Document aBzQ2073wexjZ3Dy1vrGNQ9M

AR226-2825 //LO- orti- & S International Research and Development Corporation_______ SPONSOR: COMPOUND: SUBJECT: E. I. duPont de Nemours and Company 90-Day Feeding Study in the Beagle Dog. Development Corporation Collaborators : R. H. Buller, Ph.D., Director of Pharmacology R. G. Geil, D.V.M., Director of Pathology Date: November 30, '1965 Company San'Uscd. Does? ol confa-n TSCA CBI International Research and Development Corporation T A B L E OF C O N T E N T S I. Synopsis...................... ......... II. Compound ............................... III. Clinical Studies ........ .............. A. Methods . . . ...................... 1. General Procedure ............. 2. Laboratory Tests ............... a. Hematology ................. b. Biochemical Studies ........ c. Special Sampling ............ 3. Compound Administration ........ B. Results ............. .. 1. Behavior, Appearance and Mortality 2. Physical Examination......... 3. Body Weight. '................... 4. Food Consumption ............... 5. Compound Consumption ........... 6. Water Intake and Urine Output . . 7. Laboratory Tests ............... a. Hematology ................. b. Biochemical Studies ........ IV. Pathological Studies .................... A. Methods ........................... 1. Gross Examination .............. 2. Microscopic Examination ........ B. Results .......... 1. Gross Pathology ................ 2. Histopathology ................. Page 1 3 4 4 4 5 5 5 7 7 7 7 888 9 9 9 109 12 12 1122 13 13 13 Company Sanitized. Doss no! contain TSCA CS! International Research and Development Corporation TABLE OF C O N T E N T S (Continued) TABLES Table No. 1. Individual Weekly Body Weights, Kilograms ........ 2. Average Daily Food Consumption, Grams ............ 3. Average Daily Compound Consumption, Mg./Kg./Day . . 4. Average Daily Water Intake, Urine Output, and Water Output Ratios ................................... 5-28. Results of Hematological, Biochemical and Urinalysis S t u d i e s ....................... ............ . ' 28A. Total Cholesterol.Values, Mg. per 100 Ml. Plasma . 29. Necropsy Observations ........................... 30. Actual and Relative Organ Weights 31. Histopathologic Observations ................... 32. Incidence of Histopathologic Lesions ............ Page T-l T-2 T-3 T-4 - T-7 T-8 - T-31 T-31A T-32 - T-34 T-35 - T-36 T-37 - T-38 T-39 - T-40 Com pany Sanitized. Does not contain TSCA CD International Research and Development Corporation Page 1 I. SYNOPSIS In a 90-day oral toxicity study was fed 7 days each week to male and female beagle dogs at dietary levels of 100, 500 or 2500 ppm. After 35 days of feeding, the 500 ppm. and 2500 ppm. dietary levels were increased to 1000 ppm. and 5000 ppm., respectively for the duration of the 90 days of treatment. No pharmacodynamic and/or gross toxic signs were observed. Detailed physical examination revealed all dogs to be essentially normal. No adverse body weight changes occurred among any dogs used for this study. Food consumption values remained relatively constant, and average daily water intake and urine output were not meaningfully different from values obtained in the control period. No alterations in hematologic parameters were observed which could be related to feeding the test compound. No biologically meaningful changes occurred with respect to plasma glucose, protein, albumin, urea nitrogen or albumin-to-globulin ratios. A biologically significant increase in plasma cholesterol was found for 5-of-6 dogs at the 2500 ppm. dietary level. Prothrombin time determinations and serum glutamic pyruvic trans aminase (SGPT) and eerum glutamic oxalacetic transaminase (SGOT) e activities remained within the usual ranges at all periods of measure ment. Alkaline phosphatase activities exhibited an upward trend in 2 of 6 dogs at the high dietary level. Urinalysis did not reveal compound-related changes at any period of examination. Company International Research and Development Corporation Page 3 II. COMPOUND The test compound was received from E. f. duPont de Nemours and Company, Wilmington, Delaware, on June 19, 1965. It was a brown amorphous solid in containers bearing the labelj Haskell No. 4212." Com pany Sanitized. Does not contain T SC A CL International Research and Development Corporation Page 5 After 90 consecutive days of compound administration, all dogs were sacrificed and subjected to necropsy examination, (see section on Pathology for detailed methodology;.) 2. Laboratory Tests: At least 3 times during the control period, and again after 1 2 and 3 months of compound administration, blood and 24 hour samples were obtained for clinical laboratory studies. a. Hematology: ^ Routine hematologic studies included total and differ ential leucocyte counts, hematocrits2 , hemoglobin concentrations , erythrocyte sedimentation rates4 , and total erythrocyte counts . b , Biochemical Studies.: _ (1) Plasma: Chemical determination on plasma routinely included quantitative tests for glucose5 , total protein , total albumin7 , and urea nitrogen8 . Albumin-to-globulin ratros were calculated. ______ _______ , 1 coulter Particle Site Counter, Model A., Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2 Miller S., Microcapillary Method, Textbook of Clinical Pathology, I960 Williams and Wilkins Company, Philadelphia, a., p. 3 Miller S.. Cyanmethemoglobin Method, Textbook of Clinical Pathology, W 6 0 ? V l l h m s and Wilkins Company, Philadelphia, Pa., p. 35. 4 Miller S., Westergren Method, Textbook of Clinical Pathology, 1960, Williams and Wilkins Company, Philadelphia, Pa., p. 5 Hoffman, W. S., Modified Hoffman Method, J. Biol. Chem., 120= 5 1937. (Auto Analyzer). 6 Stevens, D. t . , Modified Biuret Method, Amer. J. Clin. Path. 7: , 1946. (Auto Analyzer). 7 Stevens, D. L., Stevens Adaptation for Auto Analyzer, J. Clm. Iinveesstt-.., 33z 2a1-a1., -1"954-. OQ 8 Skeggs, L. T., Diacetyl Monoxime Method, Amer. J. Clin. Path. 311, 1957. (Auto Analyzer). . Does noi containTSCA ^ International Research and Development Corporation Page 4 III. CLINICAL STUDIES A. METHODS: I. General Procedure: Twelve male and 12 female young, purebred beagle dogs jn_ apparent good health, were used for a 90-day feeding study oi The dogs were separated into one control and 3 treated groups of 3 males and 3 females each, and were housed individually in metabolism cages in temperature and humidity controlled quarters throughout the course of study. Powdered Purina Dog Chow without ^ ^ ^ ^ ^ B | a n d the same chow with the prescribed dietary levels of the test compound were available, as was water, at all times to the respective groups of dogs. Food consumption and individual body weights were measured and recorded once each week. Water intake and urine out put were measured and recorded daily during each clinical laboratory test interval week. Prior to the initiation of the compound administration phase of this study, stool flotation studies were conducted for the detection of intestinal parasites. Positive findings were followed by appropri ate vermifuge therapy. During the control period and again during the period of compound administration, all dogs were subjected to detailed physical examination. Heart sounds were examined by five point auscultation; pulse rates were determined by palpation; the ocular fundi were viewed for abnormalities; and reflexes were evaluated. In addition to the routine physical examination described above, all dogs were observed several times daily, 7 days each week, for signs of pharmacodynamic and/or toxic effects. Com pany Sanitized. Does not contain TSCA C B l International Research and Development Corporation Page 2 Although no gross compound-related lesions were observed at necropsy, a slight compound-related liver weight increase occurred at the middle and high dietary levels. Compound-related microscopic lesions consisted of hypertrophy of centrolobular liver parenchymal cells in 4-of-6 dogs from the 5000 ppm. dietary level group. No compound-related lesions were seen in other tissues from these dogs or in livers from dogs at the lower dietary levels. Ippih Snitize Boss io contain TSC CBi International Research and Development Corporation Page 6 .. 9 (2) Liver Function: Plasma alkaline phosphatase activity , prothrombin time10 determinations, serum glutamic oxalacetic (SCOT) and ^ serum glutamic pyruvic (SGPT) transaminase activities , and cholesterol determinations, were used as an indication of liver function. In addition, serum albumin electrophoretic patterns (cellulose strip method) were obtained once during the control period and again after one and 3 months , . ..... . 13 of compound administration . (3) Urinalysis : Observations for abnormality in gross appearance and color and qualitative tests for the detection of bilirubin , occult blood,15'16'17 albumin,18'19'20'21 and glucose,21'22'23 were con ducted on th 24-hour urine specimen. Urinary pH, r specific gravity and volume were measured, and the urinary sediments were examined microscopi cally. _________ .______ ________ - Marsh, W., Modified King-Armstrong Method, Clin. Chem. 5} 119, 1959. (Auto Analyzer). ,. ,, 10 Quick, A. J., Hemorrhagic Diseases, 1957, Lea & Febiger, Phila., Pa. 11 Reitman, S., and Frankel, S., Colorimetric Method for the Determina tion of Serum Transaminase Activity, Am. J. of Clm. Path., , 1957. 12 Hycel Cholesterol Procedures - Hycel, Inc., Houston, Texas, Revised Dec. 1962. 13 "Seprophore 111", Gelman Technical Manual No. 51199-A, 1963. 14 "Ictotest" (Ames Reagent Tablets). 15 "Hemastix" (Ames Reagent Strips). 16 "Hematest" (Ames Reagent Tablets). 17 "Occultest" (Ames Reagent Tablets). 18 "Albustix" (Ames Reagent Strips). . 19 "Bumintest" (Ames Reagent Tablets). 20 Heller's Ring Test, Practical Physiologic Chemistry, Hawk, Oser and and Summerson, 13th Ed., p. 830. 2221 "Combistix" "Clinistix" (Ames Reagent Strips). (Ames Reagent Strips). 23 "Clinitest" (Ames Reagent Tablets). 24 Beckman Expanded Scale pH Meter, Model No. 76. Com pany Sanitized. D oes no! contain TSCA CB International Research and Development Corporation Page 7 c. Special Sampling: Twenty-four hour urine and fecal samples were obtained from all dogs during the period of compound adminis t r a t i ^ T h e s e were frozen and delivered to the sponsor for analysis content. Similarly, representative tissue samples (see section on Pathology) were provided following necropsy examination. 3, Compound Administration: The test c o m p o u n d w a s incorporated into the basic laboratory diet (powdered Purina Dog Chow) and fed to the respective groups of dogs throughout the^study. The 3 treated groups of dogs were fed diets containing at initial concentrations of 100, 500, or 2500 ppm. for a continuous period of 35 days. From the 6th week of compound administration to the termination of the study the 500 ppm. dietary level was increased to 1000 ppm. and the 2500 ppm. dietary level was increased to 5000 ppm. The dogs at the lowest dietary level continued to receive a diet containing 100 ppm. of the test agent throughout the study. The diets were freshly prepared each week and were constantly available to the dogs in self-feeding hoppers. The control group of 3 male and 3 female dogs was maintained on a regimen identical to that of the treated groups except that the powdered basic laboratory diet did not contain| B. RESULTS: ' l . Behavior. Appearance and Mortality: No alterations in behavior or appearance which could be con sidered to be compound-related were seen among any of the control or treated dogs employed in this study. Incidental alterations, included one female dog (65-038) m ?eaIVisySS International Research and Development Corporation Page 8 the control group that exhibited 3 small l-to-2 cm. areas of alopecia on the back throughout the study; one male dog (65-072, 100 ppm.) that exhibited slight alopecia of the right rear leg during the last half of the study; one female dog (65-085, 100 ppm.) that exhibited an enlarged right Harderian gland throughout the study; one male dog (65-087, 1000 ppm.) that exhibited conjunctivitis and opacity of the right cornea during the last 4 compound administration weeks; and one female dog (65-094, 1000 ppm.) that exhibited slight dermatitis of the right foreleg during the last month of compound administration. All dogs survived the 90-day period of compound administration. 2. Physical Examination: Routine physical examinations conducted during the study revealed all dogs to be essentially normal in behavior and appearance at all times. Heart sounds were not unusual: pulse rates were normal; reflexes were unimpaired and fundascopic examination of the eyegrounds revealed no changes. 3. Body Weight (Table 1): All control and treated dogs exhibited essentially normal body weights throughout the 90-day period of treatment. No differences in body weight gain were, seen between the control and the treated groups of dogs. 4. Food Consumption (Table 2): ' All dogs consumed essentially the same quantities of food each week during the compound administration period as they did during the control period. No differences in food consumption were seen between the control and the treated groups of dogs. SpnUhed. Does notcom* Company International Research and Development Corporation Page 9 5. Compound Consumption: Compound consumption was calculated in mg./kg./day based on the average food consumption and body weight of each animal. The results of these calculations appear in Table 3. 6. Water Intake and Urine Output (Table 4): Although considerable variation in average daily water intake and urine output was found for most dogs employed in this study, the values obtained during the period of treatment were not consistently different from values obtained during the corresponding control period. No biologically meaningful differences were found between the control and test animals. 7. Laboratory Tests (Tables 5 through 28-Al: . a. Hematology: No compound-related hematologic changes occurred among dogs used for this study. Incidental changes, not related to compound administration, included low borderline hemoglobin and hematocrit values and mild to marked hypochromasia of the erythrocytes. The incidence of occurrence was similarly distributed in the control and treated groups, particu larly in the control examination periods and in the first examination (1 month) interval after the beginning of treatment. These values tended to fall into the usual acceptable ranges as the study progressed. . An elevated total leucocyte count was observed in Dog 65-083 (control;:male)' and Dog 65-078 (male; 500 ppm.) in the final control examination period prior to treatment, and Dog 65-092 (female; 500 ppm.) after 3 months of compound administration. A decrease in the polymorphonuclear leucocyte-to-lymphocyte Company Sanitized. Does not contain TSCA C B * International Research and Development Corporation Page 10 ratio was observed at one or more periods of examination in 3-of-6 control dogs and 9-of-18 treated dogs during the period of study. An occasional elevation in erythrocyte sedimentation rate was observed in the control and treated groups of dogs at one of the control periods of examination. One dog (65-187, male, 500 ppm.) exhibited an elevation in this parameter in the treatment period. This was observed at the 60-day examination period and had returned to normal by the terminal examination. b. Biochemical Studies: (1) Plasma: No compound-related changes in plasma biochemistry were found among dogs used for this study. (2) Liver Function Tests: A dose-related increase in plasma cholesterol was found in 5-of-6 dogs after 3 months of compound administration at the 2500 - 5000 ppm. level. No consistent bio logically meaningful changes in plasma cholesterol were found at the lower dietary levels (Table 28-A). In addition, a slight upward trend in plasma alkaline phosphatase activity was noted for Dogs 65-090 (male) and 65-099 (male) at the 2500 - 5000 ppm. level. Prothrombin time determinations and serum glutamic pyruvic transaminase (SGPT) and serum glutamic oxalacetic tranaminase (SGOT) values remained within the usual acceptable ranges at all periods of examination for all groups of dogs in this study. No unusual changes were noted in the serum albumin electrophoretic patterns. ; . (3) Urinalysis: Urinalysis examination failed to reveal changes which: were considered, to be'-related :to 'treatment with ^uwipirifSinifeeH. International Research and Development Corporation Page 11 Incidental findings, not related to compound administration, included slight bilirubinuria for one control (65-086, male) and 3 treated (65-078, 65-079 and 65-087, males) dogs at the 2-month examina tion period. Bilirubinuria again was found at the terminal examination for one of these dogs (65-079, male; 500 - 1000 ppm.) V International Research and Development Corporation Page 12 IV. PATHOLOGICAL STUDIES A. METHODS: 1. Gross Examination: At the completion of the compound administration period, all dogs were anesthetized with sodium pentobarbital, sacrificed by exsanguination and subjected to necropsy examination. Major organs were weighed and representative tissues were collected into 10 per cent buffered neutral formalin for subsequent histologic processing and microscopic examination. Fresh specimens of brain, liver, kidneys, spleen, fat, muscle, testes and blood were collected from each dog, frozen and forwarded to the sponsor. 2. Microscopic Examination: The following tissues from each of the control and 5000 ppm. dosage group dogs were paraffin embedded, sectioned, stained with hematoxylin and eosin and examined microscopically. brain spinal cord peripheral nerve eye pituitary thyroid parathyroid adrenal trachea lung ' heart aorta spleen lymph node thymus bone marrow salivary gland esophagus stomach small intestine large intestine pancreas liver gall bladder kidney urinary bladder testes or ovary prostate or uterus skeletal muscle skin bone ' Liver sections from all 100 and 1000 ppm. dosage level dogs were also processed as above and examined microscopically. not contain T S C A C B Com pany Sanitized. D oes International Research and Development Corporation Page 13 B. RESULTS: 1. Cross Patholoev (Table 29) and Organ Weights (Table 30}.: No compound-related gross pathologic lesions were observed m any dogs subjected to necropsy examination. Organ weights of treated dogs were within the normal range except the liver weights of the 5000 ppm. dosage group dogs which were slightly increased. The liver weights of the 1000 ppm. dosage group dogs were also greater than the liver weights of the control dogs in this study although they were still within the normal range. 2. Histopathology (Tables 31 and 32): Compound-related changes were limited to the lrver of 3-of-3 male and l-of-3 female dogs from the 5000 ppm. dosage level group. These changes consisted of slight hypertrophy of centrolobular paren chymal cells. The cytoplasm of affected cells was more homogeneous and less coarsely granular than the cytoplasm of hepatocytes at the periphery of the lobule or of hepatocytes in control livers. These changes were not seen in any of the livers from the 100 or 1000 ppm. dosage level dogs. P&mpap: 'Poes noi con iato TSCACBS 9 fPage ompanySanitized. Does notcontain TSCACTO Ninety-Day Feeding Study in the Dog. TABLE 1. Individual Weekly Body Weights, Kilograms. Dog Control Period Number.., Sex 1 2 3 1 2 3. Compound Administration Weeks 4 5 : 6; 7 8 9 10 .11 112 Control: 65-038 65-070 65-081 65-083 65-086 65-093 F iM F M M F 7.7 7.9 6.5 7.2 4.5 4.8 4.4 4.5 4.2 4.5 3.7 3.9 8.1 8.2 8.5 7.9 8.6 9.5 5.2 6.2 6.7 5.2 5.7 6.3 5.5 6.1 6.7 4.1 4.5 4.8 8.4 9.9 7.2 6.7 7.1 4.9 8.0 8.3 8.5 8.5 8.6 8.7 8.6 8.8 8.8 9.8 10.5 11.1 11.8 12.2 12.4 13.4 13.4 13.8 1 6.9 7.7 8.1 8.4 8.4 9.0 9.0 9.5 9.5 6.3 6.9 7.5 8.1 7.8 8.3 8.7 9.1 9.1 7.0 7.6 8.1 8.3 8.8 9.1 9.1 9.2 9.6 4.7 5.2 5.3 5.5 5.7 5.7 6.2 6.3 6.7 100 ppm.: 65-072 65-074 65-076 65-077 65-085 65-091 M M M F F F 500 ppm.i * 65^-078 65-079 65-087 65-092 65-094 65-095 M M M F F F 3.9 4.5 4.6 5.5 5.4 5.9 4.5 4.9 4.5 4.8 575 6.0 4.5 5.0 3.5 3.9 6.4 7.3 3.1 3.4 5.5 6.1 4.1 4.3 5.1 5.3 6.1 6.1 77 0 7.5 6.7 7.4 7.9 5.2 6.1 6.5 5.5 5.7 6.2 6.6 7.0 7.8 6.2 8.0 8.2 7.2 6.4 8.1 5.5 6.0 6.7 7.2 4.2 4.7 5.1 5.6 B.l 9.2 9,8 10.5 3.7 4.3 4.5 4.8 6.7 7.3 7.8 8.2 4.7 5.3 5.7 6.1 6.3 6.9 7.1 7.8 8.0 8.2 8.5 9.1 9.2 7.9 8.9 9.3 9.8 10.2 10.5 10.9 11.3 11.5 1 8.3 9.1 9.8 10.4 10.9 11.3 11.6 12.0 12.4 1 6.9 7.6 8.1 8.6 8.9 8.5 9.2 9.4 10.0 6.2 6.4 6.8 6.6 6.8 7.4 7.3 7.7 7.5 7.9 8.6 8.9 9.5 9.7 9.8 9.9 10.2 10.7 7.1 5.4 10.4 4.7 8.3 5.8 7.9 6.0 11.0 5.1 9.1 6.5 8.2 6.1 11.4 5.4 9.4 6.8 8.8 6.3 11.8 5.9 10.0 7.3 9.2 6.4 12.6 6.2 10.3 7.5 9.6 6.9 11.5 5.8 10.3 7.4 9.7 6.9 12.8 6.1 10.9 8.2 10.1 7.4 13.7 6.5 10.8 8.4 10.4 7.3 13.9 6.7 11.4 8.5 1 1 2500 onm: :** 65-088 M 3.4 3.5 3.9 4.3 4.7 5.0 65-090 M 4.7 5.3 6.1 6.7 7.3 7.9 65-096 F 4.6 5.0 5.5 6.0 6.6 7.0 65-097 F 5.1 5.5 5.8 6.4 6.9 7.5 65-098 F 3.5 3.9 4.0 4.9 5.3 5 .'6 65-099 M 4.3 4.8 5.4 5.5 6.1 6.5 4.8 5.4 5.7 6.0 6.2 6.3 6.7 6.6 7.0 7.9 8.5 9.1 9.6 9.7 10.1 10.7 10.9 11.3 1 7.0 7.4 7.9 8.3 8.3 8.5 8.9 9.1 9.1 7.4 8.2 8.8 9.4 9.5 9.8 10.2 10.7 10.7 1 5.5 .0 6.5 6.8 6.8 7.2 7.2 7.5 7.8 6.5 6.9 7.4 7.5 . 7.9 8.0 8.5 8.7 8.7 * Increased to 1000 ppm In the 6th week of therapy, ** Increased to 5000 ppm in the 6th week of therapy. hi* TABLE 2. Ninety-Day Feeding Study in the Dog. Average Daily Food Consumption, Grams. TT I-)8 Control Period ______________ ______Compound Administration Weeks Number Sex 1 23 j 1 2 3 4 5 6 7 8 9 10 11 12 13 Control: 65-038 F 210 229 256 270 234 226 264 193 157 196 196 176 212 216 225 168 65-070 M 446 378 446 407 410 366 400 458 332 182 424 385 394 361 449 304 65-081 F 278 236 315 274 304 340 280 342 289 304 326 208 269 269 344 247 65-083 M 218 204 264 271 290 288 263 294 254 283 273 185 281 284 263 209 65-086 M 307 251 354 304 329 323 287 299 266 247 260 254 286 333 ' 358 210 65^093 F 190 139 191 216 152 215 157 203 177 209 222- 163 238 228 174 178 100 ppm.: o m*5lj 65-072 M 262 279 282 250 317 334 295 325 225 259 283 235 370 281 318 209 :3! 65-074 M 283 240 357 312 328 393 347 401 333 334 342 295 355 355 341 237 65-176 M 299 353 311 339 325 343 370 404 346 381 377 347 398 382 329 353 va 65-077 F 196 234 248 310 300 338 288 298 286 297 321 254 319 301 266 284 &sj Dj 65-085 65-091 F 201 206 275 262 245 269 223 279 203 183 219 187 239 223 236 169 F 344 303 347 305 368 318 314 360 327 350 315 292 335 263 296 300 COtmtf 500 ppm.:;* 3o.` 0 o 65-078 65-079 65-087 M M M 250 231 270 285 339 336 283 342 276 299 325 246 364 314 305 278 299 215 219 222 267 274 233 311 228 223 248 216 240 295 243 177 420 361 417 432 399 424 418 403 302 376 385 149 450 477 395 295 S' 65-092 F 220 risi 231 200 205 221 225 231 189 206 229 134 190 214 207 215 5* 65-094 F 336 339 401 394 384 353 353 457 331 372 315 261 348 353 309 341 fJHfii 65-095 F 181 210 225 320 260 244 241 . 299 254 294 274 205 290 275 257 282 o 5 A 2500 ppm . 65-088 65-090 65-096 65-097 65-098 65-099 M M F F F .. M 142 139 213 216 213 214 201 245 194 237 236 183 283 229 251 167 242 268 334 324 331 361 340 378 326 390 309 271 395 337 318 208 226 223 276 268 291 288 262 282 217 252 236 216 287 251 248 179 224 224 233 263 284 325. 306 323 266 306 292 281 319 347 313 202 230 206 251 238 236 242 228 259 225 238 244 204 266 218 235 176 232 215 280 257 240 284 249 294 242 249 269 225 294 277 245 192 Page T-2 ** Increasedj to 1000 ppm. in the 6th week of therapy. ** Increased to 5000 ppm. in the 6th week of therapy. 2 Ninety-Day Feeding Study in the Dog. TABLE 3 . Average Daily Compound Consumption, Mg./Kg./Day. Animai No. & Group Sex Compound Administration Weeks _ 5_______ 6 7 8 9 10 11 12 13 65-072 65-074 65=076 65=077 65=085 65-091 M M .M F F F 500 ppm.::* 4.7 4.5 4.6 5.1 4.6 4.4 5.2 4.4 4.1 4.6 4.0 4.7 5.4 4.9 4.2 4.7 4.2 3.9 4.6 4.4 4.5 4.2 3.6 4.0 4.7 4.5 4,4 3.9 4.4 4.2 3.2 . 3.3 3.6 3.4 3.5 3.7 3.5 3,5 3.0 2.8 3.7 3.7 35 3A 35 36 32 3;.2 2.9 2.8 3.1 3.0 2.5 3.0 4.4 3.3 3.4 3.5 3.3 3.4 3.1 3.1 3.2 3.2 3.0 2.6 3.5 ..2,4 3.0 2.2 2.7 3.0 2.7 3.0 3.1 2.3 2.8 3.0 ' 65=078 65-079 65-087 65-092 65-094 65=095 M M M F F F 2500 ppm. : * * 23.8 21.5 23.5 23.3 27.0 30.2 . 25.3 26.2 20.4 22.8 24.6 22.8 23.3 24.5 20.2 23.0 21.5 20.0 19.9 21.6 20.1 23.9 21.3 20.8 21.6 ` 25.9 18.3 22.6 25.1 23.0 33.7 37.4 26.5 35.0 35.2 37.4 34.0 35.4 31.9 34.9 37.2 40.3 35,,3 38,,8 30.,6 36.,9 30..6 36.,5 25.6 31.3 12.9 23.1 25.3 27.7 37.5 34.8 35,2 31.1 31.9 35.4 31.1 39.9 34.8 32.9 33.1 32.7 29.3 33.3 28.4 30.9 27.1 30.2 28.1 25.7 21.9 33.1 31.0 35.7 65-088 M 65=090 M 65-096 F 65-097 F 65-098 F 65-099 M 125.6 120.9 111.7 102.7 121.4 116.8 113.3 113.4 110.2 102.9 111.3 98.4 107.0 114.3 102.9 108.3 108.0 109.2 104.7 107.6 93.6 103.4 103.6 95.8 113.4 111.2 95.3 98.5 107.9 107.5 170.2 179.1 137.3 151.1 173.1 163.5 197.5 203.1 151.8 162.8 175.0 166.0 190.,3 159,,3 142.,2 153,,7 179,,4 170,.3 145.2 134.2 127.1 143.4 141.7 140.6 211.2 184.6 161.2 156.3 184.7 173.0 173.5 154.6 137.9 162.1 145.3 159.2 179.3 140.7 136.3 146.3 150.6 140.8 124.6 98.1 101.7 101.0 122.2 114.3 * Increased to 1000 ppm. in the 6th week of therapy. ti': ** Increased to 5000 ppm. in the 6th week of therapy. o; > OG Page T-3 Time Interval Control Weeks 1 ."I 3 Compound Adminis tration Weeks 1 9 12 Ninety-Day'Feeding Study in the Dog. Average Daily Water Intake (W.I.)', mi.; Urine Output (U.O.). ml,; and Water Intake-to-Urine Output Ratio (W/$J). Doe 65=038i;F W.I. U.O. w/u Dog W.I. U.O. w/u Control Doe 65=081. F Doe 65-083 w W.I. U.O. W/U W.I. U.O. W/U Doe 65-086 M W.I. U.O. W/U Do e 65-092l F W.I. U.O. W/U 520 190 2.7 498 234 2.1 627 265 2.4 895 128 7.0 801 168 4.8 868 298 2.9 610 90 6.8 603 121 5.0 607 170 3.6 915 468 2.0 1005 455 2.2 790 250 3.2 640 139 4.6 686 195 3.5 518 173 3.0 365 110 3.3 428 288 1.5 327 127 2.6 509 183 2.8 553 198 2.8 495 243 2.0 1425 435 3.3 1465 505 2.9 1213 426 2.8 690 109 6.3 830 174 4.8 723 238 3.0 1225 753 1.6 1248 578 2.2 1125 664 1.7 1025 380 2.7 1005 329 3.1 737 297 2.5 350 208 1.7 480 281 1.7 460 265 1.7 PempanySanitized. Does notcontain TSCA''m w H -P- f''-dJT)I T3CS*: Qti. i ai o o3 ST rfi a( f t >. o' Of Ninety-Day Feeding Study in the Dog. TABLE 4. Continued. In" ke ("-1 0 ' " L '; Url" UtPUt Time Interval Control Weeks 1 2 3 Compound Adminis tration Weeks 1 9 12 liner 65-079 M 'W.I. u.o. W/U W.I. U.O. W/U 580 70. 8.3 490 109 4.5 , 587 130 4.5 635 239 2.7 850 295 2.9 900 340 2.6 850 286 3.0 1038 265 3.9 853 319 2.7 1240 460 2.7 1488 361 4.1 1000 563 1.8 100 DDI. > M Dog CO-U// IM W.I. u.o. W/U W.I. U.O. W/U 860 213 4.0 808 286 2.8 867 307 2.8 660 128 5.2 585 210 2.8 747 233 3.2 1135 343 3.3 1150 454 2.5 1258 390 3.2 773 300 2.6 1280 433 3.0 975 465 2.1 - * ter mt.ke-to-Urine Doe 65-085 F W.I. U.O. W/U d b 65-091 F W.I. U.O. W/U 645 290 2.2 684 319 2.1 807 297 2.7 648 173 3.7 773 161 4.8 470 210 2.2 790 389 2.0 1015 489 2.1 770 430 1.8 738 176 4.2 1060 316 3.4 750 259 2.9 Page T-5 Ninety-Day Feeding Study in the Dog. TABLE 4, Continued Average Daily Water Intake Output Ratio (W/U). (W.I.), mi.; Urine Output (U.O.), ml.; and Water Intake-to-Urine Time Interval !';>] <e. Control Weeks 1 2 3 Compound Adminis tration Weeks 1 9 12 525 138 3.8 555 .159 '3.5 647 155 4.2 465 90 5.2 f.498 108 4.6 '487 145 3.4 790 230 3.4 875 266 3.3 888 245 3.6 483 191 2.5 683 290 2.4 538 240 2.2 765 171 4.5 1025 243 4.2 593 180 3.3 883 243 3.6 485 144 3.4 1100 403 2.7 415 140 3*0 558 185 3.0 460 233 2.0 438 232 1.9 270 166 1.6 380 258 1.5 1455 354 4.1 1378 553 2.5 1450 487 3.0 760 270 2.8 935 188 5.0 918 349 2.6 840 120 7.0 434 255 117 393 145 2.7 417 250 1.7 545 271 2.0 485 217 2.2 * 1-- Increased to 1000 ppm. in the 6th week of therapy. Page HrrI\ K & Page T Company Sanitized. Does no! contain TSCA ro i Ninety-Day Feeding Study in the Dog. ` TABLE 4,^ Continued Average Daily Water Intake (W.I.) Output Ratio (W/U). ml.; Urine Output (U.O.), ml.; and Water Intake-to-Urine Time Interval Control Weeks 1 2 3 Compound Adminis tration Weeks 1 9 12 Dog 65*038 M Dog 65-090 M W.I. U.O. W/U ` W.I. U.O. W/U _________2500 ppm.* _______ Dog 65-096 F Dog 65-097 F W.I. U.O. W/U W.I. U.O. W/U. Dog 65-098 F W.I. U.O. W/U Dog 65-099 M W.I. U.O. W/U 480 205 2.3 549 240 2.3 607 263 2.3 545 139 3.9 574 195 2.9 587 193 3.0 570 103 5.5 573 173 3.3 593 130 4.6 505 198 2.6 488 228 2.1 573 273 2.1 365 .95 3.8 448 156 2.9 580 157 3.7 463 149 3.1 558 214 2.6 580 195 3.0 750 430 1.7 785 389 2.0 605 329 1.8 704 185 3.8 867 249 3.5 843 280 3.0 645 115 5.6 720 188 3.8 648 175 3.7 690 414 1.7 780 320 2.4 650 343 1.9 513 203 2.5 745 191 3.9 535 225 2.4 613 183 3.3 605 268 2.3 387 210 1.8 Increased to 5000 ppm. in the 6th week of therapy. Page T - 8 Ninety-Day Feeding Study in the Dog. TABLE 5. Results of Hematological. Biochemical and Urinalysis Studies..-------------- ----- Dog No. 65-038> Female ' ' Control Periods . Compound Administration Months Dosage: Control_____________ _____ 1________ Z_______ -2-------- --------- 2---------3------ Hematology: Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, U Seg., 7 Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils,. % Appearance':of: Erythrocytes : 6.02 15.2 43 0 13.73 51 49 2 46 1 2 0 No 5.85 13.3 42 2 11.91 57 57 0 37 .3 3 0 No 5.27 13.2 40 2 12.22 61 60 1 38 0 1 0 No 5.76 14.1 44 1 12.85 47 42 47 41 01 48 51 12 45 00 SH 7.16 17.5 51 0 11.25 . 5.71 15.9 48 0 10.84 46 44 46 41 03 46 48 62 26 00 No No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. |\ Alkaline Phosphatase, units V Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml. SGPT units/ml.^ 98 6.51 2.90 0.80 11.5 11 196 8 15 15 110 6.11 2.53 0.71 15.0 6 212 7 18 15 108 5.58 2.33 0.72 15.5 8 211 7 16 17 99 5.59 2.42 0.76 . 14.2 5 200 8 16 18 104 5.90 2.86 0.94 14.0 5 178 7 15 15 100 5.48 3706 1.26 11.2 6 184 8 14 11 Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 1s6-0.c 7.3 1.052 N N N N 155 SJ.C 7.3 1.042 N N N N. 290 LS-cl 7.2 1.042 N N N N 160 S-C 7.1 1.022 N N N N 55 S-cl 7.2 1.035 N N N N 190 S"C 7.3 1.031 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria, Code: S - Straw LS - Light Straw D cl - Cloudy C - Clear 2-3 F 4-5 MM FM FF N - Negative No ~ Normal SH - Slight Hypochomia 1-3 1-2 FM F MF L - .Loaded F - Few M - Many occ - Occasional OCC F occ occ occ LM M LF * Repeat. Determinations *-Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase ty Sanitized. Dees not contain TSCA cat Page T - 9 H h Ninety-Day Feeding Study in the Dog. TABLE 6. Results of Hematological, Biochemical and Urinalysis Studies. Dog No. 65=070, Male Control Periods Compound Administration Months Dosage: Control 123 1 23 Hematology: Total Erythrocytes (s[10&/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.41 12.1 38 5 17.42 49 49 0 49 1 1 0 No 5.15 10.7 34 5 14.10 56 55 1 42 1 1 0 H 4.08 11.3 37 1 13.43 64 64 0 33 3 0 0 SH 5.52 13.4 41 2 15.10 53 53 0 44 1 2 0 No 6.66 15.6 47 0 11.75 48 48 0 43 4 4 1 SH 6.21 16.2 50 0 12.52 52 51 1 41 6 1 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml Prothrombin Time, sec.. SGOT units/ml. SGPT units/ml.2 130a 5.95 2.60 0.78 12.0 19 176 8 22 19 126 5.76 2.38 0.70 15.3 18 186 8 20 11 132 4.92 2.18 0.80 11.8 19 140 8 18 14 114 5.13 2.45 0.92 15.2 10 175 8 17 14 107 5.41 2.71 1.00 12.5 11 195 7 20 14 107 ' 5.50 2.54 0.92 13.1 10 198 8 15 13 Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 80 S=cl 6.0 1.06C1 N N N -N 105 S-cl 6.2 1.062 N N N N 150 S-cl 6.8 1.046 N N N N 455 LS-cl 6.1 1.026 N N N N 480 LS-cl 6.2 1.014 N N N N' 225 S-cl 6.8 1.032 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria Code: S - Straw LS - Light Straw cl - Cloudy 3-4 F L 5-6' MM L FF N - Negative No - Normal . SH - Slight Hypochromia H - Hypochromia: OCC OCC 1-2 2-3 1-2 F F occ F F F F. M F MMMM L - Loaded a - Repeat 141 . F - Few ; " M - Many occ - Occasional Iserum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase CSpahySanitized. Uoe9 hot contain re#' <>* Page T - 10 Ninety-Day Feeding Study in the Dog. TABLE 7. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-081, Female Control Periods Compound Administration Months Dosage: Control 1- 2 3 3* 1 1* 2 3 Hematoloev: Total Erythrocytes (xl0/cnnn. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils,. % Appearance of Erythrocytes 5.21 11.6 36 2 11.65 52 52 0 44 1 3 0 No 4.71 10.3 32 4 10.85 51 49 2 44 2 3 0 3.58 10.0 32 1 11.95 72 71 1 25 1 2 0 No 5.32 10.8 35 1 10.09 41 37 41 37 00 49 58 74 31 00 SH 7.39 13.8 44 0 9.84 51 51 0 46 2 1 0 H 6.83 13.9 44 0 13.65 66 65 1 30 3 1 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SCOT units/ml.^ SGPT units/ml.2 . 125 5.91 2.58 0.78 10.3 17 161 8 19 19 127 5.85 2.45 0.72 13.8 18 162 8 22 19 136 131a 5.00 5.05 2.29 2.73 0.85 1.17 10.8 11.6 19 10 153 * 149 88 30 28 18 18 1 19 121 5.75 3.01 1.09 12.8 12 175 7 23 11 114 5.65 2.98 1.11 13.0 12 167 7 18 19 _ Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occiilt Blood. 60 S-cl 6.4 1.062 N N N N 105 S-cl 6.2 1.048 N N N N 195 S-cl 6.5 1.035 N N N .N . 180 . S-cl 6.8 1.030 N N N N 135 S-cl 7.2 1.026 N N N N 330 LS-cl 6.8 1.022 N N N N Microscopic: Leucocytes Amorphous.Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code: 'S - Straw . LS - Light Straw cl - Cloudy 4-5 3-5 F F FF F OCC 2-3 OCC LM F MF FF F M F M, M F L F F M N - Negative No - Normal L - Loaded F - Few a - Repeat 132 SH - Slight!.Hypochromia M - Many H - Hypochromia occ - Occasional ^Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Sanitized. Does not contain TSC CBI Pa g / T- 11 Ninety-Day Feeding Study in the Dog. TABLE -8. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-083, Male Control Periods Compound Administration Months Dosage: Control 1 2 3 3* 1 2 3 Hematology: Total Erythrocytes (xl06/cmm. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, 7o Moneytes, 7= Basophils, % Appearance of Erythrocytes 4.51 11.3 35 2 14.93 63 62 1 35 0 2 0 No 4.67 10.6 34 2 16.56 63 60 3 32 0 5 0 SH Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./'100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.l SGPT units/ml.^ 127 5.95 2.80 0.89 14.8 14 116 8 22 18 136 5.93 2.58 0.77 15.2 15 138 8 24 26b Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 300 LS-cl 6.8 1.018 N N N N. 220 LS-cl 6.5 1.012 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria FF F OCC F i*>' M LL Code: LS - Light Straw N - Negative cl - Cloudy No - Normal SH - Slight Hypochromia: 3.62 10.1 35 6 24.36a 86 83 85 81 12 14 16 00 01 00 SH 5.13 12.5 40 1 15.12 62 61 1 36 0 2 0 No 6.41 14.8 44 0 14.11 49 49 0 44 3 4 0 No 6.26 15.3 47 0 12.27 45 43 2 50 0 5 0 No 127 5.35 2.45 0.85 14.8 16 122 8 19 19 124 5.13 2.69 1.16 16.6 9 123 9 15 17 105 5.49 2.85 1.06 15.0 11 142 7 13 14 100 5.40 2.90 1.16 18.8 9 157 8 9 8 375 LS-cl 6.8 1.019 N N N N 410 LS-cl :7.5 1.013 N N N N 525 LS-cl 6.0 1.016 N N N N 330 LS-cl 6.5 1.012 N N N 2-3 occ-3' F 2-5 ' FLF FM FMM F L - Loaded F ~ Few M - Many a - Repeat 23.39 b .- Repeat 26 occ - Occasional *-Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Com pany Sanitized. Does fio! confan T SC A c*i Page T"12 Ninety-Day Feeding Study in the Dog. TABLE 9. Results of Hematological. Biochemical. and Urinalysis Studies. Dog No. 65-086, Male Control Periods ComDOund Administration Months Dosage: Control 1 2 3 3* 1 1* 2 3 Hematology: Total Erythrocytes (xl0/cmm'. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm. ) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, L Monocytes, % Basophils, % Appearance of Erythrocytes 4.81 11.0 35 2 13.79 61 60 1 30 2 7 0 No 4.40 10.1 32 1 12.20 51 49 2 42 0 7 0 MH 3.70 9.6 31 1 13.57 60 59 1 35 2 2 1 No 5.18 12.8 40 1 17.48 24 32 24 32 00 70 64 21 43 00 MH 6.13 14.0 43 1 10.92 47 47 0 51 1 1 0 No 6.09 15.3 45 0 9.11 55 52 3 37 1 7 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml.2 126a 5.58 1.96 0.54 14.8 16 196 7 18 16 107 5.41 2.09 0.63 16.8 15 174 8 21 17 104 4.75 2.09 0.76 12.3. 15 142 7 28 25 10 111 4.73 2.45 1.07 10.7 9 181 8 13 11 100 4.96 2.50 1.02 9.4 11 . 203 7 10 8 102 5.04 2.70 1.15 1017: 7 200 8 13 13 Urinalysis : Volume, ini. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood . 125 S-cl 6.3 1.044 N N N N 165 LS-cl 6.8 1.018 N N N N 130 S-cl ' 6.8 1.060 N N N N 290 LS-cl 7.2 1.016 N N N N. 130 S-cl 7.0 1.016 N 2+b N N 230 S-cl 7.3 1.022 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria 4-6 8-10 3-4 1-2 8-10 1-3 FF F F OCC R F F L M OCC F M F. L T, M M M L F Code: S - Straw LS - Light Straw cl - Cloudy N - Negative L - Loaded * - Repeat Determinations No - Normal F - Few MH - Marked Hypochromia M - Many a - Repeat 134 b - Repeat 1+ 1+ - Trace-to-slight R - Rare 2t - Slight-to-moderate occ - Occasional ^Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Company Sanitized. Does not contain T SC A C P I Page T - l 3 Ninety-Day Feeding Study in the Dog. TABLE 10. Results of Hematologicai. Biochemical and Urinalysis Studies. Dog No. 65-093, Female Control Periods Compound Administration Monthi Dosage: Control 1 2 3 3s* 1 2 1 Hematology: Total Erythrocytes (xl0&/cmm.) Hemoglobin, gm./100 ml. Hematocrit, 7 Sedimentation Rate, mm./hr Total Leucocytes, (xl03/cmm.) Differential Count: Neutrophils, % Seg., 7 Non-Seg., L Lymphocytes, U Eosinophils, % Monocytes, % Basophils, 7 Appearance of Erythrocytes 5.97 12.6 40 0 15.90 61 60 1 37 1 1 0 No 4.93 11.1 33 1 14.53 57 56 1 39 1 3 0 SH 3.77 10.2 30 14 16 9.21 53 53 0 44 1 2 0 SH 5.76 12.6 40 2 17.51 67 67 0 29 1 3 0 SH 6.84 14.8 46 0 12.34 58 58 0 38 4 0 0 No 5.94 14.6 44 0 11.90 67 66 1 32 1 0 0 No ) Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml..Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT nits/ml.l SGPT units/ml.^ 127 5.63 1.89 0.51 13.75 19 144 7 16 .22 125 5.53 2.01 0.57 13.0 18 128 7 17 22 115 5.38 2.00 0.59 12.0 19 147 7 19 26 118 5.05 2.08 0.70 12.8 13 132 7 12 16 112 5.08 2.48 0.95 13.8 13 115 7 15 18 112 5.11 2.60 1.04 14.6 10 124 8 12 15 Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 50 S-C 7.4 1.050 N N N N 130 S-C 7.0 1.022 N N N N. 90 DS-cl 7.0 1.058 N N N N 80 S-C 7.4 1.041 N N N N 105 S-C 8.0a 1.027 N N N N 280 S-cl 7.3 1.031 N N N N . Microscopic: Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria F 1-3 1-2 F 6-8 OCC 1-2 ' 1-2 1-2 2-3 1-2 occ FFM F L F FF FF F F MF Code: S - Straw DS - Dark Straw Cloudy N - Negative No - Normal L - Loaded F - Few JL ^ Repeat Determinations a - Repeat 6.8 SH - Slight Hypochromia M Many occ Occasional ^Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase >'S a n iiiz es o contain tS'C 'd i' Page T-14 Ninety-Day Feeding Study in the Dog. TABLE 11. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-072, Male Control Periods Compound Administration Months Dosage: 100 ddut. 1231 23 Hematology: Total Erythrocytes (xl0&/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm,.) Differential Count: Neutrophils, % Seg., 1 Non-Seg., 7 Lymphocytes, % Eosinophils, 7o Monocytes, % Basophils, 7 Appearance of Erythrocytes 5.44 12.6 40 0 11.96 63 62 1 31 3 3 0 No 4.76 10.7 34 1 11.23 62 60 2 34 3 1 0 H 4.10 11.8 37 0 11.30 70 69 1 26 2 2 0 SH 5.61 13.7 42 0 7.47 58 58 0 36 4 2 0 SH 6.77 16.2 46 0 11.01 52 52 0 42 5 1 0 No 6.39 16.4 50 0 10.15 64 63 1 35 1 0 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units S Cholesterol, mg./100 ml. Prothrombin Time, sec. SCOT units/ml.l . SGPT units/ml.^ 114 5.63 2.53 0.82 10.2 17 132 8 22 14 . 111 5.13 2.22 0.76 10.4 16 139 8 18 14 119 . 4.60 2.14 0.87 11.8 17 120 8 19 15 112 4.65 2.28 0.96 11.0 10 118 8 17 17 113 5.45 2.53 0.86 10.7 10 158 6 16 8 106 5.15 2.72 1.12 9.5 8 163 7 20 16 Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood Microscopic : Glcium Oxalate Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria, Code: S - Straw DS - Dark Straw cl - Cloudy 90 S-cl 6.0 1.059 N N N N 105 ,S-cl 6.0 1.032 N N N N 90 DS-cl 7.1 1.055 N N N N 245 S-cl 6.5 1.020 N N N N. 160 S-cl 6.3 1.024 N N N 2+a 235 S-cl 6.5 1.023 N N .N N M 20-30 F 1-2 1-2 20 OCC LM 2-3 4-5 OCC occ 'M F M F F ML LM F M LM N - Negative L - Loaded 3 -- Repeat N No - Normal F - Few SH - Slight Hypochromia M - Many H - Hypochromia occ - Occasional ISerum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Com pany Sanitized. Does no! contain t s c a OR! Page T-15 Ninety-Day Feeding Study in the Dog. TABLE 12. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-074r, Male Control Periods Compound Administration Months Dosage: 100 ppm. 12 3 1 23 Hematology: Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlOJ/cmm.) Differential Count: Neutrophils, % Seg,, % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, I* Appearance of Erythrocytes 5.32 12.1 36 4 15.22 61 61 0 35 3 1 0 No 4.38 9.0 28 4 11.90 49 49 0 38 8 5 0 MH 4.06 11.0 33 .1 10.16 64 64 0 36 0 0 0 No 5.68 13.0 41 0 10.11 51 51 0 43 3 3 0 SH 6.47 15.2 46 0 12.23 43 42 1 48 1 8 0 SH 5.75 16.1 48 0 10.68 . 39 37 2 52 4 5 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOQ ml. Alkaline Phosphatase, units Ghlesterl, mg.'/100 ml. Prothrombin Time, sc. SGOT units/ml.-*SGPT units/ml.^ 109 5.65 2.16 0.62 13.2 15 131 8 18 19 118 5.58 2.24 0.67 15.0 17 144 8 17 18 . 119 5.00 2.00 . 0.67 12.5 15 147 8 19 16 119 4.92 2.23 0.83 13.3 9 ' 123 8 14 16 116 5.53 2.38 0.76 11.2 11 158 6 12 13 113 5.65 2.90 1.06 12.0 9 172 8 13 15 . Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 95 S-C 6.6 1.030 N N N N 180 S-cl 7.0 1.033 N N N N 300 S-cl 6.5 1.030 N N N .N 270 S-cl 6.4 1.022 N N N N 285 S-cl 6.6 1.016 N N N N 460 LS-cl 7.1 1.011 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria 1-2 5-7 2-4 2-3 LF F OCC OCC OCC OCC F F F occ R F F FF FM M F MM Code: S - Straw LS - Light Straw C - Clear cl - Cloudy N - Negative No - Normal SH - Slight Hypochromia MH - Marked Hypochromia L - Loaded F - Few M - Many R - Rare occ - Occasional 1-Serum Glutamic Oxalacetic Transaminase Serum Glutamic Pyruvic Transaminase llp p S S g -Sanitized. Does no! contain TSCA CBl Page T - 16 Hay TSiifg 'STtud in 'the Dbg. TABLE 13. Results, of Hematological. Biochemical .and Urinalysis Studies ______________ . Dog No-. 65-076, Male . Control Periods____ Compound Administration Months Dosage: ,100 ppm. .________________1 1 * 2 _______ 3______ . 1 2' .3 - Hematology , Total Erythrocytes (xlO /cmm. ) Hemoglobin, gm./100 ml. Hematocrit, % . Sedimentation Rate.~mm./hr Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, L Monocytes, % Basophils, % Appearance of Erythrocytes . 4.39 9.4 28 10 11 14.52 45 42 3 48 2 5 0 No 3.88 8.0 26 5 17.92 69 69 0 27 4 0 0 MH 3.35 9.7 32 1 11.97 64 63 1 32 2 2 0 SH . 5.02 6.06 11.6 ; 14.1 36 42 11 11.71 11.11 5.44 14.1 43 0 12.71 44 44 45 44 44 45 000 45 49 46 54 6 633 00O MH H No Plasma Biochemistry! Glucose, mg,/100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Glbulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units ^^P^Cholesterol, mg. /100 ml. --'/Prothrobin Time, sec. SGOT units/ml . SGPT units/mi. ^ 125?' 5.44 2;00 0.58 13.5 16 159 7 20 16' 135.:: 5.84 2.39 0.69 14.2 18 163 7 19 12 129 5.01 2.09 0.72 13.3 17 132 8 i1o9 123 4.89 2.35 0.92 .. 12.4 11 163 8 19 17 119 5.42 2.57 0.93 13.6 13 181 7 28 19 116 5.25 2.63 1.00 12.5 10 203 8 15 14 Urinalysis: Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 22 8-cl 6.4 1.027 N N N 305 370 S-cl 'S-cl 7.1 7.0 1.021 1.026 NN N .N NN NN 360 LS-cl 6.0 1.021 .N N N N 355 S-cl 7.0 1.018 N N N N 420 LS-cl 6.0 1.025 N N N N Microscopic: Amorphous Urates Leucocytes Epithelial Cells Erythrocytes Triple Phosphates Calcium Oxalate imonium Urates Bacteria , FFL 1-2 1-3 F 1-2 occ 3-5 occ F M- F' F F F FM MFEM ML 'ode: . S - Straw LS - Light Straw N - Negative L -Loaded No - Normal F -Few SH - SlightHypochromia M -Many MH - Marked Hypochromia 6cc -Occasional a - Repeat 150 H - Hypochromia . Serum Glutamic Oxalacetic Transaminase '*Serum Glutamic Pyruvic TtahsaminaSe Com pany Sanitized. Does not contain T S C m , Ninety-Day Feeding Study in the Dog. TABLE Results of Hematological. Biochemical and Urinalysis Studies. Control Periods Dosage: 100 Dnm. 1 1* 2 3 3* 1 2 3 Hematology: Total Erythrocytes (xl0/cmm.) Hemoglobin, mg./100 ml. Hematocrit, % Sedimentation Rate, mm,/hr. Total Leucocytes, (xlO^/cmm. ) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, 7 Monocytes, % . Basophils, % Appearance of Erythrocytes 5.13 11.5 36 3 11.0 40 41 38 40 21 58 54 2 23 00 No 4.69 9.9 31 2 11.88 54 53 1 38 _ 2 6 0 H 3.95 11.5 33 10 12 16.81 43 47 42 46 11 52 50 21 32 00 No 5.31 12.1 38 1 12.81 .61 61 32 3 4 0 MH 6.60 15.4 46 0 10.10 52 52 0 41 1 6 0 No 6.21 15.6 48 0 12.48 65 63 2 27 5 3 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. ^Alkaline Phosphatase, units ^Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml.^ 118 5.63 2.58 0.85 11.5 20 155 8 26 16 121 5.56 2.55 0.85 10.5 21 153 8 23 17 125 5.48 2.09 0.62 14.5 18 188 8 18 12 128a 4.99 2.62 1.10 12.9 12 142 8 16 14 Ik 126 5.45 2.88 1.12 13.0 15 182 7 16 11 96 5.20 2. iS 1.27 12.6 11 169 8 13 13 Urinalysis: Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood _ 105 S-cl 6.5 1.043 N N N N 140 S-cl 7.3 1.022 N N N N 255 260 S-cl LS-cl 7.3 6.8 1.025 1.020 NN NN NN N. . N 240 S-C 7.0 1.023 N N N N 180 S-cl 7.0 1.023 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria 3-4 F LF MF LM 1=2 F 1-2 3-4 FF FF F F F M OCC 1-3 occ M Code : S - Straw LS - Light Straw Clear Cloudy N - Negative L - Loaded - Repeat 128 No - Normal F - Few b - Repeat 121 MH Marked Hypochromia M - Many H - Hypochromia occ - Occasional 2^Serum Glutamic Oxalacetic Transaminase Serum Glutamic Pyruvic Transaminase (Company Sanitized. Does no! contain T SCA C B I Page T-18 Ninety-Day Feeding Study in the Dog. TABLE 15. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-085, Female Control Periods .Compound Administration Months Dosage: 100 DDm. 123 1 2 3 Hematology: Total Erythrocytes OjclO^/cmm. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophil's, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 6.17 14.1 44 1 16.47 49 47 2 44 2 5 0 No 5.19 12.1 38 1 17.52 48 47 1 44 .4 4 0 H 4.44 12.1 39 1 13.96 51 51 0 47 2 0 0 No 5.58 14.9 47 0 14.45 53 53 0 39 3 5 0 H 6.94 17.7 54 0 9.66 54 53 1 40 2 4 0 No 6.65 18.0 51 0 10.74 . 4.6 46 0 44 4 6 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. . Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units |Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml.2 142a 5.58 2.16 0.63 9.8 15 159 8 20 25 121 6.08 2.20 0.57 13.4. 15 132 8 22 19 119 5.59 2.39 0.75 11.8 13 14.8 8 19 19 122 5.39 2.60 0.92 11.0 8 128 8 15 14 106 5.69 2.82 0.98 11.7 11 141 8 16 17 106 5.82 3.14 1.17 12.1 8 161 9 11 9 Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood Microscopic : Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria 140 S-cl 7.Q 1.023 N N N N 135 LS-cl 7.0 1.019 N N N .N 325 LS-cl 6.9 1.027 N N N N. 335 LS-cl 6.8 1.011 N N N N 165 S-cl 7.0 1.015 N N N N 200 S-cl 6.8 1.018 N N N N. 6-8 4-5 F FF F 2-3 F occ F FM M FL L MMLM Code : S LS C cl Straw Light Straw Clear Cloudy N - Negative No - Normal H - Hypochromia L - Loaded a - Repeat 148 F - Few M - Many ocj - Occasional Serum Glutamic Oxalacetic Transaminase 'Serum Glutamic Pyruvic Transaminase Uoe foierfariTS'CB Page T- 19 Ninety-Day Feeding Study in the Dog. TABLE 16. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-091, Female . Control Periods Compound Administration Months Dosage: 100 ppm. 1. 2 3 1 2 2* 3 Hematology: Total Erythrocytes (xlQ6/pmm, ) Hemoglobin, gm./10Q mi. Hematocrit, % Sedimentation Rate, rgm./tn?. Total Leucocytes, (xlD^/cnsp.) Differential Count: Neutrophils, % - Seg., % Nom-Seg., % Lymphocytes, % Eosinophils, % . Monopytes,l'% Basqphils, % Appearance of Erythrocytes 5.78 12.6 40 1 10.20 49 49 0 42 3 6 0 No 4.86 11.6 36 1 12.39 45 43 2 45 5 5 0 No 4.26 11.6 38 0 11.83 46 46 0 48 3 3 0 H 5.81 14.2 43 0 11.39 56 56 0 36 ;6 2 A0 H 6.13 15.2 46 0 10.18 30 40 30 39 O1 63 52 30 48 00 No 5.60 15.3 48 0 10.96 41 41 0 53 3 3 0 No Plasma Biochemistry; Glucose, mgt/lQO ml, Protein, gm,/lQQ ml Albumin, gm./lOO ml, Albumin-to-Globulin Ratio Urea Nitrogen, mg./1Q0 mlAlkaline Phosphatase, pnjts Cholesterolf mg./lQO ml Prothrombin Time, see, SGOT units/ml,^ SGPT units/ml.2 H2 5.58 1.90 0.52 12.7 28 160 8 23 14 106 5.38 1.95 0.57 17.3 25 138 7 22 18 115 4.80' 1.98 0170 12.4 24 149 7 16 18 119 5.01 2.35 0.88 11.4 12 143 8 16 12 108 5.08 2.56 1.01 12.3 19 155 8 19 8 109 5.20 2.73 1.10 13.0 16 149 10 15 6 Urinalysis : Volume, ml. Color pH Spcifi Gravity Albumin Bilirubin Glucose Occult Blood * iso 8-cl 6.1 1.058 N N N N 205 LS-cl 6.5 1.021 N N N N 140 S-cl 6.9 1.043 N N N N 120 S-cl 6.1 1.032 N N N N' 175 S-cl 6.8 1.023 N N N N 355 S-cl 7.0 l."022 N N N N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Triple/Pho sphates Ammonium Urates Bacteria 3-4 3-4 F, F F F F occ OCC MFLM M MFM M MLLFLF Code: S - Straw LS - Light Straw el - Cloudy N - Negative L - Loaded No - Normal F - Few H - Hypochromia M - Many occ:- Occasional ^Serum Glutamic Oralacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Company Sanitized. Does not contain TSCA CS** Page T^:20 Ninety-Day Feeding Study in the Dog. TABLE 17. Results of Hematological. Biochemical and-Urinalvsis Studies. Dog No. 65-078, Male Control Periods_____ Compound Administration Months Dosaae: 500 pom. 1 2 2* 3 .1 2 2* 3 Hematoloev: Total Erythrocytes (xlOb/cmmi.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm. ) Differential Count: Neutrophils, % Seg,,, % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes Basophils ,7o Appearance of Erythrocytes 4.66 12.0 38 2 10.95 55 55 0 40 3 2 0 No 3.63 8.0 25 16 20 22.50a 26 27 26 27 00 70 68 43 02 00 H 3.41 9.3 31 3 11.66 69 " 69 0 30 1 0 0 H 4.65 11.7 36 1 7.59 52 ' 51 1 39 5 4 0 No 5.69 14.5 43 0 9.98 41 41 0 51 4 4 0 No 5.49 15.3 46 .0 II.61 54 54 0 41 4 1 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm,,/100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.l SGPT units/ml.2 - 138b 5.82 2.68 0.85 11.5 22 129 8 20 18 146 6.13 2.39 0.64 10.4 21 169 8 26 13 134 118 4.92 4.74 2.00 2.42 0,69 1.04 919 11.5 25 13 132 154 88 22 ` 19 10 l/\ 117 5.25 2.71 1.06 11.5 17 16 180 7 20 10 * 113 5.16 2.78 1.17 11.1 15 203 9 15 15 ' Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 80 S-cl 6.7 1.045 N N N N 175 LS-cl 6.8 1.026 N N N N. 150 S-cl 7.3 1.051 N N N N .140 S-cl 6.5 1.033 N N' N N 140 S-cl , 7.3 1.025 N trc N N 275 S-cl 6.7 1.025 N l+d N N . Microscopic: LeucocytesV . Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria OCC R FF FF F F' 3-4 F MM FFFF MM MM M MMM Code: S - Straw LS - Light Straw cl - Cloudy N - Negative L - Loaded a - Repeat 22.65 No Normal F - Few b - Repeat 140 H - Hypochromia M - Many c - Repeat 1+ tr - Trace R - Rare d - Repeat 2+ 1+ - Trace-to- occ - Occasional * - Repeat Determinations slight `Serum Glutamic Oxalacetic Transaminase 2+ - Slight-to- Serum Glutamic Pyruvic Transaminase moderate V ' JMpany Sanitized. Does not contain TSOA cu Page T-2.1 Ninety-Day Feeding Study in the Dog. TABLE 18. Results of Hematological. Biochemical and Urinalysis Studies.__________________ Dog No. 65-079, Male _____Control Periods_____ Compound Administration Months Dosage: 500 ppm. _______________ 1 1*_____ 2________ 3________ 1_________2 2* 3_______ ! Hematology: Total Erythrocytes (xl0/cmm.) 4.72 4.21 Hemoglobin, gm./100 ml. 11.3 9.9 Hematocrit, % 35 33 Sedimentation Rate, inm./hr. 3 1 Total Leucocytes, (xlO^/cmm.) 10.08 10.70 Differential Count: Neutrophils, % 42 43 51 Seg.,% 40 41 51 Non-Seg., 7 22 0 Lymphocytes, % 53 55 42 Eoinop"hils, % 20 0 Moneytes, 7 32 7 Basophils, % 00 0 Appearaiice of Erythrocytes No MH 4.00 10.1 34 1 9.62 56 55 1 4L 1 2 0 H 5.15 12.1 38 0 9.85 48 48 0 .46. 2 4 0 SH 5.70 14.6 44 0 10.60 41 32 40 32 10 49 59 11 98 00 H 5.49 15.1 46 0 10.34 50 48 2 47 0 3 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SCOT units/ml.. SGPT units/ml.2 142a 6.03 2.60 0.76 16.3 21 161 7 34 26 140 6.00 2.61 0.77 14.9 24 149 8 20 25 132 5.00 2.29 0.85 9.9 23 147 8 2219 124 4.98 2.60 1.09 13.3 12 135 8 18 19 1Z0 5.38 2.80 1.08 14.8 16 16 166 7 16 12 113 5.31 2.9.5 1.25 12.0 12 169 8 13 15 Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 50 S-cl 6.9 1.050 N N N .N 30 S-C 6.5 1.050 N N N N 200 S-cl 6.9 1.027 N N N N 75 S-cl 6.9 1.026 N N N N- 105 S-cl 7.5 1.033 N l+b N N- 85 DS-cl 7-.3 1.030 N 4+c N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria Flagelltes 20-30 5-7 1-2 1-3 F 3-4 F' occ 1-2 F occ LMFM LM F FF FMMM LL .R Code : S - Straw DS - Dark Straw a C - Clear cl - Cloudy N - Negative L - Loaded a - Repeat 144 No - Normal F '- Few b - Repeat 1+ SH - Slight Hypochromia M - Many c - Repeat 4+ H - Hypochromia R - Rare * - Repeat Determinations 1+ - Trace-to- occ - Occasional slight bSerinn Glutamic Oxalacetic Transaminase 4+ - Marked ^Serum Glutamic Pyruvic Transaminase Company SantizeS. Does not eonfan TSCA CBf Page T-22 Ninety-Day Feeding Study in the Dog. TABLE Results of Hematological"; Biochemical and Urinalysis Studies.. ______ Dog No. 65-087, Male _____Control Periods Compound Administration Months Dosage; 500 ppm, ______ 1 1* 2 3 3*_____ 1_________2 2* 3________ Hematology; Total Erythrocytes (xlOb/cmm. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.29 12.5 40 10 11 12.38 56 55 1 42 0 2 0 No 4.55 11.0 33 5 9.44 46 45 1 46 4 4 0 H 4.39 11.2 35 0 9.92 . 5.64 13.0 40 0 9.73 39 35 39 34 01 59 62 1. 2 11 00 H 35 35 0 60 2 3 0 No 6.38 15.1 45 11 8 10.72 57 55 2 37 0 6 0 H 6. 16. 50 0 11. 42 41 1 51 0 7 0 No Plasma Biochemistry : Glucose, mg./100 ml. Protein, gm./10Q ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml Prothrombin Time, sec. SGQT units/ml.1 SGPT units/ml.2 140a 6.37 2.30 0.57 11.5 15 . 159 8 13 10 124 6.13 2.32 0.61 11.8 13 171 7 15 18 116 116 5.14 5.30 2.55 2.90 0.98 1.20 9.6 12.7 14 . 9 125 125 88 - 16 14 11 14 103 6.05 2.72 0.82 12.3 19 17 250b 7 15 10 113 6. 3. 38 1. 8. 9 214 8 9 8 Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 125 S-cl 6.3 1.044 N N 'N N' 150 S~C 6.1 1.031 N N N N 305 S-cl 6.2 1.038 N N N N- 150 S-cl 6.2 1.049 N N N N 110 DS-cl 6.0 1.058 N 2+c N N 360 LS-c 6.1 l.i N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria Code : s Straw LS Light Straw PS Dark Straw ; cl Cloudy N No 2+H 70-80 F F M 3-4 M 1-2 ` F M 10-12 F 1-3 M 3-5 1-2 F F 8-10 8-10 M 0-3 M M Negative L = Loaded a - Repeat 150 Normal F - Few b - Repeat 215 Hypochromia M - Many c - Repeat 24- Slight-to- occ - Occasional Repeat Determinations moderate 1-Serum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase Jsffipany Sanitized. Does not contain T3CA c* Page T-2 3 Ninety-Day Feeding Study in the Dog. TABLE 20. Results of Hematological. Biochemical and Urinalysis Studies. -- ------ ---------- Dog No. 65-092 ____ Control Periods Compound Administration Months, Dosage; 500 ppm._______ ________ 1 2 --3_ 1 -2--------- -- ----- Hematology; Total Erythrocytes (xlOb/cmm.) Hemoglobin, gm./100 ml Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlC^/cmm .) Differential Count; Neutrophils, %, Seg., 7o Non=8eg. Lymphocytes, 7o Eosinophils, Monocytes, % Basophils, % Appearance of Erythrocytes 5.40 12.2 39 0 14.71 67 65 2 27 1 5 0 No 140.. 876 34 1 11.74 73 72 1 22 1 4 0 H 140.. 09 6 35 1 11.04 65 65 0 33 2 0 0 H 5.44 13.2 42 0 10.69 66 66 0 31 1 2 0 SH 6.38 .14.6 452 12.12 80 80 0 16 0 4 0 No 5.78 15.1 46 0 21.88 77 73 4 20 0 3 0 No Plasma Biochemistry; Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./10Q ml. Prothrombin Time, sec. SGOT units/ml.l SGPT units/ml.2 116 5.82 1.91 0.49 18.0 15 140 8 22 28 120 5.48 1.95 0.55 16.8 18 122 8 20 29 118 4.95 2.13 0.76 19.4 18 120 8 25 14 109 4.99 2.52 1.02 19.0 12 121 9 15 18 108 5.86 2.64 0.82 14.5 17a 191 6 11 17 107 5.45 2.83 1.08 11.3 13 160 8 13 11 Urinalysis ; Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 130 145 S-cl LS-cl 7.1 6.8 1.039 1.020 NN NN NN N -N 190 S-cl 7.4 1.034 N N N N 245 LS-cl 6.5 1.013 N N N N 105 S-C 7.5 1.026 N N N N 310 LS-cl 7.0 1.01 .N N N N* Microscopic ; Leucocytes Amorphous- Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code : S LS C cl Straw Light Straw Clear Cloudy ' 3-10 F M 'M F 8-10 F F M 4-5 F rri F M 12-15 F 3-4 3-4 OCC M occ F M FF N = Negative L - Loaded a - Repeat 18 No - Normal F - Few SH Slight Hypochromia M Many H Hypochromia occ Occasional 'Serum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase g siflp an y Sanitized. D oes Wot contain TSCA <'rr| Page T-2 4\ Ninety-Day Feeding Study in the Dog. TABLE 21 . Results of Hematological. Biochemical and Urinalysis Studies.-- -- ----- ------- --- Dog No 65=094 Femal ____ Control Periods Compound Administration Months, ' 500 p p m . ______________1 2 ___ 3-------- _1---------2_2i---- J ------- Hematology; , Total Erythrocytes (xlO /cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., 7 Non-Seg., 7, Lymphocytes, % Eosinophils, % Monocytes, % Basophils, 7o . Appearance of Erythrocytes 4.96 11.6 37 1 18.16 48 47 1 48 1 3 0 No 4.99 11.6 36 4 17.17 49 48 1 40 8 3 0 SH 4.14 10.6 34 4 16.30 55 55 0 37 2 6 0 H 4.84 12.4 38 3 13.67 58 58 0 38 2 2 0 SH 6.01 14.9 46 0 12.60 41 29 41 29 00 56 68 10 22 00 H 5.10 15.1 46 0 13.88 53 53 0 45 0 2 0 No Plasma Biochemistry; Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time-, sec. SGOT units/ml.^ SGPT units/ml.^ Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 108 5.43 1.91 0.54 10.1 23 128 7 17 13 114 5.80 2.05 0.55 11.8 21 129 8 19 11 122 5.40 2.12 0.65 10.3 25 126 ' 8 19 13 114 5.20 2.33 0.81 10.5 15 141 8 20 14 118 5.78 2.68 0.87 10.2 17 18 181 6 16 6 113 5.36 2.70 1.01 10.0 15 192 8 17 14 395 LS-cl 7.2 1.028 N N N N 500 LS-cl 6.0 1.015 N N N N 490 S-cl 7.0 1.020 N N N N 200 110 S-cl S-cl 6/0 6.8 1.035 1.031 NN NN N J- N N. N 345 S-cl 6.8 1.026 N N N N Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Flagellates 1-2 1-2 3-5 F, occ F 1-3 FF M L FM LMM L LL M Code: S - Straw N - Negative L -Loaded * - Repeat Determinations LS - Light Straw No - Normal F -Few cl = Cloudy SH - Slight hypochromia M - Many H - Hypochromia occ - Occasional ^Serurn Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase Sanitized. Does not contain TSCA Page T-2 5 Ninety-Day Feeding Study in the Dog. TABLE 22. Results of Hematological. Biochemical and Urinalysis Studies. ------------- - Dog No. 65-095, Female Control Periods_____ Compound Administration Months. Dosage; 500 ppm.____ _________ 1 1 * 2_________~L :-- -- i-- :-- :----- ----:----- ------- Hematology; Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential. Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, Jo - Eosinophils, % Monocytes, % Basophils, % Appearance qf Erythrocytes 5.19 11.6 35 1 10.71 4.34 11.9 35 1 12.48 4.22 10.4 34 2 12.51 5.19 12.4 38 0 10.23 6.18 14.9 45 0 10.78 28 30 63 25 30 62 30 67 65 35 1 2. Q 43 2 00 0 No SH 37 37 0 60 , '2 0 H 50 50 0 47 w 0 H 50 50 0 49 -: 0 0 H 5.46 15.0 45 0 9.91 51 49 2 44 'r2; 3 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to=Globulin Ratio Urea Nitrogen,.-mg./LOO'.mL* Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml. 108 5.51 1.90 0.53 ,2-0 16 142 9 19 17 122 5.36 2.11 0.65 13.3 17 162 8 20 22 121 5.01 1.99 0.66 9.0. 14 154 8 15 11 110 5.15 2.52 0.$ffi 11.9 ' 10 136 8 14 16 107 5.61 2.79 0.99 11.8 14 167 7 12 14 ' 103 5.60 3.09 1.23 12.6 11 204 9 10 15 Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 180 S-cl 7.1 1.044 N N N N 130 S-cl 7.3 1.016 N N N N- 180 S-cl 6.1 1.036 N N N N 160 S-cl 6.7 1.025 .N N N N 130 SeC `" 8.0a 1.022 N N N N 255 S-cl 7.2 1.026 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria Waxy Casts Code : S - Straw cl - Cloudy F 1-2 1-2 F 2-3 occ occ occ FFL FM F LF FF LM F F M M 4-6/LPF N - Negative L - Loaded a - Repeat 7.0 No - Normal . ' F ~ Few * " Repeat Determinations SH - Slight Hypochromia M = Many LPF - Low Powered Field H - Hypochromia occ - Occasional 'Serum Glutamic.Oxalacetic Transaminase . 2Serum Glutamic Pyruvic Transaminase_____ Page T-2 6 Ninety-Day Feeding Study in the Dog. TAB Results of Heamtological. Biochemical and Urinalysis Studies. Dog No. 65-088, Male Compound Administration Months Dosage; 2500"ppm. 1231 2 3 Hematology; Total Erythrocytes (xlO^/cm i.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm ) Differential Count: Neutrophils, 7o Seg., 7= Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.32 12.1 38 1 16.72 57 56 1 42 1 0 0 No 4.70 11.0 35 1 17.69 65 63 2 28 1 6 0 MH 4.25 10.7 35." 0 12.78 55 55 0 39 1 5 0 H 5.68 12.8 39 0 12.38 52 52 0 44 1 3 0 MH 6.16 15.8 49 0 13.25 51 51 0 40 1 8 0 No 6.35 15.9 49 0 12.29 51 50 1 41 5 3 0 No Plasma Biochemistry; Glucose, mg./100 ml Protein, gm./100 ml. Albumin, gm./100 ml. i Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml.2 1 2 8 a 119 5.99 5.73 2.53 2.55 0.73 0.80 10.1 12.5 14 16 109 119 99 17 18 29c 31 108 4.85 2.32 0.92- 13.5 14 100 8 15 18 111 4.98 2.60 1.09 11.4 12 109 8 14 19 104 5.78 3.03 1.10 12.8 17b 185 7 9 16 103 5.58 3.22 1.36 12.0 16 187 9' 12 19 .. Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 140 S-cl 6.8 1.025 N N N -N 130 S-C 7.5 1.016 N N N N 325 LS-cl 6.5 1.016 N N N N 280 LS-cl 6.5 1.011 N N N N 255 LS-cl 6.4 1.016 N N N N 215 LS-cl 6.7 1.021 N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code : Straw Light Straw Clear Cloudy 55-65 2-3 1-2 F F F occ occ occ FM M F OCC M' M MFFMLL N - Negative No Normal Marked': Hypochromia L Loaded F - Few M - Many a - Repeat 139 b - Repeat 18 c - Repeat 29 H - Hypochromia occ - Occasional l-Serum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase .Company Sanitized. Does not contain T SC A CB f Page T-2 7 Ninety-Day Feeding Study in the Dog. TABLE 24. Results of Hematological. Biochemical and Urinalysis- Studies Dog No. 65-090, Male Dosage; 2500 ppm. Control Periods 12 3 1 2 3 Hematology; Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count; Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.47 13.0 40 1 15.76 59 59 0 34 3 3 1 No 4.88 11.5 36 1 15.72 73 72 1 25 0 2 0 MH 4.76 11.6 36 0 13.47 61 60 1 34 0 5 0 SH 5.25 12.5 39 0 11.36 55 54 1 42 2 1 0 H 6.03 14.3 43 -1 14.41 52 52 0 42 5 1 0 No 6.06 14.8 45 0 12.60 53 52 1 40 1 6 0 No Plasma Biochemistry; Glucose, mg,/100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. ]Alkaline Phosphatase, units -^Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.l SGPT units/ml.2 138a 5.63 1.93 0.52 15.0 21 163 '7 19 16 133 5.38 1.98 0.58 15.8 23 146 7 19 20 132 4.80 2.05 0.75 12.9 24 140 7 18 14 124b 4.90 2.20 0.81 13.5 18 195f 7 17 16 121e 5.86 2.55 0.78 13.4 28" 208 6 13 5 120 5.60 2.58 0.86 8.7 33e 284 7 13 20 Urinalysis ; Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose . Occult Blood - ' 155 S-cl 6.8 1.036 N N N N 135 S-C 7.2 1.034 N N N N 205 S-cl 7.1 1.045 N N N N' 120 S-cl 6.8 1.033 N N N N 115 S-cl 6.2 1.029 N N N .N 360 S-cl 7.0 1.028 N N N N Microscopic; Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria F 1-2 2-4 1-2 3-5 F. F F OCC OCC 3-4 1-3 OCC MMM M MF F MM MFM M MM Code : l) S - Straw C - Clear cl - Cloudy* N re L - Loaded a - Repeat 146 e - Repeat 32 No - Normal F - Few b - Repeat 126 f - Repeat 200 MH - Marked Hypochromia M - Many c Repeat 118 g - Repeat 221 SH - Slight Hypochromia occ - O_c_casional d Repeat 23 H - Hypochromia ISerum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase ' if Sanitized. 'Does hoi contain TSOA.'"*1 Page T-2 8 Ninety-Day Feeding Study in the Dog. TABLE 25. Results of Hematological. Biochemical and Urinalysis Studies. Dog No. 65-096, Female Control Periods Compound Administration Months Dosase: 2500 ddhi. 123 1 2 3 Hematology; Total Erythrocytes (xl0/cmm. ) Hemoglobin, gm./100 ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count; Neutrophils, % Seg., % Non-Seg., 7 Lymphocytes, % Eosinophils, % Monocytes, % Basophils, L Appearance of Erythrocytes 5.58 12.2 39 1 11.15 55 54 1 43 0 2 0 No 4.55 11.3 34 1 11.96 68 67 1 27 2 3 0 H 3.98 10.5 34 0 10.40 63 63 0 36 1 0 0 H 5.26 12.3 39 0 12.51 43 43 0 55 0 2 0 H 6.03 12.8 40 0 11.82 49 49 0 43 0 8 0 H 5.94 13.1 41 0 12.66 51 48 3 46 2 1 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./100 ml. Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.b SGPT units/ml.2 109 5.78 2.12 0.58 13.0" 22 167 7 19 14 130a 5.68 2.10 0.59 13.5 22 158 7 20 11 121 4.95 2.32 0.88 11.3 22 131 8 20 16 126b 5.39 2.69 1.00 12.4 21154d 7 19 14 118 6.31 2.95 0.88 12.0 19c 269e 6 15 11 118 5.90 3.13 1.13 10.7 18 307f 8 20 15 Urinalysis s. Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 110 205 S-cl LS-C 6.5 7.1 1.057 1.025 NN NN NN N -N 150 S-cl 7.1 1.051 N N N N 125 S-C 6.8 1.048 N N N N 200 S-cl 6.8 1.020 N N N N 135 S-cl 6.8 1.045 N N N N ~ Microscopic: Leucocytes Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria Waxy Casts F F F M M 2-3/LPF 6-8 1-3 M F 1-2 M M 25-30 3-4 F F 3-4 See F M M OCC 1-3 8-10 F Code: S - Straw LS - Light Straw C - Clear cl - Cloudy . N Negative No - Normal H - Hypochromia L - Loaded F - Few M - Many a - Repeat 141 b - Repeat 121 c - Repeat 19 d - Repeat 210 e - Repeat 251 f - Repeat 300 occ - Occasional serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase LPF - Low Powered Field Com pany Sanitized. Does not contain TSCA C*** Page T- 29 Ninety-Day Feeding Study in the Dog. TART.E 26. Rpsults o f Hematological., Biochemical and Urinalysis Studies.____ ______________ Dog No. 65-09/*, Male Dosage: 2500 ppm. 123 1 2 3 Hematology: Total Erythrocytes (xlO"/cmm.) XHemoglobin, gm./100 ml. Hematocrit, Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.). Differential Count: XNeutrophils, XSeg., XNon-Seg., X... Lymphocytes, XEosinophils, Monocytes, X Basophils, X Appearance of Erythrocytes 5.26 12.1 36 1 10.67 48 47 1 45 5 2 0 No 140.. 849 33 6 10.44 57 57 0 40 2 1 0 MH 140.. 212 33 6 11.24 49 49 0 50 1 0 0 H 4.94 12.1 36 0 11.41 5.70 13.7 40 0 10.99 52 53 52 53 00 45 44 1 .1 22 00 SH H 5.71 14.5 46 0 10.95 52 52 0 43 2 3 0 No Plasma Biochemistry: . Glucose, mg./100 ml. Protein, gm./lOO ml. Albumin, gm./100 ml Albumin-to-Globulin Ratio Urea Nitfogen, mg./100 ml. (Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time,, sec. SGOT units/ml.l SGPT units/ml.2 133a 5.58 2.08 0.59 10.5 15 129 9 16 17 112" 5.63 2.05 0.57 13.1 15 133 8 18 19 112" 5.38 2.04 0.61 12.4 14 147 9 17 18 121'. 5.53 2.53 0.85 15.5 10 175 8 16 11 110 5.19 2.87 1.2i 13.8 16" 233e 7 13 12 100 5. 90 3. 15 1.: 15.15 274 8 12 14 Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood . 105 S-C 7.8 1.025 .N N N N 230 LS-cl 7.3 1.018 N N N N 380 LS-cl 7.0 1.023 N N N N -325 LS-cl 6.9 1.022 N N N N. 180 S-cl 6.6 1.027 N N N N 390 S-C 6.' U N N N N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria Code : S LS C cl > Straw Light Straw Clear Cloudy N No MH SH H 6-8 OCC L F 1-2 OCC 2-5 FF F FM F F MF F F FFM MM F Negative L - Loaded a - Repeat 138 Normal ' F - Few b - Repeat 17 Marked Hypochromia M - Many c - Repeat 214 Slight Hypochromia occ - Occasional Hypochromia ^Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase SatvSSizfidrTioet not Conta* rscA'CBii Page T ^30 Ar-V Ninety-Day Feeding Study in the Dog. Results of Hematological. Biochemical and iMinalysis Studie_s Dog No. 65-098, Female Dosages 2500 ppm. Control Periods 1 1* Compound Administration Months 1 2 2* 3_______ Hematology; Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./100 ml. Hematocrit, X, Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, X Seg., X Non-Seg., X Lymphocytes, X, Eosinophils, X, Monocytes, X Basophils, X Appearance of Erythrocytes 5.20 12.6 40 0 15.10 39 38 39 38 00 52 53 33 66 00 No 4.86 12.1 37 0 13.91 43 42 40 2 5 0 H 4.49 11.3 38 0 15.31 72 72 0 25 1 2 0 No 5.27 13.7 43 0 13.41 58 58 0 41 0 1 0 No 6.36 15.1 45 0 11.45 40 59 40 58 01 49 36 21 94 0O No No 5.70 15.4 47 0 12.61 '47' 45 2 44 3 6 0 No Plasma Biochemistry: Glucose, mg./100 ml. Protein, gm./100 ml. Albumin, gm./100 ml. Albumin-to=Globulin Ratio yUrea Nitrogen, mg./100 ml. ^Alkaline Phosphatase, units Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.-*SGPT units/ml.^ 106 5.82 2.40 0.70 14.8 23 133 8 19 21 112 5.63 2.24 0.66 14.3 20 117 8 19 19 112 4.95 2.38 0.93 11.3 25 120 8 24 13 117 5.15 2.60 1.02 11.5 20 198b 8 19 20 112 5.70 2.94 1.06 11.7 24a 244c 6 12 23d 111 5.70 3.09 1.18 12.3 24 249 8 7 16 Urinalysis : Volume, ml. Color pH Specific Gravity Albumin Bilipubin Glucose Occult Blood 80 S-cl 7.0 1.060 N N N. N 155 S-cl 7.0 1.019 N N N N' 205 S-cl 7.1 1.032 N N N N 135 S-cl 7.1 1.031 N N N N 120 S-cl 8.0e 1.024 N N N N 255 S-C .7.5 1.039 N N N N Microscopic : Leucocytes Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria cCode : S - Straw - Clear cl - Cloudy F 6-8 1-2 1-2 3-4 F 1-2 ` 2-3 occ occ FM F FM M FFF MF FFLF N - Negative L - Loaded No - Normal F-s? Few H - Hypochromia M - Many occ - 'Occasional a - Repeat 22 b - Repeat 201 c - Repeat 214 d - Repeat 28 e - Repeat 6.5 l-Serum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase Tsr mCim pany Sanitized. Does not contain a Page T-31 Ninety-Day Feeding Study in the Dog. TABLE 28. Results of Hematological. Biochemical and Urinalysis Studjeg^. Dog No. 65-099, Male Dosage; 2500 ppm.__________ _ 1 2 2* 3 1 2 3 Hematology; Total Erythrocytes (xlO^/cmm.) Hemoglobin, Hematocrit, %gm./lOO ml. Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., 7 Non-Seg., Lymphocytes, Eosinophils, %% % Monocytes, Basophils, %% Appearance of Erythrocytes 5.55 12.8 40 1 15.36 60 58 2 32 5 3 0 No 5.15 12.1 36 0 13.16 72 64 68 64 40 16 22 8 11 43 00 MH 4.41 11.3 36 0 11.67 60 '60 0 33 3 4 0 No 5.82 13.7 41 0 10.62 59 57 2 36 2 3 0 _'H 6.40 14.9 45 0 13.74 68 68 0 26 0 6 0 H 6.19 15.3 45 0 11.71 57 54 3 35 5 3 0 No Plasma Biochemistry: Glucose., m g ./100 m l . Protein, gm,/l00 ml. Albumin, gm./100 ml. Albumin-to-Globulin Ratio i\ Urea Nitrogen, mg./100 ml. vj Alkaline Phosphatase, units V Cholesterol, mg./100 ml. Prothrombin Time, sec. SGOT units/ml.^ SGPT units/ml.2 119 5.67 2.23 0.65 13.0 17 182 7 23 16 134a 5.24 1.90 0.57 12.6 20 150 7 19 15 120 4.60 2.04 0.80 10.5 17 120 8 18 22 128b 5.05 2.40 0.91 9.8 15 170f 8 12 17 121e 5.82 2.50 0.75 8.2- 28d 2338 6 11 13 118 5.21 2.70 1.07 11.5 33e 270 8 11 18 Urinalysis : Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 105 S-C 6.8 1.057 N N N *N 145 LS-C 7.0 1.017 N N N N 80 DS-cl 6.1 1.060 N N N N 150 S-cl 6.9 1.028 N N N N 200 S-cl 7.3 1.025 N N N N 210 SeC 7.4 1.036 .N N N N Microscopic : Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria F F M F F OCC 1-2 OCC F F FMM MF FM M FF M LF Code: S - Straw N - Negative LS - Light Straw No - Normal F Few b - Repeat 126 f Repeat 179 ' DS - Dark Straw MH - Marked Hypochromia M Many c - Repeat 114 g Repeat 209 4R C - Clear H - Hypochromia occ Occasional d - Repeat 24 Bim cl - Cloudy ISerum Glutamic Oxalacetic Transaminase 2Serum Glutamic Pyruvic Transaminase Sanitised. Sees m iconiali cfci Page 31A Ninety-Day Feeding Study in the Dog. TABLE 28-A. Dietary Level Total Cholesterol Values, Mg. per 100 Ml. Plasma. Control Period Compound Admin. Months Sex 1^3 123 Control: 65-038 65-070 65-081 65-083 65-086 65-093 100 ppm. : 65-072 65-074 65-076 65-077 65-085 65-091 500 ppm. : 65-078 65-079 .65-087 65-092 65-094 65-095 2500 ppm. : 65-088 65-090 65-096 .65-097 65-098 65-099 F M F M M F M M M F p F M M M F F F M M F F F M 196 212 211 176 186 140 161 162 153 116 138 122 196 174 142 144 128 147 132 139 120 131 144 147 159 163 132 155 153 188 159 132 148 160 138 149 129 169 132 161 149 147 159 171 125 140 122 120 128 129 126 142 162 154 109 119 100 163 146 140 167 158 131 129 133 147 133 117 12 182 150 120 200 178 184 175 195 198 149 175 167 123 142 157 181 203 200 132 115 124 118 158 163 123 158 172 163 181 203 142 182 169 128 141 161 143 155 149 154 180 203 135 166 169 125 215 214 121 191 160 141 181 192 136 167 204 109 185 187 195 208 284 215 269 307 175 233 274 198 244 249 170 233 270 Company Sanzetf. Does noi contain TSCA CBF Page T>32 Ninety-Day Feeding Study in the Dog. TABLE 29. Necropsy Observations. Animal Number Sex Orean Comment Control: 65-070 M small intestine !.'Fetor,hookworms'present. ileocolic junction Mild mucosal congestion. cecum, colon Few 2 to 3 mm. hemorrhages. 65-083 65-086 65-038 65-081 65-093 M small intestine Ascarid. M ileocolic junction Mild mucosal congestion. cecum Several 2 to 3 mm. mucosal hemorrhages. urinary bladder Few petechial hemorrhages. heart Tricuspid, .valve,. 2 mm hematoma. F -:. cecum Few p'etechia im'the..mucosA.i. . F ileocolic junction Mild mucosal congestion. colon Several mucosal petechiae. F small intestine Few petechial hemorrhages at the gastroduodenaljunction, fecal material was present in the stomach. 100 ppm.: 65-072 M 65-074 M 65-076 65-077 65-085 M F F 65-091 F . ileocolic junction Mucosal congestion. urinary bladder Petechial hemorrhages at the neck. small intestine Few hookworms present. ileocolic junction Mild mucosal congestion. urinary bladder Area of hyperemia at neck. small intestine Areas of hyperemia at ileocolic orifice. small intestine cecum, colon 3 mm. raised firm area in the duodenum; terminal portion of the ileum had mild mucosal hemorrhage at the ileocolic junction. Mild mucosal hemorrhage. ' stomach Fecal material present in the stomach. ileocolic junction Mild mucosal congestion. _ * cecum, colon Several 2 mm. areas of hemorrhage in the mucosa. "PSBprtSniieS. U ss B&etthari TS'CA'CB? 0 Page T-3'3 Ninety-Day Feeding Study in the Dog. TABLE 29, Continued. Necropsy Observations. Animal Number Sex Organ Comment 1000 ppm. : 65-078 M duodenum Few petechial hemorrhages at pylorus. small intestine Moderate mucosal congestion throughout the anterior half. ileocolic junction Mild mucosal congestion. 65-079 M small intestine Several 1 to 2 mm. hemorrhages at the gastroduodenal junction. ileocolic junction Mild mucosal congestion. 65-087 M urinary bladder Few petechial hemorrhages at the neck. 65-092 F urinary bladder Few petechial hemorrhages at the neck. 65-094 F stomach cecum Many scattered gray raised areas less than 1 mm. in diameter in pyloric region. Few 2 mm. hemorrhages scattered in the mucosa. 65-095 F stomach Few petechial hemorrhages in the pyloric region. small intestine Petechial hemorrhages at the gastroduodenal junction, several ascarids. ileocolic junction Mild mucosal congestion. cecum Few mucosal petechiae. 5000 ppm.: 65-088 ` M small intestine 65-090 M small intestine 65-099 65-096 65-097 M small intestine cecum F . cecum F cecum small intestine urinary bladder Few mucosal petechiae scattered throughout the middle third of the intestine. Few 1 mm. hemorrhages at the gastroduodenal junction. Ascarid Few 1 to 2 mm. mucosal hemorrhages. Several 2 mm. mucosal hemorrhages. Several mucosal petechiae. Several mucosal petechiae at the terminal portion of the ileum. Several circumscribed dark areas with light centers approximately 1 mm. in diameter scattered throughout the mucosa. . !3 W Page T-3.4 Ninety-Day Feeding Study in the Dog. TABLE 29, Continued. Necropsy Observations. Animal Number_____ Sex Organ 5000 ppm.. Cont'd.: 65-098 F heart Comment 10 mm. white streak in the left ventricular wall. not contain TSCA ^ Pom pany Sanitized. D oes Page T-35 Ninety-Day Feeding Study in the Dog. TABLE 30. Actual (Grams) and Relative (%:'Body :Wei^t) :0r^anheights. Group & Terminal NAniimimbaplr Body Wt. Sex Ke. Spleen Wt. % Liver Wt: 1 Adrenals Kidneys Wt. 1 . Wt. ? Ovaries/ Testes Wt. 7. Control: 65-070 65-083 65-086 65-038 65-081 65-093 M M M F F F 13.0 8.5 9.2 8.2 9.2 6.1 29.12 0.224 310.87 30.70 0.361 242,.42 28.58 0.311 248.83 19.98 0.244 198.81 24.32 0.264 250.50 13.59 0.223 151.11 2.391 0.90 2.852 0.98 2.705 0.98 2.425 1.40 2.723 1.06 2.477 0.78 0.007 63.99 0.012 43.25 0.011 49.53 0.017 38.58 0.012 39.62 0.013 29.28 0.492 23. 0.509 14..22 0.538 18..90 0.470 0..67 0.431 0..74 0.480 0..41 0..178 0..167 0.,205 0..008 0..008 0..007 0o0 100 ppm:': 65-072 65-074 65-076 65-077 65-085 65-091 H M M F F F 8.7 10.8 11.9 9.4 7.2 9.9 25.87 0.297 238.89 32.31 0.299 285.70 25.39 0.213 325.52 29.18 0.310 241.79 25.31 0.352 177.56 23.40 0.236 210.70 2.746 0.82 2.645 1.23 2.735 1.02 2.572 1.11 2.466 1.21 2.128 1.16 0.009 55.60 0.011 58.12 0.009 50.68 0.012 43.93 0.017 33.08 0.012 52.61 0.639 19..78 0.538 13.,86 0.426 17..71 0.46/ 0..55 0.459 0..62 0.531 0,.58 0. 227 0. 128 0. 149 0. 006 0. 009 0.006 1000 ppm; 65-078 65-079 65-087 65-092 65-Q94 65-095 M M M F "F F 9.9 6.9 .13.5 6.5 11.0 7.9 23.70 0.239 281.62 18.11 0.262 210.71 41.42 0.307 443.25 18.18 0.280 209.89 28.50 0.259 320.71 18.73 0.237 228.27 2.845 1.00 3.054 0.84 3.283 1.98 3.229 0.98 2.916 1.12 2.889 1.18 0.010 61.60 0.012 44.15 0.015 71.48 0.015 29.50 0.010 59.81 0.015 38.31 0.622 14.95 0.151 0.640 10.10 . 0.146 0.529 21.78 0.161 0.454 0.66 0.010 0.544 0.71 0.006 0.491 0.90 0.011 5000 ppm. 55-088 55-090 55-099 55-096 55-097 55-098 M M M F F F 6.7 10.6 8.4 8.8 10.0 7.2 19.79 0.295 301.90 19.67 0.186 479.03 17.88 0.213 396.70 21.99 0.250 339.91 24.09 0.241 426.29 16.50 0.229 327.31 4.506 0.84 4.519 1.41 4.723 0.93 3.863 1.02 4.263 1.00 4.546 0.60 0.013 34.61 0.013 55.24 0.011 46.71 0.012 52.03 0.010 53.12 0.008 39.72 0.517 9.71 0.521 19.00 0.556 12.76 0.591 0.60 0.531 0.72 0.552 0.54 0.145 0.179 0.152 0.007 0.007 0.008 I I Page T-3'6 Thvmus Wt. t Heart Wt. % Lung Wt. X Thyroid Wt. X Brain .Wt. lo Pituitary Wt. /o 38.20 16.13 22.71 10.08 15.53 16.61 0.294 115.72 0.190 62.81 0.247 76.21 0.123 68.12 0.169 77.50 0.272 53.34 0.890 115.40 0.739 85.70 0.828 90.44 0.831 67.13 0.842 74.62 0.874 60.60 4 0.888 1.37 1.008 0.59 0.983 0.93 0.819 0.79 0.811 0.73 0.993 0.52 0.011 84.27 0.648 0.007 78.86 0.928 0.010 82.02 0.892 0.010 69.42 0.847 0.008 83.24 0.905 0.009 70.79 1.160 0.069 0.059 0.072 0.049 0.065 0.039 0.0005 0.0007 0.0008 0.0006 0.0007 0.0006 21.59 20.81 21.01 21.13 18.00 16.51 0.248 0.193 0.177 0.225 0.250 0.167 80.53 79.67 84.59 76.89 55.00 87.09 0.926 87.30 0.738 102.91 0.711 102.98 0.818 91.10 0.764 72.12 0.880 90.40 1.003 0.72 0.953 0.90 0.865 0.82 0.969 0.74 1.002 0.86 0.913 0.72 0.008 78.35 0.901 0.008 77.45 0.717 0.007 92.08 0.774 0.008 86.68 0.922 0.012 68.21 0.947 0.007 73.05 0.738 0.072 0.0008 0.071 0.0007 0.071\ 0.0006 0.066 0.0007 0.064 0.0009 0.078 0.0008 20.29 0.205 72.22 0.729 75.96 0.767 0.73 0.007 87.77 0.887 0.060 0.0006 ^ 19.77 0.287 59.67 0.865 65.18 0.945 - - 78.20 1.133 0.091 0.0013 M'S 37.81 0.280 89.63 0.664 119.10. 0.882 1.35 0.010 84.98 0.629 0.031 0.0002 W J . 13.69 0.211 47.00 0.723 64.39 0.991 0.42 0.006 67.48 1.038 0.055 0.0008 20.10 0.183 81.71 0.743 95.25 0.866 0.88 0.008 78.13- 0.710 0.086 0.0008 14.75 0.187 63.85 0.808 76.72 0.971 0.75 - 0.009 63.71 0.806 0.071 0.0009 16.55 24.43 24.51 19.39 24.90 12.53 0.247 0.2-30 0.292 0.220 0.249 0.174 44.20 64.29 58.48 62.55 75.79 51.61 0.660 0.607 0.696 0.711 0.758 0.717 60.50 73.78 70.01 63.91 69.43 60.50 0.903 0.53 0.696 1.32 0.833 0.58 0.726 0.62 0.694 0.83 0.840 0.97 0.008 70.70 1.055 0.012 79.51 0.750 0.007 80.91 0.963 0.007 78.35 0.890 0.008 73.31 0.733 0.013 68.41 0.950 0.052 0.076 0.059 0.072 0.077 0.064 0.0008 0.0007 0.0007 0.0008 0.0008 0.0009 ISSfiipMy 1?ah fe. Does no! coniato TSC CBS Page T-37 Ninety-Day Feeding Study in the Dog. TABLE 31. Histopathologic Observations. Animal No and GrouD Sex Tissue Comment Control: 65-070 65-083 65-086 65-038 65-081 65-093 M all tissues M all tissues M all tissues F skin kidney F all tissues F kidney No lesion. No lesion, .. No lesion. Folliculitis with lymphocyte and plasma cell infiltrate in corium. Moderate subacute pyelpnephfiti-s. No lesions. Moderate subacute pyelonephritis. 100 DDm. (Liver Only): 65-072 M 65-074 M 65-076 M 65-077 F 65-085 F 65-091 F No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. . 1000 nom. (Liver Only): 65-078 M 65-079 M 65-087 M 65-092 F 65-094 F 65-095 F' No lesion. No lesion. No lesion. No lesion. No lesion. - .No lesion. - j'SCCB* Wm Page T-3 8 Ninety-Day Feeding Study in the Dog. TABLE 31, Continued. Histopathologic Observations. Animal No. and Group Sex Tissue________________________ Comment 5000 ppm.: 65-088 M liver 65-090 65-099 65-096 65-097 65-098 M kidney liver M liver F all tissues F liver F heart liver Hepatocytes appeared hypertrophied as compared to controls with less coarse granularity to their cytoplasm. Moderate subacute pyelonephritis. Hepatocytes slightly hypertrophied with cytoplasm less coarsely granular than control. Hepatocytes slightly hypertrophied with less coarse granularity of cytoplasm than control. No lesion. Slight portal lymphocytic infiltrate. Small areas of calification of myocardial fibers. Hepatocytes hypertrophied as compared to controls with less coarse granularity of cytoplasm. . ^.rnpan| Sanitized, Does not contain TSCA CBi Page T- 39 Ninety-Day Feeding Study in the Dog. TABLE 3 2 . Summary of Incidence of Histopathologic Lesions. Tissue and Lesion Control -100 ppm. 100Q ppm. . 500(T ppm. . :,Male Female !Male Female .'.Male Female Male Female brain - no lesion spinal cord - no lesion peripheral nerve - no lesion eye - no lesion pituitary - no lesion thyroid - no lesion parathyroid - no lesion adren&l - no lesion trachea - no lesion lung - no lesion heart -n o lesion - myocardial.calcification aorta - no lesion spleen - no lesion lymph node - no lesion thymus - no lesion bone marrow - no lesion salivary gland - no lesion esophagus - no lesion stomach - no lesion small intestine - no lesion large intestine - no lesion pancreas - no lesion 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 1/1 2/2 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 2/2 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 2/2 1/1 3/3 3/3 3/3 3/3 3/3 3/3 3/3 2/3 1/3 3/3 3/3 3/3 3/3 2/2 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 2/2 3/3 DoesrtolcontainTSCACB1 pcmpahySanlltoe^1 Page T-40 Ninety-Day Feeding Study in the Dog. TABLE 32, Continued. Tissue and Lesion Summary of Incidence of Histopathologic Lesions. Control 100 ppm. 1000 ppm. Male Female Male Female Male Female 5000 ppm. Male Female liver - no lesion ' 3/3 hepatocyte hypertrophy portal infiltrate gall bladder - no lesion 3/3 kidney - no lesion 3/3 - subacute pyelonephritis urinary bladder - no lesion testis or ovary - no lesion 3/3 3/3 prostate or uterus - no lesion 3/3 skeletal muscle - no lesion 3/3 skin - no lesion 3/3 - folliculitis bone - no lesion 3/3 3/3 3/3 3/3 2/3 3/3 3/3 3/3 3/3 2/3 1/3 3/3 3/3 3/3 3/3 3/3 1/3 3/3 1/3 1/3 3/3 3/3 2/3 3/3 1/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 2/2 3/3 3/3 3/3 3/3 ir? if?..3;i T S C A 8I