Document qaK8b40B76jZq2zVrjoEJgNmq

AR226-2825 ^L0-e>^f-&s International Research and Development Corporation____ SPONSOR: E. I. duPont de Nemours and Company SUBJECT: 90-Day Feeding Study in the Beagle Dog. FDriarencctisor Xo. fWRae^seetaerrc, hPh(/.^. International Research and 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 Sanded. Doss not cnnta-'n TSCA CBI International Research and Development Corporation TABLE OF CONTENTS Page I. Synopsis I ............................ II. Compound 3 .................................................... ........................... III. AC.linMiceathlodSstudies 44 1. General Procedure 4 2. Laboratory Tests 5 ................... a. Hematology 5 .................... b. Biochemical Studies 5 ..................... c. Special Sampling 7 .................................. 3. Compound Administration 7 ................ B. Results 7 1. Behavior, Appearance and Mortality 7 ........................... 2. Physical Examination 8 ........... 3. Body Weight. 8 ................... 4. Food Consumption 8 ...................... 5. Compound Consumption 9 ...................................... ............. 6. Water Intake and Urine Output 9 7. Laboratory Tests 9 a. Hematology 9 .................... b. Biochemical Studies 10 ..................................... IV. Pathological Studies 12 ...................... A. Methods 12 1. Gross Examination 12 .......................... 2. Microscopic Examination 12 ................... ................ B. Results ^ 13 1. Gross Pathology 13 .......................................................... ........ 2. Histopathology 13 Company Saniiizad. Does not contain TSCA CBI International Research and Development Corporation TABLE OF CONTENTS (Continued) TABLES Table No. Page 1. 2. 3. 4. 5-28. 28A. 29. 30. 31. 32. Individual Weekly Body Weights, Kilograms . . . . . . . . . Average Daily Food Consumption, Grams . . . . . . . . . . . Average Daily Compound Consumption, Mg./Kg./Day . . . . . . Average Daily Water Intake, Urine Output, and Water Output Ratios . . . . . . . . . . . . . . . . . . . . . . . Results of Hematological, Biochemical and Urinalysis Studies .......................... Total CholesterQl::.Values, Mg. per 100 Ml. Plasma . . . . . NecrojilBy Observations ................... Actual and Relative Organ Weights . . . . . . . . . . . . . Histopathologic Observations .......................... Incidence of Histopathologic Lesions 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 Company Sanitized. Does not contain TSCA CC International Research and Development Corporation Page 1 I. SYNOPSIS In a 90-day oral toxicity study ^------ttwas 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 transaminase (SGPT) and serum glutamic oxalacetic transaminase (SGOT) B 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. ^offipany Samfaed. Does noi contain TSCA C^- International Research and Development Corporation Page 3 II. COMPOUND The test compound was received jrom E. |E. duPont de Nemours and Company, Wilmington, Delaware, on June 19, 1965. It was a bro^ amorphous solid in containers bearing the label( Haskell No. 4212." Pompany Sanitized. Does not contain TSCA 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 1, 2 and 3 months of compound administration, blood and samples were obtained for clinical laboratory studies. again after 24-hour urine a. Hematology: studies included total and differ- Routine hematologic 3 ential leucocyte counts, 2 hematocrits , hemoglobin concentrations 1 , 4 erythrocyte sedimentation rates , and total erythrocyte counts . b. Biochemical Studies: (1) Plasma: Chemical determination on plasma routinely included quantitative tests for glucose , total protein , total 7 albumin ft and urea nitrogen . " Albumin-to-globulin ratios were , calculated. Coulter Particle Size Counter, Model A., Coulter Electronics, 590 W. 20th Street, Hialeah, Florida. 2 Miller, S., Microcapillary Method, Textbook of Clinical Pathology, Philadelphia, Pa., p. 43. 1960, Williams and Wilkins Company, 3 Miller, S., Cyanmethemoglobin Method, Textbook of Philadelphia, Clinical Pathology, Pa., p. 35. 1960, Williams and Wilkins Company, ' 4 ' Miller, S., Westergren Method, Textbook of Clinical Pathology, 48. 1960, Williams and Wilkins Company, Philadelphia, Pa., p. 5 Hoffman, W. S., Modified Hoffman Method, J. Biol. Chem., 120; 51, 1937. (Auto Analyzer). Clin. Path. T_: 40, Stevens, D. L., Modified Biuret Method, Amer. J. 1946. (Auto Analyzer). Stevens, D. L., Stevens Adaptation for Auto Analyzer, J. Clin. Q SInkvegegsst,., L3. '^:T.,21D1,iac19e5t4y.l Monoxime Method, Amer. J. Clin. Path. 28: 311, 1957. (Auto Analyzer). 'Cwwany Saniiize'd. Does not contain TSCA ^ International Research and Development Corporation Page 4 III. CLINICAL STUDIES A. METHODS: 1. General Procedure: Twelve male and 12 apparent good health, were female young, purebred beagle dogs in used for a 90-day feeding study offU 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 jfl^^^^Band 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. Company Sanitized. Does not contain TSCA CBI 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. ]CcfffipT3Stia]nf'tfee^." Qossffoi contain TSCA CB; International Research and Development Corporation Page 6 9 (2) Liver Function; Plasma alkaline phosphatase activity , prothrombin time determinations, serum glutamic oxalacetic (SGOT) and 11 12 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 of compound a - d - m i n i s.. .t.r a t i o n-1 3 (3) Urinalysis: Observations for abnormality in gross 14 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 the 24-hour urine specimen. Urinary pH7 - specific gravity and volume were measured, and the urinary sediments were examined microscopi cally. 9 Mafsh, W., Modified King-Armstrong Method, Clin. Chem. 5: 119, 1959. (Auto Analyzer). Quick, A. J., Hemorrhagic Diseases, 1957, Lea & Febiger, Phila., Pa. Reitman, S., and Frankel, S., Colorimetric Method for the Determina tion of Serum Transaminase Activity, Am. J. of Clin. Path., 28: 56, 1957. 12 Hycel Cholesterol Procedures Dec. 1962. Hycel, Inc., Houston, Texas, Revised 13 "Seprophore 14 "Ictotest" 111", Gelman Technical Manual No. (Ames Reagent Tablets). 51199-A, 1963. "Hemastix" (Ames Reagent Strips). "Hematest" (Ames Reagent Tablets). "Occultest" (Ames Reagent Tablets). "Albustix" (Ames Reagent Strips). "Bumintest" 20 (Ames Reagent Tablets). Heller's Ring Test, Practical Physiologic Chemistry, and Summerson, 13th Ed., p. 830. "Combistix" (Ames Reagent Strips). 22 "Clinistix" (Ames Reagent Strips). 23 "Clinitest" (Ames Reagent Tablets). 24 Beckman Expanded Scale pH Meter, Model No. 76. Hawk, Oser and iCompany Sanitized. Does not contain TSCA CBI 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 administration. These were frozen and delivered to the sponsor for analysis oi^HBHU content. Similarly, representative tissue samples (see section on Pathology) were provided following necropsy examination. 3, Comgound Administration: The test compound HUHHj was incorporated laboratory diet (powdered Purina Dog Chow) and fed to into the basic the respective groups of fed diets 2500 ppm. dogs throughout the study. The 3 treated groups of dogs were containing----HH^ at initial concentrations of 100, 500, or 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 ^^^^^^H B. RESULTS: 1. 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) in .. , .^(-RC^ ' w ^ ^ "-^r^W^^1"" 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; o-ne 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 normals- reflexes were unimpaired and fundascopic examination of the eyegrounds revealed no changes. 3. Body Weight (Table I): 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 2j: 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. Company Seized. Does not corn..... 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-A): a. Hematology; No compound-related hematologic changes occurred among dogs used for this study. Incidental changes, not related to compound admihi'stration, included low borderline hemoglobin and hematocrit values and mild to marked hypochro'masia 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 companySanFffzed. Does not contain TSCA CfH, 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; plasma cholesterol was found in 5-of-6 administration at the 2500 - 5000 ppm. logically meaningful changes in plasma lower dietary levels (Table 28-A). A dose-related increase in dogs after 3 months of compound level. No consistent bio cholesterol were found at the 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) Utinalysis: Urinalysis examination failed to reveal changes which^were considered, to he-related :to"treatmenC with^ ^smpmy^wWS'6 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.) 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 s tomach 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. Company Sanitized. Does nol contain TSCA CBl International Research and Development Corporation Page 13 B. RESULTS; 1. Gross Pathology (Table 29) and Organ Weights (Table 30): No compound-related gross pathologic lesions were observed in 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 liver 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 parenchymal 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. '^wywf Saniti^ol., -Soes not eonfasn TSCA CBt  ! N1 hety-13ay Feed ing S1tudy i;n the Do'g. TABLE 1. In.dividinal Week.ly Bo<iy Wei ghts, Ki.lograms. Dog Cont-rol Peri,od Number.,,, Sex 1 2 3 I 2 3: 4 C;ompoun<i Admin;Lstratic?n Weeksi 5 : 6 : 7.. 8 9 Control: 65-038 F 7.7 7.9 B.I 8.2 8.5 8.4 65-070 M 6.5 7.2 7.9 8.6 9.5 9.9 65-081 F 4.5 4.8 5.2 6.2 6.7 7.2 65-083 M 4.4 4.5 5.2 5.7 6.3 6.7 65-086 M 4.2 4.5 5.5 6.1 6.7 7.1 65-093 F 3.7 3.9 4.1 4.5 4.8 4.9 8.0 8.3 8.5 8.5 8.6 8.7 9.8 10.5 11.1 11.8 12.2 12.4 6.9 7.7 8.1 8.4 8.4 9.0 6.3 6.9 7.5 8.1 7.8 8.3 7.0 7.6 8.1 8.3 8.8 9.1 4.7 5.2 5.3 5.5 5.7 5.7 100 ppm. . 65-072 M 3.9 4.5 5.1 5.3 6.1 6.2 65-074 M 4.6 5.5 6.1 7.0 7.5 8.0 ; - 65-076 M 5.4 5.9 6.7 7.4 7.9 8.2 1'0 6655--007875 FF 44..55 44..98 55..25 65..17 66..52 76..24 H 65-091 F 575 6.0 6.6 7.0 7.8 8.1 0) 500 ppm. ;* 55 N" 65-078 M 4.5 5.0 5.5 6.0 6.7 7.2 ?S- 65-079 M 3.5 3.9 4.2 4.7 5.1 5.6 0 0 65-087 M 6.4 7.3 8.1 9.2 9,8 10.5 0 m 65-092 F 3.1 3.4 3.7 4.3 4.5 4.8 0 65-094 F 5.5 6.1 6.7 7.3 7.8 8.2 ? 65-095 F 4.1 4.3 4.7 5.3 5.7 6.1 3 ST 5" 2500 opVI.'.** 6.3 6.9 7.1 7.8 8.0 8.2 7.9 8.9 9.3 9.8 10.2 10.5 8.3 9.1 9.8 10.4 10.9 11.3 6.9 7.6 8.1 8.6 8.9 8.5 6.2 6.4 6.8 6.6 6.8 7.4 7.9 8.6 8.9 9.5 9.7 9.8 7.1 . 7.9 8.2 8.8 9.2 9. 5.4 6.0 6.1 6.3 6.4 6. 10.4 11.0 11.4 11.8 12.6 11. 4.7 5.1 5.4 5.9 6.2 5. 8.3 9.1 9.4 10.0 10.3 10. 5.8 6.5 6.8 7.3 7.5 7. 5 65-088 M 3.4 3.5 3.9 4.3 4.7 5.0 4.8 5.4 5.7 6.0 6.2 6 0 > 65-090 M 4.7 5.3 6.1 6.7 7.3 7.9 7.9 8.5 9.1 9.6 9.7 10 0 65-096 F 4.6 5.0 5.5 6.0 6.6 7.0 7.0 7.4 7.9 8.3 8.3 8 3 65-097 F 5,1 5.5 5.8 6.4 6.9 7.5 7.4 8.2 8.8 9.4 9.5 9 65-098 F 3.5 3.9 4.0 4.9 5.3 5;6 5.5 -6.0 6.5 6.8 6.8 7 65-099 M 4.3 4.8 5.4 5.5 6.1 6.5 6.5 6.9 7.4 7.5 . 7.9 8 * Increased to 1000 ppm. in the 6th week of therapy ** Increased to 5000 ppm. in the 6th week of therapy N:LnetyDay Fieeding Study in thie Dog. TABLE 2. AYi/eragei Dail:y Food Consumption , Gram;s. . Dog Cont-i-ol Pe-riod Number Sex 1 2 3 1 2 3 4 --- Cornpoi.md Adiminist ration Weeks 5 6 7 8 9 10 El .'4.^w 'We. w S ?.?' C<s p" CJ; 0 nt '-s *"^' 0' r-fa Ri 0 3 ' 5'' -i w ," ?a ? 3 Control; 65-038 F 65-070 M 65-081 F 65-083 M 65-086 M 65^093 F 210 229 256 270 234 226 264 193 157 196 196 176 212 2 446 378 446 407 410 366 400 458 332 182 424 385 394 3 278 236 315 274 304 340 280 342 289 304 326 208 269 2 218 204 264 271 290 2S8 263 294 254 283 273 185 281 2 307 251 354 304 329 323 287 299 266 247 260 254 286 3 190 139 191 216 152 215 157 203 177 209 222- 163 238 2 100 ppm, 65-072 M 65-074 M 65-176 M 65-077 F 65-085 F 65-091 F 262 279 282 250 317 334 295 325 225 259 283 235 370 2 283 240 357 312 328 393 347 401 333 334 342 295 355 299 353 311 339 325 343 370 404 346 381 377 347 398 196 234 248 310 300 338 288 298 286 297 321 254 319 201 206 275 262 245 269 223 279 203 183 219 187 239 344 303 347 305 368 318 314 360 327 350 315 292 335 500 ppm. :* 65-078 M 65-079 M 65-087 M 65-092 F 65-094 F 65-095 F 2500 ppm. -.A*- 65-088 M 65-090 M 65-096 F 65-097 F 65-098 F 65-099 M .. 250 299 420 220 336 181 231 215 361 .,181 339 210 142 139 242 268 226 223 224 224 230 206 232 215 270 219 417 231 401 2-25 . 213 334 276 233 251 280 285 222 432 200 394 320 216 324 268 263 238 257 339 267 399 205 384 260 213 331 291 284 236 240 336 274 424 221 353 244 214 361 288 325. 242 284 283 342 276 233 311 228 418 403 302 225 231 189 353 457 331 241 299 254 . 201 245 194 340 378 326 262 282 217 306 323 266 228 259 225 249 294 242 299 223 376 206 372 294 237 390 252 306 238 249 325 248 385 229 315 274 236 309 236 292 244 269 246 216 149 134 261 205 183 271 216 281 204 225 364 240 450 190 348 290 283 395 287 319 266 294 *-' Increased, to 1000 ppm. in the 6th week of therapy. ** Increased; to 5000 ppm. in the 6th week of therapy. ; N]Lnety-Da y Feedingg Study in the D S- TABLE 3. M ^erage D ally Gomi:sound Coinsumptioln, Mg./Rg ./Day. Animal No. & Compound Admini stration Weeks .Group Sex 1 2 3 4 5 6 7 8 100 ppm. . 65-072 M 65-074 M 65-076 M 65-077 F 65-085 F 65-091 F 4.7 5.2 5.4 4.6 4.7 3.2 . 3.3 3.5 4.5 4.4 4.9 4.4 4.5 3.6 3.4 3.4 4.6 4.1 4.2 4.5 4.4 3.5 3.7 3.5 5.1 4.6 4.7 4.2 3.9 3.5 3.5 3.6 4.6 4.0 4.2 3.6 4.4 3.0 2.8 3.2 4.4 4.7 3.9 4.0 4.2 3.7 3.7 3.2 500 ppm. :* 65-078 M 65-079 M 65-087 M i 65-092 F 65-094 F . 65-095 F 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 2500 ppm.:** i 65-088 M 125.6 113.3 107.0 104.7 113.4 170.2 ',', 65-090 M 120.9 113.4 114.3 107.6 111.2 179.1 65-096 F 111.7 110.2 102.9 93.6 95.3 137.3 65-097 F 102.7 102.9 108.3 103.4 98.5 151.1 ''.j 65-098 F 121.4 111.3 108.0 103.6 107.9 173.1 65-099 - M 116.8 98.4 109.2 95.8 107.5 163.5 1;. 1;' * Increased to 1000 ppm. in. the 6th week of therapy. --^ y- 1 ** Increased to 5000 ppm. in the 6th week of therapy. c ; i:" m 06: I ^^--^--^--K-- J 197.5 203.1 151.8 162.8 175.0 166.0 190.3 159.3 142.2 153.7 179.4 170.3 9 2.9 2.8 3.1 3.0 2.5 3.0 25.6 31.3 12.9 23.1 25.3 27.7 145.2 134.2 127.1 143.4 141.7 140.6 10 4.4 3.3 3.4 3.5 3.3 3.4 37.5 34.8 35.2 31.1 31.9 35.4 211.2 184.6 161.2 156.3 184.7 173.0 TABLE 4. Time Interval Control Weeks 1 2 3 Compound Adminis tration Weeks 1 9 12 Ninety-Day'.Feeding Study in the Dog. Average Daily Water Intake (W.I.), mL.; Urine Output (U.O.), mt.. ; and Water Inta Output Ratio (W/p). Dop 65-038 ?. W.I. U.O. W/U Dog 65-OiZCh.M W.I. U.O. W/U Control Doe; 65-081 F Doe 65-083 M , W.I. U.O. W/U W.I. U.O. W/U DOE 65-086 W.I. U.O. 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 1,70 3.6 915 468 2.0 1005 455 2.2, 790 250 3.2 640 139 686 195 518 173 509 183 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 1005 329 737 297 % '.{}'. a.' ^ '< ^' Jst' 7T ^ | 1 I^i ft a? %j Ninety-Day Feeding Study in the Dog. TABLE 4, Continued. Average Daily Water Intake (W.I.), -ml.,; Urine Output (U.O.). ml^; and W ; . Outiput, Ratio (W/U). '" . .,. Time Doe, 65-072 M Interval . -W,I. U.O. W/U Dog 65-074 M W.I. U.O. W/U 100 Dpm. Doe, 65-076 M Doe 65-077iM W.I. U.O. W/U W.I. U.O. W/U DOE 65-0 W.I, U.O Control Weeks 1 2 3 Compound Adminis- tration Weeks 1 9 12 580 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 1.8 860 213 4.0 808 286 2.8 867 307 2.8 1135 343 3.3 1150 454 2.5 1258 390 3.2 660 128 5.2 585 210 2.8 747 233 3.2 773 300 2.6 1280 433 3.0 975 465 2.1 645 29 684 31 807 29 790 38 1015 48 770 43 ?1 Ninety-Day Feeding Study in the Dog. TABLE 4, Time Interval Continued. Average Daily Water Intake (W.I.), ml.; Output Ratio (W/U). Dog 65-078 M W.I. U.O. W/U Dog 65-079 M WI. U.O. W/U 500 Dog 65-087 M W.I. U.O. W/U Urine Output (U.O.), * ppm. Dog-65.6092 F W.I. U.O. W/U ml.; and W . Dog 65-094 W.I. U.O. 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 '.A98 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 -. 415 140 3^0 558 185 3.0 460 233 2.0 883 243 3,6 485 144 3.4 1100 403 2.7 438 232 1.9 270 166 1.6 380 258 1.5 1455 354 1378 553 1450 487 760 270 935 188 918 349 Increased to 1000 ppm. in the 6th week of therapy. < 1 w 0 g 01 c <r 0 c ! ' ^ 0 1^ > 0 Ninety-Day Feeding Study in the Dog. ' TABLE 4,,. .Continued. - - - Avera ge Daily Water Intake Outpu t Ratio (W/U). T ime Int erval Dog 65-*088 M W.I. U.O. W/ U ' Dog 65-090 M W.I. U.O. W/U (W.I.), nil.; Urine Output (U.O.), 2500 Dog 65-096 F W.I. U.O. W/U * ppm. Dog 65-097 F W.I. U.O. W/U. ml.; and W Dog 65-098 W.I. U.O. W Con trol We eks 1 / } Connpound Aduninistrsation W(eeks 1 9 I 2 480 205 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 .95 448 156 580 157 750 430 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 1.9 513 203 745 191 535 225 * Increased to 5000 ppm. in the 6th week of therapy. Page T-8 iing Study iia the Dog. TABLE 5. Results of Hem.atological. Dog No. 65-038, Female Dosage: Control 1 HematoloEV: Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./lOO ml. Hematocrit, 7. Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm. ) Differential Count: Neutrophils, 7o Seg., 7, Non-Seg., % Lymphocytes, 7o Eosinophils, 7a Monocytes, 7o Basophils,. % Appearance-':Q Eryfehr&cytes ' 6.02 15.2 43 0 13.73 51 49 2 46 1 2 0 No 1Biochemical and Urina'.Lysis Studies. Control Pericids 2 3 I I * C&mpound Administiat ion Months 2 ^ - 5.85 13.3 42 2 11.91 5.27 13.2 40 2 12.22 5.76 14.1 44 1 12.85 7.16 17.5 51 0 11.25 . 5.71 15.9 48 0 10.84 57 6L 47 42 46 44 57 60 47 41 46 41 0 1 0 1 0 3 37 38 48 51 46 48 3 0 1 2 6 2 3 1 4 5 2 6 0 0 0 0 0 0 No No SH No No Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 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 3P06 1.26 11.2 6 184 8 14 11 Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 160 S-.C 7.3 1.052 N N N N 155 S-.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 LS - cl - t) C - Straw Light Straw Cloudy Clear 2-3 F 4-5 1-3 1-2 M M F M F M F F F M F N - No SH - Negative L - Normal F - Slight Hypochrom;t&-'..: M - OCC - .Loaded Few Many Occasional F OCC L M L OCC OCC OCC M F * Repeat. Determinations 'Serum Glutami c Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase 'w.y_ Saniti^sd. ISaes not cornain "i'SCA CB| Page T-9 Ninety-Day Feeding Study in the Dog. TABLE 6. Results of Hema1;oloeical. Bi.ochemica 1 and Urina lysis StudiLes. Dog No. 65-070, Male Coritrol Per iods Compounc1 Adminisitration Months Dosage; Control 1 2 3 1 2 3 Hematoloey: Total Erythrocytes (x:106/CInm.) Hemoglobin, gm./100ml. Hemafcocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., 7, Lymphocytes, % Eosinophils, % Monocytes, 7, 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, ing. /100 ml. Protein, gm./lOO ml. Albumin, gm./lOO ml Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml Prothrombin Time, sec.. SGOT units/ml.1- SGPT units/ml.2 ISO3 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 1.060 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 - -c Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Ammonium Urates Bacteria Code: S LS - cl - Straw Light Straw Cloudy 3-4 F L 5-6' M M L F F N - No SH - H - Negative Ne>rmal Slight Hypochromia- Hypochromia: ^^^^^^^ OCC ; occ 1-2 2-3 1-2 F F occ F F .....^ F F M F . M M M M L - Loaded F - Few , M - Many occ - Occasional Iserum Glutamic ^Serum Glutamic a - Repeat: 141 '; . : ' Oxalacetic Transaminase Pyr uvic Transaminase CimipatlySanfllzea. Does ffbl contain r '0< ri! Page T-10 Ninety-Day Feeding Study in the Dog. TABLE 7. Results of Hemeitoloeical. B:Lochemica 1 and Urinal.ysis Studi-es. Dog No. 65-081, Female Coiitrol Per iods Compounc1 Administr at ion Months Dosaee: Control 1.- 2 3 3* 1 I* 2 3 Hematoloev: Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./lOO ml. Hematocrit, 7, Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm. ) Differential Count: Neutrophils, % Seg., % Non-Seg., 7. Lymphocytes, % Eb's'inophils', % Monocytes, % Basophils,. % Appearance of Erythrocytes 5.21 11.6 36 2 11.85 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 0 0 49 58 7 4 3 1 0 0 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 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 5.00 2.29 0.85 10.8 19 153 8 30 28 18 1 131- 5.05 2.7.3 1.17 11.6 10 149 8 18 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 Occult 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 LS - cl - Straw Light Straw Cloudy 4-5 3-5 F F F F L F occ 2-3 occ L M F F M F F F F F M F M M F M N - No SH - H - Negative Normal Slight:.Hypochromia Hypochromia L - Loaded F - Few M - Many occ - Occasional '-Serum Glutamic 2serum Glutamic a - Repeat 132 Oxalacetic Transaminase Pyruvic Transaminase an^ SaniiIzecL Does not contain TSCA CB( Pag^T-11 Ninety-Day CTBLE -8. Results of Dog No. 65-083, Male Dosage; Control Feeding Study in the Dog. Hemat.oloeical. B:Lochemical and Coiitrol Periiods 1 2 Urinalysis Stiidles. Compolmd Administ ration 33* 1 2 3 Months Hematoloev: Total Erythrocytes (xlO^ciiim. ) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., 7. Lymphocytes, % Eosinophils, % Moneyfces, % 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 3.62 10.1 35 6 24.363 86 83 85 81 1 2 14 16 0010 0 0 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 Plasma Biochemistry; Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 127 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 2613 127 5.35 2.45 0.85 14.8 16 122 8 19 19 124 5.13 2.69 1.16 16.6 9 1.23 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 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 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 S Microscopic: Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code: LS - Light Straw cl - Cloudy F F F OCC F ^ M L L N No SH - Negative Normal Slight Hypochromia; 2-3 occ-3' ? F 2-5 F L F F M F M M F L - Loaded F Few M - Many occ - Occasional ^-Serum Glutamic ^Serum Glutamic a - Repeat 23.39 b.- Repeat 26 Oxalacetic Transaminase Pyruvic Transaminase j-C-- fflW. parSfayiiIHzea. Does ffol contain T8CA Ci Page T12 Ninety-Day Feeding Study in the Dog. TABLE 9. Results of Hemato:Logical, Biochemica 1 and Urina lysis Stud ies. Dog No. 65-086, Male CControl Per iods Compoumd Administ;ration Months Dosage: Control 1 2 3 3* 1 I* 2 3 Hematolopv: Total Erythrocytes (xlO^/cmm;) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, nm./hr. Total Leucocytes, (xlO^/cmrn.) Differential Count: Neiitrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % 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 0 0 70 64 2 1 4 3 0 0 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. . Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 126'1 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 10.7^ 7 200 8 13 13 Urinalysis: Volume, ml. 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+13 N N 230 S-cl 7.3 1.022 N N K N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria Code; S - Straw N LS - Light Straw No cl - Cloudy MH 1+ 2+ 4-6 8-10 3-4 1-2 8-10 1-3 F F F F OCC R F F L M OCC F M F. L T, M M M L F Negative Normal Marked Hypochromia Trace-to-slight Slight-to-moderate L - Loaded F - Few M - Many R - Rare occ - Occasional ^-Serum Glutamic 2serum Glutamic * - Repeat Determinations a - Repeat 134 b - Repeat 1+ Oxalacetic Transaminase Pyruvic Transaminase ICompanySanitized. Does not contain TSCA CR Page T-13 TABLE Dog No. Dosage: Ninety-Day 10. R esults of 65-093 , Female Contnol Feeding Study in the Dog. Hematol.ogical. Biochemica.1 and Control Per iods 1 2 Urina lysis StudiLes. Gompounci Administ ratlcfn 3 3*8" 1 2 1 Months Hematoloev: Total Erythroc:ytes (xlO^/cmm.) Hemoglobin, gm ./100 ml. Hematocrit, 7. Sedimentation Rate, nnn./hr Total Leucocytes, (xlO^/cmm.) Differential Count; Neutrophils, % Seg., % Non-Seg.,, 7o Lymphocytes;, 7, Eosindphils,, 7o Monocytes, % Basophils, 7o 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./lOO ml. Protein, gm./lOO ml.. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg ./100 ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 127 5.63 1.89 0.51 13:5 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 8.03 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 Code: S - Straw N DS - Dark Straw No cl - Cloudy SH F 1-3 1-2 F 6-8 OCC ' 1-2 1-2 1-2 2-3 1-2 OCC F F M F L F F F F F F F M F Negative Normal Slight Hypochromia L ~ Loaded F - Few M - Many occ - Occasional Serum Glutamic ^Serum Glutamic * - Repeat Determinations a - Repeat 6.8 Oxalacetic Transaminase Pyruvic Transaminase ^ipa^'S'anito^^oes-ftoieonta^riTS'C&'eBi Page T-14 Ninety-Day Feeding Study in the Dog. TABLE 11. Results of Hemsitoloaical. B:iochemicsil and Urinailvsis Stiidles. Hog No. 65-072, Male Coiatrol Periods Compotmd Adminisi:ration Months Bosaee; 100 ppm. 1 2 3 1 2 3 Hematoloev: Total Erythrocytes (xlO^cmm.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, nnn./hr. Total Leucocytes, (xlO^/cnan. ) Differential Count: Neutrophils, % Seg., % Non-Seg., 7. Lymphocytes, 7o Eosinophils, 7o Monocytes, % Basophils, 7o 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 5.8 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. | Alkaline Phosphatase, Cholesterol, mg./lOO units ml. Prothrombin Time, sec. SGO'r units/ml.l . SGPT units/ml..2 114 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 P11 Specific Gravity Albumin Bilirubin Gliicose Occult Blood Microscopic: Galciusn Oxalafce Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria, Code: S DS - cl - Straw Dark Straw Cloudy ' . 1 N - No SH - H - 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+s 235 S-cl 6.5 1.023 N N N . N M 20-30 F L 2-3 M F L M 1-2 1-2 20 occ M 4-5 occ occ M F F M L y M L M Negative Normal Slight Hypochromia Hypochromia L - Loaded F - Few M - Many occ - Occasional ISerum Glutamic 2Serum Glutamic a - Repeat N Oxalacetic Transaminase Pyruvic Transaminase Company Sanitized. Does not contain TSCA cm Page T-15 Ninety-Day Seeding Study in the Dog. W TABLE 12. Results of Hemaitologic al. B:iochemic<:il and Urinal vsis Stuidles. Dag No. 65-074?, Male Coiatrol Peiriods Compotind Administ ration Months Dosage: 100 ppm. 1 2 3 1 2 3 Hematoloev: Total Erythrocytes (xlO^cmm. ) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO'/cmm. ) Differential Count: Neutrophils, % Seg,, % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. 1|k-^ Alkaline Phosphatase, units :<3holeSter61, mg.'/IOO. ml. "" Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 Urinalysis: Volume, ml. Color PH Specific Gravity Albumin Bilirubin Glucose Occult Blood 109 5. 65 2. 16 0. 62 13. 2 15 131 8 18 19 95 S-C 6. 6 1. 030 N N N N 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 16 180 S-cl 7.0 1.033 N N N N 300 S-cl 6.5 1.030 N N N N 119 4.92 2.23 0.83 13.3 9 123 8 14 16 270 S-cl 6.4 1.022 N N N N 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 15 285 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 Code: S - LS C - -^ cl - k^ r i^BB^^B SCraw Light Straw Clear Cloudy 1-2 5-7 2-4 2-3 L F F occ occ occ OCC F F F occ R F F F F F M M F M M N - No SH MH - Negative Normal Slight Hypochromia Marked Hypochromia L - Loaded F - Few M - Many R - Rare occ - Occasional tserum Glutamic Serum Giutamic Oxalacetic Transaminase Pyruvic Transaminase ^Kp^g-SaRftized. Does not contain TSCA CBi Page T-16 'iTia-eiEy-nay "Feeding 'S'tu'dy fn the Dog. y I&BIE 13. Se.svJ.ts. of Hema;tQloaieal, B iocheioi.ca-1 ..and Urina]Lysis Stuiiies Do;g Sor. 65,076, .Male Dosage; .^100 ppm. . Co'ntrol Periods 1 I* 2 3 Compoulid Adminis trati-on Months 1 . 2 :3 HematQlofty - Total Erythrocytes (xlO /cmm.) Hemoglobin, gn./lOO ml. Hematocrit, % Sedimentation Rate, "mm../hr Total Leucocytes, (xlO /cmm. ) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % 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 11.6 36 1 11.71 44 44 0 45 5 6 0 MH . 6.06 14.1 42 1 11.11 44 44 0 49 4 3 0 H 5.44 14.1 43 0 12.71 . 45 45 0 46 6 3 a No Plasma Biochemistry!; Glucose, mg,/100 ml. Protein, gm./lOO ml. Albumin, gm./J.OOml. Albumin-tp-Gl6bulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units |cholesterol, mg./lOOml. ^Prothrobin lisas-, sec. SGOT units/ml^1 SGPT units fml-.2 125?-' 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 19 10 123 4.89 2.35 0.92 12.4 11 ' L6S 8 19 17 119 5.42 2.57 0.93 13.6 13 181 7 2.8 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 S-cl 7.1 1.021 N N N N 370 S-cl 7.0 1.026 N N N N 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 ^montum Urates Sacteria ;ode: 11 y S " LS - C cl - Straw Light Straw Clear Cloudy f^^B N - No SH MH - H - 1-2 F F F M 1-3 MF F E P 1-2 F F M F OCC M M L F 3-5 OCC L Negative Normal Slight Hypochromia Marked Hypochromia Hypochromia L - Loaded F - Few M - Many 6cc - Occasional .^erum GInfamic '^Seruffl Glut:am:ic a - Repeat 150 Oxalacetic Transaminase Pyruvitf Transam'iriase Company Sanitized. Does not contain TSC . Ninety-Day Feeding Study in the Dog. I* y TABLE 14. Results of Hemsitological, B:[ochemica,1 and Urinal-ysis StudiLes. Dog Ko. 65-077, Female Coiitrol Per iods Compounci Administr ation Months Dosage: 100 Dnm. 1 2 3 3* 1 2 3 HematoloeiV: Total Eryfchrocytes (xlo6/cmm.> Hemoglobin, mg./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO-/cmm. ) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinopnils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.13 11.5 36 3 11.0 40 41 38 40 2 1 58 54 0 2 2 3 0 0 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 1 1 52 50 2 -1 3 2 0 0 No 5.31 12.1 38 1 12.81 .61 61;. 6 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. b^Alkaline Phosphatase, units pcholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 118 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 1283 4.99 2.62 1.10 12.9 12 142 8 16 14 126" 5.45 2.88 1.12 13.0 15 182 7 16 11 96 5.20 2. S 1.J/ 12.6 11 169 8 13 13 Urinalysis; Volume, ml. Color PH Specific Gravity Albumin ill 3 rub in 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 S-cl 7.3 1.025 N N N N. 260 LS-cl 6.8 1.020 N N 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 1-2 occ F F 1-2 3-4 F 1-3 L F F F F occ M F F L M F F M M Code: ^ I S LS - C - cl - Straw Light Straw Clear Cloudy N - No MH - H - Negative Normal Marked Hypochromia Hypochromia L - Loaded F - Few M - Many occ - Occasional ^-Serum Glutamic 0 Serum Glutamic a - Repeat 128 b - Repeat 121 Oxalacetic Transaminase Pyruvic Transaminase Company Sanillzea. Does not contain TSCA CBI Page T-18 Ninety-Day Feeding Study in the Dog. TABLE 15. Results of Hemat:oloeical. B iochemical and Urin.alysis Studi es. Dog Mo. 65-085, Female Cointrol Periods . Compound Administ-ration Months Dosage; 100 oom. 1 2 3 1 2 3 Hematoloev: Total Erythrocytes CidO^/cmm.) Hemoglobin, gm./lOO ml. Hematocrit, 7o Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count; Meutrdphils, % Seg., % Non-Seg., % Lymphocytes, 7o Ebslnophils, % 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./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. | - Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/mi.2 Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 1423 5.58 2.16 0.53 9.8 15 159 8 20 25 140 S-cl 7.Q 1.023 N N N N 121 6.08 2.20 0.57 13.4. 15 132 8 22 19 ' 135 LS-cl 7.0 1.019 N N N N 119 5.59 2.39 0.75 11.8 13 1-&8 8 19 19 325 LS-cl 6.9 1.027 N N N N. 122 5.39 2.60 0.92 11.0 8 128 8 15 14 335 LS-cl 6.8 1.011 N N N N 106 5.69 2.82 0.98 3.1.7 11 141 8 16 17 165 S-cl 7.0 1.015 N N N N 106 5.82 3.14 1.17 12.1 8 161 9 11 9 200 S-cl 6.8 1.018 M N N N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria 6-8 4-5 F F F F 2-3 F F F F occ M M F L L F M M L M Code: ^ & S - LS - C - cl - Straw Light Straw Clear Cloudy 1------------ N - No H - Negative Normal Hypochromia L - Loaded F - Few M - Many occ - Occasional Q Serum Glutamic Serum Glutamic a - Repeat 148 Oxalacetic Transaminase Pyruvic Transaminase 'B.paR.y.SaniiSzsi CBoes not eorriairs TSCA 'QW Page T-19 TABLE Dog No. Dosage: Ninety-Day 16. Results of 65-091, female 100 ppm. Feeding Study in the Dog. Haro<itolo^ical,'B iochemical and Co ntrol Perio ds 1. 2 Uriilalysis Stu'dies. Compoulad Administ ration 3 1 2 (2* 3 Months Hematolo^y; Total Erytbrocytes (xlQ^/pinm,) Hemoglobin, gin./lOO n4. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xil"'/cilim, ) Differential CQunt; NeutrophUs, % - Seg., % Non-Seg., % Lymphocyt.es, % Epsinophils, % Mcinopyfce,^% BasQphils, % Appearance of Erythrocyteg 5.78 12.6 40 1 1.0.20 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 -\ H 6.13 15.2 46 0 10.18 30 40 30 39 0 1 63 52 3 0 4 8 0 0 Mo 5.60 15.3 48 0 1.0.96 41 41 0 53 3 3 0 No Plasma Biochemistry; Glucose, ing,/IQQ ml, Protein, gin,/10D ffil Albumin, gm./lQQ ml. Albumin-to-Globu:)4n Ratio Urea Nitrogen, mg'./lQO ml. Alkaline Phosphatase, URits Cholesterol, mg./lOO vul Prothrombin Time, see, SOOT units/ml,1 SQPT units/ml.2 112 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 0:70 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 Specific Gravity Albumin B.ilirubin Glucose Occult Blood 150 8-cl 6.1 1.058 M 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 1.-022 N N N N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Triple/Phosphates Ammonium Urates Bacteria Code: S LS - cl - Straw Light Straw Cloudy 3-4 3-4 F, F F F F occ occ M F L M M M F M M M L L F L F N - No H - Negative Normal Hypochromia L - Loaded F - Few M - Many occ-- Occasional ^-Serum Glutamic -Serum Glutamic Oyalacetic Transaminase Pyruvic Transaminase CompanySanitized. Does not eonfflm TSCA CW Page T^:20 ing Study in. the Dog. TABLE 17. Results of Hema toloaical. B iochemical aad-Uri.1ialysis Studies. Dog No. 65-078, Male Control Perio ds Compound Administ ration Months Dosage; 500 ppm. 1 22* 3 " - 1 . 2 2* 3 Hematology; Total Erythrocytes (ylO^cmm .) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlo3/cmm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocyes,"% 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 22.50T3 26 27 26 27 0 0 70 68 4 3 0 2 0 0 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 S1 41 0 51 4 4 0 No 5.49 15.3 46 .0 11.61 54 54 0 41 4 1 0 No Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO mio Pr' Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. - SGOT units/ml.1 SGPI units/ml.2 138" 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 . 9,.0 11.5 25 13 132 154 8 8 22 19 10 1A 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 M N 150 S-cl 7.3 1.051 N N N N .140 S-cl 6.5 1.033 N N/ N K 140 S-cl , 7.3 1.025 N trc N N 275 S-cl 6.7 1.025 N ^ N N Microscopic; Leucocyfces;.' :.'-. ; Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code: S - LS - cl - Straw Light Straw Cloudy Ifc, JH----^B -;' occ R F F F F F P ' 3-4 F M M F F F P M M M M M M M M N - Negative L - Loaded a - Repeat 22.65 No Normal F - Few b - Repeat 140 H - Hypochromia M - Many c - Repeat 1+ tr - Trace 1+ - Trace-to- R - Rare occ - Occasional d - Repeat 2+ \ * - Repeat Determinaltions slight ^Serum Glutamic Oxalacetic Transaminase Slight-to- ^Seruin Glutamic Pyruvic Transaminase moderate SBpany Sanitized. Does no? comain TSCA CP. Page T-2,1 TABLE Dog No. Dosage: Ninety-Day 18. Results of 65-079, Male 500 ppm. Feeding Study in the Dog. Hematoloeical. B iochemic al and Control Pe riods 1 I* 2 Urinalysis Stuidles. Compou.nd Administ'ration 3 1 2 2* 3 Months Hematology: Total Erythrocytes (xlO^cmin.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, innii/InTotal Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg.,7. Non-Seg., 7, Lymphocytes, 7o Eosinophils, % Moncytes, % Basophils, % Appearance of Erythrocytes 4.72 11.3 35 3 10.08 42 43 40 41 2 2 53 55 2 0 3 2 0 0 No 4.21 9.9 33 1 10.70 51 51 0 4-2- 0 7 0 MH 4.00 10.1 34 1 9.62 56 55 1 4-L 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 1 0 49 59 1 1 9 8 0 0 H 5.49 15.1 46 0 10.34 50 48 2 47 0 3 0 No Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SCOT units/ml.1 SGPT units/ml.2 1423 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 22- 19 124 4.98 2.60 1.09 13.3 12 135 8 18 19 12"0 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 1+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 Flagellates Code: S DS - C - cl - Straw Dark Straw Clear Cloudy -------------- N - No SH - H - 1+ - 4+ - 20-30 5-7 1-2 1-3 F 3-4 ' F occ 1-2 F occ L M F M L M F F F F M M M L L Negative Normal Slight Hypochromia Hypochromia Trace-toslight Marked -R L - Loaded F - Few M - Many R - Rare a - Repeat 144 b - Repeat 1+ c - Repeat 4+ * - Repeat Determinations occ - Occasional Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transannnaap Company Sanillzea; Hoes ffot contain TSCA CRf Page T-22 ; Study in the Dog. TABLE 19. Results of Hemato].oeical"; B:Lochemica:I and Urina lysis Stud ies. Dog No. 65-087, Male Coi:itrol Per:Lods Compoun d Administ:ration Months Dosage; 500 ppm. 1 I* 2 3 3* 1 2 2* 3 Hematolo^v; Total Erythrocytes (xlO^/cmm.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, nnn./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 39 35 39 34 0 1 59 62 ]. 2 1 1 0 0 H . 5.64 13.0 40 0 9.73 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 6.91 16.2 50 0 11.54 42 41 1 51 0 7 0 No Plasma Bl6 chemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. A Alkaline Phosphatase, units f Cholesterol, mg./lOO ml Prothrombin Time, sec. SGOI units/ml. 'SGPT units/ml.2 1408 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 5.14 2.55 0.98 9.6 14 125 8 - 16 11 116 5.30 2.90 1.20 12.7 9 125 8 14 14 103 6.05 2.72 0.82 12.3 19 17 2501' 7 15 10 113 6.25 3.38 1.22 8.0 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 Scl 6.2 1.049 N N N N 110 DS-cl 6.0 1.058 N 2+0 N N 360 LS-cl 6.6 1.015 N N M N Microscopic; Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Calcium Oxalate Aimnoniuai Urates Bacteria Code; S Straw N "LS - Light Straw No DS - Dark Straw H cl - Cloudy 2+ 70-80 3-4 10-12 3-5 M F ' F 1-2 1-3 1-2 F F 8-10 8-10 0-3 F M F M M L M M F F M Negative Normal Hypochromia Slight-to- moderate L -Loaded F - Few M - Many occ - Occasional ^-Serum Glutamic 2Serum Glufcamic a - Repeat 150 b - Repeat 215 c - Repeat 2+ * - Repeat Determinations Oxalacetic Transaminase Pyruvic Transaminase .Cpinpany Sanitized. Does not contain TSCA <"-" Page T-23 TABLE Dog No. Dosage; Ninety-Day 20. Results of 65-092 500 ppm. Feeding Study in the Dog. Hemat.clerical. Bi.ochemical acd Goritrol Peric>ds 1 2 Urina:lysis Stu<lies. Compoulid Administ:ration 3 1 2 3 Months Hematoloey: Total Erythrocytes (xlO /cmm. ) Hemoglobin, gm./lOO ml Hematocrit, 7 Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Ifeutrophils, % Seg.', % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes 5.40 12.2 39 0 14.71 67 65 2 27 1 5 0 No 4.76 10.8 34 1 11.74 73 72 1 22 1 4 0 H 4.09 10.6 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 45 2 12.12 80 80 0 16 0 4 0 N6 5.78 15.1 46 0 21.88 77 73 4 20 0 3 0 No Plasma Biochemistry; Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 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 17'1 191 6 11 17 107 5.45 2.83 1.08 11.3 13 160 8 13 11 Urinalvsis; Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose , Occult Blood 130 S-cl 7.1 1.039 N N N N 145 LS-cl 6.8 1.020 N N 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-G 7.5 1.026 N N N N 310 LS-cl 7.0 1.018 M . N N N' Microscopies Leucocytes Amorphous- Urafces Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code: S LS - C - cl - Straw Light Straw Clear Cloudy N No SH - H 8-10 8-10 4-5 F F M F F M F F F M M 12-15 F 3-4 3-4 OCC M OCC F M F F Negative Normal L - Loaded F - Few Slight Hypochromia M - Many Hypochromia OCC - Occasional ^Serum Glutamic ^Serum Glutamic a - Repeat 18 Oxalacetic Transaminase Pyruvic Transaminase Company Sanitized. Does not contain TSCA ^ Page T-24', ding Study in the Dog, TABLE 21. Results of Hematoloeical, B"iochemiCtll and Urinal-ysis Stu.dies. Dog No. 65-094, Female Dosaee; 500 opm. Control Pelriods 1 2 3 Gompou,nd Administ:ration Months 1 2 2* 3 Hematology; Total Erythrocytes (xlO /cimii.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, saa./hr Total Leucocytes, (xlO^/cmm.) Differential Count; Neutrophils, % Seg., % Mon-Seg., % 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 0 0 56 68 1 0 2 2 0 0 H 5.10 15.1 46 0 13.88 53 : 53 0 45 0 2 0 No Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm,/100 ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 108 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 Urinalysis: Volume, ml. Color pH Specific Gravity Albumin Bilir.ubin Glucose Occult Blood 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 S-cl 6.'0 1.035 N N N N . 110 S-cl 6.8 1.031 N N N N 345 S-cl 6.8 1.026 N N N M Microscopic; Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Flagellates Code: S - LS - dl .Straw Light Straw Cloudy ^^^^^^ : F L L 1-2 1-2 3-5 F occ F 1-3 F M F M M M L L L M N - No SH - H - Negative Normal Slight,;Hypochromia Hypochromia L - Loaded F - Few M " Many occ - Occasional -'-Serum Glutamic 2serum Glutamic * - Repeat Determinations Oxalacetic Transaminase Pyruvic Transaminase SoBlpanjf Sanitized. Dees not contain TSCA CBI Page T-25 Lng Study in the Dog. TABLE Dog No. Dosage; 22. Results of Hemat:oloeical, Bi.oche'mical and Uriiaalysis Studi es. 65-095, Female Conitrol Peri ods Compound. Administ ration Months 500 DDm. 1 I* ? 3 1 2 3 Hematoloev: Total Erythrocyfces (xlO^/cuna. ) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential. Count: Neutrophils, % Seg., 7, Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance-of Erythrocytes 5.19 11.6 35 1 10.71 28 30 25 30 3 0 67 65 1 2 4 3 0 0 No 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 63 37 50 62 37 50 a 0 0 35 60 47 .6 2 -.. -:: ' '- ': . - M2^ ---',= yr'--??.-'-:1-;.1 .. '- -" . ^ m i 0 0 0 SH H H 50 50 0 49 : '.^r' .. 0 0 H 5.46 15.0 45 0 9.91 51 49 2 44 '^2-1 3 0 No Plasma Biochemistry; Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-GlobulinRatio Urea Nitrogen, -Big, / l'0-..in3..* .. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, 1 sec. SGOT units/ml SGPT units/ml.2 108 5.51 1.90 0.53 ...U..O 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 0.9-5 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 Si-C''- s.o'1 1.022 N N N N 255 S-cl 7.2 1.026 N N N N Microscopies Leucocytes Amorphous Urates Epithelial Cells Erythrocytes Triple Phosphates Ammonium Urates Bacteria Waxy Casts F 1-2 F 2-3 OCC F F L L F L M F 4-6/LPF 1-2 F F F OCC M F M OCC F M Code; S - cl - I R H b ^^^^^^^ Straw Cloudy N ~ No SH - H - Negative Normal ' Slight Hypochromia Hypochromia L - Loaded a - Repeat 7.0 F - Few * - Repeat Determinations M Many LPF - Low Powered Field OCC - Occasional '''Serum Glutamic .Oxalacetic Transaminase 2seruffl Gtutamic Pyruvic Transaminase Page T-26 Ninety-Day TABlE^^i. Results of Dog No. 65-088, Male Do sage; 2500 ?ppm. Feeding Study in the Dog. Heamt:ological. Biochemica]L and Con trol Per.]Lods 1 2 Urinal ysis Studies; Compound Administrcition 3 1 2 3 Months Hematoloav; Total Erythrocytes (xlO^cmm. ) Hemoglobin, gm./lOO ml. Hematocrifc, % Sedimentation .Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., 7, Non-Seg., % Lymphocytes, % Eosinophils, % Mbnocytes, % Basophils, 7o 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./lOO ml Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 128a 5.99 2.53 0.73 10.1 14 109 9 17 29C 119 5.73 2.55 0.80 12.5 16 119 9 18 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 1713 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: S LS - C - cl - Straw Light Straw Clear Cloudy N - No MH - H - 55-65 2-3 1-2 F. F F OCC occ occ F M F occ M M M M F F M L L Negative Normal Marked' Hypochromia Hypochromia L - Loaded F - Few M - Many occ - Occasional 'Serum Glutamic ^Serum Glutamic a - Repeat 139 b - Repeat 18 c - Repeat 29 Oxalacetic Transaminase Pyruvic Transaminase CompanySanIHzed. Does not contain TSCA CRf Page T-27 TABLE Dog No. Dosaees Ninety-Day 24. Results of 65-090, Male 2500 oom. Feeding Study in the Dog. Hemato loeical. Bitachemic.al and Con)trol Pe:riods 1 2 Urina lysis- Studies. Compound Administi-at ion 3 1 2 3 Months Hematoloev; Total Erythrocytes (xlO^cmn.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^cmm.) Differential Count; Neutrophils, % Seg., 7o Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, % Appearance of Erythrocytes Plasma Biochemistry; Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio , Urea Nitrogen, mg./lOO ml. ^Alkaline Phosphatase, units 'Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 5.47 13.0 40 1 15.76 59 59 0 34 3 3 1 No 1383 5.63 1.93 0.52 15.0 21 163 7 19 16 4.88 11.5 36 1 15.72 73 72 1 25 0 2 0 MH 133 5.38 1.98 0.58 15.8 23 146 7 19 20 4.76 11.6 36 0 13.47 61 60 1 34 0 5 0 SH 132 4.80 2.05 0.75 12.9 24 140 7 18 14 5.25 12.5 39 0 11.36 55 54 1 42 2 1 0 H 124" 4.90 2.20 0.81 13.5 18 195f 7 17 16 6.03 14.3 43 -1 14.41 52 52 0 42 5 1 0 No 121" 5.86 2.55 0.78 13 4 28 208 6 13 5 6.06 14.8 45 0 12.60 53 52 1 40 1 6 0 No 120 5.60 2.58 0.86 8.7 336 284 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 M 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 M N Microscooic: Leucocytes Amorphous Urates Epithelial Cells Erythrocyfces Triple Phosphates Calcium Oxalafce Aimnonium Urates Bacteria F 1-2 2-4 1-2 3-5 F. F F OCC OCC 3-4 1-3 OCC M M M M M P F M M M F M M M M Code; | y S C - cl - Straw N - Clear No - Cloudy" MB - SH - H - ^|^^^^--^^--^ -- Negative L - Loaded a - Repeat 146 e - Repeat 32 Normal F - Few b - Repeat 126 f - Repeat 200 Marked Hypochromia M - Many c - Repeat 118 g - Repeat 221 Slight Hypochromia OCC - Occasional d - Repeat 23 Hypochromia ISerum Glutamic Oxalacetic Transaminase 2ser urn Glutamic Pyruvic Transaminase yany Saniitee'd. 'Does nof contain TS^a.^o-s Page T-28 NinetyDay Feeding Study in the Dog. TABLE 25. Results of Hemat;oloeical. Biochemical and Ur'iilalvsis Stuclies. Dog No. 65-096, Female Control Periods Compoulid Adminis'tration Months Dosase; 2500 Dnm. , , 1 2 3 1 2 3 Hematoloev; Total Erythrocytes (xlO'/cmrn. ) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmm.) Differential Count: Neutrophils, % Seg., 7, Non-Seg., % Lymph&cyfces, 7, Eosinophils, % Monocytes, 7o Basophils, % Appearance of Erythrocytes ^k H|| "^ Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. Albunin-to-Globulin Ratio Urea Nitrogen, mg./lOO ml. Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SGOT units/ml.1 SGPI units/ml.2 5.58 12.2 39 1 11.15 55 54 1 43 0 2 0 No 109 5.78 2.12 0.58 13.0" 22 167 7 19 14 4.55 11.3 34 1 11.96 68 67 1 27 2 3 0 H 130'1 5.68 2.10 0.59 13.5 22 158 7 20 11 3.98 10.5 34 0 10.40 63 63 0 36 1 0 0 H 121 4.95 2.32 0.88 11.3 22 131 8 20 16 5.26 12.3 39 0 12.51 43 43 0 55 0 2 0 H 126" 5.39 2.69 1.00 12.4 14^ 215d 7 19 14 6.03 12.8 40 0 11.82 49 49 0 43 0 8 0 H 118 6.31 2.95 0.88 12.0 19 2698 6 15 11 5.94 13.1 41 0 12.66 51 48 3 46 2 1 0 No 118 5.90 3.13 1.13 10.7 18 307f 8 20 15 lEr.inalvsis s. Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 110 S-cl 6.5 1.057 N N N N 205 LS-C 7.1 1.025 N N 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 Code; S - Straw LS - Light Straw ' ^I-I, I w C - cl - Clear Cloudy -^^^^^^& N - No H - F 6-8 F 1-3 . 1-2 F M M M M F M 2-3/LPF 25-30 3-4 3-4 See F F M F M occ 1-3 8-10 F Negative Normal L - Loaded F - Few a - Repeat 141 b - Repeat 121 d - Repeat 210 e - Repeat 251 Hypochromia M - Many c - Repeat 19 f - Repeat 300 occ - Occasional 9 Serum Glutamic Oxalacetic Transaminase Serum Glutamic Pyruvic Transaminase LPF - Low Powered Field (Company Sanitized. Does not contain TSCA CB Page T-29 Ninety-Day Feeding Study in the Dog. TABLE 26. Results of Hem<itoloeical. Biochemica.1 and Urinal ysis Stud ies. Dog No. 65-09?, Male Control Per iods Compoun,d Administr ation Months Dosage; 2500 ppm. 1 2 3 1 2 3 Hematology; Total Erythrocytes (xlO^cmm.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^cmin.). Differential Count: Neutrophils, % Seg., 7, Non-Seg., 7. .... Lymphocy-Ces, % Eosinophils, % Monocytes, 7o Ba&ophils, 7, Appearance of Erythrocytes 5.26 12.1 36 1 10.67 48 47 1 45 5 2 0 No 4.49 10.8 33 6 10.44 57 57 0 40 2 1 0 MH 4.12 10.2 33 6 11.24 49 49 0 50 1 0 0 H 4.94 12.1 36 0 11.41 52 52 0 45 1 2 0 SH 5.70 13.7 40 0 10.99 53 53 0 44 1 2 0 H 5.71 14.5 46 0 10.95 52 52 0 43 2 3 0 No Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml Albumin-to-Globulin Ratio Urea Nitfogen, mg./lOO ml. || Alkaline Phosphatase, units ^Cholesterol, mg./100ml. Prothrombin Time,, sec. SGOT units/ml.1 SGPT units/ml.2 133d 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 12V. 5.53 2.53 0.85 15.5 10 175 8 16 11 110 5.19 2.87 1.2g 13.8 1613 233 7 13 12 106 5.90 3.15 1.14 15.4 15 274 8 12 14 Urinalvsis: Volume, ml. Color pH Specific Gravity Albumin Bilirubin Glucose Occult Blood 105 S-C 7.8 1.025 ,N M 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 6.9 1.022 N N N N Microscooic: 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 F F F F M F F F occ L 1-2 occ 2-5 F F M F F F M M M F Negative Normal Marked Hypochromia Slight Hypochromia Hypochromia L - Loaded F - Few M - Many occ - Occasional "-Serum Glut,amic ^Serum Glutamic a - Repeat 138 b - Repeat 17 c - Repeat 214 Oxalacetic Transaminase Pyruvic Transaminase ^Wpany ganitizfi^^oe-:: W cwaw Tsr^ t;S Page T--30 Ninety-Day Feeding Study in the Dog. I I * TABLE 27. Results of Hematolc)RlC al. Biochemica 1 and U6iilalysis Studlies. Dog No. 65-098, Female Control Per iods Compounid Administ ration Months Dosages 2500 pom. 2 3 1 2 2* 3 A Hematology; Total Erythrocytes (xlO^ciiim.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^cinm.) Differential Count: Neutrophils, % Seg., % Non-Seg., % Lymphocytes, % Eosinophils, % Monocytes, % Basophils, 7. Appearance of Erythrocytes Plasma Biochemistry: Glucose, mg./lOO ml. Protein, gm./lOO ml. Albumin, gm./lOO ml. ^ Albumin-to-Globulin Ratio BftUrea Nitrogen, mg./lOO ml. 'V Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothrombin Time, sec. SCOT units/ml.1 SGPT units/ml.2 Urinalvsis; Volume, ml. Color pH Specific Gravity Albumin Bilipubin Glucose Occult Blood 5 .20 12 .6 40 0 15 . .10 - 39 38 39 38 0 0 52 53 3 3 6 6 0 0 No 106 5.82 2.40 0.70 14.8 23 133 8 19 21 80 S-cl 7. 0 1. 060 N N H N 4.86 12.1 37 0 13.91 .. 43 42 t 40 2 5 0 H 4.49 11.3 38 0 15,31 72 72 0 25 1 2 0 No 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 13 155 S-cl 7.0 1.019 N N N N 205 S-cl 7.1 1.032 N N N N 5.27 13.7 43 0 13.41 58 58 0 41 0 1 0 No 117 5.15 2.60 1.02 11.5 20 19813 8 19 20 135 S-cl 7.1 1.031 N N N N 6.36 15.1 45 0 11.45 40 59 40 58 0 1 49 36 2 1 9 4 0 0 No No 5.70 15.4 47 0 12.61 47' 45 2 44 3 6 0 No 112 5.70 2.94 1.06 11.7 243 244 6 12 23d 111 5.70 3.09 1.18 12.3 24 249 8 7 16 120 S-cl 8.06 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 Code: ?>. .t<e.<;g.) S - Straw C Clear cl Cloudy ^^^^ N - No H - F 6-8 1-2 1-2 3-4 F 1-2 2-3 occ occ F M F F M M F F F M F F F L F Negative L - Loaded a - Repeat 22 e - Repeat 6.5 Normal F ? Few b - Repeat 201 Hypochromia M - Many c - Repeat 214 occ --Occasional d - Repeat 28 ^Serum Glutamic Oxalacetic Transaminase ^gerum Glutamic Pyruvic Transaminase Company Sanitized. Does not contain TRCA ^i Page T-31 iding Study in the Dog. TABLE 28. Results of Henaatological. B:Lochemical and Urinal ysis Studies. ------------------ Dog No. 65-099, Male Dosage; 2500 Dom. Coiitrol Perilads 1 2 2* 3 Compound Administiration Months 1 2 3 Hematolosv; Total Erythrocytes (xl06/c^^n.) Hemoglobin, gm./lOO ml. Hematocrit, % Sedimentation Rate, mm./hr. Total Leucocytes, (xlO^/cmiri.) Differential Count: Neutrophils, % Seg., % Mon-Seg., % Lymphocytes, % Eosinophils, % Monpcytes, % Basophils, % Appearance of Erythrocytes 5.55 5.15 4.41 5.82 6.40 6.19 1 0 0 0 0 0 12.8 40 15.36 60 58 12.1 36 13.16 72 64 68 64 11.3 36 11.67 60 .60 13.7 41 10.62 59 57 14.9 45 13.74 68 68 15.3 45 11.71 57 54 2 4 0 0 2 0 3 32 16 22 33 36 26 35 5 8 11 3 2 0 5 3 4 3 4 3 6 3 0 0 0 0 0 0 0 No MH No -'H H .No Plasma Biochemistry: -. ^Q"-?0,?^ '"S /-100 ml Protein, gm./lOO ml. Albumin, gm./lOO ml. Albumin-to-Globulin Ratio \Urea Nitrogen, mg./lOO ml. y Alkaline Phosphatase, units Cholesterol, mg./lOO ml. Prothr.ombin Time, sec. SGOT units/ml.1 SGPT units/ml.2 119 5.67 2.23 0.65 13.0 17 182 7 23 16 1343 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 22 128 5.05 2.40 0.91 9.8 15 170f 8 12 17 m0 5.82 2.50 0.75 8.2- 28d 2338 6 11 13 118 5.21 2.70 1.07 11.5 336 270 8 11 18 TJrinalvsis: Volume, ml. Color pH Specific Gravity Albumin Bill rub in 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 M 200 S-cl 7.3 1.025 N N N N 210 S^C 7.4 1.036 .N N ' N N Microscopic: Leucocytes Amorphous Urates Epithelial Cells Triple Phosphates Ammonium Urates Bacteria Code: S LS - DS - C - > ? cl - Straw N - Light Straw No - Dark Straw MH - Clear H - Cloudy F F M F F OCC 1-2 OCC F F F M M M F F M M F F M L F Negative L - Loaded a - Repeat 125 e - Repeat 30 Normal F - Few b - Repeat 126 f - Repeat 179 Marked Hypochromia M - Many c - Repeat 114 g - Repeat 209 Hypochromia OCC - Occasional d - Repeat 24 ^Serum Glutamic Oxalacetic Transaminase ^Serum Glutamic Pyruvic Transaminase ^.oTflpany Sanliizeaf. Does no? contain TSr*^ ctii Page 31A TABLE 28-A. Dietary Level Ninety-Day 'F. eeding iStudy ]In the Dog. Total Choliesterol ^/alues,. Mg. pe r 100 Ml. Plasma, Coni:rol Pe;riod Compound Admin. Months Sex 1 2 3 1 2 3 Control: 65-038 F 65-070 M 65-081 F 65--083 M 65-086 M 65-093 F 100 ppm.: 65-072 M 65-074 M 65-076 M 65-077 F 65-085 F 65-091 F 500 ppm.: 65-078 M 65-079 M 65-087 M 65-092 P 65-094 F 65-095 F 2500 ppm.: 65-088 M 65-090 M 65-096 F .65-097 F 65-098 F 65-099 M 196 212 211 176 186 140 161 162 153 116 138 122 196 174 142 144 128 147 200 178 184 175 195 198 149 175 167 123 142 157 181 203 200 132 115 124 132 139 120 131 144 147 159 163 132 155 153 188 159 132 148 160 138 149 118 158 163 123 158 172 163 181 203 142 182 169 128 141 161 143 155 149 129 169 132 161 149 147 159 171 125 140 122 120 128 129 126 142 162 154 154 180 203 135 166 169 125 215 214 121 191 160 141 181 192 136 167 204 109 119 100 163 146 140 167 158 131 129 133 147 133 117 120 182 150 120 109 185 187 195 208 284 215 269 307 175 233 274 198 244 249 170 233 270 pompanySannTzea Does noT contain TSCA CBT Page T-^32 Ninety-Day Feeding Study in the Dog. TABLE 29. Animal Number Control: 65-070 Necropsy Observations. Sex Organ M small intestine Comment :.' Few. .hookworms-..present. 65-083 65-086 65-038 65-081 65-093 100 ppm. 65-072 65-074 65-076 65-077 65-085 65-091 small intestine ileocolic junction cecum urinary bladder heart cecum ileocolic junction colon small intestine Ascarid. Mild mucosal congestion. Several 2 to 3 mm. mucosal hemorrhages. Few petechial hemorrhages. Trtcn&p.id: .waive',. 2 nun. hematoma. Fewp'etech-a-a'-iTR'the^.mueosa.,.''. -:-. Mild mucosal congestion. Several mucosal petechiae. Few petechial hemorrhages at the gastroduodenal. junction, fecal material was present in the stomach. ileocolic junction urinary bladder small intestine ileocolic junction urinary bladder small intestine small intestine cecum, colon stomach ileocolic junction cecum, colon Mucosal congestion. Petechial hemorrhages at the neck. Few hookworms present. Mild mucosal congestion. Area of hyperemia at neck. Areas of hyperemia at ileocolic orifice. 3 mm. raised firm area in the duodenum; terminal portion of the ileum had mild mucosal hemorrhage at the ileocolic junction. Mild mucosal hemorrhage. Fecal material present in the stomach. Mild mucosal congestion. Several 2 mm. areas of hemorrhage in the mucosa. Pgfflpany SanRizeS. Does Wi coniafri TS'CA ee? 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 urinary bladder Few petechial hemorrhages at the neck. 65-092 urinary bladder Few petechial hemorrhages at the neck. 65-094 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 stomach small intestine ileocolic junction cecum Few petechial hemorrhages in Petechial hemorrhages at the junction, several ascarids. Mild mucosal congestion. Few mucosal petechiae. the pyloric region. gastroduodenal 5000 ppm.: 65-088 65-090 65-099 65-096 65-097 M small intestine M small intestine M small intestine cecum . cecum 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. "cSCACi^ fc) Page T-3.4 : Ninety-Day Feeding Study in the Dog. TABLE 29, Continued. Necropsy Observations. Animal Number____Sex Organ____;_______________Comment 5000 ppm.. Cont'd.; 65-098 F heart 10 mm. white streak in the left ventricular wall. pW^Santtri. Oo "' 'na'" ^ m Page T-35 Ninety-Day Feedin.g Stud y in this Bog. TABLE 3 0. Actual (Grams) an,d Rela,tive (%:'Bo.dy'Werght;(".Organ:^engh.(:s. Group & Animal Number irenninal Body Wt. Sex Ke. Spl een Wt. % Livisr Wt; % Adre'nals Wt. % . Kidileys Wt. % Ovar ies/ lest es Wt. % Control: 65-070 M 65-083 M 65-086 M 65-038 F 65-081 F 65-093 F 13.0 8.5 9.2 8.2 9.2 6.1 29.12 30.70 28.58 19.98 24.32 13.59 0.224 0.361 0.311 0.244 0,264 0.223 310.87 24 2,. 42 248.83 198.81 250.50 151.11 2.391 2.852 2.705 2.425 2.723 2.477 0.90 0.98 0.98 1.40 1.06 0.78 0.007. 0.012 0.011 0.017 0.012 0.013 63.99 43.25 49.53 38.58 39.62 29.28 0.492 0.509 0.538 0.470 0.431 0.480 23.08 14.22 18.90 0.67 0.74 0.41 0.178 0.167 0.205 0.008 0.008 0.007 100 ppm:: 65-072 M 65-074 M 65-076 M 65-077 F 65-085 F 65-091 F 1000 pom. '. 8.7 10.8 11.9 9.4 7.2 9.9 25.87 32.31 25.39 29.18 25.31 23.40 0.297 0.299 0.213 0,310 0.352 0.236 238.89 285.70 325.52 241.79 177.56 210.70 2.746 2.645 2.735 2.572 2.466 2.128 0.82 1.23 1.02 1.11 1.21 1.16 0.009 0.011 0.009 0.012 0.017 0.012 55.60 58.12 50.68 43.93 33.08 52.61 0.639 0.538 0.426 0.467 0.459 0.531 19.78 13.86 17.71 0.55 0.62 0.58 0.227 0.128 0.149 0.006 0.009 0.006 65-078 M 65-079 M 65-087 M 65-092 F " 65-094 F 65-095 P 5000 DDin. ; 9.9 6.9 . 13.5 6.5 11.0 7.9 23.70 18.11 41.42 18.18 28.50 18.73 0.239 0.262 0.307 0.280 0.259 0.237 281.62 210.71 443.25 209.89 320.71 228.27 2.845 3.054 3.283 3.229 2.916 2.889 1.00 0.84 1.98 0.98 1.12 1.18 0.010 0.012 0.015 0.015 0.010 0.015 61.60 44.15 71.48 29.50 59.81 38.31 0.622 0.640 0.529 0.454 0.544 0.491 14.95 10.10. 21...78 0.66 0.71 0.90 0.151 0.146 0.161 O.Q10 0.006 0.011 55-088 M 55-090 M 55-099 M 55-096 F 55-097 F 55-098 P 6.7 10.6 8.4 8.8 10.0 7.2 19.79 19.67 17.88 21.99 24.09 16.50 0.295 0.186 0.213 0.250 0.241 0.229 301.90 479.03 396.70 339.91 426.29 327.31 4.506 4.5194.723 3.863 4.263 4.546 0.84 1.41 0.93 1.02 1.00 0.60 0.013 0.013 0.011 0.012 0.010 0.008 34.61 55.24 46.71 52.03 53.12 39.72 0.517 0.521 0.556 0.591 0.531 0.552 9.71 19.00 12.76 0.60 0.72 0.54 0.145 0.179 0.152 0.007 0.007 0.008 Page T-3'6 ThviBUS ------f Wt. to WtH. e a:rt % Lui12 Wt. % Thy]cold Wt. % Bra in . Wt. % Pituit;ary Wt. 7, 38.20 16.13 22.71 10.08 15.53 16.61 0.294 0.190 0.247 0.123 0.169 0.272 115.72 62.81 76.21 68.12 77.50 53.34 0.890 0.739 0.828 0.831 0.842 0.874 115.40 85.70 90.44 67.13 74.62 60.60 0.888 1.008 0.983 0.819 0.811 0.993 1 .37 0 .59 0 .93 0 .79 6 .73 0 .53 0.011 0.007 0.010 0.010 0.008 0.009 84.27 78.86 82.02 69.42 83.24 70.79 0.648 0.928 0.892 0.847 0.905 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 0.738 0.711 0.818 0.764 0.880 87.30 102.91 102.98 91.10 72.12 90.40 1.003 0.953 0.865 0.969 1.002 0.913 0 .72 0.90 0.82 0.74 0.86 0.72 0.008 0.008 0.007 0.008 0.012 0.007 78.35 77.45 92.08 86.68 68.21 73.05 0.901 0.717 0.774 0.922 0.947 0.738 0.072 0.071 0.07U 0.066 0.064 0.078 0.0008 0.0007 0.0006 0.0007 0.0009 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 ') 37.81 0.280 89.63 0.664 119.10 0.882 1. 35 0.010 84.98 0.629 0.031 0.0002 Sy . 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 0.230 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 0.696 0.833 0.726 0.694 0.840 0. 53 1. 32 0. 58 0. 62 0. 83 0. 97 0.008 0.012 0.007 0.007 0.008 0.013 70.70 79.51 80.91 78.35 73.31 68.41 1.055 0.750 0.963 0.890 0.733 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 i5Sffipan-y'gan??fes'dD. oes-no? con^aTn T5CA CS8 Page T-37 i ! j R-. n -^ Ninety-Day Feeding Study in the Dog. TABLE 31 Animal No and Grouo Hi!stopathologic Obserrations. Sex Tissue Comment Control: 65-1)70 65-083 65-086 65-038 M all tissues M all tissues M all tissues F skin 65-081 65-093 kidney F all tissues F kidney 100 Dom. 65-072 65-074 65-076 65-077 65-085 65-091 (Liver Only): M M M F F F 1000 ppm. 65-078 65-079 65-087 65-092 65-094 65-095 (Liver Only): M M M F F F No lesion.., No lesion,. No lesion, Folliculitis with lymphocyte and plasma infiltrate in corium. Moderate subaeu&e pyeloaephrtC-i-s. cell No lesions. Moderate subacute pyelonephritis. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. No lesion. . No lesion. A ' ^,,,,p,,^--^s^s--.:=^--,.--..^^',~~--~~--~ ' ^.,----.!- !-t/iTtfu!n sStrf'A Cu/ Page T-38 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 all tissues liver heart liver Hepafcocytes 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. j^mpa^ .Sanilized. Does not contain TSCA C^ Page T" 39 Ninety-Day Feeding Study in the Dog. w-------------------------------------------------------------------------------------------------------------------------------- TABLE 32. Summary of .Incidence of Histopathologic Lesions. Tissue and Lesion GO!atrol - 100 ppm. 1000 upm. 50015" ppm. :..31ale Female : Male Female :.Male Female L.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 adrenal - no lesion trachea - no lesion lung - no lesion heart -- no 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 - n& lesion pancreas - no le-sion 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 1/1 111 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 3/3 Z/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 'pompany^sawni .^"'""""^01" Page T-40 Ninety-Day Feeding Study in the Dog. TABLE 32, Continued. Tissue and Lesion Summary of Incidence of Histopathologic Lesions. Coiitrol Male Female 100 ppm. Male Female 1000 ppm. Male Female 500() ppm. Male Female liver - no lesion 3/3 3/3 - hepatocyte hypertrophy - portal infiltrate gall bladder - no lesion 3/3 3/3 kidney - no lesion 3/3 3/3 - subacute pyelonephritis 2/3 urinary bladder testis or ovary - no lesion no lesion 3/3 3/3 3/3 3/3 prostate or uterus - no lesion 3/3 3/3 skeletal muscle - no lesion 3/3 3/3 skin - no lesion 3/3 2/3 - folliculitis bone - no lesion 1/3 3/3 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 ^^%?' "^?'y;"; ^"V'.. -^ %^"?bf?w?iTSCA CBi