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R E P O R T TO MONSANTO COMPANY TW O-YEAR CHRONIC ORAL TOXICITY WITH AROCLCR 1260 IN. ALBINO RATS NOVEMBER 12, 1971 IBT NO. 37298 L Introduction At the re q u e st of Monsanto Company, a tw o -y ear chronic o ral toxicity study was conducted using albino ra ts :o determ ine the potential toxicity of A ro c lo r 1260, Lot No. AK-3. The following report p re s e n ts the r e s u l t s o th is in v est:* ion. 00008*2 IWOR84 fT. Surr.rr.ar v 2 Food consumption and body weight gains w ere not altered at any le v e l of A r o c l o r 1260 fed. The n u m b e r of a n i m a l s dying and the time at which the deaths occurred did not vary among the test and control groups. Hematological and clinical blood chem istry studies conducted after 3, 6, 9. 12, 13, or 24 months did not r e v e a l any affects re la te d to A roc lo 1260. Urine analyses failed to reveal any differences between test and control animals. At s a c r i f i c e a f t e r 3, 6, or 12 month s on t e s t o rg a n we igh ts, o r g a n to body weigh: and organ to brain weight ratios disclosed several randomly occurring intergroup differences. The lack of any consistent dose related re sp o n se and the absence of any deleterious histopathologic change confirn that these d iff e r e n c e s w ere not re la ted to the in g estio n of Aroclor 1260. At the final s ac rifice after 24 months on test, the liver weights and liv e r to body weight or b ra in weight ratios w ere significantly elevated in the r a f t fr o m the T-UI group. Histologic e x am in atio n of the livers fro m the T-IH group revealed several anim als with vacuolar change. This lesion is m orphologically indicative of fatty degeneration. Specific fat stains c o n f i n e d the p re s en c e of fat in these vacuoles. Focal hypertrophy and focal h y p e r p la s ia w ere also found in the l i v e r s from animals fed Aroclt 1260. ADM OC3721 263 H yperplasia of the urin ary bladder was found in an anim al from the c o n tro l group but not in any of the te st anim als. The in c id e n ce s and types of all tu m o rs w ere about the same in all g ro u p s, including the control group, and a re c o n sid e re d norm al for r; of this age. Respectfully submitted, INDUSTRIAL 3 I 0 - 7 Z S 7 LA3CR A7CR 1ZS . INC, R e p o r t p rreepp t r e d by: TLVo % Phulip 3 math, B. S. Assistant Toxicologist Rat 7 oxiciry R eport approved by: ^k J k m is 3. Plan* Semor Croup Leader Rat Toxicity Section Head, Toxicology L. KepLqg/*. ?n. Manager, Toxicology N ovem ber 12, 1971 lam :sjn A uH 0 0 3 7 2 * 264 00008 e 1 |V '0 0 R R 6 m. Procedure A. E xperim ental Animals The a n im a ls em ployed in the test w ere C h arles River strain-* Albino r a t s . T o u r hundred r a ts (200 m ales and 200 fem ales) w ere selected for the experim ent, ear-punched with the animal num ber assigned and housed individually in standard w ire-bottom ed steel rat cages. Each cage bore a color-coded card identifying the rat with re spect to p ro je c t num ber, dose level assignm ent, individual anim al number and sex. B. Organization of Groups A s tru c tu ra l outline of the experim ent is given in Table L Crouo TABLE I TEST MATERIAL: A ro c lo r 1260 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Outline of E x p erim en t N um ber of Animals Male Female Dietary Level foom) Control 50 50 None Administered T - I SO 50 1 T-U 50 50 10 , T-IU 50 50 100 Charles River Breeding Laboratories, North Wilmington. M ass. ACM 0C3722 265 0 0 0 0 8 . 1 i-o n o w c . Dieta, Feeding and Food Consumption A ll diets w ere p re p a re d in the c en tral d iet room of :hia laboratory. The basic ration from which all dieta were constructed w t i a standard, pulveri2ed stock rat ration*. The diet for any given te s t group w i f p re p a re d by blending the calculated am ount of A roclor 1260 with a p re-w e ig h ed po rtio n of the atock ra tio n in a H obart m ix e r. . F resh dieta were prepared each week and every rat was offered an am ount of food sufficient for ad libitum feeding. Food consum ption was recorded for five ra ts of each sex in ev er; group weekly for the fir s t three months and m onthly for the next nine m onths. Thereafter, periodic spot checks w ere made. D. Bodv W eights and Weight Cains Initially, the. body w eight of eaeh r a t in e v ery group was d e t e r m ined and recorded. Thereafter, individual weighings were made weekly fo r the f i r s t 13 w eek s and m onthly th e r e a f te r u n til the co n clu sio n of the i n v e s tig a tio n .___________________ __________________________ - - ___________ E. M ortality and Reactions * " - Checks for m ortality and abnormal behavioral reactions were .m ade daily throughout the investigation. T -7 ` F* H em atologic Studies and Urine A nalyses Blood studies, including determ inations of hem oglobin c o n c e n tra tions, hem otocrit value, erythrocyte count and both total and differencial * P u rin a Rat Chow, Ralston Purina C o., St. Louis, Mo. adk c 0 3 ' 266 000080 FonO RRS 0 leukocyte count*, w ere conducted upon live males and five females from b o th the c o n tr o l and 100 p p m g ro u p s . U rine analyses for the presence of glucose, albumin, m icro copic e le m e n ts , and d e te rm in a tio n s of pH and specific gravity w ere c o n ducted upon urin e sam ples at the sam e time intervals and from the sam e anim als as those employed for the blood studies. T h e s e s tu d ie s w e r e conducted a f te r 3, 6, 9, 12, 18, and 24 m o n th s of feeding. G. Clinical Blood C hem istry Studies D eterm inations of blood urea nitrogen concentration (BU>0, s e ru m alkaline phosphatase activity (SAP), fasted blood glucose concen tra tio n and seru m glutam ic-pyruvic transam inase activity (SGPT) w ere conducted a f t e r 3, 6, 9, 12, 18, and 24 m onths of feeding upon the sa m e ra ts as w ere the routine blood studies. H. Pathologic Studies When an anim al succumbed during the test period, a gross autopsy w as p e rfo rm e d . In those cases when p o stm o rte m autolysis was not a d vanced, re p re se n ta tiv e tissu es w ere taken and p re se rv e d in ten p ercen t form alin solution for possible future histopathologic study. A f t e r 3, 6, and 12 m o n th s of te s tin g , five a n im a ls of each s e x fro m each group w ere sacrificed and subjected to complete gross pathologic exam inations. AOH 0 0 3 7 2 267 000087 i F n n n fi8 9 A bsolute organ w eights w ere re c o rd e d and organ to body w eight and organ to b ra in weight ra tio s computed. The following organs w ere included: liv er, kidneys, spleen, gonads, h eart and brain. There data w e re then subjected to s ta tis tic a l an aly sis. An A nalysis of V ariance w as conducted first and significant effects disclosed by that treatment were furth er studied by " f '- te s ts . Com plete m icro sco p ic examinations w ere conducted upon the t i s s u e s and o rg a n s f r o m a ll c o n tro l and 100 p p m gro u p r a ts s a c rif ic e d a f t e r 3, 6, o r 12 m o n th s of te s tin g . The follow ing tis s u e s and o rg a n s w a r included in the examinations: heart, trachea, lungs, liver, pancreas, esophagus, stomach, sm all intestine (duodenum, jejunum and ileum), caecum, colon, spleen, lymph nodes, kidneys, urinary bladder, gonads, prostate gland, seminal vesicles, uterus, pituitary gland, adrenal glands, salivary glands, thyroid gland, parathyroid glands, skeletal muscle, ' sternum , bone, peripheral nerve, spinal cord and brain (cerebrum cerebellum and pons). The aforem entioned tissues were p rep ared and stained with Hematoxylin-Eosifl stain. ' A fter two years of feeding, all surviving anim als were sacrificed and subjected to complete g ross pathologic exam ination. The absolute weights of the liver, kidneys, spleen, gonads, h eart and brain were recorded immediately after sacrifice. aOH 0 0 3 7 2 268 000085 M icroscopic exam inations wore conducted upon tissues and organs from selected anim als dying during the experim ent and upon all anim als from the final sacrifice. T issu es and organs exam ined w ere the same as those previous * m entioned. L T u m o r Incidence ar.d C lassification A tabulation of the incidence of tum or form ation in each group w as m ad e a t the conclusion of the investigation. In addition, tu m o r data fo r individual anim als ineluding location, weight, size and pathologic classification were recorded. ACM CC 37 27 269 000089 F000891 IV. Resulta A . B ody h e ig h t s and W e i g h t Gains T he m i l e and fem ale body weight data a re assem b led in Table II. T he d a ta in th is ta b le a ls o in c lu d e the 3, 12 and 24 m o n th to ta l w eight * gains. T h e re w ere no significant effects due to ingestion of the compound ACP CO 270 0000U) 1,000892 /* J dietary Level of Aroclor 1260 Ippm) Sex Control M F 1M F 10 M F 100 M F O TABLE ll TEST MATERIAL: A roclor 1260 Two-Yaar Chronic Oral Toxicity Study - Albino Rata Body Weight and Total Weight Gain Data Summary of Mean Value* Body Weight 90-Day (grama) Total Weight Week: Gain 0 1 2 3 4 5 6 7 8 9 10 II 12 13 (f*ram a / rail 133 203 245 313 362 373 391 409 424 440 440 449 467 474 136 i?a 190 219 244 254 259 265 270 276 281 278 290 288 341 152 133 192 250 322 361 374 394 416 428 4 4 a 450 474 479 490 136 167 1U9 21B 241 252 256 261 268 273 277 281 290 288 357 152 133 204 245 317 368 382 400 417 436 44B 461 467 475 481 136 174 190 217 242 254 260 263 268 274 2a i 279 285 288 348 152 133 208 247 319 363 375 394 425 4 37 451 460 479 486 500 136 173 IBS 222 240 253 25a 262 265 . 267 270 275 275 280 367 144 >o x o o :* *iiim* 6 0 0 0 0 fc f c & lR iO l r- Dietary Level of Aroclor 1260 (ppm) Sex lonlrol M F 1M F 10 M F 100 M F O TABLE II continued # TEST MATERIAL; A roclor 1260 T w o -Y u r Chronic Oral Toxicity Study - Albino Rata Body Weight and Total Weight Gain Data Summary of Mean Values Body Weight (grama) Month: 45 6 7 fl 9 10 1 1 498 533 565 593 622 642 667 688 297 310 322 333 345 359 374 383 516 547 578 600 628 643 66 8 688 298 307 314 321 333 340 353 367 496 526 551 581 606 633 660 685 291 306 314 331 340 358 370 381 522 555 580 607 633 650 681 707 289 302 307 314 326 333 342 347 O 12-Monlh Total Weight Gain 12 ( e r a m o /r a t ) 701 568 390 264 699 # 379 566 24 3 709 576 388 252 717 584 36 3 227 oX oO u ftiU U U M ' S60000 Z tM U U U i Dietary Level of Aroclor 1260 <ppm > Sex Control M F 1M F 10 M F 100 M F O O i-- > too nx U) o o OO TAEfLE II continued TEST MATERIAL; A roclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rate Body Weight and Total Weight Gain Data Summary of Mean Valuea 13 14 IS 16 Body Weight (grams) Month: 17 18 19 20 21 22 24-Monih Total Weigh Gain 23 24 (gra m s/rat] 728 746 759 768 769 767 760 758 739 * 726 687 642 426 444 466 481 500 515 533 547 551 550 564 551 721 740 760 768 776 774 762 753 733 718 715 654 390 427 466 433 445 476 481 493 514 5 30 484 525 728 745 776 761 768 780 774 761 735 715 683 645 416 434 482 449 473 508 519 530 536 542 536 584 746 760 772 775 774 769 760 750 733 714 711 64 1 380 386 417 414 435 453 471 481 500 507 485 537 509 415 521 385 512 448 508 401 1i o B. Food Consumption The data obtained fro m the food consumption m easurem ents c o n d u c te d d u rin g th e f i r s t 12 m o n th s of feeding a r e s u m m a r is e d in T a b le III T hese data revealed no significant difference between test and control ra ts . The periodic checks conducted during the rem ainder of the investigation also revealed no outstanding differences between te st and control animals. * CC37 0 0 274 'I O TABLE Ut TEST MATERIAL: Aroclor 1260 Two* Year Chronic Oral T oxIcily Study - Albino Rate i i i Food Consumption Data Summary of Mean Valuee Food Consumption ietary Level of (grama/rat/eevcn days) Average Food Aroclor 1260 Week: Consumption (ppm! Sex 1 2 3 4 5 6 7 6 9 10 11 12 13 ( g r a m e / r a t/ se v e n day Control M 94 160 175 163 137 137 225 197 204 188 191 194 196 F 73 140 144 107 104 133 208 154 165 151 146 150 151 174 140 1 *4 M l i a 154 151 169 201 116 200 198 201 193 189 187 194 F 95 1IB 97 139 160 107 162 139 165 149 150 143 147 175 136 n 10 1 100 M !06 146 144 142 190 136 196 214 214 192 191 199 200 F 94 124 128 124 179 90 190 167 155 151 150 149 152 M 121 150 156 117 187 124 121 190 196 186 184 199 189 F 89 93 123 151 151 101 193 136 140 144 144 147 146 175 143 16) 1)5 ox o o 00 275 j 'A n T A BL E III continued TEST MATERIAL: A roclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Food Consumption Data Summary of Mean Values Food Consumption letary Level of (gram s/rat/scvcn days) Aroclor 1260 Month; (ppm) Seic 4 5 6 7 8 9 10 11 12 Control M 196 189 168 147 163 184 179 170 187 F 148 154 136 121 138 152 160 141 127 1 M 196 200 189 192 179 181 182 172 164 F HB 161 I II 163 160 . 153 157 141 ' 132 10 M 186 191 188 193 197 197 1.68 164 196 F 142 118 145 144 144 151 136 139 141 100 M 179 170 180 IBS 186 ' 166 181 188 180 F 156 . 127 147 144 134 132 162 149 139 Average Food Consumption (grim o/rat/scven days) 176 142 186 151 186 142 180 141 o % o oO-J1 IP tio M n n Ji u z 00 lb C. M o rta lity and R eactions A frequency distribution of natural deaths occurring during the V_^ in v e stig a tio n a p p e a rs in T able IV, No u n to w a rd b e h a v io r a l r e a c t i o n s w e r e no ted am ong my- of the a n im als em ployed In the in v estig atio n . 9 ( AOH 0C37 0 0 277 o EOO "u * i CD Dietary Level Ippm) Sex Control M F 1M F. 10 M F 100 M F TABLE IV TEST MATERIAL: A roclor 1260 Two-Year Chronic Oral Toxicity Study * Albino Rata M ortality Data Frequency Distribution of Deatha Frequency Distribution of Deatha Months: 1-3 4-6 7-9 10-12 13-15 19-21 000 2 1 7 6 000 1 3 5 7 00 1 1 4 7 5 000 2 3 3 6 1 10 2 4 7 8 000 3 2 4 5 10 0 2 2 8 6 0 22 0 3 5 7 22-24 9 3 a 5. 6 3 9 4 Total Dead Number Tested* 25/35 19/35 26/35 19/35 29/35 ` 17/35 29/35 23/35 * Does not include the five anim als of each aex from every group aacrificed for Interim patho!ogl<c stu d ies. ia D. H em atoloeic and Clinieal Slood C hem istry Studies M ean m ale and {male hematologic and clinical blood ch em istry d a t a a r e s u m m a r i z e d in T a b le s V th ro u g h DC. Values for all p aram eters Investigated w ere within the norm al range for the albino ra t. No significant differences between test and contrc values w ere observed. F r in n sn i * ck c c 3 7 3 0 0 279 t ( Dietary Level Ippm) Control Sex 3 M 14. 0 F 9. 1 TABLE V TEST MATERIAL: Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata H em atologic Data Summary of Mean Values Total Leukocyte Count (thouaands/mm^) Month; 6 9 12 18 15.4 10. 1 11. 1 9 .9 9.4 .7 7.6 8.8 24 11.2 7.6 Erythrocyte Count (m illton a/m m ^ l Month: 36 9 12 18 8. 1 8. 2 B .7 8 .8 7 .6 7 .5 7 .7 7 .3 7. 8 7 .7 24 6.5 6. 8 M 10.8 13.1 7.9 12.8 B.6 8.4 100 F 13.2 8.2 7.9 6.5 7. B 7.4 7.5 8 .1 , 8.0 7.6 8.0 7.6 7.3 7.5 7.3 7.5 7.4 6.4 5 to 08Z JO V( * Dietary Level (ppm) Sex 3 M 1?. 1 Control F 16.9 o TABLE VI TEST MATERLAL; Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rato H em atologic Data Summary of Mean Values Hemoglobin Concentration (g/IO O m l| Month: 6 9 12 . IB 24 Hematocrit Value i%) Month; 3 6 9 12 17.7 15.7 17.6 16. 1 13.6 51 49 48 50 17.4 14. 1 16.7 16.4 14.6 50 47 43 46 o r 18 24 41 35 42 38 V_ * M u; i 17.2' 14.0 15.3 15.9 14.5 100 F 16.3 17.0 13.7 IS. 6 15.3 12.9 49 47 43 43 41 38 * 48 47 41 44 39 32 O> CD 5 tooo oo Io-* Y~- r- ; Dietary Level (ppm) Control 100 Sex 3 M 82.0 F 83.0 M 85.8 F 92.0 TABLE VII TEST MATERIAL: Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rate Hematologic Data Summary of Mean Value Differential Leukocyte Count (Number of C elle per Hundred) Lymphocyte* Neutrophils Month i Month] 6 9 12 18 24 3 6 9 12 18 24 86.6 86.6 80.4 86.8 78.8 89.0 79.0 70.2 65.4 61.4 16.0 15.4 11.4 11.6 18.6 11.8 20.6 10.0 20.0 29.2 32. 2 36.0 85.4 89.6 83.4 78.8 72.4 82.2 73.8 66.6 80.6 65.6 12.6 7.6 13.8 10.0 15.8 22.6 19.4 17.0 24.6 17.4 31.6 34.2 , t ' \f oKoi NJ >n oo 6 OO Dietary 'Level (ppm) Sex 3 Control M 0.6 F 0.6 M 0.0 100 F 0.0 TABLE VII continued TEST MATERIAL: Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Hem atologic Data Summary of Mean Values Differential Leukocyte Count (Number of Celia per Hundred) Monocyte a Eoainopliila Month: Month: 6 9 12 18 24 36 9 12 18 24 0 .0 0 .0 0.4 0. 2 1.2 1.4 2.0 1.0 0.2 0. a 1.6 0.0 0.0 0.0 0.2 1.0 1.0 1.8 1.4 0 .2 0 .6 1.6 0.0 0.0 0.0 0.4 0. 8 0.0 0.0 0.0 0.4 0.2 1 .4 0 . 8 0 . 8 1 .0 1. 2 1.0* 0 .4 0 .4 0 .8 0.8 1.6 0 .0 OC 283 oJ o oo u* NI* ( TABLEi VII continued TEST MATERIAL; A roclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Hem atologic Data Summary of Mean Values Dietary Level Ippm) Sex Differential Leukocyte Count (Number of Celle per Hundred) Basophils Month; 36 9 12 18 24 Control M 0.0 F 0.0 0 .0 0 .0 0 .0 V 0 .0 0.0 0.0 0 .0 0 .0 0.0 0.0 M 0.2 . 0.0 0 .0 0 .0 0 .0 0.0 100 F 0 . 0 0 . 0 0 . 0 0.0 0 . 0 0 . 0 O 284 Uooi Va Dietary Level Inpm) Sea 3 Control M 38 F 33 M 33 100 F 29 TABLE VHl TEST MATERIAL; Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Clinical Blood C hem istry Data Summary of Mean Value* Serum Glutamic-Pyruvic Tranaaminaae Activity (Dade Units) Month: 6 9 12 IB 48 45 45 42 39 38 42 32 24 36 30 36 Blood Urea Nitrogen Concentration (m gs %) Month: 9 12 18 24 17 15 12 10 14 15 14 16 15 9 13 11 39 42 43 31 36 37 50 40 32 33 14 15 17 16 16 15 , 15 15 14 13 12 14 L O Dietary Level (ppm) Sex 3 Control M 128 F no l* 100 M 118 F 117 TABLE IX TEST MATERIAL: Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Clinical Blood Cliemiatry Data Summary of Mean Valuea Fasted Blood Glucose Concentration (mga%) Month; 6 9 12 18 24 Scrum Alkaline Phosphatase Activity (King-Armstrong Units) Month; 3 6 9 12 IB 24 123 89 118 115 88 138 99 92 134 109 28.6 18.9 24.7 17.8 21.5 10.6 20. 3 11.9 16.2 16.8 22. 3 20. 2 118 116 135 146 98 116 115 138 146 94 37.8 12.0 21.8 21.9 12. 1 7 .6 23.9 11.7 11.9 7.8 16. 1 12. 4 ACH 0037* u , t* f . 2h E. Urina Analyses m a la and fem ale u rin e a n aly se s data a re s u m m a rise d in Tahiti X th ro u g h XII. Determination* for glucose concentration were negative for all * ra ts at ev ery in te rv a l of exam ination. No differences w ere noted between the urine from control and te st anim als at the intervals of examination. io o n w 9 ACM --0C3 0 0 287 f f) o ,. <} ^V TABLE X TEST MATERIAL: Aroclor 1260 Two-Year Chronic Oral Toxicity Stud/ - Albino Rate Urine Analyse Data Summary of Mean Values Dietary Level (ppm) Control Sex 3 Mn Fn Glucose Month: 6 9 12 nnn nnn 18 24 nn nn Albumin Month: 36 9 12 nnI t nn nn % Mn n n 100 Fn n n K) 00 00 O Oo ^1 ^0 . ' -r o Key: n s negative t = trace; le s s than 30 m g / 100 m l urine i I 5 30 to 100 m g / 100 m l urine t 2 = 100 to 300 m g / 100 m l urine | 3 = 300 to 500 m g / 100 ml urine 44 = m ore than 500 m g / 100 m l urine n n nn nn nt t t n it n . n o , 18 24 42 4 3 t 42 4 1 43 4 t 44 li1 G * i "j o Dietary Level <PPm ) _ Sex 3 Control MN rN MN 100 FN u TA BLE XI TEST MATERIAL.: Aroclor 1260 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Urine Analyaea Data Summary of Mean Value Microacople Element a Month: 6 9 12 IS NNNN NNNt 24 41 t pH Month: 3 6 9 12 776 7 8a7 8 N N N Nt N N N tt 7767 7 8 6 7 O 18 24 76 66 66 66 v { i I ( , Konreru q O '` K00J KO Key: N= N orm al I s trace; lea than 5 per low power field 4 1 s 5 to 10 per low power field 42 s 10 to IS per low power field 4 3 s m ore than IS per low power field oN> rt,o o Dietary Level (ppm) Control 100 Sex M r M F o TA&LE XII TEST MATERIAL: Aroclor 1260 .j T w o -Y ea r Chronic Oral T oxicity Study- - Albino R a il Urine Analyse Data Summary of Mean Value S 1.029 1.020 1.021 . 1.016 6 1.022 1.019 1.025 1.023 Speciilc Gravity Month: 9 12 1.033 1.027 1.025 1.024 1.031 1.035 * 1.030 1.029 18 1.042 1.032 1.043 1.028 o 24 1.051 1.039 1.039 1.045 * 290 O O*T OO U> ?<\J at\\k B ' 'J I i I 30 F . Pathologic Studies 1 T h re e -M o n th S a c rific e 4 G r o s s P a th o lo g ic F in d in g s No outstanding differences w ere noted between teat 4&d c o n tr o l r a t s upon g r o s s p a th o lo g ic a l e x a m in a tio n . b. Organ Weight and Organ to 3odv and Organ to S ra m Ufeignt Ratio Data The results of the statistical analyses conducted on absolute organ weights* organ to body weight and organ to b ra in w eight ra tio s a re su m m arized in Tables XIII through XVIII. Significant differences between a test group and the control group a re designated by a ste ris k s following the test valu es. Organ weights* organ to body weighe and organ to b ra ;; weight ratios disclosed several randomly occurring intergroup differenci The lack of any consistent dose related resp o n se and the absence of any deleterious, histopathologic change confirm that these differences w ere not re la te d to the ingestion of A roclor 1260. ADM C 0 3 7<i 291 0 I oo o s-1, . -*,, TABLE XIII TEST MATERIAL! Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data % Three-Month Sacrifice Summary of Mean Values Organ; Liver Dietary Level of Aroclor 1260 (ppm) Control ro ID i 1 10 k 100 Organ Weight <B> Males F em ales 21.4 13.0 20.4 13.2 24.0** 12.2 29.5** 14.5 Organ/Body Weight Ratio ( g / 1 0 0 g) Malee F em ales 4.13 4.16 3.90 4.59 4.48 3.61 5.73** 4.58 O rgan/Brain Weight Ratio U /gl M ales Fem ales 10.3 6.82 9.98 6.66 11. B 6.38 14.4** 7.72 -f \J \J \J ** S ta tistica lly significant d iffe re n c e at the 99 p e r c e n t confidence le v e l. O * Lo ,) o1->JJ voT fl I T E S T K \ SlfcUUUi Ia O % Dietary Level of Aroclor 1260 fppml Cont rol 1 10 100 O TABLE XIV TEST MATERIAL: Ar o d o r 1260 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-Month Sacrifice Summary of Mean Values Organ: Kidneys O Organ Weight (g) Males F em ales 4.03 2.49 4.37 2.62 4.00 2.61 4.00 2.52 Organ/Body Weight Ratio (g/100 g) Males F em ales 0.782 0.802 0. 638 0.911 0.747 0.782 0.779 0.793 O rgan/Braln Weight Ratio (g/g) M ales F em ales 1.95 1.31 2.14 1.36 1.96 1.96 1.37 1.35 n i I o o Dietary Level of Aroclor 1260 lopml S M A lU O i Coni rot 1 10 100 O o uICs>hj ofa. - on uj O i TABLE XV TEST MATERIALS A roclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-Month Sacrifice Summary of Mean Valuea Organ: Spleen Q Organ Weight (g) Mal e a Female 0.766 0.578 0.846 0.516 o .a lB 0.612 0.7IB 0.556 Organ/Body Weight Ratio (g/100 g) Males F em ales 0.150 0.184 0.161 0.180 0.156 0.189 0. M0 0.177 O rgan/Braln Weight Ratio (g/gl M ales Fem ales 0.371 0.302 0.412 0.411 0.269 0.331 0.352 0.297 Mh ft t i a Dietary Level of Aroclor 1260 o C^j to oX VUOl oo uUol L U SU U tM Control 1 10 100 TABLE XVI TEST MATERIAL! Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-Month Sacrifice Summary of Mean Values Organ: Gonada O Organ Weight (g) Males Females 3.60 0.114 3.67 0.128 3.03 0.121 3.71 0.130 Organ/Body Weight Ratio ig /1 0 0 g) Males Females 0.690 0.0370 0.704 0.0450 0.715 0.0360 0.725 0.0429 O rgan/Braln Weight Ratio (g/g) Males Females 1.74 1.80 0.0599 0.0666 1.09 0.0636 1.61 0.0728 f % Dietary Level of Aroclor 1260 Ippm) Control g ltiU O O i 1 10 O CD M o\ o2 bOol 100 TABLE XVII I TEST MATERIAL: Aroclor 1260 .Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Threa-Month Sacrifice Summary of Mean Values Organ: Heart Organ Weight (g) Males F em ales 1.59 1.05 1.5? 1.01 1.58 1.04 1.52 0.946 Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales 0.307 0.339 0.300 0.353 0.296 0.311 0.296 0.297 O rgan/Braln Weight Ratio (fi/fi) M ales Fem ales 0.767 0.551 0.765 0.526 0.781 0.546 0.743 0.505 1 aO h. i o C r> j g4. \ * Dietary Level of Aroclor 1260 (ppm) Cont rol 1 10 too TABLE XVIII TEST MATERIAL: A roclor 1260 T w o-Y ear Chronic Orni Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-Month Sacrifice Summary of Mean Value Organ: Drain Organ Weight (g) Matea Female# 2.07 1.91 2 . OS 1.92 2.04 1.91 2.05 1.89 Organ/Body Weight Ratio (g/100 g) Males F em ales 0.402 0.616 0.392 0.672 0.380 0.572 0.400 0.593 Final Body Weights of Sacrificed Rata () M ales Fem ales 518 314 523 287 536 337 517 321 r,, i 4 V> f -i in Kj. ir O' 'O P P P f t '9 ACM OC3755 00 297 J+ lU J,wii B c. Histopathologic Findings Histopathologic exam ination of tissues and organs ta k e n f r o m a l l a n im a ls fro m b o th the c o n tro l an d 100 ppm g ro u p s was conducted. J T a b le s XDC an d XX l i s t a l l h is to p a th o lo g ic changes noted. All of the lesio n s noted in the m icroscopic examina tLofl o f t i s s u e s w e r e th o se of sp o n ta n e o u s d i s e a s e and a r e not u n u s u a l for the albino ra t. The m ost frequent findings w ere lesions in the trachea and lungs, indicating chronic murine pneumonia. These oc ? c u rre d in the control as well as the rats fed A ro c lo r 1260. * 10JVW 20 AD* C037 no 298 i - I C3 I , 33 T A B L E XDC T E S T M ATERIA L: A r o c lo r 1260 T w o-Y ear Chronie O ral Toxicity Study - Albino Rata Histopathologic Changes 4 Tkree-Moath Sacrifice Group: Control N u%m b e r of A nim als 5 Males 5 Fem ales i Organ Examined Trachea Lung U rinary bladder Lung Findings Tracheitis Chronic resp irato ry disease H yperplasia Chronic resp irato ry dlseaje Averag Incidence Grade 1 1.0 1 1.0 3 1.0 1 1.0 All other tissues and organs were normal histologically. Grading System 0 . 5 * minimal 1.0 a slight 2 .0 < mild 3.0 > m oderate 4.0 * severe 5*0 * extrem e ron w i ADM 0 0 3 7 oc 299 a i rt o TABLE XX T E S T M ATERIAL; A ro c lo r 1260 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Histopathologic Changes Three-Month Sacrifice C ro u p : 100 ppm Num ber of Animals Organ Examined Findings - Averag Incidence Grade 5 Males Trachea Lung Tracheitis Chronic respiratory disease 4 2 1.0 1.0 5 Fem ales Trachea Lung Tracheitis Chronic respiratory 3 1.0 disease 2 1.0 Kidney Focal lymphoid - infiltration 1 1.0 C AU other tissues and organs were normal histologically. Grading System 0 . 5 = m inimal 1.0 s slight 2 .0 * mild 3 . 0 * m oderate 4.0 * severe 5.0 > extrem e 1(1 0 0 3 2 2 A0M 00375 0 0 300 jruj. it DI^ i ea i 40 2* Six-M onth S a c rific e 4 G r o s s Pa th o lo g ic Finding a. No outstanding differences w ere noted between test and eontrol anim als. ' b . O rg an Weight and Organ .to Body in d Organ to Brain h e ig h t Ratio Data The re s u lts of the statistic a l an aly ses conducted on a b so lu te organ w eights, organ to body weight and o rg an to b rain weight r a t i o s a r e s u m m a r i z e d in T a b le s XXI through XXVI O rgan weights, organ to body weight and organ to b ra in weight ratios disclosed several randomly occurring intergroup differences. The lack of any consistent dose related response and the absence of any deleterious histopathologic change confirm that these differences w ere not re la te d to the ingestion of A ro clo r 1260. 1000923 AC* 0C375 OC 301 o Dietary Level of A roclor 1260 fppml Control 1 10 100 o TABLE XXI TEST MATERIAL: A roclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ilatio Data Six-Month Sacrifice Summary of Mean Values Organ: Liver o Organ Weight (g) Males F em ales 22.9 13.1 14. B 15.1 ` 19.0* 10.5* 24.4 11.6 Organ/Body Weight Ratio <g/100 g) Males F em ales 3.74 3.77 2.92** 3.74 3.11* 3 . 0B* 4.69* 4.03 Organ/Braln Weight Ratio (g/g> M ales Fem ales 11.7 6.71 7.05** 7.86 9.45* 6.07 12.3 6.17 tt b U U O l S ta tistic a lly sign ific a n t d ifference at tho 95 percent confidence level. *< S ta tistic a lly sig n ific a n t diffe re n ce at the 99 percent confidence level. 3 9 U o * vor BI1 TE5 T Dietary Level of Aroclor 1260 (ppm) Coni rol 1 IO 10 O T A B L E X X II TEST MATERIAL: A roclor 1260 T w o-Y ear Chronic Oral Tonicity Study - Albino Rate Organ Weight and Ratio Data Sin-Month Sacrifice Summary of Mean Value* Organ: Kidneys o Organ Weight (g) Male* Female* 4.04 2.79 3.64 2.73 3.85 2.35 3.92 2.35 Organ/Body Weight Ratio (g/100 g) M alee _____ F e m a le 0.664 0.806 0.716 0.674*/ 0.670 0.6B4* 0.753 0.814 Organ/Braln Weight Ratio (g/g) M ale*______ F e m a le 2,06 1.43 1.73 1,42 1.92 1.36 1.97 1.25 S6U U U * Statistically significant difference at the 95 percent confidence level. o.t o Uoi Oo o % Dietary Level of Aroclor 1260 fppml _ Control 3l 3 to 100 t a &l e x x iii TEST M ATERIAL: A ro c lo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino R ats Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values Organ: Spleen Organ Weight (g) Males F em ales 0.752 0.684 0.754 0.908 0.836 0.566 0.636 0.443* Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales 0.122 0.196 0.148 0.220 0.146 0.167 0. 122 0.151 Organ/Braln Weight Ratio (g/g) M ales Fem ales 0.384 0. 350 0.359 0.472 0.416 0.320 0. 327 0.216* * Statistically significant difference at the 95 percent confidence le v el. ADM 0037 o % Dietary Level of A roclor 1260 (ppmi Control 1 10 100 O TABLE XXIV TEST MATERIAL: Aroclor 1260 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Value* Organ: Gonads o Organ Weight (el Males F em ales 3.55 0.0960 3.23 0 . 120a 3.56 0.0968 3.53 0.0710 + Organ/Body Weight Ratio lg /1 0 0 g) Males F em ales 0.593 0.0279 0.636 0.0297 0.620 0.686 0.0287 . 0.0250 O rgan/B ra in Weight Ratio (g/g) M ales Fem ales 1.81 0.0492 1.54 0.0625* 1.77 . 0.0560 1.77 0.0378+ coun> 3o: Uor>i a S ta tistic a lly sign ific a n t difference at the 95 p e rce nt confidence level. vn TABLE XXV TEST MATERIAL; Aroclor 1260 T w o-Y oir Chronic Oral Toxicity Study - Albino l U t l Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values Organ; Heart Dietary Level of Aroclor 1260 (ppm) Control 1 10 ICO Organ Weight (g) Males F em ales t.70 I.OS u s 1.12 1.63 1.05 1.49 1.06 Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales 0.202 0.302 0.206 0.277 0.203 0.307 0.206 0 .360*e gb U U U :l O t- CJ oCTi Cl oo LM a Sta tistica lly aignificant difference at the 99 percent confidence level. Organ/Braln Weight Ratio (g/g) Males F em ales 0.867 0.530 0.690 0.583 0.810 0.606 0.749 0. 564 n (i I i u>>  r* TABLE XXVI TEST MATERIAL* A ro c lo r 1260 'Two-Year Chronic O ral Toxicity Study - Albino R ata Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Valuea Organ: Brain Dietary Level of Arocl9r 1260 (ppm) Control 1 10 100 Organ Weight (8 Males F em ales 1.96 1.95 2.10 1.92 2.01 1.73 1.99 1.88 Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales t 0.320 0.560 0.412* 0.474* 0.349 0.504 0.362 0.650* Final Body Weights of Sacrificed Rats U) M ales Fem ales 613 348 509 405 575 . 343 522 289 ubU O O i O * Sta tistically significant difference at the 95 percent confidence level. -j ooIk* cr TEST 4~ C. H is to p a th o lo g ic Findings H istopathologic examination of tissu es and organs ta k e n f r o m a l l a n i m a l s f r o m both the c o n tro l and 100 p p m groups was conducted. m T a b le s XXVII and XXVIII l i s t a 11 h isto p ath o lo g ic c h a n g e s noted. All of the lesions noted in the m icroscopic exam ination of tissues w ere those of spontaneous disease and are not unusual for the albino ra t. The m o st frequent findings were lesions in the traehea and lungs, indicating chronic m urine pneumonia. These occurred in the contr' a e w ell as the r a ts fed A ra e lo r 1260. inondi* ACM 0C37.6 0( 308 ? >1 * m J l 43 TABLE XXVII * T E S T M ATERIAL: A ro c lo r 1260 T w o-Y ear C hronic O ral Toxicity Study - Albino Rats Histopathologic Changes e Six-Month Sacrifice Group: Control Number of Animals Organ Examined Findings Ave rag Incidence 1 Grade 5 Males Trachea Tracheitis 2 1.5 Focal tracheitis 2 1.0 Lung Focal pneumonitis 1 0.5 * Hyperemia 2 1.0 Live r Focal pericholangitis 1 1.0 Skeletal m uscle Focal inflammation 1* 1.0 S Females Trachea Focal tracheitis 1 1.0 / Lung H yperem ia 2 2.5 Liver H yperem ia 1 1.0 Pericholangitis 1 0.5 Kidney Focal inflammation 1 1.0 ` r All other tissues and organs were normal histologically. Grading System . 0.5 a minimal 1.0 slight 2 .0 mild 3.0 * moderate 4.0 severe 5 .0 extreme 7 J ACH 0 C 3 7 yoO O ^l 309 00 . J 1 TABLE XXVIII T E S T M ATERIAL: A ro c lo r 1260 T w o -T e ar C hronic O ral Toxicity Study - Albino Rita Hittopathologic Changes Six-Month Sacrifice G ro u p : 100 ppm Number of Animals Organ Examined Findings Ave rag Incidence Grade 5 Males Trachea Lung Liver Tracheitis Focal tracheitis Focal pneumonitis H yperem ia H y perem ia Focal pericholangitis, 2 1 4 4 l 1. 2 .0 0.5 1.0 1.5 1.0 0.5 5 Females Trachea Lung Liver Kidney Focal tracheitis Focal pneumonitis H y perem ia H y perem ia Focal pericholangitis Focal nephritis 2 2 1 2 1 3 0.5 1.0 3.0 1.5 0.5 o .s AH other tissu e s and organs w ere normal histologically. Grading System 0.5 * minimal 1.0 slight 2.0 * mild 3*0 * mode rat 4.0 * severe 5.0 * extreme AOP CG37& 310 00 -TEST ?c. SO v 3 Twelve-Month Sacrifice a Grose Patholoclc Findings G ross pathologic findings among test animals were significantly different from those noted in control anim als. b Organ Weight and Ratio Data T h e m e a n o rg a n w eig h t an d r a t i o d ata c o lle c te d a t :: tw e lv e m o n th s a c r i f i c e a r e p r e s e n te d in T a b le s XXDC through XXXIV. ^ "* * Statistically significant differences are designated by a ste risk s following the test group value. O rgan weights, organ to body weight and organ to br weight ratios disclosed several randomly occurring intergroup,differences The lack of any consistent dose related response and. the absence of any deleterious histopathologic change confirm that these differences were not re la te d to the ingestion of A roclor 1260. j O o Dietary Level (ppm) Control l 10 100 oo TABLE XXIX TEST MATERIAL: A rodo r 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data Summary of Mean Values Organ: Liver Organ Weight (g) Males F em ales 22.1 15.5 17.1* 10.7* 20.0 13.6 20.8* 14.1 Organ/Body Weight Ratio (g/100 g) Males F em ales 3.79 3.52 2.79** 3.01* 3.30 3.54 4.26 3.79 Organ/Brain Weight Ratio (g/gj Males Fem ales 10.B 7.72 9.23 5.76 10.8 7.2B 13.4* 8.52 i Slatiatically significant difference at the 95 percent confidence level. Slati*lically significant difference at the 99 p ercent confidence level. Vo UJ % H* N) oo IP .o `.J Dietary Level (ppm) Control 1 10 100 o TABLE XXX TEST MATERIAL; Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data , Summary of Mean Values Organ: Kidneys Organ Weight (g) Males F em ales 4.04 3.84 3.19 2.58** 4.00 2.78* 5.11* 2.81 Organ/Oody Weight Ratio (g/100 g) Males F em ales 0.692 0.625 0.738 0.724 0.660 0.736 0.758 0.755 Organ/Brain Weight Ratio (g/g) Males Fem ales 1.97 1.58 2.06 1.39 2.16 1.48 2.38* 1.69 * Statistically significant difference at the 95 percent confidence le v e l. Statistically significant difference at the 99 percent confidence le v el. I \ ^ JOO QtfUUtfi n u % Ul Oo ^ \i ! \ -y oo Dietary Level (ppm) Control 1 10 100 TABLE XXXI TEST MATERIAL; Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data Summary of Mean Values Organ: Spleen Organ Weight (g) Males F em ales 0.778 0.796 0.756 0.460* 0.836 0.578 0.785 0.474* Organ/Body Weight Ratio (g/100 g) Males F em ales 0.133 0.183 0 . 122 0.129* 0.139 0.150 0.116 0.127* O rgan/Braln Weight Ratio (g/g| M ales Fem ales 0.380 0.408 0.396 0.247* 0.457 0 . 308 0.365 0.284 a O Uk-1 vo oo l>* Statistically significant difference at the 95 percent confidence le v e l. y*> , * O Dietary Level (ppml Control 1 10 100 ., o o TABLE XXXII TEST MATERIAL: Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data * Summary of Mean Values Organ; Gonads Organ Weight (g) Males F em ales 3.46 0.116 3.38 0 . 103 3.51 0.112 4.03a* o.oua* Organ/Body Weight Ratio (g/100 g) Males F em ales 0.596 0.0275 0.551 0.0287 0.578 0.0294 0.598 0.0238 O rgan/Brain Weight Ratio (g/g) M ales Female s 1.70 0.0574 1.82 0.0552 1.89 1.88 0.0584 0.0527 a * o KjJ Ul va X ao Statistically significant difference at the 95 percent confidence le v e l, Statistically significant difference at kite 99 p ercent confidence le v e l . i if r o Dietary Level Ippm) Control 1 10 100 oo TABLE XXXIII TEST MATERIAL: Aroclor'1260 f Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Twelvc-Montli Sacrifice a Organ Weight and Ratio Data / Summary of Mean Values Organ: Heart Organ Weight (g) Males F em ales 1.71 1.23 1.6B 1.07 1.59 1.16 1.86 1.27 Organ/Body Weight Ratio (g/100 g) Males F em ales 0.293 0.287 0.273 0.301 0.261 0.307 0.275 . 0.340 O rgan/Braln Weight Ratio (g/g) M ales Fem ales , 0.835 0.611 0.902 0.575 0.845 0.620 0.868 0.760 f onn<r 8 OOo O <* Dietary Level fnpml Cont rot 1 10 100 TABLE XXXIV TEST MATERIAL: Aroclor 1260 Two-Year Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Twelve-Month Sacrifice Summary of Mean Values Org an Weight (e> Malea F em ales 2,04 2.02 I.B7 1.86 1.88 1.90 2.15 I .67** Organ: Drain Organ/Body Weight Ratio (g /1 0 0 gj Mates F em ales 0.349 0.460 0.304 0.522 0.310 0.493 -0.318 0.449 Final Body Weight of Sacrificed Rats (grams) Males F em ales 584 439 616 356 607 385 675 372 317 * Statistically significant difference at the 99 percent confidence le v e l, O C"5 o -X r OO ip Xf II on J ni IA vOst' c. Histopathologic Findings Histopathologic examination of tissues taken from each r a t s a c r i f i c e d f r o m the c o n tro l and 100 ppm g ro u p s a f te r twelve m o n th s of testing was conducted. * Tables XXXV and XXXVI lis t all hisopathologic changes noted. All of the lesions noted la the m icroscopie exam ination of tis s u e s w e re those of spontaneous d isea se and a re not unusual for the albino ra t. The m ost frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. These occurred in the contr as w ell as the ra ts fed A ro c lo r 1260. ADtt C 03770 318 ooc 1o TABLE XXXV TEST MATERIAL; A ro c lo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rita Histopathologic Changes Twelve-Month Sacrifice Croup; Control N um ber of Animals 5 Males 5 Females Organ Examined TracheaLung U rinary Bladder Trachea Lung Colon Findings Incidence Tracheitis Chronic respiratory disease Calculus 1 2 l Tracheitis Chronic resp irato ry disease Paras ites 1 t* 1 l Ave. Cr; 1. 1. 1. 1. 1. 1. All other tissues and organs were norm al histologically. Grading Svstcrn 0.5 = minimal 1.0 = slight 2 .0 : mild 3.0 a moderate 4 . 0 severe 5.0 * extreme ADM C 03777 00 3V* i -t J* rs 5 r ;v*i 3? TABLE XXXVI TEST MATERIAL: A ro c lo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rita Histopathologic Changes Twelve-Month Sacrifice G ro u p : 100 ppm N um ber of,.. Animals Organ Examined 5 Males Trachea Lung * Kidney Liver 5 Females Trachea Lung Findings Tracheitis Chronic resp irato ry disease Focal lymphoid infiltration Vacuolar change of .random cells Tracheitis Chronie resp irato ry disease Incidence 1 3 L 1 1 1 Ave ra Crac 1.0 1.0 1.0 1.0 1.0 1.0 All other tissues and organs were normal histologically. Grading System 0.5 a minimal 1.0 i slight 2 .0 * rnild 3*0 * moderate 4*0 * severe 5*0 extreme , ^r \ o- r*y> \ 0 * - ? V- ACM 0 0 3 7 7 8 OC 320 a i - T E 5 r ig.'vi*. 00 4. fin a l Sacrifice a. Cross Pathologic Findings G ross pathologic findings among test animals were not significantly different from those noted in control anim als. b. Organ Weight and Ratio Data The m ean organ weight and ra tio data collected at the final s a c rific e a re p re sen te d in Tables XXXVII through XLII. S tatistically significant differences a re designated by a s te ris k s following the test group value. A bsolute liv er weights and liv er to body weight or liv e r to b ra in weighe ra tio s w e re significantly elevated in those ra ts fed 100 ppn A r c e l o r 1260'. O th e r o rg a n w e ig h ts, o rg a n to body w eig h t and o rg a n to b rj weight ratios disclosed several randomly occurring Intergroup differences The lack of any consistent dose related resp o n se and the absence of any deleterious histopathologic change confirm that these differences were n o t r e la te d to the in g e stio n of A ro c lo r 1260 AOH 0C 3 7' 321 0( V. J \> zoo c *^*<7^-7* 1 S 3 1 * o 1B TW T*v ielary Level (ppm) onlrol 1 10 00 TABLE XXXVII ' TEST MATERIAL* Arocior 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rate Organ Weight and Ratio Data i Summary of Mean Value Final Sacrifice Organ: Liver Organ Weight (sl Male Female 22.0 16.3 22.0 16.6 Organ/Body Weight Ratio (g/IOOg) Males F em ale 3.47 3.05 3.40 3.35 24. 1 29.9*4 18. 1 22.7** * 2. 87 + 4.67++ 3. 19 4.42* Statistically significant d ifference at the 95 p e rcen t confidence le v e l. ` S u tisttfo lly significant difference at the 99 percent confidence level, Ul i> MKJ o? Organ/Brain Weight Ratio (e/e) Males Fcma les 10. 10 8.42 9.91 8.62 11.20 9. 26 13.40 11. 6 0 ( v 0 TABLE XXXIX TEST M ATERIAL: A ro clo r1260 * t Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata "* Organ Weight and Ratio Data ^| Sum m ary of Mean Value a . Final Sacrifice t I j Organ: Spleen * | V Organ Weight Organ/Body Weight Ratio O rgan/Brain Weight Ratio ^ ticiary Level (g) ( g / 100 g) (g/gl <ppm) ^ _____ Malea_____________F e m a le a _________ M ales _________ F e m a le s ____________ M a le s F em ales `. o n l r o l 1 **i 10 2O I 0 0 1. 15 1. 17 1.09 0.89 0.96 0.72 0.63 0.75 0. 182 0. 178 0. 1J 1 0. 138 0. 181 0. 148 0 . 142 0. 146 0.520 0.529 0. 509 0.400 0.492 0. 370 0.428 0. 379 S ytjO U U il O o ( i u> CtoJ ot o . * i LootJ o Dietary Level lonnil Control 1 10 100 o TABLE XL TEST M ATERIAL: A ro clo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data i Sum m ary of Mean Valuea Org an Weight Males <g) F em ales 2.52 0. 123 3.56* 0. M0 Final Sacrifice Organ: Gonads Organ/Body Weight Ratio (fi/IOOg) Males F em ales 0. 397 0.0222 0.550* 0.0317 3.36* 0. 177 0. 400 0.0338 2.97 0. 113 0.464 0.0229 > S ta tistica lly significant difference at the 95 p ercen t confidence le v e l. o O rgan/B rain Weight Ratio (b / c) Males F em ales 1. IS 0.0628 1.61* 0.0718 1.56* 0.09 I. 33 0.0584 tec JO 99UUU1 ADM 003782 n oo Dietary Level (ppm) Control 1 10 too TABLE XLI T E ST M ATERIAL! A ro c lo r 1260 T w o-Y ear Chronic O ral Toxicity Study - Albino R ats Organ Weight and Ratio Data Sum m ary of Mean Values Final Sacrifice Organ; H eart Organ Weight (e) Males F em ales 1.87 1.54 1.98 1.45 Organ/Rody Weight Ratio (e/ioo e) Males F em ales 0.294 0. 288 0.304 0.294 1.90 1.58 0.225*4 0 . 279 2.00 1.49 0.313 0.288 tfb U U U i 0 O u> to --1- Sta tistica lly significant d ifferen ce at the 99 p ercen t confidence le v e l. X o o u> Organ/B rain Weight Ratio t (/) Males F em ales 0 . 860 0.795 0.893 0. 747 0.884 0.809 0.904 0.764 oO c. Histooathclocic Findings Histopathologic exam ination of tissues and organs U k e n f r o m a ll a n im a ls s a c r if ic e d a f te r 24 m o n th s on teat was conducted. Table'XLfll through XLVI lis t ail histopathologic chan noted.* Table XLVU contains the re su lts of the histopathologic examinatic of the u rin a ry bladders. S ig n ific an t liv e r in ju r y w a s found in a n im a ls fed 100 p p r A r a cl o r 1260 (T-III). The compound a s s o c ia te d lesions consisted of vacut change, focal h y p ertrophy and focal h y p e rp la sia . In addition, th e re w ere lesio n s of inflam m ation, n e cro sis, fib ro sis and m inor degeneration in this g ro u p w h ich , a lth o u g h s e e n in the c o n tr o ls an d lo w e r t e s t g ro u p s , w e r e me sev ere and frequent in the T-III group. The v a c u o la r chvig w as not seen iri the c o n tro l a n im a ls b u t w as o b s e rv e d occasio n ally in liv e rs fro m T - I (lppm ) and T*ll (10 ppm) a n im a ls. It was frequent in the T-III an im als. This lesion is morphologic indicative of fatty degeneration. F o rm alin -fro z e n sections of livers from rep resen ativ e anim als whieh displayed vacuolar changes were stained with Oil Red 0 to re v e a l the p resen ce of fat. The v a c u o la r lesion in the cytopia of these cells was positively identified as fat. The hypertrophic change found in the liver was focal and Often lim ited to the central lobular a re a w here groups of cells w ere swollen to two or three times their norm al size with clear pink homogenous cytopia The h y p erp lasia was associated with the sam e cells and appeared to be an in n n *u 8 AC* C0376* 0! 32 S 1 * 0+ u i * * i < w * te n s io n of the hypertrophic lesion. The h y p erplastic cells were also usually hypertrophic. The most severe exam ples of hyperplasia appea: ae nodular grow ths with lim ited co m p ressio n of the surrounding n o rm a l hepatic tissue. * The m inor lesions of degeneration, hepatitis, ductule p ro liferatio n , n e cro sis and focal lymphoid in filtratio n seen in the contra anim als and the T -Ia n d T-H groups are lesions of spontaneous disease i a r e not re la te d to the A r o d o r 1260. This le v e l of liv e r disease is not un In old anim als. H yperplasia of the u rin a ry b la d d er was found in an an ir fro m the control group. This finding was not p re s e n t in any of the ra ts f A ro c lo r 1260. All of the other lesions in o th er tissu e s found in th e se 'an i a r e related to spontaneous disease and they a re not unusual for old ra ts .' D onovan . C o rd o n , C. V. M . , P h . D. D lplom ate, A m erican College of V eterinary Pathologists Fnnn?w 9 ACM CC2 7 oc 327 oo o Dietary Level . /ppm) Control 1 10 \B S 100 T A B LE X L II TEST MATERIAL: Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino R ate Organ Weight and Ratio Data i Summary of Mean Values Final Sacrifice Organ Weight <g) Malea F em ales Organ: Brain Organ/Body Weight Ratio tc/lOOfil Males Female Final Body Weight of Sacrificed Animals (gram s) Males Fem ales 2. 18 1.95 0. 342 0.362 642 551 2.21 2. 15 1.94 1.96 0.343 0.255** 0.407 0. 347 654 84$** 525 584 2.22 1.95 0.346 0. 378 641 644 --\ c* Statistically significant difference at the 99 percen t confidence le v e l. u* KJ ADH 00378* CO O' o y oo Number of Animals 11 Males IStiUUUft > to v> OX o oUi CLl T A R L E XL1IK TEST MATERIAL: A roclor 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Group: Control Organ Examined H eart Trachea Lang Liver Stomach Spleen Kidney T e stes Prostate Adrenal Gland Brain Eye Findings Chronic focal m yocarditis Tracheitis Chronic respiratory disease Focal degeneration Ductile hyperplasia Chronic gastritis Hem osiderosis Chronic nephritis Testicular degeneration P e ria rte ritis in flam m ation Telangiectasis Nodular hyperplasia Focal fatly change Focal encephalitis Inflammation Incidence 3 3 9 I* 2 1 3 8 2 2 1 1 1 1 2 ; o A verage Grade 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 l.d 1.0 I I i f voi OO TABLE XLIII continued TEST MATERIAL; Aroclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Histopathologic Change# Final Sacrifice Group; Control Number of Animals Organ Examined Findings Incidence N Females Heart Trachea Lung Liver Stomach O t--s u> OJ o o*r oo OD CD Colon Spleen Uterus Kidney Ovary Adrenal Gland Salivary Gland All other t i s s u e s and organs w* r* n n r m l Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal lymphoid infiltration Ductile hyperplasia Focal hepatitis Nun-lipid vacuolar change Chronic gastritis Acanthosis - squamous epithelium Parasites H em osiderosis Metritis Chronic nephritis Focal lymphoid infiltration Cyst Telangiectasis Nodular hyperplasia Chronic fibrosis and atrophy 7 9 13 3 2 1 2 3 5 1 4 3 6 1 1 9 4 i - O Average Grade 2.0 1.0 1.0 1.0 1.0 1.0 ' 0. 5 1.0 1.0 1.0 1.0 2. 0 1.0 1.0 1.0 1.0 1.0 1.0 O-I B 1u - T E S T / V XZZ I V o TABLE XLIV T E ST M ATERIA L: A r o d o r 1260 t Two-Year C h r o n ic O r a l T o x ic ity Study - A lb in o R a t a Histopathologic Changes Final Sacrifice Group: I ppm * Number of A n im a ls ________ O rg a n E x a m in e d 11 M ales Heart Tra cltea Lung Liver O k> o Pancreas Stomach Spleen Lymph Node Kidney Testes Prostate Semina* V esicle Findings Chronic focal m yocarditis Tracheitis Chronic respiratory disease Focal hepatitis Focal scarring H em osiderosis Chronic focal pancreatitis Acute focal g astritis H em osiderosis Congestion Chronic nephritis Testicular degeneration Periarteritis Inflammation Inflammation . Incidence A 7 10 1 1 1 2 1 1 1 7 1 2 A I o oU1 A verage G rade 1.0 1.0 2.0 1.0 1.0 1.0 1.0 3.0 1.0 1.0 2.0 1.0 2. 0 2.0 Oo o Number of Animals 11 M ales TABLE XLIV continued TEST MATERIAL; A roclor 1260 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats H isto p a th o lo g ic Changesi Final Sacrifice Group; I ppm * Organ Examined Adrenal Gland Findings Nodular liyperoplasia Focal fatty change Average Incidence_______________G rade _ z2 1.0 1.0 14 F e m a le s O O UUii to o oo Heart Trachea Lung Liver Stomach Chronic focal myocarditis Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal fibrosis Focal lymphoid infiltration Ductile hyperplasia Congestion Vacuolar change (fatly) Chronic gastritis Acanthosis , 3 1 9 13 1 1 1 1 1 1 2 1.0 3.0' 1.0 1.0 1.0 1.0 0 . i> 1.0 2. 0 1.0 1.0 j f Knnn955 Number of Animals 1-1 F e m a le s >o * ou* -J TABLEXLIV continued T E ST M ATERIAL: A ro c lo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rate Histopathologic Changes Final Sacrifice Group: I ppm ' Organ Examined Stomach Colon Spleen Lymph Node Kidney Uterus Adrenal Gland Findings Ulceration and acanthosis Parasites Hemosiderosis Hyperplasia Congestion Chronic nephritis Vacuolar change (fatty) Metritis Telangiectasia Nodular hyperplasia Congestion Incidence 1 1 II 1 1 3 1 4 9 3 1 All other tis s u e s and organs w ere norm al h is to lo g ic a lly . 0.5 s minimal Grading System . 0 = mi* * Average Grade t.O 1.0 1.0 1.0 1.0 2.0 . 1.0 1.0 1.0 1.0 1.0 000 333 V. J' Number of Animals 7 Males w o 2 25 s TABLE XLV T E ST M ATERIAL: A ro clo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rate Histopathologic Changes Final Sacrifice . G ro u p ; 10 p p m * Organ Examined Heart Trachea Lung Liver Stomach rS p l c e n Kidney Prostate Adrenal Gland Findings Chronic focal m yocarditis Tracheitis Chronic respiratory disease Suppurative pneumonia V acuolar change (fatly) Chronic gastritis Acanthosis H em osiderosis Chronic nephritis Inflammation Nodular hyperplasia Incidence 3 2 5 1 2 1 2 3 6 2 1 O tj ti. N Females Heart Trachea Lung Chronic focal m yocarditis Thracheitits Chronic respiratory disease 3 B 14 o Averag< G rade 1.0 1.0 1.0 3.0 1.0 1.0 1.0 1.0 1.0 1.0 . 1.0 1.0 1.0 1.0 4 C037 r r O i TABLE XLV continued T E ST M A TER IA L: A ro c io r 1260 Tw o-Y er Chronic O ral Toxicity Study - Albino R a ti Histopathologic Changes Final Sacrifice G ro u p : 10 p p m ' 335 Number of Animals I-I F c m .ilc s oX oo C D oI-KJ JU)l Organ Examined Liver Pancreas Stomach Spleen Kidney Uterus Pituitary Adrenal Gland Findings V acuolar change (fatty) Focal hyperplasia Chronic focal pancreatitis Periarteritis Acanthosis H em osiderosis Chronic nephritis M etritis Congestion Telangiectasis Nodular hyperplasia Congestion Incidence 1 1 1 1 1 12 10 . 7 1 7 1 1 All other tissu e s and organs w ere no rm al histologically in in A verage G rade 1.0 1.0 3.0 3.0 1.0 1.0 1.0 2.0 1.0 1.0 1.0 1.0 *rm<7Pver- fi /i\ o I o f TABLE XLVI o T E ST M ATERIAL; A ro c lo r 1260 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata * Histopathologic Change j Final Sacrifice G ro u p ; 100 ppm Cumber of A n im a ls ________ O r g a n E x a m in e d 10 M ales Heart Trachea Lung Liver gybU U M O O o> cn oUo--*J I. Pancreas Stomach Spleen Kidney 1 F in d in g s __________________________ Chronic focal m yocarditis Tracheitis Chronic respiratory disease Congestion Vacuolar change (fatty) Focal degeneration Congestion Centrolubular hypertrophy Telangiectasis Chronic focal pancreatitis Inflammation Acanthosis 1I c m o s id e r o s is Focal lymphoid Infiltration Calcificd-concrctions~innpelvta A verage In c id e n c e ______________ G r a d e 5 1.0 8 1.0 9 2.6 1 1.0 2 2.0 1 1.0 3 2.0 2 1.0 1 1.0 2 1.0 2 2.0 2 1.0 7 1.0 1 _________ . 0_ 1 1.0 1.0 c r r oo Number of Animals 10 M ales J 5 5 15 F e m a le s 3 oo Co Co VJ o X onlO TABLE XLVI continued TEST MATERIAL: A roclor U60 T w o-Y ear Chronic O ral Toxicity Study - Albino R ata Histopathologic Changes Final Sacrifice G ro u p : 100 p p m ' Organ Examined Kidney (continued) Testes Prostate Thymus Adrenal Gland Findings Calcified concretions in pelvis A spcrm ia Inflammation Cyst Telangiectasia Modular hyperplasia Incidence 1 1 1 1 3 1 H eart Trachea Lung Liver Chronic focal m yocarditis Tracheitis Chronic respiratory disease Congestion Edema Vacuolar change (fatty) 5 8 It 1 1 5 A verage G rade 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 r Number of Animals IS F em a les 1 >Q Tr nou> --n1 o A l l ^>11< ** TABLE XLVI continued T E S T M A T E R IA L : A r o c l o r 1ZA0 T w o-Y ear Chronic O ral Toxicity Study - Albino R ate Histopathologic Changes Final Sacrifice G ro u p : 100 ppm* Organ Examined Liver (continued) . Pancreas Spleen Kidney Uterus Pituitary Adrenal Gland Parathyroid ,_.t - Findings Focal hyperplasia Chronic inflammation of liver capsule Cenlrolobular hypertrophy Necrosis Ductile cell hyperplasia, portal fibrosis and widespread eosinophil' inclusions in hep.iiocyte cytoplasm Chronic focal pancreatitis and periarteritis H em osiderosis Chronic nephritis Metritis Congestion Telangiectasis Nodular hyperplasia Congestion 1l y p i r rplasia Incidence 4 1 5 2 1 1 9 8 7 I 6 1 1 1 Average Grade 1.0 1.0 1.0 2. 0 1.0 3.0 2.0 1.0 1.0 1.0 I. 0 1.0 1.0 1.0 1/100960 r f c i\ r oo Group C T-I * (I ppm) T -ll <10 ppm ) T-III (100 ppm) tfABLE XLVH T E ST M ATERIAL: A ro c lo r 1260 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes of the U rinary Bladder Final Sacrifice Number Sex Examined Findings* M 11 F 14 P ro tein aceo u s plug (34) Focal epithelial h y p erp lasia (62) M 10 F II P ro te in a c e o u s plug (86( 105, and 107) None M7 F 14 Proteinaceous plug (187) None M 10 F 14 P roteinaceous plug (271) . None ISfcU U U * * Individual animal num bers are. shown in parentheses. O '` uVU>> o -X ooUi Grading System 1.0 - minimal or trace 4.0= severe 2 .0 --mild 5.0 = extreme 3.0 = moderate Incidence 1 1 3 - i 1 - 1 - A verage G rade 1.0 - rAd* a iw i c j i G. D etailed D escription of Tum or Findings Tum or data for individual anim als including location, weight and pathologic classification a re presented in Tables XLVIII through LI. Nona of these tum ors could be related to the ingestion'of Aroclo 1260 and a r e co n sid ered norm al for a ran d o m population of ra ts this age. 1000962 AO* 003 0( 340 O Animal umbe r *nd Soc Location ' 1-M Abdomen 2-M Pancreas - J 6'F D S * 7' F W `B' F 50-F Abdomen Lymph node l Abdomen Abdomen -r LJ * fc *h** 5 9 - Fr O __;____ i.4- F -^a Abdomen Abdomen Adrenal gland Abdomen O .1 TABLE XLVIII TEST M ATERIAL: A roclor 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino R ats Description of Tum or Findings Group; Control W elght_ (gram s) - 11.76 Size (cm) - C lassificatio n M am m ary fibroadenoma A denocarcinom a 64.98 35.09 8x1x2 5x2x2 M am m ary fibroadenoma , M amm ary fibroadenoma ' - Reticulum cell sarcom a - 2 x 2 x 1 M am m ary fibroadenoma . 88.92 2x2x3 v* - 13 x 11 x '4 M am m ary fibroadenoma M am m ary fibroadenoma M am m ary fibroadenoma PhcocKromocy toma F ibroadenom a O ? M onths ---------o n ------- Teat 24 24 24 1 1 1 24 24 7 24 24 < ?i ii o Animal Number and Sex 9 9 -M 127-F 12B-`p 138-F 141 - F 151 - F 152-F n x oo Location Pituitary Pituitary Abdomen Pituitary Abdomen Abdomen Pituitary Ovary Abdomen Abdomen o I TABLE XUX TEST M ATERIAL: A roclor 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rate Description of Tum or Finding Group: 1 ppm Weight (gram e) - - 25.00 - -60.80*'' 20.07 - * 14.89 540.00 Size (cm) - - 6x5x1 5x6x2- - 13 x 15 x 2 * C laeeiflcatlo n 'Chromophobe adenom a / Chromophobe adenoma 1 M ammary fibroadenoma f Chromophobe adenoma *" M a m m a r y f ib r o a d e n o m a * .< *M ammary fibroadenoma t Chromophobe adenoma i 'Adenoma M ammary fibroadenoma t M ammary fibroadenoma Month on Teot 20 24 21 .1 * *24 24 24 22 - -------------------- - tttbUUUtf iV (K r KonOfUi5 Animal Number and Sex ' 205-F 20B-F 211-F 3 2 ,t-F 3 220-F 221-F Ui to ri X o TABLE L TEST MATERIAL: A ro clo r 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Description of Tum or Findings G roup; 10 ppm Location Weight (grams) Abdomen 19 0 .0 0 Pituitary - Abdomen - Right shoulder I3B.00 Abdomen Pituitary 9. 57 - Suhmaxlllary region Abdomen 14.44 29- 0 Size <c m )_____________ 9x5x4 C lassificatio n ^ M ammary fibroadenoma - <C h ro m o p h o b e a d e n o m a - i M amm ary fibroadenoma ( - ^ Subcutaneous tum or - `'M a m m a ry fibroadenom a - / Chomophobc adenoma 2 x 3 x - l -- :---------i- F ib r o a d e n o m a 3 x5x2 i Mammary fibroadenoma M onths on Teat 24 24 24 23 24 ( Animal Number and Sex V 2 2*- F 233-F 234-F Location Left femoral region Pituitary Abdomen Panercaa TABLE L continued TEST MATERIAL: A ro clo r 1260 Two-Yc&r Chronic O ral Toxicity Study - Albino Rata Description of Tum or Findings G ro u p ; 10 ppm Weight (gram s) 56.00 Size 6x8x2 C lassificatio n ^S ubcutaneous tumor 60.82 6x4x3 K Chromophobe adenoma M ammary fibroadenoma ^ Islet cell adenoma t I i M onths on Test 6 24 24 s I<n o o 9 f oo u* i o o oUft)J / V > a Animal Number and Sex Location 244-M Pancreas 26-fl-M Pancreas 2B1-F Abdomen 293-F Liver 294-F 301 iF i Abdominal cavity Liver * *r> tooo tb wmm s 2> STi Si o I TABLE U TEST MATERIALI A roclor 1260 Tw o-Y ear.C hronic O ral Toxicity Study - Albino Rata Deacriptlon o Tumor Finding! G roup: 100 ppm Weight (grama) 35.04 50.75 i. Size (cm) * m 6 x 4 at 2 6x4x3 - C la ssific a tio n * Adenoma j^Islet cell adenoma ^ M am m ary fibroadenoma * L ym phosarcom a ^ Fibroma L ym phosarcom a * * a M onths on Test 24 21 24 23 24 23 345 * 1 Animal Number and Sex ' 102-F 308-F *J l l - F Location Lymph node Pituitary Abdomen 312-M 314-F S A Z2 Co Ol o too Pituitary Abdomen Q TABLE LI continued TEST MATERIALI A roclor 1260 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rate Description of Tum or Findings G roup: 100 ppm W eight (gram a) - - 14. 00 - - 26.00 Sire (cm) - - 4x3x2 1x2x 1 - 5x4x3 C lassificatio n Y Lymphosarcoma ^'Chrom ophobe adenoma ''Mammary fibroadenom a Mammary fibroadenoma ''chrom ophobe adenoma ^ M amm ary fibroadenoma 3 M onths on Teal 24 24 24 24 24 if. * r/ B 1C T E S T ,V- R E P O R T TO MONSANTO COMPANY TW O-YEAR CHRONIC ORAL TOXICITY WITH AROCLOR 1254 IN ALBINO RATS NOVEMBER 12, 1971 13T NO. B7298 L Introduction At the req u est of Monsanto Company, a tw o -y ear chronic o ra l toxicity study was conducted using albino ra ts to determ ine the potential toxicity of A roclor 1254, Lot No. AX-38. The following re p o rt rep resen t the re su lts of this investigation. O V nnn969 ACM 0035* 00 347 B 1C JT S T Jrtc. z II, S u m m a r y A tw o -y ear chronic toxicity study was conducted using albino rats fed d ie ts c o n ta in in g 1 (T -I), 10 (T -Il) o r 100 (T -III) ppm A ro c lo r 1254. Food consum ptio n was not a lte re d in any te st g ro u p . Body weight gains A f t e r 24 m o n th s f e m a le s fed 1Q0 ppm A r o c l o r 1254 had gained le ss 'w eig h t than the co n tro l fem ales. Weight gains of the m ale rats did not differ f r o m the c o n tro ls . The num ber of anim als dying and the tim e a t w hich deat. occurred did not differ among test and-cantrol groups. H em atological and clinical blood chem istry studies conducted after 3, 6, 9. 12, 18, o r 24 months did not re v e a l any affects re lated to A ro c lo r 1254. U rine analyses failed to reveal any d ifference between test and -control rats. * *' A t s a c r i f i c e a f t e r 3, 6, o r 12 m onths on t e s t , o r g a n w e ig h ts, o r g a n to body w eight and organ to brain weight ra tio s d isc lo se d s e v e ra l random ly o ccurring in terg ro u p d ifferences. The lack of any co n sisten t dose re la te d resp o n se and the absence of any deleterious histopathologic change c o n firm that these differences w ere not related to the ingestion of A roclor 1254. A t the final s a c rific e a fte r 24 m onths on te a t, the absolute liv e r w eight and liver to body weight or brain weight ratios w ere significantly elevated i a b oth T - I U m a le s and fe m a le s . H istologic e x a m in a tio n s of the l i v e r s f r o m the T - I H g ro u p re v e a le d s e v e r a l animal.** u. ilh v a c u o la r ch an g e. Fon0970 AD* 0035 41 O C 348  [ C T = 5 T 3 T h is lesion is m orphologically indicative- of fatty degeneration. Specific f a t s ta in s c o n firm e d the p r e s e n c e of fa t in th e se v a c u o le s . F o c a l h y p e r t r o and focal h y p e rp la sia w ere also found in the liv e rs ,from anim als fed A r o c lo r 154. H y p e rp la sia of the u rin a ry b lad d er was found in an im als fro m the cor.t g ro u p and fro m each of the te st g ro u p s. This h y p e rp la sia was u su ally associated with cystitis. None of the tum ors found could be related to the ingestion of A ro c lo r 1254 and a r e co n sid e re d n o rm a l for a random population of ra ts th is age. Respectfully submitted, INDUSTRIAL BIO-TEST LABORATORIES, INC. P h ilip Sc. S m ith , B .S . A ssistant Toxicologist Rat Toxicity Jam es B. Plank Senvpr Group Leader Rat Toxicity Paul L. W right, Pii. D. Section Head, Toxicology N o vem ber 12, 1971 bb:hp 1000971 ACM OC 349 OC 3 l 0 T E S T J a ito A A ia iu c u y*c. 4 Ill- P rocedure- A. E xperim ental Animals The anim als employed in the teat w ere C harles River Strain-1 albino r a ts . P o u r hundred ra ts (200 m ale and 200 fem ale) w ere s e le c te d for the e x p e rim e n t, ear-p u n ch ed with the anim al num ber assigned and housed individually in standard w ire-bottom ed steel rat cages. Each cage bore a c o lo r-c o d e d card identifying the ra t w ith re sp e c t to p ro je c t num ber, d ie ta ry level assignm ent, individual num ber and sex. B. O rg a n iz a tio n of G roups A s tr u c t u r a l outline of the ex p erim en t is given in Table I. TABLE I TEST MATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study Albino Rats O utline of E x p e rim e n t Grouo N um ber of A nim als Male Fem ales Dietary Level (oom) C o n tro l T-I T -n T -m 50 50 None A d m in istered / 50 50 1 50 50 10 50 50 100 * Charles R iver Breeding Laboratories, North Wilmington, M ass. 100(1972 m u r. 03 541 350 0 ' B IOj r d -J.'-jjzI T C S T >*.:. s C. D ie ts t Feeding and Food Consumption A ll d ie ts w ere p re p a re d in the c e n tr a l d iet ro o m of this laboratory. The basic ration from which all diets were constructed was a standard, pulverized stock ra t ratio n -. The diet for any given te st group was p re p a re d by blending the calculated am ount of A rocior 1254 w ith a pre-w eig h ed portion of the stock ratio n in a H obart m iner. F r e s h diets w ere prepared each week and every rat was offered an amount of food sufficient for ad libitum feeding. Food consumption was recorded for five rats of each sex In ev ery group weekly for. the first th ree months and m onthly for the next nine months. T hereafter, periodic spot ehecks were made. D. Body Weights and V/eicht Gains In itially , the body weight of each r a t in every group was d e t e r mined and recorded. T hereafter, individual weighings w ere made w eekly fo r the f i r s t 13 w e e k s and m o n th ly t h e r e a f t e r u n til the c o n c lu sio n of the investigation. E. M ortality and Reactions Checks for m ortality and abnorm al behavioral reactions w ere made i daily throughout the investigation. ` r. F . H e m a to lo g ic S tu d ies *r.d U rin e A n a ly s e s Blood studies, including determ inations of hemoglobin co n cen tra tion, hem ato crit value, erythrocyte count and both total and differential * Purina R at Chow, R alston Purina Co. St. Louis. Mo. l o n n T O AO* 0 C 3 ` 351 0 s :o 7 1 1 : leukocyte counts, w ere conducted upon five m ales and five fem ales from b o th the c o n t r o l and 100 ppm g ro u p s , e U rine analyses for the presence of glucose, albumin, m ic ro scopic d e m e n t s , and d eterm in atio n s of pH and specific gravity w ere c o n d u c te d upon u r i n e s a m p l e s a t the s a m e tim e in te rv a lla and fro m the s a m e anim als as those employed for the blood studies. T h e s e s tu d ie s w e re co n d u cted a f t e r 3, 6, 9,* 12, 18, and 24 months of feeding. G. C linical Blood C hem istry Studies D e t e r m i n a t i o n s of blood u r e a n itr o g e n concie n tra tio n (BUN), s e r u m a lk a lin e p h o s p h a ta s e a c tiv ity (SAP), f a s t e d b! ood g lu c o se c o n c e n tration and seru m glutam ic-pyruvic tran sam in ase activity (SGPT) w ere conducted a f te r 3, 6, 9, 12, 18, and 24 m o n th s of feeding upon the sa m e ra ts as w ere the routine blood studies. H. P a th o lo g ic Studies When an anim al succumbed during the test period, a gross autopsy w as p erfo rm ed . In those case when p o stm o rte m autolysis was not a d vanced, rep resen tativ e tissues w ere taken and p reserv ed in ten percent form alin solution for possible future histopathologic study. - A f t e r 3, 6 , and 12 m o n th s of te s t i n g , fiv e a n im a ls of e ac h s e x f r o m each group w ere sacrificed and subjected to com plete gross pathologic exam inations. A bsolute organ weights w ere re c o rd e d and organ to body weight and organ to brain weight ratios computed. The following organs were Fnnn<m ACM 0 0 3 5 0\ 352 BIO-TEST In c lu d e d : l i v e r , k id n e y s , s p le e n , g o n a d s, h e a r t anci b r a i n . T h e s e d a ta w ere then subjected to statistic a l analysis. An A nalysis of Variance was conducted first and significant effects disclosed by that treatm ent w ere f u r t h e r s tu d ie s by " t H- t e s t s . Com plete m icroscopic examinations w ere conducted upon the t i s s u e s and o r g a n s f r o m a ll c o n tro l and 100 p p m g r o u p a n im a ls s a c r if ic e d a f t e r 3, 6, o r 12 m o n th s of te s t in g . The fo llo w in g t i s s u e s and o rg a n s w ere included in the exam inations: heart, tra c h e a , lungs, liver, p an creas, k esophagus, stom ach, sm all intestine (duodenum, jejunum and ileum), caecur colon, spleen, lymph nodes, kidneys, urinary bladder, gonads, prostate gland, sem inal vesicles, uterus, pituitary gland, adrenal glands, salivary glands, thyroid gland, parathyroid glands, skeletal m uscle, sternum , bone, perip h eral nerve, spinal cord'and brain (cerebrum , cerebellum and pons). The aforem entioned tissues w ere p rep ared and stained with Hematoxyiin-Eosin stain. e A lter two years of feeding, all surviving anim als w ere sacrificed and subjected to complete gross pathologic exam ination. The abso lu te w eights of the liv e r, k id n e y s, sp leen , gonads, h e a r t and brain w ere recorded immediately afler sacrifice. M icroscopic examinations were conducted upon tissues and organs from selected an im als dying during the e x p erim en t and upon all anim als fron the final sacrifice. F000975 ACM OG35 OC 3 5 3 ^d 0 U TEST J i 3 T issu es and organs exam ined w ere the sam e as those previous] m en tio n ed . % U Tum or Incidence and Classification A ta b u la tio n of t h e 'in c id e n c e of tu m o r f o r m a ti o n in each g ro u p w as m ade a t the conclusion of the in v e stig a tio n . In addition, tum or d a ta for individual anim als including location, weight, sice and pathologic classification were recorded. 1 I AC C03552 0 354 ( 3 1 I S 3 I -J-* * , v > v,.- ? 7 IV. Resulta A. 3 odv Weights and Weight Cains The m ale and iem ale body weight data a re assem b led in Table II. T he d a ta in th is ta b le a lso include the 3, 12 and 24 m onth to ta l w e ig h t gains. 1 O Fnnfl77 ~*v ACM 0C 35S3 355 O' }\ n Dietary Level of A ro c lo r 1254 (ppm) Sex Control M F 1M F to M F 100 M F oO >o X cLjn cr> oo LJ Uuil u> o T A B L E II 9 T E S T M ATERIA L; A ro c to r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Body Weight and Total Weight Gain Data Sum m ary of Mean Values 0 1 2 34 Body Weight (gram s) Week: 5678 9 10 I I 12 13 133 203 245 313 362 373 391 409 424 440 440 449 467 474 136 17 B 190 219 244 254 259 265 270 276 281 278 290 288 m 206 253 322 364 373 396 425 436 457 470 483 490 509 136 171 190 213 235 246 248 250 259 270 270 274 279 285 133 209 251 325 375 394 402 410 432 453 470 488 494 508 136 171 194 220 243 263 2H9 293 281 272 276 274 280 288 133 207 260 324 365 375 295 419 428 440 450 469 480 4 86 136 174 197 223 242 254 276 290 281 268 270 274 277 280 90- Day Total Weight Gain (gram s / rat) 3 11 152 376 1 19 376 152 35 3 144 / O Dietary Level, of A ro c lo r 1254 (p*m) Sex Control M F 1M F 10 M F 100 O~ M F uL>n r oX oo 4 498 297 522 289 529 300 495 292 O T A BL E II co n tin u ed T E ST MATERIALS A ro c lo r 1254 Tw o-Y ear Chronic Oral Toxicity Stud/ - Albino Rata Body W eight ur.d T otal W eight G ain D ata Sum m ary of Mean Valuea 56 Bmly Weight (grama) Month: 7 tt 9 10 II 533 565 593 622 642 667 688 310 322 333 315 359 374 383 550 581 604 633 658 680 715 295 307 322 333 340 354 367 567 593 . 621 642 667 681 700 308 321 330 341 354 367 3H0 521 541 562 586 68 627 642 300 306 316 321 326 332 340 12-Month Total Weight Gain 12 (g r a m a / r a l ) 701 390 725 3 HO 726 392 568 254 592 244 593 256 664 531 347 211 r % .r J dietary Level of Aroclor 1254 |n;m) Sex Control M F 1 z? 10 3 M 100 M F M F M F * T A B L E II continued T E ST MATERIAL A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Body Weight and Total Weight Gain Data Sum m ary of Mean Values 13 14 15 16 Body Weight (grains) Month: 17 IB 19 20 21 22 23 24-Month Tota) Weight Gai.i 24 (g r a m s /r a l) 728 746 759 768 769 767 760 758 739 726 687 642 426 444 466 481 500 515 533 547 551 550 564 551 509 415 760 780 807 800 802 795 786 769 750 728 715 656 401 426 476 483 493 510 521 532 537 542 553 540 746 774 824 7H0 804 826 823 821 813 800 767 762 421 433 485 466 475 4 8 1 485 492 298 . 500 471 500 523 404 629 364 688 714 735 730 733 726 716 700 685 652 628 656 360 367 392 374 381 394 393 398 401 400 395 41 1 523 275** ^ * Statistically significant at the 99 percent confidence limit. OJ U1 00 A0M 0 0 3 5 5 5 B. Food Consumption I The data obtained from the food consumption m easu rem en ts c o n d u c t e d . d u r i n g th e f i r s t 12 m o n th s ' of feed in g a r e s u m m a r i z e d in T a b le S I . T h e se data revealed no significant difference betw een te st and control ra ts . The periodic checks conducted during the rem ainder of the inv estig atio n also rev ealed no outstanding d iffe re n c e s betw een te s t and control anim als. AOm 0C3S5t OC 359 "^__ / O TA B LE III i T E S T M A T E R IA L : A r o c lo r 125-4 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Food Consumption Data ,, O H m ' 1/1 Summary of Mean Values K -J Food Consumption , i- Dietary Level of Aroclor 125-1 (op n| Sex 1 2 1 4 (grams/rat/taeven days) Week: 56 789 Average Food Consumption 10 11 12 13 (ffrkmfi / r a i / an p Cont rol 1 10 100 M 94 160 175 163 137 137 225 197 204 188 191 194 196 F 71 140 144 107 104 133 208 154 165 151 146 150 151- M F 112 87 148 117 156 108 168 118 148 111 214 203 160 105 193 137 218 149 166 144 184 144 187 147 189 146 M 116 F - 90 119 109 148 107 164 114 163 121 221 201 193 159 199 216 134 144 191 150 192 151 200 152 199 149 M F 116 B9 >72 Ml 163 98 185 129 231 129 185' 189 190 146 198 146 185 145 197 139 189 137 189 146 121 193 174 140 174 132 181 136 187 152 uc>n oo T. Oo Ul vl* r> 1 4- o T A B L E 111 continued TEST MATERIAL: A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Food Consumption Data Sum m ary of Mean Values Food Consumption Dietary Level of A ro c lo r 1254 (gram s/rat/eeven days) Month: Average Food Consumf Inpnl Sex 4 5 6 7 8 9 10 11 12 ( g r a m s / r a t / s c Cont rol M 196 189 168 147 16) 184 179 170 187 F 148 154 136 121 138 152 160 141 127 176 142 1 M 189 181 184 198 190 190 197 152 190 F 141 159 147 162 145 150 151 123 126 186 145 10 M 190 191 189 196 190 188 191 186 163 F 139 138 148 148 150 145 138 142 149 187 144 100 M 179 168 190 179 187 182 197 180 188 F 148 141 144 162 163 151 148 141 137 18) 148 O cr. > o x 'D VX o o uj *1 K -i , X' % V' C. M o rtality and Reactions A frequency distribution of natural deaths occu rrin g during the In v estig atio n a p p e a rs in T able IV. No untow ard behavioral reactions w ere noted among any of the anim als employed in the investigation. F0009R4 ACM OC 362 D* H e m a t o l o g i c and C lin ic a l Blood C h e m i s t r y S tu d ie s M ean m ale and fem ale hem atologic and clinical blood ch em istry d a t a a r e s u m m a r i z e d in T a b le s V th ro u g h EC. Values for all param eters investigated w ere within the norm al range for the albino rat. Ho significant differences between test and control values were observed. la n o fv * ACM C03561 00 364 OO TABLE V O t _______I 1 \r T E ST M ATERIAL; A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata H em atologic Data Sum m ary of Mean Valuea Dietary Level (pnm) Control Sex M F Total Leukocyte Count (thousands/mm3) Month: 3 6 9 12 i a 14.0 15.4 10. 1 U . 1 9 .9 9. 1 9.4 6.7 7.6 8.8 24 11.2 7.6 Erythrocyto Count (m illions/m m 3) Month: 3 6 9 12 18 8. 1 8 .2 8.7 8 .8 7.6 7.5 7.7 7.3 . 7.8 7.7 24 6.5 6.8 M 1 5 . 1 1 5 .2 1 0 .9 e1 1 .0 9.8 10.2 7.5 7.7 8. I 7.7 8.0 8.0 100 F 11.6 12.2 7.3 8.7 6.6 11.8 7.5 7.6 7.7 6.9 7.3 6 .4 cn o olIo>Ti r) T A B L E VI T E ST M ATERIA L: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Hematologic Data Sum m ary of Mean Values D ietary Level fpnml Sex Hemoglobin Concentration (g/100 ml) Month: 3 6 9 12 18 24 3 M 17. 1 1 7 .7 1 5 .7 1 7 .6 16. 1 1 3 .6 51 Control F 16.9 17.4 14. 1 16.7 16.4 14.6 50 H em atocrit Value (7.) Month: 6 _____ 9______ 12_____ Ifl 49 48 50 41 47 43 . 46 42 M ,, . 1 5 . 6 . . 1 7 .6 1 3 .8 15.6 1 5 .7 15.3 47 47 42 44 41 100 F 16.5 17.8 13.9 14.5 14.5 12.7 48 47 42 40 37 24 35 38 40 32 =1 uCCT>h\ U .o I I .I I ! I l I, % I r( oo o T A B L E VII TE ST MATERIAL; A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino R ats Hematologic Data Sum m ary of Mean Values Dietary Level (pnm) Control Sex 1 M 62.0 F 83.0 Differential Leukocyte Count (Number of Celts per Hundred) Lymphocytes Neutrophils Month; Month: 6 9 12 18 24 3 6 9 12 _18 8 6 . 6 60.4 7 8 . 8 7 9 -0 6 5 . 4 16.0 1 1 .4 1 8 .6 2 0 .6 86.6 86. 8 89.0 70.2 61.4 15.4 11.6 11.8 . 10.0 29. 2 o* o 24 32.2 36.0 M 8 8 .2 79.6 8 5 .8 .8 5 .2 6 9 .8 68.0 1 0 .8 2 0 . 2 n .8 14.2 2 9 .0 3 0 .2 100 F 9 2 .2 9 2 ,0 79.6 8 4 .6 7 9 .0 61.0 7 . 4 7 . 8 2 0 .2 1 5 .0 2 0 .4 17.6 BSbU U O l O-r ir i TABLE Vll continued TE ST MATERIALi A ro clo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Hematologic Data Sum m ary of Mean Values Dietary Level (npm) Sex 3 Control M 0.6 F 0.6 Differential Leukocyte Count (Number of Cell a per Hundred) Monocytes Eosinophils Month: Month: 6 9 IZ 18 24 3 6 9 12 10 0.0 0.0 0.4 0.2 1.2 1.4 2.0 1.0 0. 2 0. 8 0.0 0.0 0.0 0.2 1.0 1.0 1.8 1.4 0. 2 0 .6 24 1.6 1.6 M 0.0 0.0 0.0 0.0 0.0 0.0 1.0 0.2 0.4 0.6 1.2 1.0 100 F 0.0 0.0 0.0 0.0 0.0 1.0 0.4 0.2 0.2 0.4 0.6 0.4 LJ CTi CD Aon 0C 3 5 6 5 D ietary Level (ppm) Control Sex M F M 100 F T A B LE VII continued TEST M ATERIAL: A roclor 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Hematologic Data Sum m ary of Mean Value* Differential Leukocyte Cuunt (Number of C e l l s per Hundred) Basophils Month; 1 6 9 12 Ifl 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 24 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 i i i i uuu:i16 o . in r -U' O0 O TA B LE VIII T E S T M ATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic Oral Tonicity Study - Albino Rate Hematologic Data Sum m ary of Mean Valuee Serum Glutam ic-Pyruvic Blood U rea Nitrogen Tranaam lnaee Activity Concentration D ietary Luvel (Dado Units ) Month: (mga 70 Month: (|>pm) Sex 3 6 9 12 18 24 3 6 9 12 18 # M 38 48 45 45 42 36 17 15 12 10 14 Cont rol F 33 39 38 42 32 30 14 16 15 9 13 M 33 32 43 *50 38 41 14 15 13 12 11 100 F 32 46 49 61 46 78 16 15 13 14 13 24 15 11 15 15 V i ?6t> U U U .j UO't o kJ D ietary Level (ppm) Control Sex M F T A B L E IX T E ST M ATERIAL: A ro c to r 1254 T w o-Y ear Chronic O ral Toxicity Study --Albino Rata Hematologic Data Sum m ary of Mean Values Pasted Blood Glucoao Serum Alkaline Phosphatase Concentration Activity (m g a 7.) (Klng-Arm alrong Units) Mouth: Month: 3 6 9 12 18 24 3 6 9 12 18 24 128 123 89 130 118 115 88 138 99 28.6 24.7 21.5 20. 3 16.2 22. 3 92 134 109 18.9 1 7 .8 10.6 11.9 16. 8 2 0 .2 M 109 113 129 128 124 115 3 5 .4 2 3 .2 2 7 .4 27. 1 H . 6 2 3 .5 100 F 120 107 124 113 132 107 17. 1 18. 1 1 9 .3 1 6 .7 1 0 .0 2 1 . 6 e w iu o u a ut o- o> u i'j& L B I O * r 5 T e S rta i& u + i. 2* 26 . Urine Analyses M e w m ale and fem ale urine analyses data are sum m arised in T ables X thro u g h XII, No differences w ere noted between the urine from control and test anim als at the intervals of examination. ACW C 0 3 5 6 9 * 00 3 72 r t* TABLE X TEST MATERIAL! A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Urine Analyses Data Summ ary of Mean Values D ietary Glucose Albumin Level Month; Month: fppml Sex 3 6 9 12 18 24 3 6 9 12 18 24 Mn nn n n nn n t t 42 43 Control F n n n n `n n n n n nt i2 Mn n n n n nn n t t t 42 100 * F n n n n n n n n . t t t 43 ^> O> o Lj OD u> 3 Key; ? n - negative 1 - tra c e ; le s a than 30 m g / 100 m l u r in e 4 I = 30 to 100 m g / 100 m l u r i n e 42 - 100 to 300 m g / 100 m l u r i n e 4 3 = 300 to 500 m g / 100 m l u r i n e 4 *1 = m o r e Ilian 500 m g / 100 m l u r i n e r .1 ~v XS3 1 *0 IS O O vLtj> >D X o o KLjJn yi D iriary Level ! P* C r- * SrX S Si 3 T A B L E XI TEST MATERIAL: A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Urine Analyses Data Sum m ary of Mean Values Microscopic Elements pH Month: Month: 69 12 18 24 3 6 9 12 n n n n 11 7 7 7 nn nt t 88 7 8 nn nt nn Nt t776 t 887 7 7 18 24 7 *6 66 66 66 Key: A* - Normal n a ut:salive t * trace; le ss than 5 p e r low power field I - 5 lo 10 per low power field <2 s 10 to |S per low power field 41 = m or e Ilian IS per low power field N CO D ietary Level fnpmt Control Sex M F M 100 F TA BLE XII TEST MATERIAL; A ro clo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Urine Analyses Data Sum m ary of Mean Values 3 1.029 1.020 a 1.022 1.019 Specific Gravity Month: 9 12 1.033 1.027 1.025 1.024 18 1.042 1.032 1.018 1.020 1.021 1.018 1.029 1.023 1.027 1.022 1.037 1.029 24 1.051 1.039 1.027 1.031 r.i i/> t f.- JttUUUtf i vi ta#I N# m F . Pathologic Studies j . T h ree Month Sacrifice a. Gros a Pathologie Findings No outstanding differences w ere noted between test and control ra ts upon gross pathological examination. b. Organ h e ig h t and Organ to Body and O rg a n to S r a i n V.'cigiit R atio D ata T he re s u lts oi the s ta t is tic a l a n a ly s e s conducted on absolute organ w eights, organ to body w eight and organ to brain weight ra tio s a re su m m a riz e d in Tables XIII through XVIII. Significant differences between a test group and the control group are designated by asterisks following the test value. Organ w eights, organ to body w eight and organ to b ra in weight ratios disclosed several randomly occurring intergroup differences. The lack of any consistent dose relaeed response and the absence of any deleterious histopathologic change confirm that these differences were not re la ted to the ingestion of A roclor 1254. fin n o is AOH 003573 OC 376 \f Dietary Level of A r o c l o r 125*1 fppml C o n tro l 1 10 100 T E ST M ATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino R ati O rgan Weight and' Ratio Data Three-M onth Sacrifice Sum m ary of Mean Values Organ: Liver O rgan Weight (g) M ales Fem ales 21.4 13.0 24.0 13.5 22.8 13.1 26.0 13.8 O rgan/D ody Weight Ratio (g /1 0 0 g) M ales Fem ales 4.13 4.16 4.34 4.34 4.59 5.25 4.29 4.89 O rg an /D rain Weight R atio (g/g| M ales F emale s 10.3 6.62 11.7 6.85 10.9 6 . as 14.6* 7.11 6b*W W ' * Statistically significant difference at the 95 p ercen t confidence level. ** S ta tistic a lly significant d iffe re n c e at the 99 p e rc e n t confidence le v el. o o u* O' 1 <81 1 y,, i Ual 8 I 0 - T E 5 T JoKsZi :ri. j4 laoiO O O Dill ary Level of A ro c lo r 1254 ippml Coni rol 1 10 100 O> o? u -j o CO o Ul If) TA B LE XIV TEST M ATERIAL; A ro c lo r 1254 Tw o-Y ear 'Chronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data Thrcu'M onth Sacrifice Summ ary of Mean Value a Organ; Kldneya O rgan Weight Cel M ales Fem ales 4.03 2.49 4.30 2.62 4.05 4.21 2.61 2.74 O rgan/B ody Weight Ratio (g/100 g) M ales Fem ales 0.7B2 0.B02 0.77B 0.845 . 0.821 0.792 0.B52 0.975 O rgan/B raln W eight Ratio (g/gl M ales Fem ales . 1.95 1.31 2.09 1.94 2.19 1.32 1.36 1.42 ADM C03S76 Dietary Level of A ro c lo r 1254 (pom) C o n tro l 1 *10 100 2 y* T A B L E XV T E ST M ATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxlcily Study - Albino R ats Organ Weight and Ratio Data Three-M onth Sacrifice Sum m ary of Mean Values Organ: Spleen O rgan Weight M ales (g) Fern ales 0.766 ' 0.578 0.942 0.668 0.766 0.586 0.814 0.542 O rgan/B ody Weight Ratio lg /1 0 0 g) M ales F em ale# 0.150 0. 184 0. 167 0.217 0.154 0.153 0.191 0.192 O rg an /B raln W eight Ratio (g/gl M ales Fem ales 0.371 0.454 0.302 0 338 0.36B 0.425 0.308 0.281 08C 0 0 HOv fcO O llM r Dietary Level of A ro c lo r 1254 (pnml Control 1 10 too r TA B LE XVI TEST MATERIAL: A ro clo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-M onth Sacrifice Sum m ary of Mean Values Organ: Gonada O rgan Weight (g) Malca Female* 3.60 0.114 3.50 0.134 3.55 0.110 3.82 0.120 O rgan/Body Weight Ratio (g /1 0 0 g) Malca Females 0.698 0.0370 0.637 0.0431 0.720 0.0361 0.71 B 0.0426 O rg an /B rain Weight Ratio Jg/g) Malca Females 1.74 0.0599 1.70 0.0675 1.70* 0.0568 1.99 0.0618 ADM 0 0 3 5 7 9 r t O Dietary Level of A ro c lo r 1254 (ppm) C o n tro l 1 10 100 s 1> TA BLE XVII T E ST M ATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data Three-M onth Sacrifice Sum m ary of Mean Value Organ: Heart O rgan W eight (g) Male Female 1.59 1.56 1.05 1.02 1.49 0.984 1.50 0.992 O rgan/B ody Weight Ratio O rg an /B raln W eight R atio (g /1 0 0 g) (g/g) Male_______F e m a l e _______ M ale ` F e m a l e a 0.307 0.339 0.767 0.551 0.283 0.332 0.756 0.516 0.302 0.322 0.713 0.515 0.297 0.352 0.817 0.512 r rl Dietary Level of A ro c lo r 12S4 C o n tro l 1 10 100 j --------------------------- TA BLE XVIII T E ST M ATERIAL; A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino R ats O rgan Weight and Ratio Data Three-M onth Sacrifice Sum m ary of Mean Values Organ; Drain O rgan W eight (s) M ales Fem ales 2.07 1.91 2.07 1.99 Organ/D ody Weight Ratio ( u / io o g) M ales Fem ales 0.402 0.616 0.376 0.647 Final Body W eights f Sacrificed Rata <G> M ales Fem ales 518 314 553 311 2.09 1.91 0.424 0.625 499* 307 1.95 1.94 0.366 0.6B8 434 281 blSOO a ie ES i A J C. H is to p a th o lo g ic F in d in g s Histopathologic examination of tissu es and organs ta k e n f r o m a l l a n im a ls f r o m b o th the c o n tro l and 100 pp m g ro u p s w as conducted. T a b le s XIX and XX lis t a ll h is to p a th o lo g ic changes noted. A ll of the lesions noted in the m ic ro sc o p ic ex am in a tion of tis s u e s w ere those of spontaneous d isea se and a re not unusual for the albino rat. The m ost frequent findings w ere lesions in the trach ea and lungs, indicating chronic murine pneumonia. These oc c u rre d in the control as well as the rats fed A roclor 1254. yoft1 n o 5 ADP 0 0 3 5 8 C 0 0 383 Q C T A B L E XIX T E S T M A TER IA L: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Histopathologic Changes Three-Month Sacrifice Group: Control N um ber of A nim als O re m Examined Findings Aver Incidence G ra- 5 Males Trachea Lung U rinary Bladder Tracheitis Chronic resp irato ry disease H yperplasia 1 l.C 1 ' 1.0 3 1.0 1 5 Fem ales Lung Chronie respiratory disease 1 1.0 I1 All other tissues and organs w ere norm al histologically. Grading System 0.5 s m inim al 1.0 slight 2 .0 = mild 3.0 = m oderate 4.0 s severe 5.0 extrem e ) O fritvi nft6 AOM 0 035 0 ( 384 TABLE XX TEST M ATERIAL; A ro c lo r 1254 Two-Year Chronic O ral Toxicity Study - Albino Rats Histopathologic Changes Three-Month. Sacrifice G roup: 100 ppm N u m b er of Average A n i m a l s -- O r g a n E x a m i n e d - ---------- F in d in g s _____ . In c id e n c e . ,,.Grade 5 Males Trachea Lung Tracheitis 1 1.0 Chronic resp irato ry disease 3 1.0 5 Fem ales Trachea Tracheitis 1 1.0 All other tissues and organs were norm al histologically. Grading System 0.5 = minimal 1.0 = slight 2 .0 = mild 3.0 = moderate 4.0 = severe 5.0 = extreme J.001007 ACH 0 0 3 5 d OC 385 jTrlY , B IU 1 C 3 I UCJ, / A 2 S j x A f n r t h S a c r i f i c e a. G ross Pathologic Findings No outstanding differences w ere noted between te st and control anim als. b. O rgan h e ig h t ar.d Organ to Sodv and O rg a n to B ra in V.'eich; Ratio D ata The re s u lts of th e -sta tistic a l a n a ly se s conducted on absolute organ weights organ to'body weight and organ to brain weight ra tio s a re su m m arized in Tables XXI through XXVL O rgan w eights, organ to body w eight and organ to b ra in weight ratios disclosed several randomly occurring intergroup differences. The lack of any consistent dose related response and the absence of any deleterious histopathologic change confirm that these differences w ere * not re la te d to the ingestion of A ro clo r 1254. Vnfti *0w CC35d OC 386 *0seoo Dietary Level of A ro c lo r 1254 (ppm) C o n tro l 1 10 100 TA B LE XXII T E ST M ATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Valuca Organ; Kidneys O rgan Weight (g) M alea Fem ales 4.04 2.79 1.80 2.5B 3.22->' 2.50 3 .a * 2.43 O rgan/Body Weight Ratio (g /1 0 0 g) M ales Fem ales 0.664 0.806 0.715 0.784 0.703 0.7B0 0.700 0.861 O rgan/D raln W eight Ratio (g/g) M ales Fem ales 2.06 1.43 1.7S0 1.57? . 1.39 1.31 1.68* 1.25 O^ CD Ul CD Slaliatlcally Ignificant difference at the 95 p e rc en t confidence leveL ID i"s 0 C ti 4 I r^\ } ) Dietary Level of A ro clo r 1254 (pn:ul C o n tro l 1 10 S5 100 TAJ1LE XXI T E S T M A T E R IA L : A r o c l o r 1Z54 T w o-Y ear C hronic O ral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Values Organ: Liver- O rgan Weight (e> M alea Fem ales 22.9 16.!* n .i 10.3* . 12.9=* 19.2 9.54* 12.4 O rgan/D ody Weight Ratio ( g / i o o c> M ales Fem ales 3.74 3.77 3.01** 3.11** 2.81** 2.94** 4.14 4.40 O rg an /B raln Weight Ratio le^c) M ates Fem ales H .7 6.71 7.45** 5.54* 6.29** 10.0 4 .9 9 '' 6.39 O 0L0J 00 oo Ui (it * Statistically significant difference at Ihe 95 percent confidence levet. v< Staliklically significant differe nce at the 99 pe r ce nt confidence level, r~ j d I J o TA B LE XXIII TE ST MATERIAL.! A ro c lo r 1254 T w o-Y ear C hronic O ral Toxicity Study - Albino Rat* Organ Weight and Ratio Data Six-M ont 11 S a c r if ic e r Summ ary of Mean Values Organ: Spleen D.ctary Level of A ro c lo r 1254 (pm) C o n tro l 1 O rgan Weight (g) M ales Fem ales 0.752 0.684 0.830 0.602 O rgan/Body Weight Ratio (g/100 g) M alca Fem ales 0.122 0.196 .155 0.182 O rg an /B raln Weight Ratio (g/g) M ales Fem ales 0.384 0. 350 0.384 0. 324 10 0.5B8 0.594 0.128 0.184 0.287 0.311 *100 o 0,684 0.512 0.150 0.180 0.356 0.264 v** ACM 003S8& V . * o Dietary Level of A ro c lo r 1254 (onml Control 1 1 100 a 2 to o T A Bi L E XXIV 1 TEST M ATERIA L: A ro c lo r 1254 T w o-Y ear C hronic O ral Toxicity Study - Albino Rate Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Values Organ: Gonads o O rgan Weight (6) M ales Fem ales 3.55 0.0960 3.67 0.0922 3.30 .0.0866 3.44 0.104 O rgan/D ody Weight Ratio (g / 1 0 0 g) M ales Fem ales 0.593 0.691 0.0279 0.0280 0.724 0.0272 0.747 0.0364 O rg an /B raln Weight Ratio (e/&) M ales Fem ales 1.81 0.0492 1.70 0.0496 1.61 0.0454 1.79 0.0536 ACM ' 0 C 3 5 8 r-\ i*r** O Dietary Level of Aroclor 1254 Control 1 10 100 a p v O TABLE XXV TEST MATERIAL* A ro c lo r 1254 Tw o-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Valuoa Organ: Heart O Organ Weight (8) Malea Femalea 1.70 1.05 1.58 1.04 1.44 1.03 1.40 1.02 Organ/Body Weight Ratio (g /1 0 0 g) Malea Femalea 0.282 0.302 0.298 0.316 0.314 0.320 0.301 0.361 O rgan/B raln Weight Ratio Malea F em alea 0.867 0.538 0.731 0.559 0.702 0.539 0.729 0.526 ACh C C 3 5 rr J Dietary Level of A ro c lo r 1254 (pnm) Control 1 10 too T A n LtE XXVI TEST MATERIAL* A ro c lo r 1254 Tvvo-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values - Organ Weight fg) M a l e s ______ F e m a l e e 1,96 1.95 2.16 1.86 2.05 1.91 1.92 1.94 Organ: Drain Final Body Weights Organ/Body Weight Ratio of Sacrificed Rate f g /1 0 0 g) ( K) M a l e s _______F e m a l e s __________ M a l e s F em ales 0.320 0.404< 0.560 0.562 613 348 534 331 0.447** 0.593 459 322 0.414** 0.681*' 464 285 ^ * Statistically significant d ifference at the 95 p e r c e n t confidence level, O "12** Statistically significant difference at the 99 p e rc en t confidence lovel. 12 392 e. Histopathologie Findings Histopathologic examination of tissues and organs ta k e n f r o m a l l a n im a ls fr o m both the control and 100 ppm groups was conducted. Tables XXVII and XXVHI list all histopathologic .changes noted. All of the lesions noted in the m icroscopic examination of t is s u e s w e r e those of spontaneous d isea se and a r e not unusual for the albino rat. The m ost frequent findings were lesions in the traehea and lungs, indicating chronic murine pneumonia. These occurred in the control as w ell as the rats fed A roclor 1254. 003*,C i w m i ^ 393 , TABLE XXVII TE ST MATERIAL: A ro c lo r 1254 T w o-Y ear Chronic O ra l .Toxicity Study - Albino Rats Histopathologic Changes Six-Month Sacrifice Group: Control N u m b e r of Animals Organ Examined Findings 5 Males Trachea Lung Liver Skeletal Muscle .. T r a c h e i t i s Focal tracheitis Focal pneumonitis Hyperemia Focal pericholangitis Focal inflammation 5 Females Trachea Lung Liver Kidney Focal tracheitis Hyperemia Hyperemia Pericholangitis Focal inflammation Avera* Incidence Grade 2 1.5 2 1.0 1 ' 0.5 2 1.0 * 1 1.0 1 1.0 1 21 1 1 1.0 2.5 1.0 0.5 1.0 All other tissues and organs were normal histologically. Grading Sr atern 0*5 * minimal 1*0 a slight 2 .0 > mild 3 . 0 * modrat 4.0 * severe 5.0 extreme o o ^ ,v 394 (L ta b le xxvin T EST MATERIA!*: A ro c lo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rate Histopathologic Changes Six-Month Sacrifice Group: 100 ppm Numbe r of Animals Ore an Examined Findings Ave rac Incidence G rad- 5 Mile 5 Females Trachea Lung Liver Kidney Heart Trachea Lung Kidney Tracheitis Focal tracheids Focal pneumonitis Focal pericholangitis Focal nephritis Myocarditis Focal tracheitis Focal pneumonitis Hyperemia Focal nephritis 2 1 3 1 *l 1 3 4 1 2 2.0 1.0 0.5 2.0 0.5 0.5 0.5 1.0 1.0 , 3.0 All other tissues and organs were normal histologically. Grading System t, 0.5 = minimal 1 .0 * slight 2 .0 * mild 3.0* m o d e r a t e 4 .0 * severe 5.0 * extreme AOM 0 0 3 5 9 2 395 0i J \* 3. Twelve-M onth Sacrifice a. Croas Pathologie Findings Gross pathologic findings among test animals were not significantly different from those noted in control anim als, b. Organ Weight and Ratio Data The mean organ weight and ratio data collected at the 1 2 - m o n t h s a c r i f i c e a r e p r e s e n t e d in T a b l e s XX DC t h r o u g h XXXIV. Statistically significant differences, are designated by a ste risk s following the test group value. .Organ weights, organ to body weight and organ to b ra in weight ratios disclosed several randomly occurring intergroup differences. The laek of any consistent dose related response and the absence of any deleterious histopathologic change confirm that these differences were not related to the ingestion of A roclor 1254. *0h r o Dietary Level (npml Control 1 10 100 TABLE XXIX TEST MATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data * r Sum m ary of Mean Values * Organ Weight (g) Males Females 22. 1 15.5 20.6 12.9 23.5 14.6 27.1* 12.2 Organ: Liver Organ/Hotly Weight Ratio (g /1 0 0 g) Males Females 3.79 3.52 3.09* 3.52 3.41 4.34 4.50* 3.43 O rgan/B raln Weight Ratio (g/g) Males F em ales 10^0 7.72 9. B9 7. 29 11.2 7.34 12.7 A. 30 * Statistically significant difference at the 95 p e rc e n t confidence level* tu tn u m u> vo k Dietary Level loom) Control 1 10 100 O T A B L E XXX TE ST MATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxlcily Study - Albino Rate Twelve-Month Sacrifice Organ Weight and Ratio Data t Summary of Mean Valuca Organ: Kidney Organ Weight (g) Male Fem ales Organ/Dody Weight Ratio (g/1 0 0 g) Males Females O rgan/B raln Weight Ratio (g/g) Males F em ales CD 4.04 4.09 4.64 4.39 3.19 2.75 2.76* 2.78* 0.692 0.618 0.697 0.740 0.738 0.728 0.817 0.796 1.97 1.98 2.21 2. 06 1.55 1.39 1.44 Statistically significant difference at the 95 p e rc e n t confidence level. 03 . -o K001020 O tl e\ ,; I J'tatuiu el C l 0 T S I TA B LE XXXI TE ST MATERIAL,: A ro clo r 1254 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Value Organ: Spleen a Organ Weight Organ/Body Weight Ratio O rgan/B raln Weight Ratio Dietary Level (g) ( g /1 0 0 g) (g/g) ____ fanml______________Male________ F e m a l e a ____________M a le s ________ F e m a l e s ____________ M a l e s Females Cont rol 1 10 100 0.778 0.714 0. 904 0.754 0.796 0.4B4* 0. 540 a 0.976 0. 133 0. 107 0. 135 0. 126 0.103 0.129 0. 161 0.200 0. 380 ' 0.344 0.430 0.352 0.396 0. 271 0.275 0.517 ? ttc. * S ta tis tic a lly significant difference at the 95 p ercen l confidence le v e l.' LJ kD _> \I*n- r l r Dietary Level (mm) Control 1 10 100 TABLE XXXII TEST MATERIAL: A ro clo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Values m Organ: Gonads Organ Weight (g) Males Females Organ/Body Weight Ratio (g/100 g) Males Females * 3.46 0. 116 0.592 0.0275 3.68 0.111 0.557 0.0294 3.68 0.0918 0. 550 0.0270 3.56 0.121 0.603 0.0334 O rgan/B raln Weight Ratio (g/g) Males F em ales 1.70 0.0574 1.78 0.0624 1.75 0.0461 1.67 0.0624 < $ tU U 4 O 1 o .ot* X oo 1Uo*1l 41 ' Dietary Level (com) Control l *1 100 O t T A B L E X X X III o TEST MATERIAL; A roclor 1254 Tw o-Y ear Chronic O ral Toxicily Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Valuca Organ: Heart Organ Weight (g) Males F cmales 1.71 1.23 1.(8 1.13 1.84 1 . OB** 1.69 1.14 Organ/Body Weight Ratio (g/100 g) Males Females 0.293 0. 88 0.255 0.301 0. 275 0.322 0.284 0.325 O rgan/B rain Weight Ratio (g/g) Males F em ales 0.835 0.609 0.812 0.615 0.875 0.544 0.795 0. 589 % i i \ f O CD >o3 o ol>* Statistically significant difference at the 95 p e rc en t confidence level. Statistically significant difference at the 99 p e rc e n t confidence level. f Dietary Levol (ppm) Control 1 10 100 TABLE XXXIV TEST MATERIAL: A r o d o r 1254 Two-Year Chronic Oral Toxicity Study - Albino Rata Twelve-Month Sacrifice Organ Weight and Ratio Data Summary of Mean Valuea Organ Weight (g) Males Females 2.04 2.02 2.08 . 1.78 2. 10 1.99 2. 14 1.93 Organ: Brain Organ/Body Weight Ratio (g/100 g) Males Female 0. 35 0.474 0.315 0.475 0.315 0.591 0.361 0.552 Final Body Weight of Sacrificed Animals (grama) Males Fem ales 584 439 665 380 669* 338* 596 355 t f t l ) IUU.1 * Stallatlcally significant difference at tho 95 p e r c e n t confidence level. C o fO o o iOr c Histopathologic Findings ` Histopathologic examination of tissues taken from each rat s a c r i f i c e d f r o m the c o n tr o l and 100 p p m g r o u p s a f t e r 12 m onth s of t e s t i n g was conducted. Tables XXXV and XXXVI list all histopathologic changes noted. F.0010?5 acw oc3occ 403 00 D tU e3i 30 TABLE XXXV TEST MATERIAL: A rocior 1254 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Hiatopathologic Changes Twelve-Month Sacrifice Group: Control N um ber of Animals 5 Male. 5 Females - Organ Examined - Findings Trachea Lung Urinary Bladder Tracheitis Chronic respiratory disease Calculus Trachea Lung Colon Tracheitis Chronic respiratory disease Parasites Incidence 1 2 1 1 *1 1 Avei Gr* 1. 1. 1. 1. 1. 1. All other tissues and organs were normal histologically. Grading Svstcm 0 .5 = minimal 1.0 = slight 2.0 = mild 3.0 = moderate 4.0 * severe 5.0 = extreme FftM flSfi 0C34C1 0 ( 404 4jVJ B l C TES T S'# TABLE XXXVI TEST MATERIAL; A ro clo r 1254 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Twelve-Month Sacrifice Group; 100 pp m N u m b e r o O r g a n Animals Examined Findings Ave ra * - I n c id e n c e ~ ~ G r a c 5 Males Lung Chronic respiratory disease 4 1.0 5 Females Heart Trachea Lung Adrenal Focal myocarditis Tracheitis Chronic respiratory disease Congestion 1 1 1 1 1.0 1. 0 1.0 1.0 All other tissues and organs were normal histologically. Grading S'/stem 0 .5 = minimal 1.0 = slight 2.0 = mild 3.0 : moderate 4. 0 = severe 5. 0 s e x tre m e Enm nsfl ACM 00360 405 ou 4. Final Sacrifice Gross Pathologic Findings G ro ss pathologic findings among te st animals were not iignificar.tly different from those noted in control anim als, b. Organ V'eight ir.d Ratio Data The mean organ weight and ratio data collected at the f i n a l s a c r i f i c e a r e p r e s e n t e d in T a b l e s XXXVQ t h r o u g h XL11. Statistically significant d ifferen c es, a r e designated by a ste ris k s following the test group value. Absolute liver weight, liver to body weight and liv e r to b rain weight ratios were significantly elevated in both male and female r a t s fed 100 p p m A r o c l o r 1254. O th e r org a n w e i g h t s , o r g a n to bod y weight and organ to brain weight ratios disclosed sev e ra l randomly oc curring intergroup differences. The lack of any consistent dose related re s p o n se and the absence of any deleterious histopathologic change confirm th a t these differen ces w ere not related to the ingestion of A roclor 1254. F .ftM 0 9 8 ACM 0 C 3 t C 0 0 0 406 i Fnmn?9 ooo Dietary Level _ fPPonl Control I 10 100 T A B LE X X X V II TEST MATERIAL: Aroclor 1254 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data l Summary oi Mean Values Final Sacrifice Organ Weight (e) Males Females Organ: Liver Organ/llody Weight Ratio fg/100 g) . Males Females 22.0 19.5 16.3 16. 1 3.47 2.-99 3.05 3. 10 23.9 19.5 3.21 3.84* 30.2** 32.1** 4.75** 8.62** * Statistically significant difference at the 9$ percent confidence level* * ** S ta tis tic a lly significant d iff e r e n c e at the 99 p e r c e n t confidence le vel. AUH 00360* l I ! O rgan/D raln Weight Ratio 1 In /e l Males Fcnnlcj 10. 10 8.42 8. 76* 8.31 11.40* 10. 30 14.10* 17. IO->* cr V S* t G Dietary Level (ppm| Control 1 IQ 100 TABLE XXXVIII T E S T M A T ER IA L : A ro c lo r 1254 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Sum m ary of Mean Valued Organ Weight Males (g) Females 5.57 3.48 Final Sacrifice Organ; Kidneys Orgatt/1) inly Weight R a tio fg/100 g) Males Females 0.877 0.646 5.52 3.68 0.868 0.706 S.61 3.47 0.761 0.717 4.74 3.44 0.749 0.899* O rgan/B raln Weight Ratio (g/g) Males Females . 2. 57 2.48 1.79 1.88 2.70 1.84 2.21 1.82 ^ Statistically significant difference at the 05 percent confidence leveL FOft1O30 000 4Q8 A OU nnt i ii ,,-i r s \ n Dietary Level (ppml Control _J 1 O 10 . 2 100 Wv. . _ O .o <=> s u ovo oo1O*1' ... o TABLE XXXIX TE ST MATERIALI A roclor 1254 Tw o-Year Chronic Oral Toxicity Study - Albino Rale Organ Weight and natlo Data i Sum m ary of Mean Values Final Sacrifice Organ Weight Malee (gl Female Organ: Spleen Organ/Body Weight Ratio (g /lO O g ) Males Females 1. IS 0.96 0.182 0. 181 1.26 1.06 0 . 189 0.237 1.57 0.86 0.220 0,175 1.04 0.66 0.164 0. 174 I OJ O m i/i ' l E __________ ______________ O r g a n / B r a l n W e i g h t R a l lo I* lg/g) M alee Fem ales 0.520 0.492 0.568 0.562 0.749 V, 0.489 . 0.462 0.352 oi. V s. O Dietary Level . (ppm) Control 1 10 100 O TiA B L E XL T E S T M ATERIAL: A ro c lo r 1254 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data i Sum m ary of Mean Valuea Final Sacrifice Organ Weight Males <c) Females 2. 52 0.123 1. 19 0.204 Organ: Gonad* Organ/Bitdy Weight Ratio (e/ioo c) Males Females 0.397 0.0222 0.4B2 0.0390 3.28 0.135 0.415 0.0263 3.44 0. 128 0.547 0.03)6 *lfr \ c C i n t hti b 1' i; O r^ a n /B ra in Wc ight Ratio f ifi/ti) Males Females 1. 15 0.062B 1.43 0. 1010 1.58 0.0707 1.60* 0.0666 Slatlatlcally significant difference at the 95 percent confidence leveL ADH 0 0 3 6 0 7 o c 4 Eftftlft32 / r TADLE X U TEST MATERIAL: Arclor 1254 T w o -Y eir Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data I Sum m ary of Mean Valuea Final Sacrifice Organ; Heart Dietary Level (pom) Control Organ Weight Males (> Females 1.67 1.54 O r g a n /D mly Weight R atio |g/100 g) Males Females 0.294 0.288 1 1.98 1.55 0.303 10 2.08 1.37 0.279 >oo -A . . . 1.94 1.50 0.304 * Statistically significant difference at the 95 percent confidence level. `L ^ l a t l s t l c a l l y s ig nif ic a nt d i f f e r e n c e at the 99 p e r c e n t c onfi de nce l e v e l . O O ADH 0 0 3 6 0 8 0. 302 0.282 0 . 386* r. I. I, o -m' T -*J O rgan/B rain Weight Ratio l/i Males Females 0.860 0.795 0. 889 0.805 0.998* 0.727 0.909 0. 803 IOn' n i. ^> i o Dietary Level Ippml Control 1 10 100 TABLE XLII T E ST MATERIAL.: A ro c lo r 1254 Two-Year Chronic Oral Toxicity Study - Albino Rate Organ Weight and Ratio Data i Sum m ary of Mean Values t , Final Sacrifice Organ Weight () Males * Females Organ: Brain Organ/Dody Weight Ratio ( g / 100 g) Males Female Final Body Weight of Sacrificed Animals (grams) Ma les F em ales . 2. 18 2.22 2.06 . 2. 13 1.95 1.94 1.88 1.88 0. 342 0.347 0. 279 0.340 0. 362 0.176 0. 388 0.4B6 642 551 656 540 762 500 656 4 1 1 BIO- I to & i ** Statistically significant difference at the 99 p e rc e n t confidence level. ADM 0 0 3 6 0 9 OO '' 000 SmJ*#** B 1c T 5 r -iii 67 c . Histooatholocic F*:ndtncs Histopathologic examination of tissues and organs ta k e n f r o m all a n i m a l s s a c r if ic e d a f t e r 24 m onths on t e s t w as c o n d u c te d . Tables XX.ni .through XLVI list all histopathologic char, n o t e d . T a b l e X1.VXI c onta in s the r e s u l t s of the h i s t o p a t h o l o g i c e x a m i n a t i c of the u rin a ry bladders. Significant l i v e r i n j u r y was found in a n i m a l s fed 100 ppr. A r o c l o r 1254 ( 7 - III}. The co mpound a s s o c i a t e d l e s i o n s c o n s i s t e d of vacuolar change, focaVhypertrophy and focal hyperplasia. In addition, there were lesions of-inflammation, necrosis, fibrosis and m inor d e g e n e r a t i o n , w e r e m o r e s e v e r e and fr e q u e n t in the T-IXI group.. The vacuolar change was not seen in the control anim als b u t w a s o b s e r v e d o c c a s io n a ll y in l i v e r s f r o m T - I (1 ppm) and T-1I (10 p p m an im als. It was frequent is the T-III anim als. This lesion is morphologic indicative of fatty degeneration. Form alin-frozen sections of livers from representative animals which displayed vacuolar changes were stained wit! Oil Red 0 to reveal the presence of fat. The vacuolar lesion in the cytopla: of these cells was positively idenified as fat. ;- it The hypertrophic changes found in the liver was focal and often limited to the central lobular area where groups of cells were swollen to two o r th re e times their norm al size with clea r pink homogeneous cyto plasm . The hyperplasia was associated with the same cells and appeared Fhm nri5 ACIH 0 0 3 6 1 C ooc 413 eo be an e x t e n s i o n of the h y p e r t r o p h i c l e s i o n . T h e h y p e r p l a s t i c c e l l s w e r e a l s o u s u a lly h y p e rtro p h ic . The m o s t s e v e r e examples of h y p e r p l a s i a appeared as nodular growths with limited c o m p re ss io n of the surrounding normal hepatic tissue. The minor lesions of degeneration, hepatitis, ductule cell proliferation, necrosis and focal lymphoid infiltration seen in the c ontrol a n im a ls and the T -I and T - I I g ro u p s a r e le sions of spontaneous d is e a s e and a r e not related to the A ro c lo r 1254. This level of liv er diseas is not unusual in rats of this age. Hyperplasia of the tran sitio n al epithelium was p r e s e n t in the u r i n a r y b la d d e r of anim als fr o m the c o n tr o l group and each of the test groups. This lesion was usually associated with cystitis. The m o s t . severe changes were associated with the presence of mineralized calculi - in the bladder lumen. All of the o ther lesio n s in o th e r tis su e s found in these animals are related to spontaneous disease and they are not unusual for old rats. Donovan E. G ord on . D. V. M. , F h . C. Diplomate, American College of Veterinary Pathologists IW V M 36 ACM C C 3 e l l 0 0 0 414 rr' Number of Animals 11 M a l e s ^-L-j O o ^" OU o* X> -A m" D*1 <1 U-1* lonu O TABLE xliii r\ `V ['.TEST M A T E R I A L : A r o c l o r 1254 i ! Tw o-Year Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Organ Examined Group; Control Findings Incidence Heart Trachea Lung Liver i Stomach Spleen, Kidney Testes, Prostate Adrenal Gland |l* Drain |. Ev*e i Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal degeneration > puclilc hyperplasia Chronic gastritis Hemosiderosis .[ Chronic nephritis * Testicular degeneration j Periarteritis , Inflammation Telangiectasis ,| N o d u la r h y p e r p l a s i a *| 1 Focal fatty change ! `F o c a l e n c e p h a l i t i s inflammation ' j 3 3 9 12 l 3 8' * 2 1 1 1 2 ( * Average Grade 1.0 1. 0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 *ao / ' !v Number of Animals 14 F e m a l e s * s O o IaP ' l*i I TADLE XLIII continued TEST MATERiALi A ro clo r 1254 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Croupi Control Organ Examined Heart Trachea Lung 1 Ivor Stomach Colon Spleen Uterus Kidney Ovary Findings Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal lymphoid infiltration Ductile hyperplasia * Focal hepatitis Non-lipid vacuolar change Chronic gastritis Acanthosis - squamous epithelium Parasites Hemosiderosis Metritis Chronic nephritis Focal lymphoid infiltration Cyst * Incidence 7 3 13 3 2 1 2 3 5 I 4 3 6 1 1 o Average Grado 2.0 1.0 1.0 1.0 1.0 1.0 0. 5 *1.0 1.0 1.0 1.0 2. 0 1.0 1.0 1.0 0 0 C is r~ \ J r s Number of Animals U Females TADLE .XLIIl continued TEST MATERIAL: A ro c lo r 1254 , Tyo-Year Chronic O ral Toxicity Study - Albino Rata Histopathologic Changea Final Sacrifico Group: Control Organ Examined Adrenal Gland Salivary Gland Findings Telangiectasia Nodular hyperplasia Phcochromocytoma Chronic fibrosis and atrophy Incidence 9 4 1 1 All other tissues and organs w ere norm al histologically. 0. 5 3 `m i n i m a l 1. 0 s s lig h t Grading System 2.0 s mild 3. 0 = m o d e r a t e z> A0* 00361* 4.0 s severe 5.0 = extreme CD Average Grade 1.0 1.0 1.0 1.0 000 417 8 1f 0 0 ! ) Nu mb er of n i rr *1s Mali.ii b o o* * Cj o ct T A B L E XLIV* TE ST MAT ERIAL: A ro clo r 1254 Tvro-Yer Chronic Oral Toxicity Study - Albino Rail Histopathologic Changes Final Sacrifice Group: I ppm Organ Examined Heart Trachea Lung Liver Pancreas Stoma eh Spleen Kidney Testes Findings Chronic focal myocarditis T racheilis Chronic respiratory disease Congestion Ductile hyperplasia Vacuolar change (fatty) Necros is Chronic focal pancreatitis Peria rtcritis Chronic gastritis Acanthosis Dice r Hemosiderosis Chronic nephritis Testicular degeneration Incidence 5 6 *) 1 1 1 1 2 1 2 2 1 5 8 2 - Q Average Grad 1.0 1.0 1.0 1.0 0. 5 1.0 3. 0 1.0 2.0 1.0 1.0 1.0 2. 0 2. 0 1.0 J r Cumber of Animals M Males t TABLE XLIV continued T E S T M ATERIAL: A ro c lo r 1254 Two-Year Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Group: 1 ppm * Organ Examined Testca (continued) Prostate Seminal Vesicle Pituitary Adrenal Gland Parathyroid Gland Findings Periarteritis Focal calcification Inflammation Inflammation Congestion Nodular hyperplasia llypc rplasiu Incidence 2 2 6 2 1 1 1 22 F em ales oo o -- . L#i Heart Trachea Lung Liver Oo3 6i * Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal lymphoid lnfilt'ration 12 16 17 3 Average Grade 1.0 2.0 2.0 2.0 1.0 1.0 1.0 1.0 1.0 2.0 1.0 000 419 { \i VJ TABLE XLIV continued r TE ST M ATERIAL; A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study -Albino Rata Histopathologic Changea Final Sacrifice, Group; I ppm * Number of An in*. * Organ Examined Findings Incidence 22 Fe.. i s O O oO 4 3 2 J* to Liver (continued) Stomach Colon Spleen Lymph Node Kidney Uterus Pituitary Adrenal Gland Ductile hyperplaaia Vacuolar change (fatty) Congestion Necrosis Focal inflammation and acanthoale Parasites Hemosiderosis Abscesses Chronic nephritis Focal calcification Metritis Hyperplasia Telangiectasis Nodular hyperplaaia Congestion t Focal fatly change N> O .1! o t h e r tis&ues and org a na w e r e n o r m a l h i s t o l o g i c a l l y . P iratlinn 2 3 1 1 4 2 a i 8 3 6 4 17 1 1 3 ..t i l* c ^ Average Grade 1.0 2.0 1.0 1.0 2.0 1.0* 2.0 * 1.0 1.0 I. 0 1.0 1.0 1.0 1.0 1.0 1.0 $ - 4- /V Number of Animals 12 M al e s O o o 1*3 o C*3 w ou> 03 TABLE XLV T E S T M ATERIAL: A ro c lo r 1254 * Tw o-Year Chronic Oral Toxicily Study - Albino Rats Histopathologic Changes Final Sacrifice G r o u p ; 10 p p m ' Organ Examined Heart Trachea Lung Liver 1 * . Pancreas Stomach Spleen 1Kidney Tcales Findings Chronic focal myocarditis Tracheitis Chronic respiratory disease. Pneumonia Vacuolar change (fatty) Ductile hyperplasia Hypertrophy Focal degeneration Chronic focal pancreatitis Chronic gastritis and acanthosis Hemosiderosis Chronic nephritis Testicular degeneration Incidence 7 9 11 l 3 1 1 1 1 1 2 7 1 Average G rad 1.0 2.0 1.0 1.0 1.0 I/O 0. 5 0. 5 3.0 1.0 1.0 1.0 2. 0 ^J N um ber of Animalr. 12 Male:. TABLE XLV continued TEST MATERIAL: Aroclor |254 1T w o - Y e a r C h r o n i c O r a l T o x i c i t y St udy - A lb in o R a t e Histopathologic Changes Final Sacrifice G r o u p : 10 p p m ' Organ Examined Teatea (continued) Prostate Sominal Vesicle Adrenal Gland. Thyroid Gland Findings Periarleritia Inflammation Inflammation Telangiectasia Focal fatty change Focal hyperplasia Incidence 1 2 2 2 1 1 tU U f~ emaieg O* o? t o oo Lu I Heart Trachea Lung Liver Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal lymphoid infiltration Vacuolar change (fatty) Nodular hyperplasia 3 7 12 4 1 1 Average Grade 3.0 2.0 1.0 1.0 1.0 1.0 1.0 I. 0 1.0 1.0 1.0 3.0 U \ .1 tr --^ f: v ,^ i * TABLE* XLV continued T E ST M ATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice G ro u p : 10 p pm Number of Animals Organ Examined Findings 12 F e m a le s Liver (continued) Colon Spleen Lymph Node Kidney U teru s Pituitary Adrenal Gland Parathyroid Gland Thymus Ductile hyperplasia Telangiectasia Hepatoma P a ra site s H em osiderosis Congestion Chronic nephritis Focal calcification M etritis Adenoma H y perplasia Telangiectasia Hyperplasia Abscess AO* CC262C oT r'D All other tissues and organa were norm al hiatologica lly. K) Ui G r a d i n u S v a l o m Incidence 2 1 1 1 2 1 3 2 1 3 1 9 1 1 A verage G rade 1.0 1.0 1.0 1.0 1.0 1.0 2.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 9 ?u iu u i N um ber of A nim als 11 M ale oo S OO x. oui K) rv> TAD LE XLVI T E ST M ATERIAL! A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino R ats Histopathologic Changes Final Sacrifice G ro u p : 100 ppm* Organ Examined H eart Trachea Lung Liver Small Intestine Spleen Lymph Node Findings Chronic focal m yocarditis Tracheitis Chronic respiratory disease Edema Focal degeneration Vacuolar change (fatty) Ductile hyperplasia llypert rophy Focal lymphoid infiltration Portal fibrosis Focal inflammation llemottlde rosis Congestion Incidence 3 4 10 3 2 3 3 3 1 1 1 2 1 A verage Grade 2. 0 1.0 1.0 2.0 1.0 i;o 1.0 2.0 1.0 2.0 t.o 1.0 1.0 Number of Animal 11 Males TADLE XLV! continued T E ST M ATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice G ro u p : 100 ppm Organ Examined Kidney Testes P ro sta te Adrenal Gland. Thyroid Gland Findings Chronic nephritis P e ria rte ritis Inflam m ation Telangiectasis Congestion H y p erplasia A verage I n c id e n c e _______________G r a d e a 1.0 1 1.0 5 2.0 2 1.0 1 1.0 1 1.0 W W IM 15 F e m a l e s O O o k> o 2 tMnU LOO) H eart Trachea Lung Liver 1 Chronic focal m yocarditis T rach eitis Edema Focal hypertrophy H ypertrophy F o c a l h y p e r p4l a s i a * 5 6 13 1 1 5 1 1.0 1.0 2.0 2.0 1.0 3. 0 1.0 is TABLE XLV1 continued TEST MATERIAL: A roclor U64 T w o-Y ear C hronic O ral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice G ro u p : 100 ppmr Number of Animal a F em ales fJ 2 QD Organ Examined Liver (continued) - S tom ach Spleen Kidney Uterus Pituitary Pi luit Adrenal Gland Findings Ductile hyperplasia V acuolar change (fatty) Nodular hyperplasia llepalom a Chronic gastritis Acanthosis Inflam m ation H em osiderosis Chronic nephritis Focal calcification M etritis Hyperplasia Nodular hyperplasia Telangiectasis Nodular hyperplasia. Congestion * A verage I n c id e n c e _______________G r a d e 2 1.0 10 1 .0 1 1.0 1 1.0 2 1.0 4 1.0 1 1.0 5 1.0 5 1.0 1 1.0 3 1.0 4 1.0 1 1.0 3 1.0 1 1.0 1 1.0 ACM 0 C 3 6 2 3 roh All o th e r tis s u e a and o rg a n a w e r e n o r m a l h ia to lo g ic a lly a\ Grading System T A B L E X L V Il TEST M ATERIAL: A ro c lo r 1254 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rate llialopatliologlc Changes of the U rinary Bladder Final Sacrifice Group C Number Sex Examined M II F 14 Finding a P r o te in a c e o u s plug (34) Focal epithelial hyperplasia (62) T-I (1 ppm) M 10 F 19 P ro tein aceo u s plug (326) Diffuse epithelial hyperplasia associated with diffuse cystitis (377) T - II s (10 ppm) M 13 Diffuse epithelial hyperplasia and papilloma associated with focal cystitis (417) Diffuse epithelial hyperplasia associated ^r to T-III F 13 M 10 with diffuse cystitis (419) None Focal epithelial h y p erp la sia a s s o c ia te d wlt)i (100 ppm) focal cy stitis (497) o Focal epithelial hyperplasia (5) F 17 None Na*j V| * Individual animal number a a r e shown in parenthesis. % Incidence 1 1 1 1 1 1 - 1 1 1 A verage Grade 1 3 4 2 2 1 - I G. D etailed D escription of Tum or F in d in g3 . T um or data for individual anim als including Location, w eight and pathologic classification are presented in Table XLVIII through L L None of these tum ors could be re la te d to the ingestion of A ro c lo r 1254 and a re considered norm al for a random population of rats this ag e. i F,001050 ADM i i n u m (}( 42a / ' 'A r Animal Xumbc r and Sex 1-M 2-M -6-F 47-F W 4B-F O 50-F 52-F 059.F O s in o* * <= g V1O0 - F IoaSJ -F ` Location Abdomen Panereaa Abdomen Lymph node Abdomen Abdomen Abdomen Abdomen .\ilrenal gland Abdomen Abdomen TABI^E XLVIII TEST M ATERIAL; A ro clo r 1254 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rate D escription of Tum or Findings Group; Control W eight (gram s) 11.76 61.98 35.09 - - _ 88.92 2 10 . no Size (cm) 8x1x2 5x2x2 2x2x1 2x2x3 - % 13 x 11 x4 11 v II C lassificatio n M am m ary fibroadenoma A denocarcinom a M am m ary fibroadenoma M am m ary fibroadenoma Reticulum cell sarcom a M am m ary fibroadenoma M am m ary fibroadenoma - M am m ary fibroadenoma M am m ary fibroadenoma Phc oc hrm ocy toma Fibroadenom a * ** * V M onths on Test 24 24 24 24 24 7 24 24 24 6 non r Animal !'um her ..ml Sox 11 -F X 12 - F 13-F ^ ! rcat Ion Abdomen Aldorr cn Abdomen TABLE XLIX continued T E ST MATERIAL: A roclor 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Description of Tum or Findings Group: 1 ppm Weight (gram s) - - - Size (cm) - - - C lassificatio n y M ammary adenocarcinoma / l M ammary fibroadenoma Lipoma ir 3 *) *( H r VO S, ' /-*k 4/ / ' / i # *i 11 M onths on Test 4 24 24 o> C5 o o in |CUJ r o o /~~~ ii ii Animal Numlier and Srx l-M 2-M 3-F 4-F 5-F 6-F 7-F > fl-F X 9 - F oUOO' TAQLE XLIX TEST MATERIAL* A ro clo r 1254 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Description of Tum or Findings Group; I ppm Location W eight <> Parathyroid gland - Pituitary - Abdomen - Abdomen - Abdomen Parathyroid gland 8. 97 Abdomen 8.86 Abdomen Dorsal cervical region 65.0 209 Pituitary Abdomen - Abdomen Size (cm) - m 2x2x2 3x2x2 13x8x2 - *at C lassificatio n t- A d e n o m a *' C h r o m o p h o b e a d e n o m a t- M a m m a r y f ib r o a d e n o m a v " i M amm ary fibroadenoma |X 1 M a m m a r y a d en o m a -'* ''' J V Adenoma u < M amm ary fibroadenoma \ S 1 M ammary fibroadenoma v '' Fibroadenoma ; i Chromophobe adenoma w M am m ary fibroadenoma ------ ----m ------ M onths on Test 24 2) 24 24 24 24 24 24 C U U U )U i F,001054 00C 432 O I TABLE L TEST MATERIAL: A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rata Deacriptlon of Tum or Finding* G ro u p : 10 p p m \nim al Cumber nd Sex l -M # Location Pancreaa Weight (gram a) - Sixe . (cm) Claaalflcatlon B* l/Adenoma 1 ' ' 2-M Parathyroid gland - - i / Adenoma ^ 3-F Abdomen - - "Mammary fibroadenom a p - 4-F Thyroid Abdomen 5-F Abdomen -- -- 1 Adenoma ^ /M a m m a ry fibroadenoma ^ , M am m ary fibroadenoma V " ' 6-F Abdomen Abdomen 86 29 7x8x3 5x5x2 Fibroadenoma ^ I . ' F i b r o a d e n o m a * ' 7-F Pituitary - - V Chromophobe adenoma fl-F 9 -F 0- F n* IT o o ^O' rvj Abdomen Pituitary Adrenal gland 20 7.0 6x5x3 - (/F ibroadenom a {/Chromophobe adenoma t/T elanglom a / ' %' t v a C M onth* on Teat 24 24 24 24 , f 24 24 24 24 22 g ya ca ) r* 0 Animai Number and Sex l-F 2-F 3-F 4-M 5-M 6-F 7-M 8-F o* 10-F * iO>j' Location Abdomen Abdomen Abdomen Pancrcaa Abdomen Abdomen Lymph nodo Pancrcaa Lymph node Abdomen D TABLE LI TEST MATERIALI A roclor 1254 T w o -Y eir Chronlc O rai Toxiclty Study - Albino Rai D eecrlptlon of Tum or Flndinga G roup: 100 ppm Weight (grama) 48. 12 m - * 13.0 52.0 Sice (cm) 5x4x3 18 x 4 x 3 1x2x1 3x3x3 8x5x2 C laealflcatlo n /F ib ro m a 's ' is M am m ary fibroadenoma ^ is M am m ary fibroadenoma 1 / /A denom a * /' Fibroadenom a-^ j. M a m m a r y f ib r o a d e n o m a 1_ i ' Reticulum cell aarcom a is /''A d e n o c a rc in o m a -* /L ym phoaarcom a V Fibroadenoma % r M ontha on Teat 24 24 24 24 24 24 13 24 24 24 F00W 55 g o C 432 Animal Number nil Sex 11-F 12-F 13-F 14-F 15-F Location Abdomen Abdomen Abdomen Abdomen Abdomen TABLE LI continued TEST MATERIAL! A ro clo r 1254 T w o-Y ear Chronic O ral Toxicity Study - Albino Rate D escription of Tum or Flndlnga G roup: 100 ppm Weight Iff r a m e ) H I. 9 42 - 209.0 14. 63 Size |cm ) 0x8x2 6x4x2 10x9x3 - Classification . ^'M am m ary ftbroadcnom al/ * M a m m a r y f i b r o a d e n o m a u--- Fibroadenom a / M am m ary fibroadenoma l Fibroadenoma M onths on Teat 24 24 24 24 24 Enni056 00( t6 o X o l o UUoi A .... I* B I w - T S 5 T 2aJto*aJ&u*L, % R E P O R T TO MONSANTO COMPANY TWO-YEAR CHRONIC ORAL TOXICITY WITH AROCLOR 1242 IN ALBINO RATS NOVEMBER 12, 1971 IBT NO. B7298 I. Introduction At the re q u e st of Monsanto Company, a tw o-year chronic 'ral to x ic ity stu d y w a s con d u cted u sin g albino r a t s to d e te r m in e the: p o te n tia l toxicity of A ro c lo r 1242, Lot No. AK-255. The following re p o rt p re s e n ts the resu lts of this investigation. FOOTOT CC3&3 00C 435 QIC T : 5 i 2e. 1L S u m m a ry A tw o -y e a r chronic toxicity study was conducted using albiko rats fe d d ie ts c o n ta in in g 1 (T -I), 10 (T -U ) o r 1004(T -H I) ppm A ro c lJ r 1242. Food consum ption and body weight gains w ere not altered at any le v e l of A ro c lo r 1242 fed. The n u m b e r of a n im a ls dying and th e tim e at which the deaths o c c u rre d did not v ary among the test and eon:: ol groups. H em atological and clinical blood chem istry studies conducted after 3, 6, 9, 12, IS o r 24 m o n th s did not r e v e a l a n y a ffe c ts re la ted :o A ro c lo r 1242. U rine analyses failed to re v e a l any differences between test and control animals. At s a c r i f i c e a f t e r 3, 6 o r 12 m o n th s on t e s t , o r g a n weights , o r g a n to body weight and organ to brain weight ratios disclosed sev e ril random ly occu rrin g intergroup d ifferences. The lack of any consistent dose re la te d resp o n se and the absence of any deleterious histopathologic change confirm that these differences w ere not re la te d to the ingestion of A ro clo r 1242. At the final sacrifice a fter 24 months on te st, the liver weights and liv e r to body weight o r brain weight ratios w ere significantly elevated in f e m a le s f r o m the T-I1Z group. H istologic e x a m in a tio n of the liv e r s fro m the T-U I roup revealed several anim als with vacuolar change This le s io n Is m orphologically indicative of fatty degeneration, Specific fat stains confirm ed the presence of fat in these vacuoles. Focal h y p e rtro p h y and foeal h y p e rp la sia w ere also found in the livers rom an im als fed A ro c lo r 1242. K flfll058 AC* C C 3 6 3 3 00 436 j'i uoj, o i 1 I E 3 l j H yperplasia of the urinary bladder was found in animals trom the control group and from each of the test groups. This hyperplasia was usually associated with cystitis. T he incidences and types of all tum ors w ere about the sam e in all groups, including the control group, and are considered normal for rats of this age. ' Respectfully submitted, INDUSTRIAL BIO-TEST LABORATORIES, INC. Report prepared by: ! U <^g v w > \^\ P h ilip 5\ Sm ith, B. S. A ssistant Toxicologist Rat Toxicity Report approved by: P a u l L. TVrig h t, Ph. D. Section Head, Toxicology N o v e m b er 12, 1971 lm:bb:hpdcjl M* L . K e p lin ^ e r , JgJj M anager, Toxicology a]dm 0Q303<i 0 Q ( <37 > ><*=. 4 III. P ro ce d u re A. E x p e rim e n ta l A nim als The an im al* em ployed in the te s t w e re C harle* Rive: strain-*' a lb in o r a t * . P o u r h u n d re d r a t s (ZOO m a le and ZOO fem ale) were s e le c te d fo r the e x p erim en t, ear-p u n ch ed with the anim al num ber assigned and housed individually in standard wire-bottom ed steel rat cages. Each cag e b o r e a c o lo r - c o d e d c a r d identifying the r a t w ith r e s p e c t to p ro je c t num ber, dietary level assignm ent, individual anim al number apd sex. B. O rganization of Groups A s t r u c t u r a l o u tlin e of the e x p e r im e n t is given in Tabl,ie I. TABLE I TEST MATERIAL; A ro clo r 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Onrlinr of Experim ent Grouo Control T-I T -Il T.H I N um ber of A nim als M ale ____ F e m a le 50 50 50 50 50 50 50 50 Lie tary Level (ooml None A dm inistered 1 10 100 * C harles R iver Breeding L aboratories, North Wilmington, Mass AO* o03>: ) l 438 BIO i cST Jmc. 5 C. D iets, Feeding and Food Consumption iAH d ie ts w e r e p r e p a r e d in the c e n tr a l d ie t ro o m of this la b o ra to ry . The b a sic ratio n from which all diets w ere constru cted w a s a s ta n d a rd , p u lv e riz e d stock r a t ration*. The diet for any jiven t e s t group w as p re p a re d by blending the calculated am ount of Aroclor 1242 with a p re -w e ig h ed portion of the stock ra tio n in a Hobar: m ixer. F re s h diets w ere p rep ared each week and every ra t was offered an am ount of food sufficient for ad libitum feeding. Food consumption was recorded for five ra ts of each sex in every group w eekly for the fir s t three months and m onthly for the next nine m onths. T hereafter, periodic spot checks were made. D. Bodv W eights and W eight Cains Initially, the body weight of each ra t in every group was d e te r m ined and recorded. T hereafter, individual weighings were made weekly f o r the f i r s t 13 w e e k s and m o n th ly th e r e a f te r u n til the conclusion of the investigation. E. M ortality and Reactions Checks for m ortality and abnormal behavioral reactions were m ad e daUy throughout the investigation. F. Hematologic Studies and Urine Analyses Blood studies, including determ inations of Hemoglobin concentra tion, h em ato crit value, erythrocyte count and both total and differential * P urina R at Chow, Ralston Purina Company, St. Louis, M isso u ri. Cft C0363' F oeiifC f doc 439 leu k o cy te count, w e re conducted upon five m a le s and five fem ales from b o t h the c o n tro l and 100 ppm g ro u p s . i U rin e a n aly ses for the presen ce of glu co se, albumin, m ic ro s c o p ic e le m e n ts , and d e term in a tio n s of pH and sp e c ific gravity w ere co n ducted upon u rin e sam ples at the same time in terv als and from the sam e a n im a ls as tho se em ployed for the blood studies. T h e s e s t u d i e s w e r e con d u cted a f te r 3, 6, 9, 12, 13, and 24 rr.on:: of feeding. C. C linical Blood C hem istry Studies D e t e r m i n a t i o n s of b lo o d u r e a n itr o g e n c o n c e n tr a tio n (BUN*), s e r u m alkaline phosphatase activity (SAP), fa ste d blood glucose concen tra tio n and s e ru m g lu tam ic-p y ru v ic tra n sam in ase activity (SGPT) w ere c o n d u c te d a f t e r 3, 6, 9, 12, 18, and 24 m o n th s o f fe e d in g upon the s a m e r a t s as w ere the routine blood studies. H. Pathologic Studies When an anim al succumbed during the te st period, a gross autops w a s p e rfo rm e d . In those e ase s when p o stm ortem autolysis was not ad v a n c e d , re p re s e n ta tiv e tissu e s w ere taken and p re s e rv e d in ten p ercen t fo rm alin solution for possible future histopathologic study. A f t e r 3, 6 , a n d 12 m o n th s of te s t in g , fiv e a n im a ls of e ac h s e x fro n t each group w ere sacrificed and subjected to complete gross patholog exam inations. ACM C03fc3 jrn o io f? ! 0 01 440 .' 5 I TEST JsM vtn fw d . fme. A bsolute organ w eights w ere re c o rd ed and organ to body weight and organ to b ra in weight ratios computed. The following organs were Included: liv er, kidneys, spleen, gonads, h eart and brain. T iese data w e re then subjected to sta tistic a l an aly sis. An A nalysis of V ariance was conducted first and significant effects disclosed by that treatm ent were f u r t h e r s t u d i e d by Mt " * t e s t s . Com plete m icroscopic examinations w ere conducted upon the t i s s u e s a n d o r g a n s f r o m a ll c o n tro l and 100 p p m g ro u p r a t s s a c r i f i c e d a f t e r 3, 6, o r 12 m o n th s of te s tin g . The follow ing tis s u e s and o r g a n s w e r included in the exam inations: heart, trachea, lungs, liver, p an creas, esophagus, stom ach, sm all intestine (duodenum, jejunum and ileum ), caecu m , colon, spleen, lymph nodes, kidneys, u rin a ry bladder*- gonads, p ro state gland, sem inal vesicles, uterus, pituitary gland, adrenal glands, saliv ary glands, thyroid gland, parathyroid glands, skeletal m uscle, sternum , bone, peripheral nerve, spinal cord and brain (cerebrum / cerebellum and pons). The aforem entioned tissues were prep ared and staine^ with H em atoxylin-Sosin stain. A fter two y ears of feeding, all surviving anim als were sacrificed and subjected to com plete gross pathologic exam ination. The absolute weights of the liver, kidneys, spleen, gonads, h e a rt and brain were recorded immediately after sacrifice. AOK 0036 00( 441 1*^*1 B I C T E S T 2* 3 M icro sco p ic exam inations w ere conducted upon tissue^ and t o r g a n s f r o m s e le c te d a n im a ls dying during the e x p e r im e n t and upon all an im als from the final sacrifice. T issu es and organs examined were the sam e as those previously m entioned. I. Tum or Incidence and Classification A tabulation, of the incidence of tum or form ation in eac h group w as m ade a t the conclusion of the investigation. In addition, tum or data for individual anim als including location, weight, size and pathologic classification were recorded. I A C At ^435 Fn010K4 0 o!' 442 I '--it S I 0 - T SS T ^ 9 IV. R esults A. Bodv W eights and Weight Gains / T h e m a l e an d fe m a le b o d y w eight d a ta a r e a s s e m b l e d in| T a b le II. .i T h e d a t a in t h is ta b le a ls o in c lu d e the 3, 12 and 24 m o n th to ta l w eight g a in s. T h ere w ere no significant effects attributable to the ingestion of the compound. F .n n ifi^ > iAO* QflUi. o q 443 T A B L E II T E S T M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino R ats Body Weight and Total Weight Gain Data Sum m ary of Mean Values )ietary Level of Aroclor 1242 (ppnri) Sex Body Weight (grams) Week: 0 1 2 3 4 5 6 7 8 5 10 B1 12 13 lonlrol * M 133 203 245 313 362 373 391 409 424 440 440 449 467 474 F 136 170 190 219 244 254 259 265 270 276 281 278 290 288 1 M . 133 205 254 329 367 377 397 417 432 451 462 481 493 508 F 136 173 197 226 240 253 268 292 278 2 B0 284 284 288 292 10 M 133 202 251 332 362 372 392 414 428 454 475 4B1 500 509 F 136 176 196 226 244 254 26U 2BB 276 280 281 284 2 80 285 100 M 133 203 248 320 365 376 398 416 427 439 453 467 478 487 F 136 173 194 225 251 264 272 290 274 275 279 285 283 286 90-Day Total Weight Gain (grams/rat) 341 152 375 156 376 149 354 150 SfcttH L H Jl O O. u o Jt X roi r* r" TA B LE II continued T E S T M ATERIA L: A ro c lo r 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino R ats Body Weight and Total Weight Gain Data Sum m ary of Mean Values lietary Level of Aroclor 1242 (ppm) Sex 4 5 6 Body Weight (grams) Month: 78 9 10 1 1 12 lontrol M 498 533 565 593 622 642 667 668 701 F 297 310 322 333 345 359 374 383 390 1 M 525 555 580 614 640 665 690 707 743 F 302 321 326 333 342 355 367 381 388 10 M 525 553 579 600 627 641 674 693 706 F 299 312 328 33 3 346 354 365 375 384 100 M 504 533 551 580 608 633 662 686 711 F 290 307 321 333 347 360 374 388 379 a m u u i O *> o tn T O o 12-Month Total Weight Gain (grama/rat) 568 254 610 252 573 248 578 24 3 Hetary Level of A ro c lo r 1242 (ppm) Sex Control M F IM F 10 M F 100 M F , T A B L E II co n tin u ed T E ST M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Body Weight and Total Weight Gain Data Sum m ary of Mean Values 13 14 15 Body Weight (gram a) M onth: 16 17 18 19 20 21 22 728 746 759 768 769 767 760 758 739 726 426 444 466 481 500 515 533 547 551 550 767 785 805 800 804 810 BOO 804 802 800 428 443 479 468 500 514 523 531 535 538 740 750 763 780 784 7R0 785 783 780 774 393 406 422 441 462 480 500 519 529 533 724 728 723 735 728 736 733 730 725 715 428 447 463 467 472 484 481 484 485 490 '` 24-M onth T otal Weight G ain 23 24 ( e r a m a / r a t ) 687 642 564 551 509 415 808 759 535 532 626 396 796 734 537 547 601 411 743 *652 487 485' 519 349 tfy tn u u j -c o ..CuuTi BI0 - TST 13 B. Food Consumption The data obtained fro m the food consumption m easurem ents c o n d u c te d d u r in g th e f i r at 12 m o n th s o f feeding a r e s u m m a r iz e d in T a b le III. T hese data revealed no significant difference between test and control ra ts . The periodic checks conducted during the rem ain d er of the investigation also rev ealed no outstanding differences betw een te s t and control anim als. in n u iss AC* 0 0 447 r T A B L E III T E S T M ATERIAL: A ro c lo r 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Food Consumption Data ! w O ni cn Sum m ary of Mean Values Food Consumption letary Level of (gram s/rat/seven days) Average Food A ro c lo r 1242 Week: Consum ption V* (ppm) S ex 1 2 3 4 5 6 7 8 9 10 11 12 13 ( g r a m s / r a t / s e v e n d a y s Control M 94 160 175 163 137 137 225 197 204 188 191 194 196 F 73 140 144 107 104 133 208 154 165 151 146 150 151 174 140 1 M 129 154 165 201 120 191 206 210 232 185 188 189 190 F 91 109 120 164 110 |6 6 124 137 172 140 145 148 145 167 136 10 M 113 132 142 201 120 193 183 184 184 192 196 191 193 F 96 114 147 13) 110 149 102 124 166 144 143 138 144 171 131 100 M 117 149 185 230 161 172 199 172 227 192 186 190 190 F 89 1)8 129 189 98 114 142 135 180 145 142 139 140 182 135 O O CO I 7 1 5 3 1 * 0 1 8 T 'W T 'C 1 T A B L E II I continued T E ST M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Food Consumption Data Sum m ary of Mean Values Food Consumption etary Level of (gram s/rat/seven days) A roclor 1242 Month: (pp"t S e x 4 5 6 7 8 9 10 11 12 Control M 196 189 168 147 163 184 179 170 187 F 148 154 136 121 138 152 160 141 127 1 M 180 IBI 170 189 190 189 196 192 208 F 152 159 141 154 150 148 143 145 159 10 M 184 164 168 197 193 188 191 186 177 F 139 147 136 151 144 145 138 142 130 100 M 179 192 189 200 196 186 184 187 167 F 163 141 160 148 145 144 147 146 145 Average Food C o n sum ption (gram s/rat/seven days) 176 142 188 150 183 141 187"149 C o,,__ o fc* .Ck to ; ... 5 I C ; 5 7 3c. C* M o r t a l i t y and R e a c tio n s A fre q u e n c y d istrib u tio n of n a tu ra l deaths o c c u rrin g during the in v e stig a tio n a p p e a rs in Table IV, No u n to w ard b eh av io ral re a c tio n s w ere noted am ong any of the an im als em ployed in the investigation. JO M *r72 ACh 00 3*** 0U(. 450 > t B I 0 - ( E S T Jt* aa rnifc Dietary Level Sex Control M F 1M F 10 M F 100 M F T A B L E IV T E ST M A TERIA L: A ro c lo r 1242 T w o-Y ear C hronic O ral Toxicity Study - Albino Rata M ortality Data Frequency D istribution of Deaths Frequency D istribution of Deaths M onths: 1 -3 4-6 7-9 10-12 13-15 16-10 19-21 000 2 17 000 1 3 5 6 7 201 10 0 1 1 3 3 37 24 00 0 2 17 5 0 11 2 0 25 .0 0 0 3 3 6 0 10 1 2 4 7 8 22-24 9 3 B 5 8 5 10 9 Total Dead N u m b e r T e s t e d * ft, 25/35 19/35 * 25/35 16/35 23/35 * 16/35 29/35 25/35 i|J> o ea not include the five anim als of each sex from every group sacrificed for in terim pathologic stu d ie s. Co S J W B IO TES T 13 D. H em atologic and C linical Blood C hem istry Studies M ean m ale and fem ale hem atologic and,clinieal blood chem istry i d a t a a r e s u m m a r i z e d in T a b l e s V t h r o u g h DC. V alues for all p a ra m e te rs investigated w ere within the norm al ran g e for the albino ra t. No significant differences betw een test and control values w ere observed. J! J W IIT O , 00 452 B I O - T E S T Jai I G D ietary Level (ppni) Sex 3 C o n tro l M H.O F 9.1 TABLE V T E ST M ATERIAL: A ro clo r 1242 T w o-Y ear C hronic O ral Toxicity Study - Albino Rato H em atologic Data Sum m ary of Mean Values Total Leukocyte Count (thousands/m m ^) M onth: 6 9 12 18 15.4 10.1 11. 1 9 .9 9.4 6.7 7.6 8.8 24 11.2 7.6 Erythnocyte Count (m illions /m m ^) M onth: 36 9 12 18 8. 1 8. 2 8. 7 8 .8 7.6 7.5 7.7 7.3 7.8 7.7 24 6 .5 6. 8 M 15.6 10.4 9 . 7 * 12. 5 9 .4 9.3 100 F 15.6 9.0 . 7.7 7 .8 6. 2 6.4 7.7 8.0 8.0 7.6 7.4 7.6 7.6 7. 1 7.9 7.0 7.7 7.2 oO CJ > sO i tb r ** r D ietary Level (ppm) Control 100 T A B L E V! TEST MATERIAL: A roclcrI2 4 2 T w o - Y e a r C h ro n ic O ra l T o x icity Study - A lbino Rafts H em atologic Data Sum m ary of Mean Values Sex 3 Hemoglobin Concentration ( g / 100 m l) Month: 6 9 12 ' 18 24 M 17. 1 17.7 15.7 17.6 16. 1 13.6 F 16.9 17.4 14. 1 16.7 16.4 14.6 H em atocrit Value 36 <%) Month: 9 12 18 51 49 48 50 41 50 47 43 46 42 M 16.8 16.9 14.2 15.4 15.6 14.6 F 15.8 16. 1 13.6 15.7 15.5 14. 8 50 48 43 44 41 46 48 41 41 40 24 35 38 37 37 B 10 T E S T Jam HO 455 n Dietary Level (ppm) Control 100 Sex 3 M 82.0 F 83.0 TA B LE VII T E S T MATERIAL: A roclor 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Hematologic Data 6 86.6 86.6 Summary of Mean Values Differential Leukocyte Count (Number of Cells per Hundred) Lymphocytes Neutrophils Month: Month: 9 12 IB 24 36 9 12 18 80.4 78.8 79.0 65.4 16.0 I I . 4 18.6 20.6 20.0 86.8 89.0 70.2 61.4 15.4 11.6 11.8 10.0 29.2 24 32.2 36.0 M 89.6 84.4 . 79.8 87.0 66.0 58.4 F 91.4 86.0 82.8 88.4 75.6 65.2 9 . 6 15.2 18.8 13. 2 33. 0 38. 8 8.4 13.6 17.2 11.2 23.0 33.6 N o o u* ft r> V } o rw i^ vcT Dietary Level _<PPTM) Control 100 Sex 3 M 0.6 F 0.6 M 0.2 F 0.0 TADLE VII continued T E S T MATERIAL*. Aroclor 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Hematologic Data Sum m ary of Mean Values Differential Leukocyte Count (Number of Cells per Hundred) Monocytes Eosinophils Month: Month; 69 12 IB 24 3 6 9 12 0 . 0 0 .0 0.4 0.2 1.2 1.4 2.0 1 . 0 0 . 0 0 . 0 0 . 0 0 . 2 K.O 1 . 0 1.8 1.4 . 0.2 18 . 24 0. 8 1.6 0 .6 1.6 0 . 0 0.0 0.4 0.0 0.0 0 . 0 0.0 0.2 0 . 0 SI O 0.6 0.4 1.4 1.4 1 . 0 2 .0 0. 2 0.4 0 .0 0.2 1.4 1 . 0 j o O* O oo A iti Ut ir Dietary Level (ppm) Control i ``. TTAABB LL EE VVIUI ccoonnttiinnuu eedd TEST MATERIAL: Aroclor 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rata Hematologi c Data Sex M F Sum m ary of Mean Valuea * Differential Leukocyte Count (Number of Cells p er Hundred) Basophils Month* 3 6 9 12 IB 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0. 0.0 0.0 24 0.0 0.0 M 100 F 0.0 0.0 0.0 0.0 0.0 0.0 0 .0 0.0 0.0 0.0 0.0 0.0 is & K. en O LT K o n tra J1 . ^ O BIO-TEST T A B L E V ili T E S T M ATERIAL: A ro c lo r 1242 Two-Year Chronic Oral Toxicity Study - Albino Rats Clinical Blood Chem istry Data Sum m ary of Mean Values Dietary Level (PP") Sex Serum Glutamic-Pyruvic Transam inase Activity (Dade Units) Month t 3 6 9 12 M 38 Control F 33 48 45 39 . 38 45 42 IB 31 32 24 36 30 niood Urea Nitrogen Concentration (mgs Month: 3 6 9 12 18 17 15 12 10 14 14 16 15 9 13 24 15 11 M 33 35 36 57 39 32 100 F 39 41 53 40 52 46 15 15 13 14 12 20 17 14 14 11 11 14 I sL*.n. LO )1 s a r r 7 1S31*0 Ia Dietary Level (ppm) Control Sex 3 M 128 F 130 M 121 100 F 125 T A B L E IX T E S T M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rato Clinical Blood Chem istry Data Summary of Mean Values Footed Blood Glucose Concentration (mgo * ) Month; 6 9 12 18 123 89 88 138 n s 115 92 134 24 99 109 Scrum Alkaline Phosphatase Activity (King-Armstrong Units) Month: 3 6 9 12 18 28,6 24,7 21.5 20. 3 16.2 18.9 17. 8 10.6 11 .9 16. 0 24 22. 3 20. 2 123 129 145 125 115 118 124 121 135 116 26.4 27.6 23.2 20. 3 17.4 9.6 25.8 11.7 16.7 11.6 13.2 14.2 c o* N ui U VO * al B I 0 - T E S T Ja&aUusi, lb E. Urine Analyses Me&n m i l e And f e m a l e urine A naly se s dAtA Are summarized in Tables X through X1L No differen ces w e re noted between the u rin e fro m control and test animals at the intervals of examination. 1001 On a. 0 0 1 460 TADLE X T E S T MATERIAL: A ro c lo r 1242 TWo-Year Chronic Oral Toxicity Study - Albino Rata Urine Analyses Dala Summary of Mean Values f i ni i/i Dietary Glucose Level Month; <ppm> S e x 3 6 9 12 18 24 Control M n n n n nn F n n n n nn M n n n n nn 100 F n n n n nn o <? Key: n s negative t = tra c e ; le e s than 30 vng/100 m l u rin e 4 I = 30 to 100 m g / 100 m l u r i n e 2 = 100 to 300 m g / 100 m l u r i n e 3 = 300 to 500 m g / 100 m l urine. 44' = m o r e than 500 m g / 100 m l u r i n e o\ Albumin Month; 3 6 9 12 IB 24 r n n t t 42 43 n n n n t 42 n n t t 4 1 44 n n t t t 43 N- I r \, j BI O - i 6 S T J 'u T A B L E XI TEST MATERIAL: A ro clo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Urine Analyses Data Summ ary of Mean Values Vi. Dietary Level (ppm) .Control 100 Sex M F M F Microscopic Elements Month: 3 6 9 IZ NNNN NNNN 18 N t 24 41 t N N N N Nt N N N N Nt pH Month: 3 6 9 IZ 18 24 7 7 6. 7 7 6 8 8 7 8 66 7 7 7 8 6 6* 7 7 6 7 66 ta u h m Key: N- Norm al I = trace; less than S per low power field 4 1 ? 5 to 10 p e r low p o w e r fi e ld 42 = 10 to IS p e r low p o w e r fi e ld 4 3 = m o r e than 15 p e r low p o w e r field 4ot*o\ *o 00 o Dietary Level (PP*w) Control 100 T A B L E XII T E S T M ATERIAL: A ro c lo r 1242 TWo-Year Chronic Oral Toxicily Study - Albino Rata Urine Analyses Data Summary of Mean Values Specific Gravity Month: Se x 3 6 9 12 M 1.029 1.022 1.033 1.027 F 1.020 1.019 1.025 1.024 M 1.021 1.028 1.032 1.024 F 1.022 1.019 1.029 1.029 18 1.042 1.032 1.043 1.027 4A 24 1.051 1.039 1.030 1.038 Os Xcr*> LJ o ou* o VNiJ BlO *T5T jUi. 30 F. Pathologic Studies 1. T h r e e - M o n t h Sacrifice j a. Groes Pathologic Findings Gross pathologic findings among test animals were not significantly different from those noted in control animals. b. Organ Weight and Ratio Data The mean organ weight and ratio data collected at the t h r e e - m o n t h s a c r i f i c e a r e p r e s e n te d in T a b le s XIII through XVIII. ` Statistically significant differences are designated by asterisk s following the test group value. Organ weights, organ to body weight and organ to b ra in weight ratios disclosed several randomly occurring intergroup differences The la ck of any co n sisten t dose related re s p o n s e and the absence of any deleterious histopathologic change confirm that these differences were not r e la te d to the ingestion of A roclor 1242. Fnm 086 H CC3tfc 0 0 1 464 Dietary Level of A r o c lo r 1242 PPmt Control 1 10 T3 100 3 -------------------------- T A D L E XIII T E ST MATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice Sum m ary of M ean Values Organ: Liver Organ Weight (g) Males Fem alea 21.4 13.0 22.3 12.4 23.3 14.4 25.5 14.0 Organ/Dody Weight Ratio ( g / 1 0 0 g) Males Femalea 4. 13 4.16 4.31 3.92 4.41 4.31 4.80 4.39 O rgan/B rain Weight Ratio (g/g> M ales F em ales 10.3 6.62 10.6 6.59 11.9 7.93 15. 1 7.65 o\ Ul ! y Dietary Level of A ro c lo r 1242 (ppm) Control 1 10 m 100 2 ? _________________ T A B L E XIV T E S T MATERIAL: A ro c lo r 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice Sum m ary of Mean Values Organ: Kidneys Organ Weight (g) Males F em ales 4.03 2.49 4.06 2.46 4.14 2.75 4.24 2.61 Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales 0.782 0.802 0.784 0.772 0.786 0.827 0.795 0.817 O r g a n /B r a In W eight R atio (g/g) Males F em ales 1.95 I . 31 1.93 1.30 2.11 1.52 2.47 1.42 ,v* (c* c f \i i < 00 465 oo AO* c n \ t t Dietary Level of A r o c lo r 1242 (ppm) Cont rol 1 10 100 TADLE XV TEST MATERIAL: Aroclor 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice S um m ary of M ean Values Organ; Spleen Organ Weight (g) Malee Fem ales 0.766 0.578 0.768 0.544 0.756 0.596 0.814 0.528 Organ/Dody Weight Ratio ( g / 1 0 0 g> Males Fem ales 0.150 0.184 0.148 0.171 0.143 0.179 0.154 0. 166 O rgan/D rain Weight Ratio (g/g) Malee F em ales 0.371 0.302 0.364 0.287 0.385 . 0.328 0.468 0.288 i"/ 1'- f 'r.T c: C ri v . TABLE XVI T E ST MATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic Oral Toxicily Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice Sum m ary of Mean Values Organ: Gonads Dietary Level of A ro c lo r 1242 (ppm) Cont rol 1 10 100 Organ Weight (g) Males * F em ales 3.60 0.114 3.51 0.143* 3.50 0.112 3.49 0.112 Organ/Body Weight Ratio ( g / 1 0 0 g) Males F em ales 0.69B 0.0370 0.681 0.0452 0.666 0.0336 0.656 0.0356 O rgan/B rain Weight Ratio (g/g) Males F em ales 1.74 0.0599 1.66 0.075B 1.78 0.0616 2.06 0.0619 Statistically significant difference at the 95 percent confidence level. 891- ) 0 0 06Uj-UUi r r T tiin u u i nUtO Dietary Level of A r o c lo r 1242 (ppm) Control & 10 100 O j KO :> T A B L E XVII T E S T MATERIAL: A ro c lo r 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice Sum m ary of M ean Values Organ: Heart Organ Weight (g) Malea Female* 1.05 1.58 1.02 1.55 1.10 1.61 1.05 Organ/Body Weight Ratio ( g /1 0 0 g) Malea Females 0.307 0.339 0. 307 0.320 0.295 0.331 0.302 0. 330 O rgan/B rain Weight Ratio (g/g) Males Females 0.767 0.551 0.752 0.540 0.788. 0.608 0.943 0.573  Dietary Level of A r o c lo r 1242 (ppm) Cont rol 1 10 100 i T A B L E XVIII T E ST M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Three-Month Sacrifice Sum m ary of Mean Values Organ: Brain Organ Weight (g) Males F em ales 2.07 1.91 2.12 1.89 1.97 1.81 1.62 1.83 Organ/Body Weight Ratio ( g /1 0 0 g) Males F em ales 0.402 0.616 0.410 0.597 0.375 0.545 0.345 0.576 Total Body Weights of Sacrificed Rats (g) Males F em ales 518 314 520 318 527 334 534 319 K001092 "*4 O n 3 Oa- i c f i ii i r I S ic T S T Ja fa U *. f a cl Histopathologic Findings Histopathologic examination of tissues and organs taken f r o m a l l a n i m a l s f r o m b o th th e c o n t r o l and 100 p p m g r o u p s w a s c o n d u c t e d . T a b l e s XEC and XX l i s t a l l h i s t o p a t h o l o g i c c h a n g e s noted. All of the lesions noted in the m icroscopic examination of tissu es w ere those of spontaneous disease and a re not unusual for the albino ra t. The m o st frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. These occurred in the co n tro l as w ell as the ra ts fed A ro clo r 1242. linm fw a AOP C03fc 0 U 471  I O T CS T j Ui 4 33 T A B L E XDC TEST MATERIAL: Aroclor 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Histopathologic Changes a Three-Month Sacrifice Croup: Control N u m b e r "of Animals Orean Examined Findings 5 Males Trachea Lung Urinary Bladder Tracheitis Chronic respiratory disease Hyperplasia 5 Fem ales Lung Chronic respiratory disease Ave ra Incidence Grad 1 1.0 1 r.o 3 1.0 . 1 1.0 All other tissues and organs w ere normal histologically. Grading System 0 .5 = minimal 1.0 = slight 2 .0 = mild 3.0 = moderate 4.0 = severe 5.0 a extreme F n fllA M A0M CC3669 0 I 472 3 10 = S \ i j Uc 35 TABLE XX TEST MATERIAL: A roclor 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Three-Month Sacrifice Group: 100 ppm N u m b e r of Animals Orean Examined Findings 5 Males Trachea Tracheitis 5 Females Lung Chronic respiratory disease Focal interstitial pneumonia Aver: Incidence Crac 2 1.0 2 1.0 1 * 1.0 All other tissues and organs were normal histologically. Grading Svstem 0.5 = minimal 1.0 = slight 2.0 = mild 3.0= moderate 4 .0 = severe 5.0 = extreme F o n tn ss ACM 003O70 0 473 4nff txffjLud B I O * T S T J a /r n n /o u * , 40 2. SixMonth Sacrifice a. G ross Pathologic Findings No outstanding differences were noted between test and control animals. % b. Organ Weight and Organ to Body and Organ to g ra in ''eight ftatio Data ----- -------- The re s u lts of-the s ta tis t ic a l-a nla y s e j conducted on ab- - .. solute organ w eights, organ to body weight and organ to brain weight ratios are sum m arized in Tables XXI through XXVI. Organ w eights, organ-to body weight and organ to brain weight ratios disclosed several randomly occurring intergroup differences. The lack pf any consistent dose related response and the absence pf any d eleterious histopathologic change confirm that these differences were not related to the ingestion of A roelor 1242. F o n ia % ACM 0 C 3 4 7 1 0 0 ( 474 Dietary Level of A ro c lo r 1242 (ppm) Control i 10 \ . too TA BLE XXI T E S T M A TER IA L: A r o c l o r 1242 Tw o-Year Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Values Organ: Liver Organ Weight <g> Males F em ales 22.9 1 3 . B** 22.3 13. 1 9.98* 13.2 22.0 11.7 Organ/Body Weight Ratio ( g /1 0 0 g) Males F em ales 3.74 2.85** 4.08 4.58* 3.77 3.15 4.23 3.70 O rgan/B raln Weight Ratio (g/) Males F em ales 11.7 6.86** 11.0 10.8 6.71 5.76 6.95 5 .9 4 ' F001W 7 4 Statistically significant difference at the 95 p e rc e n t confidence level. O - Statistically significant difference at the 99 p e rc e n t confidence level; LTI A OH 0 0 3 6 7 2 S m rn i/i l t a O O C 476 Dietary Level of A ro c lo r 1242 (pom) Control 1 10 100 T A B L E XXII T E S T M ATER IA L: A ro c lo r 1242; Tw o-Year Chronic Oral Toxicity Study - Albino Rata i Organ Weight and Ratio Data Six-Month Sacrifice I- I Summ ary of Mean Valuea | Organ: Kidneys Organ Weight <K) Male Female 4.04 2.79 3.51 2.44 3.75 2,49* 3.54 2.33* Organ/Body Weight Ratio ( g / 1 0 0 g) Male Fem ales 0.664 0.728 0.666 0.730 0.806 0.774 0.790 j 1 ; i 0.757 O rgan/B raln Weight Ratio (g/g* Males F em ales 2.06 1.43 1.75 1.41 1.86 1.31 1.74 1.18 0 Statistically significant difference at the 95 percent confidence level. A0H 003 673 *c. TEST tS CXI y Dietary Level of A r o c l o r 1242 (ppm) Cont rol 1 10 ' 100 T A B L E XXIII T E S T M ATERIA L: A ro c lo r 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values Organ: Spleen Organ Weight (g| Males F em ales 0.752 0.684 0.754 0.542* 0.796 0.622 0.584 0.488* Organ/Dody Weight Ratio ( g / 1 0 0 g) Males F em ales oc* o 0. 122 0. 154 0.172 0.142 0. 199 0.120 0.159 O rgan/B rain Weight Ratio (g/g) Males Female s 0.364 0.350 0.375 0.313 0.394 0. 327 0.288 0.248 6bo vuui * Statistically significant difference at the 95 percent confidence level. O. 2 4* tv ico n m cL r 4* 1 / U U i-k U O i a Dietary Level of A ro c lo r 1242 (ppm) Control 1 10 100 o CO T A B L E XXIV T E ST M ATER IA L: A ro c lo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values Organ: Gonada Organ Weight (g) Males F em ales 3.SS 0.0960 3.44 0.0810 3.55 0.106 3.35 , 0.0772 Organ/Body Weight Ratio (g /1 0 0 g) Males F em ales 0.593 0.0279 0.716 0.0253 0.652 0.0335 0.697 0.0251 O rgan/B rain Weight Ratio (g/g) Males F em ales 1.81 0.0492 1.71 0.0468 1.76 0.0558 1.65 ' 0.0392 t ii c ( r i 1 ** -V & Dietary Level of A roclor 1242 Control 1 10 100 j r>" => T A B L E XXV TE ST M ATERIAL: A ro c lo r 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Organ Weight and Ratio Data Six-Month Sacrifice Summary of Mean Values Organ: Heart Organ Weight (g) Males F em ales 1.70 1.05 1.49 1.03 1.46 1.06 1.42 0.970 Organ/Body Weight Ratio (g/100 g) Males F em ales 0.282 0.302 0.309 0.325 0.267 0.335 0.293 0.314 O rgan/B rain Weight Ratio (g/g) Males F em ales 0.867 0.538 0.741 0. 595 0.722 0.558 0.700 0.492 v* ""v K 00 'I m vt ra t i*n 6LP )00 oeoo / t Dietary Level of A r o c lo r 1242 (ppm) Control 1 10 100 . TAI1LE XXVI T E S T M A TER IA L: A r o c lo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Six-Month Sacrifice Sum m ary of Mean Values Organ: Drain Final Body Weights Organ Weight Organ/Body Weight Ratio of S a c r if ic e d Rat. (gl (g /1 0 0 g) (g) . M a l e _______F e m a l e s __________ M a l e a _______F e m a l e a__________ M a l e a F e m a l e s 1.96 2.01 2.02 2.03 1.95 1.73 1.90 1.97 0.320 0.415 0.369 0.416 0.560 0.546 0.597 0.635 613 348 484 317 548 318 488 310 O ** z Z a li VI *\ in L/t -4 r * a- r n **7` B - T E S T ^tovU /vu sd * 47 c. Histopathologic Findings Histopathologic examination of tissu es and organs taker. / f r o m a ll a n i m a l s f r o m both the c o n t r o l and 100 p p m g r o u p s was c o n d u c te d . T ab les XXVII and XXVIH list all histopathologic changes noted. All of the lesions noted in the microscopic examination of tissues w ere those of spontaneous d isea se and a re not unusual for the albino rat. The m ost frequent findings were lesions in the trachea and lungs, indicating chronic murine pneumonia. These occurred in the contro as well as the ra ts fed A ro c lo r 1242. in m 1 0 3 AO* oo 0 0 481  U lu td Bi - T E S T 45 TABLE XXVII TEST MATERIAL; Aroclor 1242 / T w o -Y ear Chronic Oral Toxicity Study - Albino Rats Histopathologic .Change s Six-Month Sacrifice Group; Control N u m b e r of Animals Organ Examined Findings Aver Incidence G ra 5 Males Trachea Lung Liver Skeletal Muscle Tracheitis Focal tracheitis Focal pneumonitis Hyperemia Focal pericholangitis Focal inflammation 2 1.! 2 l.( 1 O.i 2 l.c l * l.C 1 l.c 5 Females Trachea Lung Liver Kidney Focal tracheitis Hyperemia Hyperemia Pericholangitis Focal pneumonitis 1. 2 1 I 1 1.0 2.5 1.0 0.5 1.0 All other tissues and organs were normal histologically. Grading System 0.5 s minimal 1.0 * slight 2 .0 mild 1 .0 moderate 4*0 severe a extreme 0 0 ( 482 B t O ` T E S Tf(i\J ^aaaA <\{M*i %Sme. 49 ^ TABLE XXVIH TEST MATERIAL: A roclor 1242 Two-Y ear Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Six-Month Sacrifice Group: 100 ppm Number of Animals Organ Examined Findings Averaj Incidence Gradi 5 Males Trachea Lung Tracheitis Focal tracheitis Focal pneumonitis Hyperemia 2 1.0 2 0.5 3 1.5 2 1.0 5 Females Trachea Lung Focal tracheitis Focal pneumonitis Hyperemia l 1 1. 1.0 0.5 2.0' All other tissues and organs were normal histologically. Grading System 0.5 = minimal 1.0 = slight 2 .0 = mild 3.0 = moderate 4.0 = severe 5.0 = extreme lO M iflS AG* G03t d 00( 483 I BI TEST Jk*. 50 3. T w e lv e -M o n th Sacrifice -------------------------------- _ a. Gross Pathologic Findings / G ross pathologic findings among test animals were not significantly different from those noted in control animals. b. Organ Weight and Ratio Data The mean organ weight and ratio data collected at the tw elve-m onth s a c rif ic e are presented in Tables XXIX through XXXIV, Statistically significant differenc'es are designated by a ste risk s following the test group value. f Organ weights, organ to body weight and organ.to brain weight ratios disclosed several randomly occurring intergroup differences;1 The lack of any consistent dose related re sp o n se and the absence of any deleterious histopathologic change confirm that these differences were not rela ted to the ingestion of A roclor 1342. A Cm If Ki11A6 ai '',r)( 484 ) r Dietary Level (ppm) Control 1 10 100 I O O o ooLP T A B L E XXIX TEST MATERIAL: A ro c lo r 1242 Tw o-Year Chronic Oral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Values Organ: Liver Organ Weight (g) Males Females * 22.1 15.5 Organ/Body Weight Ratio ( g / 1 0 0 g) Males Females 3.79 3.52 22.7 22.4 26.3 13.7 14.4 14.4 3.45 3.48 3.78 3.33 3.44 3.59 O rgan/B rain Weight Ratio (g/g) Males F em alcs 10. 8 7. 72 10.4 10.6 12.4 7. 05 7. 39 7. 16 r i c Dietary Level (ppm) Control 1 10 100 ta ih jex x x TEST M ATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxlcily Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data t Sum m ary of Mean Values Organ: Kidneys Organ Weight (g) Males Females 4.04 3. 19 4.31 2.93 4.27 3.24 4.98* 3.01 O r g a n / Body Weight Ratio (g /1 0 0 g) Males Females 0.692 0.738 0.656 0.735 0. 662 0. 779 0.716 0.745 O rgan/B rain Weight Ratio (g/g) Males F em ales 1.97 1.58 1.97 1. 51 2.02 1.66 2. 33 1.50 F o m in s * Statistically significant difference at the 95 p ercent confidence level. O 00 o\ > mr t ~9tts `f.t*: p r rn ut Il IA N ( V. i'} ( \ f JaJttif'**" 0 J - T 5 5 7 .V w CiLurl.$UC. Dietary Level (ppm) Control 1 10 100 i T A B L E XXXI T E S T M A TERIA L: A ro clo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats * Twelve-Month Sacrifice f Organ Weight and Ratio Data Summ ary of Mean Values Organ: Spleen Organ Weight (g) Males Females 0. 788 0.796 1.000 0. 600 0.868 0.664 0.968 0. 570 Organ/Body Weight Ratio (g/100 g) Males Females 0. 133 0. 183 0. 1S3 0. 136 0. 160 0. 138 0. 145 O rgan/B rain Weight Ratio (g/g) Males F emales 0.380 0. 396 0.458 0. 307 0. 412 0. 341 0. 454 0.285 60U U U 1 o IVSI) * Statistically significant difference at the $5 percent confidence level. *o c CO T> OkV tt in a I* Dietary Level (ppm) Control 1 10 100 T A B LE XXXII TEST MATERIAL: A roclor 1242 T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Values Organ: Gonads Org an Weight Malea (8> Females - 3.46 0. 116 3.47 0.0938 3. 00 0 . 141 3.67* 0. 122 Organ/Dody Weight Ratio ( g / 1 0 0 g) Males Females 0. 596 0.0275 0. 529 0.0239 0.457 0.0332 0. 531 0.0305 Organ/O rain Weight Ratio (g/) Males F em alcs 1.70 0.0574 1.59 0.0483 1.40 1.72 0.0719 0. 0608 J Statistically significant difference at the 95 percen t confidence level. o vJ * --t in in uj i* S Vo % in *#* O a } Dietary Level (opm) Control 1 10 100 TABLE xxxm TEST MATERIAL: A ro clo r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data Sum m ary of Mean Values Organ: Heart Organ Weight (g) Males Females Organ/Body Weight Ratio (g/100<g) . Males Females O rgan/B rain Weight Ratio (g/g) Males F em ales 1.71 1.69 1.23 1. 18 0.293 0.258 0.286 0.298 0. 835 0.776 0. 609 0.610 I.6B 1.87 1.29 1.19 0. 263 0. 268 0. 312 0.298 0.799 0. 878 0.663 0. 591 N s . ra in Ol Vj, r\ <y V -j < V *>. ty/Jt Dietary Level (ppm) Control 1 10 100 TA IiLE XXXIV T E ST MATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic O ral Toxicily Study - Albino Rats Twelve-Month Sacrifice Organ Weight and Ratio Data , Sum m ary of Mean Values Organ: Drain Organ Weight (g| Males Females 2.04 2.02 2. 19 1.95 2.11 1.95 2. 14 2.00 Organ/Dody Weight Ratio (g/lOO g) Males Females 0. 35 1 0. 474 0. 334 0. 516 0.329 . 0.473 0. 310 0. 508 Final Body Weight of Sacrificed Animals (grams) Males F em ales 584 439 660 431 642 425 698* -.409 *001112 Statistically significant difference at the 95 percent confidence level* SO >h VO o > \\ x. Iof-) _ l O -TEST JU& s c. Histopathologic Findings Histopathologic examination of tis s u e s taken fro m e; r a t s a c r i f i c e d f r o m the c o n t r o l and 100 ppm g r o u p s a f t e r twelve mont^ of testing was conducted. V Tables XXXV and XXXVI list all histopathologic char noted. All of the lesions noted in the m icroscopic examinacit w e re those of spontaneous d is e a s e and cannot be re la te d to the.ingestio; A ro c lo r 1242. ( F00T113 o o i 491 B . J *T 5 T J*a, 5 TA BLE XXXV T E S T MATERIAL: A ro c lo r 1242 Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Twelve-Month Sacrifice Group: Control N u m b e r of Animals 5 Males Organ Examined Trachea Lung Urinary Bladder Findings Incidence Tracheitis Chronic respiratory disease Calculus * 1 2 1 5 Females Trachea Lung Colon Tracheitis Chronic respiratory disease Parasites l* l1 A' C All other tissues and organs were normal histologically. Grading Svstem 0 . 5 = minimal 1.0 = slight 2.0 = mild 3.0 = moderate 4.0 = severe 5.0 = extreme / * / F n n t ii4 ACH 0 036 as 00{ 492 Forni 15 003 n o t 493 TABLE XXXVI ,, TEST MATERIAL: Aroclo r 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes s Twelve-Month Sacrifice Croup: 100 ppm Number of Organ Animals Examined Findings 5 Males Trachea Lung Liver Pancreas Kidney Pituitary Adrenal Tracheitis Chronic respiratory disease Congestion Focal atrophy Focal lymphoid infiltration Chromophobe hyperplasia Nodular hyperplasia Hematocyst 5 Females Trachea Tracheitis Lung Chronic respiratory disease Av Incidence C I 4 1 1 l l 1 1- l 1 1 1 1 1 1 1 1 1 1 1 All other tissues and organs were normal histologically. Grading 5vstem 0. 5= minimal 1*0 = slight 2. 0 * m ild 3.0 a moderate 4.0 s severe 5. 0 a extreme. AC* 003t> 0 0 ( 494 1001116 B I - T E S T a& gIa u m , 4. Final Sacrifice . Gross Pathologie Findings G ross pathologie findings among test animals were not significantly different from those noted in control animals, b. Organ Weight and Ratio Data The m ean organ weight and ratio data collected at the final sacrifice are presented in Tables XXXVII through XLII. Statistically significant differen c es a re designated by a s t e r i s k s following the test group value. The absolute liver weight and liver to body or b ra in weigf r a t i o s were- s i g n i f i c a n t l y e v a lu a te d in f e m a l e r a t s fed 100 ppm A r p c l o r 1242 Statistical evaluations of other organ weights, organ to body weight and orga .to brain weight ratios disclosed sev eral randomly occurring intergroup dif f e r e n c e s , The la ck of any consistent dose r e l a t e d r e s p o n s e indicates that th e se d if f e r e n c e s w e r e not r e l a t e d to the inge stion of A r o c l o r 1242. 1001117 AO* CC36. n p 495 \ stary Level _ (ppm) Control 1 10 100 TABLE XXXVII TEST MATERIAL: A roclot 1242 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Sum m ary of Mean Values Final Sacrifice Organ: Liver Organ Weight Malee (8) Females Organ /Body Weight Ratio ( g / 100 g) Males Females 22.0 21.9 22.3 25.6 16.1 15.7 17. 1 22. 4** 3.47 2.93 3. 18 3.95 3.05 3.00 3. 19 4.82** 0 Statistically significant difference at the 99 percent confidence level. O .U VoO\ If i < | [ yl O rg a n /B ra in Weight Ratio (g/g> Males Females 10. 10 9.97 10. 20 11.90 8.4 8.03 8. 50 1 1 . 60*a Ennius r i/ ) etary Level fppm) Control 1 10 100 TA BLE XXXVIII TEST MATERIAL: A ro c lo r 1242 Two-Year Chronic Oral Toxicity Study - Albino Rat* Organ Weight and Ratio Data Summary of Mean Values Final Sacrifice Organ Weight Male* <g) Female* 5.57 3.48 Organ: Kidneys Organ /Body Weight Ratio ( c / i o o e> Males Females 0.877 0 .6 4 6 6. n 5.63 3.45 3.43 0. 820 0. 816 0 .6 7 0 0.644 5.44 3.43 0.835 0. 725 1*. O rgan/B rain Weight Ratio (g/g) Males Fem ales 2 .5 7 1 .79 2 .7 8 1. 7 6 2.56 2. 52 1.71 1. 79 > O' t>) 1*4 .e m u u tf 6^00 clary Level (ppm) _ _ Control m1 10 i 100 O O ^ xn VO 00 o LCui TA BLE XXXIX TE ST MATERIAL: A ro c lo r 1242 Two-Year Chronic Oral Toxicity Study - Albino Rats Organ Weight and Ratio Data Summary of Mean Values Final Sacrifice Organ: Spleen Organ Weight (g) Males Females 1. 15 0.96 1.26 0.81 Organ/Body Weight Ratio (g/100 g) Males Females 0. 182 0. 181 0. 169 0.158 1.08 0. 82 P. 158 0.153 1.07 0.65 0. 165 0. 140 O rg an /B raln Weight Rati (g/gl Males Female 0. 520 0.572 0. 49> 0. 145 0.495 0. 499 0. 409 0. 339 Forti121 etary Level (ppm ) Control 1 10 100 TABLE XL TEST MATERIAL: A ro clo i 1242 Two*Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Summary of Mean Values Final Sacrifice Organ Weight Males <g> Fem ales 2.52 0. 123 1.20 0. 102 Organ: Gonads Organ /Body Weight Ratio Males (e /io o e) Females 0.397 0.0222 0.424 0.0205 3.00 0. 126 0.437 0 .0 2 3 7 3.31 0. 129 0.514 0.0278 \ u> O m ut O rgan/B rain Weight Ratio (g/g) Males Females 1. 15 1.46 0. 062 0 .0 5 2 3 1.40 0.0625 1.55 0.0671 Forti122 stary Level (ppm) Cont rol 1 10 100 TABLE XL! TEST MATERIAL: A ro clo r 1242 Two-Year Chronic Oral Toxicity Study - Albino Rata Organ Weight and Ratio Data Sum m ary of Mean Values Final Sacrifice Organ Weight (g) Male* Females Organ: Heart Organ/Dody Weight Ratio (g/100 g) Malea Femalea 1.87 1.54 0.294 0.288 2.30* 1.51 0.307 0.292 2.08* 2. 19* 1.59 1.41 0.303 0.335 0.298 0.303 o* S t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e a t t h e 95 p e r c e n t c o n f i d e n c e l e v e l , * Statistically signilicant difference at the 99 percent confidence level. ot o o ADM 00 3697 O rgan/B rain Weight Ratio (g/g) Malea Females 0. 860 1.040** 0.959* 1.010** 0. 79f 0. 770 0. 788 0. 741 o i. r Dietary Level (ppm) Control 1 10 100 TABLE XLII T E ST M ATERIAL: A r o c l o r 1242 T w o-Y ear Chronic O ral Toxicity Study - Alhino Rats Organ Weight and Ratio Data Summary of Mean Values Final Sacrifice Organ: Brain Organ Weight (g) Males Females Organ/Body Weight Ratio (g /1 0 0 g) Males Female Final Body Weight of Sacrificed Animals (grams) Males F c m a Ic s . 2. 18 1.95 0. 342 0. 362 642 551 2.20 1.96 0.294 0. 388 759 5 32 2. 18 2.01 0. 313 0. 379 734 547 2. 14 1.91 0. 330 0.415 652 485 n * o oLl xos 00 B S U IW i  l.. r k* I W - I k I c c. Histopathologic Findings Histopathologic examination of tissu es and organs :ak f f r o m a ll a n i m a l s s a c r i f i c e d a f t e r 24 montns on t e s t was conducted Tables XLIH through XLVI list all histopathologic cha: noted. Table XLVU contains the resu lts of the histopathologic examina: of the u rin a ry bladders. Sign ificant l i v e r i n j u r y was found in a n im a ls fed ICO pp A r o c l o r 1242 {T-XII)- The co mpound a s s o c i a t e d l e s i o n s c o n s i s t e d of v a cu o la r change, focal hypertrophy and focal hyperplasia. In addition, t w ere lesions of inflammation, necrosis, fibrosis and minor degeneratior t h i s g r o u p w hic h, a lth ough s e e n in the c o n t r o l s a nd l o w e r t e s t g'ro ups , w< m o re severe and frequent in the T-I1I group. The vacuolar change was no: seen in the control animal b u t wa s o b s e r v e d o c c a s i o n a l l y in l i v e r f r o m T - I (1 ppm) and 7 - U (10 ppm a n i m a l s . T h e v a c u o l a r change was o b s e r v e d f r e q u e n t l y in the T - I I I anim< This le sio n is morphologically indicative of fatty degeneration. F orm al!: frozen sections* of livers from representative animals which displayed v a c u o l a r c h a n g e s w e r e s t a i n e d with Oil R ed O to r e v e a l the p r e s e n c e of fa The vacuolar lesion in the cytoplasm of these cells was positively identifi a t fat. The h y p e r t r o p h i c change found in the l i v e r w a s focal ar.< often l im it e d to the c e n tral lobular area*where groups of cells were-sw ell to two o r t h r e e t i m e s t h e i r n o r m a l s i z e with c l e a r pink h o m o g e n e o u s cy-.o POO! 124 ACM 0C3O9S 0 0 C502 The h y p e r p la s ia was asso c iate d with the sam e cells and appeared to be extension of the hypertrophic lesion. The hyperplastic cells were also hepatic tissue. The m in o r lesions of d e g e n e ra tio n , hepatitis, ductule < p ro li fe r a ti o n , n e c r o s is and focal lymphoid infiltration seen in the control j anim als and the T-I and T-II groups are lesions of spontaneous disease a a r e not re la te d to the A ro clo r 1242. This level of liver disease is not unujual in old animals. H y p e rp la sia of the tr a n s itio n a l epithelium was p r e s e n t in the u r i n a r y b l a d d e r of a n i m a l s f r o m the c o n t r o l g ro u p and f r o m e a c h o; the test groups. This lesion was usually associated with cystitis. All of the other lesions in the other tissues found in the anim als are related to spontaneous disease and they a re not unusual for r a t s of this age. Donovan E. G o r d o n , D. V. M. , Fh. D. Diplomate, A m erican College of Veterinary Pathologists AO* C U O U 503 1001125 T A B L E XLfll T E ST MATERIAL: A ro c lo r 1242 P I Tw o-Y ear Chronic Oral Toxicity Study - Albino Rats * Number of A ni m al s________ Organ E x a m in e d 1I Males Heart Trachea Lung Liver Stomach Spleen Kidney Testes Prostate Adrenal Gland n IT Brain Eye O Histopathologic Changes Final Sacrifice Group: Control Average . Findings_____________________________ Incidence______________ Grade n Kj ! i; i' -f Chronic focal myocarditis 3 1.0 Tracheitis 3 1.0 Chronic respiratory disease 9 1.0 Focal degeneration 1 1.0 Ductile hyperplasia 2 1.0 Chronic gastritis 1 1.0 1l e m o s i d e r osi s 3 1.0 Chronic nephritis 8 1.0 Testicular degeneration 2 1.0 Periarteritis 2 1.0 Inflammation 1 1.0 Telangiectasis 1 1.0 Nodular hyperplasia 1 1.0 Focal fatty change 1 I. 0 Focal encephalitis i 1.0 Inliamma lion 2 I. 0 OC m u 27 Number of Animala M Females o,, 2S oU l o o U l VP o T A B L E X L III continued TEST MATERIAL: A roclorl242 Tw o-Year Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Group: Control Organ Examined Heart Trachea Lung Liver Stomach Colon Spleen Uterus Kidney Ovary Findings Chronic focal m yocarditis Tracheitis Chronic respiratory disease Focal lymphoid infiltration Ductile hyperplasia Focal hepatitis Non-lipid vacuolar change Chronic gastritis Acanthosis - squamous epithelium Parasites Hemosiderosis Mel rit is Chronic nephritis Focal lymplioid infiltration Cyst Incidence 7 9 13 3. 2 1 2 3 5 1 4 3 6 1 1 Average Grade 2. 0 1.0 1. 0 1.0 1.0 1.0 0. 5 1.0 1.0 1.0 .1.0 2.0 1.0 1.0 LO 9 0 s inn tf lW U j Number of Animals 14 F e m a l e s T A B L E X L Ill continued TEST MATERIAL: A roclorl242 Tw o-Y ear Chronic Oral Toxicily Study - Albino Rats Histopathologic Changes Final Sacrifice Group: Control# Organ Examined Adrenal Gland Salivary Gland Findings Telangiectasis Nodular hyperplasia Chronic fibrosis and atrophy Incidence 9 4 I All other tissues and organa w ere norm al histolgica lly. 0.5 = minimal 1.0 = slight Grading System 2.0 = mild 3.0 = moderate 4.0 = severe 5.0 = extreme A0M 0 0 3 7 0 3 Average Grade 1.0 1.0 I. 0 f I \ TADLE XLIV TEST MATERIAL: Aroclor 1242 Two-Year Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Final Sacrifice Group: I ppm * Number of Average Anim als ________ Organ E xam in e d ____________________Findings_____________________________ In cidence______________ G r ad e Heart Trachea Lung Liver Stomach Spleen Kidney Teates Prostate Adrenal Gland Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal lymphoid infiltration Cirrhosis Congestion Chronic gastritis and acanthosis 1Icmosidt: r o s is Chronic nephritis Ca Icification Pc ria rtc ritis Testicular degeneration Inflammation Telangiectasis Nodular hyperplasia S 9 12 1 1 1 2 4 9 1 2 I 1 2 1 1.0 2. 0 1.0 1.0 1.0 1 0 1.0 2. 0 2. 0 1.0 2.0 1.0 4. 0 1.0 2. 0 *i I \ i l 5 jftO 6 i l W U I un o / TARILE XLIV continued TEST MATERIAL: Aroclor 1242 Two-Year Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Group: 1 ppm . Number of Animals Organ Examined Findings M Females Heart Chronci focal myocarditis Trachea Tracheitis Lung Chronic respiratory disease Liver Ductile hyperplasia Pancreas Chronic focal pancreatitis Stomach Chronic gastritis Ulcerative gastritis Acanthosis i Spleen Hemosiderosis > Kidney Chronic nephritis "X Uterus Met ri lis o (----^ 1o>J O -s\ un o 00 Adrenal Gland Telangiectasis , All other t i s s u e s and organs w e r e normal h is to lo gic ally . Incidence 6 7 13 3 2 2 1 2 e 6 1 10 Average Grade 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 2. 0 1.0 1.0 .1.0 Font 1 3 1 0C 509 Number of Animals 13 Males - D1* :> ij -j > TARLE XLV T E S T M A T E R IA L : A r o c t o r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rais Histopathologic Changes Final Sacrifice G r ot ip ; 10 p p m * Organ Examined Heart Trachea Lung Liver Pancreas Stomach Spleen Kidney Testes Findings Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal hypertrophy and hyperplasia Hypertrophy Vacuolar change (fatty) Ductile hyperplasia Chronic focal pancreatits Acanthosi a Inflammation, ulceration anti ncc rosis Hemosiderosis Chronic nephritis Testicular degeneration Periarteritis Incidence 6 7 9 1 1 2 1 3 6 1 7 10 2 3 Ave rag Grade 1.0 1.0 2. 0 1.0 1.0 i: o 2. 0 1.0 1.0 1.0 1.0 2. 0 3. 0 3. 0 s' / N um ber of Animals 13 M ales 13 Fem ales ) l, i TABLE XLV continued T E S T M A T E R IA L : A r o c l o r 1242. T w o-Y ear Chronic O ral Toxicity Study - Albino Rats Histopathologic Changes Final Sacrifice G r o u p ; 10 p p m * Organ Examined Prostate Adrenal Gland Heart Trachea Lung Tongue Stomach Spleen Lymph Node Kidney Uterus Adrenal Gland Findings Inflammation Telangiectasis Medullary hyperplasia Nodular hyperplasia Chronic fncal myocarditis Tracheitis Chronic respiratory disease Periarteritis Chronic gastritis and acanthosis Ulceration 1I c m o s i d e r o s i s F.dema Chronic nephritis M etritis Tclangiccta sis Nodular hyperplasia Incidence 2 4 1 2 1 5 9 1 5 1 5 1 6 2 B 1 Average Grade 3. 0 1.0 1.0 1.0 1.0 1.0 1.0 2. 0 1.0 1.0 2. 0 1.0 1.0 I. 0 1.0 1.0 Form 3 2 ooo r' tV \ 1t 000 CUUUUi Number of Animals 6 Males n* Lfl no u TABLE XLVI TEST MATERIAL: A roclor 1242 Two-Year Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes Final Sacrifice Group: 100 ppm' Organ Examined Heart Trachea Lung Liver Pancreas Testes Stomach Spleen Lymph Node Kidney Findings Chronic focal myocarditis Tracheitis Chronic respiratory disease Focal degeneration Focal hypertrophy Hypertrophy Vacuolar change' (fatty) Periarteritis Periarteritis Ctironic g astritis and acanthosis Periarteritis Hemosiderosis Periarteritis Chronic nephritis Incidence 3 3 6 1 1 1 3 1 3 1 1 1 1 4 ftf 1 r ( < Average Grade 1.0 2. 0 1.0 1.0 I. 0 1.0 1.0 3. 0 2. 0 1.0 2.0 1.0 3. 0 2. 0 i i i t** \ h I K 1 Number of Animalo 6 Males TABLE XLV| continued TEST MATERIAL: Aroclor 1242 Two*Year Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Final Sacrifice Group: 100 ppm* Organ Examined Prostate Adrenal Gland Salivary Gland Eye Findings Inflammation. Focal fatty change Focal chronic inflammation Inflammation Incidence 1 1 1 1 14 F e m a l e s Heart Chronic focal myocarditis 4 A Trachea Lung Tracheitis Chronic respiratory disease B 6 Liver Focal degeneration 3 Focal hyperplasia 2 Focal hypertrophy 2 Hypertrophy 3 oO Nodular hyperplasia 1 Focal cholangi^icpatitis 1 O Ci ui X ------------- .--------------------------- -------- ---------------- -------------------- ---- -------- >-* to o o l n O m t/i I.' \ Average Grade 3.0 1.0 1.0 1.0 K 1.0 1.0 1.0 1.0 1.0 1. o Z. 0 1.0 1.0 A i TABLE XLVI continued TEST MATERIAL: Aroclor 1242 9 T wo-Year Chronic Oral Toxicity Study - Albino Rats Histopathologic Changes Final Sacrifice Group: 100 ppm Number of Animals Organ Examined Findings 14 F e m a le s Liver (continued) Pancreas Stomach Spleen Lymph Node Kidney Uterus Adrenal Gland Focal hepatitis Hype rplasia Vacuolar change (fatty) Chronic focal pancreatitis Chronic gastritis Acanthosis Ulcerative gastritis Ulcer 1l e n i o s i d e r o s i s Congestion Chronic nephritis Metritis Telangiectasis N o d u l a r hyperplasia Acanthosis All other ti s s u e s and organs were normal histologically . Incidence 1 1 11 1 2 2 1 1 4 1 7 2 8 4 1 n c_ Grading Sy s te m Average G rade 1.0 3. 0 1.0 1. 0 1.0 1.0 1.0 1. 0 2. 0 1.0 1.0 1. n t. 0 1.0 1.0 (7ADM)0 01C13375J/0 H C ? TAni.E xlvu TEST MATERIAL: A rocIorl242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rata Histopathologic Changes of the Urinary Bladder Final Sacrifice Group C Number Sex Examined Findings* M II FH Proteinaceous plug (34) Focal epithelial hyperplasia (62) T-I (1 ppm) M 12 F 13 Proteinaceous plug (582) Diffuse epithelial hyperplasia associated with diffuse cystitis (566) Diffuse epithelial hyperplasia associated with diffuse c y s t i t i s (5110) None 9C LU)U( T- II M II Diffuse epithelial hyperplasia associated (10 ppm) with diffuse cystitis (651) Diffuse epithelial hyperplasia associated oX with diffuse cystitis and a proteinaceous plug (655) o o O o y -v T-Ill IP 1100 ppm) hj F M F 13 6 13 None Proteinaceous plug (744) Focal epithelial hyperplasia (767) <J1 Individu al animal numbers arc shown in parenth eses. Gradi ng System 1 0 p minimal or trace 4 . 0 - s e v e r e a Incidence 1 1 1 1 1 - 1 1 - 1 1 jC L f. Average Grade 1 2 1 3 1 - 2 B K TEST S' W I C3 1 G. Detailed D escription of Tum or Findir.os Tum or data for individual animals including location, we: and pathologic classification are presented in Table XLVIII through None of t h e s e t u m o r s could be r e l a t e d to the ingestion c i 1242 a n d a r e c o n s i d e r e d n o r m a l fo r a r a n d o m p o p u l a t i o n of r a t s th:is ag 0037 1 p o n i l i ao" 0 0 515 Animal 'umber nd Sex J -.M 2-M - 16- F 00 8 H U M 5 47_F 48-F so .F 52 - F O ^ `O-F U*-1* O' l - F o3 o oUi - 4- i T A n L E XLVIII T E S T M A T ER IA L : A r o r l o r 1242 Tw o-Y ear Chronic O ral Toxicity Study - Albino Rats Description of Tumor Findings Group: Control Location Abdomen Panereas Abdomen Lymph node Abdomen Abdomen Abdomen Abdomen Ail renal gla nd Abdomen Weight (grama) 11.76 64.98 35.09 - - - -- - 88.92 Size (cm) - - 8x1x2 5x2x2 - 2x2x1 2x2x3 - -. - 13 X 11 X 4 Classification Mammary fibroadenoma Adenocarcinoma Mammary fibroadenoma Mammary fibroadenoma Reticulum cell sarcoma Mammary fibroadenoma Mammary fibroadenoma Mammary fibroadenoma Mammary fibroadenoma 1`h c o c h r o m o c y Ionia Fibroadenoma 1 V k IU O n V Months on Test 24 24 24 24 24 7 24 24 24 f\ V_ J Animal Number and Sex 566-M 569-M 604-F 609-F : 611 - F s 613-F ^ Q is-f o c^ tn t-* 'j Location Abdomen Spleen Abdomen Abdomen Abdomen Ovary Abdomen Abdomen AH 0 0 3 7 1 3 T A B L E XL1X TEST MATERIAL: A ro c lo r 1242 Two-Year Chronic Oral Toxicity Study - Albino Rat Description of Tum or Findings Group: 1 ppm Weight (grama) - - - 15.00 53. SO 35.00 - 335.00 Size (") 5x3x1 5x3x1 lxlxl 3x2x1 13 x 1 0 x 5 Classification Adenocarcinoma Lymphosarcoma Mammary fibroadenoma Fibroadenoma Fib roadenoma Fibroadenoma Granulosa cell tumor Fibroadenoma Mammary fibroadenoma , ' Months on Test 24 22 24 24 24 24 23 J t oNt Animal Number and Sex 621 - F 627-F 628-F 630-M "S*63l-F 5 634-F S ^S -F Location Abdomen Pituitary Abdomen Abdomen Uterus Abdomen Abdomen Abdomen Pituitary A* 003 716 TABLE XLIX continued TEST MATERIAL: A ro c lo r 1242 Tw o-Year Chronic O ral Toxicity Study - Albino Rais Description of Tumor Findings Group: 1 ppm oo Weight (grams) 18.00 - 157.20 117.90 13.41 39- 36 Size (cm > 1x3x3 6x3x3 9x6x4 7x6x2 3x2x1 6x5x3 6x5x4 Classification Fibroadenoma Chromophobe adenoma Fibroadenoma Mammary fibroadenoma Mammary fibroadenoma Fibroma Fib roadenoma Fibroadenoma Fibroadenoma - Chromophobe adenoma * Months on Test 24 24 24 23 24 24 24 ^ c i | t i Animal Number and Sex 640-M 646-M 662-M 687- F 6B9-F 690-F ps-r o o k. -F O M vo I- F o o TADLE I TEST MATERIAL: A r o clo r l2 1 2 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Description of Tumor Findings Group: 10 ppm Location Weight (grama) Abdomen Pancreas Adrenal gland 129.0 _ - Pituitary Abdomen - 280. 0 Pituitary - Abdomen - Pituitary - Abdomen Abdomen 3.90 23. 15 Abdomen 175.0 Parathyroid gland - Size (cm) 9x7x3 - - 3x 3x 2 7x6x3 8x7x5 - Classification Fibroadenoma Islet cell adenoma Medullary tumor Chromophobe adenoma Mammary fibroadenoma Chromophobe adenoma Mammary adenocarcinoma Chromophobe adenoma Mammary fibroadenoma Mammary fibroadenoma Mammary fibroadenoma Adenoma Month on Test 24 24 24 22 . 24 24 24 24 24 24 vi.; J r. Anima) Number and Sex 707- F 708- F 71 l - F 7 12 - F Location Abdomen Abdomen Abdomen Subcutaneous, abdominal T A fiL E L conti mieti TEST MATERIAL: Aroclor 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Description of Tumor Findings Group: 10 ppm Weight Size (grama) ________ (c TM> _ 74. 6 7x6x3 189.0 5x4x1 6.96 3x2x) 155.0 11x8x3 Classification Mammary fibroadenoma Mammary fibroadenoma Mammary fibroadenoma Fatly tissue fibroma * Months on Test 24 24 24 24 03 O ni co i V ocfm u u i un ro o n x O1oM t*u< Animal Numbe r and Sex 744-M 775-F 78S-F 789-F 794-F T A B L E LI TEST MATERIAL: Aroclor 1242 T w o-Y ear Chronic Oral Toxicity Study - Albino Rats Description of Tumor Findings Group: 100 ppm Location Pancreas Ovary Pituitary Adrenal gland Abdomen Weight (grams) 260.0 Site (cm) 10 x 10 x 5 Classification Islet cell adenoma Granulosa cell tumor Chromophobe adenoma Medullary tuinor Mammary fibroadenoma Months on Te at 24 24 24 24 23 /: . / Monsanto c V .H ,z Njm< o<Nomimi _C_om_o_._ny__U*llrSaInStt**l^ 1-- Vf>d. & Env. Hlth. Poi.ii" r.n* Saury Cro* Tcxicolocv Manacer 19 A*,iom*nc* 0yun.11Crow* Annuli Saury $31 ,300 Cowin 0.O.Um.nl LoCinon Creve 0*1oiun muuM 2/1/76 Cat*UAH tmpioy* Rn.w Typ* o* AiiS tri* iwr til|ory from in* oeaem* i.cu al mu w\**l wn.cn mou iop'ocx.auiy cicr.oct in* iw.ra na nirr in ca coa* i*io.| , A w ra C-it9or> Cl**or Technical ^ Accomplissent of significant results: 0 *icr>o* in* cniv*m *n( no ill l.*n,ficai>c* to M e n u n ta laiaw i lg.fi. At a recent meeting in Creve Coeur, Glenn Schweitzer, head of the Off Toxic Substances of EPA, offered some interesting comments. He obser that Monsanto's toxicologists were held in high regard at EPA. Howev since it lacked an in-house toxicology facility, Monsanto as a compan not as highly regarded overall as duPont, Carbide, or Dow. Dr. Wright's professional and personal characteristics have contribut nificantly to Monsanto's image at EPA. He has shown unusual persever and dedication, frequently involving his own time, to review and inte large volumes of data which he subsequently organized for presentatio EPA officials. Particularly noteworthy wer his efforts on polychlor biphenyls (Aroclors) and chlorinated isocyanurates (ACL products). I former instance, his excellent analysis and synthesis of widely scatt observations played a prominent role in forestalling EPA's promulgati unrealistic regulations to limit discharges of polychlorinated biphe.n EPA's proposed regulations would have precluded the use of these mate by Monsanto's customers. With respect to chlorinated isocyanurates, Dr. Wright has had several contacts with individual scientists^at EPA answer specific questions that they had raised or to inform them of t status of additional studies which had been undertaken.. Overall, by virtue of the qualities of leadership which Dr. Wright ha played, he has made an important contribution to Monsanto's image at That favorable image will become increasingly important to Monsanto a areas of interaction with EPA multiply. comminata Oyi \/ C ln* 10/7*) 0*1* ARiwCaor*nmAminotuMnti AopiOrwO By1 " / `7 -- *-- i -- c ^ --- / * UU' lo m 1 A4 O* Aw 1 rn ) 1' 7h 5SCH 0 S 3 1 MONSANTO INDUSTRIAL CHEMICALS COKPANT FUNCTIONAL PRODUCTS GROUP STANDARD MANUFACTURING PROCESS for AR0CLORS (T a k a -o v e r d i s t i l l e d ) Departm ent 246 Supercedes: S tandard M anufacturing P rocess fo r Aroclors D epartm ent 246# d a te d O cto b er 1966# and a l l amendments A through L. T e n ta tiv e P rocess fo r th e Continuous M anufacture o f A roclor 1242# d ated 9/16/63# and d esig n ated R e p o rt No. P -1 5 0 4 . P r e p a r e d by: R. M. MeCut chan r'***"*- i *r i. . i - t . .'V , _-- Iss u e d : Jan u ary 1972 Approved ? a j . ................... G eneral M anufacturing uporincenaen L u R. R c w y *'Tttr earcfc`* ^Development- -M anager' _ \ f l . r R C 'C L x Q M a n u fac tu rin g Manage r ^ j M s p ro c e ss i s th e p ro p e rty o f Monsanto In d u s tria l Q iem icals 'Company and th e r e c i p i e n t i s r e s p o n s i b l e f o r I t s s a fe k e e p in g . I t c o n ta in s c o n fid e n tia l in fo rm a tio n o f Monsanto I n d u s tr ia l C h e m ic a ls Company which m ust n o t be rep ro d u c ed # re v e a le d to u n a u th o ris e d perso n s o r s e n t o u ts id e th e company w ithout p ro p e r 'a u th o risa tio n . E ith er re ta in in a secure f ile or retu rn to the S ta n d ard Documents Departm ent. p i i t f t f r i F F 's l EXHIBIT F fifti 1 5 *23 ICM 00 6 DEPARTMENT 246 - *STANSARS NJNlTACTUr.ING PROCESS AR0C3.0R APPENDIX j SAFETY AND TOXICITY DATA I , safety e o u if ::e ::t A. F ir e E x tin g u is h e rs , 1 . C arbon d i o x i d e - 1 s t f l o o r , NE o f l e a n - t o 2 . Dry c h e m ic a l - 1 s t f l o o r , SE o f l e a n - t o 3 Dry c h e m ic a l - 2nd f l o o r , w e s t w a l l 4 Dry c h e m ic a l - 2nd f l o o r , w e s t w a l l B. Gas M asks* 1 1 s t f l o o r , on s p r i n k l e r house 2 1 s t f l o o r , o u t s i d e w e s t w a l l o f r e p a i r room 3 2nd f l o o r , on w est w a l l 4 C o n t r o l room, e a s t w a l l 5 . 4 th f l o o r , on h a n d r a i l by *1 c h l o r i n a t o r 6. 4th p la tfo rm , A roclor column (2) C. S c o tt Air Pak. 1 O u t s i d e w e s t w a l l o f l e a n - t o D. Emergency C lo th in g * 1 Box on 2nd f l o o r , w e st w all* E. S a f e t y Showers With Eye N ash , 1 B a tc h d e p a r tm e n t, 1 s t f l o o r , 2 B a tc h d e p a r tm e n t, 2nd f l o o r . 3* B a tc h d e p a r t m e n t , 3rd f l o o r . 4 C o n tin u o u s d e p a r tm e n t, 1 s t f l o o r . .. 5 C o n tin u o u s d e p a rtm e n t, 2nd f l o o r . 5 4 C o n tin uous d e p artm e n t, 3rd f l o o r . jf, 7 W est s i d e o f ta n k farm (a la rm i n c o n t r o l room ) 8 C o n tro l room (eye b atch o n ly ) F . P erso n al Safety Eguitment A v ailab le. 1. Hard h a t. 2. Safety glasses. 3 S a f e t y s h o e s . 4 G o g g le s . 5. Rubber or canvas gloves. F/M1146J1 6 Rubber overshoes. 124 AO* 0C2 department 2 46 -standard manufacturing process AROCLOR ( C o n t 'd ) APPENDIX J ( C o n t 'd ) SAFETY AND TOXICITY DATA, ( C o n t'd ) I I . DEPARTANT SAFETY RECORD (246/259) , A* L o s t tim e a c c i d e n t s - L a s t o c c u r r e d on J a n u a r y 2 8, 1948 B. S e r i o u s i n j u r i e s - `rhe l a s t two s e r i o u s i n j u r i e s v/erei 1) 8 /5 /7 0 - See A tta c h e d in fo rm a l i n v e s t i g a t i o n r e p o r t 2) 1 2 /2 /6 8 - R e fe r t o form al i n v e s t i g a t i o n r e p o r t L-17- C. Minor i n j u r i e s . Year In ju rie s No. o f Men 1969 1970 1971 12 12 13 20 20 24 III.TOXICITY The fo llo w ing to x ic r a tin g code w ill be used in d escrib in g the to x ic ity of these m aterialsi 0 - none 1 - slight -Z * J - nigh U unknown A. B ip h e n y l (Code 82601) .1 . Synonymsi ' D ip h e n y l. 2 D e sc rip tio n i ivhite flakes or s o lid o ff white mass; somewhat p leasan t odor. 3 . C o n s ta n ts : Mol. Wt. 154.2; M.P. 69*C ./ B.P, 255*C.; D e n s i t y .9910 @ 75#/4*C . * 4 f l a s h P o i n t ; 235* F. (C .C .) 5 . Xuto Ig n itio n Temperature! 1004*F. 6 . Toxic Hazard R atings- Acute L o c a l! U A cute S y s t e m a t i c ! I n g e s t i o n 2, I n h a l a t i o n 3 Chromic Local; U 7 . F i r e H azard: D e f in i t e l y when exposed to h e a t o r f l a r e ; can re a c t with oxidizing m aterials. 8 . F i r e F i g h t i n i C02 o r dry c h e m ic a l. 9 . Formulai Cfii.sC6Is5 10011M 125 AOM 002 DEPARTI ZMT 246 - STANDARD MANUFACTURING PROCESS ARQCLQR APPENDIX J ( C o n t'd ) SAFETY AND TOXICITY DATA ( C o n t'd ) III.(C o n t'd ) A. (C ont'd) 10. Biphenyl vapors are ir r ita tin g to the upper resp irato ry t r a c t . Workers should not be exposed to vapor le v e ls throughout th e ir s h if t in excess of the threshold lir.it value of 1 m illigram per cubic meter o f a ir (or about 0 .2 ppm).: The compound, o r o r g a n i c s o l u t i o n s o f t h e com pound can absorb through the in ta c t skim th erefo re, repeated skin contact should be avoided. 11. See H ygienic Guide S e r ie s oh b i p h e n y l " B. C h lo rin e (Code 81059). 1. D escrip tio n : Greenish yellow gas. 2. Formula: 12 3. C o n s t a n t s t Mol. Wt. 70.914* I!.P .-1 0 1 * C . jB .P . - 3 4 .5 #C .j D e n s i t y T . 47 8 0*C. 4. Toxic Hazard R ating: Acute lo c a l: I r r i t a n t 3; In h a la tio n 3 Acute system ic: 0 Chronic lo ca l: U Chronic system ic: U * * * -** -i. j^pur^ 5 . T o x ic o lo g y : C h lo rin e i s e x tre m e ly i r r i t a t i n g to th e mucou memoranes of th e eyes and re s p ira to ry t r a c t . I t combines w ith m o isture to lib e r a te n ascen t oxygen and from hycro- ` ch lo ric acid. Both o f these substances, i f p resen t in q u an tity , cause in f la m m a ti o n o f t h e t i s s u e s w i t h which th e y come i n contac I f t h e lu n g t i s s u e s a r e a t t a c k e d , pulm onary edema may r e s t A c o n c e n t r a t i o n o f 3 .5 ppm p ro d u c e s a d e t e c t a b l e o d o r; 15 PPM causes, im m ediate i r r i t a t i o n o f t h e t h r o a t . Con c e n t r a t i o n s o f 50 PPM a r e d a n g ero u s f o r even s h o r t exposu: 1000 PPM may be f a t a l even when t h e ex p o su re i s b r i e f . Because of i ts intensely ir r ita tin g p roperties, severe i n d u s t r i a l exposure seldom o c c u r s , as th e workman i s fo rce d to leave the area before he can be se rio u sly affec In cases where th is is im possible, the i n i t i a l i r r i t a t i o n FOOT148 126 . ach c c % irI " ' DEPARTMENT 24 6 -STANDARD MANITACTUP-T/G PROCESS AROCEOR APPENDIX J ( C o n t 'd ) SAFETY AND TOXICITY DATA ( C o n t'd ) I I I , B. 5 ( C o n t'd ) o f th e eyes and mucous membranes o f th e nose and th r o a t i s fo llo w ed by cough, a fe e lin g o f su ffo c a tio n and l a t e r p ain and a fee lin g c o n stric tio n in the ch est. If excosun h a s b een s e v e r e , pulm onary edema may fo llo w w ith r a l e s b e in g h e a r d `o v e r th e c h e s t . 6. F ire Hazard; Moderate - can re a c t to cause fire or e x p lo s io n - upon c o n t a c t w ith t u r p e n t i n e , ,e t h e r , ammonia g a s , ill u m in a t in g g a s , h y d ro carb o n s, hydrogen and powders* m etals. 7. E x p lo s io n H azardi P re s e n t by r e a c t i o n w ith re d u c in g ager.i 8 . D i s a s t e r C o n t r o l ; C an cero u s; e m its h i g h l y t o x i c fumes; .. w i l l r e a c t win., w ater to form to x ic and co rro siv e fumes o f KCl; i s h eav ier than a i r - gas w ill hug the ground. P e o p le w ith o u t adequate p r o t e c t i o n sh o u ld go a c ro ss wind u n til out of the affected area. C. HC1 O ff-G a s (Code 828.51) .1 Synonyms! M u r i a ti c a c i d , C h lo r o h y d r ie A cid , Hydrogen Chic 2 b escrictio n t Colorless gas. 3. Fo rr.-.ula: fciCl. 4. Toxic r.azard R ating: Acute lo ca l: I r r i t a n t 3, In g estio n 3, Inhalation 3 Acute Systemics U Chronic local! I r r ita n t 2 Chronic Systemic! U M .A .C .i 5 ppm i n a i r f o r 3 h r . d a y . T oxicology! Hydrogen ch lo rid e is an i r r i t a n t to the nuccu membranes of the eyes and r e s p ir a to r y t r a c t . C o n cen tratic o f 35 ppm c a u s e s i r r i t a t i o n o f t h e t h r o a t a f t e r s h o r t expo C o n c e n t r a t i o n s o f 50 t o 100 ppm a r e t o l e r a b l e f o r 1 h o u r . More s e r i o u s e x p o su re s r e s u l t in pulm onary edema and o f t e n l a r y n g e a l spasm. C o n c e n tr a tio n s o f 1000 t o 2000 ppm a r e d a n g e r o u s even f o r b r i e f e x p o s u r e s . M is ts o f HC1 a r e con sid e red less harmful than the anhydrous fora since the d r o p l e t s have no d e n y d ra tin g e f f e c t . 7 S e e H y g ie n ic Guide S e r i e s on "Hydrogen C h l o r i d e " F o rn ix 127 ACM CQ2e> DEPARTES: rr 2 46 - STANDA SP tAlXTAC TU RirG PROCESS AROCLOR APPENDIX J ( C c n t'd ) SAFETY AND TOXICITY DATA ( C o n t'd ) III . (Cont'd) D. F e r r i e C h l o r id e (Code 33500) 1 D e s c r i p t i o n ; G r a n u la r s o l i d . 2 F o rm u la" T e C l3 (A nnydrous) 3 . C o n s t a n t s : \ o l . Wgt. 1 6 6 ,2 2 , L'e l t i n g P t . s u b l i m e s , s o I u Z ir it/ in 0 - very soluble with heat r is e , 4 T o x ic H azard R a t i n e : Acute Local: I r r i t a n t 1; Ingestion 1 Acute System ic: U Chronic Local: I r r ita n t 1 Chronic Systemic: D 5. F ire H azard: Tnere is no f i r e hazard under normal c o n d it b u t i t v i 11 e r .it to x ic fumes a t high tem p eratu res, 6. H a n d lin g : P r o t e c t th e s k in v.-ith approved p r o t e c t i v e c lo t.u n g , avoid the breatni.ng of FeCl3 d u st, wear approve r e s p ir a to r w ith adquate c a rtrid g e , and p ro te c t the eyes w ith approved g o g g le s . There a re no s to ra g e regulations-? however, i t should be sto red in a dry place as heat is re le a s e d upon so lu tio n in w ater and wet f e r r ic chloride w ill not catalyze the chlorination reaction, E. .Lim e-(Code 385QG) (Calcium Cxid e ) 1 . D e s c r i p t i o n : F in e w h ite o r s l i g h t l y g ra y powder, Rhomeri< Trigonal c ry sta ls. 2 . Form ula : CaO, 3. froxic hazard P.atir.c? Acute l o c a l : I r r i t a n t 3; In g e s tio n 1; In h a la tio n 3. A cute S y s te m ic : I n g e s t i o n 2j I n h a l a t i o n 3? s k i n absorption 0. C h ro n ic l o c a l : I r r i t a n t 3? I n h a l a t i o n 2, C hronic System ic: In g e stio n 2; In h a la tio n 3; Skin absorption 0, 4 T o x ic o lo g y : Has a c a u s tic re a c tio n and, t h e r e f o r e , is i r r i t a t i n g to th w- s k i n . As a d u s t i t can c au se d e r m a t i t i s and i r r i t a t i o n o f th e eyes and mucous membranes. I t i s a g eneral nuisanc type of dust. 5, F ire Hazard: None. 6. E x p lo sicn ^h azarc: V irtually none. 7. Handling: Cust re s p ira to r, adequate protective clothing, in d u c in g rubber coated gloves, optional rubber f u ll covei a p ro n and f u l l c o v e r p l a s t i c goggles sh o u ld be used when fftm iSB 128 ADM 0C26 1 depart^ '? 246 - standard riANurAcruaiNC process AROCIOR APPENDIX J ( C o n t'd ) SAFETY AND TOXICITY DATA (C o n t'd ) E. 7. (Cont'd) h a n d lin g lime, (dust) Adequate v e n t i l a t i o n and d u st rer.ov equipment should be used in the handling area. Lime i s added t o t h e s t i l l s t o n e u t r a l i z e any l i b e r a t e d -HC prevent sublim ation of the FeCl3 c a ta ly s t, i t is handled in 50# b a g s, F . K i t r o g e n (Coda 43099) 1, D escriptioni C olorless gas 2, 'to i n u l a F I T 3. C o n s t a n t s : Mol. Wt. 2 8 ,0 2 j M.P, - 210*C> B .P . - 1 9 5 .8 ` C .j D en sity 1.2506 c r / l i t e r a t 0*C. 4. T o x ic ity : None. In high c o n c e n tra tio n s i t i s an ' ~ , asphyxiant, G. A r o c l o r s . (See H ygienic Guide S e r i e s on * C h lo ro d ip h e n y ls") Y M H 151 ADM 0 0 2 11 129 -t ( Monsanto MONSANTO INDUSTRIA! CHEMICALS CO. BOO N. Lina&argh oulavard S t. Louis. M u s o u n 63166 P uons: 014} 6 6 4 -1 0 0 0 January 20, 1972 Westinghouse E le ctric Corp. Box Q l Blocrington, Indians. ^7^02 Gentienea, C Ai ve hcve previously n o tifie d you by way o f correspondence lin e e early 1970, the m aterial described on the attached acknowledgement o f your order contains polychlorinated biphenyls (PC3). Polychlorinated biphenyls are high ly sta b le ehemleal compounds and arc not readily biodegradable. T herefore, vhen placed in the environment they may be considered con taminants and may adversely a ffe c t some species of animal and marine l i f e . You must take every precaution to prevent any entry o f polychlorinated biphenyls into the environment through s p i l l s , usage, leakage, d isp o sa l, vaporisation or otherwise. i This m aterial should'not be used by you oi-youi* customer In equipment, packaging m aterials or products involved in the processing, handling, or storage of food, food rela ted products, animal feeds, food wrapping or container m aterials, potable waters or pharmaceuticals. Very truly youra, Howard S. Bergen, J r ^ * Director Specialty Products Group Attachment u n i t Qf M O n i l i ' W C o m B * " 1 .0 0 1 1 5 2 1C 104 (T y p e d from Original) January 15, 1972 Monsanto Industrial Chemicals Co. 800 N. Lindbergh Boulevard St. Louis, Missouri 63166 Gentlemen: Monsanto Company ("Monsanto") manufactures certain polychlorinated biphenyl products ("PCB's") which Westinghouse Electric Corporation ("Buyer") desires to purchase. While Buyer desires to purchase PCB^s because o f certain desirable flame resistant and insulator properties, Buyer acknowledges that it is aware and has been advised by Monsanto that FOB'S tend to persist in the environment; th at care is required in Vs their handling, possession, use and disposition; th a t tolerance limits have been or are being established for FOB'S in various food products. Monsanto has therefore adopted certain restrictive policies with respect to its further production, sale and delivery of FOB'S, including the receipt o f undertakings from its customers as set forth below, and Buyer is willing to agree to such undertakings with r e s p e c t to sales and/or deliveries of PCB's by Monsanto to Buyer. Accordingly, Buyer hereby covenants and agrees th at, with respect to any and aB FOB'S sold o r delivered by or on behalf of Monsanto to o r for the account of Buyer on or a fte r t h ^ a t e hereof, and in consideration o f any such sale or r itjp iiy . Buyer shall defend. Indemnify and hold harmless M jp p to , its present, past and future directors, officers, e f H l^ e s and agents, from and against any and all liabilities, claims, damages, penalties, actions, suits, losses, costs and expenses arising out of or in connection with the receipt, purchase, possession, hamfling, use, sale o r disposition of 1001153 Monsanto Industriai Chemicals Co. Page Two January 15, 1972 such PCB*s by, through o r w d er Buyer, whether alone or in com bination with other substances, including, without implied lim itation, any contamination of or adverse effect on humans, marine and wildlife, food, animal feed or the environment by reason of such PCB's. The point a t and a fte r which the provisions of this agreem ent shall apply to PCS'; sold or delivered by or on behalf of Monsanto to or for the account of Buyer on or a fte r the d ate hereof, and the point a t which title and risk of loss with respect to such PCB'srfiall pass from Monsanto to Buyer, shall be the F.O.B. point at the location from which delivery to Buyer is initiated by Monsanto, and shall refer to the point of transfer of possession of the drum, tank car, tank truck, or o th er container for such PCB*s, from Monsanto to Buyer or the first receiving carrier utilized to effect delivery of such PCB*s to Buyer. The provisions of this agreement shall not be applicable to any PCB*s delivered to Buyer prior to the date hereof; and nothing herein shall c re ate or imply any duty or obligation: (i) of Monsanto to sell or deliver any FOB'S to Buyer; or (ii) of Buyer to defend, indemnify or hold harmless Monsanto or any other corporation, or any person, for any damages resulting from the negligence of Monsanto (in the absence of negligence of Buyer) in its packaging or shipping of FOB'S or from th e failw e of PCB^s to comply with the contract specifi c atio n s applicable to such FOB'S. Ho conditions, understandings j l p a m e n t s purporting to modify or vary the term s hereof shM H^a binding unless hereafter made In writing specifically re fo m f tf to this agreem ent and signed by the party to be bound and nO'modification or variance of this agreement shall be e ffe c te d by the acknowledgment or acceptance of any sale document, purchase order, shipping instruction or other forms containing term s or conditions at variance herewith. F001154 Monsanto Indict rial Chemicals Co, Page Two Jan u ary 15, 1972 In the ev en t of litigation to which these indemnity provisions shall apply, Monsanto will make available to Buyer such inform ation as Monsanto has (excluding trade secrets or proprietary inform ation of Monsanto, or any other information which Monsanto is not legally free to disclose) which may reasonably t>e required by Buyer in th e defense of such litigation, and o th erw ise will cooperate with Buyer in connection therew ith. This agreem ent shall be governed by and be construed according to the laws of the S tate of Missouri. All existing co n tracts for the sale of PCB's by Monsanto to Buyer for delivery in the future are hereby mended to contain the provisions set forth herein. WESTINGHOUSE ELECTRIC CORPORATION By (Signature)______________________ Title Vice President_________________ D ate January 15, 1972 _________ MONSANTO COMPANY ORIGINAL SIGNED BY: By E. J . Pntzcll F0011S5 Monsanto M ONSANTO INDUSTRIAL CHEMICALS CO. BOO N. Lindbareft Boulavard St. Louis, M issouri B3166 Phons: 014) 694*1000 January 20, 1972 Westinghouse E le c tr ic CorpBox 3^-1 Bloomington, Indiana ^7^02 Gentlemen, A t we have previously n o tifie d you by way of correspondence sin ce early 1970, the m aterial described on the attached acknowledgement of your order contains polychlorinated biphenyls (PCB). Polychlorinated biphenyls are highly sta b le chemical compounds and are not rea d ily biodegradable. Therefore, when placed In .the environment they may be considered con taminants and may adversely a ffe c t some sp ecies o f animal and marine l i f e . You must take every precaution to prevent any entry o f polychlorinated biphenyls in to the environment through s p i l l s , usage, leakage, d isp o sa l, vaporisation or otherwise. This m aterial should not be used by you or your customer in equipment, packaging m aterials or products Involved In the processing, handling, or storage o f food, food related products, animal feed s, food wrapping or container m aterials, potable waters or pharmaceuticals. Very truly yours Howard S. Bergen, Jry Director Sp ecialty Products Group Attachment unit of Monsanto Company M O NSANTO INDUSTRIAL CH EM ICA LS CO. . 8 0 0 N. L*na&*f3h Qowlav*rd S t. Louis. M isso u ri 63106 Phono: Ol<) 08**1000 SPECIAL UNDERTAKING BY PURCHASERS OF POLYCHLORINATED BIPHENYLS M onsanto Company ("M onsanto") m a n u fa c tu re s c e r t a i n p o ly c h lo r i n a t e d b ip h e n y l p ro d u c ts ("PC B 's") w hich G eneral E l e c t r i c Company ("B uyer") d e s ire s to p u rc h a s e . W hile B u y e r d e s i r e s to p u rc h a s e PCB's b e ca u se o f c e r t a i n d e s ira b le flam e r e s i s t a n t and in su la to r p ro p e rtie s , Buyer , acknow ledges t h a t i t is aware and has been ad v ised by M onsanto t h a t PC B 's te n d to p e r s i s t in th e environm ent; th a t care is re q u ire d in th e ir handling, p o ssessio n , use and d is p o s itio n ; th a t to leran ce lim its have been or are b e in g e s t a b l i s h e d f o r PCB's in v a rio u s fo o d p ro d u c ts . M onsanto has th e re fo re adopted c e rta in r e s t r i c t i v e p o lic ie s with- r e s p e c t to i t s f u r th e r p ro d u c tio n , s a le and d e liv e ry o f PC B 's, in c lu d in g th e r e c e ip t o f u n d e rta k in g s from i t s cu sto m ers as s e t f o r th below , and Buyer is w illin g to ag ree to such u n d e rta k in g s w ith resp ect to s a le s an d /o r d e liv e rie s o f PC B 's by M onsanto to B uyer. r. A c co rd in g ly , B uyer hereby covenants and ag rees th a t, w ith r e s p e c t t o an y an d a l l PCB's s o ld o r d e l i v e r e d by o r on b e h a l f o f M onsanto to Buyer on o r a f t e r th e d a te h e re o f and. in c o n s id e ra tio n o f any-such sa le o r d e liv e ry , Buyer sh a ll- d e fe n d , indem nify and hold h arm less M onsanto, i t s present# p a s t a n d f u t u r e d i r e c t o r s , o f f i c e r s , e m p lo y e s a n d a g e n ts , from and a g a in s t any ana a l l l i a b i l i t i e s , claim s, dam ages, p e n a ltie s , a c tio n s , s u its , lo s s e s , c o sts and expenses a ris in g o u t o f or in connection w ith the re c e ip t, p urchase, p o ssessio n , handling, use, sa le or d isp o sitio n of su ch PC B 's b y , th ro u g h o r u nder B uyer, w h e th er alo n e o r in com bination w ith o th e r substances,' in c lu d in g , w ithout im plied l i m i t a t i o n , any c o n ta m in a tio n o f .o r a d v erse e f f e c t on humans, m arine and w i l d li f e , food, anim al feed o r th e environm ent by re a s o n o f such PC B 's Foni 1177 ft -2 A l l e x i s t i n g c o n t r a c t s f o r th e s a l e o f PCB's by M onsanto to B uyer a re h ereb y amended to co n ta in th e p ro v is io n s s e t fo rth above. N othing h e re in s h a ll c re a te or im ply any d uty o r o b lig a tio n o f M o n s a n to t o s e l l o r d e l i v e r a n y P C B 's t o B u y e r . No c o n d i tio n s , u n d e rsta n d in g s o r agreem ents p u rp o rtin g to m odify o r v a ry th e te rm s h e r e o f s h a l l be b in d in g u n le s s h e r e a f t e r made in w ritin g s p e c if ic a lly re fe rrin g to th is agreem ent and sig n e d by th e p a rty to b e bound and no m o d ific a tio n o r v a ria n c e of the above u ndertaking sh a ll be e ffe c te d by the acknow ledgm ent o r a cc ep tan c e o f any s a le docum ent, p u rch ase o rd e r, sh ip p in g in s tr u c tio n o r o th e r forms c o n ta in in g term s o r co n d itio n s a t variance herew ith. GENERAL ELECTRIC CO. .MONSANTO COMPANY TITLE : V ice P resid en t and Corporate Counsel DATE: January 21. 1972 1001158 ID S J OC Monsanto MONSANTO iNOUrmtAL CMlMICALS CO. 3 0 0 N. n d b a r g n B o u t t v t r d S t Lauti. M iasoun 63160 P f t o n a : '3141 6 9 4 * 1 0 0 0 February 4, 1972 Dear S ir: ' Ve a r e w r i t i n g t o a d v is e you t h a t M onsanto h a s a d o p te d c e r t a i n p o lic ie s w ith resp ect to i t s fu rth e r sa le and d eliv ery o f a ll p o l y c h l o r in a t e d b ip h e n y l (FOB) p r o d u c ts u se d a s d i e l e c t r i c flu id s ln c lu d ln g -b u t n o t lim ite d to th o se so ld under tradenam es such as A roclorTM , In erteen iS ^ and PyranolG ^ and under the g en eric term aaX arel. E ffe c tiv e im m ediately M onsanto w ill s e l l and d e liv e r th e se prod u c ts o n ly to m an u fa ctu rers o f e l e c t r i c a l equipm ent o r components who u t i l i z e t h e p r o d u c t s a s d i e l e c t r i c f l u i d s and who h av e e n t e r e d in to agreem ent to indem nify and h o ld h arm less Monsanto In th e u se o f th e s e p ro d u cts* The two c o p ie s o f such an agreem ent a re a t* ta c h e d . The accep tan ce by M onsanto o f such an agreem ent i s sub j e c t to r e c e ip t o f f in a n c ia l and o th e r in fo rm a tio n from you (such as ev id en ce o f ad eq u ate In su ra n c e p r o te c tio n ) w hich, in M onsanto's o p in io n , maXes th e agreem ent m e a n in g fu l. As you a r e u n d o u b te d ly a w a re , . s t u d i e s I n d i c a t e FCBs may be accumu l a t i n g i n t h e e n v iro n m e n t. I n some I n s t a n c e s , PCBs have b e en found in food o r In th e food ch ain . For your in fo rm atio n , a ttac h ed i s an a r t i c l e by C a r l G. G u sta fso n o f th e F e d e ra l W ater Q u a lity A d m in istra tio n a p p e a rin g In "E nvironm ental S cien ce a Technology" w h ist d e a ls w ith t h is s u b je c t. Because o f M onsanto's concern ov er t h i e p ro b le m , we h a v e d i s c o n t i n u e d s a l e s o f FCBs e x c e p t f o r u se a s d l e l i e t r l e f lu id s In e l e c t r i c a l equipm ent and com ponents. I f you d e s ire to c o n tin u e p u rchase o f th e se p ro d u ets from M onsanto, p le a se have th e a tta c h e d copies o f agreem ent signed by an au th o rized o f f ic e r on b e h a lf o f y o u r company and forw ard a f u lly sig n ed copy, to g e th e r w ith your most rec en t au d ited fin a n c ia l statem ent and any o th e r in fo rm a tio n which you f e e l w ill a s s i s t Monsanto in I t s e v alu a tio n . Foni159 22 ADM 00Z*t Page 2 tf ou rd i I rae t an ly y tSq uMe sr.t i on! H .S . p lea se telephone B ergen, M onsanto (3 1*) 69^ Company, - P2 ^.o5 5. r Box 1 ^ 1 7 , S t. L ouis, M issouri 63178. vm s i n c e r e l y r e g r e t any h a r d s h i p s t h a t t h i s d e c i s i o n ay c a u s e W w T T + im t.ik e n i n an e f f o r t t o c o n tin u e t o make a v a ila b le th e s p roducts r th ese Im portant e le c tr ic a l a p p lic a tio n s. Vary tr u ly yours /b i E nclosures Howard Bergen D ire c to r S p e c ia lty P ro d u cts Group M onsanto I n d u s t r i a l C h e m ic a ls Co J. 0 0 1 1 6 0 V - Monsanto MONSANTO INDUSTRIAL CHEMICALS CO. 0 0 0 N. Lindbargft Boulevard St. Louis. M issouri 63160 * Phon: 014) 6 B 4 -I0 0 0 \ F eb ru ary 17, 1972 \ We a r e w r i t i n g t o a d v i s e you t h a t M onsanto h a s a d o p te d c e r t a i n p o l i c i e s w ith re sp e c t to the fu rth e r sa le and d eliv ery o f a l l p o ly ch lo rin ated b ip h en y l (PCB's) p ro d u cts in c lu d in g th o se so ld under tradenam es such a s A r o c l o r ^ ) , I n e r t e e n () , P y r a n o l ( ) * and u n d e r th e g e n e r i c t e r m a sk a re l. S t u d i e s h a v e i n d i c a t e d PCB's may b e a c c u m u la tin g in t h e e n v iro n m e n t. In some in s ta n c e s PCB's have been found in food o r in th e food c h a in . B e ca u se o f M o n s a n to 's c o n c e rn o v e r t h i s p ro b lem we h a v e d i s c o n t i n u e d s a le s o f PCB's in a l l a p p lic a tio n s ex cep t as d i e l e c t r i c f lu id s fo r use in tran sfo rm ers, c a p a c ito rs , and o th er e le c t r i c a l equipment and com ponents In the p a s t, Monsanto has sold th e se flu id s d ir e c t to transform er component m anufacturers and a lso to makers of in s u la tio n such as K raft p a p e r and p l a s t i c f ilm who u s e o n ly s m a ll amounts o f t h e d i e l e c t r i c flu id fo r te s tin g p urposes. Monsanto has decided to d isco n tin u e such d ire c t sa le s . For your future requirem ents of these d ie le c tric flu id s, we s u g g e s t you c o n t a c t t h e A r o c l o r c a p a c i t o r m a k e r s , o r i n t h e c a s e o f transform ers c o n ta c t the makers o f the a sk are l ty p es. We s i n c e r e l y r e g r e t a n y i n c o n v e n i e n c e t h i s d e c i s i o n may c a u s e y o u . I f you have any q u e s tio n s r e l a t i v e to t h i s d e c is io n p le a se telep h o n e (314) 694-2513, o r w r ite d i r e c t l y to Mr. P aul B enignus, Monsanto Company, P . O. Box 14617, S t . L o u is, M isso u ri 63178. Very tru ly .youra. T. L. GossageL/ M arketing D irector S p e c ia lty Products Group a unit of M o m anto Company 1,001161 AOM 002**9 Monsanto MONSANTO INOUSTTMAL CMIMICAUI CO. 8 0 0 N. Lindbergh B oulevard S i. Louis, M issouri 83188 Phone: (3U) 8 9 4 -1 0 0 0 F eb ru ary 28, 1972 A tten tio n : P lan t E ngineer Dear S ir: Ve a r e w r i t i n g t o a d v is e you t h a t M onsanto h a s a d o p te d c e r t a i n p o lic ie s w ith re sp e c t to the fu rth e r sa le and d e liv ery o f a l l p o ly c h lo rin a te d b ip h e n y l (PCBs) p ro d u c ts In c lu d in g t h o s e ^ o l d under tradenam es such as A ro clo rO J In erte en Pyranol 6} and under th e g en eric term a sk a re l. S t u d i e s h a v e I n d i c a t e d PCBs may be a c c u m u la tin g i n t h e e n v ir o n ment I n some i n s t a n c e s PCBs h a v e b e e n fo u n d I n fo o d o r I n t h e fo o d c h a in * B e c a u se o f M o n s a n to 's c o n c e rn o v e r t h i s p ro b le m , we h a v e d i s c o n t i n u e d s a l e s o f PCBs I n a l l a p p l i c a t i o n s e x c e p t a s d ie le c tr ic flu id s fo r use In tran sfo rm ers, c a p a c ito rs , and o th er e l e c t r i c a l equipm ent and components* In th e p a s t, M onsanto has so ld th ese flu id s d ire c t to tran sfo rm er re p a ir shops and to any one re q u irin g the flu id fo r top-up o f an e x is tin g tran sfo rm er. M onsanto has d ecid ed to d is c o n tin u e d ir e c t s a le s to tra n sfo rm e r re p a ir shops and fo r tran sfo rm er top-up. For your fu tu re req u ire m e n ts o f d i e l e c t r i c f l u i d s , we s u g g e s t you c o n t a c t t h e m a n u f a c tu r e r o f th e tra n s fo rm e r f o r which you d e s ire th e f lu id . Ve s i n c e r e l y r e g r e t a n y h a r d s h i p s t h a t t h i s d e c i s i o n may c a u se y o u , b u t I t h as been ta k e n in an e f f o r t to c o n tin u e t o make a v a ila b le th e se p ro d u e ts f o r im p o rtan t e l e c t r i c a l a p p lic a tio n s . I f you have any queetlO M r e la tiv e to th is d e c isio n , p le a se telep h o n e (314) 694-2513* o r w r ite d i r e c t l y to Mr. P a u l B e n ig n u s, M onsanto Company, P. 0 . Box 1 4 6 1 7 * S t. L o u is, M isso u ri 63178. Very tr u ly y o u rs, Al cc: Purchasing Agent ' . JLr. W N N N f t O M arketing D irec to r S p e c ia lty Products F on n 62 ADM 002^93 Mr. P aul D eFaleo, Jr Regional A dm inistrator U .S . en v iro n m en tal Pro t a c t ion Agency R agion ZX 100 C a lifo rn ia S tr e e t San F ra n c isc o , C a lifo rn ia 94111 Daar Mr. DaFalcoi Z h av e b aa n a lead t o rasp o n d t o your l a t t a r ad d raaaad t o Mr. S . J . Bock a s k in g f o r c a r t a i n in fo rm a tio n regarding sa les o f polychlorinated biphenyls by Monsanto and C e n tra l S o lv en ts and Chemicals in th e Los A ngeles County a r e a . Z know t h a t you hava d i s c u s se d t h i s by te le p h o n e w ith Mr V. B. Fapageorge and Z have review ed th e s itu a tio n w ith him. Itrhaa. *s p o lic y not^ t o d iy u lg e th e names o f o u r cu sto m ers i o r 'th e p ro ^ u c ts ' W make',' -`= nor the q u a n titie s o f products these customers . p u rc h a s e . Ke c o n s id e r t h i s to be p r o p r ie ta r y inform a tio n and th e re fo re hold i t c o n fid e n tia l. Consequently we do n o t f e e l f r e e t o comply w ith your r e q u e s t fo r d a ta on custom er names and q u a n titie s purchased. On th e o th e r h an d , l a s t ZTovenber we d id r e le a s e to g o v ern m e n tal a g e n c ie s . In c lu d in g th s SPA, M onsanto's t o t a l p ro d u c tio n and s a le s fig u re s on PCB's f o r th e y e e rs 1960 through 19Z1. These s t a t i s t i c s have been r e le a s e d p u b lic ly end e a r l i e r t h i s y e a r we d isc u sse d them in d e t a i l w ith members o f th e s c i e n t i f i c K001163 141 AOM 006 Mr; P aul D eFalco, J r . March *3, 1972 Pag 2 , cr a n ia l t y and w ith re p re s e n ta tiv e s o f th e Washington u ltl^ a g e n c y PCB ta s k fo re o f w hich FPA la a n a n b a r. For your raady referen ce I aa encloelng a copy of th is in fo sn a tlo o . We c e r t a i n l y a h a ra your con e a rn and da* I r a t o c o n tr o l th e d isc h a rg e o f PCS's in to th a environm ent. I t la b a c a u sa o f t h i s coo c a m t h a t wa im plem ented a program o f self-im posed cu rtailm en t o f aalaa o f these products so t h a t now wa a r e o n ly o f f e r i n g c o n tin u in g s u p p lie s fo r clo sed system d ie le c tr ic a p p lic a tio n s where th a p o te n tia l danger of environm ental contam ination la carafu lly controlled. Furtherm ore, ae another etep in safeguarding tha en v iro n m en t we have inform ed a l l cu sto m ers o f PCB m a te r ia La o f th e p o t e n t i a l d an g ers sh o u ld th e s e m a te ria ls escape and have stro n g ly urged them to tak e every p recau tio n to prevent loeses through s p ills , usage, leakage, d isp o sal, v ap o rlistio n or otherw ise. Z r e g r e t wa ca n n o t comply w ith your r e q u e s t f o r c u s to c a r in fo rm a tio n b u t i f wa can b a o f a s s i s t a n c e to you in o th e r ways we w i l l b e g la d to v i s i t you o r y o u r d e s ig n e e s to d is c u s s th e PCB s i t u a t i o n f u r t h e r . aT* !' S in c e re ly , *x - r W. H. C orey, D ir e c to r F u n ctio n al P roduct Groups /i* E nclosure ccs Mr. C h a rlas H. Soesmer/Tionaanto Fom164 1 4 2 40 M OQo l , MlTSL-niSin MONSANTO CHEMICAL COMPANY il Vj s \s: R. Dur i a ;er T. L. Gqssa^e ' - t C. Pa tin / `- a . J. Maiion / / . - B ru s -P. J/ A VMarsh **. . W. R. Richard - S t . R./H. xfunch - - Papageorge- * : -- O. j R/; Coleman - Newp - *_-i ./ Dear Paul:' - I am p l e a s e d t o a n s w e r y o u r q u e s t i o n s i n y o u r l e t t e r o f March 20, 1972.- - ./ . Ij The- M in is tr y o f I n t e r n a t io n a l- T r a d e - a n d - I n d u s t r y .-(M ITI - issu e d n o tic e y e s t e r d a y - t o alm ost* ever-y i n d u s t r i a l ^ a sso c ia tio n concerned, as summarized*in the fo llo w in g : --" a t N o- e l e c t r i c a l m a c h i n e r y a n d e q u ip m e n t w h i c h " ..*'-* c o n t a i n " PC-B must* be m a n u f a c t u r e d a f t e r S e p t ' 1 / -V \' J 1972. _ T> - b.- No* h e a t *e x c h a n g e e q u ip m e n t- m ust- be p r o d u c e d -- - a f t e r - J u l y J., 1972 w h ic h u se * PCB* a s a - - t r a n s f e r **'".....m edium . . - c. Exceptions- to the above are th o se w h ich a . *. .* s o l d t o t h e s p e c i f i c `u s e r s an d w h ic h c a n be --. r e t u r n e d .-a f t e r - u s e - t o .t h e - . p r o d u c e r s - o r ^ m a n u - .; . ... *. f a c t u r e r s . - f o r :PCB ""d i s p o s a l - . : They m u s tr ". - : p e r i o d i c a l l y r e p o r t - t o t h e - - m i n i s t r y how PCB--~ is u se d ;'sh ip p e d , s to re d ,- recovered, re tu rn e d . * - * V and -d isp o sed ,- in c lu d in g machinery!* in a d d itio n .' V\ '* V '. . to - th e q u an tity - d e a ltrw ith -and so and so f o r th t. ; *. \ ; ; .' r--* * *E very: u s e r - o f ~ P C B - c o n t a i n i - n g machi-ner.y-and>^.- **. e q u ip m e n t.-w il-l^ T ia v e ^ to . b e - r e c o r d e d - a n d - - r e g i s t e : in the. o f f i c i a l l i s t 't o * i n s u r e s t r i c t super.vis in the fu tu re . d. Im port of such m achinery and.equipm ent w ill be p o s s ib l e - o n ly -if- p e r m is s io n - is g ra n te d by_-theC o v ern m en t-r a f t e r 'S e p t e m b e r - -1, 1972'.- i . e.-PCB c o n ta in in g -m a c h in e ry and equipment a lre a d y in use must be id e n t i f i e d and -rep o rted to the. a u t h o r i t i e s s o t h a t t h e d i s p o s a l o f PCB i s t o be made c o m p lete..- F O O U f : i-OoiJS V/ M You will understand that the above action is not the' total-' ban of PCB usr.ge. However, who can meet such stringent regulatory requirements to continue'using PCB, other than non-civll organisations?1! * ' -. ,, * -. '. ' ./ . :* i . i i We called the MITI yesterday to learn the following: ,7> ' *' i - 1. The MITI foresee by the action taken yesterday the ** use of PCB fluid will be limited in the near future *' to the transformers used by-the Japan National-.* Railroad and certain electronic parts in missiles belonging to the Defense Ministry,-, in addition to *' the high voltage electro-furnace capacitors as a possibility. * 2. Thermal transfer systems with PCB will sooner or later undergo change in fluid or -the whole line will have to discontinue operation. 3. Kaneka agreed to follow the recommendation by the MITI to discontinue the production-of PCB, probably after September of this year. 4. Those who are able and obliged to use _PCB will have - I to import PCB, possibly from Bayer,^with permission | from the Government. : You rightly pointed out that the actions being taken by the Japanese Government appear out of line from the xest of the world today.- I can agree-to Mr. Terasaki's statement in this respect that the folks go all the way when they decide to do something in^this country.. I -t"hinlr- the latest-happening-sensati-onaHy. moved the--: Government* to-this -direction - the analysis -.of.mothers milk in Osaka showed PCB level of 0.7_to 0.1 PPM, as against the FDA's 0.2 maximum level* for-cows-' milk.- In. the Diet committee the Welfare Minister-was .at-a loss when -asked if-or not babies .can-drink-*milk"-wi-th--0 ."7 PPM--PCB. without any*~- danger "to their healthy growth.^. You might recall Yodo River flows from -Lake Biwa to OsakaBay. Two capacitor plants are-located by._the- Lake-Nichicon 1s a n d Nisshin Electric's*. Samples of the. soil' were taken from the vicinity-of Nichicon>to run* analysis of PCB with an*- unfortunate result showing. 1,000 PPM PCB1.*: in m 166 10032ia People associated the contamination of 'the'soil with the mother* milk case. Thus Kichicon was forced to announce , last week that they plan to discontinue production of PCB capacitors, after coming September. *4 * ' - i *. Today the world seems to be ruled by feeling and not reason. The pressure against PCB usage i s f a r from logical. It is- quite emotional and*-at the same time political, It was this pressure that led Kaneka to the discontinuation. It has not been 100% confirmed but I think you may rest assured Kaneka will not go after overseas markets after the fall of this year, although they are exporting substantially today. The grand funeral of PCB in Japan is close at hand. What .will replace PCB -in the -dielectric- markets is yet known to nobody exactly.' We only are aware a number of products ranging from silicone to polyisobutane, wax.and DOP are competing. The strongest candida te on the-longer term basis seemslo" me entirely new systems after technological-' innovation. .. 'I wish you good luck." * `. TK/ym - T. Katayama - P.S.-Just before. I had-this-letter typed, Kaneka, announced _ that" the"y decided to discontinue---the production of ." Kaneclor-by'.the. end of_ June,T which_was-conflrmed by . * myself today.with Kaneka. . Also Nichikon was forced" to-terminate their production of -PCB capaci tors at the end. Of- April. M n iifV 7 3