Document mbpe1oDY0yOpRXoLZ3m27krwd

flR f i - O IM I A International Research and Development Corporation SPONSOR: COMPOUND: SUBJECT: 3M Company Fluorad Fluorochemical FC-143 Ninety Day Subacute Rat Toxicity Study. Collaborators : Edwin I. Gojfdenthal, Ph.D. Vies President and Director of Research D. C. Jessup, Ph.D., Associate Director of Research R. G. Geil, D.V.M., Vice President and Director of Pathology N. D. Jefferson, B.A., Acting Director of Small Animal Toxicology R. J. Arceo, M.D., Staff Pathologist Date:____ November 6, 1978 137-089 001617 International Research and Development Corporation T A B L E OF C O N T E N T S -paga I. S y n o p s i s .......................................................... 1 II. Compound ............................. . . . . . . .............. 3 III. Clinical Methods .................................................. 4 A. M e t h o d ..........................................................4 1. General Procedure ......................................... 4 2. Compound Administration ................................... 4 3. Observations . . . . . ................................... 5 4. Laboratory Tests ......................................... 5 m in in m a. Hematology b. Biochemistry c. Urinalysis d. Serum Samples 3. Statistical Analysis ..................................... 6 B. R e s u l t s ..........................................................6 1. General Behavior, Appearance and Survival ................ 6 2. Body W e i g h t s ............................................... 6 3. Food and Compound Consumption............................... 7 4. Laboratory Tests ......................................... 7 a. H e m a t o l o g y .............................. 7 b. Biochemistry ......................................... 8 c. U r i n a l y s i s ............................................. 8 IV. Pathological Studies .............................................. 9 A. M e t h o d s ..........................................................9 1. Gross Pathology ........................................... 9 2. H i s t o p a t h o l o g y ............................................. 9 B. R e s u l t s ..........................................................9 1. Gross Pathology and OrganWeights .......................... 9 2. H i s t o p a t h o l o g y ............................................ 10 137-089 G01G18 ________ International Research and Development Corporation________ T A B L E OF C O N T E N T S (Continued) Page Table No. 1. Group Mean Body Weights; Weight Ranges; andSurvival . . . . 12 2. Individual Weekly Body W e i g h t s ........................ 13-14 3. Mean Food Consumption.................................... 15 4. Summary of Means and Significance ofHematologicalValues . . 16-17 5- 7. Individual Hematological Values ............................. 18-23 8. Summary of Means and Significance ofBiochemicalValues . . . 24-25 9-11. Individual Biochemical Values ............................... 26-31 12-14. Individual Urinalysis Values ............................... 32-37 15. Summary of Gross Necropsy Observations ................... 38 16. Absolute and Relative Organ Weights ....................... 39 17. Individual Organ Weights ................................... 40-41 18. Histomorphologic Observations.......................... 42-47 137-089 001619 International Research and Development Corporation Page 1 I. SYNOPSIS Fluorad Fluorochemical FC-143 was fed in the diet at levels of 10, 30, 100, 300 and 1,000 ppm to Charles River CD rats for 90 days. Five male and five female rats were initiated at each dosage level and in the control group. The rats were observed twice daily for overt signs of toxicity and mortality. Individual body weights and sex-group food consumption were recorded weekly. Hematologic, biochemical and urinal ysis studies were conducted during the pretest period and at 1 and 3 months of study. No changes considered to be directly related to the compound were seen in general behavior, appearance or survival. A slight decrease in body weight gain and food consumption was seen for male rats at the 300- and 1,000-ppm dosage levels. Hematologic, biochemical and urinalysis values for the female rats showed no changes considered to be related to the compound. A few values obtained for the males showed a slight deviation from the control values (i.e. slightly lower erythrocyte count, and elevated blood urea nitrogen and alkaline phosphatase values). Compound-related gross observations such as enlargement and varying degrees of discoloration on the surface of the liver were observed among male rats in the 1,000-ppm group. There were no such observations amoung female rats from the 1,000-ppm group or in males or females from lower dietary levels. Statistically significant variations in sex-group mean organ weights, which were considered compound related, occurred in the liver of rats in the 300- and 1,000-ppm dosage groups. All other variations were unaccompanied by any morphologic alterations. 137-089 G01620 International Research and Development Corporation Page 2 Microscopically, compound-related lesions were confined to the liver. The lesions consisted of focal to multifocal, very slight to slight, cytoplasmic enlargement of hepatocytes located in centrilobularmidzonal regions of the affected liver lobules, accompanied in some instances by increased amount of yellowish-brown pigment resembling lipofuscin in cytoplasm of hepatocytes and occasionally in sinusoidal lining cells. The incidence and relative severity of the above lesions were predominantly amoung males and more pronounced among rats at 1,000 ppm. The other changes recorded in the liver and other tissues were lesions of naturally occurring diseases and they were present in most instances among the control and test rats. 137-089 C01621 International Research and Development Corporation Page 3 II. COMPOUND The compound was received from 3M Company, Saint Paul, Minnesota on October 24, 1977 as indicated below: ___________ Label_____________ Description Fluorad Flurochemical FC-143 3M Stock No. 98-0211-0008-0 Lot 340 white powder 137-089 001622 International Research and Development Corporation Page 4 III. CLINICAL METHODS A. METHOD: 1. General Procedure: Thirty male (222 to 254 grams) and 30 female (151 to 179 grams) Charles River CD rats purchased from The Charles River Breeding Laboratories, Inc., Portage, Michigan were used in this study. The rats were distributed among the groups, based upon a computer-generated table of random numbers. The rats were housed individually in suspended wire-mesh cages and maintained in a temperature-, humidityand light-controlled room. During the pretest period, rats were pro vided Purina Laboratory Chow and water ad libitum. During the test period, the rats were provided the appropriate test diet and water ad libitum. This study was initiated on November 1, 1977 and terminated by sacrifice of all remaining rats on January 30, 1978. 2. Compound Administration: The test compound was mixed weekly with ground Purina Laboratory Chow (i.e., ground basal diet) to provide dosage levels of 10, 30, 100, 300 and 1,000 ppm. Five male and five female rats were used at each dosage level and in a control group. The control rats received the basal diet only, on the same regimen as treated rats. Samples of diet (100 grams each) were taken immediately after preparation and after 7 days standing in weeks 1, 4 and 12. The samples were frozen and subsequently shipped to the sponsor. Diets were prepared in the following manner: to produce a premix, the required amount of Fluorad Fluorochemical FC-143 was mixed with 500 grams of Purina Laboratory Chow using a Hobart blender. To provide the proper dosage level diets, appropriate quantities of the premix were combined with addi tional ground basal diet in a twin-shell blender. The diets were pre pared weekly. 137-089 C01623 International Research and Development Corporation Page 5 3. Observations: The rats were observed twice daily for overt signs of toxi city and for mortality. Detailed observations were recorded weekly. Individual body weights and food consumption were recorded weekly during the pretest and treatment periods. 4. Laboratory Tests: Once during the pretest period and at 1 month and 3 months of the study, blood (orbital sinus puncture technique) and urine samples were obtained for analysis from all surviving rats. Food and water were withheld overnight prior to the sample collection. a. Hematology: Hematological studies included: hemoglobin^, hematocrit^, total erythrocytes, reticulocytes^, and total and differential leucocyte counts. b. Biochemistry: Biochemical studies included: fasting glucose, blood urea nitrogen (BUN), plasma glutamic pyruvic transaminase (PGPT) and plasma glutamic oxalacetic transaminase (PGOT) activity, plasma alka line phosphatase activity, y-glutamyl peptidase, creatinine phosphokinase? and calcium. Alkaline phosphatase activity was not determined in the pretest period because of interference by the anti coagulant. c. Urinalysis: Urinalysis included: description of color and appearance; measurement of volume, pH, and specific gravity; qualitative tests for protein, glucose, ketone, bilirubin, and occult blood; and microscopic examination of the sediment. d. Serum Samples: Serum samples were obtained for all surviving rats at 13 weeks of study. The samples were pooled by sex and group, frozen, and subsequently shipped to the sponsor. 137-089 *'001624 International Research and Development Corporation -- Page 6 5. Statistical Analysis; All statistical analyses compared the treatment groups with the control group, by sex. Body weights (week 13) food consumption (weeks 1-13), hematological, biochemical and urinalysis parameters and abso lute and relative organ weights were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie^ using Dunnett's^-^ multiple comparison tables to judge significance of differences. B. RESULTS: 1. General Behavior, Appearance and Survival: No changes considered to be related to the compound were observed in general behavior or appearance. Incidental findings noted for control and treated rats included ocular discharge and pupil dila tion. Survival (prior to sacrifice) after 3 months of compound con sumption was as follows: Dosage Level No. Surviving/No. Initiated Male Female Control 10 ppm 30 ppm 100 ppm 300 ppm 1,000 ppm 5/5 5/5 5/5 5/5 5/5 5/5 5/5 4/5 5/5 4/5 5/5 5/5 Both deaths occurred following collection of blood. Neither death was preceded by any signs of toxicity. 2. Body Weights (Tables 1-2)? Comparison of group mean body weights, by sex showed a decrease in body weight gain for male rats at the 300- and 1,000-ppm dosage 137-089 001625 International Research and Development Corporation Page 7 levels. Changes in body weight were similar for control and treated female rats. At 13 weeks, the group mean body weight for male rats was significantly (p<0.05) lower than the control group mean. The group mean body weights at 13 weeks of study were as follows: Dosage Level Mean Body Weights, g Male Female Control 10 ppm 30 ppm 100 ppm 300 ppm 1,000 ppm 466 259 478 260 500 268 457 278 431 263 362 255 3. Food Consumption (Table 3 ): Declines in food consumption were noted at the higher dosage levels for male rats (100, 300 and 1,000 ppm) . Food consumption values were similar for control and treated female rats. The average food consumption through the 13--week study were as shown below: Dosage Level Average Food Consumption (g/rat/day) Male Female Control 10 ppm 30 ppm 100 ppm 300 ppm 1,000 ppm 27.0 26.7 28.7 25.8 25.7 23.0 19.7 19.2 20.7 21.5 19.6 19.5 4. Laboratory Tests (Tables a. Hematology: A comparison of male rats, by dosage group, to the control group, showed a slight decrease in erythrocytes at 3 months of study. However, the individual values were within the normal range for Charles River CD rats of this age in this laboratory. A similar comparison of female rats showed no variations that could be attribu table to compound consumption. 137-089 001626 International Research and Development Corporation Page 8 b. Biochemistry; A comparison of male rats, at the higher dosage levels, to the control male rats, showed a slight increase in the BUN and alka line phosphatase values. A similar comparison of female rats showed no variations that could be attributable to compound consumption. c. Urinalysis; The presence of occult blood was of a higher frequency in females than males at all dosage levels. No changes considered to be related to compound consumption were observed in urinalysis values. 137-089 001627 International Research and Development Corporation Page 9 IV. PATHOLOGICAL STUDIES: A. METHODS : 1. Gross Pathology: After 90 days of compound administration, five rats/sex/group were sacrificed with carbon dioxide and were necropsied. At necropsy, or gans and tissues were examined for gross abnormalities and collected in 10% neutral buffered formalin (eyes in Russell's fixative). Liver samples, obtained from all of the rats at terminal sacrifice, were frozen and subsequently shipped to the sponsor. Two female rats which died prior to termination were also nec ropsied and tissues collected as above. 2. Histopathology: Microscopic examination of formalin-fixed, hematoxylin and eosin stained, paraffin sections was performed for all rats in control, 100-, 300-, and 1,000-ppm groups. The following tissues were examined histo logically. brain with cervical cord lumbar spinal cord peripheral nerve eyes pituitary thyroid with para thyroid adrenals lung heart with coronary vessels aorta pancreas spleen liver mesenteric lymph node kidneys thymus urinary bladder bone with marrow testes (sternum) ovaries salivary gland prostate small intestines uterus (duodenum, jejunum, skin (mammary gland) ileum) any tissue(s) with gross colon lesions In addition, the livers from rats from the 10- and 30-ppm dosage level were also microscopically examined. B. RESULTS: 1. Gross Pathology (Table 15 ) and Organ Weights (Tables 16-17) : Gross necropsy observations in liver, such as enlargement, and varying degrees of discoloration on the surface were present among male rats at the 1,000-ppm level and were considered compound related. No such observation was present among the females at 1,000 ppm or in males or females from lower dietary-level groups. 137-089 001628 International Research and Development Corporation Page 10 Statistically significant variations in sex-group mean weights of several organs occurred between the control and experimental groups. These variations were of unknown biological significance with the ex ception of the increase in liver weight noted in males at the 300- and 1,000-ppm dosage levels. This variation in liver weights was accompanied by morphologic alterations. One female rat at 1,000-ppm, also had morphologic alterations noted in the liver. Organ Group Sex Weight Change P< Liver 30 ppm M absolute, relative increase 0.01, 0.05 300 ppm M absolute, relative increase 0.01, 0.01 1,000 ppm M absolute, relative increase 0.01, 0.01 F absolute, relative increase 0.05, 0.05 Kidney 10 ppm 30 ppm 100 ppm 300 ppm 1,000 ppm F M M M M absolute relative relative relative relative increase increase increase increase increase 0.05 0.05 0.05 0.05 0.01 Brain 1,000 ppm M relative increase 0.01 2. Histopathology (Tabie 18): Compound-related liver lesions occurred in almost all male test rats at 100, 300 and 1,000 ppm and one female at 1,000 ppm. The lesions consisted of focal to multifocal, very slight to slight cytoplasmic en largement (hypertrophy) of hepatocytes in centrilobular to midzonal regions of the affected liver lobules. These were accompanied in some instances by increased amount of yellowish-brown pigment resembling lipofuscin in cytoplasm of hepatocytes and occasionally in sinusoidal lining cells. The incidence and relative severity of the above lesions were more pronounced among male rats at the 1,000-ppm dietary level. 137-089 001629 International Research and Development Corporation Page 11 References 1. Coulter Hemoglobinometer, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2. Microhematocrit, John B. Miale, 3rd Ed., 1967, The C. V. Mosby Company, p. 1154. 3. Coulter Particle Size Counter, Model Zg, Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 4. Gradwhol's Clinical Laboratory Methods and Diagnosis, Frankel and Reitman, Editors 6th Ed., 1963, The C. V. Mosby Company, p. 1132. 5. Technicon Auto Analyzer 6/60 Micro Methodology. 6. Glutamyl Peptidase - Sigma GGTP Procedure Bulletin #545, Sigma Chemical Co., St. Louis, M0. 7. Micro Auto Analyzer II, 6/60 Micro Methodology. 8. Photovolt PV4, Photovolt Corporation. 9. Multistix (Ames Reagent Strips). 10. Steel, R. G. D. and Torrie, J. H. (1960), Principles and Procedures of Statistics, McGraw-Hill, New York, N. Y. 11. Dunnett, C. W., New Tables for Multiple Comparisons with a Control, Biometrics, Sept. 1964. 137-089 001630 Kl Kltiittot hi^tulcnl Fi:--14 1: TAlll,K 1. Week f Kl tiriy Ouiil m l tlumi Hndy U i'l|.|it Wl . lllMIKI'H -- - Surv 1va 1 __ 10 |l|IM Mi'.iii Hotly Ui'ly.lK Wl . Nllll'ly ll;iy Siiti.iiu1r- H; rnnp Mr'-'in llinly UcIf.lilH , C rnan; S u i vi vu I Ht'mi III |>|ia llinlv H nlclil S u r- Wr. 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S i t AO. 5<x I n d i v id u a l '- a k ly 3ody V a i j h t a , C ra c * . F rtait -1 G 12 3! k o : icudv 5 6 ' 3 9 10 l * ^ 1 j C ontre! '353: *3333 7355*3335 73356 73357 T3535 *5359 rjooO 73561 10_222: 73562 *3363 *3363 73563 *3366 73567 73563 7 3569 *3570 *3371 30 r e = : 73575 73573 735*73373 735*6 73377 73573 7337 5 * 2560 M M M V M r ?T T? >1 M M a a f F f F >.f \< F r r 211 276 225 250 213 2S3 251 293 'i ; US 167 17" 151 167 171 137 16- 175 15- 166 251 273 233 230 252 233 215 230 239 263 159 170 171 135 163 130 133 169 162 163 14 * 237 23? 262 242 230 250 26? 22? 253 10 176 13 3 131 172 136 151 165 162 1*3 316 310 336 394 U S 440 136 171 171 437 502 301 133 296 313 353 3 6 - 394 H O -2 0 152 150 - 6 - 4 2 < -6 3 44 313 260 100 400 -11 112 117 132 190 502 508 512 133 321 372 106 100 124 -5 0 150 183 430 504 510 5C6 139 233 313 310 310 368 373 333 412 420 123 -3 7 44 t -2 0 212 226 210 240 265 280 258 293 290 299 313 300 233 206 223 136 231 233 262 237 253 270 230 271 260 24 220 232 23 2 253 253 213 259 266 210 223 216 211 253 27-3 262 265 232 * 238 267 23- 275 236 25*11 193 195 214 220 226 213 219 231 2 3 i 233 210 210 313 337 366 360 390 ill 420 44 7 51 170 131 138 159 291 310 338 332 363 384 336 373 376 375 392 103 290 333 3*3 108 104 433 462 453 499 500 503 521 522 493 323 352 391 338 420 452 156 494 494 511 521 S1 1 323 320 353 391 398 434 466 163 510 310 527 512 544 513 200 213 220 220 224 246 237 247 252 262 253 235 H O 207 227 211 234 260 253 252 271 278 27* 2*7 282 260 220 230 252 260 276 294 291 301 310 313 322 326 303 202 207 231 226 245 218 232 211 216 253 262 260 23* 193 208 223 218 243 211 231 256 260 259 273 2*1 256 336 362 108 336 445 - 7 . 136 523 530 539 356 530 523 3 0 - 337 361 360 392 113 4 },4 152 150 163 4 1 4 1*9 162 3-3 330 10 402 140 176 33 509 516 533 552 5-0 313 335 3*2 334 412 HO 120 169 162 432 133 -9 3 4 ;4 523. 315 370 33C 405 -32 -6 0 170 439 198 317 4i 203 220 220 230 244 53 253 261 2*2 220 .239 260 260 2*3 ZSS 233 295 306 220 226 211 i n 261 276 270 235 294 27" 324 297 231 299 298 231 310 297 ZzC Z l: Z~ z 203 213 230 236 255 52 256 267 230 210 103 225 236 213 259 260 239 266 290 27* 296 263 1:Z 12*-039 001632 ^ ^ U /A Ui B U ?uoraa' "IuOT3C:'.i3 icai FC---3 : Nina:;' Oay Suacuea Sac Taxicicy Scudy- Cone. la-ii'.'laal Vaa&lv Body '.'alinea, Orana. *U-c-rNo. Sax - 3 1 ; ; js*;0 Ve*k oz 5eu.a** - : 3 - 5 o * 2 CO 11 * li 100 J3=: 0 -- *733558552385 *2588 73337 '3553 7333* *3590 *3591 SCO ~ra: 73593 73593 73593 73595 73594 *35 9 r 73593 7 ' 335-O99C 7301 1 . 3C0 dia: 73OI 7 3 6 C3 *3003 73405 r2C6 `' 3 8 C7 jO 73d9 *2-j10 II M r re r r M M M\l T 7 7 7 7 f :> u z.< ? r 7? : - ^ 553 52S.52 573 53o 3-e 530 :; 29* -a i 9 l 353 IT 569 15-* 161 L2L73725 IC4 -T 341 260 523394 2*6-6 235 ^1~"t C~i 133 179 lIT2 I1S3O3 133 130 557 5-5 a5i-3l.5. 530 570 563 530 573 IC653T -1773- i rLLo* : a I*73-; 3I 330353 350 319 351 374 534 384 333340 388 iU 354 450 433 3*2 444 433 243 .4 5 45 405 433 460 405 -34 320 336 370 360 339 io. 373 580 250 353 363 3SC 386 415 433 .41 470 453 23 520 550 593 215 23 503 225 593 550 258 55M6400~ 5->7' 02 540 Oad 275 267 256 544 550 561 590 594 563 570 534 533 555 23 301 303 560 377 304 320 270 277 473 -15 500 333 -45 317 3-0 239 233 570 5*5 300 512 308 343 345 380 385 572 276 290 306 323 350 336 373 380 234 232 290 310 329 350 352 385 394 3 IO 300 325 322 33343 3364 330 3S0 404 408 412 413 436 433 430 436 203 506 209 526 222070 553340 25334 22* 530 249 243 . 235 552 353 253 230 238 563 254 563 570 253 260 21+ 221 240 540 224 56 357 563 353 203 2X5 530 Diad 533 22523C 229 253 3 IO 2S1 240 210 ,273 237328 594 510 300 11993556 550970 537 55C ,,J` 525001 210 520 556 510 530 340 330 231-2315 510 530 354 550 228 373 2*5 330 333415 234 223754 553456 400 350 334784 370 236 233.225 25- 384 310 323 355 353 ?\ 2226 530 252 .14 309 35- / 29 21 2290 25273 414 3C0 352 23 4C0 ir 243 294 554 570 397 400 405 475 -56 553 551 554 2! t 433 223 362 -31073 2*3 149 293 263 27 : 49 a 500 430 436 456 -02 315 513 500 .L -43 455 -97 514 .77 32- 313 300 23 335 303 2S- 590 283 237 590 5*0 419 420 02 412 418 07 423 430 13 492 495 73 431 477 58 2*5 575 270 376 260 270 532 373 53 5 258 i -- 435 338560 340355 455 233 339 .32240 C 2285505 -C8 T 553 228 257 300 565 375 253C7544? 256 222 22?582-- 001633 Klmirnil K liioruH icm lcnl Kl!- 143: IAHI.K I. u..,.k "f Study Cimtrnl R/ ' Ry n il/ kg/ ilny tiny HAI.KK: 1 2 1 4 5 6 7 8 9 10 II 12 11 FHHI.es: 1 2 3 4 5 6 7 8 9 10 II 12 11 26.3 24.2 26.3 27.1 27.8 29.0 26.0 21.9 28.9 25.5 27.5 211.4 25.7 85.6 70.7 69.6 71.8 68.9 68.5 60.8 60.7 62,5 51.4 57.4 58.6 55.1 19.6 17.1 IH.6 21.9 19.2 21.1 IH.9 20.3 19.8 19.5 19.6 21. 1 19.0 94.7 78.2 79.6 93.7 76.2 76.5 77.0 77.4 73.8 71.1 71.2 77.4 73.5 ___ 10 jijim 8/ ru t/ lay " / >8/ lay N lniily liny Sulim-ille Kill T o x l r l l y S illily. Ilrnn Knml rim niniiptInn. ___ 30 1`J'J*._____ R/ r/ r u t / kK/ ilny Iny _ R/ rn t/ lay fs/ Wr / Iny 24.9 24.4 24.3 27.6 27.9 2H.I 25.8 26.8 2 8 .0 26.2 26.8 29.3 27.3 72.9 70.7 64.1 7 1.4 67.9 64.5 59.0 57.6 60.0 54.9 5 4 .J 58.5 57.1 19.3 1 8.I 19.3 20.6 20.J 19.6 12.7 18.5 19.8 18.3 19.6 19.6 19.6 94.4 83.5 8 1 .6 88.8 79.9 76.0 71.3 70.4 73.7 67.2 70.4 70.3 75.4 27.4 25.2 25.4 28.2 28.6 10.5 2 /.7 29.7 10.9 28.6 30.0 30.4 10.2 84.1 71.6 65.9 71.8 68.1 68.0 61.7 61.5 61.6 57.0 58.6 58.6 60.5 20.3 18.9 20.6 22.7 21.1 22.0 18.6 20.2 21.4 19.9 21.4 20.1 21.4 95.6 85.6 87.4 94.2 83.0 82.7 70.6 73.6 75.8 68.2 73.7 69.4 80.0 25.8 21.9 24.1 27.1 21.2 27.9 25.1 26.2 24.8 25.5 26.8 28.1 26.8 20.1 20.0 20.4 24.8 19.0 24.8 20.4 21.6 22.7 21.5 21.9 20.9 20.6 80.1 69.4 65.5 73.1 59.9 67.8 61.1 59.1 57.5 57.3 57.0 58.5 58.7 93.4 91.5 81.6 98.9 71.8 88.2 75.1 75.8 77.5 69.6 71.8 68.3 71.8 300 |ipw r/ g / r n t / It*/ ilny Iny 19.9 21.1 22.7 27.7 24.2 28.7 25.3 26.9 27.9 27.1 27.2 28.1 27.9 69.4 71.3 71.8 83.8 70.3 76.9 67.2 66.2 68.3 63.5 61.2 62.8 64.8 20.6 16.5 19.0 20.2 19.0 22.2 18.0 20.1 20.4 18.6 19.4 20.1 20.8 98.6 75.8 81.8 85.8 77.1 86.4 72.0 76.9 77.1 69.4 70.4 72.1 79.1 1,000 pp K/ m l/ ilny It/ kg/ dny 14.7 18.3 22.2 26.5 21.8 28.1 22.7 20.3 24.9 23.6 24.1 75.0 26.5 60.2 71.4 78.5 88.8 69.2 82.2 68.5 58.1 71.2 64.1 64.5 65.9 73.3 20.0 17.4 19.4 21.0 18.1 21.0 17.1 20.2 20.3 18.2 19.6 20.5 20.4 97.7 82.5 86.3 92.1 74.9 83.1 70.9 77.5 6788..10 72.7 74.3 80.0 09 E$T COPY AVAILABLE 001634 II im tl 09 Page 16 Fluor;1 Fluorocbecical FC-143: Kin}- Day Subacuta Hat Toxicity Study. IASLZ 4. HA1ZS Summary of Means and Signiflcanceaof Hematological Values. Eemacology Study Month Control 10 ppm 30 ppm 100 ppm 300 ppm Erthrocvtes, 10"/CBtt Hematocrit. Hemoglobin, g/100 ml leucocytes, lO^/emm Neutrophils, Lymphocytes. m eosinophils. W Honocvces, x Sasophils, Reticulocytes, Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 2 6.01 6.88 7.95 47 50 49 15.9 16.4 16.2 12.57 12.67 10.64 9 9 11 90 SS 88 1 1 1 0 2 0 0 0 0 7.7 3.1 2.4 6.55 7.36 7.46 49 50 47 16.6 17.0 14.7* 10.58 12.57 8.38 13 10 11 86 88 88 1 1 1 0 1 0 0 0 0 6.3 2.8 2.9 6.00 6.89 7.05* 44 47 46* 15.6 16.2 15.0 10.39 11.27 9.33 12 9 16 87 90 82 1 1 2 0 0* 0 0 0 0 7.5 3.0 3.2 5.93 6.62 7.16* 46 47 46 15.0 15.7 15.4 9.94 13.54 9.35 11 10 11 88 88 86 1 2 2 0 0* 1 0 0 0 5.5 2.8 2.3 5.91 6.34 6.72" 46 46 45* 15.2 15.1 14.9 8.50 10.71 7.63* 12 u 16 87 87 82 1 1 2 0 C 0 0 c 6.9 3.5 2.8 1,000 ppm 6.39 6.93 6.94" 50 47 47 16.2 15.9 15.1 13.01 14.13 8.06 9 8 17 90 89 82 1 1 1 0 2 0 0 0 0 6.9 2.6 2.8 137-089 Significantly different "Significantly different * Statistical analysis no: lacerai group mean, p<0.05. lontroi erouo mean,_o<0.01. jetad on pretest values 001635 Page 17 Fluorad4 Fluorochemical FC-143: Ninety Day Subacute Hat Toxicity Study. TABLE 4. Cone FEMALES: Summary of Means and Significance*of Hematological Values. Senato logy Study Month Control 10 ppm 30 ppm 100 ppm 300 ppm Erythrocytes, l6/eam Hematocrit * Hemoglobin, g/100 ml Leucocytes, 103/ cam Neutrophils, * Lvmpbocvtes, Eosinophils, Monocytes, * Basophils, 2 Retieulocvtes, r Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 Pretest 1 3 6.19 6.99 7.13 45 30 46 13.6 16.3 15.6 7.35 7.33 6.60 11 17 15 88 80 84 1 2 1 0 1 0 0 0 0 4.7 2.7 3.0 6.33 6.96 7.07 47 49 46 16.4 16.4 15.4 . 8.61 9.56 5.77 9 11 17 90 86 82 1 2 1 0 1 0 0 0 0 7.3 1.8 2.4 6.41 7.15 6.94 46 52 47 16.2 17.1 15.1 7.22 9.35 6.74 8 14 20 91 84 79 1 1 1 0 1 0 0 0 0 3.8 2.0 2.2 6.12 6.94 6.90 46 50 47 13.2 16.5 15.3 7.87 9.63 5.74 16 8 19 84 91 80 0 1 1 0 0 0 0 0 0 5.2 2.6 3.3 6.18 - 6.74 6.86 46 49 47 15.1 16.6 16.1 7.28 9.70 5.00 11 IS 19 88 SO 79 l 2 0 0 0 0 0 0 3.5 2.7 2.4 1,000 ppm 6.49 6.85 7.31 49 48 47 16.2 16.5 15.8 10.72 10.39 6.04 6 13 16 S3 S3 33 I - 0 c 0 0 0 0 3.2 2 . a. 137-089 * Statistical analysis not conducted on pretest values 001638 BEST COPY AVAILABLE 001637 At F It, rati H u n ro c I w I r h I H ' . - H l s N in e t y Hay S u b -M ill<* Hat T o x i c i t y S tm ly . TAHI.I* S Im flv fitn n l H em atol or le n t V atin - l`n*tti , Hut Niiwlu-r Sex K iyll.rucylea* I0 r7rww llemat o c rlt X Ileumg lo litn r/ IIHI ml I.CIICOc y te s I O V uMI N eulrupItJIa Seg. Nnn-Seg. XX l.ywplicyt en X Foulnoplil la X liiiilrul : 73512 71V), 71114 7 ssn 71556 Hi'iiii IB t) 71518 71159 ? 160 71561 Hi-iiii 10 )>!>>: 71162 73561 71164 73565 71166 Ik'mi 7r.fi 7 7 108 71109 7 ra ti 7117 Mono 30 (i|il 71172 7 17 7 174 711/1 71177. Menu 71177 / 1/8 7117') 711110 7 I1H1 Hi ni o H H M II II V f H H II H H f H M H H M V 117--OH 1.7(>n fi. 21" fi.14 (..on 1. A4 fi.tll 6.04 1.91 5.49 6.69 6.32 6.19 7.07 6. 76 6.46 6.27 6.21 6.11 6.11 6.26 5.31 7.12 6.13 6.11 47 10 47 48 41 47 46 44 45 49 40 45 51 52 47 49 47 49 50 48 40 50 47 47 15.8 16.9 16.2 16.1 4.1 15.9 15.8 14.6 15.1 16.9 15.7 15.6 17.0 17.2 6.5 16.2 15.9 16.6 18.) 16.2 11.5 17.8 16.6 16.4 9.19 12.84 14.27 15.48 11.08 12.17 7.29 7.HH 7.86 7.22 6.49 7.35 9.84 11.88 11.38 10. 12 9.68 10.58 13.93 8.00 5.43 6.22 9.45 8.61 6.04 6.46 5.81* 5.36 6.72 45 46 46 41 44 15. 1 16.9 15.6 14.4 15,9 6. (Ml 44 15.6 6.11 6.20 6.22 7. 12 6 . 14 41 47 48 49 41 16.1 16.6 16.4 16.2 15.1 6.41 46 16.2 ...... ......... .............. . . - .............. . * 11 r u l yI'tuottutHlii' n ] | rn t h n Hupent itctcriiiin al Ion 8 .2 9 10.87 8 .9 6 8.67 15.16 10.39 7.67 6. 71 6.74 7.44 7.56 l.T > 50 II 0 12 0 50 II 0 90 80 90 10 0 14 0 13 0 II 0 13 (1 10 0 17 0 14 0 10 0 11 0 12 0 60 13 0 80 60 90 94 89 85 93 89 90 91 91 89 84 87 88 85 89 82 85 86 86 88 94 87 91 91 90 1 0 1 0 1 1 0 1 2 0 1 2 1 1 1 2 1 0 0 0 1 3 1 9 0 90 19 0 80 12 0 8 8 6 0 94 14 0 81 1 0 0 1 12 0 87 1 1 0 92 14 0 81 6 0 94 12 0 87 5 0 94 3 1 0 1 1 8 0 91 1 . ^ ...................... ................... - . . . . . . . . ........ .. Humc y le a X 0 0 0 \ 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 . .. _ -- , . . . . . HaAOpli 11 a X 0 0 1) 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Rol li nio cylt'H X 7.8 H. 2 9.5 6.5 6.4 7.7 1.6 6.3 4.8 4 .7 2.3 4.7 5.6 7.3 6 .7 5.9 6 .0 6 .3 9 .3 12.0 3. 6.4 1.B 7. 10.8 5.0 3.4 9 .6 8.5 7.5 1.2 4. 3 3.3 2.9 5.1 1.8 ii *I = + . BEST COPY AVU ABLE Page 19 N-- -- -- 9 N c r** N u" *** sn x x *r *9 x x r ~ -- r* f 9 C <** f- vr O' C N ^ X x -- C f l N <C 9 9 f-* < ^ o ^ c <c -- N r i-- ! 3 ecco e e cci cecee c e c ee< eeee e cecee e * ! 2 *M ! y e c o e e e acece e cree e e c e -- c ceceo e eeeee c X \ " _> -- -- e -- c c e c -- e -- -- e -- -- i-' c c <* M C - e - -- -- e <- c -- i* "i - M 1X >> M **. <-* iT P*4 X 9 1 9 C ^ V* {-i9f**i**e c <9.w < * kr -- 9 x x 9 9 st* T e* c * T 9* BjiX cecee e eeecc e eeeee e eoeec e e ec c e & !z X m X 9* up x e 9 e c 9 x i-- 9 x x f* xp * *e xc e *r xX X 9* ***r* -- XIT NC *^f f--* *Xf r*4 ? p* x 9 9 9 e x x c e N e T In -- X -- <N < / IT C 1^ X X u* i/f iff X *P* T iT T m- r** (M 9 P* 9 -- X U* X X X X W' f Ifl U*. U"1 C N " ff> 9 <N XXXXX X Iml IV Ilimi I IU'Miitnlii|i Ich ) ViiI ih-m - I'm U 'i i t . * Il H.ilv lir.uHaKlii , ,, | | rnlH Ho | hiiI <l(*ltriNliuit Ion i * N -U 9- -- T" W * e x s x p* 9 x " x u" x *r x x w* x x x : f -- * WI X pp p**pc 9 *C IT 1^ > X X *X X X --i x N w* p* X 9 X e ^ u^ " iT C If %r X Pi X X X X C P* x 9 "" i**r**ps c XX X X X X x x x x x X rarer 1 U*i X , C. ~ Z X. <j- : 2m fS p* X W* X e , iXf X if f X :*. U. ^ u rr r r e Si. ^ 'a,X X ^ 9 -- s a. <s "* X x!^ iXf tXf iXf i9f i9f Xt C 9X 9X 9X 9X 9if C f f r- i-* f->; is N r<. **. s- ? - s 5* I f I f i C r X Xr X Si.X u.^ u. n/-(IH*l ;g; 2 -- x x e XXXXX . - f - f --* -- ; n s *** p ** p * ? X Xe cX oX -X - X r 001638 Page 20 -- r X tm . N e x -- -- xe --x p* iN i r* i" 8N !-> f\i <n ! r. as esi x < *r ac I n c* fS - -- - N m -- x e*; e x e N / N O * e * * * ^* N N - N (N 1 i* --* i f !t ce ce e c secce c seeee c secco c cocco c coese c ! Ii II -!N (N -- C - C N - -- [i xI ec------ -- -- CNN -- -- -- /-ic -- x e r -- -- N C C --C C Pi -- -- -- iN --. C -- C -- e^<N- !I ! !k 1 : *>>.b x X v* -- C s* C C -- x C K S 9> O' S X X C X X ; i c i;v: !i -- IM , UI coese c secce c sili i ; ? I!xsr** C O' X -- O t* cocce e ceco-- e cocce e ceeee e r . (N K C 1ft C X I/* N -- vT ?*4 X e X O -- C O X * * X !1 1 _ :*i o; --C X X *1 -- -- f" -- <N X X X I*"* X c x x c ^V! i*NcC'nO'vCsP--^ xV* ** >r n Z1 cn {% o e o x x o c o o -- *r -- x o -- x o ! : :=* i ! ! lie I x * c s* : x ^ -- n ?- C V* > < s X C li* < >S C X ^ Xe OX C c N * rs C ^ f** I fs I/I N I/ X I sX ^ 1" N X O X - -- -- X* tf*! X X* X X* X X * P* ^ Nliu ly ll;ty Suliiii i i l r Hnl T i.xli l l y St inly. KIiio iiii liii lriiI I T - 141: i= -- ** -- c -- c e o e -- e X s T " " W" I T I T C <* V Nat m;tt x- Xx i ; >s X i- U c J C x -- fN r* x u* O X O X X X X X X X rs. PS. fs X % ip ^ *** *N <N -- X fs. P. -S. n X n. X P* X X OX w X 1 X IN X X O xxs Xo X X* X X X b X , '4. b XXXXX s : s - s : W* iWP>* i/*/ J* ^ i - X X ; C N - X c* C -- c o -s r* ^ w- o vC* s^ W- xW* VX- XU" X1.- XL- XU* --* *s ^ X X X rs* ** ` IT ir M* X J*fc fs. p* ^ I i . N ?* < IT i W*"* xsn*uen*e *U-- rs. ps. s. fw* r*. 001639 'I..... . BEST COP III m r Page 21 Pv ? C " - X iff# p* C N X z >* I1 PM fs !"*P" PN PS! (N i (S - - PN S N * e * f X* N N C P* X P-*X PSPX * rs -- -m -- rs X r* X ^ > O *ff*"* -- * j:h I x & ; s c cc c secce s secce e cec c e e 1? 5Zm z5 >S ss--ce c c--ccc e ----c--c -- c-ecc c < - N c m e s c e -- c xx "* !! I XC& M*x N 9>*v>* U* PM -- -- PN C >-- P*<N -- N s* C -- C -- C -- PM X -- N X ^ XXXXc Xx Xx &r* x9- xX n --Cl ip r* iff X X O* X O' rs. 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V -- x ir x "x <*x x rwsT eU* x Uc"*--l/ffsr Wcff O C iffc <c x rs. ~ as gr < Iff9 Iff41 X T X U"ix x x :* J i j i n ff;c pXm Xx X *Xr xiff!xrs S<*r X X X X rs X X --C P--*sC X& 1e" x Cfflr00ff *Csr xrs.X x x X X X X X **sX X X - C s- N X i*' < C r* ifi X p* c ^ < c x 1 !x CI H H H H M ^^XXX z zz zs X . b X , 9. #s aWe 9z z CO,' iPXS*. /--X 1XX Iff X"*" XX f f Iff rs rs.ps,r^ Z?i vxrr*s"xxripxfssfoirp^fssrffirfcfffffsfri--!*"sf.f* Sj S <CO"V pm -> -r v- x sf*f r^Ke** iffev* ffs!rs ^ rs ^ 5 iZ W--/^--y**k^W*1^--# IP^?cf-f5x-icS cxIC---! rs rm rs rm X5 \S* -?^ SC <c: rv"C r" 4r rC- Z -s X Sr C -- <-* 5rr i* rffrS C i 001640 rt 5 P* I; x e e c x c m * N * e c ^ <A N 0* C " ** ** X Nf*r M r*J N(NM(N!N Page 22 x *: p">x ir r* s; e* f* X IT* y f*. (M f*i"1'" N N i* ! * tH * * *5. !! im e S- M cecee c cocce e cooec c eccee c cc c c c cecee c c e c e e c cecc< occcc c c--c--c c ccecc e cceee c c--x c -- <n -- o n n e -- e* e s < n - I V a l u e s - !l M o n th A ! * ^ s e xe ece ccee ne cc sc <^* <n jx j z\- w I T il 2r1l It/X*:N ceceo e ccc cc e eccee e cceee c -- x e -- * h, e r* x ecee e cecee e Iw U v Itln al X -- f"* e 3* C '** in wn * ir x a- x C C X X ^ ia in y y x x ^ n ^ y y * f*. c ili I i N < M * N i*4 (N - e Sp N C y x x x x c ia sc c e y r. Nfl^NNC I** f*y O X e X y ^ X X y C X y X X y y ^ y Xa* x y, m x y x x y y x x x x y n *is y y c r*r ^ y x x x y x x x x x x x x c x x y* e x x x -c x x x I ! x- %a 2a ; w:k uec" x -i I P* rrsn <e r* r ^ ^ m v9 A> v N <C f> U. u. i . i . 4. C X s 4 x !b !h & Et 1 *_ i ~ * X5 i d- yy yy *y"yy yy * *5 ^ f \ S IS N *XC" C -- yyyxc y y u" y y = --_fcy_ xy xxy yxy*xxy* C"{ yA*(^n <^ ^y ^y py^-X*'X^piXy>CpwX**` p^Ciyiy--^* XsS- ba , f3p rp~nrA**y*-/yy-*"y<i^y**<yaA^y* A^y^*c*-" XjS-- '` X y yy yCyyCysc'"yce p*. p p* pp p% _S2=ev 001641 M liU s.. ji i -is I C C I A C C X -- e* c ! 5 r (v * N N *m ^ r*. f I v iI *f ic-" eeecece ee e < c >e * < ^ P" fMP* P CM PM-*fMfM Page 23 P C IT >C N OC - * C P C P N f N P M P CMM CM CM* osee e eeeo s cocee o oceec o li. C rfi- -- CCC C S CCCCC C COS secce e secce e S- -- fM" I M-- ' sr sm -- pi I S.X* M >* M 4 ir. N ? x p* -- ee p* * c2 oc X p. M i afx I -i H i! 6C OH e e c c e c e -- -- -- .. s e s e e c e c e e e c e e e c e c c c c c X P* m. x -- --< P X ^ X e fl --P -- gp Pte o* C P"* " P* c ifl P CN P nC a. vi N ^ N O' P O P fM P sP I N N N fM |P *p -- x ac P M ^ ^ y M iJ = * p* - <* >y c N iP' p* / i r 4 / t c *p c X <o up up ip . c - c e ve e o i r P P ^ i r >y < \ i r 4 -- uC <r c p c -- p p* ^ e *p <m p* ip p* ->- x <<p ip ip ^ ip In .l iv M u a i l l c w a l n l o f i l c n ! V a l u e s - J Ho m iIia . Nui'Mill 2 JS .011 ;; . .P M P c p >e e x *e ve *e >c p* x x ss p* x x x ve x x ve vc p- m. * " ! = t3 i !i Zs ZZZ ZZZZ XXX XX XXXXX r !s :5 - f' p*ex --5 S SM ^ P 'C 5 p * o* o - 2 -*2 IO ' ixP xP iXP *P " z p P P P P - I ; -M -- - i r* f - p' p* p p p' s Np < p i 5 n * ? c ip*'piPpL.-*ni-*/* Z X O' S' c c fPiP Pf*P PPiP >!c"5 sc5 Z 3' ' =s p4 pC e4 p s Cr e p4 Z s p4C p-fi n -- p 'i SM FM "M *M *M -- : * M " M f M IMi IM. 001642 BEST COPY AVAR ABLE 001643 Fino rad FI uorocbemleal PC-143: Ninety Day Subacute Rat Toxicity Study. TABLE 8. MALES: Summary of Means and Slgntflcance*'of Biochemical Values. Biochemistry C llicose , mg/ 100 ml. li.ll.N., mg/100 ml Study Mouth Pretest l 1 Pretest 1 3 Control 91 112 121 24.7 15.4 16.2 10 ppm 92 112 120 11.3 14.8 18.8 30 ppm 89 133* 136** 9.6 17.9 18.0 100 ppm 94 127 134 10.9 17.0 20.4* 300 ppm 106 127 143* 11.0 19.6** 23.9* 1-Glut amy l., Pretest 19 11 1 1 Peptidase 1 322 2 2 Sigma unlts/ml 3 111 1 1 C.P.K. , Pretest 7 13 15 Sigma unlts/ml l 17 17 14 3 11 8 10 P.G.O.T., Pretest 94 89 89 int'l units/] 1 155 143 128 3 113 105 94 16 19 13 114 121** 128 10 15 14 106 108* 108 P.G.P.T., Int'l unlts/l. Calcium, mg/100 ml Aik. I'lios. , Int'l unltB/l Pretest I 3 Pretest 1 3 c Pretest 1 3 78 89 38 9.6 12.7 9.8 194 104 90 78 39 10.4 11.6* 9.3 225 137 83 71 41 10.0 11.3* 9.2** 220 120 67 76 63 9.7 12.0* 9.5 216 147* 61 75 54 9.5 11.8* 9.3 249 204* 1,000 ppm 100 121 135** 14.1 20.9* 35. 1 0 1 3 12 13 15 105 113* 119 116 97 54 10. 3 12.0* 9.5 299 212 137--OM9 *S Ign I1 Icaul Iy different from Control group mean, p<0.01. **SIgnIfleant Iy different from Control jrt>111> mean p<0.05. ''(rent Inlno pliosphok Itinne. Statistical analysis not conducted on protest values. Not deLermJned because of ant (ooai'.ulanl. Interference J? h ** 001644 FI uorad^ Pluorocliemicnl FC-143: Ninety Day SubacnLe Hat Toxic!ty Study. TAlll.h 8. Coot. Hiocliomt stry FF.MAl.IiS: Summary of Means and Sign ifIcanee^of Biochemical Values. Study Mon lit Control 10 ppm 30 ppm 100 ppm 300 ppm Glucose, mg/100 ml Pretest 91 100 99 108 107 l 111 117 120 124 106 3 119 126 131 127 122 B.U.N., mg/ 100 ini Y-Glutamyl , Peptidase Sip,mn unl.ts/ml Pretest 1 3 Pretest l 3 11.7 18.1 21.A 1 2 1 11.9 18.3 17.5 1 2 l 8.0 17.0 16.7 0 .2 1 10.6 16.1 19.4 0 2 2 9.9 15.4 17.6 0 2 2 C.P.K.**, Pretest 9 13 13 14 17 Sigma unlts/ml 1 14 17 12 25 17 3 14 9 7 18 12 l'.G.O.T., Pretest 75 86 74 96 111 lot'l units/| 1 156 149 158 135 133 3 110 131 96 109 113 P.G.P.T., Pretest 80 88 75 64 67 Int'l. units/I 1 71 78 80 82 71 3 25 50 26 32 39* Calcium mg/100 mi Alka. i'lios., lut'l unlts/1 Pretest 1 3 1 rrLHt i 3 10.4 11.8 9.7 115 69 10.3 11.6 9.4 133 69 9.7 11.4 9.4 121 57 9.8 12.2* 9.8 106 52 9.5 12.2* 9.0 106 53 137-OH'J *SI |>nl fieanf.ly different from Control group mean, pO.05 **0reat 1no pliosplink inane Statistical analynIs not conducted on pretest values (Not dele mil nod because of ant Icnnpnlant liirovrori'iv'n 1,000 ppm 89 116 125 12.4 19.3 20.6 0 1 2 10 15 15 112 135 117 103 89 38 10.2 12.1 9.4 r ase 112 64 f S 0 m 0m0 fo Ui Fluord* Fluorochaaieal FC-143: TABLE 9. Croup, Sat Glucosa Suaber Sax ag/100 al Ninety Day Subacute Hat Toxicity Study Individual Biochaalcal Values - Fratast. 3.C.K. ag/100 al >'-Glutanyl Paptldasa Signa units/ai C.F.JC.* Sigma u n i t s /'cl P.G.O.T. 1st '1 uaits/1 Control: 73552 73553 73551 73555 73556 U9 73557 73558 73559 73360 73561 Maas 10 nom: 73362 73563 73564 73365 73566 Mean 73567 73568 73569 73570 73571 Maan 30 ono: 73572 73573 73574 73575 73576 Maan 73577 73578 73579 73380 73381 Maan M M M M M F F F F F M M M M M F r F F F M M M M M F F F F F 87 93 90 90 93 91 90 87 96 90 90 91 99 102 99 78 81 92 90 103 87 111 102 100 84 78 78 102 102 89 120 93 99 93 90 99 12.3 15.0 66.0 14.7 15.3 24.7 10.2 8.7 9.3 15.0 15.3 11.7 14.7 15.0 9.3 9.0 8.7 11.3 9.3 10.8 11.4 14.4 13.3 U.9 9.9 8.7 10.2 7.5 11.7 9.6 6.9 6.6 7.2 9.3 10.2 8.0 0 1 88 2 2 19 1 1 1 1 1 1 1 0 1 1 2 1 1 0 1 1 2 1 0 2 2 I 1 1 0 0 0 0 0 0 9 90 7 114 5 87 9 96 7 81 7 94 10 69 7 78 14 78 5 78 7 72 9 75 13 99 14 93 18 84 12 81 8 87 13 89 17 878 e 19 90 12 90 10 90 13 86 16 84 14 120 22 90 13 66 11 34 15 89 13 84 18 34 16 69 10 72 10 63 13 74 Page 26 9.G .P .T . int'l unies/1 Calcium aeq/ lit 69 9.6 96 8.8 60 9.2 87 10.3 78 9 .9 78 9.6 78 10.0 72 9.3 87 9.5 78 12.8 64 10.2 80 10.4 84 9.9 117 10.4 93 11.1 87 10.2 69 10.5 90 10.4 90 10.8 34 10.2 99 10.9 87 9.6 81 9.9 88 10.3 69 10.0 90 10.2 96 9.7 72 9.5 87 10.4 52 10.0 87 9.1 66 10.2 66 9.4 84 10.2 72 9.5 75 9.7 137-OS9 C r e a t in in e p'noscholcinasa 001645 H IT COPY AVAI1ABIE Fluorad" Fluoro caeelcal FC-1.3 : iaecy Day Subacuce Sac Toxic!cy 5cudy. 'A3L* 9. Cont. Individual biochemical ."aluas - prvraac. Group. Xac Glucose '"caber Sex ag. 100 al 3wM. ng;100 al -Olucasvl PepCidase 3Igea unica al c. '_r.a un l "5 r*., 7.3. .:. inc'1 unica/; ?- ir.c'l unica.'; 130 3on: 72332 72332 7354 73535 73506 M M M :t 1! Mean 735a* 73533 :3; 9 73390 73591 F ff r F f Mean 300 non: 73592 73393 7359i 73395 73596 M M M M M Mean 7339' 73593 73599 73600 73601 ff r r F ? Mean l.OCO 33=: 73602 73603 7360 73506 \r M M '.f Mean 73607 736C6 rjoO ? 73610 70611 y ? r r ? Mear. 111 105 31 31 90 94 114 99 108 102 117 108 90 117 105 111 103 106 99 111 102 111 111 107 132 90 99 73 102 ICC ?3 ICI 96 90 53 39 13.6 9.3 ii .* 9.3 * 1 10.9 9.0 9.0 1* . 9.3 11.4 0. o 10.2 12.0 9.6 12.0 11.4 11.0 9.0 9.0 9.0 11.4 11.1 9.9' 17.* 15.0 15.0 10.3 ** \ 1* 12.3 ir 13.0 11.7 li / 12.4 1 1 0 0 1 T_ 0 0 1 0 0 0 0 1 1 1 0 1 0 0 0 0 1 0 1 0 0 1 0 0 1 0 0 0 0 15 34 i_,, li* 13 105 23 117 20 150 15 11o 90 20 96 15 93 12 102 11 99 14 96 3 99 9 U1 10 120 15 111 * 37 10 106 13 111 14 99 19 99 >? 129 10 \ ** 1y 111 15 123 10 93 9 1-. 1? 131 5 93 13 105 i; 1*5 13 123 10 110 7 IIS 7 99 1G 111 53 37 5- 35 *?7 5i , 5. 60 59 6- 50 59 57 60 5C 51 57 *5 75 37 56 67 ili 99 119 11? 90 115 117 117 99 n* a^ 133 Page 27 Calu--:-' -ic.r 10.3 9.4 9.i 9. \ 9.3 9.7 9.7 11.2 9.5 9.6 10.1 " 9.3 9.5 9.7 10.0 9.7 9.7 9.5 9.3 9.1 9.5 9.9 9.3 9.5 10.7 1C. ? 1C a.C 1-3.2 10.2 9. ; 10.1 *r . 10. 5 10.2 -JV? ! ;rea sin i ne ?r.cs3ho icir.as 00164G Fluorad -Fluorochecical FC-143: Ninety Day Subacute Hat Toxicity Study Z i3 l 10. Individual Biochemical Values - 1 Month. Croup, Rat Nushar Sex Glucose as/100 al 8.17..V. ag/100 al T-Glutanyl Fepcidaae Sigma units/al C.P.K.* Sigma units/ml P.G.0.7. iat'l unics/1 Control: 73552 73353 73554 73555 73556 Mean 73557 73358 73539 73560 73561 Mean 10 noe: 73562 73563 73564 73565 73366 Mean 73567 73568 73569 73570 73571 Mean V M w V V ; F F F F M M M M M F F F F r 30 one: 73572 73573 73574 73575 73576 Mean 73577 73578 73579 73580 73581 Mean M M M w M F F F F F 108 120 108 117 108 112 111 105 117 108 114 111 1-20 105 111 108 117 112 117 120 117 114 117 117 117 129 123 144 153 133 132 123 123 114 108 120 15.6 16.8 14.7 14.7 15.0 15.4 12.0 9.6 10.8 19.5 38.7 18.1 12.0 14.7 15.0 17.7 14.4 14.8 14.7 17.7 23.7 17.4 18.0 18.3 20.7 16.8 15.3 15.3 21.6 17.9 21.0 15.0 18.3 15.3 15.3 17.0 5 4 3 2 V 3 2 2 1 1 2 1 1 2 3 3 2 1 -> 3 3 OMS 2 3 2 3 1 1 2 3 3 2 0 3 11 129 13 180 20 180 19 132 20 156 17 155 9 129 14 141 16 180 11 162 20 168 14 156 20 123 22 153 15 138 11 138 16 165 17 143 ' 9 150 18 153 15 144 28 150 13 147 17 149 15 123 la 138 8 114 15 123 15 141 14 128 16 129 9 147 13 165 12 195 12 156 12 158 Page 28 F.C.F.T. Caldine inc *1 aeq/ units/1 liter Alk. Phos int '1 units/1 87 13.0 93 12.8 93 12.6 90 12.6 84 12.6 89 12.7 66 11.6 -T 11.S 78 11.8 63 12.2 75 11.4 71 11.8 72 11.8 87 11.4 66 11. S 75 11.4 90 11.4 78 11.6 96 11.6 78 11.6 54 11.8 93 11.6 69 11.6 78 11. 171 22 S 156 222 192 194 114 102 165 87 105 115 168 201 318 210 228 225 105 126 147 138 150 133 60 U . 4 84 11.8 48 11.2 69 11. 2 93 11. 71 11.3 93 11.6 60 jZ 96 11.6 78 11 4 SC i '* 267 240 198 177 21 220 OC 117 171 108 108 121 137-089 QMS - Quantity not sufficient Creatinine phosphokinase 001647 Fluorad Fluorocheaical FC-143: Nlnsty Day Subacuta Rat Toxicity Study t a b l e 1 0 . Cout. Individual Biochemical Values - 1 Month. Group, v-Gluta=vl C.P.K. P.G.O.T. Rat Glucose B.O.K. Peptidase Sigma ine '1 Number Sex og/100 cl s/100 ml Sigma units/ml usits/sl units/I 100 nom: 73582 73583 7358A 73585 73586 X X V V II Mean 73557 73588 73589 73590 73591 F F F F F Maan 30C nom: 73592 73593 73594 73595 7359 V M M V Maan 72597 72598 73599 73600 73601 F F F r Mean 1.000 poo: 73602 73603 73604 73605 73606 M M M M M Mean 73607 73608 73609 736 IQ 73611 F F F F Mean - 105 135 138 132 123 127 114 105 138 144 120 124 123 132 123 132 123 127 102 105 105 117 102 106 126 i14 120 120 126 121 105 120 129 114 114 116 15.0 17.7 15.3 18.3 18.6 17.0 14.7 14.7 18.3 17.7 15.0 16.1 20.7 17.7 18.0 20.7 21.0 19.6 19.5 15.0 15.3 12.3 15.0 15.4 24.0 20.4 33.4 17.4 19.2 ' 20.9 18.9 15.3 18.0 22.8 21.3 19.3 2 2 2 3 1 2 3 1 3 2 QNS 2 0 1 1 7 3 2 3 1 3 .1 1 2 1 1 2 1 1 1 0 1 1 2 1 1 IS 135 18 135 17 96 24 126 16 114. 19 121 12 132 55 132 17 120 31 174 11 117 25 135 11 108 15 117 11 84 10 117 28 114 15 108 21 123 10 125 12 108 14 144 28 156 17 133 9 99 14 120 18 126 13 105 11 114 13 113 16 183 10 114 10 132 17 120 20 126 15 135 Page 29 P.G.P.T. Calcium ine '1 meq/ units/1 liter Aik. Phos. int'l units/1 78 12.4 90 12.2 63 11.8 81 11.8 66 11.8 76 12.0 81 12.6 72 12.0 87 12.2 108 a . e 60 12.4 82 12.2 78 11.4 81 11.8 48 11.8 78 12.0 90 12.2 75 11.8 63 12.2 !4 ll .l 57 12.6 9 66 71 12.2 93 12.2 96 12.0 123 12.0 96 12.2 78 11.8 97 22.0 117 12.2 66 12.0 90 12. C 87 87 1 1 r. 39 12.1 231 246 188 219 195 216 123 75 111 123 99 106 213 258 186 22S 360 249 132 78 PC 103 123 106 168 2&L 5al 246 255 299 141 108 /5 132 105 112 137-089 SS - Quantity not sufficient Creatinine phosphokinase C-01648 Fluorsi Flucrothsmicai FC-143: Kinsey Say Subacut* Rat Toxicity Study. TA3IE II. Individual Biochaoicai Valuas - 3 Month*. Crou?. v-Glutamyl Glucose &.C.K. Feptldase NUS3*? Six mg/100 el mg/100 ml Sigma units/ml C.P.K.* Sigma uni cs/'sl P.C.O.T. int'l units/I Control: 73552 72553 7255 73555 72556 Maac 73557 73558 73559 73560 73561 Mean V V V V V y F F F F 114 125 119 126 123 121 122 114 125 117 116 119 15.9 17.4 17.0 15.0 15.9 16.2 18.8 16.1 16.1 19.9 36.1 21.4 1 1 1 0 0 1 0 1 1 1 1 1 9 95 14 138 10 106 12 111 9 115 11 113 7 95 28 99 13 107 10 116 10 130 14 n o o ou a 73562 73563 7356 72565 73566 Meat 73567 73568 72569 73570 73571 Mean 30 nos: 73572 73573 73574 73575 72576 Mean 73577 73578 72579 72580 73581 Mean K M V M M F r r F F M V w V y F r F F T 125 104 111 126 134 120 117 125 135 119 132 126 135 129 134 137 145 136 129 123 124 141 132 131 16.6 22.0 17.0 20.4 18.2 18.8 16.9 19.0 16.8 16.1 18.9- 17.5 17.0 16.0 17.1 16.9 23.0 18.0 16.0 15.9 15.1 16.6 20.0 16.7 0 1 1 1 0 1 2 1 0 0 1 1 1 1 1 n i i i i 2 2 X i 5 88 9 126 12 111 8 115 8 84 8 105 6 106 10 96 7 92 16 245 8 111 0 131 6 90 7 80 5 91 10 102 22 105 10 94 6 71 4 80 10 100 9 105 6 125 7 96 Page 30 int'l units/I Calcium meq/ liter .41k. ?ho* int'l units/1 33 9.8 31 10.1 43 5.7 30 10.3 55 9.2 5.6 38 30 10.1 28 9.4 17 9.5 29 9.8 21 9.9 25 9.7 33 o.? 36 9.4 52 9.8 42 9.3 30 9.0 39 9.3 40 5.5 40 8.8 37 9.5 105 9.9 30 9.1 50 9.4 35 9.0 32 9.4 1 c.2 54 8.7 44 9.6 41 0.2 21 9.2 22 9.1 25 9.2 21 10.2 43 9 . 2 26 9.4 95 125 86 97 119 104 54 42 101 45 104 69 86 127 196 130 144 137 48 S3 86 65 97 69 126 124 127 85 129 120 41 56 /a 53 66 57 337-089 NS - Quantity not sufficient *Creaclcina phosphokinase 001649 t Fluorad Fluorochcslcal FC-143: Xinecy 0; Subacuts Sat Toxicity Study. TABL2 11 Cont. Group, 3a: Xuaber Sex Glucoee ng/100 ml Individual Blocbasical Values - 3 Months. B.U.K. mg/100 si T-Clutamvl Peptidase Sigaa uni:*/ml C.F.K.* Siena units/mi P.G.O.T. iat'l units/I IOC p p c : 73582 73563 73554 73585 73586 V X w X X Mean 735S7 73588 73589 73590 73591 F r f F F Mean 300 ose: 73592 73593 73594 73595 73596 M X V X X Mean 73597 72598 73599 73600 73601 F F F F F Mean 1.00C non: 73602 736C3 73604 73605 73606 M M M V V Mean 73607 73608 73609 73610 73611 T F F F F Mean Tube broke in cent:rifuge - no sample 121 20.1 154 20.7 2 t 130 20.0 1 130 20.7 1 134 20.4 1 126 140 125 Died 116 16.4 15.9 24.2 21.0 1 2 2 2 127 19.4 2 144 145 144 139 144 143 121 116 123 127 Died 122 29.0 22.1 20.1 23.0 25.5 23.9 17.1 17.0 19.1 17.1 17.6 1 1 1 1 1 1 2 2 2 1 2 130 27.0 136 23.5 140 79.1 I 2 u 21.1 144 24.8 135 35. 1 139 21.0 122 17.0 121 18.8 117 22.1 126 24.0 125 20.6 2 2 7 2 1 3 1 2 2 1 2 2 19 14 7 12 13 20 16 13 24 18 22 13 11 13 11 14 14 12 10 12 12 13 12 16 14 22 15 16 21 12 17 7 15 192 83 106 130 128 105 no 120 101 109 95 143 91 120 91 108 98 127 117 111 113 90 83 139 141 141 119 150 112 126 97 99 117 Page 31 P.G.F.T. inr'l units/1 Calcium ae;/ liter Aik. Pboe. int'l units/1 101 9.8 42 9.7 45 9.2 62 9.4 63 9.5 30 9.8 24 10.3 42 9.3 30 9.6 32 9.8 42 9.5 86 9.1 37 8.8 50 C S 57 9.6 54 9.3 29 6.9 41 8.4 41 9.2 44 9.6 39 9.0 48 10.0 26 9.3 76 9.4 37 9.9 81 3.S 54 9.5 49 9.0 30 10.0 5 9.8 23 S.6 31 $.4 38 9 .4 15C 151 141 144 *14t,.* 51 56 44 55 52 249 210 148 184 225 204 59 46 50 56 53 121 152 350 -I 181 2 ** 95 70 34 64 JO 54 137-089 ^Creatinine phospbokinase 001650 BEST COPY AVARABLE 001651 Kl iur(Ul<f| KIuitrtu lii-ml rii 1 FC-141: TAHI.K 12. Crimp, K.ll Number Color Vl)| HUM! and Sex ml Appear. l'll Control : m s2 m st m sa 71SS5 7 ISSA 7ISS7 7IS SO 71559 71460 71461 10 ppm: 71562 71561 7 1566 71565 /1466 7156 7 7156 7156 715/0 715/1 10 ppm: 71S72 7 IS 71 71574 71575 7IS 76 71577 7157 7157') 71580 715 1 M H H M M K K F K F H M H II II F F F F F M H H H M K F F F F 2.0 1.0 1.5 5.5 2.5 2.5 3.0 2.0 2.0 I.S 1.0 1.5 2.5 5.0 2.5 2.0 1.5 0.5 2.5 1.0 4.0 2.0 0.5 4.5 5.0 4.0 1.5 2.5 0.5 1.0 S-C I.S-C I.S-C IlS-r.l I.S-C OS-c 1 I.S-C IlS-r.l I.S-C S-C 7. 1 7.0 7.1 7.0 7.1 6.0 7.2 fl.O 6.4 7.0 I.S-C LS-C l,S-cl I.S-C S-C IIS-cl l)S-cl I.B-C I.S-.1 S-i 1 7.2 7.2 7.2 6.4 6.5 H.O 7.9 5. 7 6.H R.O I.S-C I.S-C I.S-C I.S-0 S-C I.S-C I.S-C IIS-C I.S-C S-C 6. 6.6 5.6 6. 1 6.1 5.9 6.1 6.2 5.9 6.5 Nliiely Day S u b a c u te Hat T o x l e l l y Stm ly . Iiiilluliln.il llrlnnlynls Values - k i e l e s t . Spee. Crav. Total Krolelu Chicime III I l (l o c u l i Ku- l.e n r n rub In nlutul Innen ryten Krytlirucytea Kpl. Amor. T r i p l e C ulls U rates l'Ima. 1 .011 N N NH N 1.016 N N N H N 1.012 N N N tr N 1.012 N N N ir N 1.07 N N N ir N 1.045 N N N A N 1.024 N N II I r N 1.025 H N N 4+ N 1.012 N N N 1+ N 1.041 N N N 2+ N l.03t N N N N N 1.010 N N N tr N 1.029 N N N 4+ N 1.011 N N N N N 1.017 H N N Ir N 1. Oil N N N 4+ 1.050 N N N 4+ 1.047 N N N II 1.011 N N N ir 1.017 N N N 21 N N N N N 1.017 N N N N N 1.019 N N N N N 1.057 N N N Ik N 1.015 N N N Ik H 1.014 N N N N N 1.029 N N N N N 1.021 N N N t r N 1.040 H N N tr N l .052 N N N N N 1.029 N N N Ik N occ occ orr orr ore f orr. orr F occ f r r ore K M f orr r r H o r e oc.r. r orr K orr. r occ H ore F 1-3 H F 1-1 r ore r oc.r occ M orr K ore ocr ore ore ocr. f ore oro F M oc.c oc.r occ ICC r orr ore r oc.r. r nei* h Calo Ox. Harterla m m M M M M H m m M h M h H H M H M H H N H H H M M M m r m I1/ IIH'I Cmle: Ir Trace s - St raw II Truce In S l i g h t I.S - l.ff'.lit SI r.*iw 21 S 11 |>lit tu n ie l lile OS - O.uk Straw II Muderai e I.An - l.if.lil Ai>4>cr Al Mal keil OAm - Oil I k Ambo r r 1 - rtodity t: - 01 (Ml1 N - Nopal I ve K - Kou I. - l.ii.ulcil M - Many - Hare ore - Ocean Inna I (fl P w it Is) f l im r u i i* Kl iiororlii-iul rii t KC-IAIi TAIH,K 12. Coni. Nioup, Nrtl Mouther Vo I time Sex nl Color nml Appear. pll 1**0 ppm: 71582 /15B 1 73584 71585 71586 1 587 I15BB 7 1589 7:1590 7 1591 iOO H 71 71 H 71 r r 7 92 n s 71594 )W A 71 71 71 71 71 7 59 7 7 9 8 71599 7 1600 1 1601 K K 7' 7 7 l,0l)0|i|>w: rm i iv m 71004 74805 7 1606 7 160 7 7 1008 7 U>09 7)810 7181) 71 71 H H M 7 5.0 8.0 2.5 2.5 3.5 5.0 3.5 2.0 3.0 5.5 3.0 1.5 3.5 5.5 3.5 1.0 3.5 5.0 5.0 3.0 3.0 3.5 7.(1 1.5 7.5 1.5 2.0 I.U 3.0 7.0 8-C 1*8- I.S-C S-C. OS-cl I.S-C I.S-C I1.S-C I.S-C I.S-C 7.0 7.0 8.1 6. 7 8.8 8.7 6.8 7.2 7.0 6.0 SC I.S-C I.S-C I.S-C IIS-e1 0S-C I.S-C I.S-C S-C S-C 6.5 7.3 6.6 6.9 7.9 8.0 5.9 7.0 7.3 7.0 S-C. I.S-C 1.S-C S-C I.S-C ns c S-C its c use l.s c 6.8 7.0 6.9 6.9 6.8 6.2 6.3 6.1 /. 6 7.2 N i n e t y Hay S n l i a r t i l r Hal T o x I H t y S t u d y , hullvldnal llrInnIyHtN Valuea - P r ten t. Spec. Tola! C*rv. P r o t e i n 01 urone H i l l - O ri'iill Ke- I.ciicO'riililn Hlooil toneu eylon 1.028 N N N N N 1.026 N N N N N 1.028 N N N 17 N 1.026 N N N N II 1.045 N N N 27 N 1.040 N N N tr N 1.035 N N H 17 N 1.021 N N N 37 N 1.028 N N H H N 1.03(1 N N N N N 1.009 N N M tr N 1.020 N N HH N 1.040 N N H N N 1.033 N N MN N 1.034 N N N IV N 1.034 N N N Af 1.023 N N N lr 1.022 N N N tr 1.036 N N N tr 1.036 N N 77 31 N N N N N 1.028 N N 77 1r N 1.012 N N N 17 N 1.036 N N N 27 N 1.02 7 N N N N N 1.021 N N N N N 1.045 N N N 1r N 1.018 N N N It N 1.060 N N N lr N 1.028 N N 77 17 N 1.020 N II NNN Krytliroeyte F.pt. C elia Amor, lit M e n F occ ore ore <icc occ F ore ori: ore K 1-3 o r e nr.r ncc F ore oer ore K ore occ nec ore oer Off ore F ore ore ncr ore ore occ oer. ore oce ore urr T riple Coir, I'lmn. Ox. Bar| orla H 71 V7 7' 71 KH MM MM 7 71 H o r e 71 7M o r e 71 ore H H H H n c c 71 77 H 71 71 71 o r e 71 o c r 71 H 7 H 71 H 71 71 Page 33 G01652 11/ 0Hl 1r M21 1 / ,v - Irare Ira* l o a l l p l i t SII|*li 1 io m oderate Moderate Harked SI.S NS I.Am HAm rl - C- Si raw I.Jpjit Straw Hark Straw l.lp,lit Anther Hark Anther Cloudy Clear N - Nopal Ivo K - Kow I. - l.ondod H - Many H - Hm e ore - OrenHionnt \, Page 34 i.5fcZX^. X X X X t t . b. b. z a t. :> Z Z &- --x ! <I : !i u. ^ x Z v. w e. e ss: 53 Z b . k . S ^ Z b ^ C a. t,tb 'z U k i. V U. t; W 6 S C e U. X X b ec c c e- wu w uc ue uo U '- - e Ifc. c e c sc b. c Vc bu ll vi tina I Ur Inn Iyu tn Value - 1 Menili wc I * * I >. >s i 1* ! ** i r >; i- f! FI I C-- W s r* r" f* * v i;i 5; 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2. *w xr r 331^ * X 4- * X U i p"i -- Z Z v. Z Z ; ^ 3 S H 'z r 1 III1Ii I z XX z Z V z -* ; e e--e vw: z *s C< |_ T* > 2. 0 S- 1 1 im e 22' X2 2222 Z2 2 2 2 22222 2 2 2 2 2 ZZ2ZZ 22222 22222 ,2X2 2 2 2 2 2 22222 22222 222 22 2 2222 yn^ 2 ^ Cinir G' >C*CX ,'^ y'C X C 22222 2 2 2 2 2 222 ^*c s*p*x se*--e a !* CC C GC G )a5a:5<r2--E3c igl*Ce*yx xc"1GX - C. C. C. X*. n **. xX >c fs. e 2 <N G (-t o sC sX 2 se u - r --r J 1i ik V. X y. 2 -r a X v: A zn 05 - sr PMN > -- PS 'C sO X sC fs sC se -c I U0 u 'J ii 2 2 X X 2 eg 05 z c c n x^ ff> er -- so 0* 4 ^ X 4 / / 4 X X X u i --a a yi t/.iy.ly.iv*. ^: ^i 5t5ii*l?: 5 J; W * 4 - y. < s ir. < 3- r s (iiii V*. 2 2 * s -- - < < ~ 2^5 --c i ! z-- t X "S ;I y. ' ii i i i GG 4 e4 ece S S X X Xta-a-i- w* O G <-*J ~ ^ --eJ --<r U4 % ^ - s i- < ^ --------- jM S S Z Z Sb,^abfck. Z S Z Z Z ^ ^ ^ N <- 4 X* 4 yit** V* 4" wJ"* *Fr ^^ aft.': PS ,F*,ff,/c*-. ,Fa .*a1f-f^* "* Ss* PnS^ F^s1!f*i^F p- *0"G p*. -s f. ; E S s s S " s g a S > s s c j s s s * ,/* V*kF. " ' * f f* ps. *. 001653 l'AHI.K 11, 001654 F l u n r a d * V l u n o r l t e m l r ) H'. l V l ; TAHU-1 l . C o n i . ClOup, Hal Vn I limi* NumHer S ex ml Colar imi Appear. pll N i n e t y Day S a t n e n l e lint T u x li l l y S t u d y . I n d i v i d u a l ( I r t n n l y a t H Val u r n - \ Gioitili. Spec. Crnv. To I n l Cl u - H! 11I'rn tetn vane ruHtn O r n ili Ke- l.etiruIII noil t o n e s r y t e f i K ry tliro - K p l. Amor. cytoR C olls tirle T r i p l o On I r . Oh . WarIella UHI pprnt 71482 ? 1581 71484 11585 21586 J 1587 71488 715*) /1500 715*11 H H H H M r F F F 1* 300 ppw: 71592 7159 J 7159/. 71595 71596 H M H H M 7159 7 71598 7 1599 71600 71601 F F F F F 1,000 ppm; 71607. 71601 71604 71605 71606 71607 71608 71609 71610 71611 H H II II II F F F F F 6.0 8.0 6.0 4.0 8.0 6.0 6.0 7.5 4.0 4.0 4.0 6.0 7.0 12.0 10.0 1.5 2.0 4.0 1.0 <0.5 9.0 6.5 9.0 8.5 6.0 2.0 5.5 8.0 4.0 6.0 IlS-rl 8.4 1.044 N N Nm N i.s-<: 7 . 0 1.018 N N N N N S-0 7.1 1.046 11 N N rr N OS-il 8.1 1.062 N N N ir N 1.8-0 6 .9 1.016 N N N N N S r i 8.8 1 . 0 17 N N N 2) N i.s-c 7.9 1.014 H N N N N S-.: t 8.1 1.044 N N N 11 N s-ci 8.4 1.041 N N N 11 N I.S-C 6 .1 1.042 H N N N N IIS-cl 8. 1 1.045 N N N 11 N I.S-C 8 .2 1.016 N N N H N 1.8-0 6 . 8 1.060 N N N N N I.S-0 7. 1 1.040 N N N N N I.S-0 6.5 1.041 N N N N H IIS-cl 8 .9 1.041 H H H 21 N I.S-0 5.9 1.064 H N N N N S -rl 8.0 1.060 H H N 11 N I.S-0 7.1 1.047 N N N lr N IIS -cl <)NS l)MS QHS QHS QNS <)NS QNS I.R-C 7.2 1.019 N N N N N I.S-0 6 .8 1.017 N N N 1i N I.S-0 7.2 1.040 H N N tr H I.S-0 8 .8 1.026 N N N tr N S r i 7.2 1.042 N N N Lr H I.S -c 1 OS 0 IIS-cL S-cl OS-cl 7,1 8.8 8.7 7.2 8.2 1.049 1.041 1 . 0 19 1.062 1.041 H N N N N H N IL N N 2* N N 2+ H N tr N N 2C N N N N H l-l iter noe ocr 1-3 mtr 1-3 ocr <icc 1-3 ocr F iter F F nee F ore ore oe e irr ore F F *>rc ore ore ore ore F ur.r ore ore orr F F orr F lire H F M F lier F M tirr F F ocr H F M F F M F n i '.' F F H ter F orr F orr orr ore FH II H KH II M H nee M H M H M ore H II M M nee F M F II H H M F H H F H F H 117-089 .......- - - - - - - . - Cota: ' ` - - ............... -- - 1r - Trm:e II - Traite to a l l gilt 21 - S I I giti t u m o d e r a t e 1 - Hndei .Me Al Marked . . . . . . -- - --........... -- S - SI raw I.S - M gilt S t ra w ita - Hark St l aw I.Am - 1.1 gilt Amtier HAih - Hark Amtier cl - Ctnudy C - Clear - -- . . . . -- -- ............ -- N - Negative F - Few 1, - Handed M - Many H - Hart o r r - Orean 1mint QNS - Quaal I t y aol .-ml f I r h-nl - ------- - -- * ....... - - - *- <3_ m m m OnQ w en IlMorml**' riUIMiU lu'wllit| IV. 161: -- TAHI.K IA Croni, Hat Nuulici* Color Volumi. lOll Sl*X mi Appesir I'll '.imirul : 71 5 5 2 71551 71556 /1555 /1556 M H M H 7155/ 7 I55H 71559 7 156 71561 F F F F F IO p|)ta: 71562 71561 7 1565 71565 71566 71 71 il 71 71 7156 7 71568 77569 7157 71571 F V F F 1. ppm: 71572 71571 7157 71575 71576 71 M II H H 71577 7157H 71579 7580 715HI H F F F F 1. 5.5 7.5 5.0 <0.5 1.5 1.0 <.5 6.5 1.5 2.0 6.5 2. 5 6. 5.5 1.0 2.5 2. 1.0 2. 2.0 1.0 6.0 6.0 2.5 1.5 2.0 2. 1.0 0.5 IIS-I-I I.S-C I.S-C 1.8-- S-i-l I.S-0 I.S-C s-c lS-.:J S-irl 6.0 7.0 7.1 6.0 0.0 6. 1 6.1 6. 1 6.6 6.6 S-C I.S-C IIS-i 1 S-cl I.S-rl S-r 1 llS-rl I.S-C I.S-C I.S-I-1 6.5 6.6 8.0 6.1 6.2 H.O 7.0 6.0 6.0 fl.O OS-rl I.S-C I.S-C S-C llSr 1 I.S-C I.S-C IIS-I-I i .s - i: IIS-I-I 6.0 6.2 6.9 6.1 6.2 6.0 6.2 6.9 6.9 6.1 Spur. Cr.-iv. Nlnnly Ifciy Sol..mm <* ll.it T n x l r l l y Slm ly . Imi Ivi ilu.il III Im il y n In V.i Iiu-h - 1 MiiiiIIih. rolli inl'roli-ln limo i i i i i - n . c u i i m - iH I orullili llloiul loni'n r y lc a .. ...... ..... -------- - ............. -- F.ryllir" K|il. r.y< C uli Amur. Tripli* IliIr. l l n i l i ' I'Imih. Ox. liniIni 1.HO N N N II N 1.052 N N N ir N l.niH N N N 1r N 1.056 N NN NN 1.070 N N N II N 1.HO N N N N N 1.096 II NN NN 1.096 H 1 N -N II 1.062 N N N N N 1.0/0 N NN NH 1.002 N N N N N 1.066 N N N N N 1.078 N N N ir N 1.067 N N N N N 1.062 N N N tr N 1.056 N N N 21 H 1.062 N N N 1+ N 1.076 N N N 11 N 1.076 N N N N N 1.055 N N N li N 1.092 N N N N N 1.096 N NNNN 1.066 N N N Al N 1.066 H N N Ir N 1.071 N N N N N 1.066 H N N tr N 1.067 N N N 1r N 1.066 N N N Al N 1.050 N N N Ir N 1.090 N N N N N orr F F ocr F 71 71 o rr ori- F II 1-1 FF F o r e F II o r r II FF H 1-3 FH F ore F F ocr H 1-3 MF H FF M oci- F F ocr oi:r F 1-1 ore D F 1-1 F H nr.c. o r e o ri F F II II H M li II F F F II F F ore F oro F Ore F 1-1 FF H orr F F ncc o r e II F 1. FF II 5-8 orr. ori: F F II o r r H 1-1 o r r F F F orr F F ce FF II ocr F ORI- F or.r re o r r o r r H BEST CQF AVAII ABLE 001655 11/ HI CmI*: Ir - Trarr Il - T r a r r io Mllf'lit 2* - S| I}'lat (o RMiiloralo U - Hoitrralr Al - Haikml Sl.S PS I.Arn |>Aw - ri V. - Si raw 1.1 |*t*l Straw Dark Straw 1.1phl AihIh*i Paik Amhrr ('Itmily CI r a i N - Nepal 1vr F - Few 1. - l.oailnl M Many H Ka r r orr - Orraalona 1 P> OQ 19 Ui ON BEST COPY AVAH ABLE Page 37 x s s z x r a.x x s x *. z s z z a k N in e ty Day Snlmcoto Rat T o x i c i t y Sr oily c l l ! tkx X 'j>Ui X X * a.a..a.a. x:- ! S9 II * a. ta. b. U. X X owUcb Vou 0 si i ^X x*> u IJS s zb --C s& w !f ! aCIc. *S: zzzzz zzz X ^ k & ti. Z x. Z2ZZZ SZZ I* i I= W * "* I ZZ Z ZZZZ SbX X k X k !k^ X --rI* bbcr ZZZZ ZZZZZ ZwwZZ +*ZZ w - cm n*. zzzzz zzzzz ZZZZZ zzz z zzzzz zzzzz zzzzz I _--% Cc &ec. 'wJ t II 0 *0 *o 5 < ^ (N N < /I fN f n I* ^ < c < ** cceec eco n* m x O ^ C C CD*4 ^ < B ** s us s s s u o /I. Iwf ! I k *fji tnI vI. 'SOw*! inCCSC ;X n >r. e-c^S -- s z s x 'j- x x x x zzzzz zzz i<enr.esimctfccx <re'w cCoBnvC ece n n ces On1! n. nl <o sfl x * b -u s u I k ai: I wt: I k 5IJSI W: K y. Z Z Z Z Z ZW W ZZ O' n <* X C C C O s. eI- cN- cC e c<** Xo cc cc e>e N n B C O ooeein X n* -Is : :u s sI Is Iu Iw y k cr. y; 7. a m inm e : 3 or ni j" n I . . J *g in.c o s e o c c e c n i r ce n -- m -- ni x r x x x >x x x x X X X X X a. au *. u. & 4 C5w a-Qe1z5 5C i n*e^-->ji*n m^^Sw#iI--nXm^xn* ^pmx*,.I--**n^nXc*fscC-<n*n^^w--* -- ^ n <iriC ^rm""Im-" <i--n^rw*^n* ixn-nk!*mxc>fsix'n^n*3S5<---<c` c5`--*een <ex-----crnw*rxe* m 5c-- nci*?c~ n--* P* F* mb1 * *, p nn N. X >4C :. = 1 : t ; I i !z -- x sc s 5 =2 rr ^ 2 -i r v. x- < *<3 > ZZZ 2 2-- : --SS ^ :i Xs o4b 4b --w J4* 1i iW-sV- t--er* 2= 'I I I ! ' -- n* ?" -ff 001656 Finora) KhiororliHMlral pi!-14): Fluitirti! HiiiiriiiliriHlcitl Hi-IVI; TAHI.K IS. Silo 1.0* Inn Notulur no r rope 1ml No g r o s s l e s i o n s KxlPin.il dark red Material around eyea/noae/moiith Kyra r l | ',lil eyvHMiill, lena I n n in g r 1|li 1 e y e , e n ln r n i .t lung wli 11e / g r n y Inli/ye 1Inu f o c i dark liruuu tnr. 1 l*y*ipl Node s l i g h t l y e n l a r g e d - sulimax t H o r y .Stuxurli mined white (oct da Ik red f oc 1 Uirgo I n t e s t i n e - (`e cu out) Colon semi-sol Id, blood tinged contenls muon h<!1 c onges 1 1mi l.l ver enlarged da rk hinw n/hrow nlah III r u l u r niri i'nl Hilled l o b u l a t i o n yelInv/graylah while fori ry a t, yellow ish In ro lo r Kidney hydronephrosis grunular eurfoce Ulema hyilrniartra N inety 0y S u b a c u te Hut T o x i c i t y SLmly. Summary o f Cron* Necropsy Ohftervnt Ion. l e rial iin t Sac r I f 1ce Control HF I_Pi! HF 30 jipia HF 100 jijn* H F' S5 25 55 42 55 33 '4 32 1 1 300 ppw M~ F 54 33 11 1000 jtjua H ~ F" 55 4 1 1 1 1 1 1 l 2 3 11 14 1 1 11 1 1 222 l 1 PeAllia 100 pps F 300 pp F i1 1 i i1 best copy avau able oo m <L hmiho pi (M IS u> 00 K h iorn il* TAHI.K 16. (ro u p , Sex Hod y Wt . K C ontrol : H 1 0 p |ii M F T llj'll ! H 100 |i|na: H F 30(1 J ' l ' a i H _iooo_ ||>ns H 663 271 6112 73/ 500 2S6 A IR 271 612 266 360 260 f 0-163: S p le e n KX 0 . 70 0 .6 / 0 .1 6 0.17 0 .6 9 0 .6 9 0.16 0 .2 0 0.67 0 .6 9 0 .1 6 0 .1 9 0.75 0.57 0.17 0.21 0.66 0.65 0.16 0. IH 0 .6 9 0 .6 6 0.16 0 .1 9 N t tie l y IViy S u in ic o le Mol T o x i c i t y S t u d y . A b so lu t* ((ra m s ) mid He. l a t i v e ( X Hud y We Ip , lit ) O rg a n W e lg lit a , 1.1v e r Rx K id n e y s 8X B ra in KX A dren ala 8 X x lO * T hyro id Pa ra lliy ru ld 8 XxlO * P itu ita ry 8 X x l0 ` 13.63 7.66 3.01 2.85 15.26 7.25 3.18 1.06 2 0 .3 1 * 7.73 6 .0 9 3.06 18.59 7.97 6.21 2.95 2 0 .1 3 ** 7.66 6 .8 8 ** 3.03 1 9 .1 6 * 8 .7 6 * 5 .7 0 ** 3 .6 5 * 3.56 2.16 0 .7 9 0,81 6.13 2 .5 0 0.86 1 .0 5 * 6 .6 0 * 2.37 0.HH 0.96 6.19 2.67 0 .9 6 * 0.91 3.91 2.60 0 .9 5 * 0.911 3.67 2.15 1 .0 3 ** 0 .9 0 2.25 2.02 0.51 0 .7 5 2.26 1.95 2.21 2.01 0.67 0.82 0.66 0 .7 9 2.29 2.10 0.52 0 .7 8 2.11 2.00 0 .5 2 0.82 2.17 2.08 0 .6 5 ** 0.87 80 1 .7 9 60 0 .9 0 101 3 .8 0 35 1 .1 3 71 1 .5 0 35 0 .7 2 79 3.3 2 27 1 .1 5 76 1 .6 8 37 0 .7 6 83 3 .2 5 27 1.0 7 70 1 .6 1 33 0 .7 5 89 3 .2 7 27 0 .9 8 67 1.6 2 36 0 .8 7 89 3 .6 6 25 1.02 69 2 .0 6 36 1.0 6 92 3 .8 9 28 1.18 17 0 .3 8 18 0 .6 5 17 0 .3 b 17 0 .7 2 15 0 . 30 16 0 .6 2 17 0 .1 9 17 0 .6 0 16 0 .3 8 17 0 .7 0 11 0 .3 8 18 0 .7 5 o<r> OD I17-OH9 ('i im i |> e iin l u l m lu e o rg a n ve 1lit h shown In t h i s t a b l e w e re c a l c u l a t e d Iiy a v e ra g in g tlin I ml I v illin i I ly c n ln iliU u . l r e l a t i v e organ w e lg lita . ` S lm ili f I o m it I y d i f f e r e n t f r o * c o n t r o l g ro u p u n ii, |><0.05. " S ig n if i c a n t l y d if f e r e n t frm a c o n tro l groiiii mean, P < 0 .0 l. Page 39 Page 40 001659 PIunimi1* PItinrnclit-MIrn I h :-W i TAIII.R 1?. (roup Hoi No. Conirol: 71552 ?m i 7.ISSA 71555 nssfi 71557 71558 71559 73560* 73561 10 iijiii : 71562 73561* 73564 73565 73566 71567 73568* 73569* 73570* 715/1 10 73172 731/3* 73574 715/5* 71576 73577 71578 73171 731110 735HI [00 |i|i: 715H2 71581 7 ISHA 715H5 715H6 7 ISH7 71S8H 71 SII) 711*11 Sex H M H II H P P P P P H H H H N F P P P P H H M H H P P P P P H M II H M P P P P I 17-0119 Ilotly Ul. P. Ninety Pay Siilimnie Hat T n x lc lty Stanly. I mil vi lina I DrRan U clglitn - T e n t liuti S e r r i f I r e . Spleen R LI v e i 8 1 Kidneys K Brain R Adrenals *8 A57 0.60 14.46 A22 0.62 12. 15 A74 0 . BA 11. HA A7I 0.BA 1S.0A 4(12 0 , SA 11.64 2/2 0. A1 8.10 2SI 0.S6 7. HO 2A4 0.A2 6 .'96 2 SA 0.A7 6.8S 315 0,47 7.57 AA2 0.53 16.37 177 0.66 10.61 AHI 0 . 74 15.87 501 0.79 21.56 499 0.6B 7.25 210 0.A6 7. OS 24 7 0.50 7.82 294 0.72 10. 72 226 0.37 7.78 2A1 0.51 7.44 516 0.68 19.91 441 0.50 17.80 519 0.52 18.51 449 0.77 16.70 466 0.82 22.52 248 0.18 7.91 273 0.58 8.58 261 0.48 7.14 253 0.59 7.51 215 0.41 7.47 456 0 .7 / 16.12 184 0.65 14.92 4110 0 . 77 29. 52 406 0.85 16.10 467 (1. 70 16. 10 281 0.59 8.24 791 0.5 5 8.61 7 54 (1.61 7.45 754 0.5 1 7.57 * -- It 1eil i n i l o w i n g 1 1' i inI n a l l i t r i . lllll|< * Hula n u t a vii 11ali 1e . 1.81 2.99 3.94 3.73 1.22 2.00 2.25 2.40 2.01 1.97 2.18 2.41 2. 30 2. 16 2.21 2.03 2.00 1.97 2.22 2.06 91 70 80 82 75 101 no 91 92 81 3.88 3.82 3.85 4.14 4.66 2.27 2.35 2.72 2.26 2. 72 2.16 2.36 2.25 2.31 2.21 1.90 1.91 1.96 1.95 2.01) 56 68 64 99 72 76 87 130 99 81 4.12 4.21 4.74 4.22 4.11 2. 12 2.46 2.17 2.10 2.62 2. 33 2.15 2.14 2.27 2.17 2.06 2.06 1.85 2.00 2.09 62 60 93 88 68 68 97 80 86 82 4.12 4.01 5.21 1. 79 1.79 2.75 2.67 2.11 2. 14 2..19 2.09 2.27 2.25 2.41 2.16 2.05 1.99 2. 18 77 57 69 HI 64 102 86 80 86 In*'I oileil In Hi ni IHI l i- n l o ii a ly H li i Tliy m i t i / Parathyroid 8 47 45 16 44 28 32 56 25 34 28 - 2 40 15 31 10 25 25 23 24 31 47 39 34 38 12 27 22 28 26 25 19 17 29 11 12 11 29 15 I'l t u l t a r f 19 16 It 19 19 17 21 12 20 18 21 17 13 18 16 18 14 19 18 16 17 16 11 20 15 18 15 15 12 18 18 14 20 17 16 22 18 17 9 ^1 Klnul KliiorurlieiiilenI H.- IAl : TAHI.K 1?. Crnup Mal Nu. ------- -Se* -- Hotly Ut. K 300 71592 73591 71596 71595 71596 7159/ 73598 71599 716(10 l,0*1(1 ppm; 71607 71601 71606 73605 71606 71607 71608 71609 71610 71611 N H H H H r K K K H H H H H K F F F F 386 181 196 659 619 26 7 262 2 19 255 181 306 161 2HH IHI 221 223 267 216 252 Spleen R Nliiely Day Suliaeule Hat Toxtrlly K ltu ly . Imliviunl Ornail Wel pilla - Terminal Karr IfIre. 1.1ver 8 Kldneyg 8 Brnlji R Adrenal8 8 0.78 0.50 0.6 7 0. 73 0.71 0.66 0.6 7 0.61 0.65 0.67 0.18 0.56 0.62 0.62 0.69 0,39 0.52 0.63 0.68 20.06 17.51 17.91 21.85 23.31 7.20 7.91 7.26 7.17 19.98 19.62 18.29 17.87 20.25 7.90 8.20 9.81 8.59 9.27 6.21 1.61 1.88 3.82 3.98 2.62 2.51 2.27 2.60 3.89 3.67 3.16 3.20 3.66 2.11 2.10 2.17 2.11 2.26 2.11 1.98 2.10 2.11 2.15 1.62 2. 0? 2.00 2.12 2.19 2.05 2.15 2.08 2.19 2.28 1.88 1.96 2.20 2.06 56 69 59 76 78 78 107 91 81 79 67 75 60 61 111 93 85 99 71 Tliyrn 1d/ l*orat liy roi il 8 21 30 36 66 67 27 28 22 23 66 28 16 36 38 32 11 23 26 30 PHultary K 15 15 15 18 15 16 18 15 20 6 11 16 12 19 17 15 17 26 1? Page 41 Fluorad |?|nnroclieini cal FC-1A3 : TABLE 18. Ninety Day Subacute Rat Toxicity Study Illstomorphologlc Observations. Tissue l.eaIon X 0> * t/j x r. a CM cn m D ou . m m m m urto CO n CO n U (A S5 t"- 10 ppm X U* tO tO mm mn Pm (M 1*1 00 o% O v> tO h* m oi r> in n m mr-* m ro Liver focal perlportal/alnuaoldal lymphoid Inf titrates focal bile duct proliferation congestion, diffuse focal vacuolatlon In cytoplasm of liepatocytes 22 2 2 2 22222 22 2 2 23 2 2 Page 42 001661 137-089 Code; x - Condition present - = Not available 1 - Not remarkable 2 - Very slight 3 - Slight 4 - Moderate 5 - Marked 6 - Extreme Fluorad Fluorochemlcal FC-143: TA1H.1 18. Cont Ninety Day Subacute Rat Toxicity Study Iliatomorphologic Observt lona. Tissue Lea Ion 30 ppm X r. X. X r. (X lx lx lx fn P3. N oU h4o Opd NCO CO 4 Nm m00 N uo CO m fO vD N in ro in CO N 00 in CO oi N in CO O 00 m CO N H 00 in CO h- l.lver focal periportal and sinusoidal lymphoid Infiltrates focal sinusoidal dilatation hepatocellular necrosis sinusoidal congestion, diffuse l1 22 2 22 32 2 2 222 2 2 Page 43 001662 137-089 Code : x - Condition present - = Not available 1 - Not remarkable 2 - Very slight 3 - Slight 4 - Moderate 5 - Marked 6 - Extreme Kl l l o r a d FC-1A3: Flnoruchem lrn TABLE 8 . C o i i t . Tittaiie L esion N i n e t y l)ay S u h a c u t e Rat T o x i c i t y S t u d y . llsto m orp ho lo glc O bservt Iona. vy, t/> uo. g o rl S C o nirul T, . tu tutr. r. r. u in i>< cfn sjio i< )f> o o o iO H ifliOir|ioir\if\iOOv)< io in io vi m in in nm m m n n n n rtn n n n h f s N i** i> r> fs 100 ppm N 1 m 6 h> 0 o o H OOOOCOaOflOOOOOCOOkOt n m in m iA in in m in in n n n rtm c o n n n n f> | s t s h> I- N In N N 3 00 ppm X K X X X Ih tfiM h .ix N n 4 n iO N 0 O H O M M M M h Oi Qt O O om m iA tfttA trktnkpkO rin n n n n p in n rt N K fsfslN fsN N N N 73602 73603 1 . 0 0 0 nnm i0 0!50 f0i 0t 0 5* H^ eo- <h 4>O i0iiO fl4)4)iO n n m m M riin n ts M s rs r> rs is |s R raln (W ith C e rv ic a l Cord) fo c a l p e r iv a s c u la r lymphoid I n f i l t r a t e s S p i n a l Cord (Liimhnr) P e r i p h e r a l Nerve fo c a l p e r i v a s c u l a r lymphoid I n f i l t r a t e s F. yea acute focal m yositis o c u la r m uscles Involving e x tra - focal re tin a l degeneration P itu itary focal cytoplasm ic v acu olatlon o f b aso p h ils remnant o f c ra n to p h a ry n g e a l c y s t Thy r a i d remnant o f u ltim o b ra n c lila l r e s t focal I n t e r s t i t i a l lymphoid I n f i l t r a t e s P arathyroid Adrenal fora! cytop lasnlc vacuolatlon o f c o rtic a l lie liem atocyat c o n g e stio n LunRS fo c a l p e r ib r o n c h ia l lymphoid h y p e r p la s ia fo c a l p e r i v a s c u l a r lymphoid i n f i l t r a t e s fo c a l m in e r a li s a t io n o f pulm onary a r t e r y fo c a l I n t e r s t i t i a l Inflam m atory c e l l In filtra te s con g estio n (agonal) fo c a l a g g re g a te s o f a lv e o l a r mnrrophagea H eart focal I n t e r s t i t i a l lymplmld I n f i l t r a t e s myocardium fo c a l n e c r u s ls o f m ononurlenr c e l l l r a t e s , myocardium Inf II- Aorta i ii ii ii iii 1 1l 11 I l 1l l 11 1 11 1 11 1 2 11i i i i i i i i i- i- i- ii ii iiiiiiiiii i ili tit i 2 22 1 1 1 1 1 1 1 1. 22 1111I 11111 1 1 1 1 1 1- 1- 1 11i i i - i i i i I i i I l l l l 11 1 1 1 1 1 1 1 1 1- 1 1iti iii i 2 il l ll l l lll 1 11 1 1 1 1 1- 111 I 1 11 11 2 23 lll-l 22 3 2 X 111111 2232 11111 2 2222 1 1111 X XX X 2 X ___________________________ I I l 11 322 2 2 2 3 111 X XXX 11 2 1 - - 1 1 --------------1 1 1 111 32 2 2 2 2 22 111 1 1 1 X X XX 11 11 X till X 2 -------------------------1 - l - - 1 -111 -1I 1 111 11 1 11 3 A3 A 22 2 22 222 3223232222 2223 3 22 2223222223 2 2 2 222 2 2222 2 1 22232 22 2 2 2 22222222 22 23 2 222 .A 2 111t I 1I 22 2 22 111 II 22 3 2 22 I 1IIIIII 2 22 I1 IIl II IIIIIIIII lI1 IIIII11 l1II1IIIII IIIIIIIIII lU-ORM Canle: H - Climi l i o n p r e n e o l - Not a v a l lu tile 12I- Not re m a rk a b le Very a l i g h t S lig ht A - Hoileratc S - Harked fi - K..t l i ' ' htf 0I0 lb 4N 001663 F tn o r a d FI tairorhem leal FC- Mi l : TAlll.li Ifl. (` t i l . TI anno I.l*Hlull N in e ty liny S u b a c u te Hat T o x i c i t y Study. Il I si muni'plmlngI c Olise rvnt loon. Control l OOpi ' m 300^ ppm............. ............ L ift1?0. ..Bl* r,j : t , x:r.totou.tou. 1Mm0m`niOoiTii}fiitroiiln`O/iiffi'/iiiiofiloiAOiO`OAi`HCo nnnnMrinnnM >: x . as >: >: i* m t* u* N n>4lA <A M S O iO H OtM^) iCrfO)ifinlOnni(OArl1iO0PlC/KO)i(OniCn/O3r0io1ninOOt 1" |x h. I- N h . IN fv IS h T. T. r. T. r. ^ U4 U* U* Oi<h0iChO<OiOlOiuO 1 fv is h* r> i> I' n OtrDiOtnOO*0O*in0O<tOOo^iOs OtoOrtq*oi4io0r -trlOi nfnnrtnriMnnn M v (> Bi Is M > rs 1.1 ver f o r a i p e r i p o r t a l and sin u s o id a l lymplmld lo f i II ra te a forai p o rta l and alnnanldal extramedul lary hemalopolnala forai cytoplaanlr varimi a t Inn (probably lipid) focal rnpaulac llbrosls forai atm isu td al ill lu ta i Ion focal hepatocellular hypertrophy m ultifocal hepatocellular hypertrophy hepatocellular necroala lu e ronged yel lowlali-hrown pigment In ryliiplanm 1 h e p a to c y le a and o c c a a l o u a l l y In nluiiHiilihil lin i n g c e l l a alnuanldal congestion, diffuse Kidney focal I n t e r s t i t i a l lymphultl I n f i l t r a t e s liydiuneplnoaln tubular nuphrnala yelInwlnh-hruwn pigment In cytoplasm of proximal ciuivolute.il tiihules proteinaceous tubular rants m i n e r a l i z e d ml crocoite r e t Ions In tn h u le n Urinary Hlodder suhmiiriiaal edema p r o t e i n a c e o u s p lu g In lumen fileni suhmnrnaut lympltold I n f i l l ra te a 'leal es furai lenticular degeneration Ovary I*run I a I n fu m i I n t e r s t i t i a l lymphoid I n f i l t r a t e s III eron hydinmet r.t S k e l e t a l Muse le foca I myndugnneral Ion IIJ-IM'I 322 32 22 1 2 22 22 2 1 2 2 2 2 2 2 2 22 2 2 22 2 2 2 22 22 2 1 22 2 32 3 3 2 I 22 3 22 2 2 2 3323 22 24 2 l1 2 222 22 22 2 2 12 1 3452 2 ___2_2_______ 2 2 2 2 ___ 2 111 111 2 22 22 22 2 22 33 22 22 2 22 22 2 22 22 2 32 II II l 11I I I I 1l 1I IJI II 37 27 III 22 Il II 2 11111 IIIII I 111 4 IIIII II1 I I I I I I I I I I I III I I I I ! I I 1 I l I I I I I I I I 1 l I 1 1 t 22 Code : x - Condii loti p r e a e n l - - Not oval I uh le 1 - Not remarkable 2 - Very a ltg h l I - Slight 4 - Moderate 5 - Harked f> - Kxtreme 001664 99X09 I II UH*! ('itili*: X - O rnili ( Im i i im hi iiI l i n i n v a l Inli l<* ' - N' " r u w i r k n b l e i! - V e r y n l l y . l i l 1 _ s 11 filli i i f 9^ 7 aSej M I * k m s ia I I I I I roui> > Ra: : n o . Sex -- Ni -- Ni W> Ni NI w N i 73552 * 73553 ; 73551 73555 j 73556 1 73557 73558 73559 73560 73561 Vi .M ! M M V Ir V ^ r r- 7> 7! NI NI -- -- U NI W m 73582 M 73583 M 73584 M 73585 V 73586 73587 73588 M F F 73589 F 73590 r 73591 F i 1 `e .9 2 i >-- a i n z 9 2, < 9 * NI -- NI W 1 m -- 73592 V 73593 M 73594 M 73595 M 73596 M 73597 F 73598 F 73599 F 73600 F 73601 r . i i 1 j l. .i 1 : M -- - - NI -- 73602 M 73603 M 73604 V 73605 M 73606 73607 73608 73609 73610 M F y r ? 73611 ? j :9 ; i N hiolv Day Siibn:ule tt/it T n xlc .lty Slotly. i J 9 * - H->*li r:ti* 5 - Mnikfil fi - Kxlr*iwt S - Hmked ? - Very Hllf.lit Code: x - C ondition present " " N" * nvnllniili* I W-Oll'l I - `Not rem/tiloiliIn h - Modernio a 999T00 & a8?a SjrA -4 8**9 50 V *1<s : j i i Group, j Rat No. Sex i I7723555523 X M - 73554 X H- 73555 M 73556 M ? -- P-- 73557 F 73558 F s --- 73559 F 73560 F 73561 F 11 *tm 73582 X 73583 M 73584 M i -- ** 73585 M 73586 X 5S " 73587 F 73588 F 1 73589 F *- 73590 F 73591 F -- 73592 y. *- 73593 M -- ** pm 73594 M 73595 M 73596 M 73597 F W o 9 -- 73598 F -- 73599 F * 73600 F 73601 F -- 73602 X pm 73603 X 73604 M *-- 73605 M 73606 M 73607 F o s -- 73608 F i 73609 F -- pm 73610 F 73610 F IIIntoMorpliologic Obaervnl Iona. TAIll.K 18 Cimt.