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I 9*ul~tLt'uzl B t O - T E S T ^ab&iaiivues, jttc. SEVEN-MONTH STATUS SUMMARY TO MANUFACTURING CHEMISTS ASSOCIATION CHRONIC VAPOR INHALATION TOXICITY STUDY WITH VINYL CHLORIDE (ETHYLENE DERIVED) IN ALBINO RATS, ALBINO MICE AND GOLDEN HAMSTERS JUNE 19, 1974 IBT NO. 663-03222 I. Introduction - A chronic vapor inhalation toxicity study with Vinyl Chloride (Ethylene Derived) was initiated on September 10, 1974. A summary of all data obtained through the seventh month of exposures is reported herein. i <r i I * 4 J 1 j 2 j ; 1 J 1 j i j j * i i KSV 0003174 9ruLuiuzl B I O - T E S T J.zbvuilo'XieJ., 9*tc. 2 II. Summary After seven months of inhalation exposures, dose related gross and histopathologic findings have been observed in all test levels of the mice. These findings have included test material related lesions consisting of alveologenic adenomas of the lung, hemangiosarcomas of the liver and malignant mammary tumors. Studies of other parameters including behavioral reactions, body weights and mortality have not revealed definite dose related responses to inhalation of Vinyl Chloride. Respectfully submitted. INDUSTRIAL BIO-TEST LABORATORIES, INC. Kenneth J. .Schadeberg Senior Group Leader Inhalation and Pharmacology Report approved by: Manager Decatur Research Laboratories M .4-. Keplinger, Ph.D. Manager, Toxicology / lb RSV 0003175 B 1 O - T E 5 T Jahx'ialMiei, 9*tc~ 3 III. Chamber Concentration Data The daily range and mean of the Vinyl Chloride concentrations in each test chamber are shown in Table I. The overall average daily vapor concentrations were calculated to be 49.5, 201, 2548 and 2487 ppm for the TE-I through TE-IV chambers, respectively. RSV 0003176 Day Number I 2 3 4 5 8 q in 11 12 lA 1 h 70 1 7 Ccn 1A iq 7? O UJ 0 u oc. 26 TABLE I TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data eExxppoosure Number TE-I RanRe 1 39 55 2 42 51 3 45 53 4 45 54 5 50 56 6 40 62 7 51 63 8 41 61 9 49 65 10 38 77 11 45 69 12 42 63 13 52 61 14 56 64 15 41 66 16 43 62 17 47 78 18 44 55 19 43 54 20 55 69 Mean 43 48 50 5L 52 57 53 56 58 62 60 60 58 59 47 49 60 51 50 62 Chamber Concentration (ppm) 'l E-Il RanSS______ Mean TE~1I1 Ran_______ Mean 130 164 170 24 182 128 186 115 188 174 160 54 170 84 96 196 202 178 194 200 180 190 214 162 237 332 260 280 274 198 224 266 228 200 178 222 224 208 220 264 173 181 207 87 218 194 199 164 242 186 202 156 207 162 160 211 219 201 214 242 1820 1700 1290 1190 1160 1600 1990 2240 2010 1150 2230 2400 2750 1870 2200 1990 2470 2220 1610 1690 2610 2600 2550 3600 3100 2850 2610 2840 2650 2900 2690 3100 2480 2666 2630 2510 3000 2530 2830 2740 2510 2548 2098 2540 2202 2401 2475 2555 2283 1770 2510 2653 1972 2544 2556 2391 2922 2356 2690 2488 Range 2030 2240 2140 1980 1900 2000 2300 1850 1970 2390 3010 2430 1160 1150 2320 2540 2370 2570 1810 2390 2880 2600 2590 2490 2580 2480 2980 2310 2690 2930 3570 2920 1920 2400 2610 2640 2560 2980 2150 2650 Mean 2355 2467 2261 2293 2330 2329 2675 1915 21922481 3236 2733 1664 1794 2545 1 d. 2531 2777 1969 2510 ~rr-n*-*F7 1 5 3 1 * 0 1 8 Sl 3 i - O I fl 7*?KP * T ,C *c Day ?Q tn \i X2 'i'i Ik 7R IQ 4f\ 42 73 44 a< dk o A7 o o cn U) - c 1 OD CO C0 54 TABLE 1 continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Exposure Number TE-I Ranee 21 48 66 22 47 63 23 31 51 24 42 47 25 29 58 45 60 27 46 58 2B 48 58 29 42 55 30 45 52 31 45 60 32 41 58 33 39 5b 3 4 47 53 35 46 55 36 40 62 37 43 51 28 55 39 38 49 40 45 57 Mean 58 56 46 45 51 47 55 52 43 50 52 48 44 50 54 60 50 38 45 49 Chamber Concentration (ppm) TE-II TE-III Ranee Mean Ranp:e Mean 192 248 219 216 340 265 200 256 220 196 232 106 172 232 212 92 280 203 210 242 225 168 190 184 188 216 209 204 212 209 106 238 180 98 190 177 178 240 215 168 206 200 210 224 217 166 198 171 172 214 190 190 220 198 182 212 193 134 238 278 1090 2000 1900 2120 2200 1680 1600 2210 1970 1740 2070 1810 1900 1850 2180 1670 2220 2010 1980 1610 2490 2870 2770 3960 2840 2640 2600 2830 2770 2800 2900 2570 3010 2790 2600 2510 2610 2750 2460 2590 1561 2567 2659 2855 2496 1899 2337 2587 2474 2141 2659 1920 2190 2002 2377 2083 2451 2225 2208 2018 TE-IV Range Mean 2400 2030 1960 2020 1360 1530 . 2670 2070 2590 2600 2610 2250 1890 1980 2050 2310 3160 3090 2530 2070 1560 2710 2600 2900 1920 2000 3350 3510 2890 2930 3040 2610 2190 2560 2350 2920 3670 4090 2740 2540 2488 2105 2295 2441 1655 1799 2998 3356 2686 2750 2891 2564 1920 2379 2213 2692 3307 Jbbb 2638 2525 ' , "Was***. TABLE I continued py- s 2 1 O I 9'i TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Day Exposure Number TE-I Ranee Mean 57 41 58 42 59 43 44 A1 45 64 46 65 47 66 48 67 49 68 50 71 51 72 7> <s> 52 73 <L 53 74 54 75 55 78 o CP 56 79 rsi 57 86 O 58 81 59 82 60 47 59 48 - 56 51 59 46 80 43 61 42 58 114 136 48 114 43 60 24 39 Eouip. failed 42 51 45 58 Holiday Holiday 44 60 48 74 45 60 28 49 42 47 53 54 56 63 52 53 119 84 52 32 - 48 49 48 56 54 46 45 Chamber Concentration (ppm) TE-II TE-III Range Mean Ra nge Mean 96 188 128 148 248 219 196 262 238 200 240 211 178 220 195 188 210 199 172 452 298 146 416 255 178 240 206 96 124 105 --194 226 210 178 211 202 1950 2240 2400 2110 2040 1690 1140 2240 2280 2180 - 2380 2310 2900 2660 3100 2680 2780 2690 1750 4000 2590 2460 2700 2650 2686. 2579 2835 2344 2640 1968 1659 2910 2498 2348 " 2565 2516 TE-IV Ra nge Mean 2210 2610 2900 1560 1920 2040 2550 1160 2500 1520 2410 2340 2630 3220 3310 1990 2340 2660 2670 1940 2610 1700 2560 2590 2310 2616 3203 1752 2149 2281 2569 1754 2573 1612 2528 2460 180 229 196 304 390 347 220 364 243 198 248 218 214 262 240 2190 1740 2020 2060 2080 2700 2400 2760 2500 2580 2445 2141 2404 2333 2229 2320 1375 1940 1940 2100 2620 1870 2580 2560 2800 2525 1576 2231 2306 2388 . ( '*'C `w y n n p T 1 S 3 1 l Q0 Day Number 85 86 87 88 89 92 93 94 95 96 99 100 75 (/> 101 < 102 O 103 C o 106 tn 107 UJ 108 o 109 no TABLE I continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Exposure Number TE-I Range 61 29 47 62 47 - 54 63 46 80 64 35 50 65 50 61 66 28 53 67 37 56 68 40 45 69 32 46 70 37 47 71 29 31 72 27 52 73 * - 74 * - 75 38 55 76 Holiday 77 Holiday 78 37 55 79 36 47 80 36 50 Mean 43 49 60 48 53 42 48 42 39 43 29 36 -- 51 46 43 44 Chamber Concentration (ppm) TE-I1 TE-III Range Mean _______ Range Mean 148 216 191 200 220 210 98 224 185 174 220 211 208 232 214 136 192 172 110 302 209 206 238 216 170 216 190 170 230 199 258 310 277 168 310 256 -- 1620 2J 60 400 2080 2220 1200 1600 2080 2000 1880 2740 1900 2280 2560 1960 2380 2540 2980 2900 3500 2840 2810 3940 3340 2077 2380 1659 2246 2394 1963 2401 2722 2367 2448 3185 2499 180 230 203 "" -- 228 260 247 158 248 235 166 242 201 1680 2620 2585 1800 2120 ,1960 2580 2600 3020 2397 2409 1448 TE-IV Range Mean 1220 2500 2500 2940 2320 2720 2520 2680 2320 2520 Equip .failure 2000 2680 Equip failure 2220 2500 1880 2810 3280 3680 2440 3340 2306 2725 2457 2506 2428 - 2503 - 2328 2448 3516 2578 2210 2640 2470 2360 2240 2200 2900 2560 2680 2633 2464 2400 * Unable to run exposures due to weather. mm ituauma Nur 113 114 115 116 117 120 121 122 123 124 127 128 129 130 131 134 135 136 TABLE I continued TEST MATERIAL; Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Exposure TE-I Number_______ Range 81 21 50 82 Holiday 83 37 - 54 84 26 55 85 Equip .failure 86 45 46 87 32 54 88 48 60 89 20 58 90 39 52 91 37 55 92 39 58 93 43 55 94 42 63 95 35 70 96 52 77 97 25 48 98 40 43 Mean 42 47 47 45 44 54 44 46 47 51 50 53 53 68 38 41 Chamber Concentration (ppm) TE-ll TE-III Range Mean Rang e Mean 180 244 211 1620 2520 2306 164 260 201 178 214 200 2180 1980 2500 2780 2385 2393 168 232 199 160 250 184 140 204 173 202 388 295 124 180 175 196 200 197 186 226 200 136 266 230 180 228 201 190 250 220 20B 262 230 135 248 186 118 200 172 1960 2200 2500 2410 1980 1600 1660 1600 2680 1740 2180 1560 2080 2960 2820 2920 3960 2600 2560 2500 2620 3100 2800 2960 3480 2800 2565 2513 2664 3090 2396 2414 2191 2145 2883 2259 2624 2983 2410 TE-IV Range Mean Equip . failure - 1780 2100 2240 2380 2006 2176 2200 2840 2529 2040 2800 2390 1040 1120 1083 2000 2780 2377 2120 2280 2236 Equip .failure - Equip,, failure Equip.. failure -- One sample on Iy2900 1940 3000 2333 1700 2160 2180 2080 3660 3513 1860 2700 2170 w f `f t w p u y v i S 3 1 - 0 19i Day 137 138 1 a1 1 4? \ 43 1 44 1 4ft 1 4ft 1 40 \ *>(1 1 ft] \O 1^ 1 1 ft? 1 kQ 1 kl 1 kk ) t.ft 169 TABLE I continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data co O m on Exposure Number TE-I Ranee Mean Chamber Concentration (ppm) TE-II TE-III Ranee Mean Ranp:e Mean TE-IV Ran&S___________ Mean 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 73 115 C 11 h O 117 O 11 ft O * 119 120 N> 121 41.0 31.9' 19.0 32.5 42.0 31.5 38.5 22.0 29-5 35.0 32.0 41.5 45.0 43-0 35.0 38.0 47.0 42.5 28.0 40.0 37.0 25.0 39-5 .. - 63.0 37.4 100.0 52-0 49-0 55.5 70-0 32.5 70.0 58.0 62 .0 110.0 66.0 61 .0 58.0 60.5 60.0 67.0 60.5 58.0 55.5 66.5 51 -0 50.0 35.2 46.3 48.8 47.8 51.0 49.0 29.6 49.9 49.3 44.0 58.9 52.3 49.7 54.1 57.7 54.3 57.1 46.1 49.4 50.3 53.0 48.0 176 252 222 158 200 187 152 266 189 104 306 202 180 296 222 190 224 205 154 240 196 180 212 193 156 314 220 90 288 200 150 234 193 170 252 198 178 260 216 164 246 198 160 258 222 176 212 200 160 210 195 104 252 203 178 260 202 164 214 197 178 214 184 172 194 187 158 264 213 1600 2000 1860 2620 2080 2340 2320 2240 2140 1780 1280 2300 2620 2300 2220 2220 2180 1460 2240 2280 2280 2400 24 00 3840 2643 2620 3540 2900 2920 2980 2640 3460 2920 2800 2800 2800 2900 2700 2820 2700 2840 3020 2920 2640 2740 2740 -------- ---------------------------______________---..........................------------------------------- 2745 2354 2346 3100 2580 2546 2408 2393 2614 2566 23 49 2497 2683 2573 2519 2392 2538 2592 2535 2922 2428 2529 2543 - 1920 1200 1740 2400 1820 2200 2220 2120 1880 2080 2060 2140 2300 2400 2420 2340 1960 2340 2100 2370 2120 2380 2100 3600 3440 2600 3320 2620 2820 3160 2270 2040 2860 3000 2700 2900 3240 2560 26B0 2660 3080 2400 2540 2740 2480 3020 2875 2352 2046 2676 2306 2494 2542 2245 1946 2534 2529 235 j 2700 2706 24b / 2502 2408 2642 2360 2455 2361 2426 25(>4 hixm .mJigs**1rKi>Mft Mf*c Of?'** Day 17 n 1 71 1 77 173 1 7ft 177 178 179 ISO 183 184 70 185 186 < 187 o i on o o 191 u> 192 00 193 w 194 TABLE I continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Exposure Number TE-I Rang:e 122 123 124 125 126 127 128 129 130 131* 132 133 134 135 136 137 138 139 140 45.0 35.0' 17.5 39.5 35.0 43.0 42-0 41-0 37.5 48.5 39.5 47.0 46.5 46.0 43.0 46.0 43.0 35-0 51.0 55-0 57.5 51.5 66 - 5 62.5 60.0 65.0 60.0 57.5 57.5 53.0 55.5 51.0 52.0 54.O 61.0 o o Mean 48.5 48.0 37.5 48.7 54.2 52.9 48.2 53.3 50.1 52.9 52.0 49.6 50.7 48.0 47-6 49-7 48.9 54.3 Chamber Concentration (ppm) TE-II TE-III Ranee Mean Ra j}H5______ M ean 180 208 192 186 210 197 148 248 198 178 204 197 190 222 211 174 214 195 184 214 195 192 228 210 190 206 198 2260 2320 2000 2360 2360 2360 2400 2520 2340 2440 3020 2800 2620 3060 2860 2B00 2800 2560 2461 2708 2488 2505 2787 2739 2512 2671 2467 170 206 196 186 220 206 184 224 209 180 262 194 170 220 201 196 212 202 178 206 197 174 200 187 158 246 205 2280 2320 2040 2180 2480 2460 2300 2340 2160 2580 2800 2680 3400 2800 2620 2640 2520 2700 2452 2551 2419 2515 2575 2512 2462 2424 2537 TE-IV Ran ee Mean 2200 2080 2400 2460 3060 2140 2440 2500 2400 2440 3140 2920 2620 3100 2880 2900 2740 2600 2355 2347 2640 2543 3080 2551 2644 2657 2500 2380 2220 2380 2400 2480 2340 2360 2220 2020 2540 2800 2580 2540 3280 2540 2540 2460 3900 2453 2434 2480 2472 2753 2445 2440 2343 2590 o uai B IO -TE S T h'JuUutd B IO -TE S T Day 1 07 198 199 ?nn ?ni ?Ci*\ ?nA 7n7 7fl 7>1 212 TABLE I continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Chamber Concentration Data Exposure Number TE-I Rang e 141 142 143* 144 145 146 147 148 149 150 151 152 40.0 29.0 38.5 37.5 41.5 41.5 40.5 47.0 48.0 42.5 36.0 55.0 64.5 56.0 55.5 61.0 52.5 51.5 56.5 54.5 51.0 64.5 Mean 45.1 57.4 49.0 48.0 51.0 47.0 49.2 51.6 51-4 47.0 48.1 Chamber Concentration TE-IJ Ran fie Mean (ppm) TE-III Rang e 178 216 196 170 220 177 2400 2460 2700 2800 Mean 2535 2594 178 310 223 174 212 197 188 248 218 184 234 207 178 272 223 180 206 193 170 242 200 160 230 189 154 282 194 2340 2340 2320 2280 2500 2300 2260 2320 2160 3120 2740 2700 2840 2800 2820 3420 2520 3200 2561 2500 2552 2541 2613 2444 2627 2413 2583 TE-IV Range Mean 2320 2400 2480 2520 2391 2440 2100 1980 1980 2420 2260 2200 2600 2200 2200 3200 2740 2800 2600 2420 2720 2700 2660 2600 2480 2553 2352 2523 2352 2524 2654 2440 2435 * Equipment failure, exposures not conducted. jo U) < o oo u> OD rv*. *L-*-*"'.****''K<-4*4*~<[1'. -W. -M`ft- D I O - f t t> I jnc. 12 IV. Body Weight Data The mean body weight and weight gain data are presented in Table II. Below is a discussion of the data from each species. Rats: The average seven-month weight gain of the TE-IV rats was found to be less than the control or other test group animals. This difference was attributed to the greater initial weights of the TE-IV group at the start of inhalation exposures. There were no other abnormalities or dose related trends in the other test groups. Mice: There are no adverse body weight effects among the mice which can definitely be attributed to inhalation of the test material. Although the seven-month body weights and weight gains of the highest test level are less than the lower dose groups and the control mice, the differences are only slight. SV 0003185 2+uiit.itual B I O - T E S T jnc. ij Hamsters: Mean body weights of hamsters through the sixth month of the inhalation period revealed dose related decreases in body weight for both sexes from control down to TE-III animals. However, evaluation of body weight gains for all groups between the fifth, sixth and seventh months of the investigation indicated that gains of all test groups were nearly as great or greater than the control group gains. Below is a table showing average gains of each group of hamsters during the third, fourth, fifth and sixth months of the study. Sex Grouo Mean Gain During Month Indicated (grams) Third Fourth Fifth Sixth Males Control 9 1 3 -3 TE-I 6 1 16 TE-II 20 11 12 -2 TE-III -2 -3 24 -2 Females Control TE-I TE-II TE-III 2 6 -1 0 1 0 -1 -2 1 8 -2 8 RSV 00031Q6 ftSV 0 0 0 3 1 8 ? TABLE If TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Sex Males Group Control TE-I TE-1I TE-III Females Control TE-I TE-II TE-III TE-IV 0 205 209 201 200 160 168 171 165 181 Summary of Mean Body Weights - Albino Rats Week Number 1 23 258 294 335 246 286 331 261 501 335 245 302 326 188 214 223 184 207 223 200 208 228 185 216 228 209 223 236 Mean Body Weights (grams) 4 2 .3 Month Number 45 6 363 346 360 351 456 498 517 537 543 448 491 526 545 554 457 490 522 549 567 453 499 529 550 567 235 232 242 240 251 275 274 289 287 282 299 297 302 303 288 315 310 313 312 291 320 308 316 321 314 326 323 329 329 324 Overall Weight 7 Gain 550 345 567 358 565 364 576 376 344 184 348 180 342 171 346 181 338 157 'K r-'o p w fv ]- 1 s 2 J. - o I a V ^ F t { TABLE II continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Summary of Mean Body Weights - Albino Mice Sex______ Group j Males Control TE-I TE-II TE-III 35 33 36 36 Females Control TE-I TE-II TE-III 29 30 28 28 Week Number l 23 36 37 39 ' 34 35 37 37 37 40 35 35 38 29 29 30 29 31 31 29 29 31 28 27 30 Mean Body Weights (grams) 4 2345__67 Month Number Gain 40 41 43 46 43 46 39 39 43 44 42 47 40 38 42 44 42 45 38 40 43 44 38 45 32 33 35 36 35 38 34 34 37 39 38 40 31 34 35 37 36 38 31 34 35 36 37 37 Overall Weight 52 45 43 41 . 37 41 36 34 17 12 7 5 8 11 8 6 RSV 0 0 0 3 1 8 8 BIO- TES T TEST M ATER IAL: V in y l C h lo rid e (E thylene D e rive d ) C h ro n ic V a p o r In h a la tio n T o x ic ity S tudy - A lb in o R ats, A lb in o M ice and G olden H am sters a ll ght in 4) ^ > 4! o O5 r-- r- m o m in m in O OO CO o r- m nj --< --i CO CM CO O' in m -o in o cm so *--N ^ ^ f--i ^H H f H vO u 4) X E -- in Z r~> --t C O 2^ m c-J o <m M ro N -h i--^ rS O'--f CQ CO (M O CO r-H O' o a- r-H N (M H O' l CNfO N Nh #-H *"H CO vC 'T - (rsi O O F H F--"1 --H o =o r-- -o <NJ "H O O i-H r-H r-H /UJ o6 U 3 oo J00 vj Xw cfl X '<5 oO <m 5V 5 >- T3 O TJ CO O CQ c o C nj <D 2 o >> V. cm E 3 CO 41 X .3 <M z o 0) 5 i-- o O' n IS] M O' O' f--4 ^H CO N CO sO ^H O -H f-H *"H O --i ^ O O' O' r--* f-H CO CM O' O O O O' o i--1 r--4 co o O' nff' O' CO rr in 'f N O O' O' O' f*^ O' O' m so O' CO CO CQ N O Ifl U1 O O' O' O' vO O' N M CO t-- CO QO -h n nj rO' CO OO 00 ^ N -h >13 n- o -so o oo m o co r~- c-- r-- o rO r--i m o n- co 'r o- r- t-- xo so r- r-- n- no cL ,, - - --< --* h-H c5- C1 ' o W U4 u C> O H H H W 41 >< -r 3j ,2 KJ) 2 o_ u-- ^1 I 1 o w cu ua OHHH in 41 Cfl g 4) Uh 10 RSV 0003189 j`rtdH.iC'uai B i O - T E S T JicMoAalosu&i' y^c. ii V. Mortality Data The cumulative monthly mortality data are presented in Table III. No definite dose related trends have been observed. RSV 0003190 9+uuUual B 1 O - T E 5 T laluyta&uei, 5'ric. id TABLE III TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice, and Golden Hamsters Summary of Mortality Data Month No. Cumulative Number of Mortalities at End of Month ALBINO RATS Control T-I T-II T-III MF MF MF MF 1 00 00 00 00 2 00 20 10 00 3 01 20 10 14 4 02 41 30 14 5 23 51 61 34 6 34 62 61 54 7 44 86 62 65 Control Month No. M F ALBINO MICE T -I T*-II MF MF T- III MF 1 00 00 2 00 03 3 2 0 64 4 51 19 5 5 82 26 6 6 12 2 30 6 7 18 5 31 11 00 00 30 41 42 83 9 12 00 00 10 47 87 10 9 13 23 T-IV F 0 0 0 0 0 0 0 Control Month No. M F 1 54 2 8 11 3 8 13 4 9 15 5 9 18 6 13 18 7 13 28 GOLDEN HAMSTERS T -I T--II MF MF 44 10 12 12 14 16 16 16 16 16 16 24 19 75 9 16 12 18 15 19 16 20 20 21 22 33 T- III MF 25 10 11 14 13 15 13 15 15 16 16 18 26 RSV 03l9l 4 ? $ l i B l O - I S T JtolMyiakvu&i; `)nc. 19 VI. Gross Pathology Noteworthy gross pathologic findings are presented in Table IV. Animals not listed showed only postmortem changes or were too badly cannabalized or decomposed for valid examination. R.SV 0003 B I O -T S T 9nc. 20 TABLE IV TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex Control Rats 32-M 173--F 75-M 51-M Gross Pathologic Findings Grade Focal consolidation of all lobes of lung Focal consolidation of all lobes of lung Focal consolidation of all lobes of lung 6x4x5 cm subcutaneous multilobular fibrotic mass in abdominal region 5 3 5 - TE-1 Rats Z15-M 211-M 283-M Dark red discoloration of all lobes of lung Congestion of lung Small consolidated foci in all lobes of lung Congestion of all lobes of lung Spleen enlarged, 2 times normal 1 5 - 4 " TE-II Rats TE-III Rats 499-M 521-F 518-F 657-M 635-M 721-F Diffuse red discoloration of all lobes of lung Spleen enlarged, 3 times normal Draining abscess in inguinal region Congestion of all lobes of lung Congestion of lung with small consolidated foci Consolidation of all lobes of lung Congestion of all lobes of lung 1 4 3 3 4 Control 1750-F Hamsters 1773-F 1784-F Congestion of all lobes of lung Congestion of all lobes of lung Congestion of all lobes of lung 4 4 3 TE-I 1861-M Hamsters 1912-F 1910-F Congestion of all lobes of lung Congestion of all lobes of lung Dilatation of both uterine horns with clear fluid (hydrometra) 5 4 - RSV 0003193 Jncluii'ual B I O T H S T ^ahvuz&yuei' $kc. 21 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group' Animal and Number Species and Sex Gross Pathologic Findings Grade TE-II 2189-F Hamsters 2004-M 2180-F 2166-F 2155-F Congestion of all lobes of lung Congestion of all lobes of lung Congestion of all lobes of lung Congestion of all lobes of lung Congestion of all lobes of -lung 3 4 4 5 2, TE-III 2220-M Hamsters 2312-F 2311-F Congestion of all lobes of lung Congestion of all lobes of lung Right kidney has focus of white discoloration extending from capsule into cortex 4 3 - Control Mice 835 -M 859-M Focal consolidation of all lobes of lung Enlarged kidney 1/2 times normal, w/granular surface 1 TE-I Mice 1033-M 1048-M 1023-F 1110-F 119-F Pale kidneys - Enlarged seminal vesicle, 5 times normal - Small (1-3 mm) dark red foci in all lobes of liver. One small lobe has large (2 cm) dark focus which is slightly raised. There are also discolored foci with depressed centers. A small (5 mm) yellow nodule is also attached to the larger mass. Multiple, small (2-4 mm) white foci in all lobes of lungs. Several small (2 mm) dark red to white foci in right anterior lobe of lung. Large (5x5x7 cm) firm subcutaneous mass on right side of head in para-aural region which encircles neck and extends dorsally on other side of head toward left ear. Small (1-20 mm) dark red foci in all lobes of the liver and dark red fluid in abdominal cavity. - RSV 0003194 9*tdu'i.Lrial B I O - T E S T JtaJtoAGl&.u&i, 9*c. 22 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex Gross Pathologic Findings Grade TE-I Mice 1200-F 1071-M Dark red raised focus (1 cm) in major lobe of liver with adhesions to diaphragm. Multiple small (1-2 mm) white to dark foci in all lobes of lungs. Large subcutaneous tumor mass (4x4x2 cm) in right femoral region. Abdominal cavity contained moderate amount of dark red fluid. All lobes of lung congested 2 TE-II Mice 1301-F 1268-M 1309-F 1341-F 1289-M 1382-F 1350-F Gall bladder distended with bile - Enlarged gall bladder - Congestion of all lobes of lung 4 Large (6 mm) nodular red focus in major lobe of liver with adhesions between capsular surface and mesenteric fat. Congestion of all lobes of lung . 3 Enlarged spleen, 3 times normal - Multiple small (1-3 mm) white foci in all lobes of lung. Large (2x2x2 cm) dark red focus in one lobe of liver. Abdominal cavity contains moderate amount of dark red fluid. Large (3x2x3 cm) dark red focus in one lobe of liver and smaller foci (0.5 cm) in other lobes . Abdominal cavity contains moderate amount of dark red fluid. Small (1-2 mm) white foci in all lobes of the lungs. Large (3 cm) nodular focus in major lobe of liver with adhesions between capsular surface and mesentery. All lobes of liver have small depressed red foci. Abdominal cavity contains moderate amount of dark red fluid. KSV 0003195 !}nduii,uai B I O - T E S T laltosiaiiyueA, 5nc. 23 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex Gross Patholoeic Findings Grade TE-II Mice 1299-F Multiple small (1-2 mm) white foci in all lobes of lung. Large (2x2x2 cm) subcutaneous tumor mass in inguinal region. 3 TE-III Mice 1405-M 1538-F 1532-F 1562-F 1598-F 1574-F Irregular surface on right kidney Multiple small to large (1 mm - 1 cm) dark red foci in all lobes of the liver some of which are slightly raised and others have depressed centers. Multiple white foci (1-3 mm) in all lobes of lung . Enlarged thymus Congestion, of all lobes of lung Multiple small (1-2 mm) white foci in all lobes of lung Multiple small (1 mm) dark red foci in all lobes of liver. Large (1 cm) raised lesion in one lobe of liver with adhesions between surface of lesion and adjacent mesentery and abdominal fat. Abdominal cavity filled with dark red fluid. Multiple small (1-2 mm) white foci in all lobes of lung. Diffuse dark red discoloration of one lobe of liver which was enlarged and smaller (1-3 mm) lesions in all other lobes . Adhesions between surface of lesions and mesenteric fat. Abdominal cavity filled with dark red fluid. Small (1-2 mm) white foci in all lobes of lung Large (2.5 cm) dark red nodular focus in one small lobe of liver. The lesion involved almost the entire lobe . The other lobes of liver were pale in color. Abdominal cavity filled with dark red fluid - - 3 RSV 0003196 ynctuiiiial B I O - T E 5 T Jlaiuyiai&U&i, 9*.c. 24 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex_______Gross Pathologic FindingsGrade TE-HI Mice 1531-F 1588-F 159 3--F 1505-F Congestion of all lobes of lung Large (5x3x5 cm) subcutaneous mass in right femoral region extending into musculature of limb and abdomen. Few small (1 mm) white foci in all lobes of lung. Large (2-3 cm) dark red raised foci in two lobes of liver with smaller (1-3 mm) lesions in other lobes . Adhesions between larger lesions and mesentery. Spleen enlarged 3 times normal. Abdominal cavity filled with dark red fluid Few small (1 mm) white foci in all lobes of lung. Small (1-3 mm) dark red foci in all lobes of the liver. Some of the lesions on the surface were raised while others had depressed centers . 1 Spleen enlarged 1? times normal Abdominal cavity filled with dark red fluid Several 1-5 mm white foci involving all lobes of lung. Large (3x3x3 cm) dark red focus in one lobe of liver which involved almost the entire lobe with smaller (1-5 mm) similar lesions in all other lobes of liver. There are adhesions between the surface of the larger liver lesion and'mesentery. Abdominal cavity filled with dark red fluid. RSV 0003197 BIO-T E S t 2nc. 25 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex Gross Pathologic Findings Grade T-III Mice 1565-F 1409-M 1543-F 1544-F 1546-F Few small (1 mm) white foci in all lobes of lung. Diffuse dark red discoloration of one entire lobe of liver with adhesions to mesentery. Small (1-2 mm) dark red foci in other lobes of liver . Multiple small (1-3 mm) white foci in all lobes of lung. Small (1-4 mm) dark red foci in all lobes of liver. Some liver lesions on surface had depressed centers . Abdominal cavity filled with dark red fluid Multiple 1 mm - 2 cm white foci involving all lobes of lung. Hepatomegaly with multiple dark red foci (1-3 mm) in all lobes and adhesions between diaphragm and surface of liver. Also adhesions between liver lobes, liver to intestine, liver to mesentery. Abdominal cavity filled with dark red fluid Multiple small (1-2 mm) white foci in all lobes of lung . Diffuse dark red discoloration of one lobe of liver with smaller (1-3 mm) dark red foci in other lobes. Adhesions between surface of liver lesions and mesentery. Abdominal cavity filled with dark red fluid Several 1-5 mm white foci involving all lobes of lung. Large (3x3x3 cm) focus in one lobe of liver which involved almost the entire lobe with smaller (1-5 mm) similar lesions in all other lobes of liver . There are adhesions between the surface of the larger liver lesion and mesentery. Abdominal cavity filled with dark red fluid. 00031^ Jnd^Usuxil B I O - T E S T Jlahyi&iiyUeA, !)kc. 26 TABLE IV continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Gross Pathologic Data Group Animal and Number Species and Sex Gross Pathologic Findings Grade T-IH Mice 1535-F 1432-M 1477-F 1494-M Multiple small (1-2 mm) white foci in all lobes of the lung. Dark red focus (3 cm) involving most of one major lobe of liver and smaller (1-3 mm) lesions in other lobes. Adhesions between lobes of affected liver and between liver and mesentery. Congestion of all lobes of lung 4 Multiple small (1-3 mm) white foci in all lobes of lung - Left diaphragmatic lobe of lung congested, multiple white parenchymal foci in all lobes of lung ranging from 1 mm to 1 cm in size. - Liver has small (1-5 mm) dark red foci in all lobes . Some liver lesions are raised and some depressed. Subcutaneous multi-lobular fibrotic mass (5x5x3 cm) in inguinal region with retroperitoneal invasion . Several areas filled with brown fluid Two similar masses in left axillary region ' extending into para-aural region, each approxi mately 1.5 cm in diameter. - Two small subcutaneous masses (1 cm dia.) in right abdominal region filled with dark red fluid Large mass (2.5 cm) located in left axillary region -- Multiple small (1-2 mm) white foci in all lobes of lung. Small (1-5 mm) dark red foci in all lobes of liver. Abdominal cavity contains dark red fluid. RSV 0003199 ^nd^-iixuU. BIO-TEST 9nc. 27 VII. Histopathology Histopathologic examinations were conducted on all mice which showed grossly visible lesions through the end of the seventh month of inhalation exposures. All mice which showed neoplastic findings are presented in Tables V and VI. RSV 0003200 Iroup '-I '-II -III TABLE V TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Summary of Tumor Data Among Mice No. Mortalities with Neoplasms Location of Tumors Lung Liver Skin Metastasis to Lung 4 (1 Male, 3 Females) 2 (50%) 2 (50%) 2 (50%) 2 6 (1 Male, 5 Females) 19 (4 Males, 15 Females) 3 (50%) 17 (S9.5%) 4 (66.7%) 17 (89.5%) 2 (33%) 3 (15.8%) 1 V* 3D CO < oO o ui f\J o ro 03 5 I O -TEST ^<l&QSiai&fue<; Otis' 29 TABLE VI TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Tumors Observed Among Mice Group Animal Number and Sex Lung Neoplastic Findings Liver Skin Date of Death T-I 1123 Male 1110 Female 1119 Female 1200 Female AA (s) HS (s) AA (s), Metastatic Mammary Tumor HS (s) Metastatic Mammary Tumor MT (Para-aural) " 3-15-74 3-20-74 3-24-74 MT (Femoral region) 3-30-74 T-Il 1347 Female 1309 Female 1289 Male 1382 Female 1350 Female 1399 Female Metastatic ' Mammary Tumor HS (s) AA (s) HS HS (s) AA (s) HS (s) AA (s) MT (Abdomen) 3-5-74 3-18-74 3-25-74 4-2-74 4-5-74 MT (Inguinal region) 4-9-74 T-III 1538 Female 1532 Female 1562 Female 1598 Female 1405 Male 149 4 Male 1574 Female 1531 Female 1588 Female 1593 Female AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) HS (s) HS (s) HS (s) HS (s) HS (s) HS (s) HS (s) HS (s) HS (s) 3-6-74 3-7-74 3-8-74 3-18-74 2-25-74 3-22-74 3-22-74 MT (Femoral region) 3-23-74 3-25-74 3-30-74 RSV 0003202 !}rtdu4iJ/ual BIO-TEST 9rtc. 30 TABLE VI continued TEST MATERIAL: Vinyl Chloride (Ethylene Derived) Chronic Vapor Inhalation Toxicity Study - Albino Rats, Albino Mice and Golden Hamsters Tumors Observed Among Mice Group Animal Number and Sex Lung Neoplastic Findings Liver Skin Date of Death T-III continued 1505 Female 1565 Female 1409 Male 1543 Female 1544 Female 1546 Female 1535 Female 1432 Male 1577 Female AA (s) AA (s) AA (s) AA (s) AA (s) AA (s) HS (s) HS (s) HS (s) HS (s) HS HS (s) AA (s) HS (s) AA (s) AA (s) HS (s) Metastatic Mammary Tumor 4-3-74 4-3-74 4-5-74 4-5-74 4-5-74 MT (Axillary region) 4-5-74 4-7-74 4-8-74 MT (Para-aural) 4-9-74 MT (Abdomen) MT (Pelvic region) Key to Symbols AA = Multiple Alveologenic Adenomas of Lung HS = Hemangiosarcoma of Liver MT - Malignant Mammary Tumor (s) = Multiple Lesions RSV 0003203