Ames assay Salmonella typhimurium TA1530 2, 7. 12. and 20% R-59 TEST CONDITIONS The mutagenicity of VC in S. typhi murium TA1530 without metabolic activation at the above cones was evaluated. In tests to evaluate the effect of a metabolic activation system, a 2% VC cone was used. The metabolic activation system consisted of S-9 liver fraction from adult male NMR1 mice either left untreated or treated with Aroclor 1254. RESULTS In the absence of a metabolic activation sys tem. VC increased the number of his- revertants in a doserelated manner. At the highest cone (20%) there were 101 revertants in the treated plate compound to 10 in the con trols. The addition of the S-9 fraction enhanced the mu tagenicity of VC. This effect was even more pronounced when liver S-9 from pretreated mice was used. 30 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT < ,:Vp*vV; ' V' j,4 (v;/r J v'/V'Jv.pv*: U..';, R&S 024691 mmmk ^ffs&VTs CHEMICAL REVIEW MUTAGENICITY: CHROMOSOMAL EFFECTS STUDIES ,4ueY Typf In vivo cytogenetics (.rU Typr Chinese ham. bone marrow Human lymphocytes TEST CONDITIONS Bone marrow cells from Chinese hamsters treated with VC in the above doses and routes were studies to determine whether chromosomal aber rations in the bone marrow cells were significantly higher in comparison to control groups. A similar analysis ol workers from a PVC plant was undertaken, using lym phocytes from 20 workers with symptoms of VC illness, from 10 workers with no symptoms of VC illness, and from 10 controls matched according to age. A total of 100 cells per individual were scored for gaps, breaks, fragments, dicentrics, rings, chromatid and chromosome transloca tions, and deletions. UlUltf K'f Ihl. ipr Ihl 2.500 or 5.000 ppm by Ihl followed by 600 and 300 mg/kg ipr NG R-3 R-3 RESULTS In humans, only the.group consisting of work ers with VC illness showed a significant increase in the rate of aberrations in comparison to the control group (statistical lnlortr.ation and exact data not given). In the hamsters, chromosomal aberrations were also signifi cantly higher in the treated animals as compared to con trols Dominant lethal CD-I mus Ihl 3.000. 10.000, 30,000 ppm R-S5 RESULTS No mutagenic effects were seen on any matu ration stage of sjrermatogenesis in male CD-I mice ex posed by inhalation to 7.8, 26, or 70 1 VC in air for 6 H/D for 5 D as compared to controls. In Vivo cytogenetics Hmn-peripheral blood lymphocytes TEST CONDITIONS Seven occupationally exposed male workers and 3 nonexposed control subjects, all employed in the same PVC factory, were studied for chromosomal effects of VC exposure. In weeks prior to blood sample collection, air cone was approximately 20-30 ppm. Work ers who were studied had been exposed to VC for periods ranging from 9 to 29 Y. In vivo cytogenetics Chinese ham, bone marrow TEST CONDITIONS Groups of 4 adult (10 to 15 W old) Chinese hamsters weighing 30 g were exposed to 2.5% VC in air for 6. 12, or 24 H. The male-female ratio was 1:1. Another group of 10 hamsters was exposed to 5% VC lor 24 H only. Hamsters received ipr injection of 8 mg colchicine/kg body weight 24 H after beginning VC ex posure. Bone marrow chromosomes were analyzed for gaps, breaks, fragments, deletions, and exchanges 2 H later. Ihl 20-30 ppm R-28 RESULTS Investigators found that the average frequency of chromosomal aberrations in this group (9.52%) was sig nificantly (p < 0.001) greater than in the controls (1.94%). This was found to be true for chromatid and isochromatid breaks. Ihl 2.5% or 5.0% R-49 RESULTS The frequency of chromosome aberrations de pended on dose and exposure time. After B and 12 H of exposure at the 2.5% level, aberrations (breaks and frag ments) were induced in 0.8% of the metaphase. After 24 H the frequency of induced breaks and fragments in creased to 4.5%. In 1.400 metaphases of 14 control ham sters only 1 break (0.1%) was found. Gaps including chro mosome aberrations increased from 0.6% in controls to 7,3% in group exposed 24 H to 2.5% VC. The highest mea sured effect was 25.7% metaphases with aberrations when hamsters were exposed to 5% VC tor 24 H (p < 0.02). Significance of differences in the number of metaphases with aberrations was verified using the Chi-square test. Micronucleus test CBA mus TEST CONDITIONS Three CBA male mice were exposed to 5% VC for 4 H. Controls consisted of 3 untreated mice. Ihl 15% R-64 RESULTS Exposure to VC caused a significant increase in the number of polychromatic micronucleated cells as compared to controls. Statistical evaluation was per formed with f tests and combined probability analysis according to Fisher. In vivo cytogenetics Hmn. joeripheral blood lymphocyte Occupational NG R-60. R-94 IULY/AUG 1986 30 fio CO o IO 0) <0 ro i FEATURES MUTAGENICITY: CHROMOSOMAL EFFECTS STUDIES {Continu'd) Assay Type Species-Cell Type Routt Dosrs Rrf TEST CONDITIONS The 12 subjects were male workers who had received repeated exposure to VC in an Upstate New York PVC polymerization plant. Duration Of recurrent occupational exposure in the 11 men ranged from 4 to 28 Y with an average of 15 Y. Of the 10 healthy male controls, 4 were from within the same factory population without known VC exposure. Six controls were also selected from outside the factory environment. The chromosome studies were performed on cultures of peripheral blood lympho cytes. Fifty metaphases from each individual were eval uated. RESULTS Exposure to VC increased the frequency ot chromosomal aberrations. Much of this increased dam* age was due to cells with unstable chromosome changes such as fragments, dicentrics, and rings. In vivo cytogenetics Hmn-lyrophocytes TEST CONDITIONS Lymphocytes from humans who were exposed occupationally to VC for periods ranging from 10 to 27 years to cones most frequently between 20 and ISO ppm were examined. Ihl 20-ISO ppm R-BS RESULTS There were 5.2% of the examined lymphocytes from exposed workers that had chromosomal aberrations as compared with 1.8% in the control workers. The ab errations included chromatid and chromatin breaks; chro matid and chromosome exchanges were frequent. m MUTAGENICITY: DNA DAMAGE/REPAIR STUDIES Aitoy Type Species-Cell Type See Chinese ham TEST CONDITIONS Groups of 4 adult Chinese hamsters (10--15 W old) were used in a 1:1 male to female ratio. Hamsters were exposed to VC 6. 12. and 24 H at cones of 1.25 or 2.5% (v/v). The Brd-U-tabiet method was used to obtain in vivo induced sister chromatid exchanges (SCE). Route Doses Ref Ihl 1.25-2.5% R-49 RESULTS The number of in vivo-induced SCEs depended omdose and length of exposure to VC. Data were statis tically analyzed using the f test. The 6-H exposure of the low dose doubled the SCE frequency with 4.41 SCEs/cell in controls, and 8.72 in the experimental group. Length ening of exposure time increased frequency oi SCE. Alter 12 H. 17.51 SCEs/cell were found and 22.33/cell were found after 24-H exposure. SCE frequency increased in all ex posure-time groups after exposure *o 2.5% as compared to the lower dose: 12.66 (6 H), 18.80 (12 H). The highest measured effects were 33.25 SCEs/cell alter a 24 H ex posure to 2.5% VC. See Hmn. lymphocytes TEST CONDITIONS Lymphocytes from humans who were exposed occupationally to VC for periods of 10-27 Y (to cones most frequently between 20-150 ppm) were exam ined. Ihl 20-150 ppm R-66 RESULTS The number of sister chromatid exchanges was increased from 9.41 to 13.30 per lymphocyte. Mitotic gone conversion Saccharomyces cerevisiae > TEST CONDITIONS VC was bubbled through a liquid cell suspension to give cones of 16 and 48 mmol. The assay was performed in the presence and absence of purified mouse liver mierosomes. Induction of gene conversion was measured at the ade 2 and tip 5 loci of this strain of yeast. 16 and 48 mmol mM R-20 RESULTS Both gene conversion systems (ade 2 and trp 5) showed a positive response which was dependent on the presence of purified mouse liver mierosomes. 32 DANGEROUS properties of industrial materials report R&S 024694 1,500 ppm TEST CONDITIONS Pregnant (first trimester) CFY rats (13-28/group) were allocated to experimental groups as follows: Groups IA. 1C, IIA, and IILA inhaled air in an Inhalation chamber for 24 H/D on D of pregnancy 1-9, 8-14, and 14-21, respectively: Groups IB, ID, IIB, and II1B were exposed to VC (4,000 mg/m3 or approximately l.SOO ppm) for the same length of time during the same periods cf gestation as their respective controls. The rats in groups IC and ID were given, surxrutaneously, 2 injections (50 mg/kg bw) of trypan blue (1% solution) on the 7th and 8th D of gestation. Group IV was another control. On the 21st D of gestation, the position of fetuses living, dead, or resorbed was noted. Fetuses and placentae were excised and weighed and macroscopic examination was canied out. The t test was used for statistical comparison of means. The Mann-Whitney U test was used to compare number aifected/total fetuses ratio. Mus Ihl Rat Ihl Rbt Ihl 50, 500 ppm 500. 2.500 ppm 500. 2.500 ppm TEST CONDITIONS Three groups of each specie^ (CF-1 mice, Sprague-Dawley rats, New Zealand rabbits) were tested: control, inhalation of VC only, and inhalation Of VC and ethanol (15%) in drinking water (ethanol blocks metabolism). RESULTS VC was shown to be present in the fetal and maternal blood as well as in the amniotic fluid, indicating the permeability of the placenta to the agent. 24 H/D RESULTS The maternal liver weight and liver weight/body weight ratio increased in response to rrypan blue as well as to VC applied in the 1st or 2nd W of pregnancy (p < 0.01 and p < 0.05). The number of resorbed fetuses as well as fetal loss (% total implants) was significantly in creased in the group exposed to VC during the first 9 D of pregnancy (p 0.05). Author concluded that VC in itself has no teratogenic effect on CFY rats, but an embryotoxic effect dung the early stages of pregnancy (at 1.500 ppm). Fetal losses and induction of CNS mallormations due to trypan blue administration were not potentiated by a combined exposure of pregnant rats to VC and the dye. 7 H/D 7 H/D. D G-15 ol gestation 7 H/D. D 6-18 of gestation R-15 R-15 R-15 RESULTS While maternal tox was observed, VC alone did not produce any significant anomalies when com pared to controls (p > 0.05). There were significant in creases in the number of fetal anomalies in the group that was given 15% ethanol in their drinking water, while receiving 500 ppm VC (mice). Also among mice exposed to VC in combination with 15% ethanol, several skeletal anomalies occurred at an incidence significantly greater than among mice exposed to VC alone (modified Wilcoxon test, p < 0.05). Authors concluded that exposure ol pregnant mice, rats, and rabbits to VC (ihl) at cones high enough to cause maternal tox was not teratogenic in any of the 3 species. Exposure of VC alone was not consis tently embryotoxic in the 3 species studies. Among mice. @ 2.500 ppm, the incidence of resorptions was signifi cantly higher (13%) than among the concurrent controls (7%). Ingestion of 15% ethanol in the drinking water en hanced the tox effects of the inhaled VC. Maternal tox was enhanced to an extent greater than embryotoxicity. 33 l. 1S&RV- FEATURES TERATOGENICITY: HUMAN STUDIES Hum/ l)u\/i Enviromental expoture NG TEST CONDITIONS Thrf>o Ohio communities that had polyvinyl production facilities were studied. Since 1968, information for specific congenital malformations in Ohio residents has been recorded on birth certificates. Any information recorded under the congenital anomalies Section of the certificate were analyzed. Data for deaths resulting from cancer of the CNS, leukemia, and lym phomas in the adult population aged 45 Y and older were also analyzed. Uuung Sih/itul/ NG Hr/ R-92 RESULTS The findings suggest that mothers living in communities with PVC production facilities gave birth to an excess number of children, with congenital malfor mations as compared to the expected based on the state average or based on the experience ir. the balance of counties in which these cities are located. With regard to specific malformations, anomalies of the CNS appear to be of the greatest concern. Deaths from CNS tumors in adult male residents of two of the cities were also sig nificantly greater than expected. On a community basis, excess deaths from the other cancers were not apparent. R&S 024695 TERATOGENICITY: MAMMALS--NEGATIVE REFEREN CES R-15, R-2<>. PLACENTAL TRANSFER: POSITIVE REFERENCES R-26. PHYTOTOXICITY: TERRESTRIAL PLANTS Research was designed 10 sutdy flic cl feet of VC on die rale of production of excess hydrogen peroxide, which is (ox to germinating oat seeds. The etl'eci of the increased HvOv by VC on the sulfhydryl coniem in germinating seeds and in potatoes was also studied. No apparent increase in the HjO.j level was found when germi nated seeds were exposed to 50, 100, or 200 ppm VC gas. Results showed that the amount of H-jOa grad ually increased from 0.35 to 0.-15, 0.05, 0,92. and 1.15 meg H.jOVg seed when VC gas was successively in creased to 300, -400, 500, and 1.000 ppm. The 2,000 ppm VC gave an effect very similar to that obtained with 1,000 ppm. There was a ten-fold increase in the sulfhydryl content of the seeds after 72 H germination without exposure to VC. The sulfhydryl content was decreased gradually by 5.5, 15.2, 21.7, and 30.4% when VC gas was sucessively increased to 300, 400, 500, and 1,000 ppm. The increased production of in the germinating seeds exposed to VC gas decreased their sulfhydryl content and thereby produced adverse effects and caused abnormalities in growth. Author concluded threshold levels of VC are > 200 ppm and that saturation level is 1,000 ppm. (R-34) OTHER ADVERSE EFFECTS Male CD-I mice were exposed to 10, 100, or 1,000 ppm VC for 2--8 \V (S' 6 H/D, 5 D/W. A slight increase in the spleen weight of mice was noted at the highest level. Spleens were obtained from these animals (4 mice/group after 2. 4, and 8 W exposure) and their lymphocytes cultured in vitro with or whhout the presence of phytomito- gens, phytohcmagglutinin (l'HA). and pokeweed mi togen (PWM), Relative blast formation and the UNA synthesis was measured by the incorporation of 3Hihymidinc in the cultured cells. The response to splenic lymphocytes to the phvtomitogens was increased sev eral fold by VC exposure. The effects were apparent (u 1,000 ppm VC after 2 W of exposure and at all levels of VC exposure after 4-8 W. The effects were generally more pronounced at 100 ppm VC exposure than those (w 1,000 ppm. In vitro culture of splenic lymphoctves from control or VC-exposed mice in the VC atmosphere did not show exhanccment of blast formation. Alteration of VC metabolism during the VC exposure in \ iso yielded results that indicated that metabolites of VC may be responsible for the stimu lation of lymphocyte transformation observed in splenic cultures. (R-50) Male, but not female, rats were sus ceptible to the acute hepatotoxic effects of inhaled VC. In phenobarhital-pretreated male rats, pyrazole, and SKK-525A. inhibitors of ethanol metabolism and mixed function oxidase system (MKO) activity, pro tected against tox. When disulfirsm and ethanol were given acutely, a slightly increased tox effect of VC was observed. Ethanol given in drinking water (10% for 7 D or an equivalent dose of 10 mLAg/D) did not, by itself, enhance VC hepatotoxicity in male rats, even though this dose regimen did slightly increase mixed function oxidase system activity. Apparently, inhibi tion of either liver alcohol dehydrogenase or micro somal oxidase protects rats from acute hepatotoxicity of VC. But, since pyrazole also has some inhibitory action on microsomal oxidases, it is possible that in hibition of reactions catalyzed by the mixed function oxidase system alone could account for protection against VC. (R-52) Single exposure to VC induced acute liver injury in rats whose mixed function oxidase system was stimulated by pretreatment with Aroclor 1254 or phenobarbital. The endoplasmic reticulum 34 DANGEROUS PRCPERT.ES OF INDUSTRIAL MATERIALS REPORT R&S 024696 was involved in the primary morphological injury, with denaturation of the smooth membranes. The increased hepatotoxicity of VC may involve their met abolic activation via free radical or epoxide interme diates. (R-53) Male rats were pretreated by gavage with the PCB mixture Aroclor 1254 (300 /itnol of PCB/kg) for 3 consecutive D. On D 4, these rats were exposed by inhalation (4 H) to 24,000 ppm VC. An imals were sacrificed 24 H later and acute hepatic responses were estimated by measurement of serumalamine alpha-ketoglutarate transaminase (SAKT) and by light microscopy. VC caused significant elevations of (SAKT) and produced severe degeneration and necrosis of liver. SAKT elevations (mg pyruvatc/mL serum-H) were as follows. Untreated controls: 0.17 0.01. PCB pre-treated, not exposed: 0,19 0.02. PCB plus VC: 2.58 1.25. (R-5) Absorption through the skin is minor. Calculations based on the percutaneous absorption of VC by Rhesus monkeys, indicate that a 6-ft, 90 kg man exposed to 7.000 ppm (dermal) for 2 H would absorb the equivalent of a 0.2 ppm, 8-H inhalation exposure. (R-l 1) VC reacted to a greater extent with denatured than with native herring sperm DNA, in vitro, in aqueous soln. How ever. VC failed to react with previously acylated calf thymus DNA in vitro in citrate buffer. (R-38) VC may be anaesthetic above 500 ppm. Handling of ma terial has caused circulatory and bone changes. (R-47) [I4C] VC, 0.5 mmole/kg in 0.5 mL/kg meth anol, was given ipr for 1-6 D to male Sprague-Dawley rats. After administration of the VC, hepatic' P-450 wras not significantly decreased after 1 dose, but pro gressively decreased after repeated doses. Hepatic glutathione and SGPT activity were unchanged and histologic examination of liver specimens obtained after 1,3, or 6 doses showed no liver necrosis. The amount of [14C]-material irreversibly bound to proteins in creased in various tissues during administration of the first 3 doses but then tended to decrease in the liver and in the kidney. (R-68) PHARMACOHNETICS/METABOUSM In rats inhaling 20,000 ppm [14C]-VC for 5 M7, [14C] was found in the liver, bile duct, digestive lumen, and kidneys 10 M from the beginning of the inhalation exposure. The amount of VC and its metabolites increased up to 3 H postexposure. Additional deposition sites showing [14C] activity included urinary tract, salivary glands, lacrimal glands, skin, and thymus. (R-l 1) "The tissue deposition of [14C]-vinyl chloride has been studied. Immediately after exposure by inhalation of 50 ppm VC for 5 H in a closed system, the % incorporated as [14C]-radioactivity per gram tissue was highest for kidney (2.13%), liver (1,86%), and spleen (0.73%). Forty-eight H after the beginning of exposure, la- beled material could still be found in these tissues. (R-l 1) Present data indicate that VC is metaljolized to an activated carcinogen electrophile that is capable of covalently reacting with nucleophilic groups or cel lular macromolecules. There is also ainple evidence that the mixed function oxidase (MFO) system may be involved in the metabolism of vinyl chloride. Rat liver microsomes catalyze the covalent binding of vinyl chloride metabolites to protein and nucleic acids. Chloroethylene oxide is thought to be. the primary microsomal metaljolite capable of alkylating these cel lular macromolecules. (R-l 1) The metabolism of VC may be inhibited by administering to rats, 320 mg/kg of pyrazole, 1 H prior to inhalation of the gas. Pyrazolc is an inhibitor of alcohol dehydrogenase and xanthine oxidase. Pretreaimcni of rats with ethanol, 5 mg/kg, 95%, also inhibited vinyl chloride metabo lism. (R-l 1) * When a mixture of VC/oxygen (1:1 v/v) was passed through a medium consisting of liver microsomes from phenobarbitone-pretreated mice, and an NADPH-generating system, a volatile metabolite was formed; this was trapped by its reaction with 4-(4-nitrobenzyl)pyridine, in ethylene glycol. (R-l3) Radioactivity from [ 14C]-labeled VC was covalently bound to protein and nucleic acids in vivo and in vitro, in the presence of rat liver microsomal fractions of highly purified cytochrome P-450 and NADPH-cytochrome P-450 reductase preparations. The ratio of bound to total nonvolatile metabolites increased from the in vivo to the microsomal to the purified system. In vivo, total metabolism of [14C]-labeled VC was not induced by phenobarbital pretreatment (0.1% in drinking water for 5 D) in rats exposed to either 10 ppm or 250 ppm of the [14CJ-VC; however, binding to protein and RNA was enhanced but only at the lower exposure level. In vitro, phenobarbital pretreat ment increased microsomal conversion of [14C]-VC to both total and bound metabolites. The metabolites of [14C]-VC metabolism in an in vitro liver micro somal fraction were distributed among many micro somal proteins and not localized to cytochrome P-450. (R-25) [ 14C]-Labeled VC was studied in rats. Rats exposed to 10 ppm VC for 6 H eliminated 68% of the absorbed radioactivity in their urine and 2%. (as VC) in the expired air over 72 H. Six-H exposures to 1,000 ppm resulted in 56% of the dose appearing in the urine, with 12% in the expired air as VC. The pulmonary excretion of VC followed first order ki netics with similar half lives at both treatment levels: 20.4 M @ 10 ppm and 22.4 M @ 1,000 ppm. (R-29) * The mechanisms responsible for and protecting against metabolic activation of VC were investigated in male Sprague-Dawley rats. Inhalation of 5% VC for 18 H was utilized. W'hen [14CJ-VC was incubated with hepatic microsomes, a f 14C]-labelod material be- IULY/AUG 1986 35 3BBSB3flEi5ffi^S5S*SSaus3sii^ A .i-.Wi-.W^M FEATURES came irreversibly bound to microsomal proteins. Binding required NADPH; was decreased by CO. SKF525A (2-diethylaminoethyl 2,2-diphenylvalerate hy drochloride, 75 mg/kg, ipr), or glutathione; and was increased by l,l,l-trichloropropenc-2,3-oxide (TCPO). Inhalation of a 5% VC atmosphere decreased hepatic cytochrome P-450 and glutathione. Pretreatment of the animals with DDT or phenobarbital had the fol lowing effects: increased in vitro irreversible binding to microsomal proteins measured in the presence but not in the absence of TCPO. and increased the in vivo loss of cytochrome P-450 during inhalation of the VC; and decreased the in vitro irreversible binding to 10.000 g supernatant proteins and the in vitro loss of glu tathione during inhalation of VC. (R-32) In rats exposed to 400 ppm VC for 6 H and then treated ipr with 20 mg 3,4-dichlorobenzenethiol, and again ex posed to 400 ppm VC for 12 H, S-2-(3,4-dichlorothiophenyl)acetic acid was detected in the urine. Au thors concluded that the formation of nucleophilic carcinogens from nonelcctrophilic precursors can be proven by the use of nucleophilic reagents, in vitro as well as in vivo. (R-33) Rats were exposed to 5,000 ppm of VC, via inhalation, 6 H/D, 5 D/W for 7 W. This VC was nonla!>e!ed. On the last day of repeated exposure, [14CJ-VC was used. The fate of the [14C]VC was compared in a group of rats exposed re peatedly, to a group exposed simultaneously for a single 6-H period to 5,000 ppm of [14CJ-VC. The routes and rates of excretion of (14C]-activity were the same for the two experimental groups. The ac tivity of microsomal enzymes, as reflected by aniline hydroxylase and p-nitroanisole-o-demethylase de rived from 9,000 g liver supernatants, was essentially the same in rats exposed repeatedly or in nonexposed control rats. Covalent binding to hepatic macromol ecules was greater in rats repeatedly exposed as com pared to those subjected to a single exposure. Thus, repeated exposure to VC does not induce its biotrans formation. However, the increase in hepatic macromolecular binding indicates that repeated exposure augments the reaction of electrophilic metabolites with macromolecules, and this may be expected to enhance potential toxicity including carcinogenicity. (R-37) After a 5-H inhalation exposure, rats metabolized [14C]-labeled VC much faster than carbon tetrachlo ride (CCl,,). The half-life was found to be 1.1 H. [14C]-VC bound covalently to tissue proteins, partic ularly in the liver. In kidney, small intestine, and other organs much less radioactivity was observed. (R-39) VC uptake rate and proportion metabolized by iso lated perfused rat livers remained constant for VC cones of 50--25,000 ppm. The overall VC conversion was 14.6% of the offered cone. ETOH, pyrazole, and 6-bromobenzothiazole inhibited VC metabolism by 12.7. 31.6. and 48.9%, respectively. Phenobarbital and fasting increased VC metabolism by 20.9 and 31.2%, respectively. VC had no effect on marker enzymes, but slight liver damage occurred after increased met abolic VC transformation. Mixed function oxygen ation was apparently involved in VC metabolism. (R-42) The metabolic elimination of VC in Rhesus monkeys is a dose-dependent, saturable process, as in rats. Below 200-300 ppm of VC in atm, elimination obeys a first-order law; the clearance rate is much closer to that found in man than that for rats, mice, or gerbils. The maximal velocity of metabolic elimi nation of VC at high cones in Rhesus monkeys is only about half that of rats when related to kg body weight. Thus, the Rhesus monkeys mimic the quantitative as pects of VC metabolism better than rats or mice do. (R-46) In the presence of hepatic microsomes, VC produced a Type I difference spectrum and stimu lated coinhibitable NADPH consumption. A compar ison of the binding and Michaelis parameters for the interaction of VC with uninduced phenobarbitol-, and 3-methylcholanthrene-induced microsomes. indicates that the binding and metabolism of VC was catalyzed by > 1 type P-450 cytochrome, but predominately by cytochrome P-450. Metabolites of VC from this en zyme system decreased the levels of cytochrome P450 and microsomal heme, but not cytochrome 65 or NADPH-cytochrome c reductase, in vitro. (R-51) Thiodiacetic acid and S-(carboxy-methyl) cysteine were found in the urine of rats after a 48-H exposure to 1,000 ppm VC. The structures of both compounds were clarified by means of gas chromatography/mass spectroscopy. Chloroethylene oxide, chloroacetaldehyde, and chloroacetic acid are assumed to be inter mediates in VC metabolism. Compounds that can be transformed to one of these alkylating agents in vivo may also lead to renal excretion of thiodiacetic acid and S-(carboxy-methyl)cysteine. (R-54) Strong evi dence has been obtained that the biotransformation of VC involves microsomal mixed-function oxidase, i.e., the metabolic activation of VC by a liver micro somal system from rats, mice, or humans, and de pends on the presence of necessary cofactors for a NADPH generating system and oxygen. Cioroeihylene oxide rearranges to 2-chloroacetaldehyde spon taneously. In aqueous soln @ pH 7.4 and 37 C, the epoxy compound has a half-life of 1.6 M. Chloroeth ylene oxide is capable of reacting with glutathione and with nucleophilic groups of macromolecules. N-acetyl-S-(2-hydroxyethyl)cysteine (a major metabolite), S(carboxymethyl)cysteine and N-acetyl-S-vinyl cysteine are metabolites of VC after inhalation or oral admin istration in rats. Chloroethylyene oxide and chloroacetaldehyde alkylate to 4-(4-nitrobenzyl)pyridine and adenosine. Rat liver microsomes catalyze the co- 36 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT R&S 024697 * CHEMICAL REVIEW valent binding of [14CJ-VC to proteins and nucleic acids. (R-57) Ethylene and its analogues (i.e., VC, vinyl bromide) are converted to the corresponding ethylene oxides by cell-free preparations from mature cotyledons of the broad bean (Vicia faba). VC acts as a competitive inhibitor in the first-order oxidation of ethylene. The measured Ki where Ki (gas) = 3.19E6 M; Ki (liquid) = 1.5E-6M. (R-73) Postmitochondrial supernatants of liver, kidney, and lung tissue from rats and mice that had been exposed to 20% VCM were assayed for their capacity to generate VCM metabolites mutagenic for Salmonella typhimurium TA1530. Data indicate that the liver efficiently con verted VCM into mutagenic metabolites. (R-60) After oral administration of VC to rats and rabbits, maxi mum blood level peaks occurred 4-5 H after high dose and 3--4 after lower doses. No VC was observed in blood 24 H later. Liver cytochrome P-450 was el evated by higher VC doses. EEGs in rats were altered following oral administration of VC and the alteration varied with sex. VC @ 45 and 135 mg/kg altered learning ability. The compound (gj 12 mg/kg had im munosuppressant activity in rabbits. (R-36) ENVIROMENTAL IMPACT AIR POLLUTION High. ACTION LEVELS Evacuate area. Enter from up wind side after gas levels have subsided. Notify fire and air authority. Remove ignition sources. IN SITU AMELIORATION Use carbon or peat on dissolved portion. Seek professional environmental engineering assistance through EPA's Environmental Response Team (ERT), Edison, NJ, 24-H No. (201)3216660. AVAILABILITY OF COUNTERMEASURE MATERIAL Carbon: water treatment plants, sugar refineries. Peat: nurseries, floral shops. DISPOSAL METHOD Dilute to 1% soln and remove .phenol inhibitor as Nal. (1) Pour onto vermiculite, sodium bicarbonate, or a sand-soda ash mixture (90/10). (Add slaked lime if fluoride is present.) Mix in paper boxes, place in incinerator, cover with scrap wood and paper, ignite with excelsior train. Stay upwind. Or dump in closed incinerator with afterburner. (2) Dis solve in flammable solvent and spray in incinerator firebox equipped with afterburner and alkali scrub ber. DISPOSAL NOTIFICATION Local air authority. MAJOR WATER USE THREATENED Recreation. PROBABLE LOCATION AND STATE OF MATERIAL Colorless gas. Heavy vapors will cling near ground. Some will dissolve. Polymerizes readily in air or sun light. WATER CHEMISTRY Subject to polymerization. COLOR IN WATER Colorless. ENVIRONMENTAL FATE: TRANSPORT PROCESSES-- SORPTION Sorption measurements of VC by four basic food constituents (water, corn oil, casein, and sucrose) were conducted. For water, oil/water emulsions, and casein, it was found that the partition coefficient val ues (defined as the equilibrium cone of VCM sorbed over the equilibrium VCM in headspace) were fairly constant within the sorbate (VCM) cones studied. At 24 C. the partition coefficient values for oil, casein, and water were 23.7E3, 11.7E3, and 2.IE3, respec tively. Sucrose did not sorb detectable amounts of VCM under the experimental conditions employed. (R-75) ENVIROMENTAL FATE: MICROBIAL EFFECTS Serum bottles (125 mL) were used in the anaerobic toxicity assay (ATA). This allowed gas production to be mea sured periodically with a syringe and analyzed. The bottles were purged w'ith 70% Nj and 30% CO_>. and then the following were added: 30 mL of a nutrient anci buffer soln (NaHCOu, 5.7 g/L, and FeCL, 0.37 g/L); 20 mL of sludge from a laboratory digester to serve as a "seed" of anaerobic microorganisms; and 0.100 mL of ethanol to serve as a substrate. VC was added to the ethanol in various cones prior to its ad dition. The bottles were incubated (g> 35 C, and a reduction in the rale or extent of gas production in chemical-containing samples in comparison with con trols served as an indicator of inhibition. Inhibition was quantified approximately by determining the cone of VC that causes a 50% reduction in total gas pro duction over a fixed period of time (50% inhibition). Semicontinuous bioassays were conducted using con tinuously stirred 1.5-L digesters, operated at a 15-D dentention time, and a temperature of 35 C 1C. The digesters were initially seeded with digested mu nicipal sludge. Primary sludge was used as feed. Each day 100 mL of digested sludge was removed, and an equal amount of feed sludge was added. 4, 16, or 64 mg/L of VC were added to ethanol and 0.1 mL of the mixture was added each day prior to feeding. Digester performance was evaluated from daily gas production and routine analysis of COD, total and volatile solids, volatile acids, pH, alkalinity, and gas composition. Batch JULY/AUG 1986 ^ i '4 V-.J.V '`..Lvj f o'-V-'T-w- R&S 024698 Yf FEATURES results for VC indicate that 5.4 mg/L was marginally inhibitory and 32 mg/L was strongly inhibitory, al* though some acclimation did occur. A cone of ap proximately 40 mg/L was required for 50% inhibition of 3.5 D. Seniicontinuous digestion with VC did not result in adverse digester performance, even at the highest cone of 64 mg/L. Volatile acids were slightly higher with VC (a1 16 and 64 mg/L than in the con trols, but no significant signs of stress were apparent. (R-99) ENVIROMENTAL FATE: OTHER PROCESSES The level of VC found in potable water as a result of PVC piping is directly proportional to the level of residual VC in the pipe- Pipe containing < 1.0 ppm residual showed no VC in the water with a test sensitive to 2 ppb. TOXICOLOGIAL DATA MUTAGEN DATA mmo-sat 2,000 ppm/48H mma-sat 2 pph ntma-esc 10,600 /imol/L dnr-esc 100 pg/plate sln-dmg-ilil 1 pph sln-dmg-orl 850 ppm mma-sme 25,000 ppm mre-sme 48 mmol/L/3H mmo-ssp 130 ppm mma-ssp 16 mmol/L/30M mrc-ssp 48 mmot/L cyt-man-unr 25 ppm/lOY cyi-hmn:hla 10 mmol/L otr-rat-ihl 2,000 ppm/14W-I dnd-rat-orl 18 g/kg/2Y-C oms-rat:lvr 1 nmol dnd-rat-ihl 2,000 ppm dnd-rat-ihl 203 ppm/5H dns-rat:lvr 2,100 pmol/L dni-rat-ivn 9,500 pg/kg cyt-rat-ihl 150^tg/m*/14W*G hma-rat/sme 1 pph/24H-C mnt-rnus-ihl 5 pph/4H hma-mus/ssp 700 mg/kg hma-mus/sme 700 mg/kg mma-hamdng 20 pph/5H cyt-ham-ihl 12,500 ppm/6H cyt-ham-mul 600 mg/kg CODEN BBRCA9 63,363,75 ATSUDG (4).63,80 BCPCA6 24,`>013,75 M U REA V 54.101.78 MURF.AV 57.307.78 EVSRBT 24,175,81 MUREAV 91.381.81 MUREAV 40,85.76 CMMUAO 5,25,78 MUREAV 40,85,76 IARCCD 12.505.76 MUREAV 51.271.78 TXCYAC 9,21.78 ARTODN 47.71,81 CBINA8 22,21 1.78 NATUAS 257,134,75 JCROD7 94,139,79 CB1NA8 37.219.81 CRNGDP 5,1629.84 CBINA8 17,239,77 GISAAA 43(7), 1 1 1.78 MUREAV 91.381.81 MUREAV 75,191.80 MUREAV 40,85.76 TOERD9 3,131,81 MUREAV 67.173.79 ARTODN 45,1,80 MUREAV 53,187.78 scc-ham-ihl 12.500 ppm/6H msc-hani:ovr 10 pph ART ODN 45.1,80 EVSRBT 25,91,82 TERATOGENIC DATA ihl-man TCLo:30 mg/in1 (5Y male) ihl-rat TCl,o: 1.000 ppm/6H (55D male) ihl-rat TCI.o:500 ppm/7H (6*151) Pteg) ihl-rat TCI.o: 1,500 ppm/24H (I-9D Pteg) ihl-rat TCl.o:500 ppm/7H (6-15D preg) ihl-rat TCLo:2,500 ppm/7H (6-151) preg) ihl-rat TCLo:250 ppm/6H (551) Pteg) ihl-mus TCLo:30,000 ppm/6H (51) male) ihl-tnus TCLo:500 ppm/7H (6-15D preg) ihl-rbt TCl.o:500 ppm/7H (6-18D preg) CODEN GTPZAB ' 24(5),28.80 JTEUD6 3,965,77 TXAPA9 33.134.75 TXCYAC I 1.45.78 EVHPAZ 41,171,81 EVH 1*AZ 41,171.81 JTEHD6 3.965.77 EVHPAZ 21,71.77 EVHPAZ 41.171.81 EVHPAZ 41.171.81 TUMORIGENIC DATA ihl-man TDLo:200 ppm/14Y-l orl-rat TDI.o:3.463 mg/kg/52W'-l ihl-rat TCI.o: 1 ppm/4H/52W-I ihl-rat TCLo: 10.000 ppm/4H (12- 181) preg) irp-rat Tl)Lo:21 mg/kg/65W-I scu-rat TDLo:21 mg/kg/67W-I ihl-mus TCl.o:5t) ppm/30\V-I ihl-ham TCLo:50 ppm/4H/30W-I ihl-rat TC:50 ppm/7H/26\V-C ihl-rat TC:100 ppm/7H/26\\`-C ihl mus TC:50 ppm/47W-I orl-rat TD:34 gm/kg/3Y-I ihl-mus TC:50 ppm/0H/4\V-l ihl-mus TC:50 ppm/4H/30U'-I ihl-rat TC:250 ppm/2Y-I ihl-hmn TC:300 mg/m'AV-C ihl-rat TG:5 ppm/4 H/52W-I ihl-rat TC:50 ppin/6H/43VV-I CODEN VAPHDQ 372.195.76 EVHPAZ 41.3,81 EVHPAZ 41,3,81 CSHCAL 4,119,77 APDCDT 3,216,76 APDCDT 3.216,76 ANYAA9 271.431.76 APDCDT 3.216.76 TXAPA9 68,120.83 1XAPA9 68.120.83 JTEHD6 4,15,78 EVHPAZ 21,1,77 JTEHD6 7.909.81 CSHCAL 4.1 19,77 AANl.AW 56,1.74 GTPZAB 26( 1 ),28.82 EVHPAZ 41.3,81 JTEHD6 7,909,81 TOXICITY DATA orl-rat LD50;500 mg/kg ihl-gpg LCLo;20 ppm/30M CODEN DOU'CC* 85DVA7 -.1160.38 DATA REFERENCES Agricultural Chemical Turnorigen Mutagen Teratogen Toxicology Re\ iew Toxicology Review CODEN FAZMAE 18,365.74 J'l EHD6 1(1),47.75 38 DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT H&S 024699 R&S 024700 CHEMICAL REVIEW Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Toxicology Review Carcinogenic Review: Human Positive Carcinogenic Review: Animal Positive Carcinogenic Review: Human Suspected Carcinogenic Review: Animal Positive TLV: Human Carcinogen TLV: TWA 5 ppm OSHA: Cancer Suspect Agent OSHA Standard:air:TWA 1 ppm: CL 5 ppm/15M DOT:Hazard:Klammable Gas; Label:Flammable Gas Occupational Exposure to Vinyl Chloride Recommended Standard:Air:TWA 1 ppm; CL 5 ppm/15M NTP Fourth Annual Report on Carcinogens, 1985 NIOSH Manual of Analytical Methods, 3rd Ed. See: Method 1007 NIOSH Current Intelligence Bulletin as, 1978 CM I VAS I0(3).49.73 CHWEAP 70,5,74 CANCAR 39.1792.77 MUREAV 32(2),93,76 ZHPMAT 166.113.78 BNYMAM 54.413.78 ABM HAM 35, 585.77 CBINA8 22,117.78 GTPZAB 20(4),46.76 VHTODE 22,31.80 MUREAV 41.131.7 I ARC** 19.377.7 1ARC** 7.291.74 1ARC** 7.291.74 I ARC** 19.377.79 DTLVS* 4,427.80 DTLVS* 4,427.30 CFRGBR 29.1910.1017.31 FEREAC 40.23073.75 CFRGBR 49.172.101.S4 Reported in EPA 1 SCA Inventory. 1983 EPA Genetic Toxicology Program, January 1984 EPA TSCA Section 8(e) Status Report 8EHQ*0680-0345;8EHy0982-0457:8EHQ-0378-0104 Meets Criteria for Proposed OSHA Medical Records Rule FEREAC 47.30420.82 RECENT FEDERAL REGISTER CITATIONS CITATION NUMBER 48.207.1088 (48FR49408rf. 1025-83) PROPOSED RULE Revision of 40CFR415, Envi ronmental Protection Agency, Clean Water Act; in organic chemicals manufacturing point source cate gory; effluent limitation guideline, pretreatment standard. New Stationary Source Performance Stan dard; comments solicited by 12-27-83: toxic pollutant. CTTATION NUMBER 48.209.1088 (48FR498081T. iO27-83) FINALHULE.PROPOSEDRULERevision of40CFR439, Environmental Protection Agency, Clean Water Act; two documents, pharmaceutical manufacturing point source category: effluent limitation guideline, pretreatment standard. New Stationary Source Perform ance Standard; effective date 12-12-83 with excep tions; comments solicited by 12-27-83 for proposed rule. (41FR50(')7(), 42FR6814. 47FR53584, 44FR4450, 44FR50732, 47FR49176) CITATION NUMBER 48.223.1088 (48FR523801T, 1117-83) FINAL RULE Revison of 40CFR465. Environmen tal Protection Agency. Clean Water Act; effluent lim itation guideline, pretreatment standard. New Sta tionary Source Performance Standard, coil coating point source category, canmaking subcategory; effec tive date 1-2-84. (48FRG268) REFERENCES 1. Lewis, Richard J. el al. (Ed.). Oct. 1980. Registry oi Toxic Effects of Chemical Substances (RTECS). Mi crofiche Edition. DHHS (NIOSH). Publ. No. 81-116- 1. 2. Drevon, C. et al. June 1979. Mutagenicity of vinyl chloride, vinylidiene chloride and chloroprene in V79 Chinese hamster cells. Aful. Res. 67:173-182. 3. Fleig. I. et al. April 1978. External chromosome stud ies undertaken on persons and animals with vinyl chlo ride illness. Mvt. Res. 53:187. Agrelo. C. 1978. The effect of carcinogens on the nuclear size of HeLa cells. Toxicol, 9:21--27. Connelly, R.B. et al. 1977. Acute hepatotoxicity of ethylene, vinyl Huoride, vinyl chloride and vinyl bro mide after Aroclor 1254 pretreatment. Toxicol. Applied Pharmacol. Verschuereo, K.. 1977. Handbook ofEnvironmental Data on Organic Chemicals. Van Nostrand Rcinhold Co.. NY. Hawley. G.G. 1977. The Condensed Chemical Dictionary, 9th Ed. Van Nostrand Reinhold Co.. NY. JULY/AUG 1966 39 FEATURES 8. Key, M,, A. Henschel, et al. (Eds.). June 1977. Occu pational Diseases, a Guide to Their Recognition. U.S. Department of Health, Education and Welfare. Puhlich Health Service. GDC, NIOSH. DHEW/NIOSH Publ. No. 77-181. Sax, N.I. 1984. Dangerous Properties of Industrial Ma terials, 6th Ed. Van Nostrand Reinhold Co., NY. U.S. Dept, of Transportation. Oct. 1978. Chemical Hazard Response Information System (CHRIS). US Coast Guard. Washington. DC. US EPA. Oct. 1980. Ambient Water Quality Criteria for Vinyl Chloride. NTIS. Springfield. VA. EPA 440/580-078. Viola, P. 1970. Pathology of Vinyl Chloride. Medita del Lavora 61:174. From CAS: 72:85988. Barbin, A, Aug. 1975. Liver-microsomc-inediatcd formation of alkylating agents from vinyl bromide and vinyl chloride. Biochem. Biophys. Res. Comm. 63(2):363-370. NIOSH. Dec. 1974, Current intelligence bulletin. J. Occup. Med. 16:809. John, J.A. el al. 1977. The effects of maternally in haled vinyl chloride on embryonal and fetal devel opment in mice, rats and rabbits. Toxicol. Applied Phar macol. 39:497. Suzuki Y, 1978. Pulmonary tumors induced in mice by vinyl chloride monomer. Env. Res. 16:285. Vazin, A.N. et al. 1968. Pathogenic effect of chronic exposure to vinyl chloride on rabbits. Medica del Lavora 31:369-372. From CAS:69:50599. 18. Vazin, A.N. et al. 1969. Changes in cardiac activity of rats chronically exposed to vinyl chloride vapors. Med ico del Lavora 32:220-222. From CAS:70:113464. 19. Maltoni, C. 1977. Recent findings on the carcino genicity of chlorinated olefins, Env. Health Perspect. 21:1-6. 20. Loprieno, N. 1976. Evaluation of the genetic effects induced by vinyl chloride monomer (VCM) under mammalian metabolic activation: Studies in vitro and in vivo. Mut. Res. 40:85. 21. Speck, W. et al. 1978. An evaluation of the prophage- induction (inductest) for the detection of potential car cinogens. Mut. Res. 54:101-103. 22. Bartsch, H. et al. 1975. 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Articles of general interest: Vinyl chloride: Metabolism. Food Cosrnrt. Toxicol. 17:403. 30. Feron, V.J. et al. June 1979. One year lime sequence inhalation toxicity study of vinyl chloride in rats. III. Morphological changes in the liver. Toxicol. 13:143-154. 31. Feron. V.J. and R. Kroes. June 1979. One year time sequence inhalation toxicity study of vinyl chloride in rats: Morphological changes in the respiratory tract, ceruminous glands, brain, kidney, heart and spleen. Toxicol. 13:131. 32. Pcssayre, D. et al. 1979. Formation and inactivation of a chemically reactive metabolite of vinyl chloride. Toxicol. Applied Pharmacol. 49:505-515. 33. Mueller, G.et al. 1978. In vivo trapping of a vinyl chloride metabolite by means of 3.4-di-chlorobcnzenethiol. Int. Arch. Occup. Env. Health 42:137. 34. Ibrahim, F. 1978. Effect of vinyi chloride on me tabolites of germinated seeds. Dissertation Abstr. 3282. Volume 39. 35. Anderson, H.A. et al. 1978. Levels of CEA among vinyl chloride and poly(vinyl chloride) exposed work ers. Cancer 42:1560-1567. 36. Hollo, A. et al. 1978. Gas chromatographic determi nations of vinyl chloride levels in the blood of treated laboratory animals and the effect of VCM on different toxicological parameters. Proc. Hungarian Ann. Mtg. Jar Biochem. 18.97-98. From CAS:90:17202. 37. Watanabe, P.G. et al. 1978, Comparison of the fate of vinyl chloride following single and repeated exposure in rats. Toxicol. Applied Pharmacol 44(2):391-399. 38. Maly, E, 1978. On the reaction of vinyl chloride with DNA. Internat'l. Congress Series--Excerpta Medica 440:270-273. 39. Bolt, H, andJ.G. Filser. 1977. Irreversible binding of chlorinated ethylencs to macromolecules. Env. Health Perspect. 21:107-112. 40. Radike. M. et al. 1977. Effect of ethanol and vinyl chloride on the induction of liver tumors: Preliminary report. Env. Health Perspect. 21:153--155. 41. Lee, C.C. et al. 1977. Inhalation toxicity of vinyl chlo ride and vinylidene chloride. Env. Health Perspect. 21:25-32. 42. Radwan, Z. and D. Henschler. 1977. Uptake and rate of metabolism of vinyl chloride by the isolated per fused rat liver preparation. Internat'l. Arch. Occup. Env. Health 40(2): 101-1 10. 43. Lee, F.I.etal. 1977. Screening for liver disease in vinyl chloride workers. Br.J. Indus. Med. 34(2): 142--147. 44. Maricq, H.R. et al. 1976. In vivo skin capillary abnor malities in vinyl chloride workers. Microcirculation [Proc. World Congress], 1st, 1975. 2:235-237. 45. Wisniewska. J. et al. 1980. Mono-oxygenase activity and ultrastructural changes of liver in the course of chronic exposure of rats to vinyl chloride. Internat'l Arch. Occup. Env. Health 46(3):241-249. DANGEROUS PROPERTIES OF INDUSTRIAL MATERIALS REPORT 33 in o N> J* -4 O ^W l.u .`fcjut>:4 R&S 024702 46. Buchter, A. et al. 1980. Pharmokinetics of vinyl chlo ride in the Rhesus monkey. Toxicol. Letters 6(J):33-36. 47. NIH-EPA. 1981. 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