Document o2X780G1b62Jbr5rnzazxV3D

AR226-3185 DuPont-4739 TRADE SECRET Study Title H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations Volume 2 of 5 Laboratory Project ID: DuPont-4739 TEST GUIDELINES: U.S. EPA Health Effects Test Guidelines OPPTS 870.3100 (1998) AUTHOR: Don A. Delker, Ph.D. STUDY COMPLETED ON: October 23,2001 PERFORMING LABORATORY: E.L du Font de Nemours and Company Haskell Laboratory for Health and Environmental Sciences Elkton Road, P.O. Box 50 Newark, Delaware 19714-0050 WORK REQUEST NUMBER: nBBI| SERVICE CODE NUMBER:jiHVj SPONSOR STUDY NUMBER:!------1 Page 296 of 1537 'QeMpaySasaOjEwS. Doe^nol contain TSCA GBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM LIVER NO ABNORMALITY.DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. | TREATMENT | (mg/kg/day) LESION INCIDEN 0 50 II IV j (10) (10) 641344 6 641240 641260 6 641245 641298 6 641249 641311 6 641257 641312 6 641283|641313 6 641290]641336 6 641293|641355 6 641335 641361 6 641384 641369 6 641396 6 641283 641311 6 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 297 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT | (ing/kg/day) LESION INCIDEN 0 50 | II IV | PANCREAS NO ABNORMALITY DETECTED ATROPHY. (10) 641240 641245 641249 641283 641293 641384 [ [ | 641257 641290 641335 641344 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 298 -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT [ (nig/kg/day) 1 LESION INCIDEN 0 50 II IV ESOPHAGUS NO ABNORMALITY DETECTED . FIBROSIS. (10) 641240 641245 641249 641257 641283 641290 641293 641335 641384 641344 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 299 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFEE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM [ LESION INCIDEN | TREATMENT 0 50 | (mg/kg/day) II IV STOMACH NO ABNORMALITY DETECTED CYST, KERATIN. (10) 641240 641245 641257 641283 641290 641293 641335 641344 641384 641249 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 300 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDEN | TREATMENT 0 50 | (ing/kg/day) II IV DUODENUM (10) NO ABNORMALITY DETECTED . 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 . Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 301 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM JEJUNUM NO ABNORMALITY DETECTED . , | TREATMENT | (mg/kg/day) 1 LESION INCIDEN 0 | 50 II | IV \ (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 302 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFF NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT | (nig/kg/day) 1 LESIONIST INNCCIIDDEISN 0 50 II IV ILEUM NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 303 .-s '^:: .wliggi?6*^^' Xiay H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT | (mg/kg/day) LESION INCIDEN 0 50 II IV CECUM NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 304 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDENC 0 | 50 | II | IV | COLON NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 305 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM ( TREATMENT | (ing/kg/day) 1 LESION INCIDEN 0 50 II IV RECTUM NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 306 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS DIGESTIVE SYSTEM 1 LESION INCIDEN TREATMENT (mg/kg/day) | 0 II | 50 IV SALIVARY GLANDS (10) NO ABNORMALITY DETECTED - I S 3 S 0 641240 641245 641249 641257 641283 641290 641293 641335 [641344 |641384 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 307 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS URINARY SYSTEM | LESION INCIDEN | TREATMENT 0 50 | (mg/kg/day) II IV KIDNEYS NO ABNORMALITY DETECTED - NEPHROPATHY, CHRONIC PROGRESSIVE. INFLAMMATION, SUBACUTE/CHRONIC. HYDRONEPHROSIS, UNILATERAL. (10) 641240 641245 641249 641257 641283 641293 641344 641384 641290 641335 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 308 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS EN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS URINARY SYSTEM | LESION INCIDEN TREATMENT 0 50 (mg/kg./day) II IV URINARY BLADDER NO ABNORMALITY DETECTED " (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 309 1-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM | TREATMENT | (nig/kg/day) 1 LESION INCIDEN 0 50 II IV LUNGS NO ABNORMALITY DETECTED - INFLAMMATION, SUBACUTE/CHRONIC. (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 310 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 | 50 | I I II | IV | TRACHEA NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 311 -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS RESPIRATORY SYSTEM | LESION INCIDEN | TREATMENT 0 50 | (mg/kg/day) 1 II IV PHARYNX/LARYNX NO ABNORMALITY DETECTED . (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 312 H-24616: Subchronic Toxicity 90-Day Oavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESION INCIDEN LESIONS RESPIRATORY SYSTEM | TREATMENT 0 50 | (mg/kg/day) II IV NOSE (10) (10) NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. HYPERPLASIA/HYPERTROPHY, TRANSITIONAL CELL, EPITHELIUM. DEGENERATION/NECROSIS, OLFACTORY, EPITHELIUM. 641240 641260 6 641245 641298 6 641249 641311 6 641257 641312 6 641283 641336 6 641290 641355 6 641293 641361 641335 641396 641344 641384 6 6 641313 6 641369 6 6 6 | | Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates 'the lesion specified was not identified 313 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CARDIOVASCULAR SYSTEM | TREATMENT 0 50 | (ing/kg/day) II IV HEART NO ABNORMALITY DETECTED . - CARDIOMYOPATHY. (10) 641249 641257 641283 641290 641293 641335 641344 641384 641240 641245 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 314 W -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CARDIOVASCULAR SYSTEM | TREATMENT [ (mg/kg/day) LESION INCIDEN 0 50 II IV AORTA NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 315 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | TREATMENT | (mg/kg/day) LESION INCIDEN 0 | 50 II | IV SPLEEN NO ABNORMALITY DETECTED - PIGMENT INCREASED. (10) 641240 641245 641257 641283 641290 641293 641335 641344 641384 641249 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 316 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | TREATMENT [ (mg/kg/day) LESION INCIDEN 0 50 II IV THYMUS NO ABNORMALITY DETECTED . (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 317 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | LESION INCIDEN | TREATMENT | 0 | 50 | | (ing/kg/day) | | I I | II | IV | MAMDIBULAR LYMPH NODE NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 318 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AMD HEMATOPOIETIC SYSTEM | LESION INCIDEN | TREATMENT | 0 50 | (mg/kg/day) | 1 1 11 IV MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 |641335 |641344 |641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 319 -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDEN 0 50 II IV w & I s BONE MARROW NO ABNORMALITY DETECTED < (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified ^ ^ Q 320 '^'s^iy H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDENC 0 | 50 | II | IV PITUITARY GLAND NO ABNORMALITY DETECTED - (9) 641240 641245 641249 641283 641290| 641293[ 641335| 641344 641384| 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 321 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM THYROID GLAND NO ABNORMALITY DETECTED - HYPERTROPHY, FOLLICULAR. | TREATMENT | (mg/kg/day) LESION INCIDEN 0 50 II IV (10) (10) 641240 641260 6 641249 641311 6 641257 641336 6 641283 641361 6 641293 641396 641335 641384 6 6 ALTERATION, COLLOID. 641245 641298 6 641290 641312 6 641344 641313 6 641355 6 641369 6 6 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 322 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTTC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM | LESION INCIDENC | TREATMENT | (mg/kg/day) 1 | 0 | 1 II 50 IV V THYROID GLAND ALTERATION, COLLOID. (10) (10) Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 323 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Oeneration Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM TREATMENT (mg/kg/day) LESSIIOONNM INNCCIIDDEI3NNC 0 50 II IV PARATHYROID GLANDS NO ABNORMALITY DETECTED (8) 641240 641245 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 324 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS ENDOCRINE SYSTEM | LESION INCIDENC | TREATMENT 0 50 | (ing/kg/day) II IV ADRENAL GLANDS NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 325 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM | LESION INCIDEN | TREATMENT 0 50 [ (mg/kg/day) II IV BRAIN NO ABNORMALITY DETECTED . ? (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 326 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM | TREATMENT | (mg/kg/day) LESION INCIDEN 0 50 II IV SPINAL CORD NO ABNORMALITY DETECTED - (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 327 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS NERVOUS SYSTEM | TREATMENT 0 50 | (mg/kg/day) 1 II IV SCIATIC .NERVE NO ABNORMALITY DETECTED - (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 328 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 50 II IV SKELETAL MUSCLE NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 329 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM | LESION INCIDENC | TREATMENT 0 50 2 (mg/kg/day) II IV V FEMUR/KNEE JOINT NO ABNORMALITY DETECTED . (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 330 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM | LESION INCIDEN TREATMENT 0 50 (mg/kg/day) II IV STERNUM NO ABNORMALITY DETECTED , , (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 331 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDEN 0 50 II IV OVARIES NO ABNORMALITY DETECTED - (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 332 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFRE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS 0 REPRODUCTIVE SYSTEM UTERUS 3 ST 3" NO ABNORMALITY DETECTED . S i DILATATION, LUMEN. | LESION INCIDEN | TREATMENT 0 50 | (ing/kg/day) 1 II IV (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 333 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS REPRODUCTIVE SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDEN o 50 II IV | MAMMARY GLAND (FEMALE) NO ABNORMALITY DETECTED (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 334 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AEFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS CUTANEOUS SYSTEM | LESION INCIDEN | TREATMENT 0 50 [ (mg/kg/day) II IV SKIN NO ABNORMALITY DETECTED - (10) 641240 641245 641249 641257 641283 641290 641293 641335 641344 641384 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 335 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (90-DAY EXPOSURE EVALUATION) LESIONS SPECIAL SENSES SYSTEM [ TREATMENT | (mg/kg/day) LESION INCIDEN 0 50 II IV EYE(S) WITH OPTIC NERVE NO ABNORMALITY DETECTED . OPTIC NERVE NOT PRESENT. FOLD/ROSETTE, RETINAL. (10) 641240 641245 641249 641257 641283 641293 641335 641344 641384 |641335 [641290 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 336 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT [ (mg/kg/day) LESION INCIDEN 0 | 50 | II | IV | LIVER NO ABNORMALITY DETECTED NECROSIS, FOCAL. INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. (10) 641253 641266 641281 641294 641325 641331 641359 641364 641383 641400 641266 641383 641400| | 1 1 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 337 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 | 50 | II | IV | PANCREAS NO ABNORMALITY DETECTED ESOPHAGUS NO ABNORMALITY DETECTED STOMACH NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 338 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDENC I TREATMENT | 0 | 50 | (mg/kg/day) II IV DUODENUM NO ABNORMALITY DETECTED JEJUNUM NO ABNORMALITY DETECTED ILEUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 339 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM | TREATMENT [ (mg/kg/day) 1 LESION INCIDEN 0 50 II IV CECUM AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. COLON AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. RECTUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 340 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS DIGESTIVE SYSTEM | LESION INCIDENC | TREATMENT 0 50 | (ing/kg/day) II IV SALIVARY GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 341 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS URINARY SYSTEM | LESIOM INCIDEN TREATMENT (nig/kg/day) | 0 | j II | 50 | | IV KIDNEYS NO ABNORMALITY DETECTED URINARY BLADDER NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion-specified was not identified 342 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDENC 0 50 | II IV | LUNGS NO ABNORMALITY DETECTED TRACHEA NO ABNORMALITY DETECTED PHARYNX/LARYNX NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 343 H-24616: Subchronic Toxicity -w 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS RESPIRATORY SYSTEM | TREATMENT | (mg/kg/day) 1 LESION INCIDENC 0 50 II IV NOSE NO ABNORMALITY DETECTED . (10) 641253 641266 641281 641294 641325 641331 641359 641364 641383 641400 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 344 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS CARDIOVASCULAR SYSTEM | LESION INCIDENC TREATMENT | 0 | 50 (mg/kg/day) | | | II | IV V HEART NO ABNORMALITY DETECTED CARDIOVASCULAR SYSTEM AORTA NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 345 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LYMPHATIC AND HEMATOPOIETIC SYSTEM ] LESION INCIDEN | TREATMENT 0 50 | (ing/kg/day) II IV SPLEEN NO ABNORMALITY DETECTED THYMUS NO ABNORMALITY DETECTED MANDIBULAR LYMPH NODE NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 346 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS LYMPHATIC AMD HEMATOPOIETIC SYSTEM TREATMENT (mg/kg/day) LESION INCIDEN 0 50 II IV MESENTERIC LYMPH NODE NO ABNORMALITY DETECTED BONE MARROW NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion'specified was not identified 347 -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS APEE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM PITUITARY GLAND NO ABNORMALITY DETECTED THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. | TREATMENT | (mg/kg/day) 1 LESION INCIDEN 0 | 50 II | IV 1 (10) 641253 641281 641294| 641331 1 1 1 ALTERATION, COLLOID. 641266 641325 641359 641364 641383j 641400| AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 348 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS ENDOCRINE SYSTEM | LESION INCIDENC TREATMENT | 0 | 50 | (ing/kg/day) | | | I II | IV | V PARATHYROID GLANDS NO ABNORMALITY DETECTED ADRENAL GLANDS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 349 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS NERVOUS SYSTEM LESION INCIDEN TREATMENT (ing/kg/day) | 0 | I II 50 | IV | BRAIN MIXED GLIOMA [M]. SPINAL CORD NO ABNORMALITY DETECTED SCIATIC NERVE NO ABNORMALITY DETECTED [M] Malignant tumor Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 350 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFRE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS MUSCULAR AND SKELETAL SYSTEM | TREATMENT 0 50 | (mg/kg/day) 1 II IV SKELETAL MUSCLE NO ABNORMALITY DETECTED FEMUR/KNEE. JOINT NO ABNORMALITY DETECTED STERNUM NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 351 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS REPRODUCTIVE SYSTEM LESION INCIDEN - ---- - ] TREATMENT 0 50 [ | (mg/kg/day) II IV | OVARIES NO ABNORMALITY DETECTED UTERUS NO ABNORMALITY DETECTED Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion 'specified was not identified 352 ^y 4616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFEEC NEOPLASTIC AND NON-NEOPLASTIC LESIONS (ONE-MONTH RECOVERY EVALUATION) LESIONS SPECIAL SENSES SYSTEM | LESION INCIDENC TREATMENT | 0 | 50 | 2 (mg/kg/day) | | | I II | IV | V EYE(S) WITH OPTIC NERVE AUTOLYSIS: NECROPSY AND HISTOLOGY PERFORMED. Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 353 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERYEVALUATION) LESIONS DIGESTIVE SYSTEM TREATMENT (ing/kg/day) LESION INCIDENC 0 50 II IV LIVER NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. FATTY CHANGE, MEDIAN CLEFT. FATTY CHANGE, FOCAL. (5) (5) 641241 641321 6 641309 6 641285 641247 6 641288 641319 6 J641394 641340 6 641391 641247 6 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 354 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFFE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERYEVALUATION) LESIONS RESPIRATORY SYSTEM | LESSIIOOLN1 INCIDE:NN TREATMENT 0 50 (mg/kg/day) II IV NOSE NO ABNORMALITY DETECTED INFLAMMATION, SUBACUTE/CHRONIC. ATROPHY, UNILATERAL, NASAL GLANDS. (5) (5) 641241 641247 6 641309 641321 6 641340 6 641391 6 6 641285 641319 641288 641394 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 355 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 42 (CONTINUED) MICROSCOPIC OBSERVATIONS IN FEMALE RATS LISTING INDIVIDUAL ANIMALS AFPE NEOPLASTIC AND NON-NEOPLASTIC LESIONS (3-MONTH RECOVERYEVALUATION) LESIONS ENDOCRINE SYSTEM | TREATMENT [ (mg/kg/day) 1 LESION INCIDENC 0 50 II IV THYROID GLAND NO ABNORMALITY DETECTED HYPERTROPHY, FOLLICULAR. ALTERATION, COLLOID. (5) (5) 641285 6 641288 641241 641247 6 641309 641319 6 641394 641321 6 641340 6 641391 Figure in parentheses is number of animals microscopically examined for this tissue The absence of a number indicates the lesion specified was not identified 356 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 43 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS (grams) OF Pi MALE RATS GROUP DOSE (mg/kg/day) N TEST DAYS 71 78 85 92 100 1-0 III-0 V -0 VII-0 0 50 2 50 1000 20 20 20 20 MEAW BODY WEIG1HT (g ramis) 545.2(60 .4)^ 558.9(63 .3) 570.7(65 .7) 582.3(66 .8) 591.7(70 .6) 543 .0(41 -7) 551 .9(46 .1) 561 .7(42 .6) 570 .7(44 .3) 578 .8(43 -3) 535 .4 (42 .5) 548 .4 (48 .1) 556 .4 (49 .1) 567 .8 (53 .1) 576 .4 (54 .6) 489.8(50. 6)* 502.3(54. 4)* 506.7(52. 6)* 519.6(52. 3)* 526.7(55. 0)* GROUP 1-0 III-0 V-0 VII-0 DOSE 0 50 250 1000 (mg/kg/day) N 20 20 20 20 TEST DAYS3 MEAN BODY WEIGHT GAIN (grams) 71-78 78-85 85-92 92-100 13.7 ( 11.8( 11.6( 9.4( 7. 4)A 4. 7) 8. 9) 9. 4) 8 .9(16 .7) 9 .8(10 .1) 9 .0(14 .7) 8 .!( 8 .7) 13 .0 (11 .0) 8 .0 ( 7 .7) 11 .3 ( 8 .3) 8 .7 ( 9 .6) 12.5 ( 8. 6) 4.4(14. 8) 12. 9 ( 6. 9) 7.1( 9. 3) 71-100 46-5(19.0) 35.8(15.9) 41.0(16.8) 36.9(14.2) a Cohabitation period = Test days 69-92. b Standard deviation is reported in parentheses. * Statistically significant difference from control by One-Way Analysis of Variance and Dunnett's tests; (p < 0.05). 357 BWBlpattySanRfzed. Does not c""'*-'- -'' oiqj H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 44 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS (grams) OF Pi FEMALE RATS DURING GESTATION GROUP DOSE (mg/kg/day) N GESTATION DAY 0 7 14 21 II-O 0 16 IV-0 50 18 VI-0 250 13 306. 0(23.0)3 335. 3(24.6) 366. 6(29.8) 456. 6(27.8) MEAN BODY WEIGHT (grams) 310.0(28.0) 336.8(31.5) 366.0(34.9) 461.6(39.5) 299 .9(21.7) 325 .5(22.9) 356 .9(28.8) 450 .7(28.0) VIII-0 1000 18 295. 3(26.9) 317. 9(28.6) 350. 4(32.2) 445. 1(44.1) GROUP DOSE (mg/kg/day) N II-O 0 16 IV-0 50 18 VI-0 250 13 VIII-0 1000 18 GESTATION DAYS MEAN BODY WEIGHT GAIN (grams) 0-7 7-14 14-21 29.3( 7.9) 31.3( 8.6) 90.2(12.9) 26.8( 8.3) 29.2( 6.1) 91.6(14.6) 25.6( 6.6) 31.4( 7.2) 92.!( 7.3) 22.6( 7.6) 32.5( 6.0) 93.9(14.7) 0-21 151.7(17.8) 148.8(22.4) 148.3(14.4) 149.0(20.7) a Standard deviation is reported in parentheses. There were no statistically significant differences from control by One-Way Analysis of Variance (p < 0.05). Company Sanitized. Does not contain TSCA CBt 358 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 45 MEAN BODY WEIGHTS AND BODY WEIGHT GAINS (grams) OF Pi FEMALE RATS DURING LACTATION GROUP DOSE (mg/kg/day) N LACTATION DAY 0 7 14 21 11-0 0 18 IV-0 50 18 VI-0 250 13 349 .6(28 .5)3 347 .6(24 .1) 364 .8(24 .0) 349 .6(23 .0) MEAN BOIDY WE:IGHT (graitis) 350 .5(34 .1)^ 344 .4(26 .7) 362 .1(26 .6) 347 .6(25 .5) 337 .7(29 -0) 343 .6(26 .3) 356 .4(23 .9) 344 .8(22 .5) \/III-13 1000 18 336 .8(35 .6) 337 .4(32 .7) 356 .3(29 .9) 339 .2(27 .5) GROUP DOSE (ing/kg/day) N II-O 0 18 IV-0 50 18 VI-0 250 13 VIII-0 1000 18 LACTATION DAYS MEAN BODY WEIGHT GAIN (grams) 0-7 7-14 14-21 -2.0(12.3) 17.2(15.7) -15.2(10.0) -7.1(17 .2) 17.6(13 .5) -14.5( 9 .1) 5.8 (15.6) 11.6 ( 9.6) -11.6 (12.5) 0.6(15.2) 18.9(14.7) -17.1(12.7) 0-21 0.0(17.9) -4.1(23 .7) 7.5 (18.4) 2.3(16.8) a Standard deviation is reported in parentheses. h N = 17. There were no statistically significant differences from control by One-Way Analysis of Variance (p < 0.05). 359 .Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 46 MEAN DAILY POOD CONSUMPTION (grams) AND FOOD EFFICIENCY (grams weight gain/grams food consumed) BY Pi FEMALE RATS DURING GESTATION. GROUP DOSE (mg/kg/day) N GESTATION DAYS 0-7 7-14 0-14 II-O 0 16 IV-0 50 18 VI-0 250 13a VIII-0 1000 18 MEAN DAILY FOOD CONSUMPTION (grams) 24.9( 1.9}b 27.4( 2.6) 26.2( 2.1) 25.0( 3.2) 26.9( 3.5) 26.0( 3.2) 23.8( 2.2) 25.9( 3.0) 24.9( 2.6) 23.3( 2.8) 25.0( 3.0) 24.!( 2.8) GROUP DOSE (mg/kg/day) N II-O 0 16 IV-0 50 18 VI-0 250 13 VIII-0 1000 18 GESTATION DAYS MEAN POOD EFFICIENCY (grains weight gain/grams food consumed) 0-7 7-14 0.168(.045) 0.162(.038) 0.15K.037) 0.155(.025) 0.153(.035) 0.173(.026) 0.138(.040) 0.185(.024) 0-14 0.165(.026) 0.153(.020) 0.163(.023) 0.163(.019) a N = 17 for Days 7-14 and Days 0-14 intervals. b Standard deviation is reported in parentheses. There were no statistically significant differences from control by One-Way Analysis of Variance (p < 0.05). 360 ysmpsny Sanitized. Does not contain TSCA CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 47 SUMMARY OF CLINICAL OBSERVATIONS IN Pi RATS PI MALE RATS DOSE GROUP (nig/kg/day) N OBSERVATIONS Alopecia Lung Moise Sore Tail Total Ho. of Rats with Masses Number of Rats with Given Sign 1-0 III-O V-0 VII-0 0 50 250 1000 20 20 20 20 6 3 2 4 0 1 0 0 1 0 1 0 0 0 0 0 PI FEMALE RATS DURING GESTATION DOSE GROUP (mg/kg/day) N OBSERVATIONS Alopecia Total No. of Rats with Masses Number of Rats with Given Sign II-O IV-0 VI-0 VIII-0 0 50 250 1000 18 18 13 18 PI FEMALE RATS DURING LACTATION DOSE GROUP (mg/kg/day) N Number of Rats with Given Sign II-O IV-0 VI-0 VIII-0 0 50 250 1000 18 18 13 18 OBSERVATI:ONS Alopecia 2 6 4 6 Total No. of Rats wi.th Masses 0 0 0 1 Site: Mass IFOa (3 .5 cm) Side(s) 0 0 0 1 Mass 2FO (2 .0 cm) Side(s) 0 0 0 1 a FO = First Observed. There were no statis tically significant trends by Cochran-Armitage test; p < 0. 05. 361 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 48 MEAN ESTROUS CYCLE PARAMETERS AND PRECOITAL INTERVAL Pi FEMALE RATS Mean Dose Perciant Percerit Percienfc Mean Cycle Precoifcal (mg/kg/day) of Days in of Days in of Dasrs in Length Interval Group M Estrus Diestrus Proes fcrus (days) (days) II-O 0 18 19(8 -I)3 69(9. 5) IV-0 50 20 22(7 .9) 67(9. 5) VI-0 250 20 22(7 .2) 63(8. 8) VIII-0 1000 20 24(8 .8) 64(10 .8) a Standard deviation is presented in parentheses. jb N = 18 c N = 19 12(7 .6) 11(6 .4) 15(7 -9) 11(8 .3) 4.9(1.6) 4.8(0.7)b 4.5(0.9) 4.6(0.6)d There were no significant trends by Jonckheere-Terpstra test; p < 0.05. 2.8(1.6) 3.8(3.0) 2.6(2.3)c 2.7(1.7) 362 .Company Sanitized. Does not ww" ''"WA ir*R| H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 49 SUMMARY OF SPERM PARAMETERS IN Pi MALE RATS Gr oup 1-0 Dose (mg/kg/day) 0 MOTILII'Y Perc;ent Motile S.D. 92 .9 3 .3(10)a MORPHOLOGY Percent Normal S.D 98 .6 1 .0(10) EPIDIDYMAL SPERM (Millions) Per Cauda S.D 313 .9 26 .1(10) Per gram Cauda S.D 1109 .8 179 .7(10) TESTICUIAR SPERMATIDS Per Tesfcis S-D. (Millions3) 150 .2 29 .0(10) Per gram Testis S.D. 93 .8 10 .9(10) ] :II-0 50 92 .9 3 .2(10) 98 .1 1 .1(10) 324 .4 30 .5(10) 1182 .8 136 .4(10) 152 .5 18 .5(10) 99 .2 10 .7(10) V-0 250 92 .4 1 .8(10) 97 .9 1 .4(10) 321 .4 41 .6(10) 1175 .0 118 .4(10) 155 .9 36 .5(10) 99 .3 19 .6(10) VII-0 1000 90 .1 6 -5(9) 97 .7 1 .4(9) 321 .3 39 .2(10) 1134 .9 151 .3(10) 150 .5 25 .4(10) 100 .3 10 .6(10) a Number in group is in parentheses. There were no significant trends by Jonkheere-Terpstra test; p < 0.05. 363 ampany Sanitized, n^, ,,,,, ,,.,,.,,,, -r^ ggt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 50 SUMMARY OF REPRODUCTIVE INDICES: Pi GENERATION MM'ERNAL GROUP DOSE (mg/kg/day) II-O 0 IV-0 50 VI-0 250 VIII-0 1000 MATING INDEX (%) (# copulated/cohoused) 100.0 (20/20) 100.0 (20/20) 95.0 (19/20) 100.0 (20/20) FERTILITY INDEX (%) (# delivered/copulated) 90.0 (18/20) 90.0 (18/20) 68.4 (13/19) 90.0 (18/20) GESTATION LENGTH (days) 21.9 21.9 22.0 21.9 Number of Implantation Sites per pregnant female 14.9 (3.47)a 14.9 (2.19) 15.7 (1.87) 15.4 (2.04) Implantation Efficiency (%)^' 91.2 (10.54) 91.2 (12.51) 87.1 (9.88) 93.8 (7.13) a Standard deviation for Number of Implantation Sites and Implantation Efficiency is reported in parentheses. h Number of pups born/number of implantation sites X 100. Determined for each litter. There were no statistically significant trends in mating or fecundity indices by Cochran-Armitage test; p < 0.05. There was no statistically significant difference from control in gestation length by One-Way Analysis of Variance; p < 0.05. There were no statistically significant trends in number of implantation sites or implantation efficiency by Jonckheere-Terpstra test; p < 0.05. 364 BaiflpaagBf asRtod. Does not contain TSCA CBJ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 51 MEAN PUP NUMBERS AND SURVIVAL: Fi GENERATION MATERNAL GROUP DOSE (xng/kg/day) N II-O 0 18 IV-0 50 18 VI-0 250 13 VIII-0 1000 18 Bom Born Alive Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 MEAN NUMBER OF PUPS/LITTER 13.9 13.7 13.4 7.9 7.9 7.9 7.9 13.8 13.8 13.5 7.8 7.8 7.8 7.8 13.5 13.4 13.2 8.0 7.4a 7.9a 7.93 14.8 14.6 14.5 7.9 7.9 7.9 7.9 Born Born Alive Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 MEAN NUMBER OF MALE PUPS/LITTER 6.6 6.4 6.6 6.4 6.5 6.2 3.9 3.8 3.9 3.8 3.9 3.8 3.9 3.8 7.2 7.1 7.2 6.9 7.2 6.8 4.0 4.1 3.73 4.1 4. a3 4.1 4. a3 4.1 Born Born Alive Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 MEAN NUMBER OF FEMALE PUPS/LITTER 7.3 7.4 7.1 7.4 6.9 7.3 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 6.3 7.7 6.2 7.7 6.0 7.7 4.0 3.8 3.78 3.8 3.93 3.8 3. 9s 3.8 Sex Ratio^ 0.48 0.45 Gestation Index0 Mean % Pups Born Alive 0-4 Day Viability 100.0 98.3 98.4 100.0 99.6 98.2 Lactation Indexd 100.0 100.0 Litter Survivals 100.0 100.0 a N = 12. jb Number of male fetuses/total number of fetuses per litter. c Percent litters delivered having at least one live pup. d Mean percent survival from day 4 postculling to day 21. e Percent litters born with at least one pup-alive on day 21. 0.53 100.0 98.9 98.3 99.0 92.3 0.48 100.0 98.5 99.3 100.0 100.0 No statistically significant trend in sex ratio by linear contrast of least square means; p < 0.05. No statistically significant trend in mean numbers of pups, mean % born alive, 0-4 Day Viability, Lactation Index, or Litter Survival by Jonckheere-Terpstra test; p < 0.05. Statistics were performed on combined pups per litter only. Male and female data are presented for information only. 365 i|BWBsyanRteetf. Does not ewan TgeA CBt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLEi52 MEANPUP WEIGHTS (GRAMS): FiGENERATION<1 MATERNAL (5ROUP DOSE (mg/kg;'day) N II-O 0 18 IV-0 50 18 VI-0 250 13 M[EAN PUI? WEIGHTS Day 0 Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 6.6 (0.6)^ 11.2 (1.5) 11.3 (1.5) 18.0 (1.9) 37.6 (2.4) 60.0 (4.1) 6 .6 (0.5) 11 .0 (1.4) 11 .0 (1.4) 17 .7 (2.0) 37 .3 (2.9) 59 .5 (5.1) 6.5 (0 .6) 10.6 (1 .7) 10.6 (1 .8) 17.5 (1 .9)C 37.1 (2 .8) 59.4 (4 -2)C VIII- 0 1000 18 6.3 (0 .4) 10.4 (1 .0) 10.4 (1 .1) 17.2 (1 .5) 36.3 (2 .5) 57.8 (3 .9) MEAN MALE PUP WEIGHTS Day 0 Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 6.8 (0.7) 11.5 (1.4) 11.5 (1.4) 18.3 (1.9) 38.1 (2.6) 61.5 (4.7) 6 .8 (0.6) 11 .4 (1.7) 11 .4 (1.6) 18 .2 (2.3) 38 .2 (3.4) 61 .4 (6.4) 6.7 (0 .6) 10.9 (1 .8) 10.8 (1 .8) 17.8 (1 .8)C- 37.7 (2 .6)0 61.0 (3 .8)0 6.5 (0 5)d 10.6 (1 .1) 10.7 (1 .1) 17.5 (1 .5) 37.0 (2 .7) 59.4 (4 .1) MEAM FEMALE PUP WEIGHTS Day 0 Day 4 Preculling Day 4 Postculling Day 7 Day 14 Day 21 6.5 (0.6) 11.0 (1.6) 11.1 (1.6) 17.8 (1.9) 37.1 (2.4) 58.8 (3.9) 6 .4 (0.5) 10 .7 (1.3) 10 .8 (1.4) 17 .2 (2.0) 36 .6 (3.0) 58 .2 (5.1) 6.4 (0 .6) 10.4 (1 .7) 10.4 (1 .7) 17.2 (1 .9)c 36.5 (3 .0)'=- 58.0 (4 .4)c 6.1 (0 .4)d 10.2 (0 .9) 10.2 (1 .0) 16.8 (1 .5) 35.6 (2 .3) 56.1 (3 .5) a Individual pup weights are presented in Appendix EE. b Standard deviation is reported in parenthe.ses. c N = 12. d One litter was excluded due to one pup being missexed. There were no statistically significant trends by linear contrast of least square means; p < 0.05. Note: Statistical analyses were conducted on the combined pup weights. female data are presented for information only. Male and 366 tesspany Sanitized. Boes not cwta ire^ ^ H-24616: Subchronic Toxicity ______ 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 53 SUMMARY OF PUP CLINICAL OBSERVATIONS DURING LACTATION MATERNAL GROUP DOSE (mg/kg/day) II-O 0 IV-0 50 VI-0 250 VIII-0 1000 OBSERVATIONS Corneal Opacity Swollen Head 0 0 0 TOTAL NUMBER OF SIGNS NUMBER OF LITTERS AFFECTED TOTAL NUMBER OF LITTERS 0 1(1) 18 18 Id)3 0 0 13 18 0 1 0 1 a Numbers outside the parentheses are the number of pups affected; the numbers in parentheses are the number of litters affected. There were no statistically significant trends by Cochran-Armitage test; p < 0.05. 367 B^ompanySanitized. Daes mf w"o'-> re^a i H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 54 MEAN BODY WEIGHTS (grams) AND MEAN BODY WEIGHT GAINS OFFi MALE RATS GROUP DOSE (mg/kg/day) N DAYS ON TESTS 1 8 15 22 29 36 43 I -1 III-1 V-1 0 50 250 L8 18 12 60 .8 ( 4 .8)^ 104 .2 ( 6 .2) 168 .5 (.9 .2) 229 .4 (18 .5) 295 .3 (21 .1) 358 .1 (25 .9) 410 .0 (32 .5) MEAN BOOY WESIGHT (granis) 59 .8( 6 .5) 105 -3( 9 .8) 171 .3(13 .5) 232 .8(20 .1) 299 .8(22 -2) 362 .2(25 .5) 419 .5(30 .8) 61 .7( 4 .4) 103 -8( 7 .4) 167 .8(11 .2) 226 .8(16 .8) 291 .8(25 .1) 350 .1(35 .6) 396 .3(40 .3) VII-1 1000 18 58 .5( 5.0) 100 .8(10.2) 162 .8(14.8) 224 .3(19.7) 287 .5(24.0) 347 .8(28.7) 399 .2(32.2) GROUP 1-1 DOSE 0 (mg/kg/day) N 18 III-1 50 18 V-1 VII-1 250 1000 12 18 DAYS ON TEST'3 MEAN BODY WEIGHT GAIN (grams) 1-8 8-15 15-22 22-29 29-36 36-43 43.5( 4.0) 64.3( 5.2) 60.9(12.4) 65.9(10.8) 62.8( 7.1) 52.0( 9.8) 45.5( 5.2) 66.0( 5.1) 61.6(11.7) 67.0(12.7) 62.4(10.2) 57.3( 7.5) 42.1( 4.3) 63.9( 5.0) 59-0( 8.1) 65.0(14.2) 58.4(12.8) 46.1(10.0) 42.2( 6.1) 62.!( 5.6) 61.4( 8.1) 63.2(10.1) 60.4( 8.2) 51.4( 5.3) 1-43 349.3(31.1) 359.7(28.1) 334.5(37.6) 340.6(29.1) a Day of Weaning = Test Day 1. > Standard deviation is reported in parentheses. There were no statistically significant differences from control by One-Way Analysis of Variance (p < 0.05). 368 , Does not eontatn rsra i^m H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 55 MEAN BODY WEIGHTS AND MEAN BODY WEIGHT GAINS (grams) OP Fi FEMALE RATS GROUP DOSE (mg/kg/day) N DAYS ON TEST*3 1 8 15 22 29 36 43 11-1 0 18 IV-1 50 18 VI-1 250 12 59. K 4.5) 98. 3( 4.8) 144. 5( 7.4) 182. 2( 9.9) 206. 6(11.5) 229. 2(13.1) 247. 8(16.5) MEAN BODY WEIGHT (grams) 56.6( 5.5) 95.2( 6.4) 143.8(10.7) 177.8(13.0) 204.1(17.4) 227.3(21.9) 248.8(25.1) 57.2( 6.5) 96.0( 9.8) 144.8(13.2) 182.4(18.0) 206.1(19.9) 229.0(25.4) 251.2(33.4) VIII-1 1000 18 55.2( 3.8) 92.5( 6.0) 139.6( 8.8) 174.7( 9.2) 197.9(12.7) 224.1(16.7) 240.1(17.2) GROUP DOSE (mg/kg/da^r) N I:[-1 0 : L8 IV--1 5C1 !i VI-1 250 12 /^ II:r-l 10130 113 DAYS OM TEST MEAN BOI)Y WEIG:HT GAIW (g:rams) 1-8 8-15 15-22 22-29 29-36 36-43 39.2 ( 46.2 ( 37.7 ( 24.4 ( 22.7 ( 18.6 ( 4 .3) 4 -7) 6 .8) 5 .3) 5 -4) 8 .2) 38. 7( 48. 5( 34. 0( 26. 3( 23. 2( 21. 5( 4 .2) 5 .7) 7 .6) 8 .0) 7 .3) 7 .0) 38.7( 4 .8) 48.8( 4 .7) 37.7( 6 .1) 23.6( 8 .8) 22.9( 7 .5) 22.3( 9 .1) 37 3( 3.8) 47 -0( 4.9) 35 2( 5.5) 23 2( 5.8) 26 -2( 8.0) 15 9( 5.7) 1-43 188.7 (14 .4) 192. 3(24 .4) 194.0(29 .7) 184 .8(16.4) a Day of Weaning = TeiSt Day 1. Jb Standard deviation is reported in parentheses. There were :no statistically signifi<;an t diff('rences from control by One-Way Analysis of Variance (p < 0.05) . 369 Company Sanitized. Does ist eorrtain TSCA CBi H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 56 MEAN DAILY FOOD CONSUMPTION (grams) AND MEAN FOOD EFFICIENCY (grams weight gain/grams food consumed) BY Fi MALE RATS GROUP DOSE (mg/kg/day) N DAYS ON TESTa 1-8 8-15 15-22 22-29 29-36 36-43 1-43 I- 1 III-3 V- 1 VII--1 0 50 25 0 100 0 li3 18 1;2 18 MEAN DAILY PiOOD C(3MSUMPTK3N (grains) 13 -9( 21 -3( 25 -1( 29 -9( 31 .8( 32 .7( 25 .8( 0.9)^ 1.3) 2.2) 2.1) 1.8) 3.1) 1.4) 14 .0( 21 .8( 26 .0( 30 .7( 32 .!( 34 .0( 26 .4( 1 .5) 1 .8) 2 -4) 2 .9) 3 .0) 3 .4) 2 .1) 14 -2( 1.7) 21 -3( 2.1) 25 -3( 2.1) 29 8( 2.8) 31 5( 3.5) 31 -4( 3.2) 25 6( 2.2) 13 -3( 1.3) 20 6( 1.9) 25 .2( 2.5) 29 4( 3.2) 31 -4( 3.1) 31 6( 4.8) 25 -2( 2.3) GROUP 1-1 DOSE 0 (ing/kg/da^ r) W 18 III- 1 50 18 V-1 2501 12 VI:1-1 1C100 1.8 DAYS ON TEST MEAN POOD EFFTCIENC;y (gi-ams t /eight gain/grains foo<i consi;imed!1 1-8 8-15 15-22 22-29 29-36 36-43 0.448(. 031) 0.432(. 031) 0.345(. 049) 0.315(. 042) 0.282(. 026) 0.226(. 029) 0 .463(. 026)) 0 -434(. 029) 0 .338(. 053) 0 -310(. 033) 0 277(. 031) 0 .241(. 018) 0.428( .051) 0.433( .045) 0.333( .039) 0.310( .045) 0.263( .033) 0.209( .040) 0. 452 (.038) 0. 431 (.028) 0. 348 (.033) 0. 307 (.031) 0. 275 (.029) 0. 239 (.057) 1-43 0.322(. 017) 0 .324(. 011) 0.311( .021) 0. 322 (.016) a Day of Weaning = Test Day 1. jb Standard deviation is reported in parentheses. There were no statistically significant differen ces from control by One-Way Analysis of Variance (p < 0. 05). 370 iKcwmpanSy anitized. Does not contain TSCA 6B) H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 57 MEAN DAILY POOD CONSUMPTION (grains) AND MEAN FOOD EFFICIENCY (grams weight gain/grams food consumed) BY Fl FEMALE RATS GROUP DOSE (mg/kg/day) N DAYS ON TEST'3 1-8 8-15 15-22 22-29 29-36 36-43 1-43 II--1 0 li3 IV--1 51) li3 VI--1 25 0 1;2 VII I- 1 10 00 1 8 MEAN DAILY piOOD CONSUMPTK)N (grams) 13 4( 18 7( 20 3( 21 6( 21 -3( 21 -9( 19 -5( 2 .2)b 1 -1) 1 .7) 1 .5) 1 .9) 2 .3) 1 .2) 12 -7( 18 -7( 19 -3( 20 .8( 21 -6( 22 .4( 19 -2( 0 -9) 1 -6) 4 .4) 2 .0) 2 .2) 2 .7) 1 .7) 13 .0( 18 -7( 21 -Of 21 .3( 21 .7( 22 6( 19 .7( 0 -9) 1 -4) 1 .4) 1 -9) 3 -2) 3 .3) 1 .8) 12 -7( 18 -0( 19 .9( 20 -0( 21 .6( 21 K 18 -9( 0 .9) 1 .1) 1 .7) 3 .2) 2 .3) 2 .4) 1 .5) GROUP DOSE (mg/kg/da:;^) N II-]L 0 18 IV-1 50 18 .VI-:L 250i 12 VII:r-l 10100 I!3 DAYS ON TEST3 MEAN FOOD EFFI CIEMCY (girams w<sight igain/cframi3 f001i consulmed) 1-8 8-15 15-22 22-29 29-36 36-43 0.429(. 086) 0.353(. 036) ) 0.265(. 044) 0.16K. 029) 0.15K. 028) 0.12K. 052) 0 .437(. 044) 0 371(. 027) 0 -310(. 307) 0 -178(. 046) 0 .152(. 040) 0 -136(. 038) 0 .425( .038) 0 -372( .032) 0 256( .029) 0 .157( .058) 0 148( .033) 0 -137( .045) 0. 420 (.030) 0. 373 (.026) 0. 252 (.035) 0. 169 (.054) 0. 172 (.047) 0. 108 (.037) 1-43 0.230(. 012) 0 238(. 019) 0 .233( .022) 0. 233 (.011) a Day of Weaning = Test Day 1. > Standard deviation is reported in parentheses. There were no statistically significant diffe:rences from control by One-Way Analysis of Variance (p < 0. 05). 371 'Company Sanitized. Does not contain TSCA C^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 58 SUMMARY OP CLINICAL OBSERVATIONS IN Fi RATS Fi MALE RATS DOSE GROUP (mg/kg/day) N OBSERVATIONS Corneal Opacity Total No. of Rats with Masses Number of Rats with Given Sign 1-1 III-l V-l VII-1 0 50 250 1000 18 18 12 18 0 0 0 1 0 0 0 0 Fi FEMALE RATS DOSE GROUP (mg/kg/day) N Number of Rats with Given Sign II-l IV-1 VI-1 VIII-l 0 50 250 1000 18 18 12 18 OBSERVATIONS There were no abnormal clinical signs observed, in the FI Female Rats. Total No. of Rats with Masses There were no statistically significant p < 0.05. trends 0 0 0 by Cochran-Armitage 0test; 372 Company Sanitized. Does not contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 59 SUMMARY OF DEVELOPMENTAL LANDMARKS IN Fi RATS PREPUTIAL SEPARATION - Fi MALE RATS III-l GROUP 1-1 V-l DOSE (mg/kg/day) 0 50 250 M 18 18 lia AGE (Days)^ 48.8 1.9 48.8 2.7 48.9 3.4 VII-1 1000 18 48.8 1.9 VAGINAL OPENING Fi FEMALE RATS DOSE GROUP (mg/kg/day) N II-l 0 18 IV-1 50 18 VI-1 250 12 VIII-1 1000 18 AGE (Days)-13 32.3 3.2 34.6 3.6 34.5 3.7 32.9 2.6 Data summarized as: Mean Standard Deviation a One animal in this group (n=12) had incomplete preputial separation. b Test day preputial separation or vaginal patency was complete (Appendix LL) +20 days (Day of Weaning = Test Day 1) There were no statistically significant trends by Jonckheere- Terpstra test; p < 0.05. 373 Qossfwsy SoiiSIzed, Does not sonta'n TSCA if^S H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 60 MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - Pi ADULTS Group 1-0 0 ing/kg/day Group III-0 50 mg/kg/day Group V-0 Group VI1-0 250 mg/kg/day 1000 mg/kg/day THYROID 0.023 0.006(20 ) 0.024 0.005(20 ) 0.022 0.003(20 ) 0.024 0.006(19 ) FINAL BODY 602.387 79.955(15 ) 592.060 41.996(15 ) 594.387 55.508(15 ) 537.547# 61.934(15 ) THYROID/FINAL BODY * 100 0.004 0.001(15 ) 0.004 0.001(15 ) Data summarized as: Mean Standard Deviation (n) ^Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. 0.004 0.001(15 ) 0.005 0.001(14 ) 374 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 61 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Pi ADULTS Group II-O 0 mg/kg/day Group IV-0 50 mg/kg/day Group VI-0 Group VIII-0 250 nig/kg/day 1000 mg/kg/day THYROID 0.018 0.006(19 ) 0.020 0.005(20 ) 0.019 0.005(19 ) 0.017 0.005(20 ) FINAL BODY 347.616 22.976(19 ) 351.930 27.966(20 ) 352.084 27.217(19 ) 339.920 27.685(20 ) THYROID/FINAL BODY * 100 0.005 0.002(19 ) 0.006 0.002(20 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. 0.006 0.001(18 ) 0.005 0.002(20 ) 375 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 62 MEAN FINAL BODY AND ORGAN WEIGHTS PROM MALE RATS - Pi ADULTS MEAN FINAL BODY AMD ABSOLUTE ORGAN WEIGHTS (grams) Group 1-1 0 mg/kg/day BRAIN 1 .944 0 .092(18 ) EPIDIDYMIDES 0 .838 0 .090(17 ) TESTES 3 .216 0 .181(18 ) SEMINAL VESICLES 1 .266 0 .208(18 ) PROSTATE 0 .480 0 .118(18 ) THYROID 0 .024 0 .004(18 ) LIVER 18 .588 2 .117(18 ) FINAL BODY 410 .044 32 .544(18 ) III-l Gnoup 50 mg/kg/day 1 .992 0 .046(18 ) 0 .816 0 .064(18 ) 3 .220 0 .182(18 ) 1 .211 0 .125(18 ) 0 .510 0 .112(18 ) 0 .023 0 .005(18 ) 18 .910 1 .909(18 ) 419 .539 30 .808(18 ) Group V-1 Group VI1-1 25 0 mg/kg/day 1000 mg/kg/day 1 .957 0 .135(12 ) 1.945 0.069(18 ) 0 .816 0 .110(12 ) 0.797 0.084(18 ) 3 .289 0 .298(12 ) 3.230 0.262(18 ) 1 .176 0 .355(12 ) 1.233 0.232(18 ) 0 .442 0 .117(12 ) 0.494 0.079(18 ) 0 .018# 0 .002(12 ) 0.017# 0.004(18 ) 17 .638 2 .933(12 ) 17.538 1.846(18 ) 396 .267 40 .274(12 ) 399.172 32.215(18 ) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group 1-1 0 mg/kg/day Group III-l 50 mg/kg/day SEMINAL VESICLES/FINAL BODY * 100 0.311 0.058(18 ) 0.289 0.029(18 ) PROSTATE/FINAL BODY * 100 0.117 0.029(18 ) 0.122 0.028(18 ) THYROID/FINAL BODY * 100 0.006 0.001(18 ) 0.005 0.001(18 ) LIVER/FINAL BODY * 100 4.530 0.299(18 ) 4.508 0.324(18 ) Group V-1 250 mg/kg/day 0.292 0.072(12 ) 0.111 0.029(12 ) 0.005# 0.000(12 ) 4.429 0.415(12 ) Group VI1-1 1000 mg/kg/day 0.309 0.053(18 ) 0.124 0.019(18 ) 0.004# 0.001(18 ) 4.394 0.333(18 ) 376 jp^fflparaySanitized. Does not eonta'ii TSCA CBJ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 62 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FROM MALE RATS - Fi ADULTS MEAN RELATIVE ORGAN WEIGHTS (organ to brain weight ratio) Group 1-1 0 mg/kg/day EPIDIDYMIDES/BRAIN * 100 43.092 4.880(17 ) TESTES/BRAIN * 100 165.640 9.696(18 ) SEMINAL VESICLES/BRAIN * 100 65.199 10.721(18 ) PROSTATE/BRAIN * 100 24.737 6.146(18 ) THYROID/BRAIN * 100 1.226 0.193(18 ) LIVER/BRAIN * 100 957.214 107.680(18 ) Group II1-1 50 mg/kg/day Group V-l Group VI1-1 250 mg/kg/day 1000 mg/kg/day 40.980 3.106(18 ) 41.625 4.514(12 ) 41.005 4.152(18 ) 161.745 10.539(18 ) 167.892 6.878(12 ) 166.283 14.473(18 ) 60.796 6.240(18 ) 59.705 17.228(12 ) 63.447 12.062(18 ) 25.601 5.600(18 ) 22.671 6.578(12 ) 25.415 4.149(18 ) 1.140 0.267(18 ) 0.913# 0.128(12 ) 0.862# 0.183(18 ) 949.177 94.524(18 ) 898.080 116.996(12 ) 901.506 87.354(18 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpsfcra). # Statistically significant difference at p < 0.05. 377 JOssapsaSyanitized. Does not conSabi TSCA CBi H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 63 MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fi ADULTS MEAN FINAL BODY AMP ABSOLUTE ORGAN WEIGHTS (grams) Group II-l 0 mg/kg/day Group IV-1 50 mg/kg/day Group VI-1 Group VIII-l 250 mg/kg/day 1000 mg/kg/day BRAIN 1.805 0.054(18 ) 1.836 0.068(18 ) 1.810 0.145(11 ) 1.783 0.071(18 ) UTERUS 0.473 0.149(18 ) 0.561 0.184(18 ) 0..512 0.125(12 ) 0.433 0.100(18 ) THYROID 0.019 0.003(18 ) 0.019 0.003(18 ) 0.016# 0.004(12 ) 0.011# 0.003(17 ) LIVER 10.263 1.384(18 ) 10.586 1.378(18 ) 10.412 2.058(12 ) 9.953 1.230(18 ) FINAL BODY 247.844 16.469(18 ) 248.817 25.141(18 ) 251.233 33.378(12 ) 240.067 17.203(18 ) MEAN RELATIVE ORGAN WEIGHTS (% of body weight) Group II-l 0 mg/kg/day Group IV-1 50 mg/kg/day BRAIN/FINAL BODY * 100 0.732 0.056(18 ) 0.744 0.070(18 ) UTERUS/FINAL BODY * 100 0.192 0.062(18 ) 0.227 0.073(18 ) THYROID/FINAL BODY * 100 0.008 0.001(18 ) 0.008 0.002(18 ) LIVER/FINAL BODY * 100 4.132 0.394(18 ) 4.255 0.338(18 ) Group VI-1 Group VIII-l 250 mg/kg/day 1000 mg/kg/day 0.728 0.078(11 ) 0.747 0.066(18 ) 0.207 0.055(12 ) 0.182 0.050(18 ) 0.006# 0.002(12 ) 0.004# 0.001(17 ) 4.117 0.368(12 ) 4.140 0.350(18 ) 378 Ssss^ssySwWzeS. Does not ew^"'" fR^m r>?|| H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 TABLE 63 (CONTINUED) MEAN FINAL BODY AND ORGAN WEIGHTS FROM FEMALE RATS - Fi ADULTS MEAN RELATIVE ORGAN WEIGHTS (organ to brain weight ratio) Group II-l 0 mg/kg/day Group IV-1 50 mg/kg/day Group VI-1 Group VIII-l 250 mg/kg/day 1000 mg/kg/day UTERUS/BRAIN * 100 26.161 7.794(18 ) 30.535 9.999(18 ) 28.099 7.050(11 ) 24.296 5.596(18 ) THYROID/BRAIN * 100 1.078 0.162(18 ) 1.011 0.186(18 ) 0.881# 0.186(11 ) 0.601* 0.166(17 ) LIVER/BRAIN * 100 569.033 77.812(18 ) 576.000 67.159(18 ) 576.128 103.469(11 ) Data summarized as: Mean Standard Deviation (n) Statistical Methods: Trend test (Jonckheere-Terpstra). # Statistically significant difference at p < 0.05. 557.992 63.193(18 ) 379 eempMy Sanifeed. Does not con^n T^ ^, H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 64 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Pi ADULTS SITE/LESION: GROUP DESIGNATION: 1-0 DOSE (nig/kg/day) : 0 NUMBER IN GROUP: 20 III-O V-0 50 250 20 20 LUNGS DISCOLORATION 0 EPIDIDYMIDES 0 0 DISCOLORATION ii TESTES w SOFT w 1 0 0 0 1 SKIN ALOPECIA 0 0 0 1 j - NOTE: !C 0 1 0 0 , 0 INCIDENCES REFLECT THE NUMBER OF ANIMALS WITH A GIVEN LESION. 1 3' . g 0 0 380 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 65 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Pi ADULTS SITE/LESION: URINARY BLADDER DILATATION KIDNEYS CALCULUS VAGINA FLUID DISCOLORATION SKIN ALOPECIA GROUP DESIGNATION: DOSE (mg/kg/day): NUMBER IN GROUP: II-O 0 20 0 0 0 0 0 IV-0 50 20 0 0 0 1 1 NOTE: 0 INCIDENCES REFLECT THE NUMBER OP ANIMALS WITH A GIVEN LESION. VI-0 250 20 1 1 1 0 0 381 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations MALE PUPS SITE/LESION: TABLE 66 INCIDENCES OF GROSS OBSERVATIONS IN RATS - Pi PUPS DAM GROUP DESIGNATION: II-0 IV-0 VI-0 V DOSE (MG/KG/DAY): 0 50 250 1 NUMBER PUPS/LITTERS: 1/1 0/0 0/0 STOMACH NO MILK SPOT LUNGS NOT EXPANDED WHOLE BODY AUTOLYSIS 1(1) 1(1) 0 ( 0) 0(0) 0(0) 0 ( 0) 0(0) 0(0) 0 ( 0) TOTAL LITTERS AFFECTED TOTAL PUPS AFFECTED 1 0 0 1 0 0 For each group: The count of pups only includes those which underwent pathological examinat The count of litters only includes those in which pups underwent pathologic For each site/lesion: Numbers outside the parentheses are the number of pups affected. Numbers in parentheses are the number of litters affected. 382 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations FEMALE PUPS SITE/LESION: TABLE 66 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN RATS - Fi PUPS DAM GROUP DESIGNATION: II-O IV-0 VI-0 V DOSE (MG/KG/DAY): 0 50 250 1 NUMBER PUPS/LITTERS: 4/3 1/1 3/2 STOMACH NO MILK SPOT PERITONEAL CAVITY FLUID LUNGS NOT EXPANDED - 4(3) 1(1) 2(2) 0(0) 0(0) 1(1) 4(3) 1(1) 2(2) TOTAL LITTERS AFFECTED TOTAL PUPS AFFECTED For each group: The count of pups only includes those which underwent pathological examina The count of litters only includes those in which pups underwent pathologic For each site/lesion: Numbers outside the parentheses are the number of pups affected. Numbers in parentheses are the number of litters affected. 383 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations UMSEXABLE PUPS SITE/LESION: TABLE 66 (Continued) INCIDENCES OF GROSS OBSERVATIONS IN RATS - Fi PUPS DAM GROUP DESIGNATION: II-O IV-0 VI-0 V DOSE (MG/KG/DAY): 0 50 250 1 NUMBER PUPS/LITTERS: 0/0 0/0 0/0 TOTAL LITTERS AFFECTED TOTAL PUPS AFFECTED For each group: The count of pups only includes those which underwent pathological examinat The count of litters only includes those in which pups underwent pathologic For each site/lesion: Numbers outside the parentheses are the number of pups affected. Numbers in parentheses are the number of litters affected. 384 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 67 INCIDENCES OF GROSS OBSERVATIONS IN MALE RATS - Fi WEANLINGS SITE/LESION: GROUP DESIGNATION: 1-1 DOSE (mg/kg/day): 0 NUMBER IN GROUP: 52 THERE WERE NO GROSS OBSERVATIONS III-l V-l 50 250 49 35 385 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 68 INCIDENCES OF GROSS OBSERVATIONS IN FEMALE RATS - Fi WEANLINGS SITE/LESION: LUNGS DEFORMITY KIDNEYS DILATATION GROUP DESIGNATION: DOSE (mg/kg/day): NUMBER IN GROUP: II-l 0 53 0 1 IV-1 50 54 0 0 NOTE: o INCIDENCES REFLECT THE NUMBER OF ANIMALS WITH A GIVEN LESION. VI- 1 250 35 1 0 386 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 69 INCIDENCES OP GROSS OBSERVATIONS IN MALE RATS - Fi ADULTS SITE/LESION: KIDNEYS DILATATION GROUP DESIGNATION: 1-1 DOSE (mg/kg/day): 0 NUMBER IN GROUP: 18 2 III--1 V-1 50 250 18 12 1 2 NOTE: 0 INCIDENCES REFLECT THE NUMBER OF ANIMALS WITH A GIVEN LESION. 387 '^K-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 70 INCIDENCES OP GROSS OBSERVATIONS IN FEMALE RATS - Fi ADULTS SITE/LESION: GROUP DESIGNATION: DOSE (mg/kg/day): NUMBER IN GROUP: II-l 0 18 IV-1 50 18 VI-1 250 12 LIVER MASS KIDNEYS DILATATION 2 0 12 20 0 '''ff BRAIN g, SOFT rNOTE: gg 0 INCIDENCES REFLECT THE NUMBER OF ANIMALS WITH A GIVEN LESION. 0010 & ? I 0 388 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 71 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - Pi GROUP DESIGNATION: 1-0 LESIOM GRADES DOSE (mg/kg/day): 0 TISSUE/LESION (P,1,2,3,4) NUMBER IN GROUP: 20 TESTIS" DEGENERATION/ATROPHY, SEMINIFEROUS TUBULES TESTES III-O V-0 50 250 20 20 3 4 EPIDIDYMIS5' GRANULOMA, SPERM OLIGOSPERMIA/GERM CELL DEBRIS EPIDIDYMIDES PROSTATE INFLAMMATION, SUBACUTE/CHRONIC SEMINAL VESICLES 0 1 2 3 7 1 (-,!,-,-,- 2 3 7 COAGULATING GLAND 2 3 7 389 H-24616: Subchronic Toxicity 90-Day Gavage Study in Ratswith One-Generation Reproductive Evaluations TABLE 71 (CONTINUED) INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN MALE RATS - Pi OTHER LUNGS: FOREIGN MATERIAL LUNGS: INFLAMMATION, GRANULOMATOUS SKIN: INFLAMMATION/ULCER NOTES: 0- - 11 (-,!,- 0- ,-,-) 1 o THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. o LESION GRADES: P = PRESENT; 1 = MINIMAL; 2 = MILD; 3 = MODERATE; 4 = SEVERE. o LESION GRADES CORRESPOND BY POSITION WITH THE NUMBERS IN PARENTHESES, WHICH INDICATE HOW OFTEN E (-,1,2,-,-) WAS OBSERVED. FOR EXAMPLE: MEANS NO LESIONS WERE GRADED "PRESENT" (NON-GRADED LESIO 1 LESION WAS GRADED "MINIMAL", 2 LESIONS WERE GRADED "MILD", NO LESIONS WERE GRADED "MODERATE" A WERE GRADED "SEVERE". a One of the pair available for microscopic examination. second of the pair. Sperm parameter evaluation was perf 390 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 72 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - P LESION GRADES TISSUE/LESION (P.I,2,3,4) GROUP DESIGNATION: DOSE (nig/kg/day) : NUMBER IN GROUP: II-O 0 20 IV-0 50 20 VI-0 250 20 OVARIES ATROPHY UTERUS 2 8 1 (-,-,!.-,- 2 8 VAGINA OTHER HYDROMEPHROSIS, BILATERAL KIDNEYS: INFLAMMATION, ACUTE URINARY BLADDER: INFLAMMATION, SUBACUTE/CHRONIC 2282 0 1 1 (-,-,!,-,1 (-,-,-,-,1 1 (-,-,!,-,- NOTES: o THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. o LESION GRADES: P = PRESENT; 1 = MINIMAL; 2 = MILD; 3 = MODERATE; 4 = SEVERE. o LESION GRADES CORRESPOND BY POSITION WITH THE NUMBERS IN PARENTHESES, WHICH INDICATE HOW OFTEN E (-,1,2,-,-) WAS OBSERVED. FOR EXAMPLE: MEANS NO LESIONS WERE GRADED "PRESENT" (NON-GRADED LESI 1 LESION WAS GRADED "MINIMAL", 2 LESIONS WERE GRADED "MILD", NO LESIONS WERE GRADED "MODERATE" A WERE GRADED "SEVERE". 391 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 73 INCIDENCES AND LESION GRADES OP MICROSCOPIC OBSERVATIONS IN MALE RATS - F GROUP DESIGNATION: 1-1 LESION GRADES DOSE (MG/KG): 0 TISSUE/LESION (P,1,2,3,4) NUMBER IN GROUP: 18 VII-1 1000 18 + THYROID GLAND ALTERATION, COLLOID 18 18 - 1 (-,!,-,-, NOTES: o THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. o LESION GRADES: P = PRESENT; 1 = MINIMAL; 2 = MILD; 3 = MODERATE; 4 = SEVERE. 0 LESION GRADES CORRESPOND BY POSITION WITH THE NUMBERS IN PARENTHESES, WHICH INDICATE HOW OFTEN (-,1,2,-,-) WAS OBSERVED. FOR EXAMPLE: MEANS NO LESIONS WERE GRADED "PRESENT" (NON-GRADED LE 1 LESION WAS GRADED "MINIMAL", 2 LESIONS WERE GRADED "MILD", NO LESIONS WERE GRADED "MODERATE" WERE GRADED "SEVERE". 392 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations TABLE 74 INCIDENCES AND LESION GRADES OF MICROSCOPIC OBSERVATIONS IN FEMALE RATS - P LESION GRADES TISSUE/LESION (P,1,2,3,4) GROUP DESIGNATION: DOSE (MG/KG): NUMBER IN GROUP: II-l 0 18 VIII-1 1000 18 THYROID GLAND 18 18 NOTES: o THE NUMBER OF ORGANS EXAMINED FOR EACH GROUP IS UNDERLINED. o LESION GRADES: P = PRESENT; 1 = MINIMAL; 2 = MILD; 3 = MODERATE; 4 = SEVERE. 0 LESION GRADES CORRESPOND BY POSITION WITH THE NUMBERS IN PARENTHESES, WHICH INDICATE HOW OFTEN (-,1,2,-,-) WAS OBSERVED'. TOR EXAMPLE: MEANS NO LESIONS WERE GRADED "PRESENT" (NON-GRADED LES 1 LESION WAS GRADED "MINIMAL", 2 LESIONS WERE GRADED "MILD", NO LESIONS WERE GRADED "MODERATE" WERE GRADED "SEVERE". 393 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 FIGURES 394 company Sanitized. Does no8 contain TSCA CBI H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations FIGURES EXPLANATORY NOTES DuPont-4739 Critical Date Day 69 and 90 Day 91 Body weights at these time points were collected prior to sacrifice or removal from study and are not included in the figures. Recovery period begins for rats designated for the one-month and 3-month recovery periods. 395 tSempanyBaniHzefi. Does not eon6an TSCA C31 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 1 MEAN BODY WEIGHTS OF MALE RATS Days on Test 396 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 2 MEAN BODY WEIGHTS OP FEMALE RATS One-Month Recovery Period (Days 91-119) --- 0 ra -B- 50 m -A-250 -X-1000 Days on Test 397 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURES MEAN FORELDMB GRIP STRENGTH (kg) OF MALE RATS 2.50 2.00 g 1.50 I) s .a 1.00 n 0 mg B50mg ^250 m 1000 0.50 0.00 Baseline Error bars represent standard deviation. Week 12 Assessment Period 398 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 4 MEAN FORELIMB GRIP STRENGTH (kg) OF FEMALE RATS DOmg/ HSOmg E3250m 1000 Baseline Error bars represent standard deviation. Week 12 Assessment Period 399 Recovery H-24616: Subchronic Toxidty 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 5 MEAN fflNDLIMB GRIP STRENGTH (kg) OF MALE RATS DOmg/ B 50 in E^250m 1000 Baseline Error bars represent standard deviation. Week 12 Assessment Period 400 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 6 MEAN fflNDLIMB GRIP STRENGTH (kg) OP FEMALE RATS Baseline Error bars represent standard deviation. Week 12 Assessment Period 401 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE? MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR MALE RA DOmg @150m i1250m 1000 Baseline Error bars represent standard deviation. Week 12 Assessment Period 402 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURES MOTOR ACTIVITY ASSESSMENT: MEAN DURATION OF MOVEMENTS FOR FEMALE R DOmg ^50 in E3250 1000 Baseline Error bars represent standard deviation. Week 12 Assessment Period 403 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 9 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR MALE RA D 0m IB 50 m E3250 100 Baseline Error bars represent standard deviation. Week 12 Assessment Period 404 Recovery -24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations FIGURE 10 MOTOR ACTIVITY ASSESSMENT: MEAN NUMBER OF MOVEMENTS FOR FEMALE RA DOmg ia50m ^250m 1000 Baseline Biror bars represent standard deviation. Week 12 Assessment Period 405 Recovery H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 APPENDICES 406 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations_______ ____DuPont-4739 APPENDIX A INDIVIDUAL DOSE VOLUMES 407 ssllwfsm^.^<^^^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 INDIVIDUAL DOSE VOLUMES EXPLANATORY NOTES Critical Dates Day 69 Male and female rats designated for reproduction evaluations were co-housed. Dose volumes administered during the cohabitation and post-mating periods are doscumented in study records. Day 90 Last day of test substance administration for male rats designated for the 90-day exposure and one-month and 3-month recovery periods, and female rats designated for one-month and 3-month recovery periods. Day 91 Last day of test substance administration for female rats designated for the 90-day exposure period. 408 SseapSHjfSWSkQS.Does noiwnWn "e^a .> H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day o Day 1 Male, I - 0 mg/ kg/d,ay 641149 0. 98 0.98 641155 1. 00 1.00 641222 1. 00 1.00 641214 1. 00 1.00 641069 1. 00 1.00 641070 1. 10 1.10 641147 1. 00 1.00 641172 1. 00 1.00 641206 1. 10 1.10 641094 1. 10 1.10 641098 0. 94 0.94 641066 0. 98 0.98 641115 1. 10 1.10 641220 0. 95 0.95 641104 1. 10 1.10 641114 1. 20 1.20 641217 1. 10 1.10 'jS 664411210548 10.. 9010 0.91 1.00 641100 0. 95 0.95 Q 641060 1. 10 1.10 5 641188 0. 98 0.98 641106 1. 10 1.10 641175 0. 97 0.97 641079 0. 99 0.99 5 641125 1. 10 1.10 641186 1. 00 1.00 Q. 641052 1. 10 1.10 5 641140 1. 20 1.20 0 ^ 641135 641174 1. 00 1. 10 1.00 1.10 3 641107 0. 98 0.98 ~a 641072 1. 00 1.00 Q 641053 1. 10 1.10 1 641168 1. 00 1.00 5as" 664411105844 10.. 9090 0.99 1.00 a 641085 1. 00 1.00 ^ 641105 1. 20 1.20 ! 641215 1. 00 1.00 "> 641123 0. 97 0.97 a- 641101 1. 20 1.20 641165 0. 99 0.99 641083 1. 10 1.10 641159 1. 00 1.00 D ay 2 I:MDIVIDUAL DOS E VOLUMES (mL ) FOR t IALE RATS Day 3 Day 4 Day 5 Day 6 0 .98 1 .00 1 .00 1 .00 1 .00 1 .10 1 .00 1 .00 1 .10 1 .10 0 .94 0 .98 1 .10 0 .95 1 .10 1 .20 1 .10 0 .91 1 .00 0 .95 1 .10 0 .98 1 .10 0.97 0 .99 1 .10 1 .00 1 .10 1 .20 1 .00 1 .10 0 .98 1 .00 1 .10 1 .00 0 .99 1 .00 1 .00 1.20 1 .00 0 .97 1 .20 0.99 1 .10 1 .00 0.98 1.00 1.00 1.00 1.00 1.10 1.00 1.00 1.10 1.10 0.94 0.98 1.10 0.95 1.10 1.20 1.10 0.91 1.00 0.95 1.10 0.98 1.10 0.97 0.99 1.10 1.00 1.10 1.20 1.00 1.10 0.98 1.00 1.10 1.00 0.99 1.00 1.00 1.20 1.00 0.97 1.20 0.99 1.10 1.00 0.98 1.00 1.00 1.00 1.00 1.10 1.00 1.00 1.10 1.10 0.94 0.98 1.10 0.95 1.10 1.20 1.10 0.91 1.00 0.95 1.10 0.98 1.10 0.97 0.99 1.10 1.00 1.10 1.20 1.00 1.10 0.98 1.00 1.10 1.00 0.99 1.00 1.00 1.20 1.00 0.97 1.20 0.99 1.10 1.00 0. 98 1. 00 1. 00 1. 00 1. 00 1. 10 1. 00 1. 00 1. 10 1. 10 0. 94 0.98 1. 10 0. 95 1. 10 1. 20 1. 10 0. 91 1. 00 0. 95 1. 10 0. 98 1. 10 0. 97 0. 99 1. 10 1. 00 1. 10 1. 20 1. 00 1. 10 0. 98 1. 00 1. 10 1. 00 0. 99 1. 00 1. 00 1. 20 1. 00 0. 97 1. 20 0. 99 1. 10 1. 00 0.98 1.00 1.00 1.00 1.00 1.10 1.00 1.00 1.10 1.10 0.94 0.98 1.10 0.95 1.10 1.20 1.10 0.91 1.00 0.95 1.10 0.98 1.10 0.97 0.99 1.10 1.00 1.10 1.20 1.00 1.10 0.98 1.00 1.10 1.00 0.99 1.00 1.00 1.20 1.00 0.97 1.20 0.99 1.10 1.00 409 Diay 7 1 .20 1 .20 1 .30 1 .30 1 .30 1 .30 1 .20 1 .20 1 .40 1 .30 1 .10 1 .10 1 .30 1 .10 1 .30 1 .50 1 .30 1 .10 1 .30 1 .10 1 .40 1 .20 1 .30 1 .20 1 .20 1 .40 1 .30 1 .30 1 .50 1 .20 1 .30 1 .20 1 .30 1 .30 1 .20 1 .20 1 .30 1 .20 1 .40 1 .20 1 .20 1 .40 1 .20 1 .20 1 .20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 11 INDIVIDUAL DOSE VOLUMES Day 12 Day 13 (mL) FOR MALE HATS 641149 641155 641222 641214 641069 641070 1 .20 1 .20 1 .30 1 .30 1 .30 1 .30 1 .20 1 .20 1 .30 1 .30 1 .30 1 .30 641147 1 .20 1 .20 641172 1 .20 1 .20 641206 1 .40 1 .40 641094 1 .30 1 .30 641098 1 .10 1 .10 641066 1 .10 1 .10 641115 1 .30 1 .30 641220 1 .10 1 .10 641104 1.30 1 .30 641114 1 .50 1 .50 641217 1 .30 1 .30 641204 1 .10 1 .10 641158 1 .30 1 .30 m 641100 1 .10 1 .10 tS 641060 1 .40 1 .40 Hi 641188 1 .20 1 .20 RT 641106 1 .30 1 .30 SL 641175 1 .20 1 .20 "~ 641079 1 .20 1 .20 0 S 641125 1 .40 1 .40 64.11.86 . .- 1. 3Q. ,, , - - 1.3.0 641052 1 .30 1 .30 1 641140 1 .50 1 .50 f 641135 1 .20 1 .20 641174 1 .30 1 .30 & 641107 1 .20 1 .20 3" 641072 1 .30 1 .30 641053 1 .30 1 .30 ^ 641168 1 .20 1 .20 2 641084 1 .20 1 .20 Sa 641154 1 .30 641085 1 .20 Sg 1 .30 1 .20 641105 1 .40 1 .40 641215 1 .20 1 .20 641123 1 .20 1 .20 641101 1 .40 1 .40 641165 1 .20 1 .20 641083 1 .20 1 .20 641159 1 .20 1 .20 1.20 1.20 1.30 1.30 1.30 1.30 1.20 1.20 1.40 1.30 1.10 1.10 1.30 1.10 1.30 1.50 1.30 1.10 1.30 1.10 1.40 1.20 1.30 1.20 1.20 1.40 .1.30 1.30 1.50 1.20 1.30 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.40 1.20 1.20 1.40 1.20 1.20 1.20 1.20 1.20 1.30 1.30 1.30 1.30 1.20 1.20 1.40 1.30 1.10 1.10 1.30 1.10 1.30 1.50 1.30 1.10 1.30 1.10 1.40 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.50 1.20 1.30 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.40 1.20 1.20 1.40 1.20 1.20 1.20 1.20 1.20 1.30 1.30 1.30 1.30 1.20 1.20 1.40 1.30 1.10 1.10 1.30 1.10 1.30 1.50 1.30 1.10 1.30 1.10 1.40 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.50 1.20 1.30 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.40 1.20 1.20 1.40 1.20 1.20 1.20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations D ay 14 Day 15 Male, I - 0 i ng/ kg/das/ 641149 1 .30 1.30 641155 1 .30 1.30 641222 1 .50 1.50 641214 1 .50 1.50 641069 1 .60 1.60 6.41070 1 .60 1.60 641147 1 .40 1.40 641172 -. . 1 .40 - .1.40 .. 641206 1 .60 1.60 641094 1 .50 1.50 641098 1 .30 1.30 641066 1 .30 1.30 641115 1 .60 1.60 641220 1 .20 1.20 641104 'CT 641114 1 .40 1 .70 1.40 1.70 9 641217 n 641204 1 .50 1 .30 1.50 1.30 641158 1 .40 1.40 '% 641100 1 .30 1.30 641060 1 .60 1.60 641188 a 641106 & 641175 & 641079 0 641125 0 641186 641052 3 641140 & 641135 a 641174 0 641107 S" 641072 3- 641053 ^ 641168 0 641084 & 641154 :" 641085 3- 641105 641215 641123 641101 641165 641083 641159 1 .40 1 .50 1 .40 1 .30 1 .60 1 .40 1 .50 1 .70 1 .40 1 .40 1 .40 1 .40 1 .50 1 .40 1 .30 1 .50 1 .40 1 .60 1 .40 1 .40 1 .60 1 .40 1 .50 1 .40 1.40 1.50 1.40 1.30 1.60 1.40 1.50 1.70 1.40 1.40 1.40 1.40 1.50 1.40 1.30 1.50 1.40 1.60 1.40 1.40 1.60 1.40 1.50 1.40 INDIVIDOAL DOSE VOLUMBS (mL) 1?OR MALE I IATS Day 16 Day 17 Day 18 D ay 19 Day 20 1.30 1.30 1.50 1.50 1.60 1.60 1.40 1.40 - 1.60 1.50 1.30 1.30 1.60 1.20 1.40 1.70 1.50 1.30 1.40 1.30 1.60 1.40 1.50 1.40 1.30 1.60 1.40 1.50 1.70 1.40 1.40 1.40 1.40 1.50 1.40 1.30 1.50 1.40 1.60 1.40 1.40 1.60 1.40 1.50 1.40 1.30 1.30 1.50 1.50 1.60 1.60 1.40 1.40-- - 1.60 1.50 1.30 1.30 1.60 1.20 1.40 1.70 1.50 1.30 1.40 1.30 1.60 1.40 1.50 1.40 1.30 1.60 1.40 1.50 1.70 1.40 1.40 1.40 1.40 1.50 1.40 1.30 1.50 1.40 1.60 1.40 1.40 1.60 1.40 1.50 1.40 1.30 1.30 1.50 1.50 1.60 1.60 1.40 1.40 1.60 1.50 1.30 1.30 1.60 1.20 1.40 1.70 1.50 1.30 1.40 1.30 1.60 1.40 1.50 1.40 1.30 1.60 1.40 1.50 1.70 1.40 1.40 1.40 1.40 1.50 1.40 1.30 1.50 1.40 1.60 1.40 1.40 1.60 1.40 1.50 1.40 1 .30 1.30 1 .30 1.30 1 .50 1.50 1 .50 1.50 1 .60 1.60 1 .60 1.60 1 .40 1.40 - - -. l.,4@ - - - . -1.40 1 .60. 1.60 1 .50 1.50 1 .30 1.30 1 .30 1.30 1 .60 1.60 1 .20 1.20 1 .40 1.40 1 .70 1.70 1 .50 1.50 1 .30 1.30 1 .40 1.40 1 .30 1.30 1 .60 1.60 1 .40 1 .50 1.40 1.50 1 .40 1 .30 1.40 1.30 1 .60 1 .40 1.60 1.40 1 .50 1.50 1 .70 1.70 1 .40 1 .40 1.40 1.40 1 .40 1.40 1 .40 1.40 1 .50 1.50 1 .40 1.40 1 .30 1.30 1 .50 1.50 1 .40 1.40 1 .60 1.60 1 .40 1.40 1 .40 1.40 1 .60 1.60 1 .40 1.40 1 .50 1.50 1 .40 1.40 411 Day 1.50 1.50 1.60 1.70 1.80 1.70 1.50 1-.6 1.70 1.70 1.40 1.40 1.90 1.40 1.60 1.90 1.70 1.50 1.60 1.40 1.90 1.50 1.60 1.60 1.50 1.90 1.60 1.60 1.90 1.50 1.60 1.60 1.50 1.70 1.60 1.50 1.60 1.60 1.80 1.50 1.60 1.70 1.60 1.60 1.60 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 23 Day 24 Male, I - 0 nig/kg/day 641149 641155 1.50 1.50 641222 1.60 641214 1.70 641069 1.80 641070 1.70 641147 1.50 641172 1.60 641206 1.70 641094 1.70 641098 1.40 641066 1.40 641115 1.90 641220 1.40 641104 1.60 ','ff 641114 1.90 S 641217 1.70 'S 641204 1.50 641158 1.60 ^ 641100 1.40 as 641060 1.90 3 641188 1.50 ss 641106 1.60 S. 641175 1.60 s~^ 641079 1.50 a 641125 1.90 641186 1.60 S 641052 1.60 3 641140 1.90 a 641135 1.50 <s 0 641174 1.60 641107 1.60 S? 641072 1.50 5" 641053 1.70 641168 1.60 a 641084 1.50 ^ 641154 1.60 0 641085 1.60 (B 641105 1.80 --a 641215 1.50 641123 1.60 641101 641165 641083 641159 1.70 1.60 1.60 1.60 1.50 1.50 1.60 1.70 1.80 1.70 1.50 1.60 1.70 1.70 1.40 1.40 1.90 1.40 1.60 1.90 1.70 1.50 1.60 1.40 1.90 1.50 1.60 1.60 1.50 1.90 1.60 1.60 1.90 1.50 1.60 1.60 1.50 1.70 1.60 1.50 1.60 1.60 1.80 1.50 1.60 1.70 1.60 1.60 1.60 IMDIVI:DUAL DOSE VOI..UMES (niL) FOR MALE I (ATS Day 25 Day 26 Day 27 Da:y 28 1.50 1.50 1.60 1.70 1.80 1.70 1.50 1.60 1.70 1.70 1.40 1.40 1.90 1.40 1.60 1.90 1.70 1.50 1.60 1.40 1.90 1.50 1.60 1.60 1.50 1.90 1.60 1.60 1.90 1.50 1.60 1.60 1.50 1.70 1.60 1.50 1.60 1.60 1.80 1.50 1.60 1.70 1.60 1.60 1.60 1.50 1.50 1.60 1.70 1.80 1.70 1.50 1.60 1.70 1.70 1.40 1.40 1.90 1.40 1.60 1.90 1.70 1.50 1.60 1.40 1.90 1.50 1.60 1.60 1.50 1.90 1.60 1.60 1.90 1.50 1.60 1.60 1.50 1.70 1.60 1.50 1.60 1.60 1.80 1.50 1.60 1.70 1.60 1.60 1.60 1.50 1.50 1.60 1.70 1.80 1.70 1.50 1.60 1.70 1.70 1.40 1.40 1.90 1.40 1.60 1.90 1.70 1.50 1.60 1.40 1.90 1.50 1.60 1.60 1.50 1.90 1.60 1.60 1.90 1.50 1.60 1.60 1.50 1.70 1.60 1.50 1.60 1.60 1.80 1.50 1.60 1.70 1.60 1.60 1.60 1 .60 1 .60 1 .80 1 .90 2 .00 1 .90 1 .70 1 .80 1 .80 1 .80 1 .50 1 .50 2 .00 1 .50 1 .70 2 .10 1 .80 1 .70 1 .80 1 .60 2 .10 1 .70 1 .80 1 .80 1 .60 2 .10 1 .70 1 .70 2 .10 1 .70 1 .70 1 .70 1 .70 1 .90 1 .80 1 .60 1 .80 1 .70 1 .90 1 .70 1 .80 1 .90 1 .70 1 .80 1 .70 412 Day 29 1 .60 1 .60 1 .80 1 .90 2 .00 1 .90 1 .70 1 .80 1 .80 1 .80 1 .50 1 .50 2 .00 1 .50 1 .70 2 .10 1 .80 1 .70 1 .80 1 .60 2 .10 1 .70 1 .80 1 .80 1 .60 2 .10 1 .70 1 .70 2 .10 1 .70 1 .70 1 .70 1 .70 1 .90 1 .80 1 .60 1 .80 1 .70 1 .90 1 .70 1 .80 1 .90 1 .70 1 .80 1 .70 Day 1.6 1.6 1.8 1.9 2.0 1.9 1.7 1.8 1.8 1.8 1.5 1.5 2.0 1.5 1.7 2.1 1.8 1.7 1.8 1.6 2.1 1.7 1.8 1.8 1.6 2.1 1.7 1.7 2.1 1.7 1.7 1.7 1.7 1.9 1.8 1.6 1.8 1.7 1.9 1.7 1.8 1.9 1.7 1.8 1.7 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations laps S is s 3 1OS 1 0 a 3" J y & Q Da:y 32 Male, I - 0 mg/'kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 . 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 1 .60 1 .60 1 .80 1 .90 2 .00 1 .90 1 .70 1 .80 1 .80 1 .80 1 .50 1 .50 2 .00 1 .50 1 .70 2 .10 1 .80 1 .70 1 .80 1 .60 2 .10 1 .70 1 .80 1 .80 1 .60 2 .10 1 .70 1 .70 2 .10 1 .70 1 .70 1 .70 1 .70 1 .90 1 .80 1 .60 1 .80 1 .70 1 .90 1 .70 1 .80 1 .90 1 .70 1 .80 1 .70 Da:y 33 1 .60 1 .60 1 .80 1 .90 2 .00 1 .90 1 .70 1 .80 1 .80 1 .80 1 .50 1 .50 2 .00 1 .50 1 .70 2 .10 1 .80 1 .70 1 .80 1 .60 2.10 1 .70 1 .80 1 .80 1 .60 2 .10 1 .70 1 .70 2 .10 1.70 1 .70 1 .70 1 .70 1 .90 1 .80 1 .60 1 .80 1 .70 1 .90 1 .70 1 .80 1 .90 1 .70 1 .80 1 .70 INDI\riDUAL DOSE VOLU1MES (inL) FOR MALE RATS Day 34 Day 35 Day 36 Day 37 1.60 1.60 1.80 1.90 2.00 1.90 1.70 1.80 1.80 1.80 1.50 1.50 2.00 1.50 1.70 2.10 1.80 1.70 1.80 1.60 2.10 1.70 1.80 1.80 1.60 2.10 1.70 1.70 2.10 1.70 1.70 1.70 1.70 1.90 1.80 1.60 1.80 1.70 1.90 1.70 1.80 1.90 1.70 1.80 1.70 1.70 1.70 1.90 2.00 2.10 2.00 1.70 1.90 1.90 1.90 1.60 1.60 2.20 1.60 1.90 2.20 1.90 1.80 1.90 1.70 2.10 1.70 1.90 1.80 1.70 2.20 1.90 1.80 2.20 1.80 1.80 1.80 1.70 2.00 1.80 1.80 2.00 1.90 2.10 1.80 1.90 2.00 1.80 1.90 1.80 1.70 1.70 1.90 2.00 2.10 2.00 1.70 1.90 1.90 1.90 1.60 1.60 2.20 1.60 1.90 2.20 1.90 1.80 1.90 1.70 2.10 1.70 1.90 1.80 1.70 2.20 1.90 1.80 2.20 1.80 1.80 1.80 1.70 2.00 1.80 1.80 2.00 1.90 2.10 1.80 1.90 2.00 1.80 1.90 1.80 1.70 1.70 1.90 2.00 2.10 2.00 1.70 1.90 1.90 1.90 1.60 1.60 2.20 1.60 1.90 2.20 1.90 1.80 1.90 1.70 2.10 1.70 1.90 1.80 1.70 2.20 1.90 1.80 2.20 1.80 1.80 1.80 1.70 2.00 1.80 1.80 2.00 1.90 2.10 1.80 1.90 2.00 1.80 1.90 1.80 413 Day 38 1.70 1.70 1.90 2.00 2.10 2.00 1.70 1.90 1.90 1.90 1.60 1.60 2.20 1.60 1.90 2.20 1.90 1.80 1.90 1.70 2.10 1.70 1.90 1.80 1.70 2.20 1.90 1.80 2.20 1.80 1.80 1.80 1.70 2.00 1.80 1.80 2.00 1.90 2.10 1.80 1.90 2.00 1.80 1.90 1.80 Da:y 1 .70 1 .7 1 .9 2 .0 2 .1 2 .0 1 .7 1 .9 1 .9 1 .90 1 .6 1 .6 2 .2 1 .6 1 .9 2.2 1 .9 1 .8 1 .9 1 .7 2 .1 1 .7 1 .9 1 .8 1 .7 2.20 1 .9 1 .8 2 .2 1 .8 1 .8 1 .8 1 .7 2 .0 1 .8 1 .8 2 .0 1 .9 2 .1 1 .8 1 .9 2 .0 1 .8 1 .90 1 .8 ^i..j... tAfa-^-fefe .^u&.sKfs H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 41 Male, I - 0 mg/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 1.70 1.70 1.90 2.00 2.10 2.00 1.70 1.90 1.90 1.90 1.60 1.60 2.20 1.60 1.90 2.20 1.90 1.80 1.90 1.70 2.10 1.70 1.90 1.80 1.70 2.20 1.90 1.80 2.20 1.80 1.80 1.80 1.70 2.00 1.80 1.80 2.00 1.90 2.10 1.80 1.90 2.00 1.80 1.90 1.80 Day 42 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 43 Day 44 Day 45 Day 46 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00. 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 414 Day 47 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 Day 4 1.80 1.80 2.00 2.10 2.20 2.10 1.80 2.00 2.00 2.10 1.70 1.70 2.30 1.70 1.90 2.40 2.00 1.80 2.00 1.80 2.40 1.80 2.00 2.00 1.80 2.30 1.90 1.90 2.40 1.80 1.90 2.00 1.80 2.00 1.90 1.80 2.00 2.00 2.10 1.90 2.00 2.00 1.90 2.00 2.00 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 50 Male, I - 0 mg/kg/day s 641149 V 641155 fi 641222 & 641214 sr 641069 641070 641147 a 641172 f0 641206 ,, 641094 i Q 641098 641066 Q 641115 3. 641220 & 641104 3 641114 1 641217 641204 y 641158 0 641100 s 641060 641188 641106 A 641175 S 641079 3 641125 9 641186 a! 64.1052 as 641140 ft 641135 & 641174 R 641107 2 641072 ? 641053 641168 B 641084 a . 641154 i 641085 641105 ^ 641215 1, 641123 1' 641101 1 641165 641083 641159 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.30 2.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 Day 51 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.302.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 52 Day 53 Day 54 Day 55 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.30 2.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.30 2.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.30 2.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 1.80 1.90 2.00 2.20 2.30 2.10 1.80 2.10 2.10- 2.10 1.80 1.70 2.40 1.80 2.00 2.50 2.20 1.90 2.10 1.80 2.50 1.90 2.00 2.00 1.80 2.30 2.00 2.00 2.50 1.90 1.90 2.00 1.90 2.20 2.00 1.90 2.10 2.10 2.20 2.00 2.10 2.10 2.00 2.10 2.00 415 Day 56 1.80 1.90 2.10 2.30 2.30 2.30 1.90 2.20 2.20 2.20 1.80 1.80 2.60 1.80 2.10 2.60 2.20 2.00 2.20 1.90 2.60 1.90 2.20 2.10 1.90 2.40 2.10 2.10 2.60 2.00 2.00 2.10 1.90 2.20 2.10 2.00 2.20 2.20 2.30 2.10 2.10 2.20 2.10 2.30 2.10 Day 5 1.80 1.90 2.10 2.30 2.30 2.30 1.90 2.20 2.20 2.20 1.80 1.80 2.60 1.80 2.10 2.60 2.20 2.00 2.20 1.90 2.60 1.90 2.20 2.10 1.90 2.40 2.10 2.10 2.60 2.00 2.00 2.10 1.90 2.20 2.10 2.00 2.20 2.20 2.30 2.10 2.10 2.20 2.10 2.30 2.10 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations IMDIV3:DUAL 130SE VOIJJKES 1[inL) FOR KiLE RATS Day 59 Day 60 Day 61 Day 62 Day 63 Day 64 Day 65 Day Male, I - 0 ing/kg/day 641149 1.80 1 .80 1. 80 1. 80 1 .90 1.90 1.90 1 . 641155 1.90 1 .90 1. 90 1. 90 2 .00 2.00 2.00 2 . 641222 2.10 2 .10 2. 10 2. 10 2 .20 2.20 2.20 2 . 641214 2.30 2 .30 2. 30 2. 30 2 .30 2.30 2.30 2 . 641069 2.30 2 .30 2. 30 2. 30 2 .40 2.40 2.40 2 . 641070 2.30 2 .30 2. 30 2. 30 2 .30 2.30 2.30 2 . 641147 1.90 1 .90 1. 90 1. 90 1 .90 1.90 1.90 1 . 641172 2.20 2.20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641206 2.20 2 .20 2. 20 2. 20 2 .10 2.10 2.10 2 . 641094 2.20 2 .20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641098 1.80 1 .80 1. 80 1. 80 1 .80 1.80 1.80 1 . 641066 1.80 1 .80 1. 80 1. 80 1 .70 1.70 1.70 1 . 641115 2.60 2 .60 2. 60 2. 60 2 .50 2.50 2.50 2 . 641220 1.80 1 .80 1. 80 1. 80 1 .80 1.80 1.80 1 . 641104 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641114 2.60 2 .60 2. 60 2. 60 2 .60 2.60 2.60 2 . 641217 2.20 2.20 2. 20 2. 20 2 .30 2.30 2.30 2. 641204 2.00 2 .00 2. 00 2.00 2 .00 2.00 2.00 2 . 641158 2.20 2 .20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641100 1.90 1 .90 1. 90 1. 90 2 .00 2.00 2.00 2 . 641060 2.60 2 .60 2. 60 2. 60 2 .70 2.70 2.70 2 . 641188 1.90 1 .90 1. 90 1. 90 2 .00 2.00 2.00 2 . 641106 2.20 2 .20 2. 20 2. 20 2 .20 2.20 2.20 2 . 641175 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641079 1.90 1 .90 . 1. 90 1. 90 1 .90 1.90 1.90 1 . 641125 2.40 2 .40- 2. 40 2. 40 2 .60 2.60 2.60 2 . 641186 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641052 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641140 2.60 2 .60 2. 60 2. 60 2 .60 2.60 2.60 2 . 641135 2.0Q 2 .00 2. 00 2. 00 2 .00 2.00 2.00 2 . 641174 2.00 2 .00 2. 00 2. 00 2 .00 2.00 2.00 2 . 641107 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641072 1.90 1 .90 1. 90 1. 90 2 .00 2.00 2.00 2 . 641053 2.20 2 .20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641168 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641084 2.00 2 .00 2. 00 2. 00 2 .10 2.10 2.10 2 . 641154 2.20 2 .20 2. 20 2. 20 2 .20 2.20 2.20 2 . 641085 2.20 2 .20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641105 2.30 2 .30 2.30 2. 30 2 .40 2.40 2.40 2 . 641215 2.10 2 .10 2. 10 2. 10 2 .20 2.20 2.20 2 . 641123 2.10 2 .10 2. 10 2. 10 2 .10 2.10 2.10 2 . 641101 2.20 2 .20 2. 20 2. 20 2 .30 2.30 2.30 2 . 641165 2.10 2 .10 2. 10 2. 10 2 .20 2.20 2.20 2 . 641083 2.30 2 .30 2. 30 . 2. 30 2 .40 2.40 2.40 2 . 641159 2.10 2 .10 2. 10 2. 10 2 .20 2.20 2.20 2 . 416 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 68 Day 69 Male, I - 0 mg/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 ysa 641115 nss 641220 3 641104 641114 3 641217 1f 664411210548 641100 w 641060 641188 p, 641106 '8 {. 641175 < 641079 1(9 641125 641186 641052 0 641140 iS 664411113754 s 641107 641072 s 641053 > 641168 0 641084 E 641154 641085 641105 641215 641123 641101 641165 641083 641159 1. 90 2. 00 2. 20 2. 30 2. 40 2. 30 1. 90 2. 30 2. 10 2. 30 1. 80 1. 70 2. 50 1. 80 2.10 2. 60 2.30 2. 00 2. 30 2. 00 2. 70 2. 00 2. 20 2. 10 1. 90 2. 60 2. 10 2. 10 2. 60 2. 00 2. 00 2. 10 2. 00 2.30 2. 10 2. 10 2. 20 2. 30 2. 40 2. 20 2. 10 2. 30 2. 20 2. 40 2. 20 1 .90 2 .00 2.20 2 .30 2.40 2 .30 1 .90 2 .30 2 .10 2 .30 1 .80 1 .70 2 .50 1 .80 2 .10 2 .60 2 .30 2 .00 2 .30 2 .00 2 .70 2 .00 2.20 2 .10 1 .90 2 .60 2 .10 2 .10 2 .60 2 .00 2 .00 2 .10 2 .00 2 .30 2 .10 2 .10 2 .20 2 .30 2 .40 2 .20 2 .10 2 .30 2 .20 2 .40 2 .20 INDI^/IDITAL DOSE VOI..UMES (:niL) FOR MALE 1iATS Day 70 Day 71 Da:y 72 Day 73 2.00 2.00 2.30 2.40 2.50 2.40 2.00 2.40 2.50 2.40 1.90 1.80 2.60 1.90 2.20 2.00 2.00 2.30 2.40 2.50 2.40 2.00 2.40 2.50 2.40 1.90 1.80 2.60 1.90 2.20 2 .00 2 .00 2 .30 2 .40 2 .50 2 .40 2 .00 2 .40 2 .50 2 .40 1 .90 1 .80 2 .60 1 .90 2 .20 2 .00 2 .00 2 .30 2.40 2 .50 2 .40 2 .00 2 .40 2 .50. 2.40 1 .90 1.80 2 .60 1 .90 2 .20 2.20 2.30 2.40 2.50 2.20 2.30 2.30 2.20 2.40 2.20 2.20 2.30 2.40 2.50 2.20 2.30 2.30 2.20 2.40 2.20 2.20 2 .30 2.40 2 .50 2.20 2.30 2 .30 2 .20 2 .40 2 .20 2 .20 2 .30 2 .40 2 .50 2 .20 2 .30 2 .30 2 .20 2 .40 2 .20 417 Day 74 2.00 2.00 2.30 2.40 2.50 2.40 2.00 2.40 2.50 2.40 1.90 1.80 2.60 1.90 2.20 2.20 2.30 2.40 2.50 2.20 2.30 2.30 2.20 2.40 2.20 Day 2.0 2.0 2.3 2.4 2.5 2.4 2.0 2.4 2.5 2.4 1.9 1.8 2.6 1.9 2.2 2.2 2.3 2.4 2.5 2.2 2.3 2.3 2.2 2.4 2.2 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Da:y 77 Male, I - 0 tag/'.kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 2 .10 2 .10 2 .40 2 .50 2 .60 2 .50 2 .10 2 .40 2 .50 2 .50 1 .90 1 .90 2.70 1 .90 2 .20 - 2 .20 2.40 2 .40 2 .50 2 .30 2 .30 2 .40 2 .30 2 .60 2 .30 Da:y 78 2 .10 2 .10 2 .40 2 .50 2 .60 2 .50 2 .10 2 .40 2 .50 2 ,50 1 .90 1.90 2.70 1 .90 2 .20 2 .20 2 .40 2 .40 2 .50 2 .30 2 .30 2 .40 2 .30 2 .60 2 .30 IMDI\TOUAL IX>SE VOI.iVKES (inL) FOR MALE RATS Day 79 Day 80 Day 81 Day 82 2.10 2.10 2.40 2.50 2.60 2.50 2.10 2.40 2.50 2.50 1.90 1.90 2.70 1.90 2.20 2. 10 2. 10 2. 40 2. 50 2. 60 2. 50 2. 10 2. 40 2. 50 2. 50 1. 90 1. 90 2. 70 1. 90 2. 20 2.10 2.10 2.40 2.50 2.60 2.50 2.10 2.40 2.50 2.50 1.90 1.90 2.70 1.90 2.20 2.10 2.10 2.40 2.50 2.60 2.50 2.10 2.40 2.502.50 1.90 1.90 2.70 1.90 2.20 2.20 2.40 2.40 2.50 2.30 2.30 2.40 2.30 2.60 2.30 2. 20 2. 40 2. 40 2. 50 2. 30 2. 30 2.40 2.30 2. 60 2.30 2.20 2.40 2.40 2.50 2.30 2.30 2.40 2.30 2.60 2.30 2.20 2.40 2.40 2.50 2.30 2.30 2.40 2.30 2.60 2.30 418 Day 83 2.10 2.10 2.40 2.50 2.60 2.50 2.10 2.40 2.50 2.50 1.90 1.90 2.70 1.90 2.20 2.20 2.40 2.40 2.50 2.30 2.30 2.40 2.30 2.60 2.30 Da:y 8 2 .10 2 .00 2 .30 2 .60 2 .70 2 .50 2 .10 2.50 2.60 2 .50 1 .90 1 .90 2 .80 2 .00 2 .30 2 .30 2 .50 2 .40 2 .60 2.30 2.30 2 .50 2 .30 2 .50 2 .40 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 86 Da:y 87 Male, I - 0 rag/ kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 [ ^. 641217 641204 'B 641158 x 641100 Gj 641060 "t 641188 S 641106 a, 641175 B 641079 s 641125 p' 641186 641052 641140 641135 1 3 641174 1& 641107 St 641072 641053 & 641168 3 641084 31 641154 0 641085 > 641105 -$ 641215 5 641123 641101 641165 641083 641159 1 .10 2 .00 2 .30 2 .60 2 .70 2 .50 2 .10 2 .50 2 .60 2 .50 1 .90 1 .90 2 .80 2 .00 2 .30 2 .10 2 .00 2 .30 2 .60 2 .70 2 .50 2.10 2 .50 2 .60 2 .50 1 .90 1 .90 2 .80 2 .00 2 .30 - 2 .30 2 .50 2 .40 2 .60 2 .30 2 .30 2 .50 2 .30 2 .50 2.40 2 .30 2 .50 2 .40 2 .60 2 .30 2 .30 2 .50 2 .30 2 .50 2 .40 IMDI\7IDUAL DOSE V01:,UMES I[mL) FOR MALE RATS Day 88 Day 89 Day 90 2 .10 2 .00 2 .30 2 .60 2 .70 2 .50 2 .10 2 .50 2 .60 2 .50 1 .90 1 .90 2 .80 2 .00 2 .30 2 .10 2 .00 2 .30 2 .60 2 .70 2 .50 2 .10 2 .50 2 .60 2 .50 1 .90 1 .90 2 .80 2.00 2 .30 2 .20 2 .10 2 .30 2 .60 2 .70 2 .50 2 .10 2 .50 2 .70 2 .60 1 .90 1 .90 2 .80 2 .00 2 .30 2 .30 2 .50 2 .40 2 .60 2 .30 2 .30 2 .50 2 .30 2 .50 . 2 .40 2 .30 2 .50 2 .40 2 .60 2 .30 2 .30 2 .50 2 .30 2 .50 2 .40 2.30 2 .50 2 .40 2 .60 2 .30 2 .30 2 .50 2 .30 2 .50 2 .40 419 A H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 0 Day 1 Day 2 INDIVIDUAL DOSE VOLUMES Day 3 Day 4 (niL) FOR MALE RATS Day 5 Day 6 Day 7 Male, III - 50 mg/kg/day 641146 641218 641073 641056 641178 0. 05 0. 05 0. 05 0. 05 0. 05 641055 641144 641198 0. 05 0. 05 0. 05 641081 0. 05 641224 0. 06 641194 0. 05 641059 0. 05 641160 0. 05 641113 0. 05 641225 0. 05 641087 0. 06 BB 641108 0. 05 || 641118 0. 05 S 641128 0. 05 jg 641091 0. 05 3 641199 0. 06 ^ 641209 0. 05 Ji 641163 0. 05 3 641129 0. 05 H 641138 0. 05 641103 0. 05 "^ 641181 0. 05 0 664411117111 00.. 0066 m 664411105662 00.. 0055 -- 641173 0.05 0 641121 0. 05 S 641074 0. 05 3. 641191 0. 05 I 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0 03 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0..05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.05 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.07 0.07 0.06 0.06 0.06 0.06 0.07 0.06 420 '''^'w^sS^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 9 Day 10 Day 11 INDIVIDUAL DOSE VOLUMES Day 12 Day 13 (mL) FOR MALE RATS Male, XII - 50 rog/kg/day 641146 641218 641073 0.06 0.06 0.06 641056 0.06 641178 641055 641144 641198 641081 641224 0.06 0.06 0.06 0.06 0.06 0.07 641194 641059 0.06 0.05 641160 641113 641225 641087 0.06 0.06 0.06 0.07 641108 0.06 M 641118 0.06 Iff 641128 0.06 19.1 641091 641199 0.05 0.07 5 641209 0.06 W 641163 0.06 5 664411113289 00..0066 & 641103 0.07 641181 0.06 pi 641171 0.07 a 641111 0.07 ? 641062 0.06 641156 0.06 3 Q 641173 0.06 641121 0.06 s 641074 0.07 fl 641191 0.06 S3 S' < ,9 } s 3 J 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.05 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.07 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.05 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.07 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.05 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.07 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.05 0.07 0.06 0.06 0.06 0.06 0.07 0.06 0.07 0.07 0.06 0.06 0.06 0.06 0.07 0.06 421 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 14 Day is Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/to3/day 0. 06 0. 07 0. 07 0.07 0. 07 0. 07 0. 07 0. 07 0. 07 0. 08 0. 06 0. 06 0. 07 0. 08 0. 07 0. 08 0. 07 0. 07 0. 07 0. 06 0. 08 0. 07 0. 07 0. 07 0. 07 0. 08 0. 07 0. 08 0. 08 0. 07 . 0. 07 0. 07 0. 07 0. 08 0. 07 0 .06 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .08 0 .06 0 .06 0 .07 0 .08 0 .07 0 .08 0 .07 0 .07 0 .07 0 .06 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0 .07 0 .08 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0 .07 Day 16 I:NDIVII)UAL DOS:E VOLIMES (fflL ) FOR MALE ]UVTS Da:y 17 Da;y 18 Da:y 19 Day 20 0.06 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.08 0.06 0.06 0.07 0.08 0.07 0.08 0.07 0.07 0.07 0.06 0.08 0.07 0.07 0.07 0.07 0.08 0.07 0.08 0.08 0.07 0.07 0.07 0.07 0.08 0.07 0 .06 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .08 0 .06 0 .06 0 .07 0 .08 0 .07 0 .08 0 .07 0 .07 0 .07 0 .06 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0.07 0 .08 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0 .07 0 .06 0 .07 0 .07 0.07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .08 0 .06 0 .06 0 .07 0 .08 0 .07 0.08 0 .07 0 .07 0 .07 0 .06 0 .08 0 .07 0 .07 0 .07 0 .07 0.08 0 .07 0 .08 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0 .07 0 .06 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .07 0 .08 0 .06 0 .06 0 .07 0 .08 0 .07 0 .08 0 .07 0 .07 0 .07 0 .06 0 .08 0 .07 0 .07 0 .07 0 .07 0.08 0 .07 0 .08 0 .08 0 .07 0 .07 0 .07 0 .07 0 .08 0 .07 0.06 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.07 0.08 0.06 0.06 0.07 0.08 0.07 0.08 0.07 0.07 0.07 0.06 0.08 0.07 0.07 0.07 0.07 0.08 0.07 0.08 0.08 0.07 0.07 0.07 0.07 0.08 0.07 Day 21 0 .07 0 .07 0 .08 0.08 0 .07 0 .08 0 .08 0 .09 0 .07 0 .09 0 .07 0 .06 0 .07 0 .09 0 .08 0 .09 0 .08 0 .07 0 .08 0.07 0 .09 0 .07 0 .08 0 .07 0 .08 0 .09 0 .08 0.10 0 .08 0 .08 0 .08 0 .08 0 .08 0 .09 0 .08 422 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 23 Day 24 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 0 .07 0 .07 0 .08 0 .08 0.07 0 .08 0 .08 0 .09 0 .07 0 .09 0 .07 0 .06 0 .07 0 .09 0 .08 0 .09 0 .08 0 .07 0 .08 0 .07 0 .09 0 .07 0 .08 0 .07 0 .08 0 .09 0 .08 0 .10 0 .08 0 .08 0 .08 0 .08 0 .08 0 .09 0 .08 0.07 0.07 0.08 0.08 0.07 0.08 0.08 0.09 0.07 0.09 0.07 0.06 0.07 0.09 0.08 0.09 0.08 0.07 0.08 0.07 0.09 0.07 0.08 0.07 0.08 0.09 0.08 0.10 0.08 0.08 0.08 0.08 0.08 0.09 0.08 Day 25 INDIVIDUAL DOSE VOLUMES (fflL) Day 26 Day 27 FOR MALE RATS Day 28 Day 29 0.07 0.07 0.08 0.08 0.07 0.08 0.08 0.09 0.07 0.09 0.07 0.06 0.07 0.09 0.08 0.09 0.08 0.07 0.08 0.07 0.09 0.07 0.08 0.07 0.08 0.09 0.08 0.10 0.08 0.08 0.08 0.08 0.08 0.09 0.08 0.07 0.07 0.08 0.08 0.07 0.08 0.08 0.09 0.07 0.09 0.07 0.06 0.07 0.09 0.08 0.09 0.08 0.07 0.08 0.07 0.09 0.07 0.08 0.07 0.08 0.09 0.08 0.10 0.08 0.08 0.08 0.08 0.08 0.09 0.08 0.07 0.07 0.08 0.08 0.07 0.08 0.08 0.09 0.07 0.09 0.07 0.06 0.07 0.09 0.08 0.09 0.08 0.07 0.08 0.07 0.09 0.07 0.08 0.07 0.08 0.09 0.08 0.10 0.08 0.08 0.08 0.08 0.08 0.09 0.08 0.08 0.08 0.09 0.08 0.08 0.08 0.09 0.10 0.08 0.10 0.08 0.07 0.08 0.10 0.09 0.09 0.08 0.08 0.09 0.08 0.09 0.08 0.08 0.08 0.08 0.10 0.08 0.10 0.09 0.08 0.09 0.09 0.08 0.10 0.09 0 .08 0 .08 0 .09 0 .08 0 .08 0 .08 0 .09 0 .10 0 .08 0 .10 0 .08 0 .07 0 .08 0 .10 0 .09 0 .09 0 .08 0 .08 0 .09 0 .08 0 .09 0 .08 0 .08 0 .08 0 .08 0 .10 0 .08 0.10 0 .09 0 .08 0 .09 0 .09 0 .08 0 .10 0 .09 Day 30 0 .08 0 .08 0 .09 0 .08 0.08 0 .08 0 .09 0 .10 0 .08 0 .10 0 .08 0 .07 0 .08 0 .10 0 .09 0 .09 0 .08 0 .08 0 .09 0 .08 0 .09 0 .08 0 .08 0 .08 0 .08 0 .10 0 .08 0 .10 0 .09 0 .08 0 .09 0 .09 0 .08 0 .10 0 .09 423 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 32 Day 33 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 0 .08 0 .08 0 .09 0 .08 0 .08 0 .08 0 .09 0.10 0 .08 0 .10 0 .08 0 .07 0 .08 0 .10 0 .09 0 .09 0 .08 0 .08 0 .09 0 .08 0 .09 0 .08 0 .08 0 .08 0 .08 0 .10 0 .08 0 .10 0 .09 0 .08 0 .09 0 .09 0 .08 0 .10 0 .09 0.08 0.08 0.09 0.08 0.08 0.08 0.09 0.10 0.08 0.10 0.08 0.07 0.08 0.10 0.09 0.09 0.08 0.08 0.09 0.08 0.09 0.08 0.08 0.08 0.08 0.10 0.08 0.10 0.09 0.08 0.09 0.09 0.08 0.10 0.09 Day 34 I MDIVIDUAL DOS:E VOLUMES (mL,) Day 35 Day 36 FOR MALE RA.TS Day 37 Day 38 0.08 0.08 0.09 0.08 0.08 0.08 0.09 0.10 0.08 0.10 0.08 0.07 0.08 0.10 0.09 0.09 0.08 0.08 0.09 0.08 0.09 0.08 0.08 0.08 0.08 0.10 0.08 0.10 0.09 0.08 0.09 0.09 0.08 0.10 0.09 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 Day 39 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 424 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 41 Da;y 42 Male, III - 50 mg/k(3/day 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 0.08 0.08 0.10 0.09 0.09 0.09 0.10 0.10 0.08 0.11 0.08 0.07 0.09 0.11 0.09 0.10 0.09 0.09 0.09 0.08 0.09 0.09 0.09 0.09 0.09 0.10 0.09 0.11 0.10 0.09 0.10 0.10 0.09 0.10 0.09 0 .09 0 .09 0 .10 0 .09 0 .09 0 .09 0 .10 0 .11 0 .09 0 .11 0 .09 0 .08 0 .09 0 .11 0 .10 0.10 0 .09 0 .09 0 .10 0 .09 0 .10 0 .09 0 .09 0 .09 0 .09 0 .11 0 .10 0 .12 0 .10 0 .10 0 .10 0.10 0 .10 0 .11 0 .10 Day 43 I:NDIVir)UAL DC)SE VOLUMES (mL ) FOR MALE 1WTS Da:y 44 Day 45 Day 46 Da:y 47 0.09 0.09 0.10 0.09 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.11 0.10 0.10 0.09 0.09 0.10 0.09 0.10 0.09 0.09 0.09 0.09 0.11 0.10 0.12 0.10 0.10 0.10 0.10 0.10 0.11 0.10 0 .09 0 .09 0 .10 0 .09 0 .09 0 .09 0 .10 0 .11 0 .09 0 .11 0 .09 0 .08 0 .09 0.11 0 .10 0 .10 0 .09 0 .09 0 .10 0 .09 0 .10 0 .09 0 .09 0 .09 0 .09 0 .11 0 .10 0 .12 0 .10 0 .10 0 .10 0.10 0 .10 0 .11 0 .10 0.09 0.09 0.10 0.09 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.11 0.10 0.10 0.09 0.09 0.10 0.09 0.10 0.09 0.09 0.09 0.09 0.11 0.10 . 0.12 0.10 0,10 0.10 0.10 0.10 0.11 0.10 0.09 0.09 0.10 0.09 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.11 0.10 0.10 0.09 0.09 0.10 0.09 0.10 0.09 0.09 0.09 0.09 0.11 0.10 0.12 0.10 0.10 0.10 0.10 0.10 0.11 0.10 0 .09 0 .09 0 .10 0 .09 0 .09 0 .09 0 .10 0 .11 0 .09 0 .11 0 .09 0 .08 0 .09 0 .11 0 .10 0 .10 0 .09 0 .09 0 .10 0 .09 0 .10 0 .09 0 .09 0 .09 0 .09 0 .11 0 .10 0 .12 0 .10 0 .10 0.10 0 .10 0 .10 0 .11 0 .10 Da:y 48 0 .09 0 .09 0 .10 0 .09 0 .09 0 .09 0 .10 0 .11 0 .09 0 .11 0 .09 0 .08 0 .09 0 .11 0 .10 0 .10 0 .09 0 .09 0.10 0 .09 0 .10 0 .09 0 .09 0 .09 0 .09 0 .11 0 .10 0 .12 0 .10 0 .10 0 .10 0 .10 0.10 0 .11 0 .10 425 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 50 Day 51 Male, III - 641146 641218 641073 64.1056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 0 .09 0 .09 0 .10 0 .10 0 .09 0 .09 0 .10 0 .11 0 .09 0 .11 0 .09 0 .08 0 .09 0 .12 0 .11 0 .11 0 .09 0 .10 0 .11 0 .09 0 .10 0 .09 0 .09 0 .10 0 .10 0 .11 0 .11 0 .12 0 .10 0 .10 0 .11 0 .10 0 .10 0.11 0.10 0.09 0.09 0.10 0.10 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.10 0.09 0.09 0.10 0.10 0.11 0.11 0.12 0.10 0.10 0.11 0.10 0.10 0.11 0.10 Day 52 111DIVIDUAL DOSE VOLUMES (mL ) FOR MALE R B.TS Day 53 Day 54 Day 55 Day 56 0.09 0.09 0.10 0.10 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.10 0.09 0.09 0.10 0.10 0.11 0.11 0.12 0.10 0.10 0.11 0.10 0.10 0.11 0.10 0.09 0.09 0.10 0.10 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.10 0.09 0.09 0.10 0.10 0.11 0.11 0.12 0.10 0.10 0.11 0.10 0.10 0.11 0.10 0.09 0.09 0.10 0.10 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.10 0.09 0.09 0.10 0.10 0.11 0.11 0.12 0.10 0.10 0.11 0.10 0.10 0.11 0.10 0.09 0.09 0.10 0.10 0.09 0.09 0.10 0.11 0.09 0.11 0.09 0.08 0.09 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.10 0.09 0.09 0.10 0.10 0.11 0.11 0.12 0.10 0.10 0.11 0.10 0.10 0.11 0.10 0. 09 0. 09 0. 11 0. 10 0. 10 0. 10 0. 11 0. 12 0. 10 0. 12 0. 09 0. 09 0. 10 0. 12 0. 11 0. 11 0. 09 0. 10 0. 11 0. 09 0.11 0. 10 0. 10 0. 10 0. 10 0. 12 0. 11 0. 12 0. 10 0. 10 0. 11 0. 11 0. 11 0. 11 0. 11 Day 57 0.09 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.11 0.10 0.10 0.10 0.10 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.11 0.11 0.11 426 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 Day 59 50 ing/kg/day 0 .09 0 .09 0 .11 0 .10 0 .10 0 .10 0 .11 0 .12 0 .10 0 .12 0 .09 0 .09 0 .10 0 .12 0 .11 0.11 0 .09 0 .10 0 .11 0 .09 0 .11 0 .10 0 .10 0 .10 0 .10 0 .12 0 .11 0 .12 0 .10 0 .10 0 .11 0 .11. 0 .11 0.11 0 .11 Day 60 0.09 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.11 0.10 0.10 0.10 0.10 0.12 0.11' 0.12 0.10 0.10 0.11 0.11 0.11 0.11 0.11 Day 61 INDIVIDUAL DOSE VOLUMES (mL) Day 62 Day 63 FOR MALE RATS Day 64 Day 65 0.09 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.11 0.10 0.10 0.10 0.10 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.11 0.11 0.11 0.09 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.09 0.10 0.11 0.09 0.11 0.10 0.10 0.10 0.10 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.11 0.11 0.11 0.09 0.09 0.11 0.11 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.10 0.11 0.11 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.10 0.12 0.11 0.09 0.09 0.11 0.11 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.10 0.11 0.11 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.10 0.12 0.11 0.09 0.09 0.11 0.11 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.10 0.11 0.11 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.10 0.12 0.11 Day 66 0.09 0.09 0.11 0.11 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.10 0.11 0.11 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.10 0.12 0.11 427 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations D ay 68 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 mg/kg/day 0 .09 0 .09 0 .11 0 .11 0 .10 0 .10 0 .11 0 .12 0 .10 0 .12 0 .09 0 .09 0 .10 0 .12 0 .11 0 .11 0 .10 0 .11 0.11 0 .09 0 .11 0 .10 0 .10 0 .10 0 .11 0 .12 0 .11 0 .12 0 .10 0 .10 0 .11 0 .11 0 .10 0 .12 0 .11 Day 69 0.09 0.09 0.11 0.11 0.10 0.10 0.11 0.12 0.10 0.12 0.09 0.09 0.10 0.12 0.11 0.11 0.10 0.11 0.11 0.09 0.11 0.10 0.10 0.10 0.11 0.12 0.11 0.12 0.10 0.10 0.11 0.11 0.10 0.12 0.11 D ay 70 I NDIVIDUAL DOE!E VOLCIMES (mL ) FOR MALE RATE Day 71 D,ay 72 D,ay 73 D,ay 74 0 .10 0 .10 0 .11 0 .11 0 .11 0 .10 0 .12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0 .13 0 .11 0.10 0.10 0.11 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.11 0 .10 0 .10 0 .11 0 .11 0 .11 0 .10 0 .12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0.13 0 .11 0 .10 0.10 0 .11 0 .11 0 .11 0 .10 0.12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0 .13 0 .11 0 .10 0 .10 0 .11 0 .11 0 .11 0 .10 0 .12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0.13 0 .11 Day 75 0. 10 0. 10 0. 11 0. 11 0. 11 0. 10 0. 12 0. 13 0. 10 0. 13 0. 10 0. 09 0. 10 0. 13 0. 11 428 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 77 Day 78 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 0 .10 0 .10 0 .12 0 .11 0 .11 0 .10 0 .12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0 .13 0 .12 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.12 Day 79 I MDIVXDUAL DOSE VOLUMES (mL ) FOR MALE RAT!S Day 80 Day 81 Day 82 Day 83 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.12 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.12 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.12 0 .10 0 .10 0 .12 0 .11 0 .11 0 .10 0 .12 0 .13 0 .10 0 .13 0 .10 0 .09 0 .10 0 .13 0 .12 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.13 0.10 0.13 0.10 0.09 0.10 0.13 0.12 Day 84 0.10 0.10 0.12 0.11 0.11 0.10 0.12 0.14 0.10 0.13 0.10 0.09 0.10 0.14 0.12 429 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 86 Day 87 Male, III -- 50 rog/kg/day 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 0 .10 0 .10 0 .12 0.11 0 .11 0 .10 0 .12 0 .14 0 .10 0 .13 0 .10 0 .09 0 .10 0 .14 0 .12 0 .10 0 .10 0 .12 0 .11 0 .11 0 .10 0 .12 0 .14 0 .10 0 .13 0 .10 0 .09 0 .10 0 .14 0 .12 Day 88 I MDIVIDITAL DOS E VOLTOIES (inL) FOR MALE RATS Day 89 Day 90 0. 10 0.10 0. 12 0. 11 0. 11 0. 10 0. 12 0. 14 0. 10 0. 13 0. 10 0. 09 0. 10 0. 14 0. 12 0. 10 0. 10 0. 12 0. 11 0. 11 0. 10 0. 12 0. 14 0. 10 0. 13 0. 10 0. 09 0. 10 0. 14 0. 12 0. 10 0. 10 0. 12 0. 12 0. 11 0. 11 0. 12 0. 14 0. 11 0. 13 0. 10 0. 09 0. 10 0. 14 0. 12 430 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 0 250 ing/kg/day 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 Day 1 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 Day 2 INDIVIDUAL DOSE VOLUMES Day 3 Day 4 (TOL) FOR MALE RATS Day 5 Day 6 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 0.25 0.25 0.27 0.26 0.25 0.27 0.26 0.24 0.25 0.28 0.23 0.24 0.25 0.26 0.28 0.29 0.26 0.23 0.25 0.24 0.27 0.24 0.26 0.24 0.26 0.27 0.25 0.27 0.28 0.26 0.27 0.24 0.28 0.29 0.26 0.31 0.29 0.33 0.31 0.31 0.33 0.29 0.29 0.32 0.33 0.27 0.28 0.31 0.32 0.33 0.33 0.33 0.27 0.30 0.29 0.32 0.31 0.32 0.31 0.32 0.34 0.30 0.33 0.32 0.32 0.31 0.27 0.34 0.35 0.33 ^ If 3 ' 3 " S3 9 9 3 a f Q 3 s aani 3 ^ CS 0 24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 9 Day 10 Male, V - 250 mg/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0.31 0.29 0.33 0.31 0.31 0.33 0.29 0.29 0.32 0.33 0.27 0.28 0.31 0.32 0.33 0.33 0.33 0.27 0.30 0.29 0.32 0.31 . 0.32 0.31 0.32 0.34 0.30 0.33 0.32 0.32 0.31 0.27 0.34 0.35 0.33 . 0.31 0.29 0.33 0.31 0.31 0.33 0.29 0.29 0.32 0.33 0.27 0.28 0.31 0.32 0.33 0.33 0.33 0.27 0.30 0.29 0.32 0.31 0.32 0.31 0.32 0.34 0.30. 0.33 0.32 0.32 0.31 0.27 0.34 0.35 0.33 Day 11 INDIVIDUAL DOSE VOLUMES (inL) Day 12 Day 13 FOR MALE RATS 0 .31 0 .29 0 .33 0 .31 0 .31 0 .33 0 .29 0 .29 0 .32 0.33 0.27 0 .28 0 .31 0 .32 0 .33 0 .33 0 .33 0 .27 0 .30 0.29 0 .32 0 .31 0 .32 0 .31 0 .32 0 .34 0 .30 0 .33 0 .32 0 .32 0 .31 0.27 0 .34 0 .35 0 .33 0.31 0.29 0.33 0.31 0.31 0.33 0.29 0.29 0.32 0.33 0.27 0.28 0.31 0.32 0.33 0.33 0.33 0.27 0.30 0.29 0.32 0.31 0.32 0.31 0.32 0.34 0.30 0.33 0.32 0.32 0.31 0.27 0.34 0.35 0.33 0.31 0.29 0.33 0.31 0.31 0.33 0.29 0.29 0.32 0.33 0.27 0.28 0.31 0.32 0.33 0.33 0.33 0.27 0.30 0.29 0.32 0.31 0.32 0.31 0.32 0.34 0.30 0.33 0.32 0.32 0.31 0.27 0.34 0.35 0.33 ---------------- 432 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 14 250 ing/kg/day 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 Day 15 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 Day 16 INDIVIDUAL DOSE VOLUMES (mL) Day 17 Day 18 FOR MALE RATS Day 19 Day 20 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 0.36 0.33 0.37 0.35 0.36 0.37 0.34 0.34 0.37 0.38 0.31 0.32 0.36 0.37 0.36 0.39 0.38 0.32 0.34 0.34 0.38 0.36 0.36 0.35 0.38 0.39 0.34 0.37 0.38 0.36 0.36 0.32 0.40 0.40 0.38 "K-24616: Subchronic Toxicity '-"a<" 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 23 Day 24 Male, V - 250 nig/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0. 42 0. 36 0. 42 0. 40 0. 41 0. 40 0. 37 0. 37 0.40 0. 42 0. 35 0. 34 0. 41 0. 42 0. 41 0. 41 0. 41 0. 36 0. 38 0. 39 0. 42 0. 42 0. 37 0. 38 0. 43 0. 44 0. 37 0. 43 0. 42 0. 40 0. 39 0. 36. 0. 45 0.46 0. 42 0.42 0.36 0.42 0.40 0.41 0.40 0.37 0.37 0.40 0.42 0.35 0.34 0.41 0.42 0.41 0.41 0.41 0.36 0.38 0.39 0.42 0.42 0.37 0.38 0.43 0.44 0.37 0.43 0.42 0.40 0.39 0.36 0.45 0.46 0.42 Day 25 INDIVIDUAL DOSE VOLUMES Day 26 Day 27 (idL) FOR MALE RATS Day 28 Day 29 0.42 0.36 0.42 0.40 0.41 0.40 0.37 0.37 0.40 0.42 0.35 0.34 0.41 0.42 0.41 0.41 0.41 0.36 0.38 0.39 0.42 0.42 0.37 0.38 0.43 0.44 0.37 0.43 0.42 0.40 0.39 0.36 0.45 0.46 0.42 0.42 0.36 0.42 0.40 0.41 0.40 0.37 0.37 0.40 0.42 0.35 0.34 0.41 0.42 0.41 0.41 0.41 0.36 0.38 0.39 0.42 0.42 0.37 0.38 0.43 0.44 0.37 0.43 0.42 0.40 0.39 0.36 0.45 0.46 0.42 0.42 0.36 0.42 0.40 0.41 0.40 0.37 0.37 0.40 0.42 0.35 0.34 0.41 0.42 0.41 0.41 0.41 0.36 0.38 0.39 0.42 0.42 0.37 0.38 0.43 0.44 0.37 0.43 0.42 0.40 0.39 0.36 0.45 0.46 0.42 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 Day 30 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 434 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 32 Day 33 Male, V - 250 ing/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 Day 34 INDIVIDUAL DOSE VOLUMES (mL) Day 35 Day 36 FOR MALE RATS Day 37 Day 38 0.44 0.39 0.46 0.39 0.45 0.45 0.40 0.41 0.45 0.44 0.37 0.36 0.44 0.44 0.44 0.46 0.44 0.38 0.40 0.40 0.43 0.45 0.41 0.42 0.48 0.47 0.40 0.45 0.46 0.43 0.41 0.39 0.48 0.49 0.45 0.47 0.41 0.48 0.43 0.46 0.47 0.42 0.43 0.46 0.46 0.39 0.38 0.46 0.48 0.47 0.48 0.45 0.41 0.43 0.44 0.46 0.48 0.44 0.44 0.51 0.51 0.43 0.47 0.49 0.46 0.44 0.42 0.52 0.52 0.48 0.47 0.41 0.48 0.43 0.46 0.47 0.42 0.43 0.46 0.46 0.39 0.38 0.46 0.48 0.47 0.48 0.45 0.41 0.43 0.44 0.46 0.48 0.44 0.44 0.51 0.51 0.43 0.47 0.49 0.46 0.44 0.42 0.52 0.52 0.48 0.47 0.41 0.48 0.43 0.46 0.47 0.42 0.43 0.46 0.46 0.39 0.38 0.46 0.48 0.47 0.48 0.45 0.41 0.43 0.44 0.46 0.48 0.44 0.44 0.51 0.51 0.43 0.47 0.49 0.46 0.44 0.42 0.52 0.52 0.48 0 .47 0 .41 0 .48 0 .43 0 .46 0 .47 0 .42 0 .43 0 .46 0 .46 0 .39 0 .38 0 .46 0 .48 0 .47 0.48 0 .45 0 .41 0 .43 0.44 0 .46 0 .48 0 .44 0 .44 0 .51 0 .51 0 .43 0 .47 0 .49 0 .46 0 .44 0 .42 0 .52 0 .52 0 .48 Day 39 0.47 0.41 0.48 0.43 0.46 0.47 0.42 0.43 0.46 0.46 0.39 0.38 0.46 0.48 0.47 0.48 0.45 0.41 0.43 0.44 0.46 0.48 0.44 0.44 0.51 0.51 0.43 0.47 0.49 0.46 0.44 0.42 0.52 0.52 0.48 435 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 43 INDIVIDUAL DOSE VOLUMES (mL) Day 44 Day 45 FOR MALE RATS Day 46 Day 47 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0.47 0.41 0.48 0.43 0.46 0.47 0.42 0.43 0.46 0.46 0.39 0.38 0.46 0.48 0.47 0.48 0.45 0.41 0.43 0.44 0.46 0.48 0.44 0.44 0.51 0.51 0.43 0.47 0.49 0.46 0.44 0.42 0.52 0.52 0.48 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 0.50 0.42 0.51 0.45 0.49 0.48 0.44 0.44 0.47 0.49 0.40 0.37 0.38 0.48 0.51 0.53 0.47 0.43 0.44 0.46 0.48 0.50 0.48 0.47 0.54 0.54 0.45 0.49 0.51 0.47 0.48 0.45 0.54 0.54 0.50 ft ,8 5 (^ 5 R" 8. 0 1 ffl 0 aT 5" 3 0 v 0 SS H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 50 250 ing/kg/day 0.50 0.44 0.53 0.47 0.51 0.51 0.45 0.46 0.50 0.50 0.41 0.37 0.44 0.51 0.51 0.54 0.50 0.45 0.44 0.48 0.51 0.53 0.51 0.50 0.56 0.57 0.46 0.51 0.53 0.50 0.48 0.45 0.55 0.55 0.54 Day 51 0 .50 0 .44 0 .53 0 .47 0 .51 0 .51 0 .45 0 .46 0 .50 0 .50 0 .41 0 .37 0 .44 0 .51 0 .51 0 .54 0 .50 0 .45 0 .44 0 .48 0 .51 0 .53 0 .51 0 .50 0 .56 0 .57 0 .46 0 .51 0 .53 0 .50 0 .48 0 .45 0 .55 0 .55 0 .54 Day 52 INDIVIDUAL DOSE VOLUMES (mL) Day 53 Day 54 FOR MALE RATS Day 55 Day 56 0.50 0.44 0.53 0.47 0.51 0.51 0.45 0.46 0.50 0.50 0.41 a 0.44 0.51 0.51 0.54 0.50 0.45 0.44 0.48 0.51 0.53 0.51 0.50 0.56 0.57 0.46 0.51 0.53 0.50 0.48 0.45 0.55 0.55 0.54 0 .50 0 .44 0 .53 0 .47 0 .51 0 .51 0 .45 0 .46 0 .50 0 .50 0 .41 0.44 0 .51 0 .51 0 .54 0 .50 0 .45 0 .44 0 .48 0 .51 0 .53 0 .51 0 .50 0 .56 0 .57 0 .46 0 .51 0 .53 0 .50 0 .48 0 .45 0 .55 0 .55 0 .54 0 .50 0 .44 0 .53 0 .47 0 .51 0 .51 0 .45 0 .46 0 .50 0 .50 0.41 0 .44 0 .51 0 .51 0 .54 0 .50 0 .45 0 .44 0 .48 0 .51 0 .53 0 .51 0 .50 0 .56 0 .57 0 .46 0 .51 0 .53 0 .50 0 .48 0 .45 0 .55 0 .55 0 .54 0.50 0.44 0.53 0.47 0.51 0.51 0.45 0.46 0.50 0.50 0.41 0.44 0.51 0.51 0.54 0.50 0.45 0.44 0.48 0.51 0.53 0.51 0.50 0.56 0.57 0.46 0.51 0.53 0.50 0.48 0.45 0.55 0.55 0.54 0. 52 0. 45 0. 56 0. 50 0. 51 0. 54 0. 48 0. 49 0. 52 0. 52 0. 43 0.49 0. 53 0. 52 0. 59 0. 51 0. 48 0. 45 0. 50 0. 53 0. 56 0.53 0. 51 0. 59 0. 59 0. 48 0. 53 0. 56 0. 52 0. 48 0. 47 0. 57 0. 56 0. 56 Day 57 0.52 0.45 0.56 0.50 0.51 0.54 0.48 0.49 0.52 0.52 0.43 0.49 0.53 0.52 0.59 0.51 0.48 0.45 0.50 0.53 0.56 0.53 0.51 0.59 0.59 0.48 0.53 0.56 0.52 0.48 0.47 0.57 0.56 0.56 Animal num]her 641090 was sacrificed in extremis cin test day 51. ------------ 437 -- y 3 ' g "S y 3. S? P- 0 a & 0 S 3" a 8 > 0 CO H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 59 250 mg/kg,/day 0.52 0.45 0.56 0.50 0.51 0.54 0.48 0.49 0.52 0.52 0.43 0.49 0.53 0.52 0.59 0.51 0.48 0.45 0.50 0.53 0.56 0.53 0.51 0.59 0.59 0.48 0.53 0.56 0.52 0.48 0.47 0.57 0.56 0.56 Day 60 0. 52 0.45 0. 56 0. 50 0. 51 0. 54 0. 48 0. 49 0. 52 0. 52 0. 43 0. 49 0. 53 0. 52 0. 59 0. 51 0. 48 0. 45 0. 50 0. 53 0. 56 0. 53 0. 51 0. 59 0. 59 0. 48 0. 53 0. 56 0. 52 0. 48 0. 47 0. 57 0. 56 0. 56 Day 61 IMDIVIDTJAL DOSE VOLUIIBS (mL ) Day 62 Day 63 FOR MALE 1UVTS Day 64 Day 65 0.52 0.45 0.56 0.50 0.51 0.54 0.48 0.49 0.52 0.52 0.43 0.49 0.53 0.52 0.59 0.51 0.48 0.45 0.50 0.53 0.56 . 0.53 0.51 0.59 0.59 0.48 0.53 0.56 0.52 0.48 0.47 0.57 0.56 0.56 0. 52 0. 45 0. 56 0. 50 0. 51 0. 54 0. 48 0. 49 0. 52 0. 52 0. 43 0. 49 0. 53 0. 52 0. 59 0. 51 0. 48 0. 45 0. 50 0.53 0. 56 0. 53 0. 51 0. 59 0. 59 0. 48 0. 53 0. 56 0. 52 0. 48 0. 47 0. 57 0. 56 0. 56 0. 54 0. 46 0. 57 0. 51 0. 53 0. 56 0. 50 0. 50 0. 54 0. 53 0. 43 0. 49 0. 54 0. 53 0. 58 0. 51 0. 49 0. 47 0. 51 0. 55 0. 57 0. 55 0. 53 0. 60 0. 60 0. 49 0. 52 0. 58 0. 54 0. 50 0.47 0. 58 0. 60 0. 56 0 .54 0 .46 0 .57 0 .51 0 .53 0 .56 0 .50 0 .50 0 .54 0 .53 0 .43 0 .49 0 .54 0 .53 0 .58 0 .51 0 .49 0 .47 0 .51 0 .55 0 .57 0 .55 0 .53 0 .60 0 .60 0 .49 0 .52 0 .58 0 .54 0 .50 0.47 0 .58 0 .60 0 .56 0. 54 0. 46 0. 57 0. 51 0. 53 0. 56 0. 50 0. 50 0. 54 0. 53 0. 43 0.49 0. 54 0. 53 0. 58 0. 51 0. 49 0. 47 0. 51 0. 55 0. 57 0. 55 0. 53 0. 60 0. 60 0. 49 0. 52 0. 58 0. 54 0. 50 0. 47 0. 58 0. 60 0. 56 Da:y 66 0 .54 0 .46 0 .57 0 .51 0 .53 0.56 0 .50 0 .50 0 .54 0 .53 0.43 0 .49 0 .54 0 .53 0 .58 0 .51 0 .49 0 .47 0 .51 0 .55 0 .57 0 .55 0 .53 0 .60 0 .60 0 .49 0 .52 0 .58 0 .54 0 .50 0.47 0 .58 0 .60 0 .56 438 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 68 Day 69 Male, V - 250 ing/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0.54 0.46 0.57 0.51 0.53 0.56 0.50 0.50 0.54 0.53 0.43 0.49 0.54 0.53 0.58 0.51 0.49 0.47 0.51 0.55 0.57 0.55 0.53 0.60 0.60 0.49 0.52 0.58 0.54 0.50 0.47 0.58 0.60 0.56 0 .54 0 .46 0 .57 0 .51 0 .53 0 .56 0 .50 0 .50 0 .54 0 .53 0 .43 0.49 0 .54 0 .53 0 .58 0 .51 0 .49 0 .47 0 .51 0 .55 0 .57 0 .55 0 .53 0 .60 0 .60 . 0.49 0 .52 0 .58 0 .54 0 .50 0.47 0 .58 0 .60 0 .56 Day 70 I NDIVXDUAL DOSE VOLUMES (rnL ) FOR 11ALE ]RATS Day 71 Day 72 Day 73 Day 74 0.56 0.48 0.60 0.54 0.54 0.56 0.52 0.51 0.56 0.55 0.45 0.51 0.56 0.55 0.56 0.48 0.60 0.54 0.54 0.56 0.52 0.51 0.56 0.55 0.45 0.51 0.56 0.55 0.56 0.48 0.60 0.54 0.54 0.56 0.52 0.51 0.56 0.55 0.45 0.51 0.56 0.55 0. 56 0. 48 0. 60 0. 54 0. 54 0. 56 0. 52 0. 51 0. 56 0. 55 0. 45 0. 51 0. 56 0. 55 0. 56 0. 48 0. 60 0. 54 0. 54 0. 56 0. 52 0. 51 0. 56 0. 55 0.45 0. 51 0. 56 0. 55 Day 75 0 .56 0.48 0 .60 0 .54 0 .54 0 .56 0 .52 0 .51 0 .56 0 .55 0.45 0 .51 0 .56 0 .55 439 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 77 Da:y 78 Male, V - 250 n ig/kg/day 641190 641134 641202 64.1197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 0. 56 0. 49 0. 61 0. 54 0. 56 0. 58 0. 53 0. 53 0. 57 0. 56 0. 45 0. 53 0. 59 0. 57 0 .56 0.49 0 .61 0 .54 0 .56 0 .58 0 .53 0 .53 0 .57 0 .56 0.45 0 .53 0 .59 0 .57 Day 79 I MDIVII)UAL DOS E VOLT.)MES (inL ) FOR I 1ALE RATS Da:y 80 Da:y 81 Day 82 Da:y 83 0. 56 0. 49 0. 61 0. 54 0. 56 0. 58 0. 53 0. 53 0. 57 0. 56 0.45 0. 53 0. 59 0. 57 0 .56 0 .49 0 .61 0 .54 0 .56 0 .58 0.53 0 .53 0 .57 0 .56 0.45 0 .53 0 .59 0 .57 0 .56 0 .49 0 .61 0 .54 0 .56 0 .58 0 .53 0 .53 0 .57 0.56 0.45 0 .53 0 .59 0 .57 0. 56 0. 49 0. 61 0. 54 0.56 0. 58 0. 53 0. 53 0. 57 0. 56 0.45 0. 53 0. 59 0. 57 0 .56 0.49 0 .61 0 .54 0 .56 0 .58 0 .53 0 .53 0 .57 0 .56 0 .45 0 .53 0 .59 0 .57 Day 84 0.56 0.49 0.61 0.55 0.56 0.59 0.53 0.53 0.58 0.55 0.46 0.51 0.59 0.59 440 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 86 250 ing/kg/day 0.56 0.49 0.61 0.55 0.56 0.59 0.53 0.53 0.58 0.55 0.46 0.51 0.59 0.59 Day 87 0.56 0.49 0.61 0.55 0.56 0.59 0.53 0.53 0.58 0.55 0.46 0.51 0.59 0.59 Day 88 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 89 Day 90 0.56 0.49 0.61 0.55 0.56 0.59 0.53 0.53 0.58 0.55 0.46 0.51 0.59 0.59 0.56 0.49 0.61 0.55 0.56 0.59 0.53 0.53 0.58 0.55 0.46 0.51 0.59 0.59 0.56 0.50 0.62 0.55 0.56 0.60 0.53 0.53 0.59 0.57 0.46 0.51 0.59 0.59 441 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 D Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 1000 ing/kg/day 0 .97 1 .00 0 .99 1 .00 0 .99 1 .10 1 .00 0 .98 1 .00 1 .10 0 .94 0 .98 1 .10 1 .00 1 .10 1 .20 1 .00 0 .89 0 .99 0 .95 1 .10 0 .91 1 .10 0 .97 1 .00 1 .00 1 .00 1 .20 1 .10 1 .00 1 .10 0 .95 1 .00 1 .00 0 .98 1 .00 0 .98 1 .00 1 .20 1 .10 0 .94 1 .20 0 .96 1 .10 1 .10 0.97 1.00 0.99 1.00 0.99 1.10 1.00 0.98 1.00 1.10 0.94 0.98 1.10 1.00 1.10 1.20 1.00 0.89 0.99 0.95 1.10 0.91 1.10 0.97 1.00 1.00 1.00 1.20 1.10 1.00 1.10 0.95 1.00 1.00 0.98 1.00 0.98 1.00 1.20 1.10 0.94 1.20 0.96 1.10 1.10 0.97 1.00 0.99 1.00 0.99 1.10 1.00 0.98 1.00 1.10 0.94 0.98 1.10 1.00 1.10 1.20 1.00 0.89 0.99 0.95 1.10 0.91 1.10 0.97 1.00 1.00 1.00 1.20 1.10 1.00 1.10 0.95 1.00 1.00 0.98 1.00 0.98 1.00 1.20 1.10 0.94 1.20 0.96 1.10 1.10 0.97 1.00 0.99 1.00 0.99 1.10 1.00 0.98 1.00 1.10 0.94 0.98 1.10 1.00 1.10 1.20 1.00 0.89 0.99 0.95 1.10 0.91 1.10 0.97 1.00 1.00 1.00 1.20 1.10 1.00 1.10 0.95 1.00 1.00 0.98 1.00 0.98 1.00 1.20 1.10 0.94 1.20 0.96 1.10 1.10 0.97 1.00 0.99 1.00 0.99 1.10 1.00 0.98 1.00 1.10 0.94 0.98 1.10 1.00 1.10 1.20 1.00 0.89 0.99 0.95 1.10 0.91 1.10 0.97 1.00 1.00 1.00 1.20 1.10 1.00 1.10 0.95 1.00 1.00 0.98 1.00 0.98 1.00 1.20 1.10 0.94 1.20 0.96 1.10 1.10 0 .97 1 .00 0 .99 1 .00 0 .99 1 .10 1 .00 0 .98 1 .00 1 .10 0 .94 0 .98 1 .10 1 .00 1 .10 1 .20 1 .00 0 .89 0 .99 0 .95 1 .10 0 .91 1 .10 0 .97 1 .00 1 .00 1 .00 1 .20 1 .10 1 .00 1 .10 0 .95 1 .00 1 .00 0 .98 1 .00 0 .98 1 .00 1 .20 1 .10 0 .94 1 .20 0 .96 1 .10 1 .10 0 .97 1 .00 0 .99 1 .00 0 .99 1 .10 1 .00 0 .98 1 .00 1 .10 0 .94 0 .98 1 .10 1 .00 1 .10 1 .20 1 .00 0 .89 0 .99 0 .95 1 .10 0 .91 1 .10 0 .97 1 .00 1 .00 1 .00 1 .20 1 .10 1 .00 1 .10 0 .95 1 .00 1 .00 0 .98 1 .00 0 .98 1 .00 1 .20 1 .10 0 .94 1 .20 0 .96 1 .10 1 .10 1 .10 1 .20 1 .20 1 .20 1 .20 1 .20 1 .20 1 .20 1 .20 1 .30 1 .10 1.10 1 .30 1 .30 1 .30 1 .40 1 .20 1 .10 1 .20 1 .10 1 .30 1 .10 1 .30 1 .20 1 .30 1 .20 1 .20 1 .40 1 .30 1 .30 1 .30 1 .10 1 .20 1 .20 1 .20 1 .30 1 .20 1 .30 1 .40 1 .20 1 .20 1 .40 1 .10 1 .30 1 .30 442 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 9 Day 10 Male, VII - 1000 ing/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 1.10 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.30 1.10 1.10 1.30 1.30 1.30 1.40 1.20 1.10 1.20 1.10 1.30 1.10 1.30 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.30 1.10 1.20 1.20 1.20 1.30 1.20 1.30 1.40 1.20 1.20 1.40 1.10 1.30 1.30 1.10 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.30 1.10 1.10 1.30 1.30 1.30 1.40 1.20 1.10 1.20 1.10 1.30 1.10 1.30 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.30 1.10 1.20 1.20 1.20 1.30 1.20 1.30 1.40 1.20 1.20 1.40 1.10 1.30 1.30 Day 11 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 12 Day 13 1.10 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.30 1.10 1.10 1.30 1.30 1.30 1.40 1.20 1.10 1.20 1.10 1.30 1.10 1.30 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.30 1.10 1.20 1.20 1.20 1.30 1.20 1.30 1.40 1.20 1.20 1.40 1.10 1.30 1.30 1.10 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.30 1.10 1.10 1.30 1.30 1.30 1.40 1.20 1.10 1.20 1.10 1.30 1.10 1.30 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.30 1.10 1.20 1.20 1.20 1.30 1.20 1.30 1.40 1.20 1.20 1.40 1.10 1.30 1.30 1.10 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.20 1.30 1.10 1.10 1.30 1.30 1.30 1.40 1.20 1.10 1.20 1.10 1.30 1.10 1.30 1.20 1.30 1.20 1.20 1.40 1.30 1.30 1.30 1.10 1.20 1.20 1.20 1.30 1.20 1.30 1.40 1.20 1.20 1.40 1.10 1.30 1.30 443 y,.. H g g '^ | 3 3 | ? J 3 S 8 3 tig, 3 J > 0 g H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 14 Da:y 15 Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 i: 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 100 0 nig/kg/da:y 1 .30 1 .30 1 .30 1 .40 1 .40 1 .40 1 .40 1 .40 1 .40 1 .50 1 .20 1 .20 1 .60 1 .50 1 .40 1 .60 1 .40 1 .20 1 .40 1 .30 1 .50 1 .20 1 .50 1 .50 1 .50 1 .40 1 .40 1 .60 1 .50 1 .50 . 1 .40 1 .30 1 .30 1 .40 1 .40 1 .50 1 .40 1 .50 1 .70 1 .50 1 .30 1 .60 1 .30 1 .40 1 .50 1 .30 l .30 l .30 l .40 l .40 l .40 1.40 l .40 l .40 l .50 i .20 l .20 l .60 l .50 l .40 l .60 l .40 l .20 l .40 l .30 l .50 i .20 l .50 l .50 l .50 l .40' l .40 l .60 l .50 l .50 l .40 l .30 l .30 1.40 1 .40 1 .50 1 .40 1 .50 1 .70 1 .5'0 1 .30 1 .60 l .30 1 .40 1 .50 INDB/IDUAL DOSE VOI.-UMES (itiL) FOR MALE I IATS Day 16 Da;y i7 Day 18 Day 19 1.30 1.30 1.30 1.40 1.40 1.40 1.40 1.40 1.40 1.50 1.20 1.20 1.60 1.50 1.40 1.60 1.40 1.20 1.40 1.30 1.50 1.20 1.50 1.50 . 1.50 1.40 1.40 1.60 1.50 1.50 1.40 1.30 1.30 1.40 1.40 1.50 1.40 1.50 1.70 1.50 1.30 1.60 1.30 1.40 1.50 1 .30 1 .30 1 .30 1 .40 1 .40 1 .40 1 .40 1 .40 1 .40 1 .50 1 .20 1 .20 1 .60 1 .50 1 .40 1 .60 1 .40 1 .20 1 .40 1 .30 1 .50 1 .20 1 .50 1 .50 1 .50 1 .40 1 .40 1 .60 1 .50 1 .50 1 .40 1 .30 1 .30 1 .40 1 .40 1 .50 1 .40 1 -50 1 .70 1 .50 1 .30 1 .60 1 .30 1 .40 1 .50 1.30 1.30 1.30 1.40 1.40 1.40 1.40 1.40 1.40 1.50 1.20 1.20 1.60 1.50 1.40 1.60 1.40 1.20 1.40 1.30 1.50 1.20 1.50 1.50 1.50 1.40 1.40 1.60 1.50 1.50 1.40 1.30 1.30 1.40 1.40 1.50 1.40 1.50 1.70 1.50 1.30 1.60 1.30 1.40 1.50 1 .30 1 .30 1.30 1 .40 1 .40 1 .40 1 .40 1 .40 1 .40. 1 .50 1 .20 1 .20 1 .60 1 .50 1 .40 1 .60 1 .40 1 .20 1 .40 1 .30 1 .50 1 .20 1 .50 1 .50 1 .50 1 .40 1 .40 1 .60 1 .50 1 .50 1 .40 1 .30 1 .30 1 .40 1 .40 1 .50 1 .40 1 .50 1 .70 1 .50 1 .30 1 .60 1 .30 1 .40 1 .50 444 Da:y 20 1 .30 1 .30 1 .30 1 .40 1 .40 1 .40 1 .40 1 .40 1 .40 1 .50 1 .20 1 .20 1 .60 1 .50 1 .40 1 .60 1 .40 1 .20 1 .40 1 .30 1 .50 1 .20 1 .50 1 .50 1 .50 1 .40 1 .40 1 .60 1 .50 1 .50 1 .40 1 .30 1 .30 1 .40 1 .40 1 .50 1 .40 1 .50 1 .70 1 .50 1 .30 1 .60 1 .30 1 .40 1 .50 Day 1 .4 1 .4 1 .5 1 .5 0 .5 1 .5 1 .6 1 .6 1 .5 1 .6 1 .4 1 .3 1 .8 1 .7 1 .5 1 .8 1 .5 1 .3 1 .5 1 .4 1 .7 1 .4 1 .7 1 .7 1 .6 1 .5 1 .6 1 .9 1 .7 1 .7 1 .6 1 .5 1 .4 1 .5 1 .5 1 .6 1 .6 1 .6 1 .9 1 .6 1 .5 1 .8 1 .4 1 .6 1 .7 OS S M &J" g S 1 0 . s 0 00 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 23 Day 24 Male, VII - 1000 nig/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 1.40 1.40 1.50 1.50 1.50 1.50 1.60 1.60 1.50 1.60 1.40 1.30 1.80 1.70 1.50 1.80 1.50 1.30 1.50 1.40 1.70 1.40 1.70 1.70 1.60 1.50 1.60 1.90 1.70 1.70 1.60 1.50 1.40 1.50 1.50 1.60 1.60 1.60 1.90 1.60 1.50 1.80 1.40 1.60 1.70 1.40 1.40 1.50 1.50 1.50 1.50 1.60 1.60 1.50 1.60 1.40 1.30 1.80 1.70 1.50 1.80 1.50 1.30 1.50 1.40 1.70 1.40 1.70 1.70 1.60 1.50 1.60 1.90 1.70 1.70 1.60 1.50 1.40 1.50 1.50 1.60 1.60 1.60 1.90 1.60 1.50 1.80 1.40 1.60 1.70 INDIVIDUAL DOSE VOLUMES (inL) FOR MALE RATS Day 25 Day 26 Day 27 Day 28 1.40 1.40 1.50 1.50 1.50 1.50 1.60 1.60 1.50 1.60 1.40 1.30 1.80 1.70 1.50 1.80 1.50 1.30 1.50 1.40 1.70 1.40 1.70 1.70 1.60 1.50 1.60 1.90 1.70 1.70 1.60 1.50 1.40 1.50 1.50 1.60 1.60 1.60 1.90 1.60 1.50 1.80 1.40 1.60 1.70 1.40 1.40 1.50 1.50 1.50 1.50 1.60 1.60 1.50 1.60 1.40 1.30 1.80 1.70 1.50 1.80 1.50 1.30 1.50 1.40 1.70 1.40 1.70 1.70 1.60 1.50 1.60 1.90 1.70 1.70 1.60 1.50 1.40 1.50 1.50 1.60 1.60 1.60 1.90 1.60 1.50 1.80 1.40 1.60 1.70 1.40 1.40 1.50 1.50 1.50 1.50 1.60 1.60 1.50 1.60 1.40 1.30 1.80 1.70 1.50 1.80 1.50 1.30 1.50 1.40 1.70 1.40 1.70 1.70 1.60 1.50 1.60 1.90 1.70 1.70 1.60 1.50 1.40 1.50 1.50 1.60 1.60 1.60 1.90 1.60 1.50 1.80 1.40 1.60 1.70 1.50 1.50 1.50 1.60 1.60 1.50 1.70 1.60 1.60 1.70 1.40 1.40 2.00 1.90 1.60 2.00 1.60 1.50 1.60 1.50 1.80 1.40 1.80 1.80 1.70 1.60 1.70 2.00 1.70 1.80 1.70 1.50 1.50 1.60 1.70 1.70 1.70 1.80 1.90 1.80 1.60 2.00 1.50 1.60 1.90 445 Day 29 1.50 1.50 1.50 1.60 1.60 1.50 1.70 1.60 1.60 1.70 1.40 1.40 2.00 1.90 1.60 2.00 1.60 1.50 1.60 1.50 1.80 1.40 1.80 1.80 1.70 1.60 1.70 2.00 1.70 1.80 1.70 1.50 1.50 1.60 1.70 1.70 1.70 1.80 1.90 1.80 1.60 2.00 1.50 1.60 1.90 Day 1.5 1.5 1.5 1.6 1.6 1.5 1.7 1.6 1.6 1.7 1.4 1.4 2.0 1.9 1.6 2.0 1.6 1.5 1.6 1.5 1.8 1.4 1.8 1.8 1.7 1.6 1.7 2.0 1.7 1.8 1.7 1.5 1.5 1.6 1.7 1.7 1.7 1.8 1.9 1.8 1.6 2.0 1.5 1.6 1.9 8 . 3 'S 9 ? 5 P" 8 II' 8 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 Day 32 Day 33 1000 ing/kg/day 1 .50 1 .50 1 .50 1 .60 1 .60 1 .50 1 .70 1 .60 1 .60 1 .70 1 .40 1 .40 2 .00 1 .90 1 .60 2 .00 1 .60 1 .50 1 .60 1 .50 1 .80 1 .40 1 .80 1 .80 1 .70 1 .60 1 .70 2 .00 1 .70 1 .80 1 .70 1 .50 1 .50 1 .60 1 .70 1 .70 1 .70 1 .80 1 .90 1 .80 1 .60 2 .00 1 .50 1 .60 1 .90 1 .50 1 .50 1 .50 1 .60 1 .60 1 .50 1 .70 1 .60 1 .60 1 .70 1 .40 1 .40 2 .00 1 .90 1 .60 2 .00 1 .60 1 .50 1 .60 1 .50 1 .80 1 .40 1 .80 1 .80 1 .70 1 .60 1 .702 .00 1 .70 1 .80 1 .70 1 .50 1 .50 . 1 .60 1 .70 1 .70 1 .70 1 .80 1 .90 1 .80 1 .60 2 .00 1 .50 1 .60 1 .90 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 34 Day 35 Day 36 Day 37 1 .50 1 .50 1 .50 1 .60 1 .60 1 .50 1 .70 1 .60 1 .60 1 .70 1 .40 1 .40 2 .00 1 .90 1 .60 2 .00 1 .60 1 .50 1 .60 1 .50 1 .80 1 .40 1 .80 1 .80 1 .70 1 .60 1 .70 2 .00 1 .70 1 .80 1 .70 1 .50 1 .50 1 .60 1 .70 1 .70 1 .70 1 .80 1 .90 1 .80 1 .60 2 .00 1 .50 1 .60 1 .90 1.70 1.60 1.60 1.70 1.70 1.50 1.70 1.80 1.70 1.80 1.50 1.50 2.20 2.00 1.70 2.10 1.70 1.50 1.70 1.60 1.90 1.50 1.90 1.90 1.80 1.70 1.90 2.10 1.80 1.90 1.80 1.70 1.50 1.60 1.80 1.80 1.80 1.80 2.10 1.90 1.70 2.20 1.60 1.80 2.00 1 .70 1 .60 1 .60 1 .70 1 .70 1 .50 1 .70 1 .80 1 .70 1 .80 1 .50 1 .50 2 .20 2 .00 1 .70 2 .10 1 .70 1 .50 1 .70 1 .60 1 .90 1 .50 1 .90 1 .90 1 .80 1 .70 1 .90 2 .10 1 .80 1 .90 1 .80 1 .70 1 .50 1 .60 1 .80 1 .80 1 .80 1 .80 2 .10 1 .90 1 .70 2 .20 1 .60 1 .80 2 .00 1.70 1.60 1.60 1.70 1.70 1.50 1.70 1.80 1.70 1.80 1.50 1.50 2.20 2.00 1.70 2.10 1.70 1.50 1.70 1.60 1.90 1.50 1.90 1.90 1.80 1.70 1.90 2.10 1.80 1.90 1.80 1.70 1.50 1.60 1.80 1.80 1.80 1.80 2.10 1.90 1.70 2.20 1.60 1.80 2.00 Test substance was observed on lips; aniltial may not hiive received the entire close. 446 Day 38 1.70 1.60 1.60 1.70 1.70 1.50 1.70 1.80 1.70 1.80 1.50" 1.50 2.20 2.00 1.70 2.10 1.70 1.50 1.70 1.60 1.90 1.50 1.90 1.90 1.80 1.70 1.90 2.10 1.80 1.90 1.80 1.70 1.50 1.60 1.80 1.80 1.80 1.80 2.10 1.90 1.70 2.20 1.60 1.80 2.00 Day 1.70 1.60 1.60 1.70 1.70 1.50 1.70 1.80 1.70 1.80 1.50 1.50 2.20 2.00 1.70 2.10 1.70 1.50 1.70 1.60 1.90 1.50 1.90 1.90 1.80 1.70 1.90 2.10 1.80 1.90 1.80 1.70 1.50 1.60 1.80 1.80 1.80 1.80 2.10 1.90 1.70 2.20 1.60 1.80 2.00 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations F f } ' i ] i " a > > s | Day 41 Day 42 Male, VII - 1000 ing/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 1.70 1.60 1.60 1.70 1.70 1.50 1.70 1.80 1.70 1.80 1.50 1.50 2.20 2.00 1.70 2.10 1.70 1.50 1.70 1.60 1.90 1.50 1.90 1.90 1.80 1.70 1.90 2.10 1.80 1.90 1.80 1.70 1.50 1.60 1.80 1.80 1.80 1.80 2.10 1.90 1.70 2.20 1.60 1.80 2.00 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.802.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 INDIVIDUAL DOSE VOLUMES (inL) FOR MALE RATS Day 43 Day 44 Day 45 Day 46 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80. 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 447 Day 47 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 Day 1.70 1.70 1.70 1.70 1.80 1.60 1.80 1.90 1.80 1.80 1.50 1.60 2.30 2.10 1.80 2.10 1.80 1.60 1.70 1.70 2.00 1.50 1.90 2.00 1.80 1.80 2.00 2.20 1.90 2.00 1.90 1.70 1.60 1.70 1.80 1.90 1.90 1.90 2.20 1.90 1.70 2.30 1.60 1.80 2.00 fS g ,g g ^ Sg S" S 0 9 " 0 S" H -- i S, > " '- -- H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 50 Day 51 Male, VII - 1000 ing/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 1 .70 1 .70 1 .70 1 .70 1 .80 1 .60 1 .90 1 .90 1 .80 1 .90 1 .60 1 .60 2 .50 2 .20 1 .90 2 .10 1 .80 1 .70 1 .80 1 .70 2 .00 1 .60 2 .00 2 .00 1 .90 1 .90 2 .00 2 .40 2 .00 2 .10 1 .90 1 .80 1 .70 1 .70 2 .00 2 .00 2 .00 2 .00 2 .30 1 .90 1 .80 2 .40 1 .70 1 .90 2 .10 1.70 1.70 1.70 1.70 1.80 1.60 1.90 1.90 1.80 1.90 1.60 1.60 2.50 2.20 1.90 2.10 1.80 1.70 1.80 1.70 2.00 1.60 2.00 2.00 1.90 1.90 2.00 2.40 2.00 2.10 1.90 1.80 1.70 1.70 2.00 2.00 2.00 2.00 2.30 1.90 1.80 2.40 1.70 1.90 2.10 INDIVIDUAL DOSE VOLUMES (mL) FOR MALE RATS Day 52 Day 53 Day 54 Day 55 1.70 1.70 1.70 1.70 1.80 1.60 1.90 1.90 1.80 1.90 1.60 1.60 2.50 2.20 1.90 2.10 1.80 1.70 1.80 1.70 2.00 1.60 2.00 2.00 1.90 1.90 2.00 2.40 2.00 2.10 1.90 1.80 1.70 1.70 2.00 2.00 2.00 2.00 2.30 1.90 1.80 2.40 1.70 1.90 2.10 1.70 1.70 1.70 1.70 1.80 1.60 1.90 1.90 1.80 1.90 1.60 1.60 2.50 2.20 1.90 2.10 1.80 1.70 1.80 1.70 2.00 1.60 2.00 2.00 1.90 1.90 2.00 2.40 2.00 2.10 1.90 1.80 1.70 1.70 2.00 2.00 2.00 2.00 2.30 1.90 1.80 2.40 1.70 1.90 2.10 1.70 1.70 1.70 1.70 1.80 1.60 1.90 1.90 1.80 1.90 1.60 1.60 2.50 2.20 1.90 2.10 1.80 1.70 1.80 1.70 2.00 1.60 2.00 2.00 1.90 1.90 2.00 2.40 2.00 2.10 1.90 1.80 1.70 1.70 2.00 2.00 2.00 2.00 2.30 1.90 1.80 2.40 1.70 1.90 2.10 1.70 1.70 1.70 1.70 1.80 1.60 1.90 1.90 1.80. 1.90 1.60 1.60 2.50 2.20 1.90 2.10 1.80 1.70 1.80 1.70 2.00 1.60 2.00 2.00 1.90 1.90 2.00 2.40 2.00 2.10 1.90 1.80 1.70 1.70 2.00 2.00 2.00 2.00 2.30 1.90 1.80 2.40 1.70 1.90 2.10 448 Day 56 1.80 1.80 1.80 1.70 1.90 1.70 1.90 2.00 1.80 1.90 1.60 1.70 2.50 2.30 2.00 2.20 1.90 1.80 1.80 1.70 2.10 1.60 2.00 2.10 2.00 1.90 2.00 2.40 2.10 2.20 1.90 1.80 1.80 1.70 1.90 2.00 2.00 2.00 2.30 2.00 1.80 2.50 1.70 1.90 2.10 Day 1.80 1.80 1.80 1.70 1.90 1.70 1.90 2.00 1.80 1.90 1.60 1.70 2.50 2.30 2.00 2.20 1.90 1.80 1.80 1.70 2.10 1.60 2.00 2.10 2.00 1.90 2.00 2.40 2.10 2.20 1.90 1.80 1.80 1.70 1.90 2.00 2.00 2.00 2.30 2.00 1.80 2.50 1.70 1.90 2.10 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 Day 59 Day 60 1000 mg/kg/day 1 .80 1 .80 1 .80 1 .70 1 .90 1 .70 1 .90 2 .00 1 .80 1 .90 1 .60 1 .70 2 .50 2 .30 2 .00 2 .20 1 .90 1 .80 1 .80 1 .70 2 .10 1 .60 2 .00 2 .10 2 .00 1 .90 2 .00 2 .40 2 .10 2 .20 1 .90 ' 1 .80 1 .80 1 .70 1 .90 2 .00 2 .00 2 .00 2 .30 2 .00 1 .80 2 .50 1 .70 1 .90 2 .10 1 .80 1 .80 1 .80 1 .70 1 .90 1 .70 1 .90 2 .00 1 .80 1 .90 1 .60 1 .70 2 .50 2 .30 2 .00 2 .20 1 .90 1 .80 1 .80 1 .70 2 .10 1 .60 2 .00 2.10 2 .00 1 .90 2 .00 2 .40 2 .10 2 .20 1 .90 1 .80 1 .80 1 .70 1 .90 2 .00 2 .00 2 .00 2 .30 2 .00 1 .80 2 .50 1 .70 1 .90 2 .10 INDIVIDUAL DOSE VOLUMES (rnL) FOR MALE RATS Day 61 Day 62 Day 63 Day 64 1. 80 1. 80 1. 80 1. 70 1. 90 1. 70 1. 90 2. 00 1. 80 1. 90 1. 60 1. 70 2. 50 2. 30 2. 00 2. 20 1. 90 1. 80 1. 80 1. 70 2. 10 1. 60 2. 00 2. 10 2. 00 1. 90 2. 00 2. 40 2.10 2.20 1. 90 1. 80 1. 80 1. 70 1. 90 2. 00 2. 00 2. 00 2. 30 2. 00 1. 80 2. 50 1. 70 1. 90 2. 10 1 .80 1 .80 1 .80 1 .70 1 .90 1 .70 1 .90 2 .00 1 .80 1 .90 1 .60 1 .70 2 .50 2 .30 2.00 2 .20 1 .90 1 .80 1 .80 1 .70 2 .10 1 .60 2 .00 2 .10 2 .00 1 .90 2 .00 2 .40 2 .10 2 .20 1 .90 1 .80 1 .80 1 .70 1 .90 2 .00 2 .00 2 .00 2.30 2.00 1 .80 2 .50 1 .70 1 .90 2 .10 1.90 1.80 1.80 1.80 1.90 1.70 1.90 2.00 1.90 2.00 1.70 1.60 2.60 2.30 2.10 2.20 1.90 1.80 1.90 1.80 2.20 1.60 2.10 2.20 2.00 2.00 2.10 2.40 2.20 2.20 1.90 1.90 1.80 1.80 2.00 2.10 2.00 2.10 2.40 2.00 1.80 2.60 1.80 1.90 2.20 1 .90 1 .80 1 .80 1 .80 1 .90 1 .70 1 .90 2 .00 1 .90 2 .00. 1 .70 1 .60 2 .60 2 .30 2.10 2 .20 1 .90 1 .80 1 .90 1 .80 2 .20 1 .60 2 .10 2 .20 2 .00 2 .00 2 .10 2 .40 2 .20 2.20 1 .90 1 .90 1 .80 1 .80 2 .00 2 .10 2 .00 2 .10 2.40 2 .00 1 .80 2 .60 1 .80 1 .90 2 .20 a Test substance was observed on lips; aninial may not liiave recei'red the entire dose. 449 Day 65 1 .90 1 .80 1 .80 1 .80 1 .90 1 .70 1 .90 2 .00 1 .90 2 .00 1 .70 1 .60 2 .60 2 .30 2.10 2 .20 1 .90 1 .80 1 .90 1 .80 2 .20 1 .60 2 .10 2 .20 2 .00 2 .00 2 .10 2 .40 2 .20 2.20 1 .90 1 .90 1 .80 1 .80 2 .00 2 .10 2 .00 2.10 2 .40 2 .00 1 .80 2 .60 1 .80 1 .90 2 .20 Day 1 .90 1 .80 1 .80 1 .80 1 .90 1 .70 1 .9 2 .0 1 .90 2 .00 1 .70 1 .6 2 .6 2.30 2 .1 2 .2 1 .9 1 .8 1 .9 1 .8 2.20 1 .60 2 .10 2 .2 2 .0 2 .00 2 .10 2 .4 2 .20 2 .20 1 .90 1 .90 1 .8 1 .80 2 .00 2 .10 2 .00 2 .10 2 .40 2 .00 1 .80 2 .60 1 .80 1 .90 2 .20 y,,3" S 'S> r | 1? P" 0 S 3 " S 3 IS 23S 31 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 Day 68 Day 69 1000 ing/kg/day 1.90 1.80 1.80 1.80 1.90 1.70 1.90 2.00 1.90 2.00 1.70 1.60 2.60 2.30 2.10 2.20 1.90 1.80 1.90 1.80 2.20 1.60 2.10 2.20 2.00 2.00 2.10 2.40 2.20 2.20 1.90 1.90 1.80 1.80 2.00 2.10 2.00 2.10 2.40 2.00 1.80 2.60 1.80 1.90 2.20 1 .90 1 .80 1 .80 1 .80 1 .90 1 .70 1 .90 2 .00 1 .90 2 .00 1 .70 1 .60 2 .60 2 .30 2 .10 2 .20 1 .90 1 .80 1 .90 1 .80 2 .20 1 .60 2 .10 2.20 2 .00 2 .00 2 .102 .40 2 .20 2 .20 1 .90 1 .90 1 .80 1 .80 2 .00 2 .10 2 .00 2 .10 2 .40 2 .00 1 .80 2 .60 1 .80 1 .90 2 .20 INDIVIDUAL DOSE VOLUMES (ML) FOR MALE RATS Day 70 Day 71 Day 72 Day 73 1 .90 1 .90 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 1 .90 2 .00 1 .70 1 .70 2.70 2.40 2 .10 1 .90 1 .90 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 1 .90 2 .00 1 .70 1 .70 2 .70 2 .40 2 .10 1 .90 1 .90 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 1 .90 2 .00 1 .70 1 .70 2 .70 2.40 2 .10 1 .90 1 .90 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 1 .90 2 .00- 1 .70 1 .70 2 .70 2 .40 2 .10 2 .20 2 .10 2 .10 2 .50 2 .00 1 .90 2 .60 1 .80 2 .00 2 .30 2 .20 2 .10 2 .10 2 .50 2 .00 1 .90 2 .60 1 .80 2 .00 2 .30 2 .20 2 .10 2 .10 2 .50 2 .00 1 .90 2 .60 1 .80 2 .00 2 .30 2.20 2 .10 2 .10 2 .50 2 .00 1 .90 2 .60 1 .80 2 .00 2.30 -------------------------------- a Test substance was observed on lips; animal may not 1iiave received the entire dose. 450 Day 74 1.90 1.90 1.90 1.80 2.00 1.80 2.00 2.10 1.90 2.00 1.70 1.70 2.70 2.40 2.10 2.20 2.10 2.10 2.50 2.00 1.90 2.60 1.80 2.00" 2.30 Day 7 1 .90 1 .90 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 1 .90 2 .00 1 .70 1 .70 2 .70 2 .40 2 .10 2 .20 2 .10 2 .10 2 .50 2 .00 1 .90 2 .60 1 .80 2 .00 2 .30 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 77 Da:y 78 Male, VII - 641201 641095 641223 641157 641086 6.41067 641097 641132 641166 641077 641130 641057 641205 641196 641169 1000 ing/kg/ day 2. 00 1. 90 1. 90 1. 90 2. 10 1. 80 1. 90 2. 10 2. 00 2. 00 1. 80 1. 70 2. 70 2. 30 2. 20 2 .00 1 .90 1 .90 1 .90 2.10 1 .80 1 .90 2 .10 2 .00 2 .00 1 .80 1 .70 2 .70 2 .30 2.20 INDn7IDUAL I30SE VOIjUMES I;niL) FOR MALE RJVTS Day 79 Day 80 Da:y 81 Day 82 2. 00 1. 90 1. 90 1. 90 2. 10 1. 80 1. 90 2. 10 2. 00 2. 00 1. 80 1. 70 2. 70 2. 30 2. 20 2. 00 1. 90 1. 90 1. 90 2. 10 1. 80 1. 90 2. 10 2. 00 2. 00 1. 80 1. 70 2.70 2. 30 2. 20 2 .00 1 .90 1 .90 1 .90 2 .10 1 .80 1 .90 2 .10 2 .00 2 .00 1 .80 1 .70 2 .70 2 .30 2 .20 2. 00 1. 90 1. 90 1. 90 2. 10 1. 80 1. 90 2. 10 2. 00. 2. 00 1. 80 1. 70 2. 70 2. 30 2. 20 Day 83 2. 00 1. 90 1. 90 1. 90 2. 10 1. 80 1. 90 2. 10 2. 00 2. 00 1. 80 1. 70 2. 70 2. 30 2. 20 Da:y 8 2 .00 1 .70 1 .90 1 .80 2.00 1 .80 2 .00 2 .10 2 .00 2 .10 1 .80 1 .60 2.70 2 .30 2 .20 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 451 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.20 2.60 2.20 1.90 2.70 1.90 2.00 2.40 2.20 2.10 2.10 2.50 1.90 1.80 2.70 1.80 1.90 2.20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 86 Day 87 Male, VII - 1000 ing/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 2. 00 1. 70 1. 90 1. 80 2. 00 1. 80 2. 00 2. 10 2. 00 2. 10 1. 80 1. 60 2. 70 2. 30 2. 20 2. 00 1. 70 1. 90 1. 80 2. 00 1. 80 2. 00 2. 10 2. 00 2. 10 1. 80 1. 60 2. 70 2. 30 2. 20 . 2. 20 2. 10 2. 10 2. 50 1. 90 1. 80 2. 70 1. 80 1. 90 2. 20 2. 20 2. 10 2. 10 2. 50 1. 90 1. 80 2. 70 1. 80 1. 90 2. 20 IMDIVI:DUAL DOSE VO]'JMES i(niL) FOR MALE RATS Day 88 Day 89 Day 90 2.00 1.70 1.90 1.80 2.00 1.80 2.00 2.10 2.00 2.10 1.80 1.60 2.70 2.30 2.20 2 .00 1 .70 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 2 .00 2 .10 1 .80 1 .60 2 .70 2 .30 2 .20 1 .90 1 .80 1 .90 1 .80 2 .00 1 .80 2 .00 2 .10 2 .00 2 .10 1 .80 1 .60 2.70 2 .30 2.20 2.20 2.10 2.10 2.50 1.90 1.80 2.70 1.80 1.90 2.20 2 .20 2 .10 2 .10 2 .50 1 .90 1 .80 2 .70 1 .80 1 .90 2 .20 2 .20 2 .10 2 .10 2 .50 1 .90 1 .80 2 .70. 1 .80 1 .90 2 .20 452 24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 2 INDIVIDUAL DOSE VOLUMES (mL) Day 3 Day 4 FOR FEMALE RATS Day 5 Day 6 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 0.71 0.75 0.72 0.81 0.73 0.73 0.78 0.85 0.85 0.77 0.72 0.79 0.71 0.70 0.75 0.74 0.76 0.75 0.81 0.73 0.72 0.76 0.81 0.78 0.76 0.76 0.78 0.76 0.76 0.75 0.77 0.75 0.87 0.74 0.74 0.81 0.80 0.75 0.70 0.81 0.81 0.79 0.77 0.70 0.75 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations & ay 9 Day 10 Female, I]L - 0 ing/kgf/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 .80 0 .86 0 .81 0 .84 0 .79 0 .85 0 .92 0 .93 0 .91 0 .88 0 .80 0 .86 0 .76 0.75 0 .83 0 .83 0 .83 0 .82 0 .84 0 .78 0 .81 0 .86 0 .93 0 .86 0 .81 0 .85 0 .87 0 .85 0 .85 0 .82 0 .88 0 .88 0 .98 0 .82 0 .84 0 .87 0 .87 0 .87 0 .81 0 .92 0 .86 0 .93 0 .89 0 .78 0 .84 0. 80 0. 86 0. 81 0. 84 0. 79 0. 85 0. 92 0. 93 0. 91 0. 88 0. 80 0. 86 0. 76 0. 75 0. 83 0. 83 0. 83 0. 82 0. 84 0. 78 0. 81 0. 86 0. 93 0. 86 0. 81 0. 85 0. 87 0. 85 0. 85 0. 82 0. 88 0. 88 0. 98 0. 82 0. 84 0. 87 0. 87 0. 87 0. 81 0. 92 0. 86 0. 93 0. 89 0. 78 0. 84 Da:y 11 I :NDIVIDUJ\L DOSE VOLUMI33 (mL) FOR I T3MALE RATS Day 12 Day 13 Da:y 14 Da:y 15 0 .80 0 .86 0 .81 0 .84 0.79 0 .85 0 .92 0 .93 0 .91 0 .88 0.80 0 .86 0 .76 0 .75 0 .83 0 .83 0 .83 0 .82 0 .84 0 .78 0 .81 0 .86 0 .93 0 .86 0 .81 0 .85 0 .87 0 .85 0 .85 0 .82 0 .88 0 .88 0 .98 0 .82 0.84 0 .87 0 .87 0 .87 0 .81 0 .92 0 .86 0 .93 0 .89 0 .78 0 .84 0. 80 0. 86 0. 81 0. 84 0. 79 0.85 0. 92 0. 93 0. 91 0. 88 0. 80 0. 86 0. 76 0. 75 0. 83 0. 83 0. 83 0. 82 0. 84 0.78 0. 81 0. 86 0. 93 0. 86 0.81 0. 85 0. 87 0. 85 0. 85 0. 82 0. 88 0. 88 0. 98 0. 82 0. 84 0. 87 0.87 0. 87 0. 81 0. 92 0. 86 0. 93 0. 89 0. 78 0. 84 0. 80 0. 86 0. 81 0. 84 0. 79 0.85 0. 92 0. 93 0. 91 0. 88 0. 80 0. 86 0. 76 0. 75 0. 83 0. 83 0. 83 0. 82 0. 84 0. 78 0. 81 0. 86 0. 93 0. 86 0. 81 0. 85 0. 87 0. 85 0. 85 0. 82 0. 88 0. 88 0. 98 0. 82 0. 84 0. 87 0. 87 0. 87 0. 81 0. 92 0. 86 0. 93 0. 89 0. 78 0.84 0 .90 0 .94 0 .88 0 .96 0 .90 0 .94 1 .00 1 .00 1 .10 0 .92 0 .88 0.91 0 .78 0 .91 0 .87 0 .88 0 .91 0 .88 0 .97 0 .85 0 .84 0 .90 1 .00 0 .96 0 .88 0 .95 0 .98 0 .95 0 .94 0 .89 0 .91 0 .93 1 .00 0 .91 0 .86 1 .00 0.90 0 .94 0 .87 0 .99 0 .95 1 .00 0 .95 0 .83 0 .90 0 .90 0 .94 0 .88 0 .96 0 .90 0 .94 1 .00 1 .00 . 1 .10 0 .92 0 .88 0 .91 0.78 0 .91 0 .87 0 .88 0 .91 0 .88 0 .97 0 .85 0 .84 0 .90 1 .00 0.96 0 .88 0 .95 0 .98 0 .95 0.94 0 .89 0 .91 0 .93 1 .00 0 .91 0 .86 1 .00 0 .90 0 .94 0 .87 0 .99 0 .95 1 .00 0 .95 0 .83 0 .90 454 Day 16 0.90 0.94 0.88 0.96 0.90 0.94 1.00 1.00 1.10 0.92 0.88 0.91 0.78 0.91 0.87 0.88 0.91 0.88 0.97 0.85 0.84 0.90 1.00 0.96 0.88 0.95 0.98 0.95 0.94 0.89 0.91 0.93 1.00 0.91 0.86 1.00 0.90 0.94 0.87 0.99 0.95 1.00 0.95 0.83 0.90 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 18 Day 19 Female, II - 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 nig/kg/day 0.90 0.94 0.88 0.96 0.90 0.94 1.00 1.00 1.10 0.92 0.88 0.91 0.78 0.91 0.87 0.88 0.91 0.88 0.97 0.85 0.84 0.90 1.00 0.96 0.88 0.95 0.98 0.95 0.94 0.89 0.91 0.93 1.00 0.91 0.86 1.00 0.90 0.94 0.87 0.99 0.95 1.00 0.95 0.83 0.90 0.90 0.94 0.88 0.96 0.90 0.94 1.00 1.00 1.10 0.92 0.88 0.91 0.78 0.91 0.87 0.88 0.91 0.88 0.97 0.85 0.84 0.90 1.00 0.96 0.88 0.95 0.98 0.95 0.94 0.89 0.91 0.93 1.00 0.91 0.86 1.00 0.90 0.94 0.87 0.99 0.95 1.00 0.95 0.83 0.90 Day 20 INDIVIDUAL DOSE VOLUMES (inL) FOR FEMALE RATS 0.90 0.94 0.88 0.96 0.90 0.94 1.00 1.00 1.10 0.92 0.88 0.91 0.78 0.91 0.87 0.88 0.91 0.88 0.97 0.85 0.84 0.90 1.00 0.96 0.88 0.95 0.98 0.95 0.94 0.89 0.91 0.93 1.00 0.91 0.86 1.00 0.90 0.94 0.87 0.99 0.95 1.00 0.95 0.83 0.90 455 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 21 Day 22 Female, TI - 0 mg/kg/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 .96 1 .10 0 .95 1 .00 0 .94 0 .98 1 .20 1 .10 1.20 1 .00 0 .90 0 .95 0 .86 0 .96 0 .97 0.90 0 .99 0 .98 1 .00 0 .92 0 .94 1 .00 1 .00 1 .00 0 .96 0 .98 1 .00 1 .00 0 .99 0 .94 1 .00 1 .10 1 .10 0 .91 0 .94 1 .10 0 .98 1 .00 0 .93 1 .10 0 .99 1 .10 1 .00 0 .85 0 .94 0.97 1.10 0.95 1.00 0.94 0.98 1.20 1.10 1.20 1.00 0.90 0.95 0.86 0.96 0.97 0.90 0.99 0.98 1.00 0.92 0.94 1.00 1.00 1.00 0.96 0.98 1.00 1.00 0.99 0.94 1.00 1.10 1.10 0.91 0.94 1.10 0.98 1.00 0.93 1.10 0.99 1.10 1.00 0.85 0.94 Day 23 INDIVIDUAL DOSE VOLUMES (mL) Day 24 Day 25 FOR FEMALE RATS Day 26 Day 27 0.96 1.10 0.95 1.00 0.94 0.98 1.20 1.10 1.20 1.00 0.90 0.95 0.86 0.96 0.97 0.90 0.99 0.98 1.00 0.92 0.94 1.00 1.00 1.00 0,96 0.98 1.00 1.00 0.99 0.94 1.00 1.10 1.10 0.91 0.94 1.10 0.98 1.00 0.93 1.10 0.99 1.10 1.00 0.85 0.94 0.96 1.10 0.95 1.00 0.94 0.98 1.20 1.10 1.20 1.00 0.90 0.95 0.86 0.96 0.97 0.90 0.99 0.98 1.00 0.92 0.94 1.00 1.00 1.00 0.96 0.98 1.00 1.00 0.99 0.94 1.00 1.10 1.10 0.91 0.94 1.10 0.98 1.00 0.93 1.10 0.99 1.10 1.00 0.85 0.94 0.96 1.10 0.95 1.00 0.94 0.98 1.20 1.10 1.20 1.00 0.90 0.95 0.86 0.96 0.97 0.90 0.99 0.98 1.00 0.92 0.94 1.00 1.00 1.00 0.96 0.98 1.00 1.00 0.99 0.94 1.00 1.10 1.10 0.91 0.94 1.10 0.98 1.00 0.93 1.10 0.99 1.10 1.00 0.85 0.94 0.96 1.10 0.95 1.00 0.94 0.98 1.20 1.10 1.20 1.00 0.90 0.95 0.86 0.96 0.97 0.90 0.99 0.98 1.00 0.92 0.94 1.00 1.00 1.00 0.96 0.98 1.00 1.00 0.99 0.94 1.00 1.10 1.10 0.91 0.94 1.10 0.98 1.00 0.93 1.10 0.99 1.10 1.00 0.85 0.94 0 .96 1 .10 0 .95 1 .00 0 .94 0 .98 1 .20 1 .10 1 .20 1 .00 0 .90 0 .95 0 .86 0 .96 0 .97 0.90 0 .99 0 .98 1 .00 0 .92 0 .94 1 .00 1 .00 1 .00 0 .96 0 .98 1 .00 1 .00 0 .99 0 .94 1 .00 1 .10 1 .10 0 .91 0 .94 1 .10 0 .98 1 .00 0 .93 1 .10 0 .99 1 .10 1 .00 0 .85 0 .94 456 Day 28 0.99 1.20 1.10 1.10 1.00 1.10 1.30 1.10 1.30 1.00 1.00 1.10 0.88 1.00 1.00 0.99 1.00 1.10 1.10 0.99 1.00 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.00 1.10 1.20 1.30 1.00 1.00 1.10 1.10 1.00 1.00 1.10 1.00 1.20 1.10 0.93 1.10 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 30 Day 31 Female, II - 641257 641290 641283 64.1344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 nig/kg/day 0 .99 1 .20 1 .10 1 .10 1 .00 1 .10 1 .30 1 .10 1 .30 1 .00 1 .00 1 .10 0 .88 1 .00 1 .00 0 .99 1 .00 1 .10 1 .10 0 .99 1 .00 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .00 1 .10 1 .20 1 .30 1 .00 1 .00 1 .10 1 .10 1 .00 1 .00 1 .10 1.00 1 .20 1 .10 0 .93 1 .10 0.99 1.20 1.10 1.10 1.00 1.10 1.30 1.10 1.30 1.00 1.00 1.10 0.88 1.00 1.00 0.99 1.00 1.10 1.10 0.99 1.00 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.00 1.10 1.20 1.30 1.00 1.00 1.10 1.10 1.00 1.00 1.10 1.00 1.20 1.10 0.93 1.10 Day 32 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 33 Day 34 Day 35 Day 36 0 .99 1 .20 1 .10 1 .10 1 .00 1 .10 1 .30 1 .10 1 .30 1 .00 1 .00 1 .10 0 .88 1 .00 1 .00 0 .99 1 .00 1 .10 1 .10 0 .99 1 .00 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .10 1 .00 1 .10 1 .20 1 .30 1 .00 1 .00 1 .10 1.10 1 .00 1 .00 1 .10 1 .00 1 .20 1 .10 0 .93 1 .10 0.99 1.20 1.10 1.10 1.00 1.10 1.30 1.10 1.30 1.00 1.00 1.10 0.88 1.00 1.00 0.99 1.00 1.10 1.10 0.99 1.00 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.00 1.10 1.20 1.30 1.00 1.00 1.10 1.10 1.00 1.00 1.10 1.00 1.20 1.10 0.93 1.10 0.99 1.20 1.10 1.10 1.00 1.10 1.30 1.10 1.30 1.00 1.00 1.10 0.88 1.00 1.00 0.99 1.00 1.10 1.10 0.99 1.00 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.10 1.00 1.10 1.20 1.30 1.00 1.00 1.10 1.10 1.00 1.00 1.10 1.00 1.20 1.10 0.93 1.10 1.10 1.20 1.10 1.00 1.10 1.10 1.40 1.10 1.30 1.10 1.00 1.10 0.97 1.00 1.00 1.00 1.10 1.10 1.20 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.20 1.00 1.10 1.10 1.20 0.96 1.10 1.30 1.10 1.10 1.00 1.20 1.10 1.10 1.10 0.99 1.10 1.10 1.20 1.10 1.00 1.10 1.10 1.40 1.10 1.30 1.10 1.00 1.10 0.97 1.00 1.00 1.00 1.10 1.10 1.20 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.20 1.00 1.10 1.10 1.20 0.96 1.10 1.30 1.10 1.10 1.00 1.20 1.10 1.10 1.10 0.99 1.10 457 Day 37 1.10 1.20 1.10 1.00 1.10 1.10 1.40 1.10 1.30 1.10 1.00 1.10 0.97 1.00 1.00 1.00 1.10 1.10 1.20 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.20 1.00 1.10 1.10 1.20 0.96 1.10 1.30 1.10 1.10 1.00 1.20 1.10 1.10 1.10 0.99 1.10 H-24616: Subchronic Toxicity 90-Day GavageStudy in Rats with One-Generation Reproductive Evaluations Day 39 Day 40 Female, I :I - 0 mg/kg/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 1.10 1.20 1.10 1.00 1.10 1.10 1.40 1.10 1.30 1.10 1.00 1.10 0.97 1.00 1.00 1.00 1.10 1.10 1.20 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.20 1.00 1.10 1.10 1.20 0.96 1.10 1.30 1.10 1.10 1.00 1.20 1.10 1.10 1.10 0.99 1.10 1 .10 1 .20 1 .10 1 .00 1 .10 1 .10 1 .40 1 .10 1 .30 1 .10 1 .00 1 .10 0 .97 1 .00 1 .00 1 .00 1 .10 1 .10 1 .20 1 .00 1 .00 1 .10 1 .20 1 .10 1 .10 1 .10 . 1 .10 1.20 1 .20 1 .00 1 .10 1 .10 1 .20 0 .96 1 .10 1 .30 1 .10 1 .10 1 .00 1.20 1 .10 1 .10 1 .10 0 .99 1 .10 Day 41 IMDIVIDIIAL DOSE VOUJIIBS (mL) Day 42 Day 43 FOR FEMALE R ATS Day 44 Day 45 1.10 1.20 1.10 1.00 1.10 1.10 1.40 1.10 1.30 1.10 1.00 1.10 0.97 1.00 1.00 1.00 1.10 1.10 1.20 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.20 1.00 1.10 1.10 1.20 0.96 1.10 1.30 1.10 1.10 1.00 1.20 1.10 1.10 1.10 0.99 1.10 1 .10 1 .30 1 .20 1 .10 1 .10 1 .10 1 .40 1 .10 1 .40 1 .10 1 .00 1 .10 0.98 1 .00 1 .10 1 .10 1.10 1 .20 1 .20 1 .10 1 .10 1 .20 1 .20 1 .20 1 .10 1 .20 1 .20 1 .20 1 .20 1 .10 1 .10 1 .20 1 .30 1 .00 1 .10 1 .30 1 .10 1 .20 1 .00 1 .20 1 .10 1 .20 1 .10 0 .99 1 .10 1 .10 1 .30 1 .20 1 .10 1 .10 1 .10 1 .40 1 .10 1 .40 1 .10 1 .00 1 .10 0 .98 1 .00 1 .10 1 .10 1 .10 1 .20 1.20 1 .10 1 .10 1 .20 1 .20 1 .20 1 .10 1 .20 1 .20 1 .20 1 .20 1 .10 1 .10 1 .20 1 .30 1 .00 1 .10 1 .30 1 .10 1 .20 1 .00 1 .20 1 .10 1 .20 1 .10 0 .99 1 .10 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.10 1.40 1.10 1.00 1.10 0.98 1.00 1.10 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.10 1.20 1.20 1.20 1.20 1.10 1.10 1.20 1.30 1.00 1.10 1.30 1.10 1.20 1.00 1.20 1.10 1.20 1.10 0.99 1.10 1 .10 1 .30 1 .20 1 .10 1 .10 1 .10 1 .40 1 .10 1 .40 1 .10 1 .00 1 .10 0 .98 1 .00 1 .10 1 .10 1 .10 1 .20 1 .20 1 .10 1 .10 1 .20 1 .20 1 .20 1 .10 1 .20 1 .20 1 .20 1 .20 1 .10 1 .10 1 .20 1 .30 1 .00 1 .10 1 .30 1 .10 1 .20 1 .00 1 .20 1 .10 1 .20 1 .10 0 .99 1 .10 458 Day 46 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.10 1.40 1.10 1.00 1.10 0.98 1.00 1.10 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.10 1.20 1.20 1.20 1.20 1.10 1.10 1.20 1.30 1.00 1.10 1.30 1.10 1.20 1.00 1.20 1.10 1.20 1.10 0.99 1.10 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 48 Day 49 Female, I]C - 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 ing/kg/day 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.00 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.20 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1 .10 1 .30 1 .20 1 .10 1 .10 1 .10 1 .40 1 .20 1.40 1 .10 1 .10 1 .10 1 .00 1 .10 1 .00 1 .10 1 .10 1 .20 1 .20 1 .10 1 .10 1 .20 1 .20 1 .20 1 .20 1 .30 1 .20 1 .30 1 .20 1 .10 1 .10 1 .30 1 .30 1 .00 1 .20 1 .40 1 .10 1 .20 1 .10 1 .20 1 .10 1 .20 1 .20 1 .10 1 .20 Day 50 I :NDIVIDUAL DOSE VOLUMES (mL) Day 51 Day 52 FOR FEMALE E ATS Day 53 Day 54 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.00 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.20 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.00 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.20 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.00 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.20 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.10 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.00 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.10 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.20 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.10 1.10 1.40 1.20 1.40 1.10 1.10 1.10 1.10 1.10 1.00 1.10 1.10 1.20 1.20 1.10 1.20 1.20 1.20 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.00 1.20 1.40 1.10 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 459 Day 55 1 .10 1 .30 1 .20 1 .10 1 .10 1 .10 1 .40 1 .20 1 .40 1 .10 1 .10 1 .10 1 .00 1 .10 1 .00 1 .10 1 .10 1 .20 1 .20 1 .10 1 .10 1 .20 1 .20 1 .20 1 .20 1 .30 1 .20 1 .30 1 .20 1 .10 1 .10 1 .30 1 .30 1 .00 1 .20 1 .40 1 .10 1 .20 1 .10 1 .20 1 .10 1 .20 1 .20 1 .10 1 .20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 59 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 60 Day 61 Day 62 Day 63 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 1 .10 1 .30 1 .20 1 .20 1 .20 1 .10 1 .50 1 .20 1 .40 1 .20 1 .10 1 .20 1 .10 1 .10 1 .10 1 .10 1 .20 1 .30 1 .30 1 .10 1 .10 1 .30 1 .30 1 .20 1 .20 1 .30 1 .20 1 .30 1 .30 1 .10 1 .20 1 .20 1 .30 1 .10 1 .20 1 .40 1 .20 1 .20 1 .10 1 .20 1 .10 1 .20 1 .20 1 .10 1 .20 1.10 1.30 1.20 1.20 1.20 1.10 1.50 1.20 1.40 1.20 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.30 1.30 1.10 1.10 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.20 1.30 1.10 1.20 1.40 1.20 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.20 1.10 1.50 1.20 1.40 1.20 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.30 1.30 1.10 1.10 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.20 1.30 1.10 1.20 1.40 1.20 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.20 1.10 1.50 1.20 1.40 1.20 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.30 1.30 1.10 1.10 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.20 1.30 1.10 1.20 1.40 1.20 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.20 1.10 1.50 1.20 1.40 1.20 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.30 1.30 1.10 1.10 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.20 1.30 1.10 1.20 1.40 1.20 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.20 1.10 1.50 1.20 1.40 1.20 1.10 1.20 1.10 1.10 1.10 1.10 1.20 1.30 1.30 1.10 1.10 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.30 1.10 1.20 1.20 1.30 1.10 1.20 1.40 1.20 1.20 1.10 1.20 1.10 1.20 1.20 1.10 1.20 1.20 1.40 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.20 1.10 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.40 1.10 1.20 1.30 1.30 1.10 1.30 1.40 1.20 1.30 1.10 1.30 1.10 1.30 1.20 1.10 1.20 1.20 1.40 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.20 1.10 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.40 1.10 1.20 1.30 1.30 1.10 1.30 1.40 1.20 1.30 1.10 1.30 1.10 1.30 1.20 1.10 1.20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 66 Da:y 67 Female, I][ - 0 ing/kg/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 1.20 1.40 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.20 1.10 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.40 1.10 . 1.20 1.30 1.30 1.10 1.30 1.40 1.20 1.30 1.10 1.30 1.10 1.30 1.20 1.10 1.20 1 .20 1 .40 1 .30 1 .20 1 .20 1 .20 1 .50 1 .30 1 .50 1 .20 1 .20 1 .20 1 .10 1 .20 1 .20 1 .10 1 .20 1 .30 1 .30 1 .10 1 .20 1 .30 1 .30 1 .20 1 .20 1 .30 1 .20 1 .30 1 .40 1 .10 1 .20 1 .30 1 .30 1 .10 1 .30 1 .40 1 .20 1 .30 1 .10 1 .30 1 .10 1 .30 1 .20 1 .10 1 .20 Day 68 ][NDIVIDUAL DOSE VOLtttES (mL) FOR FEMALE R ATS Day 69 Da:y 70 Day 71 Da:y 72 1.20 1.40 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.20 1.10 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.20 1-20 1.30 1.20 1.30 1.40 1.10 1.20 1.30 1.30 1.10 1.30 1.40 1.20 1.30 1.10 1.30 1.10 1.30 1.20 1.10 1.20 1.20 1.40 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.20 1.10 1.20 1.30 1.30 1.10 1.20 1.30 1.30 1.20 1.20 1.30 1.20 1.30 1.40 1.10 1.20 1.30 1.30 1.10 1.30 1.40 1.20 1.30 1.10 1.30 1.10 1.30 1.20 1.10 1.20 1 .20 1 .50 1 .30 1 .20 1 .30 1 .20 1 .50 1 .30 1 .50 1 .20 1 .10 1 .20 1 .10 1 .20 1 .30 1 .40 1 .20 1 .30 1 .20 1 .30 1 .20 1 .30 1 .20 1 .20 1 .30 1.20 1.50 1.30 1.20 1.30 1.20 1.50 1.30 1.50 1.20 1.10 1.20 1.10 1.20 1.30 1.40 1.20 1.30 1.20 1.30 1.20 1.30 1.20 1.20 1.30 1 .20 1 .50 1 .30 1 .20 1 .30 1 .20 1 .50 1 .30 1 .50 1 .20 1 .10 1 .20 1 .10 1 .20 1 .30 1 .40 1 .20 1 .30 1 .20 1 .30 1 .20 1 .30 1 .20 1 .20 1 .30 461 Day 73 1 .20 1 .50 1 .30 1 .20 1 .30 1 .20 1 .50 1 .30 1 .50 1 .20 1 .10 1 .20 1 .10 1 .20 1 .30 1 .40 1 .20 1 .30 1 .20 1 .30 1 .20 1 .30 1 .20 1 .20 1 .30 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 75 Day 76 Female, II - 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 mg/kg/day 1 .20 1 .50 1 .30 1 .20 1 .30 1 ,20 1 .50 1 .30 1 .50 1 ,20 1 .10 1 .20 1 .10 1 .20 1 .30 1 .40 1 .20 1 .30 1 .20 1 .30 1 .20 1 .30 1 .20 1 .20 1 .30 1.20 1.50 1.30 1.20 1.30 1.20 1.50 1.30 1.50 1.20 1.10 1.20 1.10 1.20 1.30 1.40 1.20 1.30 1.20 1.30 1.20 1.30 1.20 1.20 1.30 Day 77 INDIVIDUAL DOSE VOLUMES (inL) FOR FEMALE RATS Day 78 Day 79 Day 80 Day 81 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 . 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 462 Day 82 1.20 1.50 1.30 1.20 1.20 1.20 1.50 1.30 1.50 1.20 1.20 1.20 1.10 1.20 1.30 1.50 1.20 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 '^^-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 84 Day 85 Female, II - 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 0 mg/kg/day 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 Day 86 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 87 Day 88 Day 89 Day 90 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.20 1.60 1.40 1.30 1.20 1.30 1.50 1.30 1.50 1.30 1.20 1.20 1.00 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 1.50 1.30 1.30 1.20 1.30 1.20 1.30 1.30 1.20 1.30 463 Day 91 1.30 1.60 1.40 1.20 1.20 1.30 1.60 1.30 1.50 1.30 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 0 Day 1 Female, IV - 50 ffig/kg/day 641396 641369 641336 64.1355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 Day 2 INDIVIDUAL DOSE VOLUMES (inL) FOR FEMALE RATS Day 3 Day 4 Day 5 Day 6 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.04 0.04 0.04 0.04 0.04 0.04 0.03 0.03 0.04 0.04 0.04 0.04 0.04 0. 04 0. 03 0. 04 0. 03 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 03 0. 04 0. 03 0. 03 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 03 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 03 0. 03 0. 04 0. 04 0. 04 0.04 0.04 Day 7 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 464 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 9 Day 10 Female, IV - 50 nig/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0. 04 0.04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 05 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0.04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 04 0. 05 0. 04 0. 04 0.04 0. 05 0. 04 0. 04 0. 04 0. 04 0. 04 0.05 0. 04 Day 11 INDIVIDUAL DOSE VOLUMES (iriL) Day 12 Day 13 FOR FEMALE RATS Day 14 Day 15 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0,04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0 .04 0 .04 0 .05 0 .04 0 .05 0 .04 0 .04 0 .05 0 .05 0 .05 0 .04 0 .04 0 .04 0 .04 0 .04 0 .05 0 .04 0 .05 0 .05 0 .05 0 .04 0 .04 0 .05 0 .05 0 .04 0 .04 0 .04 0 .05 0 .04 0 .04 0 .04 0 .05 0 .05 0 .05 0 .05 0.04 0.04 0.05 0.04 0.05 0.04 0.04 0.05 0.05 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.05 0.05 0.05 0.04 0.04 0.05 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.05 0.05 0.05 Day 16 0.04 0.04 0.05 0.04 0.05 0.04 0.04 0.05 0.05 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.05 0.05 0.05 0.04 0.04 0.05 0.05 0.04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.05 0.05 0.05 465 ^s^-^3 "say H-24616: Subchronic Toxicity ^ 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations 1 IMDIVIDtB\L DOS!E VOLUMES (itiL) FOR E?EMALE RATS Day 18 Day 19 Day 20 Day 21 Day 22 Da:y 23 Day 24 S* Female, I\^ - 50 mg/kg/daY a 2641396 641369 3 641336 S. 64.1355 641260 g, 641312 gg, 641313 3 641311 d 641298 0 641361 ^ 641321 'S 641391 g 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 'VS 641258 'je 641276 H 641350 641376 0. 04 0. 04 0. 05 0. 04 0. 05 0. 04 0. 04 0. 05 0. 05 0. 05 0. 04 0. 04 0. 04 0. 04 0. 04 0. 05 0. 04 0. 05 0. 05 0. 05 0. 04 0. 04 0. 05 0. 05 0. 04 0. 04 0.04 0.04 0.05 0.04 0.05 0.04 0.04 0.05 0.05 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.05 0.05 0.05 0.04 0.04 0.05 0.05 0.04 0.04 ^ 641315 SS 641286 9 641231 SS 641338 8 641318 & 641373 , 641365 ^ 641348 g 641323 0. 04 0. 05 0. 04 0. 04 0.04 0. 05 0. 05 0. 05 0. 05 0.04 0.05 0.04 0.04 0.04 0.05 0.05 0.05 0.05 0.04 0.04 0.05 0.04 0.05 0.04 0.04 0.05 0.05 0.05 0.04 0.04 0.04 0.04 0.04 0.05 0.04 0.05 0.05 0.05 0.04 0.04 0.05 0.05 0..04 0.04 0.04 0.05 0.04 0.04 0.04 0.05 0.05 0.05 0.05 0. 05 0. 04 0. 05 0. 05 0. 05 0. 04 0. 05 0. 05 0. 05 0. 05 0.05 0. 05 0. 04 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 0. 05 0. 06 0. 05 0. 05 0. 05 0. 05 0. 05 0. 04 0. 05 0. 05 0. 05 0. 06 0. 05 0.05 0.04 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 . 0.05 0.05 0.04 0.05 0.05 0.05 0.06 0.05 0 .05 0 .04 0 .05 0 .05 0 .05 0 .04 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .04 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .04 0 .05 0 .05 0 .05 0 .06 0 .05 0.05 0.04 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.06 0.05 Day 25 0.05 0.04 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.06 0.05 ? ? I 9 Si 9 1 466 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 27 Day 28 Female, IV - 50 ing/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.05 0.04 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.04 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.05 Day 29 INDIVIDUAL DOSE VOLUMES (mL) Day 30 Day 31 FOR FEMALE RATS Day 32 Day 33 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .05 0 .05 0 .06 0 .06 0 .07 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0.05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .05 0 .05 0 .06 0 .06 0 .07 0 .05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .05 0 .05 0 .06 0 .06 0 .07 0 .05 Day 34 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .05 0 .05 0 .06 0 .06 0 .07 0 .05 467 ''^24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUt1ES (mL) FOR FEMALE R ATS Day 36 Da:y 37 Da:y 38 Day 39 Da:y 40 Day 41 Da:y 42 Da:y 43 D Female, 1\7-50 mg/1eg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.07 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0.06 0 .05 0.05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .05 . 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0.06 0 .07 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0.06 0 .06 0 .05 0.05 0 .05 0 .05 0 .05 0 .05 0 .06 0.05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0.06 0 .07 0 .06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.07 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .05 0 .05 0 .05 0.06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0,05 0 .05 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0.06 0 .07 0 .06 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.05 0.05 0.05 0.06 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.07 0.05 0.05 0.06 0.06 0.05 0.05 0.05 0.06 0.06 0.07 0.06 0 .06 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 . 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0.06 0 .07 0 .06 0 .06 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0.06 0 .05 0 .06 0 .06 0 .06 0 .05 0.05 0 .06 0 .07 0 .05 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .06 0 .07 0 .06 468 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 45 Day 46 Female, IV - 50 ing/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0 .06 0 .50 0 .06 0 .50 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .05 0 .06 0 .06 0 .06 0.05 0 .05 0 .06 0 .06 0 .07 0 .06 0. 06 0. 05 0. 06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 06 0. 05 0. 05 0. 05 0. 06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0.07 0.05 0. 05 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0. 06 0. 07 0. 06 Day 47 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 48 Day 49 Day 50 Day 51 0 .06 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 ,05 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .06 0 .07 0 .06 0.06 0.05 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.06 0.05 0.05 0.05 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.07 0.05 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.06 0.07 0.06 0. 06 0. 05 0.06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0. 07 0. 05 0. 06 0. 06 0. 06 0.06 0. 05 0. 06 0.06 0. 06 0. 07 0. 06 0 .06 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .07 0 .06 0. 06 0. 05 0. 06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0. 05 0. 06 0. 05 0. 06 0. 06 0. 06 0. 05 0. 05 0. 06 0. 07 0. 05 0. 06 0. 06 0. 06 0. 06 0. 05 0. 06 0. 06 0. 06 0. 07 0. 06 Day 52 0.06 0.05 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.05 0.05 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.05 0.05 0.06 0.07 0.05 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.07 0.06 ' Animal was misdosed with 0.50 mLs test substance. 469 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 54 Day 55 Female, IV - 50 ing/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0 .06 0 .05 0.06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 . 0 .06 0 .06 0 .07 0 .06 0 .06 0 .05 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .05 0 .06 0 .05 0.06 0 .06 0 .06 0 .05 0 .05 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 ' 0 .06 0 .05 0 .06 0 .06 0 .06 0 .07 0 .06 Day 56 INDIVIDUAL DOSE VOLUMES (inL) Day 57 Day 58 FOR FEMALE RATS Day 59 Day 60 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0 .06 0 .05 0 .06 0 .05 0 .06 0.06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 0.05 0 .06 0 .06 0 .07 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0.06 0 .06 0.06 0 .07 0 .06 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0.06 0.05 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.07 0.06 0 .06 0.05 0 .06 0 .05 0 .06 0 .06 0 .06 0.06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0.06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .07 0 .06 Day 61 0 .06 0 .05 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .07 0 .06 470 fS 6 3 B 3 fsa & w 0 0 w i a 0 3. 3S". 5J g 0 va H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 64 Female, r\1 - 50 ing/kg/'day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 . 0.06 0.06 0.06 0.08 0.06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0.07 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .06 0 .06 . 0 .06 0 .06 0 .06 0 .06 0.06 0 .06 0 .06 0 .08 0 .06 Day 65 3[NDIVIDUAL DOS3E VOLUMES (inL) FOR I 'EMALE RATS Day 66 Day 67 Day 68 Day 69 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0.06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .08 0 .06 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.08 0.06 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.05 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.08 0.06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0.06 0.06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .08 0 .06 0 .06 0 .05 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 . 0 .06 0 .06 0 .06 0 .06 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .05 0 .06 0 .06 0 .07 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .06 0 .08 0 .06 471 Day 70 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 W g ^ ^ ? a Ki" , S,,- < 3 0 S, 3' ^ t0 -5 SB . .3 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 72 Day 73 Female, IV - 50 mg/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 Day 74 INDIVIDUAL DOSE VOLUMES (mL) Day 75 Day 76 FOR FEMALE RATS Day 77 Day 78 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 Day 79 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 472 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 81 Day 82 Female, I :V - 50 mg/kg/dciy 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 - Day 83 IMDIVIDUAL DOSE VOLUMES (n-iL) Day 84 Day 85 FOR FEMALE RATS Day 86 Day 87 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 Day 88 0. 06 0. 05 0. 06 0. 06 0. 07 0. 06 0. 06 0. 07 0. 07 0. 07 0. 06 0. 06 0. 06 0.06 0. 06 473 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations ytV 3 s S 3 s I.4 1 <n w 1 I s 3^ a ^ s 0 3 Day 90 Day 91 Female, IV - 50 nig/kg/day 641396 641369 641336 64.1355 641260 641312 641313 641311 641298 641361 . 641321 : 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 0.06 0.05 0.06 0.06 0.07 0.06 0.06 0.07 0.07 0.07 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.07 0.07 0.07 - INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS 474 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 2 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 3 Day 4 Day 5 Day 6 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 0.20 0.18 0.19 0.17 0.20 0.19 0.19 0.18 0.22 0.22 0.19 0.17 0.20 0.18 0.16 0.19 0.18 0.18 0.20 0.20 0.18 0.18 0.18 0.21 0.18 0.19 0.20 0.20 0.20 0.18 0.20 0.20 0.19 0.21 0.20 ' 'j l.y ss "S to D w 3 ? a : ;1 s y 0 B H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 11 INDIVIDUAL DOSE VOLUMES (mL) Day 12 Day 13 FOR FEMALE RATS Day 14 Day 15 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.22 0.19 0.23 0.20 0.22 0.21 0.20 0.20 0.25 0.26 0.20 0.19 0.23 0.20 0.18 0.19 0.20 0.22 0.21 0.23 0.20 0.20 0.19 0.23 0.20 0.22 0.22 0.22 0.23 0.21 0.22 0.23 0.21 0.23 0.22 0.22 0.19 0.23 0.20 0.22 0.21 0.20 0.20 0.25 0.26 0.20 0.19 0.23 0.20 0.18 0.19 0.20 0.22 0.21 0.23 0.20 0.20 0.19 0.23 0.20 0.22 0.22 0.22 0.23 0.21 0.22 0.23 0.21 0.23 0.22 0.22 0.19 0.23 0.20 0.22 0.21 0.20 0.20 0.25 0.26 0.20 0.19 0.23 0.20 0.18 0.19 0.20 0.22 0.21 0.23 0.20 0.20 0.19 0.23 0.20 0.22 0.22 0.22 0.23 0.21 0.22 0.23 0.21 0.23 0.22 0.22 0.19 0.23 0.20 0.22 0.21 0.20 0.20 0.25 0.26 0.20 0.19 0.23 0.20 0.18 0.19 0.20 0.22 0.21 0.23 0.20 0.20 0.19 0.23 0.20 0.22 0.22 0.22 0.23 0.21 0.22 0.23 0.21 0.23 0.22 0. 22 0. 19 0. 23 0. 20 0. 22 0. 21 0. 20 0. 20 0. 25 0. 26 0. 20 0. 19 0. 23 0. 20 0.18 0. 19 0. 20 0. 22 0. 21 0. 23 0. 20 0. 20 0. 19 0. 23 0. 20 0. 22 0. 22 0. 22 0. 23 0. 21 0.22 0. 23 0. 21 0.23 0. 22 0.25 0.21 0.25 0.21 0.25 0.23 0.22 0.22 0.26 0.27 0.22 0.22 0.25 0.25 0.20 0.22 0.22 0.24 0.24 0.25 0.22 0.22 0.19 0.25 0.21 0.25 0.25 0.24 0.25 0.22 0.25 0.25 0.23 0.26 0.23 0 .25 0 .21 0 .25 0 .21 0 .25 0 .23 0 .22 0 .22 0 .26 0.27 0 .22 0 .22 0 .25 0 .25 0 .20 0 .22 0 .22 0 .24 0 .24 0 .25 0 .22 0 .22 0 .19 0 .25 0.21 0.25 0 .25 0 .24 0 .25 0 .22 0 .25 0 .25 0.23 0 .26 0 .23 0.25 0.21 0.25 0.21 0.25 0.23 0.22 0.22 0.26 0.27 0.22 0.22 0.25 0.25 0.20 0.22 0.22 0.24 0.24 0.25 0.22 0.22 0.19 0.25 0.21 0.25 0.25 0.24 0.25 0.22 0.25 0.25 0.23 0.26 0.23 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 18 Day 19 Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 64.1363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.25 0.21 0.25 0.21 0.25 0.23 0.22 0.22 0.26 0.27 0.22 0.22 0.25 0.25 0.20 0.22 0.22 0.24 0.24 0.25 0.22 0.22 0.19 0.25 0.21 0.25 0.25 0.24 0.25 0.22 0.25 0.25 0.23 0.26 0.23 0.25 0.21 0.25 0.21 0.25 0.23 0.22 0.22 0.26 0.27 0.22 0.22 0.25 0.25 0.20 0.22 0.22 0.24 0.24 0.25 0.22 0.22 0.19 0.25 0.21 0.25 0.25 0.24 0.25 0.22 0.25 0.25 0.23 0.26 0.23 Day 20 INDIVIDUAL DOSE VOLUMES (TOL) FOR FEMALE RATS 0.25 0.21 0.25 0.21 0.25 0.23 0.22 0.22 0.26 0.27 0.22 0.22 0.25 0.25 0.20 0.22 0.22 0.24 0.24 0.25 0.22 0.22 -0.19 0.25 0.21 0.25 0.25 0.24 0.25 0.22 0.25 0.25 0.23 0.26 0.23 477 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 21 Day 22 Day 23 Day 24 Day 25 Day 26 Day 27 Day 28 D Female, VI - 250 mg/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0.27 0.23 0.29 0.22 0.27 0.24 0.24 0.23 0.28 0.30 0.25 0.24 0.29 0.24 0.21 0.23 0.25 0.26 0.25 0.28 0.24 0.24 0.21 0.27 0.22 0.27 0.28 0.27 0.27 0.24 0.27 0.28 0.24 0.28 0.26 0. 27 0. 23 0. 29 0. 22 0. 27 0. 24 0. 24 0. 23 . 0.28 0. 30 0. 25 0. 24 0. 29 0. 24 0. 21 0. 23 0. 25 0. 26 0. 25 0. 28 0. 24 0. 24 0. 21 0. 27 0. 22 0. 27 0. 28 0. 27 0. 27 0. 24 0. 27 0. 28 0. 24 0. 28 0. 26 1.18 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 ' Due to error, the animal was misdosed with 1.18 mL; it was given a dose of 0.29 mL then given an additional dose of 0.89 mL. 478 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 32 INDIVIDUAL DOSE VOLUMES (mL) Day 33 Day 34 FOR FEMALE RATS Day 35 Day 36 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 Q 641233 641238 Si . 641235 jj 641392 ,H 641360 g 641381 641333 5 641239 R" 641228 H 641334 m 641347 ;- 641367 (D 641303 M 641339 0 641316 5T 3' ^ g 0 ra 0.29 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 0.29 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 0.29 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 0.29 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 0.29 0.25 0.28 0.23 0.29 0.26 0.25 0.25 0.31 0.32 0.25 0.27 0.29 0.25 0.22 0.26 0.26 0.27 0.26 0.30 0.27 0.26 0.22 0.29 0.24 0.28 0.31 0.29 0.29 0.25 0.28 0.30 0.25 0.30 0.27 0.30 0.26 0.31 0.24 0.29 0.26 0.26 0.25 0.32 0.33 0.25 0.27 0.31 0.25 0.24 0.28 0.27 0.29 0.27 0.31 0.28 0.28 0.22 0.30 0.25 0.30 0.32 0.30 0.30 0.26 0.29 0.31 0.26 0.29 0.27 0. 30 0. 26 0. 31 0. 24 0.29 0. 26 0. 26 0. 25 0. 32 0. 33 0. 25 0. 27 0. 31 0. 25 0. 24 0. 28 0. 27 0. 29 0. 27 0. 31 0.28 0.28 0. 22 0. 30 0. 25 0. 30 0. 32 0. 30 0. 30 0. 26 0. 29 0. 31 0. 26 0. 29 0. 27 0.30 0.26 0.31 0.24 0.29 0.26 0.26 0.25 0.32 0.33 0.25 0.27 0.31 0.25 0.24 0.28 0.27 0.29 0.27 0.31 0.28 0.28 0.22 0.30 0.25 0.30 0.32 0.30 0.30 0.26 0.29 0.31 0.26 0.29 0.27 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 41 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE KATS Day 42 Day 43 Day 44 Day 45 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.30 0.26 0.31 0.24 0.29 0.26 0.26 0.25 0.32 0.33 0.25 0.27 0.31 0.25 0.24 0.28 0.27 0.29 0.27 0.31 0.28 0.28 0.22 0.30 0.25 0.30 0.32 0.30 0.30 0.26 0.29 0.31 0.26 0.29 0.27 0.30 0.26 0.31 0.24 0.29 0.26 0.26 0.25 0.32 0.33 0.25 0.27 0.31 0.25 0.24 0.28 0.27 0.29 0.27 0.31 0.28 0.28 0.22 0.30 0.25 0.30 0.32 0.30 0.30 0.26 0.29 0.31 0.26 0.29 0.27 0.30 0.26 0.31 0.24 0.29 0.26 0.26 0.25 0.32 0.33 0.25 0.27 0.31 0.25 0.24 0.28 0.27 0.29 0.27 0.31 0.28 0.28 0.22 0.30 0.25 0.30 0.32 0.30 0.30 0.26 0.29 0.31 0.26 0.29 0.27 0.29 0.27 0.32 0.24 0.31 0.28 0.27 0.26 0.34 0.34 0.27 0.29 0.31 0.26 0.25 0.29 0.28 0.30 0.28 0.33 0.28 0.29 0.24 0.30 0.26 0.31 0.33 0.31 0.31 0.27 0.30 0.31 0.27 0.31 0.27 0 .29 0 .27 0 .32 0 .24 0 .31 0 .28 0.27 0 .26 0 .34 0 .34 0 .27 0 .29 0 .31 0 .26 0 .25 0 .29 0 .28 0 .30 0.28 0 .33 0 .28 0 .29 0 .24 0 .30 0 .26 0 .31 0 .33 0 .31 0 .31 0 .27 0 .30 0 .31 0 .27 0 .31 0 .27 0.29 0.27 0.32 0.24 0.31 0.28 0.27 0.26 0.34 0.34 0.27 0.29 0.31 0.26 0.25 0.29 0.28 0.30 0.28 0.33 0.28 0.29 0.24 0.30 0.26 0.31 0.33 0.31 0.31 0.27 0.30 0.31 0.27 0.31 0.27 0 . 29 0 27 0 32 0 24 0 31 0 28 0 27 0 26 0 34 0 34 0 27 0 29 0 31 0.26 0.25 0 29 0.28 0 . 30 0 28 0 33 0 28 0 29 0 24 0 30 0 26 0 31 0 33 0 31 0 31 0 27 0 , 30 0 31 0 27 0 31 0 27 0.29 0.27 0.32 0.24 0.31 0.28 0.27 0.26 0.34 0.34 0.27 0.29 0.31 0.26 0.25 0.29 0.28 0.30 0.28 0.33 0.28 0.29 0.24 0.30 0.26 0.31 0.33 0.31 0.31 0.27 0.30 0.31 0.27 0.31 0.27 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 50 INDIVIDUAL DOSE VOLUMES (mL) Day 51 Day 52 FOR FEMALE RATS Day 53 Day 54 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 9 641238 s 641235 s 641392 9 641360 '3 641381 w> 641333 1 641239 a 641228 R 641334 5 641347 a 641367 641303 641339 3 641316 & ft 0 3 ff 3 3 s ss 0 ea 0.29 0.27 0.32 0.24 0.31 0.28 0.27 0.26 0.34 0.34 0.27 0.29 0.31 0.26 0.25 0.29 0.28 0.30 0.28 0.33 0.28 0.29 0.24 0.30 0.26 0.31 0.33 0.31 0.31 0.27 0.30 0.31 0.27 0.31 0.27 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 . 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 . 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 0.30 0.26 0.32 0.25 0.31 0.28 0.28 0.27 0.34 0.35 0.28 0.30 0.32 0.27 0.25 0.30 0.29 0.30 0.28 0.32 0.30 0.28 0.25 0.31 0.27 0.31 0.36 0.31 0.33 0.27 0.30 0.32 0.28 0.32 0.29 fjj & 3 5 3 1CO a, 0 0 a> (0 3 S 0 Q 3' SI 0 > 0 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 57 Day 58 Female, VI - 250 ing/kg/day . 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0. 30 0. 27 0. 33 0. 25 0. 32 0. 29 0. 29 0.28 0. 36 0. 36 0. 28 0. 31 0. 33 0. 27 0. 26 0. 31 0. 30 0. 31 0. 29 0. 32 0. 31 0. 29 0. 26 0. 31 0. 26 0. 32 0. 36 0. 33 0. 33 0. 28 0. 32 0. 34 0. 28 0. 32 0. 30 0.30 0.27 0.33 0.25 0.32 0.29 0.29 0.28 0.36 0.36 0.28 0.31 0.33 0.27 0.26 0.31 0.30 0.31 0.29 0.32 0.31 0.29 0.26 0.31 0.26 0.32 0.36 0.33 0.33 0.28 0.32 0.34 0.28 0.32 0.30 Day 59 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 60 Day 61 Day 62 Day 63 0.30 0.27 0.33 0.25 0.32 0.29 0.29 0.28 0.36 0.36 0.28 0.31 0.33 0.27 0.26 0.31 0.30 0.31 0.29 0.32 0.31 0.29 0.26 0.31 0.26 0.32 0.36 0.33 0.33 0.28 0.32 0.34 0.28 0.32 0.30 0.30 0.27 0.33 0.25 0.32 0.29 0.29 0.28 0.36 0.36 0.28 0.31 0.33 0.27 0.26 0.31 0.30 0.31 0.29 0.32 0.31 0.29 0.26 0.31 0.26 0.32 0.36 0.33 0.33 0.28 0.32 0.34 0.28 0.32 0.30 0.30 0.27 0.33 0.25 0.32 0.29 0.29 0.28 0.36 0.36 0.28 0.31 0.33 0.27 0.26 0.31 0.30 0.31 0.29 0.32 0.31 0.29 0.26 0.31 0.26 0.32 0.36 0.33 0.33 0.28 0.32 0.34 0.28 0.32 0.30 0 .30 0 .27 0 .33 0 .25 0 .32 0 .29 0.29 0 .28 0 .36 0 .36 0.28 0 .31 0 .33 0 .27 0 .26 0 .31 0 .30 0 .31 0 .29 0 .32 0 .31 0 .29 0 .26 0 .31 0 .26 0 .32 0 .36 0 .33 0 .33 0 .28 0 .32 0 .34 0 .28 0 .32 0 .30 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0.33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0.33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations S? 3 '0 W pi Is aa o 8 1 a 0 a? 3" ea 2 i> 0 S Day 66 Day 67 Female, VI - 250 nig/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 . 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0.33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0.33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 Day 68 INDIVIDUAL DOSE VOLUMES (mL) Day 69 Day 70 FOR FEMALE RATS Day 71 Day 72 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0.33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 0.31 0.28 0.34 0.27 0.32 0.31 0.29 0.29 0.37 0.37 0.28 0.30 0..33 0.28 0.27 0.31 0.30 0.32 0.30 0.33 0.31 0.30 0.25 0.31 0.27 0.33 0.36 0.33 0.33 0.28 0.32 0.34 0.29 0.32 0.29 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 483 Day 73 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 75 Day 76 Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 0.33 0.29 0.32 0.28 0.34 0.31 0.30 0.29 0.38 0.38 0.29 0.32 0.34 0.28 0.27 Day 77 INDIVIDUAL DOSE VOLUMES (ML) Day 78 Day 79 FOR FEMALE RATS Day 80 Day 81 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 Day 82 0.33 0.28 0.34 0.28 0.34 0.31 0.31 0.29 0.40 0.37 0.29 0.34 0.35 0.28 0.27 484 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 84 Day 85 Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 0.33 0.29 0.36 0.29 0.33 0,33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 - Day 86 INDIVIDUAL DOSE VOLUMES (KiL) FOR FEMALE RATS Day 87 Day 88 Day 89 Day 90 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 0.33 0.29 0.36 0.29 0.33 0.33 0.32 0.30 0.41 0.38 0.30 0.34 0.38 0.29 0.26 Day 91 0.33 0.29 0.36 0.29 0.34 0.33 0.31 0.30 0.41 0.39 485 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 0 Day 1 Female, VIII - 1000 mg/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0 .77 0 .66 0 .72 0 .71 0 .80 0 .71 0.72 0 .77 0 .86 0 .89 0 .84 0 .73 0 .77 0 .71 0 .70 0.75 0 .76 0.70 0 .76 0 .80 0.72 0 .75 0 .75 0 .78 0 .75 0 .76 0 .77 0 .78 0 .75 0 .72 . 0 .73 0 .82 0 .82 0 .81 0 .73 0 .73 0 .73 0 .81 0 .72 0 .74 0 .82 0 .83 0 .75 0 .81 0 .73 0.77 0.66 0.72 0.71 0.80 0.71 0.72 0.77 0.86 0.89 0.84 0.73 0.77 0.71 0.70 0.75 0.76 0.70 0.76 0.80 0.72 0.75 0.75 0.78 0.75 0.76 0.77 0.78 0.75 0.72 0.73 0.82 0.82 0.81 0.73 0.73 0.73 0.81 0.72 0.74 0.82 0.83 0.75 0.81 0.73 Day 2 INDIVIDUAL DOSE VOLUMES (rnL) FOR FEMALE RATS Day 3 Day 4 Day 5 Day 6 0.77 0.66 0.72 0.71 0.80 0.71 0.72 0.77 0.86 0.89 0.84 0.73 0.77 0.71 0.70 0.75 0.76 0.70 0.76 0.80 0.72 0.75 0.75 0.78 0.75 0.76 0.77 0.78 0.75 0.72 0.73 0.82 0.82 0.81 0.73 0.73 0.73 0.81 0.72 0.74 0.82 0.83 0.75 0.81 0.73 0.77 0.66 0.72 0.71 0.80 0.71 0.72 0.77 0.86 0.89 0.84 0.73 0.77 0.71 0.70 0.75 0.76 0.70 0.76 0.80 0.72 0.75 0.75 0.78 0.75 0.76 0.77 0.78 0.75 0.72 0.73 0.82 0.82 0.81 0.73 0.73 0.73 0.81 0.72 0.74 0.82 0.83 0.75 0.81 0.73 0.77 0.66 0.72 0.71 0.80 0.71 0.72 0.77 0.86 0.89 0.84 0.73 0.77 0.71 0.70 0.75 0.76 0.70 0.76 0.80 0.72 0.75 0.75 0.78 0.75 0.76 0.77 . 0.78 0.75 0.72 0.73 0.82 0.82 0.81 0.73 0.73 0.73 0.81 0.72 0.74 0.82 ' 0.83 0.75 0.81 0.73 0 .77 0 .66 0 .72 0 .71 0 .80 0 .71 0 .72 0 .77 0 .86 0 .89 0 .84 0 .73 0 .77 0 .71 0 .70 0 .75 0 .76 0 .70 0 .76 0 .80 0 .72 0 .75 0 .75 0 .78 0 .75 0 .76 0 .77 0 .78 0 .75 0 .72 0.73 0 .82 0 .82 0 .81 0 .73 0 .73 0 .73 0 .81 0 .72 0 .74 0 .82 0 .83 0 .75 0 .81 0 .73 0.77 0.66 0.72 0.71 0.80 0.71 0.72 0.77 0.86 0.89 0.84 0.73 0.77 0.71 0.70 0.75 0.76 0.70 0.76 0.80 0.72 0.75 0.75 0.78 0.75 0.76 0.77 0.78 0.75 0.72 0.73 0.82 0.82 0.81 0.73 0.73 0.73 0.81 0.72 0.74 0.82 0.83 0.75 0.81 0.73 486 Day 7 0.83 0.76 0.79 0.83 0.89 0.80 0.80 0.89 0.95 0.99 0.93 0.80 0.84 0.79 0.81 0.84 0.79 0.79 0.82 0.91 0.78 0.81 0.83 0.91 0.86 0.81 0.85 0.90 0.80 0.82 0.80 0.95 0.88 0.94 0.81 0.78 0.84 0.94 0.87 0.82 0.91 0.89 0.85 0.93 0.81 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 9 Day 10 Day 11 Day 12 Day 13 Day 14 Day 15 Day 16 D Female, VIII - 1000 ing/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0.83 0.76 0.79 0.83 0.89 0.80 0.80 0.89 0.95 0.99 0.93 0.80 0.84 0.79 0.81 0.84 0.79 0.79 0.82 0.91 0.78 0.81 0.83 0.91 0.86 0.81 0.85 0.90 0.80 0.82 0.80 0.95 0.88 0.94 0.81 0.78 0.84 0.94 0.87 0.82 0.91 0.89 0.85 0.93 0.81 0.83 0.76 0.79 0.83 0.89 0.80 0.80 0.89 0.95 0.99 0.93 0.80 0.84 0.79 0.81 0.84 0.79 0.79 0.82 0.91 0.78 0.81 0.83 0.91 0.86 0.81 . 0.85 0.90 0.80 0.82 0.80 0.95 0.88 0.94 0.81 0.78 0.84 0.94 0.87 0.82 0.91 0.89 0.85 0.93 0.81 0.83 0.76 0.79 0.83 0.89 0.80 0.80 0.89 0.95 0.99 0.93 0.80 0.84 0.79 0.81 0.84 0.79 0.79 0.82 0.91 0.78 0.81 . 0.83 0.91 0.86 0.81 0.85 0.90 0.80 0.82 0.80 0.95 0.88 0.94 0.81 0.78 0.84 0.94 0.87 0.82 0.91 0.89 0.85 0.93 0.81 0 .83 0.76 0.79 0 .83 0 .89 0 .80 0 .80 0 .89 0 .95 0 .99 0 .93 0 .80 0 .84 0 .79 0 .81 0 .84 0 .79 0 .79 0 .82 0 .91 0 .78 0 .81 0 .83 0 .91 0 .86 0 .81 0 .85 0 .90 0 .80 0 .82 0 .80 0 .95 0 .88 0.94 0 .81 0 .78 0 .84 0 .94 0 .87 0 .82 0 .91 0 .89 0 .85 0 .93 0 .81 0 .83 0 .76 0 .79 0 .83 0 .89 0 .80 0 .80 0 .89 0 .95 0 .99 0 .93 0 .80 0 .84 0 .79 0 .81 0 .84 0 .79 0 .79 0 .82 0 .91 0 .78 0 .81 0 .83 0 .91 0 .86 0 .81 0 .85 0 .90 0 .80 0 .82 0 .80 0 .95 0 .88 0 .94 0 .81 0 .78 0 .84 0 .94 0 .87 0 .82 0 .91 0 .89 0 .85 0 .93 0 .81 0.86 0.81 0.84 0.93 0.94 0.82 0.84 0.99 1.00 1.10 0.97 0.90 0.97 0.89 0.90 0.90 0.89 0.85 0.89 1.00 0.83 0.88 0.91 0.98 0.98 0.92 0.95 0.96 0.87 0.89 0.87 1.00 0.97 1.00 0.88 0.85 0.91 1.10 0.93 0.90 1.00 0.94 0.92 1.00 0.91 0 .86 0 .81 0 .84 0 .93 0 .94 0 .82 0 .84 0 .99 1 .00 1 .10 0 .97 0 .90 0 .97 0 .89 0 .90 0 .90 0 .89 0 .85 0 .89 1 .00 0.83 0 .88 0 .91 0 .98 0 .98 0 .92 0 .95 0 .96 0 .87 0 .89 0.87 1 .00 0 .97 1 .00 0 .88 0 .85 0 .91 1 .10 0 .93 0 .90 1 .00 0 .94 0 .92 1 .00 0 .91 0 .86 0 .81 0 .84 0 .93 0 .94 0 .82 0 .84 0 .99 1 .00 1 .10 0 .97 0 .90 0 .97 0 .89 0 .90 0 .90 0 .89 0 .85 0 .89 1 .00 0 .83 0 .88 0 .91 0 .98 0 .98 0 .92 0 .95 0 .96 0 .87 0 .89 0 .87 1 .00 0 .97 1 .00 0 .88 0 .85 0 .91 1 .10 0 .93 0 .90 1 .00 0 .94 0 .92 1 .00 0 .91 487 ''ay H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 18 Day 19 Female, VIII - 1000 nig/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0 .86 0 .81 0 .84 0 .93 0 .94 0 .82 0 .84 0 .99 1 .00 1 .10 0 .97 0 .90 0 .97 0 .89 0 .90 0.90 0 .89 0 .85 0 .89 1 .00 0 .83 0 .88 0 .91 0.98 0 .98 0.92 0 .95 0 .96 0 .87 0 .89 0 .87 1 .00 0 .97 1 .00 0 .88 0 .85 0 .91 1 .10 0 .93 0 .90 1 .00 0 .94 0 .92 1 .00 0 .91 0.86 0.81 0.84 0.93 0.94 0.82 0.84 0.99 1.00 1.10 0.97 0.90 0.97 0.89 0.90 0.90 0.89 0.85 0.89 1.00 0.83 0.88 0.91 0.98 0.98 0.92 . 0.95 0.96 0.87 0.89 0.87 1.00 0.97 1.00 0.88 0.85 0.91 1.10 0.93 0.90 1.00 0.94 0.92 1.00 0.91 Day 20 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS 0.86 0.81 0.84 0.93 0.94 0.82 0.84 0.99 1.00 1.10 0.97 0.90 0.97 0.89 0.90 0.90 0.89 0.85 0.89 1.00 0.83 0.88 0.91 0.98 0.98 0.92 0.95 0.96 0.87 0.89 0.87 1.00 0.97 1.00 0.88 0.85 0.91 1.10 0.93 0.90 1.00 0.94 0.92 1.00 0.91 488 <f @ 1"g 3 ^ y 3 I? J I ^ % ~ 0 & S. - fS P v S H-24616: Subchronic Toxicity 90-Day Gavage Study in Rate with One-Generation Reproductive Evaluations Day 21 Day 22 Female, VIII - 1000 nig/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 ' 641387 641282 641234 641256 641356 641352 641366 641399 641377 0 .88 0 .89 0 .87 0 .98 1 .00 0 .88 0.91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0 .93 0 .97 0 .99 0 .98 0 .92 0 .94 1 .20 0 .90 0 .94 0 .94 1 .00 1 .00 1 .00 1 .00 1 .00 0 .91 0 .98 . 0 .90 1 .20 1 .00 1 .10 0 .88 0.88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0 .92 0 .88 0 .89 0 .87 0 .98 1 .00 0 .88 0 .91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0 .93 0 .97 0 .99 0 .98 0 .92 0 .94 1 .20 0 .90 0 .94 0 .94 1 .00 1 .00 . 1 .00 1 .00 1 .00 0 .91 0 .98 0 .90 1 .20 1 .00 1 .10 0 .88 0 .88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0.92 Day 23 INDIVIDUAL DOSE VOLUMES (KiL) FOR FEMALE RATS Day 24 Day 25 Day 26 Day 27 0 .88 0 .89 0 .87 0 .98 1 .00 0 .88 0 .91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0 .93 0 .97 0 .99 0.98 0 .92 0 .94 1 .20 0 .90 0 .94 0.94 1 .00 1. .00 1 .00 1 .00 1 .00 0 .91 0 .98 0 .90 1 .20 1 .00 1.10 0 .88 0 .88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0 .92 0.88 0.89 0.87 0.98 1.00 0.88 0.91 1.10 1.00 1.10 1.10 0.92 1.10 0.93 0.97 0.99 0.98 0.92 0.94 1.20 0.90 0.94 0.94 1.00 1.00 1.00 1.00 1.00 0.91 0.98 0.90 1.20 1.00 1.10 0.88 0.88 0.97 1.20 0.97 0.95 1.10 0.97 0.90 1.10 0.92 0 .88 0 .89 0 .87 0 .98 1 .00 0 .88 .0 .91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0 .93 0 .97 0 .99 0 .98 0 .92 0 .94 1 .20 0 .90 0 .94 0 .94 1 .00 1 .00 1 .00 1 .00 1 .00 0 .91 0 .98 0 .90 1 .20 1 .00 1 .10 0 .88 0 .88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0.92 0 .88 0 .89 0 .87 0.98 1 .00 0 .88 0.91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0.93 0 .97 0 .99 0 .98 0 .92 0.94 1 .20 0 .90 0 .94 0 .94 1 .00 1 .00 1 .00 1 .00 1 .00 0 .91 0 .98 0 .90 1 .20 1 .00 I .10 0 .88 0 .88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0 .92 0 .88 0 .89 0 .87 0 .98 1 .00 0 .88 0 .91 1 .10 1 .00 1 .10 1 .10 0 .92 1 .10 0 .93 0 .97 0 .99 0 .98 0 .92 0 .94 1 .20 0 .90 0 .94 0 .94 1 .00 1 .00 1 .00 1 .00 1 .00 0 .91 0 .98 0 .90 1 .20 1 .00 1 .10 0 .88 0 .88 0 .97 1 .20 0 .97 0 .95 1 .10 0 .97 0 .90 1 .10 0 .92 489 Day 28 0.95 0.92 0.93 1.10 1.10 0.89 1.00 1.10 1.20 1.20 1.20 1.00 1.10 0.99 1.00 1.00 1.00 0.96 0.98 1.10 0.97 1.00 1.00 1.10 1.10 1.00 1.10 1.10 1.00 1.00 1.00 1.20 1.10 1.10 0.97 0.97 1.00 1.20 1.00 1.00 1.20 1.10 0.97 1.20 0.97 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 30 Day 31 Female, VIII - 1000 ing/kg/day 641299 641275 641326 64.1380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0 .95 0 .92 0 .93 1 .10 1 .10 0 .89 1 .00 1 .10 1 .20 1 .20 1 .20 1 .00 1 .10 0 .99 1 .00 1 .00 1 .00 0 .96 0 .98 1 .10 0 .97 1 .00 1 .00 1.10 1 .10 1 .00 1 .10 1 .10 1 .00 1 .00 1 .00 1 .20 1 .10 1 .10 0 .97 0 .97 1 .00 1 .20 1 .00 1 .00 1 .20 1 .10 0 .97 1 .20 0 .97 0.95 0.92 0.93 1.10 1.10 0.89 1.00 1.10 1.20 1.20 1.20 1.00 1.10 0.99 1.00 1.00 1.00 0.96 0.98 1.10 0.97 1.00 1.00 1.10 1.10 1.00 . 1.10 1.10 1.00 1.00 1.00 1.20 1.10 1.10 0.97 0.97 1.00 1.20 1.00 1.00 1.20 1.10 0.97 1.20 0.97 Day 32 INDIVIDUAL DOSE VOLUMES (inL) Day 33 Day 34 FOR FEMALE RATS Day 35 Day 36 0.95 0.92 0.93 1.10 1.10 0.89 1.00 1.10 1.20 1.20 1.20 1.00 1.10 0.99 1.00 1.00 1.00 0.96 0.98 1.10 0.97 1.00 1.00 1.10 1.10 1.00 1.10 1.10 1.00 1.00 1.00 1.20 1.10 1.10 0.97 0.97 1.00 1.20 1,00 1.00 1.20 1.10 0.97 1.20 0.97 0.95 0.92 0.93 1.10 1.10 0.89 1.00 1.10 1.20 1.20 1.20 1.00 1.10 0.99 1.00 1.00 1.00 0.96 0.98 1.10 0.97 1.00 1.00 1.10 1.10 1.00 1.10 1.10 1.00 1.00 1.00 1.20 1.10 1.10 0.97 0.97 1.00 1.20 1.00 1.00 1.20 1.10 0.97 1.20 0.97 0.95 0.92 0.93 1.10 1.10 0.89 1.00 1.10 1.20 1.20 1.20 1.00 1.10 0.99 1.00 1.00 1.00 0.96 0.98 1.10 0.97 1.00 1.00 1.10 1.10 1.00 1.10 1.10 1.00 1.00 1.00 1.20 1.10 1.10 0.97 0.97 1.00 1.20 1.00 1.00 1.20 1.10 0.97 1.20 0.97 0 .95 0 .99 0 .97 1 .00 1 .10 0 .97 1 .00 1 .20 1 .20 1 .30 1 .20 1 .10 1 .20 1 .00 1 .10 1 .10 1 .00 0 .97 0.97 1 .10 0 .98 1 .00 1 .00 1 .10 1 .20 1 .10 1 .10 1 .10 1 .00 1 .10 1 .10 1 .30 1 .00 1 .20 1 .00 1 .00 1 .00 1 .30 1 .00 1 .10 1 .20 1 .10 1 .00 1 .20 1 .00 0.95 0.99 0.97 1.00 1.10 0.97 1.00 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.00 0.97 0.97 1.10 1.00 0.98 1.00 1.10 1.20 1.10 1.10 1.10 1.00 1.10 1.10 1.30 1.00 1.20 1.00 1.00 1.00 1.30 1.00 1.10 1.20 1.10 1.00 1.20 1.00 490 Day 37 0 .95 0 .99 0 .97 1 .00 1 .10 0 .97 1 .00 1 .20 1 .20 1 .30 1 .20 1 .10 1 .20 1 .00 1 .10 1 .10 1 .00 0 .97 0 .97 1 .10 0 .98 1 .00 1 .00 1 .10 1 .20 1 .10 1 .10 1 .10 1 .00 1 .10 1 .10 1 .30 1 .00 1 .20 1 .00 1 .00 1 .00 1 .30 1 .00 1 .10 1 .20 1 .10 1 .00 1 .20 1 .00 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUMES (rnL) FOR FEMALE RATS Day 39 Day 40 Day 41 Day 42 Day 43 Day 44 Day 45 Day 46 D Female, VIII - 1000 nig/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0.95 0.99 0.97 1.00 1.10 0.97 1.00 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.00 0.97 0.97 1.10 0.98 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.00 1.10 . 1.10 1.30 1.00 1.20 1.00 1.00 1.00 1.30 1.00 1.10 1.20 1.10 1.00 1.20 1.00 0.95 0.99 0.97 1.00 1.10 0.97 1.00 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.00 0.97 0.97 1.10 0.98 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.00 1.10 1.10 1.30 1.00 1.20 1.00 1.00 1.00 1.30 1.00 1.10 1.20 1.10 1.00 1.20 1.00 0.95 0.99 0.97 1.00 1.10 0.97 1.00 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.00 0.97 0.97 1.10 0.98 1.00 1.00 1.10 1.20 1.10 1.10 1.10 1.00 1.10 1.10 1.30 1.00 1.20 1.00 1.00 1.00 1.30 1.00 1.10 1.20 1.10 1.00 1.20 1.00 0 .99 1 .00 0.99 1 .10 1 .20 0 .91 1.10 1 .20 1 .20 1 .30 1 .20 1 .10 1 .20 1 .00 1 .10 1 .10 1 .10 0 .96 0 .95 1 .20 1 .00 1 .10 1 .00 1 .20 1 .30 1 .20 1 .20 1 .20 1 .10 1 .10 1 .10 1 .30 1 .10 1 .20 1 .00 1 .10 1 .10 1 .30 1 .10 1 .10 1 .30 1 .10 1 .00 . 1 .30 1 .10 0.99 1.00 0.99 1.10 1.20 0.91 1.10 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.10 0.96 0.95 1.20 1.00 1.10 1.00 1.20 1.30 1.20 1.20 . 1.20 1.10 1.10 1.10 1.30 1.10 1.20 1.00 1.10 1.10 1.30 1.10 1.10 1.30 1.10 1.00 1.30 1.10 0.99 1.00 0.99 1.10 1.20 0.91 1.10 1.20 1.20 1.30 1.20 1.10 1.20 1.00 1.10 1.10 1.10 0.96 0.95 1.20 1.00 1.10 1.00 1.20 1.30 1.20 1.20 1.20 1.10 1.10 1.10 1.30 1.10 1.20 1.00 1.10 1.10 1.30 1.10 1.10 1.30 1.10 1.00 1.30 1.10 0 .99 1 .00 0 .99 1 .10 1.20 0 .91 1 .10 1 .20 1 .20 1 .30 1 .20 1 .10 1 .20 1 .00 1 .10 1 .10 1 .10 0 .96 0 .95 1 .20 1 .00 1 .10 1 .00 1 .20 1 .30 1 .20 1 .20 1 .20 1 .10 1 .10 1 .10 1 .30 1 .10 1 .20 1 .00 1 .10 1 .10 1 .30 1 .10 1 .10 1 .30 1 .10 1 .00 1 .30 1 .10 0 .99 1 .00 0 .99 1 .10 1 .20 0 .91 1 .10 1 .20 1 .20 1 .30 1 .20 1 .10 1 .20 1 .00 1 .10 1 .10 1 .10 0 .96 0 .95 1 .20 1 .00 1 .10 1 .00 1 .20 1 .30 1 .20 1 .20 1 .20 1 .10 1 .10 1 .10 1 .30 1 .10 1 .20 1 .00 1 .10 1 .10 1 .30 1 .10 1 .10 1 .30 1.10 1 .00 1 .30 1 .10 491 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 48 Day 49 Day 50 Day 51 Day 52 Day 53 Day 54 Day 55 D Female, VIII - 1000 ing/kg/day 641299 0 .99 641275 641326 1 .00 0 .99 641380 1 .10 641314 1 .20 641237 0 .91 641300 1 .10 641279 641390 1 .20 1 .20 641327 641259 641264 1 .30 1 .20 1 .10 641301 1 .20 641395 641278 1 .00 1 .10 641265 1 .10 641393 641402 641246 1 .10 0 .96 0 .95 1 641320 1 .20 641353 1 .00 641401 1 .10 641307 1 .00 sa 641368 1 .20 641343 1 .30 641254 1 .20 RT 641242 1 .20 1.S. 641284 1 .20 641230 1 .10 641273 1 .10 641296 1 .10 -- 641248 I .30 0 641370 1 .10 641243 641329 1 .20 1 .00 J S 641385 1 .10 3' 641387 1 .10 641282 1 .30 641234 1 .10 0 641256 1 .10 ^s> 641356 1 .30 i 641352 1 .10 641366 1 .00 641399 1 .30 641377 1 .10 0.96 1.00 1.00 1.10 1.20 0.97 1.10 1.30 1.20 1.40 1.30 1.20 1.30 1.10 1.10 1.10 1.10 1.00 1.00 1.20 1.00 1.10 1.10 1.20 1.30 1.20 1.20 1.30 1.10 1.10 1.10 1.40 1.20 1.20 1.00 1.10 1.10 1.40 1.10 1.10 1.30 1.10 1.10 1.30 1.10 0.96 1.00 1.00 1.10 1.20 0.97 1.10 1.30 1.20 1.40 1.30 1.20 1.30 1.10 1.10 1.10 1.10 1.00 1.00 1.20 1.00 1.10 1.10 1.20 1.30 1.20 1.20 1.30 1.10 1.10 1.10 1.40 1.20 1.20 1.00 1.10 1.10 1.40 1.10 1.10 1.30 1.10 1.10 1.30 1.10 0 .96 1 .00 1 .00 1 .10 1 .20 0 .97 1 .10 1 .30 1 .20 1 .40 1 .30 1 .20 1.30 1 .10 1 .10 1 .10 1 .10 1 .00 1 .00 1 .20 1 .00 1 .10 1 .10 1 .20 1 .30 1 .20 1 .20 1 .30 1 .10 1 .10 1 .10 1 .40 1 .20 1 .20 1 .00 1 .10 1 .10 1 .40 1 .10 1 .10 1 .30 1 .10 1 .10 1 .30 1 .10 0 .96 1 .00 1 .00 1 .10 1 .20 0 .97 1 .10 1 .30 1 .20 1 .40 1 .30 1 .20 1 .30 1 .10 1 .10 1 .10 1 .10 1 .00 1 .00 1 .20 1 .00 1 .10 1 .10 1 .20 1 .30 1 .20 1 .20 1 .30 1 .10 1 .10 1 .10 1 .40 1 .20 1 .20 1 .00 1 .10 1 .10 1 .40 1 .10 1 .10 1 .30 1 .10 1 .10 1.30 1 .10 0.96 1.00 1.00 1.10 1.20 0.97 1.10 1.30 1.20 1.40 1.30 1.20 1.30 1.10 1.10 1.10 1.10 1.00 1.00 1.20 1.00 1.10 1.10 1.20 1.30 1.20 1.20 1.30 1.10 1.10 1.10 1.40 1.20 1.20 1.00 1.10 1.10 1.40 1.10 1.10 1.30 1.10 1.10 1.30 1.10 0.96 1.00 1.00 1.10 1.20 0.97 1.10 1.30 1.20 1.40 1.30 1.20 1.30 1.10 1.10 1.20 1.10 1.00 1.00 1.20 1.00 1.10 1.10 1.20 1.30 1.20 1.20 1.30 1.10 1.10 1.10 1.40 1.20 1.20 1.00 1.20 1.10 1.40 1.10 1.10 1.30 1.20 1.10 1.30 1.10 0 .96 1 .00 1 .00 1 .10 1 .20 0 .97 1 .10 1 .30 1 .20 1 .40 1 .30 1 .20 1 .30 1 .10 1 .10 1 .10 1 .10 1 .00 1 .00 1 .20 1 .00 1 .10 1 .10 1 .20 1 .30 1 .20 1 .20 1 .30 1 .10 1 .10 1 .10 1 .40 1 .20 1 .20 1 .00 1 .10 1 .10 1 .40 1 .10 1 .10 1 .30 1 .10 1 .10 1 .30 1 .10 492 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 57 Day 58 Female, VIII - 1000 nig/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 0.99 1.00 1.00 1.20 1.30 0.94 1.10 1.30 1.20 1.40 1.20 1.20 1.30 1.10 1.20 1.20 1.10 1.00 1.00 1.30 1.10 1.10 1.10 1.20 1.30 1.20 1.30 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.00 1.20 1.10 1.30 1.10 1.10 1.30 1.20 1.10 1.30 1.10 0.99 1.00 1.00 1.20 1.30 0.94 1.10 1.30 1.20 1.40 1.20 1.20 1.30 1.10 1.20 1.20 1.10 1.00 1.00 1.30 1.10 1.10 1.10 1.20 1.30 1.20 . 1.30 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.00 1.20 1.10 1.30 1.10 1.10 1.30 1.20 1.10 1.30 1.10 Day 59 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 60 Day 61 Day 62 Day 63 0.99 1.00 1.00 1.20 1.30 0.94 1.10 1.30 1.20 1.40 1.20 1.20 1.30 1.10 1.20 1.20 1.10 1.00 1.00 1.30 1.10 1.10 1.10 1.20 1.30 1.20 1.30 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.00 1.20 1.10 1.30 1.10 1.10 1.30 1.20 1.10 1.30 1.10 0.99 1.00 1.00 1.20 1.30 0.94 1.10 1.30 1.20 1.40 1.20 1.20 1.30 1.10 1.20 1.20 1.10 1.00 1.00 1.30 1.10 1.10 1.10 1.20 1.30 1.20 1.30 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.00 1.20 1.10 1.30 1.10 1.10 1.30 1.20 1.10 1.30 , 1.10 0.99 1.00 1.00 1.20 1.30 0.94 1.10 1.30 1.20 1.40 1.20 1.20 1.30 1.10 1.20 1.20 1.10 1.00 1.00 1.30 1.10 1.10 1.10 1.20 1.30 1.20 1.30 1.20 1.10 1.20 1.10 1.30 1.20 1.20 1.00 1.20 1.10 1.30 1.10 1.10 1.30 1.20 1.10 1.30 1.10 0 .99 1 .00 1 .00 1 .20 1 .30 0 .94 1 .10 1 .30 1 .20 1 .40 1 .20 1 .20 1 .30 1 .10 1 .20 1.20 1 .10 1 .00 1 .00 1 .30 1 .10 1 .10 1 .10 1 .20 1 .30 1 .20 1 .30 1 .20 1 .10 1 .20 1 .10 1 .30 1 .20 1 .20 1 .00 1 .20 1 .10 1 .30 1 .10 1 .10 1 .30 1 .20 1 .10 1 .30 1 .10 1.00 1.00 1.10 1.20 1.30 1.00 1.20 1.30 . 1.30 1.50 1.30 1.30 1.40 1.10 1.10 1.20 1.20 1.10 1.00 1.30 1.10 1.20 1.10 1.20 1.40 1.20 1.30 1.30 1.10 1.10 1.10 1.40 1.20 1.30 1.10 1.20 1.20 1.40 1.20 1.10 1.40 1.20 1.20 1.30 1.20 493 Day 64 1 .00 1 .00 1 .10 1 .20 1 .30 1 .00 1 .20 1 .30 1 .30 1 .50 1 .30 1 .30 1 .40 1 .10 1 .10 1 .20 1 .20 1 .10 1 .00 1 .30 1 .10 1 .20 1 .10 1 .20 1 .40' 1.20 1 .30 1 .30 1 .10 1 .10 1 .10 1 .40 1 .20 1 .30 1 .10 1 .20 1 .20 1 .40 1 .20 1 .10 1 .40 1 .20 1 .20 1 .30 1 .20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 66 Day 67 Female, VIII - 1000 ing/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 1.00 1.00 1.10 1.20 1.30 1.00 1.20 1.30 1.30 1.50 1.30 1.30 1.40 1.10 1.10 1.20 1.20 1.10 1.00 1.30 1.10 1.20 1.10 1.20 1.40 1.20 1.30 1.30 1.10 1.10 1.10 1.40 1.20 1.30 1.10 1.20 1.20 1.40 1.20 1.10 1.40 1.20 1.20 1.30 1.20 1.00 1.00 1.10 1.20 1.30 1.00 1.20 1.30 1.30 1.50 1.30 1.30 1.40 1.10 1.10 1.20 1.20 1.10 1.00 1.30 1.10 1.20 1.10 1.20 1.40 1.20 1.30 1.30 1.10 1.10 1.10 1.40 1.20 1.30 1.10 1.20 1.20 1.40 1.20 1.10 1.40 1.20 1.20 1.30 1.20 Day 68 INDIVIDUAL DOSE VOLUMES (mL) Day 69 Day 70 FOR FEMALE RATS Day 71 Day 72 1.00 1.00 1.10 1.20 1.30 1.00 1.20 1.30 1.30 1.50 1.30 1.30 1.40 1.10 1.10 1.20 1.20 1.10 1.00 1.30 1.10 1.20 1.10 1.20 1.40 1.20 1.30 1.30 1.10 1.10 1.10 1.40 1.20 1.30 1.10 1.20 1.20 1.40 1.20 1.10 1.40 1.20 1.20 1.30 1.20 1 .00 1 .00 1 .10 1 .20 1 .30 1 .00 1 .20 1 .30 1 .30 1 .50 1 .30 1 .30 1 .40 1 .10 1.10 1 .20 1 .20 1 .10 1 .00 1 .30 1 .10 1 .20 1 .10 1 .20 1 .40 1 .20 1 .30 1 .30 1 .10 1 .10 1 .10 1 .40 1 .20 1 .30 1 .10 1 .20 1 .20 1 .40 1 .20 1 .10 1 .40 1 .20 1 .20 1 .30 ' 1 .20 1.00 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.30 1.50 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.00 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.30 1.50 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.00 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.30 1.50 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 494 Day 73 1.00 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.30 1.50 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 75 Day 76 Female, VIII - 1000 ing/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 ? 641353 641401 641307 641368 641343 641254 ^ 641242 ! 641284 f 641230 ' 641273 641296 641248 * 641370 [ 1 641243 641329 > 641385 l '641387 1 641282 641234 ^ 641256 641356 S 641352 > 641366 ' 641399 1 641377 1 .00 1 .10 1 .10 1 .30 1 .30 1 .00 1 .20 1 .40 1 .30 1 .50 1 .30 1 .30 1 .30 1 .20 1 .20 1 .20 1 .20 1 .50 1 .20 1 .20 1 .50 1 .20 1 .20 1 .40 1 .20 1.00 1.10 1.10 1.30 1.30 1.00 1.20 1.40 1.30 1.50 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 Day 77 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 78 Day 79 Day 80 Day 81 1.00 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.00 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.00 1.10 1.10 1.20 1.30 1.00 .1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.00 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.00 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 495 Day 82 1.00 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.30 1.60 1.30 1.30 1.30 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.20 1.40 1.20 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations ? ? X S 5, ,,|f g 3 & S 1 f j 4 i ,, j. "- Day 84 Day 85 Female, VIII - 1000 ing/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 ' 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 1 .10 1 .10 1 .10 1 .30 1 .40 1 .00 1 .20 1 .50 1 .30 1 .60 1 .30 1 .30 1 .40 1 .20 1 .20 1 .20 1 .20 1 .50 1 .20 1 .20 1 .50 1 .20 1 .30 1 .40 1 .20 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.20 1.20 1.50. 1.20 1.20 1.50 1.20 1.30 1.40 1.20 Day 86 INDIVIDUAL DOSE VOLUMES (mL) FOR FEMALE RATS Day 87 Day 88 Day 89 Day 90 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.10 1.10 1.10 1.30 1.40 1.00 1.20 1.50 1.30 1.60 1.30 1.30 1.40 1.20 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.30 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.30 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.30 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.30 1.40 1.20 1.20 1.20 1.50 1.20 1.20 1.50 1.20 1.30 1.40 1.20 496 Day 91 1.10 1.10 1.10 1.20 1.30 1.00 1.30 1.50 1.40 1.60 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 APPENDIX B INDIVIDUAL BODY WEIGHTS 497 Company ganfced. Does not eonSadn TSCA-CBt H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 INDIVIDUAL BODY WEIGHTS EXPLANATORY NOTES Critical Dates Day 69 Male and female rats designated for reproduction evaluations were co-housed. Body weights that were collected during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section. Day 91 Fasted final body weights of male 90-day exposure rats scheduled for sacrifice. Day 92 Fasted final body weights of female exposure rats scheduled for sacrifice. Days 122 and 123 Fasted final body weights for male and female one-month recovery rats scheduled for sacrifice, respectively. Day 182 Fasted final body weights for male and female 3-month recovery rats scheduled for sacrifice. 498 Company Sanitized. Does not contain TSCA CB\ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 0 INDIV]DUALBODY WEIGHTS(g)OFM/UJ3RATS Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 D Male, I - 0 mg/:kg/day | "g .3 0$ 1 1 p" 0 @ w "3 -- s ? ^ 2 &' ,- &- 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 . 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 2.40 .9 248 .4 254 .8 255 .1 249 .5 266 .8 247 .9 247 .8 264.3 271 .4 231 .2 241 .2 259 .5 232 .4 261 .9 288.8 267 .5 222 .5 254 .7 232 .8 278 .5 241 .3 266 .6 238 .8 243 .4 271 .1 252 .5 271 .6 290 .0 246 .5 259 .0 240 .0 258 .5 263 .5 245 .3 242 .9 249 .2 248 .9 289.3 250 .8 237 .2 300 .5 242 .8 260 .0 253 .4 285.4 291.5 307.7 319.6 318.5 328.2 293.4 301.9 332.5 320.9 274.4 273.5 322.6 273.2 311.4 357.9 324.3 275.4 306.6 278.4 338.5 295.6 318.3 296.2 291.1 343.7 306.3 323.7 358.1 292.3 307.1 294.3 313.2 319.0 294.6 292.7 312.6 302.4 347.2 298.9 298.6 350.7 290.0 303.5 296.5 328.7 326.9 356.5 368.6 383.0 378.4 333.3 346.6 378.6 363.2 312.1 312.6 381.3 300.5 352.2 411.1 373.1 327.5 353.4 317.0 389.7 330.6 367.2 344.0 322.9 401.9 351.9 358.8 417.7 340.7 351.2 341.2 341.9 368.7 340.3 323.1 358.6 337.9 389.8 331.3 347.9 388.3 333.6 354.9 338.3 363.9 365.9 388.4 422.7 433.7 423.3 371.5 399.1 408.2 403.8 351.4 346.5 451.4 341.7 390.5 468.9 412.4 367.2 391.7 352.9 452.8 363.9 399.0 386.1 358.6 452.8 386.0 394.5 464.2 374.8 394.6 387.3 366.4 417.7 380.8 365.8 400.9 381.7 431.2 362.3 384.5 422.3 386.9 391.7 379.2 398.7 398.3 430.8 466.8 475.9 465.3 403.0 434.1 451.1 444.6 356.0 372.5 489.2 373.3 421.1 510.8 440.0 404.5 436.1 379.1 506.9 404.3 435.5 428.4 383.7 505.8 423.2 424.3 514.6 407.1 421.3 416.1 403.1 460.8 428.0 400.1 443.8 415.9 472.2 414.3 428.8 462.7 418.3 438.3 418.8 418.8 416.9 456.5 493.1 510.0 491.0 411.6 467.7 468.4 472.4 383.0 388.6 529.2 387.2 456.2 541.1 471.7 429.5 464.9 408.9 521.4 410.2 456.2 450.8 411.2 531.6 452.2 443.7 548.1 428.4 437.7 450.5 426.4 484.9 446.9 429.2 477.8 458.7 502.8 438.2 467.1 477.5 450.0 468.9 451.1 435.6 442.3 484.5 524.1 543.0 515.9 435.3 496.7 ' 496.7 502.7 412.6 406.0 569.5 408.0 462.9 580.3 499.7 449.1 488.9 430.2 576.9 442.3 478.6 479.3 428.5 551.3 473.7 471.6 578.8 447.5 452.5 475.9 441.6 497.4 461.2 446.8 483.1 485.5 521.5 467.1 481.6 495.9 468.9 494.2 476.4 446 .1 462 .6 494 .6 533 .0 551 .7 515 .7 438 .1 505 .4 505.4 513 .6 431 .2 418 .0 583 .8 428 .6 490 .3 614 .0 527.2 466 .3 503 .8 449 .6 604 .1 466.2 496 .6 498 .5 441 .0 571 .3 499 .1 492 .2 601 .5 460 .2 469 .1 489 .6 451 .5 528 .3 478 .3 473 .7 506 .8 513 .4 547 .6 481 .3 503 .9 520 .8 492 .0 521 .8 492 .4 499 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Male, I - 0 ing/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 475.6 485.5 533.4 569.8 589.9 569.5 473.0 552.8 522.6 559.2 435.4 424.2 605.2 447.4 512.1 644.3 565.0 491.6 550.8 480.1 659.4 489.7 541.1 523.0 470.3 626.4 516.7 520.7 638.0 489.9 490.5 523.8 479.0 552.1 516.9 511.7 538.4 558.9 588.6 527.9 522.0 556.9 528.6 576.9 536.8 Day 69 658 .5 572 .6 500 .6 548 .8 490 .3 671 .6 502 .7 557.7 539 .3 482.3 644 .3 523 .2 536 .8 654 .0 502.4 506 .1 535 .2 497 .3 569 .7 530 .9 INDIVBDUAL:BOD'YWEIGHTS;(g)OFMALERATS Day 70 Day 77 Day 84 Day 90 Day 91 495.5 497.6 549.9 595.4 614.7 589.2 480.7 574.9 602.6 586.5 458.4 440.5 638.9 463.3 524.6 511. 3 508. 2 574.7 613. 3 632. 6 605. 3 500. 7 588. 3 619. 8 611. 7 465. 2 456. 3 666. 4 474. 6 545. 8 523 .5 498 .0 572 .8 631 .3 656 .1 610 .3 508 .8 602 .0 637 .7 619 .5 451 .8 454 .1 673.9 483 .8 560 .6 532.5 514.2 572.8 635.1 662.7 613.4 509.4 605.0 654.8 629.2 509.1 500.4 556.0 612.4 629.0 587.7 491.3 580.9 636.8 608.4 476.8 436.3 638.0 495.8 562.5 528.0 554.0 577.4 603.2 534.9 550.7 571.2 545.0 593.0 542.4 538. 2 580. 5 589. 4 619. 7 549.3 563. 0 582. 3 553. 0 622. 6 555. 5 548 .8 603 .2 594 .7 633 .5 565 .1 565.4 599 .2 565 .6 621 .4 574 .3 500 561.6 621.8 611.0 650.4 555.4 577.3 605.8 575.6 623.2 583.0 Day 99 476.9 431.6 651.4 501.2 557.5 554.7 627.3 616.2 641.8 578.0 575.0 607.4 579.6 624.3 585.1 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIV][DUAL BODY WEIGHT;(g)OPMALERATS Day 112 Day 119 Day 122 Day 126 Day 133 Day 140 Day 147 Day 154 D Male, I - 0 ing/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 493 .8 424 .3 696 .6 513 .0 569 .5 503.1 432.2 707.7 517.3 570.0 " 553 .4 652 .0 625 .7 658 .8 599 .3 605 .4 631 .5 599 .2 653 .2 610 .9 566.0 668.6 625.8 673.3 613.2 606.7 631.5 610.9 667.1 629.0 558.2 660.0 603.3 653.2 596.4 593.8 623.2 590.9 644.7 618.6 518.3 441.3 708.4 530.9 580.0 512.8 451.5 723.2 533.7 586.9 509.5 454.7 728.3 531.1 585.6 522.5 466.6 742.2 529.0 596.8 529.8 474.1 765.5 533.8 608.0 501 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 168 Day 175 Male, I - 0 nig/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 Q 641158 S 641100 v 641060 S 641188 ^ 641106 : 641175 641079 sE 641125 B 641186 Q, 641052 0 641140 641135 s 641174 s 641107 S 641072 641053 641168 & 641084 S 641154 s 641085 641105 641215 a 641123 OS 641101 641165 641083 641159 533.1 473.4 777.3 531.1 615.4 539.9 488.2 787.0 537.7 604.8 Day 182 517.0 470.9 764.5 515.4 586.9 502 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIV:IDUAL BOE>Y WEIGHT S(g)0]FWO.E RATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 D Male, III - 50 nig/kg/day 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 240.1 254.2 261.4 253.6 246.8 268.7 259.4 242.4 238.3 280.3 238.2 234.5 252.1 261.9 264.5 276.9 263.9 230.7 263.0 228.0 279.5 241.9 251.7 229.0 249.7 260.4 252.3 279.6 282.1 247.4 264.2 235.1 269.6 267.1 245.8 277.8 292.7 309.3 304.0 294.6 314.8 317.6 303.3 285.4 340.1 287.5 259.9 293.3 324.4 305.3 327.0 300.4 276.6 319.7 270.7 341.0 291.3 304.5 277.3 301.1 327.5 298.9 354.4 334.7 296.6 315.4 298.3 313.4 333.7 303.0 316.5 335.5 363.5 347.1 344.4 352.0 371.6 371.2 326.9 386.1 323.7 285.3 327.8 388.5 349.3 381.3 343.4 327.0 373.2 309.2 395.0 332.8 343.4 327.6 349.9 391.3 334.9 419.4 379.0 347.7 371.9 347.0 358.9 388.2 353.2 357.7 368.2 409.3 391.6 373.0 390.0 422.7 426.5 358.2 444.7 364.1 312.6 369.6 457.9 398.9 431.5 385.3 371.7 414.5 350.5 429.8 367.1 380.8 363.1 389.8 439.7 383.3 478.3 418.6 388.8 422.2 393.1 390.7 434.9 400.6 389.4 391.7 446.4 403.6 413.2 415.7 456.3 476.3 386.6 505.0 398.1 333.6 389.7 483.2 431.1 451.4 394.2 405.3 441.2 381.4 466.4 390.1 398.1 399.3 414.1 479.1 406.3 520.7 443.5 422.1 454.1 435.7 413.2 476.3 435.2 415 .1 416 .4 476 .6 438 .9 440 .5 438 .6 485 .8 517 .0 415 .3 525 .4 414 .1 368 .7 425 .8 532 .7 465 .7 483 .6 428 .0 437 .7 471 .6 414 .3 441 .3 432 .8 433 .1 437 .1 450 .9 514 .6 450 .6 561 .4 482.4 461 .2 488 .5 478.4 461 .7 521 .8 469.2 431.0 442.0 494.0 467.8 456.2 454.7 505.8 551.7 438.0 549.8 425.4 389.9 441.6 563.5 481.5 501.3 451.2 465.3 501.4 430.7 485.2 449.5 448.2 460.2 474.7 547.7 489.2 586.3 490.3 475.1 516.9 502.1 481.0 535.8 495.1 445.2 448.5 508.5 485.9 474.0 473.8 524.1 561.4 453.6 563.4 443.8 417.0 464.7 590.8 548.4 532.1 469.9 492.9 526.6 450.9 524.0 468.8 472.5 486.7 493.0 564.3 530.9 604.8 503.7 496.5 541.8 522.8 506.2 562.5 520.3 503 ws 0 3 , <B J~ " ( 3 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 69 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 459 .3 461 .7 552 .1 527 .3 515 .5 500 .0 554 .8 609 .9 490.2 614.3 470 .5 443 .4 482 .6 620 .3 544 .5 561.7 493 .7 545 .7 555 .3 471 .7 554 .4 488 .3 493 .6 510 .9 536 .6 608 .1 549 .6 603 .4 512 .4 . 520 .6 570 .5 570 .5 524 .1 583 .6 553 .3 572.9 497.8 566.8 578.3 481.0 558.4 502.2 496.6 525.8 552.1 625.5 565.7 602.9 529.7 529.1 582.7 584.2 522.2 596.5 563.5 INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 70 Day 77 Day 84 Day 90 Day 91 486.5 480.1 568.0 549.0 533.9 506.6 576.7 637.9 513.6 628.1 488.6 455.4 494.3 643.9 567.7 481. 0 477. 7 576. 2 561. 4 545.2 521. 3 588.7 658.4 512. 2 651. 4 496. 9 470. 1 504. 5 661. 8 586. 9 495.2 493.6 598.4 571.3 551.5 519.9 589.9 675.6 519.6 654.4 503.3 474.3 516.2 685.8 593.7 501.2 495.3 612.3 580.8 562.3 530.0 600.1 685.9 531.2 670.7 482 .4 481 .0 580 .9 560 .0 540 .6 507 .3 582 .2 653 .4 498 .9 652 .1 510 .9 476 .0 510.4 687 .8 610.3 Day 99 517.1 485.2 518.4 693.3 598.5 3 fS S> a 504 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 112 Day 119 Day 122 Day 126 Day 133 Day 140 Day 147 Day 154 Da Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 536.6 499.0 531.7 712.6 625.8 551.4 497.8 537.9 729.3 627.9 558.3 500.2 539.8 732.0 631.7 562.8 509.1 548.0 732.4 634.6 562.2 512.5 550.6 739.9 632.0 575.0 525.3 556.6 748.7 647.0 470.0 524.2 568.9 761.3 655.2 505 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 168 Day 175 Male, III - 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 50 ing/kg/day 563.7 538.0 579.7 767.7 673.4 587.3 547.1 589.3 785.6 695.0 INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 182 571.6 521.8 565.5 747.9 660.5 506 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Da Male, V - 250 mg/kg/day 641190 242 .8 300 .2 355.5 410.2 436.0 456. 7 485 .4 494.1 5 641134 246.4 282 .4 319.0 349.9 380.7 398. 7 416 .5 427.3 4 641202 261 .5 319 .5 363.5 407.6 448.0 472. 9 499 .0 519.3 5 641197 255 .5 301 .9 347.3 390.6 381.8 423. 9 445 .5 460.0 4 641200 244.5 302 .7 355.4 401.1 439.5 454. 1 478 .5 496.9 5 641061 262 .6 323 .0 359.0 394.9 438.7 457. 0 465 .7 498.8 5 641162 251 .7 288 .9 331.9 367.2 390.2 414. 5 430 .2 442.7 4 641089 231 .5 288 .1 332.3 365.0 403.1 425.2 432 .3 449.3 4 641137 248 .2 309 .1 359.3 388.3 437.8 452.2 465 .5 494.0 5 641102 276 .1 321 .6 375.1 407.2 427.4 447. 1 475 .5 488.8 5 641076 222 .1 267.2 300.8 342.4 360.1 381.2 389 .6 405.6 4 641090 234 .7 271 .6 309.8 334.9 353.6 371. 9 366 .3 358.1 641141 247 .1 304 .1 350.4 397.2 428.8 452. 3 370.5 434.1 4 641187 254 .2 313 .3 358.7 412.5 435.7 469. 1 472 .1 496.7 5 641148 270 .2 319 .2 357.7 400.0 431.1 456. 8 495 .6 497.6 5 641170 280 .0 327 .8 382.4 402.3 450.3 473. 7 516 .5 534.1 5 641065 258 .2 327 .3 374.2 401.5 432.5 438. 6 461 .4 495.0 4 641126 223 .2 267 .5 310.4 352.1 369.5 401. 7 422 .5 439.5 4 641058 245.3 296 .6 334.0 373.0 394.0 421. 2 431 .6 435.1 4 641131 236 .9 281 .1 333.2 378.5 396.9 429. 2 450 .6 471.9 4 641176 269 .2 315 .4 368.1 413.5 419.7 448. 9 471 .5 501.9 5 641119 238 .0 301 .0 355.6 408.1 444.3 467. 7 492 .9 518.6 5 641075 253 .2 313 .0 357.8 367.2 404.5 434. 1 467 .4 496.2 5 641180 239 .0 300.4 345.0 377.1 410.9 435. 0 458 .8 485.7 4 641117 256 .2 317.9 ' 371.3 424.3 473.6 502. 5 527 .4 547.9 5 641124 266 .2 329 .0 384.0 430.6 464.2 501. 7 528 .1 559.0 5 641082 247 .8 289 .4 330.2 366.0 394.2 416. 7 441 .5 453.3 4 641151 269 .5 324 .5 365.2 421.4 437.4 463. 9 484 .1 498.7 5 641195 271 .4 . 314 .8 372.4 410.2 453.6 479. 0 501 .4 522.1 5 641122 252 .0 312 .3 357.7 390.3 422.7 449. 1 465 .6 491.8 5 641184 2-63 .4 308 .7 349.8 386.0 401.9 434. 8 469 .0 469.7 4 641142 232 .3 266 .1 310.0 348.4 382.9 411. 7 438 .0 440.0 4 641120 275 .0 335 .4 392.2 442.2 473.5 505. 0 526 .9 540.8 5 641179 280 .6 347 .9 396.5 447.9 478.0 506. 1 531 .6 537.2 5 641164 250 .1 319 .3 370.1 415.9 446.0 469. 9 489 .5 532.2 5 " Animal number 641090 was sacrificed in extremis on test day 51. 507 ^ijy H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 63 250 mg/kg/day 525.6 453.4 559.0 503.8 517.1 549.1 491.0 492.0 525.1 518.3 422.8 482.2 529.6 520.7 572.0 502.5 482.3 456.8 500.7 536.6 560.6 541.3 521.1 587.3 587.6 479.2 505.2 564.5 528.8 489.1 463.0 572.0 589.5 552.7 Day 69 583.2 511.9 495.6 465.8 510.1 541.4 580.6 530.9 531.4 591.8 602.3 484.7 521.6 575.6 544.8 504.8 477.9 601.4 585.2 566.7 INDIVIDUALBODY WEIGHTS>(g)OPMALERATS Day 70 Day 77 Day 84 Day 90 Day 91 545.8 470.7 583.9 526.8 531.7 548.3 510.5 503.2 551.4 540.8 439.7 498.0 553.3 538.3 547.1 477.6 599.3 533.3 548.3 565.8 524.1 516.4 554.6 551.5 442.2 517.8 574.8 555.1 547.2 476.3 600.2 536.2 551.0 578.0 523.4 519.1 570.8 542.8 449.3 500.1 576.7 574.1 552.9 488.8 603.8 538.9 546.6 589.0 522.7 516.4 577.8 559.0 532.7 463.7 580.3 511.0 526.8 557.6 507.3 ' 500.7 547.7 524.6 451.3 504.9 565.8 564.0 Day 99 454.5 506.3 592.7 561.0 508 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS Day 112 Day 113 Day 122 Day 126 Day 133 Day 140 Day 147 Day 154 Da Male, V - 250 aig/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 478.7 541.5 634.9 591.5 492.5 558.7 645.5 598.6 497.1 576.6 643.2 610.6 505.9 590.8 660.3 613.8 506.2 599.7 665.5 620.0 518.9 608.1 656.3 628.8 511.2 621.6 676.1 638.5 509 |9 J 3 Q S 3 S 3 B? 5" ; S 0 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 168 Day 175 Male, V - 250 mg/kg/day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 524.9 627.8 687.7 651.3 530.6 633.6 686.3 664.3 INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 182 517.5 643.2 665.2 633.3 510 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OP MALE RATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Da Male, VII - 1000 nig/kg/day 641201 237 .8 275. 8 308.9 350.2 371 .6 405.8 422. 0 425.4 4 641095 249 .0 287. 4 320.3 352.2 376 .5 386.5 405. 8 421.3 4 641223 241 .5 287. 2 327.1 355.3 376 .5 395.6 417.9 420.0 4 641157 254 .3 302. 1 339.7 369.9 378.9 403.4 412. 8 412.0 4 641086 242 .8 294. 5 343.3 370.2 378 .8 416.6 438. 9 451.1 4 641067 263.3 304. 5 338.3 365.2 373.7 373.4 382. 4 398.5 4 641097 255 .9 299. 5 340.0 382.0 411 .1 420.5 441. 5 455.2 4 641132 239 .1 296. 1 343.1 393.1 401 .5 428.5 458. 8 461.9 4 641166 248 .6 291. 9 333.1 363.9 391 .3 416.3 432. 5 431.8 4 641077 273 .3 315. 1 360.6 398.2 412 .7 442.9 445. 5 452.4 4 641130 229 .3 269. 5 304.0 334.2 333 .9 365.3 373. 2 396.7 4 641057 241 .4 270. 2 300.3 311.2 341 .3 368.2 383. 4 398.4 4 641205 261 .8 318. 6 388.5 450.0 489 .5 530.5 555. 2 604.4 6 641196 245 .9 307. 9 368.1 426.0 462 .5 488.2 500. 1 527.9 5 641169 262 .6 309. 0 349.6 367.9 400 .1 425.9 447. 5 472.2 4 641110 284 .1 339. 0 388.1 446.8 480 .2 510.3 519. 2 510.9 5 641096 258 .5 298. 6 334.4 374.5 386 .5 415.5 431. 6 450.1 4 641212 218 .8 259. 6 297.0 325.6 357 .6 376.2 396. 8 425.2 4 641068 243 .2 293. 9 333.4 371.3 389 .6 408.4 425. 7 432.2 4 641093 233 .2 276. 9 316.0 347.6 374 .6 392.4 416. 8 418.1 4 641054 268 .5 325. 5 371.3 418.5 442 .6 474.9 491. 7 495.3 5 641208 222 .5 268. 7 304.5 330.3 334 .0 357.7 371. 9 387.3 3 641193 261 .3 319. 5 370.1 406.6 431 .8 456.1 472. 7 482.6 4 641207 238 .8 289. 7 354.2 404.2 449 .9 467.1 487. 3 499.9 5 641139 246 .6 307. 7 363.5 385.5 409 .5 433.7 445. 4 461.8 4 641080 255 .0 293. 7 335.4 365.8 381 .6 406.1 431. 0 457.3 4 641078 255 .3 284. 8 341.0 379.3 426 .3 452.5 475. 9 494.9 4 641177 284 .4 349. 1 397.8 451.8 486 .4 507.9 538. 3 575.3 5 641112 271 .7 324. 7 373.5 417.5 421 .2 449.2 464. 0 489.6 5 641210 252 .5 306. 6 354.7 409.9 441 .0 467.6 490. 0 515.3 5 641152 263.4 312. 5 350.9 388.0 410 .9 440.8 461. 9 464.5 4 641182 232 .1 279. 0 320.5 360.5 370 .6 410.5 417. 1 441.9 4 641150 248 .8 286. 3 314.2 336.4 360 .0 375.2 393. 5 419.9 4 641211 257.7 291. 7 334.4 364.0 384 .5 399.7 408. 6 416.1 4 641145 239 .7 293. 4 340.2 376.1 403 .1 430.9 447. 5 475.7 4 641185 256 .4 315. 3 360.6 389.5 422 .0 429.2 459. 3 483.5 4 641064 240 .1 294. 0 343.0 384.1 418 .2 442.8 453. 2 480.0 4 641216 258 .5 310. 9 361.2 391.2 428 .2 444.7 457. 9 477.2 4 641092 287 .0 346. 2 402.9 454.9 472 .6 514.7 534. 7 566.3 5 641167 267 .6 304. 7 357.0 393.9 432.2 457.9 466. 1 472.5 4 641189 229 .9 282. 5 322.3 371.1 390 .8 423.1 425. 8 443.0 4 641213 289 .0 336. 0 392.2 442.1 483 .3 526.6 561. 3 581.3 6 641153 235 .7 277. 5 308.6 340.5 365 .7 383.5 401.4 411.8 4 641203 271.4 311. 1 343.9 381.7 400 .3 427.8 439. 3 460.2 4 641143 264 .0 313. 5 365.8 422.2 462 .3 486.9 480. 9 512.4 5 511 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 63 Day 69 Day 70 Day 77 Day 84 Day 90 Day 91 Day 99 D Male, VII - 1000 ing/kg/day 641201 468.3 474.5 490.7 479.8 466.2 446.9 641095 449.4 459.1 472.6 425.1 440.4 422.6 641223 439.7 453.4 458.5 458.5 464.3 445.9 641157 433.8 451.0 457.7 447.2 449.1 420.2 641086 456.0 490.0 509.9 490.2 492.1 464.6 641067 418.7 441.6 448.1 441.9 442.3 426.5 641097 461.5 479.0 474.5 477.6 482.9 462.1 641132 493.3 514.8 521.0 510.0 510.3 490.9 641166 460.2 475.3 478.0 482.6 479.8 456.2 641077 486.2 498.3 499.2 508.9 519.8 499.5 641130 413.0 426.1 435.5 435.0 421.5 423.2 4 641057 402.2 411.7 419.2 400.5 417.8 430.7 4 641205 641196 641169 640.4 559.1 502.4 657.4 586.5 519.1 668.8 570.9 535.1 663.3 572.1 528.7 677.0 694.1 7 571.6 581.1 5 533.5 544.1 5 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 546.4 463.7 447.7 454.7 438.1 525.0 401.8 513.4 542.4 488.1 486.6 513.5 597.0 525.8 543.6 474.8 455.0 571.4 460.8 464.0 468.5 454.4 534.7 404.6 524.9 549.2 502.1 504.5 508.6 591.5 534.3 575.8 487.0 453.9 641150 641211 435.8 431.5 439.2 435.7 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 492.2 512.6 480.5 507.3 585.6 482.6 443.9 632.3 428.1 470.3 527.0 507.1 531.6 516.4 524.1 605.5 498.0 452.0 632.0 440.0 488.1 551.6 542.6 507.1 540.2 627.6 528.1 451.7 653.4 457.1 499.2 578.2 546.5 508.6 524.3 616.1 474.0 437.0 653.2 440.2 452.0 545.2 554.4 548.2 5 519.8 539.7 5 530.8 538.5 5 624.5 644.1 6 488.4 527.9 5 452.8 482.9 4 665.9 669.4 6 438.9 444.7 4 443.9 489.9 5 573.7 584.3 6 512 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 112 Day 119 Male, VII - 1000 mg/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 442.9 459.9 713.9 611.2 576.3 564.6 574.0 575.5 673.1 593.4 499.8 699.3 456.4 522.1 619.0 459.1 475.1 736.2 634.5 595.7 584.3 576.7 593.1 692.7 608.7 514.9 709.0 473.2 535.5 634.8 INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 122 Day 126 Day 133 Day 140 Day 147 459.5 489.3 749.8 639.0 593.4 474 .6 496 .8 767 .3 650 .1 602 .8 483 .0 507 .9 782 .0 644 .6 612 .1 489.4 513.7 786.7 649.4 621.3 564.2 550.0 567.1 686.9 591.5 509.5 699.0 459.1 518.5 614.1 513 Day 154 495. 5 522. 9 819. 5 658. 1 635. 7 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF MALE RATS Day 168 Day 175 Male, VII - 1000 ing/kg/day 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 504.3 539.2 838.5 671.6 653.9 513.7 553.4 849.6 670.8 660.3 Day 182 514.4 524.7 816.8 645.3 640.5 514 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVD3UALBODY WEIGHTS i(g) OF EEM^\LERATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Da Female, I 1-0 rog/ki?/day 641257 173.4 196 .8 220.3 236.4 241.7 262.7 270.8 274.5 2 641290 185.0 210 .9 231.5 260.0 290.1 295.8 312.6 319.9 3 641283 177.1 197 .8 216.0 232.5 259.1 263.5 288.2 292.3 3 641344 199.0 206 .8 234.2 251.8 260.9 254.8 277.3 281.0 2 641384 179.9 193 .3 220.2 230.1 257.5 262.0 264.1 277.4 2 641293 179.0 208 .7 230.8 240.7 270.2 270.2 270.1 278.8 2 641249 192.3 225 .4 253.0 284.4 315.7 353.8 354.0 347.9 3 641245 208.8 227 .2 252.9 269.9 279.9 280.4 280.2 293.1 2 641240 209.3 223 .6 275.7 290.2 309.8 322.2 348.2 350.6 3 641335 189.3 215 .0 225.5 246.4 256.6 267.9 279.7 276.6 2 641309 176.7 196 .5 216.2 221.4 249.9 256.7 256.2 264.7 2 641285 194.7 211 .1 223.8 232.1 262.9 270.2 278.7 280.0 3 641241 173.6 185 .5 191.6 211.6 216.5 238.6 239.2 256.3 2 641288 172.2 183 .1 222.3 234.3 256.1 255.0 253.8 278.8 2 641394 183.3 204 .3 214.1 236.9 257.2 256.9 262.2 250.6 2 641345 181.9 202 .5 215.1 220.7 241.8 254.6 261.8 264.8 2 641236 185.3 204 .3 223.0 242.7 258.0 261.9 270.4 273.4 2 641337 184.4 201 .8 216.0 240.3 262.2 274.6 292.0 290.3 3 641328 198.0 206 .1 238.2 256.9 276.4 284.8 306.3 298.7 3 641310 178.3 192 .3 209.1 225.1 242.0 249.0 260.7 274.5 2 641324 176.0 198 .8 206.0 230.1 247.4 251.3 266.5 281.5 2 641371 186.4 210 .7 221.0 244.5 274.4 280.8 293.2 299.8 3 641332 199.2 227 .0 249.5 257.7 281.2 285.1 299.0 299.1 3 641358 190.6 210 .3 234.. 3 250.9 265.0 266.7 284.6 289.7 2 641389 187.1 199 .5 216.2 234.6 263.4 278.4 278.4 287.5 2 641317 187.1 207 .4 232.7 241.0 275.8 273.0 284.4 314.1 3 641255 192.2 213 .6 239.8 255.6 . 274.2 272.7 291.4 298.4 2 641403 185.8 207 .2 233.0 249.6 263.8 285.2 304.7 307.6 3 641388 187.0 . 208 .1 229.3 241.6 272.1 291.1 302.8 307.5 3 641261 182.9 200 .8 218.9 229.6 248.6 252.6 268.0 263.0 2 641306 189.4 216 .6 224.2 244.1 264.9 265.5 281.4 282.3 2 641349 184.9 216 .8 227.9 261.1 290.8 282.1 284.0 312.7 2 641346 213.4 241 .4 247.4 270.3 317.4 305.5 312.9 323.3 3 641308 180.8 201 .8 221.9 224.0 247.2 235.6 258.3 246.7 2 641289 180.5 205 .2 210.5 230.2 253.9 263.1 276.1 284.0 2 641253 197.4 214 .4 248.0 276.0 277.7 308.6 309.5 334.5 3 641359 194.9 212 .2 221.1 241.2 272.4 260.0 263.3 280.4 2 641325 184.8 212 .2 229.4 244.6 257.6 275.8 284.1 288.1 2 641281 171.2 198.7 213.7 227.9 250.6 254.8 256.2 273.2 2 641294 198.6 226 .7 242.9 270.8 282.3 288.6 298.4 304.6 3 641383 197.8 211 .6 233.2 243.6 248.8 271.4 270.0 273.0 2 641364 194.8 229 .1 250.9 261.1 284.9 278.1 301.9 287.7 2 641331 188.0 218.4 233.4 , 244.8 266.1 280.4 274.8 297.1 2 641400 171.7 190 .8 203.8 208.3 228.0 241.8 242.6 266.3 2 641266 183.1 206 .6 219.5 230.9 262.2 268.3 272.1 288.9 3 515 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 69 Female, I I - 0 m 0/k(j/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 280. 8 346. 6 308. 5 282. 0 300. 0 289. 0 371. 1 305. 0 358. 0 289. 4 280. 6 291. 6 256. 8 282.3 287.2 265. 6 287. 9 306. 8 327. 0 270. 4 281. 8 311. 3 320. 9 293. 5 290.8 312. 7 295. 6 318. 1 333. 1 278. 4 300. 3 320. 5 315. 5 267. 1 304. 9 344. 3 287. 8 305. 3 274. 6 307. 3 276. 8 312. 2 295. 6 270. 5 300.4 261.5 281.5 321.5 337.6 278.2 292.8 317.2 321.2 299.3 296.1 319.1 295.3 331.0 346.1 282.9 294.5 321.7 315.8 271.9 297.8 INDIVH)UALIiODY-WEICrHTS (g) OP FEMALE R ATS Day 70 Day 77 Day 84 Day 91 Dai{ 92 291.4 359.6 317.8 291.8 306.6 298.2 373.6 312.5 359.1 304.4 275.2 299.1 268.7 288.4 305.4 295 .4 366 .0 325 .4 303 .0 299 .4 300 .8 360 .7 314 .0 368 .8 296 .1 289 .8 296 .1 260 .0 297 .4 313 .3 302 .6 378 .9 329 .5 310 .7 300 .0 314 .5 377 .8 307 .0 374 .0 310 .8 295 .8 304 .3 255.4 292 .1 311 .7 308.4 379.6 340.4 287.6 299.2 307.5 387.1 311.3 376.3 310.3 288.9 312.7 260.2 296.9 316.7 28!9.2 36'7.6 31i3.6 28().8 28fi.9 30:i.7 36().8 29().4 34i9.9 29(3.7 352.4 284.9 313.7 285.7 308.2 282.5 321.2 301.5 281.2 309.0 358 .0 299 .6 307 .1 293 .2 312 .5 288 .6 326 .2 307 .4 281 .7 315.7 368 .2 305 .0 317 .2 290 .9 328 .0 292 .3 328 .1 311 .5 290 .5 318 .5 516 366.4 307.2 318.9 286.9 327.3 296.1 327.2 320.5 282.3 321.0 Day 99 306.3 310.4 279.7 313.8 324.9 366.8 316.7 328.0 293.4 342.8 295.1 337.5 320.4 298.6 328.4 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVII)UALBOD^' WEIGHTS'(g)OFFEM.?\LERATS Day 112 Day 119 Day 123 Day 126 Day 133 Day 140 Day 147 Day 154 D Female, 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 I 1-0 ing/kig/day 303.9 326.6 279.1 312.6 344.8 308 .6 330 .1 290 .5 315 .0 311 .4 381.4 329.6 333.3 314.9 347.1 312.5 334.6 317.5 313.0 342.4 402 .0 321.7 333 .3 311 .9 347.2 315.7 331.4 324 .5 313 .8 355 .0 389.7 309.5 314.2 293.3 336.0 295.5 322.6 311.1 290.4 336.6 309.0 328.3 286.7 309.1 280.7 318.4 332.0 287.5 317.3 335.8 332.6 337.0 289.4 323.4 353.2 321.3 338.1 302.5 316.5 319.0 330.6 338.4 268.5 325.2 345.5 517 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 168 Day 175 Female, II - 0 nig/kg/day 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 334.9 345.6 295.2 330.7 352.3 346.3 351.2 302.5 330.6 359.7 INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 182 318.5 326.9 300.8 317.5 342.3 518 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIEUAL Bom' WEIGHTS (g)OFFEM^\LERATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 D Female, I V - 50 mg/:kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 185 .8 170 .4 189 .4 158 .9 187 .2 180 .1 178 .6 188 .3 204 .7 199 .7 190 .5 173 .1 183 .0 169 .5 159 .1 197 .7 178.3 184 .6 196 .2 195 .9 176 .3 173 .8 181 .1 195 .4 185 .0 184 .3 184 .2 200 .8 174 .3 169 .1 188 .5 201 .3 196 .5 199 .5 181 .9 216.7 187.2 216.2 191.1 217.3 188.5 194.3 214.0 236.8 209.4 202.0 187.2 197.9 195.9 190.8 206.0 197.6 204.3 209.4 214.6 190.6 196.0 222.6 231.0 ' 194.4 195.1 205.1 225.1 196.8 178.7 201.9 214.3 217.1 241.2 206.4 223.9 208.5 239.9 212.4 227.8 219.3 222.9 240.3 251.9 236.6 219.1 209.2 204.3 214.3 214.2 251.1 209.5 235.5 236.4 238.0 216.5 219.3 233.8 257.0 217.9 221.0 223.8 239.4 219.8 205.0 224.4 236.7 240.9 273.0 228.9 241.9 216.4 254.1 225.6 251.5 216.0 236.6 250.4 262.5 256.3 241.6 230.6 224.0 229.8 226.1 266.6 233.8 246.8 252.3 256.5 227.3 226.9 253.6 286.2 229.3 235.5 239.3 267.3 245.2 220.5 237.1 257.5 265.3 296.5 251.2 269.0 240.2 263.6 250.5 265.5 243.5 261.4 276.9 281.1 271.2 252.4 231.9 234.7 253.2 251.7 291.3 243.2 283.1 269.2 274.7 248.7 248.9 280.5 317.7 248.9 250.1 273.5 287.7 250.7 233.8 255.0 293.8 277.8 331.3 273.6 258.9 242.9 269.1 253.9 266.0 246.5 271.2 283.6 283.6 274.9 264.9 263.5 235.9 251.6 264.8 298.6 254.3 290.7 276.0 289.3 257.3 256.2 282.5 328.1 256.8 262.0 277.6 294.0 269.1 247.2 261.2 279.5 276.5 338.7 282.6 292.5 255.5 284.4 259.4 277.6 261.3 287.5 292.2 289.5 297.6 272.6 267.1 256.7 277.3 270.9 316.2 261.9 298.1 291.6 291.0 265.6 270.1 306.1 339.5 266.0 273.5 284.5 314.1 281.8 263.2 270.0 304.0 287.8 361.3 288.3 277.1 259.2 287.7 267.5 279.5 265.5 281.1 296.9 290.7 302.5 280.4 266.1 258.6 278.0 271.6 320.8 264.2 308.6 302.3 310.9 263.1 274.4 311.5 341.1 267.0 282.2 289.3 312.5 290.9 266.3 279.2 316.3 292.8 368.2 303.8 519 0' s 3 s ^5 OS ss is s? a. a 0 3 S, 0 Q 3" 3" 3 3 a H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 69 Female, IV - 50 ing/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 299.6 253.6 298.0 275.9 299.0 280.0 305.0 317.0 311.0 311.3 281.8 307.8 270.6 280.3 285.8 326.5 274.2 312.5 302.9 337.4 274.7 289.4 324.8 365.1 279.8 285.7 305.4 320.5 286.4 284.3 292.4 324.4 294.3 387.8 300.9 336. 6 274. 1 318.7 313. 5 348. 5 276. 3 301.4 316. 5 374.7 288. 5 291. 6 304. 8 328. 3 288. 5 288. 6 299. 0 323. 6 299. 6 381. 0 304. 5 INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 70 Day 77 Day 84 Day 91 Day 92 287.6 262.1 308.4 280.3 311.1 287.7 308.0 317.5 332.8 323.1 301.8 314.3 279.4 291.1 286.9 306.2 270.8 308.4 285.8 330.2 301.3 299.9 326.3 328.9 331.6 303.5 304.9 286.4 279.1 305.5 300.2 272.6 310.4 289.8 326.7 294.2 311.2 333.1 334.3 328.2 298.0 303.4 286.7 301.2 302.5 305.4 279.4 300.9 287.1 316.5 300.5 318.9 326.0 330.5 327.3 298.4 309.4 278.4 300.5 321.6 283 .3 266 .8 289 .8 276 .0 306 .0 281 .1 300 .5 311 .6 320 .3 309 .7 Day 99 315.6 295.8 286.2 312.2 328.5 520 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 112 Day 119 Day 123 Day 126 Day 133 Day 140 Day 147 Day 154 D Female, IV 50 mg/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 326.6 296.6 309.1 327.2 322.2 , 641263 641297 3 641304 5 641274 8 641351 J"S 641272 641258 641276 3 641350 j 641376 & 641315 0 641286 0 641231 (C 641338 3 641318 S 641373 641365 3 641348 I? 641323 3" a ."a > a s 332.1 305.2 316.9 321.4 325.4 336.8 298.8 317.1 329.0 326.0 349 .0 341 .0 318 .8 325 .3 336 .2 344.7 310.8 322.4 334.6 341.6 348.4 313.2 320.9 339.8 347.5 356 .2 307 .4 326 .1 344 .8 364 .9 521 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 168 Day 175 Female, IV - 50 nig/kg/day 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 361.6 317.9 332.0 344.5 347.6 375.2 336.2 338.2 351.6 339.0 INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 182 350.6 326.9 318.4 334.9 314.9 522 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 D Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 193 .0 175 .1 186 .0 169 .3 196 .5 186 .0 182 .6 176 .3 218 .5 211 .1 189 .2 169 .7 199 .9 173 .2 159 .2 181 .8 180 .8 179 .8 193 .0 195 .2 172 .8 173 .0 173 .9 204.2 175 .0 188 .5 195 .9 195 .3 200 .5 172 .8 194 .3 198 .3 184 .9 210 .7 195 .0 212 .1 185 .0 228 .6 192 .9 216 .7 206 .6 199 .4 194 .9 240 .8 253 .1 200 .4 182 .9 222.4 200 .4 178 .9 191 .1 197 .1 214.4 210 .7 228 .5 197 .5 192 .9 184.2 224 .8 195.1 212 .8 210 .8 215 .9 223 .6 203 .7 219 .5 225 .0 205 .1 222 .8 212 .3 243.7 208.8 249.3 205.8 242.2 220.8 210.8 215.5 259.0 263.5 214.3 214.4 246.8 246.8 192.7 213.4 217.5 232.3 233.4 245.9 218.1 218.9 183.0 245.3 208.1 243.8 244.5 239.6 246.6 219.7 240.8 242.9 222.9 252.9 229.1 269.5 226.8 286.6 214.4 267.3 238.4 231.9 223.2 278.6 299.0 240.3 230.7 281.9 231.7 207.8 230.1 241.2 259.3 248.4 275.0 235.2 232.2 203.0 263.1 219.3 265.9 275.6 264.7 262.2 235.6 260.7 276.5 233.8 277.1 254.4 283.0 240.5 270.3 228.0 282.3 253.7 248.5 243.4 302.8 317.6 247.9 262.3 283.7 247.6 212.2 255.8 254.2 263.6 259.0 297.5 262.4 251.2 214.9 287.9 237.5 275.8 304.9 281.7 287.2 248.8 275.7 290.3 246.4 293.4 265.7 293 .4 253 .8 300 .7 237 .8 288 .9 259 .4 255 .7 249 .8 315 .5 322 .6 245.9 265 .3 299 .4 248 .1 232 .8 269 .8 263 .4 283 .8 267 .4 307 .3 271 .4 269 .7 216 .5 295 .2 242 .9 294 .4 311 .1 289 .4 296 .4 253 .5 286 .6 301 .2 256 .4 286 .8 265 .3 280.9 260.1 311.1 232.1 304.0 274.3 267.2 259.1 335.4 332.2 260.9 280.1 303.9 254.3 242.7 286.3 279.2 290.4 278.0 319.3 277.1 282.2 234.7 295.2 253.9 300.5 322.3 300.6 305.3 261.3 292.7 305.8 264.0 306.4 266.1 292. 5 253. 8 317. 7 247. 0 301. 6 276. 8 279. 0 263. 6 337. 6 343. 8 271. 0 295. 8 311. 8 262. 1 243. 4 295. 5 281. 9 289. 5 273. 9 314. 9 294. 6 275.4 244. 6 302. 2 264. 6 308.2 350. 9 304. 8 325. 0 263. 3 295. 2 315. 7 274. 5 312. 9 283.2 523 Iliia ^^^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 69 Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 306. 5 278. 3 336. 7 262.7 315. 0 300. 1 288. 1 283.7 361. 0 362. 1 273. 6 299. 0 326. 5 274. 1 261. 5 300. 6 292. 0 313. 3 295. 6 321. 1 306. 4 299. 0 249. 3 301. 4 264. 7 319. 8 354. 1 328. 0 324. 6 274. 3 314.3 329. 4 283. 3 316. 1 289. 1 294.9 288.6 311.0 296.0 321.3 313.7 296.1 254.3 309.9 263.9 332.3 368.1 331.1 330.7 276.7 315.9 332.8 280.4 317.3 286.6 INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 70 Day 77 Day 84 Day 91 Day 92 322.5 285.7 313.7 271.7 336.6 305.9 294.0 287.9 374.2 368.6 285.5 314.1 329.8 276.5 267.8 321.7 273.2 329.7 277.9 334.0 303.6 307.0 285.8 391.8 367.4 283.1 332.2 338.8 277.1 260.3 318.7 284.4 354.6 282.2 328.1 323.2 309.0 291.0 402.0 372.8 293.8 332.8 368.2 281.4 257.5 323. 5 282. 8 351. 9 280. 5 335. 3 323. 5 305. 9 294. 6 405. 5 378. 5 284. 1 338.2 356. 0 282. 8 262. 9 306.3 265.9 331.1 265.9 320.1 300.4 295.5 284.6 387.9 355.6 Day 99 302.6 343.1 371.2 285.0 266.3 524 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 112 Day 119 Day 123 Day 126 Day 133 Day 140 Day 147 Day 154 Female, VI - 250 nig/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 306.3 308.1 641262 351.8 363.0 641232 385.4 396.4 0 641305 641372 295.5 277.9 298.1 293.3 641271 641280 *<< 641252 0 641386 OS 641277 S 641233 S 641238 & 641235 0 641392 0 641360 (D (9 641381 1 641333 641239 100 641228 641334 641347 I3" 641367 641303 641339 641316 0 1&- 314.0 364.4 396.6 298.4 301.7 320 .4 370 .7 400 .0 302 .8 315 .6 317.4 374.7 407.6 306.8 314.3 323 .7 377 .1 410 .1 311 .5 320.7 323 .4 390.7 410 .5 317 .8 323 .2 525 i-.-yi^. ^^^JS^SSS^S^SSSSS^S^.^^SSS^-S, H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 168 Day 175 Female, VI - 250 ing/kg/day 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 322.2 401.4 413.7 328.5 332.7 329.7 397.6 426.2 340.0 341.8 Day 182 305.5 374.5 410.8 320.4 317.3 526 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 D Female, VIII - 1000 ing/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 188 .7 160 .7 175 .4 174 .7 195 .2 173 .7 177 .1 189 .7 209 .9 218 .5 205 .2 179 .0 188 .6 175 .2 171 .8 184 .5 187 .4 172 .3 187 .3 195 .3 177 .0 183 .1 184 .6 191 .0 184 .9 186 .0 189 .5 191 .7 184 .9 . 177 .1 179 .2 201 .6 202 .2 198 .5 178 .5 180 .0 178.6 198 .0 177 .0 182 .0 201 .4 203 .8 184 .8 197 .8 179 .2 204.2 187.4 192.5 202.6 217.7 196.5 196.9 217.7 231.7 242.9 229.1 196.6 206.8 194.3 199.2 205.9 194.6 194.2 201.3 222.7 190.2 198.2 203.3 222.3 . 211.9 198.0 209.3 220.6 196.7 201.6 196.3 233.8 216.6 230.5 198.4 192.1 204.7 230.6 213.5 200.2 224.0 217.7 208.3 227.9 199.5 210 .1 199 .3 205 .9 228 .3 230 .0 200 .3 205 .6 243 .8 247 .0 259 .5 237 .8 220 .9 236 .6 217 .8 221 .8 221 .3 217.3 207 .6 217 .8 251 .6 203 .2 215 .7 222 .7 239 .1 241 .3 225 .0 232 .9 235 .2 213 .0 219 .1 209 .7 253 .0 238 .2 249 .3 216 .6 208 .1 223 .8 260 .9 228 .4 220 .7 249 .1 230 .5 225 .6 252 .5 222 .0 216.5 219.1 212.1 239.8 252.2 216.1 222.4 264.4 255.0 281.4 266.8 226.7 261.7 228.0 237.7 241.7 239.4 226.2 230.3 285.0 220.2 229.6 229.5 257.3 256.1 246.1 246.1 251.5 223.7 240.5 220.6 283.4 246.1 260.3 214.9 215.7 237.8 284.8 238.3 232.1 259.0 237.1 , 221.5 271.7 226.5 233.6 226.7 227.8 264.3 270.2 217.4 248.1 281.9 284.6 307.3 283.9 251.7 280.2 242.9 245.1 247.5 254.2 236.4 241.1 278.8 237.8 244.3 246.6 267.7 276.8 255.7 277.4 280.8 249.5 249.6 251.3 296.8 267.1 279.0 238.4 238.0 246.7 299.0 250.2 251.4 290.4 264.4 238.2 288.2 238.2 232.0 242.1 237.5 247.1 280.6 237.3 254.0 296.4 287.3 317.3 292.2 259.0 291.4 257.4 260.9 262.4 253.6 237.3 238.1 274.9 239.7 257.8 257.7 282.1 295.1 264.8 278.3 278.5 252.5 264.4 262.3 309.8 256.6 283.8 245.8 247.4 258.1 318.4 251.4 259.8 294.0 270.1 249.2 296.9 248.6 242.9 254.0 242.6 277.8 300.3 223.5 . 265.6 313.2 296.8 320.6 299.2 275.0 306.6 255.2 266.9 273.1 273.2 236.0 233.3 303.1 245.0 266.2 257.9 289.8 318.7 291.6 299.4 286.8 269.2 272.6 268.2 324.8 278.1 301.8 250.8 265.8 265.3 317.1 273.3 268.5 317.6 270.5 254.3 311.4 260.6 236.1 250.1 251.0 276.6 294.2 238.8 270.2 321.0 299.5 339.0 322.7 287.6 314.3 273.3 266.2 281.7 274.3 250.7 248.9 303.5 252.3 274.1 263.4 290.5 322.8 292.5 294.2 309.7 267.8 279.0 273.4 334.2 291.1 302.7 250.8 281.4 274.3 333.5 268.0 273.0 313.4 282.1 276.3 316.5 273.5 527 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 63 Day 69 Female, VIII - 1000 mg/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 245.7 253.5 256.9 293.5 307.7 245.3 285.8 329.1 312.4 365.3 313.8 306.4 330.9 280.3 276.2 293.1 282.5 257.8 255.4 315.3 263.3 283.4 272.5 300.3 337.2 291.6 324.8 313.5 263.5 . 279.9 278.6 337.9 302.1 310.3 258.4 282.1 283.3 347.0 281.3 279.3 342.9 288.2 295.7 328.6 285.3 309.2 292.7 262.5 260.5 318.3 266.5 286.2 264.9 320.5 352.3 304.6 326.5 314.5 269.3 287.3 275.4 342.0 302.5 318.9 258.9 INDIVIDUAL BODY WEIGHTS (g) OP FEMALE RATS Day 70 Day 77 Day 84 Day 91 Day 92 252.5 259.6 257.6 309.5 305.9 244.9 290.7 341.8 319.6 370.6 327.3 308.0 320.9 293.9 292.9 253 .5 262 .9 264 .1 303 .8 326 .1 234 .0 305 .8 358.3 319 .2 385 .8 324 .6 323 .5 328 .8 300 .7 301 .5 258.3 270.2 262.6 315.9 330.4 253.9 301.2 372.9 325.2 383.2 320.6 318.6 350.0 289.5 300.6 258.6 273.7 266.8 303.9 328.1 253.3 315.6 356.1 331.4 392.8 335.0 322.7 351.1 292.6 291.0 244.2 253.3 253.0 300.7 313.7 235.7 297.9 348.5 318.0 371.2 286.8 292.6 358.7 294.9 282.6 366.6 292.0 295.6 335.1 288.7 296 .1 300 .9 372 .9 283.2 291.1 367 .5 301 .0 . 302 .5 337.1 287 .5 298. 9 295. 9 375. 2 293. 8 286. 4 368. 0 302. 2 315. 9 338. 5 290. 0 528 302.7 302.3 385.9 297.7 290.9 365.5 304.7 309.5 345.4 281.3 Day 99 343.8 339.0 357.6 301.0 302.4 309.2 306.8 392.7 301.6 297.2 380.1 310.6 322.4 359.5 296.9 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 112 Day 119 Day 123 Day 126 Day 133 Day 140 Day 147 Day 154 Da Female, VIII - 1000 mg/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 360.2 349.1 365.2 318.0 311.9 365.3 358.9 368.6 322.0 312.0 361.2 369.0 373.4 332.6 324.7 387.2 373.6 368.2 334.6 327.8 398.8 379.9 379.9 336.0 329.7 411.7 383.4 383.2 337.9 328.6 423.8 385.6 402.3 350.0 342.2 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 334.2 317.0 438.0 311.1 307.9 319.0 322.5 339.7 363.6 308.6 342.6 318.2 440.1 311.8 307.0 342.7 329.2 335.1 358.7 313.8 320.5 301.2 414.9 301.3 288.1 303.5 310.1 342.2 293.4 " Animal number 641090 was found dead on test day 123. 529 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 168 Day 175 Female, VIII 1000 aig/kg/day 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 433.5 422.1 413.4 361.4 338.9 436.6 ^410.3 422.2 368.2 341.7 INDIVIDUAL BODY WEIGHTS (g) OF FEMALE RATS Day 182 409.8 381.3 392.3 349.6 325.9 530 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations_____________DuPont-4739 APPENDIX C INDIVIDUAL FOOD CONSUMPTION DATA 531 Cwfflpany SanRTzed. Does "nff e""s<' W*K fn\ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 INDIVIDUAL FOOD CONSUMPTION DATA EXPLANATORY NOTES Critical Dates Day 69 Day 83 Day 90 Day 91 Day 119 Male and female rats designated for reproduction evaluations were co-housed. Last day of food consumption data collection for these animals. Rats designated for the 3-month recovery period were temporarily housed in metabolism cages for urine and feces collection. Last day of food consumption data collection for these animals during the 90-day dosing period. Last day of food consumption data collection for male rats designated for the 90-day exposure period. Last day of food consumption data collection for female rats designated for 90-day exposure period. Food consumption data collection continues for animals designated for the one-month and 3 -month recovery periods. Last day of food consumption data collection for animals designated for the one-month and 3-month recovery periods. 532 KtB^aray^anRIzed. Does not contain TSCf^ ^ "WS "'11-24616: ;iubchronic Toxic;ity 90-Day Ga'rage Study in Rats with One-(Seneration R eproductive Ei/aluations Day 7 Male, I - 0 nig/kg/day 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 ... 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 26.8 25.2 29.1 30.1 31.4 30.6 26.8 27.4 35.0 26.9 25.0 26.0 29.6 25.2 26.9 34.1 32.5 27.6 28.3 19.3 32.5 27.1 28.9 30.1 26.0 33.7 29.6 a 34.4 27.2 28.8 27.9 29.8 29.3 27.6 26.3 30.8 29.9 31.9 28.6 28.1 31.3 26.5 26.1 27.3 I NDIVIDU ALFOOD<CONSUMEriON (g/da;^)BYMAL]ERATS Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 27.0 26.4 31.0 32.5 34.3 32.8 27.2 29.4 34.4 29.3 26.6 28.3 33.6 26.1 28.7 37.0 33.5 29.6 30.4 28.8 35.8 27.8 32.5 31.4 26.9 36.6 31.0 32.0 38.6 30.6 31.0 31.4 27.7 30.6 28.2 25.9 31.9 29.9 30.8 28.2 30.0 30.6 28.5 26.9 28.4 29.1 28.4 32.1 35.4 35.3 33.6 30.2 34.0 33.6 31.8 28.5 30.2 38.3 27.2 30.0 40.2 35.6 30.4 30.8 29.4 40.2 27.1 33.8 33.7 29.6 38.0 33.9 33.3 37.9 30.3 33.7 32.2 30.4 33.0 29.1 28.6 31.7 32.6 33.2 30.6 30.8 30.8 31.7 26.9 29.4 27.9 29.9 34.7 36.8 36.2 36.4 30.6 32.2 37.1 32.8 23.6 31.0 37.6 29.0 30.6 38.5 35.5 29.8 32.7 30.6 42.9 29.3 33.9 35.5 28.4 37.7 33.4 32.1 37.7 30.7 30.5 31.8 30.4 32.0 31.0 28.7 33.9 32.5 32.0 33.8 30.9 33.3 31.2 31.1 30.2 27.7 27.4 32.2 34.8 34.3 33.4 26.5 31.6 32.1 33.0 26.1 27.3 36.1 25.4 29.6 39.4 34.5 29.0 31.8 28.4 40.4 26.2 33.0 31.9 26.6 34.8 31.5 31.8 36.7 29.5 29.8 30.7 29.2 32.3 28.8 28.0 31.7 34.0 32.2 31.5 33.2 30.9 31.3 30.0 29.1 29.5 30.6 34.5 37.0 36.2 35.0 29.7 31.9 39.2 33.9 27.4 26.4 37.7 28.4 28.9 39.2 37.6 29.1 32.3 29.3 39.2 29.1 32.9 32.0 28.4 32.8 31.7 32.5 38.0 28.2 29.3 32,1 28.5 30.4 28.5 27.8 30.4 34.5 33.1 33.2 31.5 32.0 32.4 31.5 29.8 27.1 27.8 29.1 32.1 32.5 29.8 24.9 30.9 35..5 31.2 28.7 27.0 37.4 28.8 30.6 39.9 35.9 28.7 30.2 29.4 41.0 27.5 31.9 32.0 28.0 28.5 32.0 33.5 36.2 28.2 29.7 30.6 27.0 33.8 29.8 28.7 31.6 35.3 33.4 30.8 31.4 32.2 33.5 32.5 29.7 29.6 30.5 33.4 38.1 35.9 36.4 31.6 33.5 40.9 34.2 28.1 27.4 38.8 27.9 30.3 37.0 36.7 29.2 32.3 29.4 42.1 26.6 32.9 31.1 29.5 37.9 32.1 33.9 37.6 30.3 30.5 31.3 28.0 33.5 31.2 30.3 31.0 36.9 33.2 34.9 30.4 32.0 32.4 34.9 30.9 Day 63 30.6 30.5 33.1 37.8 36.6 35.6 30.2 34.5 43.8 35.2 25.9 22.0 33.3 25.6 28.9 37.5 38.9 28.3 32.7 29.5 43.4 31.5 33.2 30.1 28.8 37.6 28.2 32.1 36.7 28.9 29.5 32.4 28.3 28.3 29.0 30.3 33.1 35.6 35.4 34.4 29.8 32.6 33.2 34.2 30.5 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Day 70 Male, I - 0 mg/kg/d.ay 641149 641155 641222 641214 641069 641070 641147 641172 641206 641094 641098 641066 641115 641220 641104 641114 641217 641204 641158 641100 641060 641188 641106 641175 641079 641125 641186 641052 641140 641135 641174 641107 641072 641053 641168 641084 641154 641085 641105 641215 641123 641101 641165 641083 641159 30.8 27.3 32.7 37.5 35.8 36.4 29.1 32.0 41.9 35.3 29.4 29.2 36.6 28.1 28.7 28.9 33.0 35.7 32.4 32.9 31.9 31.6 32.8 33.5 28.3 Day 77 30.6 28.3 32.3 36.9 35.6 34.6 30.5 32.7 41.7 35.6 27.6 27.7 38.5 28.1 30.3 28.5 32.5 34.5 33.5 30.2 30.1 31.5 32.3 32.2 30.4 I NDIVIDUA.L FOOD CONS1UMPTION (g/day) BY MAL:ERATS Day 83 Day 84 Day 90 Day 91 Day 99 Day 106 26.5 24.0 34.3 26.1 30.0 29.2 23.6 30.9 35.0 35.3 34.0 28.0 30.1 40.1 32.7 30 .3 26 .2 30 .7 34 .6 36 .1 32 .0 28 .2 31 .3 41 .1 33 .6 28.5 23.7 31.9 27.8 28.6 29.7 24.2 36.1 25.9 27.7 28.9 33.7 30.7 32.3 34.3 29.3 31.8 32.5 32.0 30.1 28.1 31.9 33.7 33.4 29.3 26.9 29.9 32.6 32.3 30.6 26.5 32.7 31.9 30.0 33.1 28.0 27.4 29.7 30.3 28.0 24.1 34.2 31.9 31.5 34.1 29.3 29.4 33.5 32.5 30.6 Day 112 27.0 23.8 38.2 25.2 26.5 23.6 33.7 33.5 30.8 31.1 28.8 29.2 31.2 32.1 29.5 534 --fe H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations I NDIVIDU ALFOOD<SONS1JMFriON (g/da]^)BYMALjERA1rs Day 7 Day 14 III Male, 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 - 50 :nig/k'g/day 26 .6 27 .0 28 .4 27 .1 28 .7 28 .3 30 .1 27.7 25 .5 32 .1 28 .2 23 .2 28 .9 31 .2 28 .9 30 .6 28 .2 27 .3 31 .2 24 .2 28.7 27 .6 28 .9 27 .0 28 .8 32 .8 26 .7 33 .3 32 .5 28 .3 27 .7 29 .5 29 .8 31 .6 29 .2 28.5 28.9 29.0 28.3 32.0 29.4 31.2 32.6 27.4 33.5 29.3 22.9 28.9 34.7 30.4 33.4 29.3 28.4 33.6 24.9 37.2 31.8 29.1 30.2 31.4 37.6 . 27.0 36.7 33.3 30.0 29.7 31.1 29.0 31.9 31.2 Day 21 31.2 28.4 31.7 30.1 30.3 30.1 34.2 35.1 27.1 37.8 31.2 25.3 31.1 38.6 33.6 36.8 31.8 31.7 34.6 28.2 37.0 31.6 30.9 30.5 32.9 39.5 30.4 39.1 32.9 31.7 32.1 32.3 29.3 33.1 33.5 Day 28 31.7 28.6 32.4 31.2 32.6 29.6 34.6 34.6 29.5 38.8 29.6 25.8 31.2 39.0 35.2 36.2 29.7 33.1 35.3 27.6 37.3 30.6 28.3 31.9 31.1 39.2 28.6 38.6 35.0 30.8 30.2 34.7 30.2 35.8 33.0 Day 35 31. 8 26. 8 32. 9 29. 7 30. 1 29. 2 33. 6 34. 7 29. 8 38. 4 28. 3 25. 9 32. 2 37. 9 35. 4 34. 3 29. 8 30. 7 32. 1 26. 2 24. 8 30. 5 28. 5 30. 6 30. 5 37. 1 29. 5 37.4 32. 5 30. 9 29. 2 32. 8 31. 3 35. 6 30. 6 Day 42 32.8 29.3 30.5 31.3 30.6 29.8 34.3 34.7 30.1 38.5 25.0 24.9 30.1 37.4 31.4 32.4 29.9 30.6 34.4 26.0 27.4 29.4 27.2 31.1 30.5 37.9 33.1 36.0 30.4 29.2 30.6 33.3 32.2 34.3 31.5 Day 49 28.8 25.7 28.7 30.1 28.7 29.8 32.3 30.9 26.2 33.3 25.3 26.0 29.2 37.5 31.1 35.6 31.2 33.3 34.9 27.1 37.5 30.2 27.8 31.8 31.0 36.7 31.2 35.9 31.8 29.1 30.2 32.9 30.6 32.9 33.2 Day 56 31 .2 25 .9 34 .9 33 .6 30 .0 30 .7 33 .0 32 .3 28 .8 36 .0 28 .0 26.3 30 .5 38 .8 34 .1 33 .6 30 .0 32.3 31.9 26 .9 31 .1 29 .4 28 .6 32 .3 32 .5 36 .9 33 .2 35 .7 31 .0 29 .8 31 .2 32 .3 31.7 32 .4 30 .6 Day 63 30.9 27.2 33.2 31.0 31.0 32.1 33.5 35.4 28.7 38.8 27.4 24.1 29.0 34.0 32.5 33.3 29.3 33.5 33.5 27.6 33.6 28.7 29.8 31.7 31.9 38.1 30.0 29.3 25.3 31.7 30.2 34.9 30.1 32.3 32.0 535 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Gteneration Reproductive Evaluations Day 70 Day 77 Male, III - - 50 nig/kg/day 641146 641218 641073 641056 641178 641055 641144 641198 641081 641224 641194 641059 641160 641113 641225 641087 32. 9 29. 6 32. 3 31. 1 31. 0 29. 8 34. 0 34. 0 31. 7 37. 1 29. 1 27. 6 30. 0 36. 7 33.1 30.2 27.6 32.4 31.8 30.5 30.8 34.2 33.6 29.7 39.8 30.3 28.2 29.5 36.9 35.3 641108 641118 641128 641091 641199 641209 641163 641129 641138 641103 641181 641171 641111 641062 641156 641173 641121 641074 641191 INDIVIDUFAL FOOD(CONSUMPTION (g/da:^BYMALERATS Day 83 Day 84 Day 90 Day 91 Day 99 Day 106 26.2 25.3 28.4 32.2 30.4 31.9 28.4 33.5 32.4 31.3 30.4 32.6 34.2 28.9 38.0 29.7 27.6 32.3 31.0 31.8 30.8 35.2 32.6 28.3 38.0 29.7 25.5 29.1 34.3 30.2 29.3 24.5 28.6 35.3 33.5 Day 112 27.4 24.2 27.2 34.4 31.9 536 w - '^3aWy H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL FOOD CONSUMPTION (g/day) BY MALE RATS Day 7 Day 14 Male, V - 250 mg7kg /day 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 28. 1 23. 7 29. 0 26. 8 27. 6 28. 5 25. 2 25. 5 30. 3 27. 6 23. 8 23. 6 27. 2 28. 9 25. 9 28. 1 31. 7 23. 8 25. 9 24. 6 29. 2 27. 2 29. 7 29. 5 28.7 31. 5 25. 1 28. 7 27. 5 27. 7 27. 0 24. 6 33. 1 33. 0 29. 4 31.3 24.6 30.3 29.4 31.4 29.0 28.5 28.1 33.2 31.3 24.9 27.7 31.2 31.7 28.6 33.0 35.0 26.7 29.7 28.7 31.6 32.0 33.4 27.5 31.9 34.1 28.7 32.5 31.9 30.3 29.6 28.5 35.9 35.0 30.9 Day 21 34.0 26.7 33.3 33.0 33.5 29.7 29.5 28.9 32.9 30.4 27.5 27.9 33.2 32.8 30.2 29.1 33.4 27.8 29.7 30.6 32.7 33.3 31.5 31.8 34.9 33.8 30.1 36.9 33.0 29.8 30.6 28.9 35.6 37.4 31.7 Day 28 32 .2 27 .0 32 .7 24 .4 33 .3 32 .0 28 .8 29 .2 33 .4 28 .1 26 .7 26 .1 30 .9 32 .6 29 .0 34 .9 33 .2 28 .5 29 .3 28.2 28 .8 33 .6 31 .4 31 .0 33.7 33 .2 28.3 31 .0 33 .1 30 .9 27 .8 28 .4 33 .7 32 .5 30.3 Day 35 30.2 25.9 32.3 28.1 33.2 31.5 28.5 29.6 31.1 29.4 25.8 26.1 32.1 32.1 30.5 31.7 30.1 26.4 29.7 28.1 30.5 32.0 33.8 29.1 32.6 34.1 27.0 31.9 31.0 29.6 29.6 28.7 33.9 32.6 28.9 Day 42 31 .1 25 .6 32 .3 29 .6 31 .5 29 .1 28 .2 29 .1 30 .8 29.4 24 .5 25 .8 7 .7 28 .0 31 .6 36 .0 31 .0 25 .4 26 .7 27.2 30 .5 29 .4 33 .6 30 .9 31 .7 32 .2 26 .3 30 .5 ' 30 .7 27 .2 31 .4 29 .6 32 .0 34 .9 28 .4 Day 49 30 .5 25 .2 31 .5 28 .2 29 .0 30 .3 26 .4 27 .7 29 .6 28 .2 25 .3 21 .6 28 .1 32 .3 27 .6 36 .3 33 .9 26 .1 23 .4 28 .1 29 .7 32 .5 37 .6 29 .4 30 .9 33 .3 24 .4 31 .1 30 .8 27 .6 25 .6 27 .2 33 .4 30 .3 32 .6 Day 56 34. 2 28. 3 36. 0 35. 0 32. 3 34. 7 30. 9 33. 5 32. 8 29. 5 26. 8 35. 3 31. 0 27. 9 37. 0 32. 5 28. 1 26. 1 27. 6 31. 7 33. 5 34. 9 31. 6 33. 3 35. 8 25.5 32.5 30. 8 28.3 28. 5 29. 0 32. 7 32. 4 32. 0 Day 63 32.0 29.6 29.5 36.7 31.7 34.4 33.8 32.2 26.2 31.1 26.4 33.0 32.1 27.0 34.5 29.7 27.5 27.0 28.7 32.0 32.7 35.7 32.7 31.8 33.9 26.9 28.6 32.6 30.5 30.2 29.5 33.0 36.9 30.9 537 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, V - 641190 641134 641202 641197 641200 641061 641162 641089 641137 641102 641076 641090 641141 641187 641148 641170 641065 641126 641058 641131 641176 641119 641075 641180 641117 641124 641082 641151 641195 641122 641184 641142 641120 641179 641164 Day 70 25i0O mmogr//kkgcr//ddaayv 31.1 27.3 34.3 30.6 31.7 29.0 30.6 30.2 32.7 30.7 25.4 Day 77 28.5 27.1 33.0 29.3 32.6 31.7 29.5 30.7 32.7 29.6 26.2 29.3 30.6 27.9 28.5 33.3 29.8 INDIVIDUAL POOD CONSUMPTION (g/day) BY MALE RATS Day 83 Day 84 Day 90 Day 91 Day 99 Day 106 24.0 25.6 30.7 29.8 29.1 24.5 28.6 28.7 30.3 32.4 28.8 27.4 33.7 27.2 29.9 27.3 30.6 26.8 26.8 30.8 25.7 25.8 31.9 27.7 25.1 25.9 32.9 26.4 26.9 27.3 35.4 28.3 Day 112 28.1 29.6 36.0 30.2 538 ,,. .....,^^^^^.^..,..-.^-^--^ 11 ^111V H-24616: ;Subchronic'Toxicity 90-Day Ga vage Study:in Rats with Onei-Generation Repiroductive E'valuations INDIVIDUAI.FOODICONSUMETION (g/da]f) BY MAL:ERATS Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 Male, VII - 1000 mg /kg/day. 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 ^ 641196 641169 0! 641110 641096 iai 641212 641068 641093 641054 641208 641193 a 641207 a 641139 641080 0 641078 3" 641177 S 641112 S 641210 0 641152 > 641182 0 641150 a 641211 issa 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 24.8 26.4 25.7 28.3 27.8 29.4 26.8 26.0 25.1 26.6 24.7 23.3 31.2 28.1 27.1 30.8 25.8 23.4 26.4 24.3 30.3 24.5 31.4 27.8 31.3 27.3 23.5 34.6 32.1 30.8 27.3 27.9 27.3 25.6 26.7 30.5 27.4 30.3 33.1 28.2 26.6 30.4 26.2 29.4 34.5 26.0 27.7 27.5 28.8 29.2 29.0 28.3 28.7 25.9 28.6 25.9 23.5 37.5 31.1 29.0 34.0 26.9 25.5 27.2 27.6 31.1 25.9 33.5 31.2 34.2 28.9 32.4 35.0 33.7 32.0 28.0 29.5 26.5 28.1 30.3 32.3 31.5 34.1 33.2 29.5 27.3 34.8 25.4 28.2 35.1 26.9 29.5 27.2 28.1 30.0 29.0 31.4 31.6 28.1 29.7 26.5 19.1 41.5 32.8 28.3 35.5 29.1 26.8 29.5 28.5 33.8 26.3 34.1 33.9 31.5 29.8 35.8 37.4 37.7 35.7 30.5 31.2 27.3 29.7 30.7 32.5 33.7 30.7 36.5 33.7 29.9 37.6 27.2 31.1 37.7 28.4 27.1 25.7 23.7 26.4 26.5 30.1 27.4 26.9 28.0 22.5 25.9 40.9 32.2 29.4 36.0 27.7 27.7 25.0 27.5 30.7 23.4 32.8 33.7 29.5 28.6 35.2 35.7 30.8 33.3 27.2 24.1 26.5 25.6 30.2 28.6 32.6 30.8 29.2 29.2 26.5 35.6 26.6 27.5 37.2 28.8 26.7 25.6 26.4 27.7 24.1 27.8 27.6 27.7 29.1 23.6 24.0 40.3 31.9 29.8 36.8 26.9 25.5 26.4 28.5 31.4 24.2 28.7 31.1 31.1 27.0 35.8 32.4 30.2 33.8 28.8 31.3 25.4 25.9 29.7 24.6 32.2 30.5 35.9 32.7 28.6 35.6 27.5 32.3 35.7 28.8 26.7 26.2 25.3 27.7 23.4 27.6 32.0 27.0 25.4 23.6 24.4 39.9 28.7 30.6 31.4 27.0 27.3 27.3 28.2 32.0 25.1 24.3 27.5 27.4 29.3 34.2 31.9 29.3 30.7 27.7 25.8 26.1 25.2 28.8 32.8 31.5 29.3 35.3 29.5 24.4 35.3 28.1 29.8 31.7 25.7 26.4 24.3 23.7 26.0 26.3 23.8 26.6 24.5 25.4 26.7 24.6 42.1 31.1 30.4 29.2 27.9 28.7 27.5 28.3 31.9 25.7 27.5 28.0 27.4 30.0 33.5 34.6 32.4 32.5 26.2 25.4 26.4 24.8 29.4 31.2 31.8 30.8 34.9 29.8 24.8 35.0 26.5 29.0 35.8 29.1 29.5 26.1 28.1 27.3 28.3 26.3 30.0 28.9 28.6 24.9 24.8 40.8 32.2 28.9 33.0 28.3 28.5 27.4 26.8 30.9 25.7 33.5 32.4 25.9 29.4 31.6 30.4 33.5 33.1 26.6 29.1 25.9 25.5 26.8 30.4 33.7 33.7 28.3 32.1 24.9 37.7 25.0 31.9 30.3 Day 63 30.6 29.8 26.3 28.8 27.8 26.7 25.7 30.5 29.4 28.6 25.7 22.3 37.7 38.8 30.9 33.8 27.3 28.8 27.7 27.5 32.6 25.6 32.9 33.2 29.7 30.3 32.9 34.9 35.9 33.2 27.2 28.0 26.0 25.6 28.7 31.4 25.4 30.a 33.7 30.1 23.5 36.2 27.3 29.9 32.6 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Male, VII - 641201 641095 641223 641157 641086 641067 641097 641132 641166 641077 641130 641057 641205 641196 641169 641110 641096 641212 641068 641093 641054 641208 641193 641207 641139 641080 641078 641177 641112 641210 641152 641182 641150 641211 641145 641185 641064 641216 641092 641167 641189 641213 641153 641203 641143 Day 70 Day 77 1000 ing/kg/day 29.4 29.9 25.9 27.6 29.7 28.5 27.1 30.5 27.6 29.4 25.9 20.5 36.1 33.0 32.8 29.9 28.2 25.7 28.4 30.5 26.2 25.0 31.4 27.2 27.2 27.0 22.0 38.5 28.1 32.6 33.2 35.3 31.8 36.9 34.0 23.6 35.0 30.6 31.7 36.1 32.6 30.1 33.9 36.1 34.9 24.5 34.9 30.7 30.8 37.0 INDIVIDUAL POOD CONSUMPTION (g/day) BY MALE RATS Day 83 Day 84 Day 90 Day 91 Day 99 Day 106 24.7 22.6 33.4 26.2 33.1 27.1 24.4 25.9 25.9 25.7 25.6 25.0 28.5 25.5 28.9 29.4 24.6 26.0 25.4 23.1 23.6 25.3 27.3 23.1 27.6 23 .8 22 .9 37 .0 29 .3 31 .5 24 .9 24 .7 34 .2 31 .6 31 .9 31.4 32.4 30.6 35.7 24.1 21.8 34.2 24.7 24.6 29.5 29.5 31.6 29.1 28.6 20.5 25.3 33.4 23.6 12.5 29.6 28.4 30.9 31.2 35.5 38.5 29.0 34.4 26.7 35.8 35.0 30.3 35.9 34.7 36.9 36.7 25.8 36.1 25.9 33.8 35.6 Day 112 25 .1 24 .4 34 .9 32 .3 32 .5 30.2 34.6 33.7 33.0 36.0 25.4 37.7 26.6 31.5 32.9 540 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL POOD CONSUMPTION (g/day) BY FEMALE RATS Female, 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 Day 7 Day 14 II - 0 nig/kg/day 19.7 22.3 20.9 56.7 19.7 22.1 20.2 22.3 17.8 18.9 22.6 24.1 23.5 26.6 21.7 24.0 22.8 29.6 20.3 21.6 19.0 21.4 17.9 20.0 18.5 18.3 17.1 22.3 18.9 18.4 19.5 20.2 20.3 21.1 18.5 20.7 18.2 21.1 17.5 " 20.4 18.2 18.7 20.5 22.0 18.2 22.4 20.1 22.3 19.7 21.1 19.8 22.2 20.8 24.3 21.7 23.5 19.6 21.1 32.1 22.9 19.7 24.3 20.1 18.6 23.6 22.9 19.0 19.8 19.5 19.1 21.0 23.6 20.3 19.7 24.2 22.3 19.7 19.7 22.7 23.7 19.3 22.1 22.3 23.9 20.8 20.6 18.1 18.9 23.8 19.3 29.7 25.5 23.1 20.6 19.1 22.7 28.1 25.0 29.6 22.0 20.4 20.7 22.2 21.7 20.5 19.9 23.5 23.1 22.9 20.5 20.4 23.1 21.3 22.7 21.5 21.1 23.8 24.1 21.7 22.6 21.0 25.2 23.7 18.1 20.9 25.4 21.3 23.3 20.1 24.0 21.0 23.7 21.2 18.5 19.8 22 .1 27 .4 21 .6 20.7 21.2 16 .5 30 .0 25 .3 28 .5 21 .5 24 .3 23 .0 22 .9 19 .9 20 .9 23 .8 23 .8 24 .6 25 .4 20 .9 22 .3 24 .8 24 .3 22 .9 22 .3 21 .8 23 .6 23 .3 23.2 23 .0 22 .1 23 .9 26 .0 20 .8 21 .0 23.4 21 .7 25 .3 22 .3 25 .7 22 .6 28 .7 23 .4 20 .4 '23 .1 21 .5 24 .0 23 .9 18 .8 21 .3 22 .3 31 .8 21 .8 28 .0 20 .2 20 .6 20 .9 22 .9 20 .7 20 .8 20 .9 23 .9 23.7 23 .6 19 .8 19 .4 24 .7 21 .1 21 .7 22 .2 20 .5 22.2 24 .3 22 .8 22 .5 21 .2 21 .7 22 .8 17 .9 19 .6 23 .6 19 .7 25 .6 19 .3 23 .8 22 .6 22 .2 22 .8 24 .1 21 .5 22.1 25.7 26.2 22.3 21.0 20.3 32.0 23.2 32.3 21.1 21.6 22.4 22.7 21.7 21.8 21.4 22.5 24.1 25.7 20.3 21.0 23.2 22.7 21.6 21.5 22.2 22.8 24.6 23.5 23.7 22.0 22.3 24.3 21.1 21.8 24.0 22.6 23.3 21.4 24.3 22.5 26.3 22.5 21.3 22.1 19.3 22.2 23.2 17.9 18.0 18.2 22.3 19.3 24.7 18.0 22.1 20.1 22.9 22.4 12.3 20.2 18.5 19.1 22.0 19.6 20.0 23.5 21.6 20.0 20.2 22.9 22.5 23.1 21.5 21.8 20.6 25.2 22.7 18.1 20.8 24.0 21.0 23.5 21.3 24.7 21.5 24.4 22.3 21.9 22.1 19.9 25.7 25.2 20.9 24.9 19.5 30.1 21.0 25.4 19.9 21.9 21.7 23.8 20.6 23.4 18.9 21.2 24.0 23.6 17.8 20.1 21.5 21.6 19.8 20.1 22.7 20.6 23.4 20.6 23.0 19.4 21.4 22.6 20.5 19.7 22.8 21.3 24.1 18.3 24.3 22.3 21.6 21.0 20.0 21.6 20.8 25.9 24.9 20.8 22.6 21.4 30.3 23.4 26.6 19.9 19.7 19.1 24.5 22.9 21.0 18.9 21.9 22.5 24.7 18.3 19.4 22.3 21.4 22.3 19.5 20.7 20.9 23.8 23.4 22.3 23.1 23.0 22.3 19.8 21.6 22.4 20.5 25.5 20.0 23.5 23.7 26.9 21.1 21.1 22.0 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL FOOD CONSUMPTION (g/day) BY FEMALE RATS Female, 641257 641290 641283 641344 641384 641293 641249 641245 641240 641335 641309 641285 641241 641288 641394 641345 641236 641337 641328 641310 641324 641371 641332 641358 641389 641317 641255 641403 641388 641261 641306 641349 641346 641308 641289 641253 641359 641325 641281 641294 641383 641364 641331 641400 641266 Day 70 Day 77 II-O ing/kg/day 19. 6 27. 2 25. 3 20. 0 22. 2 21. 8 25. 7 22. 2 26. 8 21. 0 20. 3 20. 8 24. 2 22. 0 21. 3 18. 6 24. 2 26. 4 19. 2 17. 5 19. 0 24. 7 20. 5 26. 1 18.3 23. 6 20. 1 23. 0 23. 2 22.4 24. 6 21. 3 26. 2 22.2 26. 2 20. 6 23.7 21. 7 22. 1 20. 7 23. 9 23. 0 22. 2 20. 8 23. 7 22. 1 24.9 21. 9 20. 7 22. 4 Day 83 22.0 20.7 22.5 19.8 22.7 Day 84 21.2 25.1 26.4 20.8 19.6 23.0 24.9 20.6 25.3 21.0 26.0 22.3 23.0 20.3 26.3 22.5 24.4 23.0 21.8 23.2 Day 91 19.9 23.6 25.5 19.0 17.9 21.5 28.2 21.9 26.3 20.2 20.7 20.4 23.4 19.7 22.4 22.6 23.5 23.5 19.2 20.6 Day 99 Day 106 Day 112 Day 119 24 .5 20 .5 28 .1 24 .1 23 .5 21 .9 18 .9 24 .3 20 .7 26 .4 21.1 22.2 25.2 22.2 23.2 21 .5 22.7 26 .6 22 .0 15 .9 22 .0 24 .1 23 .9 21 .9 27 .1 21.4 22 .9 21 .2 21 .3 22 .1 25 .0 22 .1 24 .8 23 .1 24 .2 23 .8 23 .9 21 .7 20 .9 22.4 23. 2 21.2 22. 8 24.1 25. 9 24. 5 22. 1 18.0 22. 0 21. 5 26.4 20.5 24.3 22.4 24.9 22.4 21.1 20.8 20.6 23.1 542 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Female, 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 Day 7 Day 14 IV - 50 ing/kg/day . 19.6 16.8 20.1 18.6 19.9 17.7 18.5 20.1 21.6 18.9 19.2 18.8 19.2 19.9 18.9 20.0 20.3 20.8 21.3 20.6 19.2 19.5 23.1 22.8 16.2 19.5 21.2 22.5 19.8 17.2 18.7 20.8 22.0 23.5 20.6 2--0 . - 8 18.6 20.8 21.7 21.5 20.4 20.1 22.6 22.0 23.5 20.9 20.5 18.3 20.9 22.3 25.7 21.4 22.6 23.9 23.4 - 20.8 18.7 22.9 25.4 19.8 21.0 22.1 21.2 23.2 20.1 19.5 23.2 22.6 26.7 23.8 INDIVIDU ALPOODISONSUMFnoN (g/da:/)BYFE1VLVLERATS Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 20.7 19.3 21.0 21.5 22.7 18.2 19.9 21.1 21.5 21.3 21.6 22.7 19.9 22.6 22.2 23.8 21.9 22.2 22.4 23.6 21.1 21.5 26.0 26.7 19.1 21.6 23.1 24.8 22.0 19.4 19.5 22.3 20.8 23.9 24.6 23.7 20.3 23.4 26.0 25.0 18.6 24.0 24.8 24.0 23.2 21.6 24.4 20.8 22.4 24.8 27.0 22.1 29.8 23.7 25.8 24.3 24.1 25.7 27.7 20.2 22.6 24.4 25.1 24.3 21.2 21.2 26.6 22.2 28.4 24.4 22.0 19.1 21.1 23.8 21.5 20.0 23.3 23.4 21.4 22.4 20.8 23.9 19.2 21.8 23.6 26.7 22.8 25.3 23.4 24.6 21.7 23.1 24.0 26.9 19.3 20.8 22.4 23.9 24.0 20.8 20.3 22.5 19.7 25.5 22.5 25. 4 22. 0 22. 5 22. 2 25. 5 21. 8 23. 5 a 23. 5 24. 4 22. 1 25. 6 21. 7 24. 7 21. 7 24. 4 22. 2 23. 8 24. 1 23. 9 21. 5 24. 1 28. 5 26. 0 19. 7 22. 0 22. 5 27. 3 25. 3 23. 4 22. 8 26. 3 21. 8 26. 9 24. 3 19.9 19.0 20.0 21.1 23.0 21.9 21.5 21.7 21.7. 22.2 21.9 22.2 21.6 22.8 23.2 22.8 21.1 25.2 23.8 26.0 22.0 22.8 25.5 25.9 19.1 23.3 24.0 25.9 25.0 25.3 22.5 27.6 20.0 22.1 25.1 21.5 34.0 21.0 18.7 22.5 20.7 20.2 23.1 18.9 21.0 18.9 26.0 19.2 20.7 18.9 20.7 20.0 20.8 22.4 24.6 17.9 21.3 22.7 27.3 19.0 20.6 22.5 23.0 21.2 20.3 22.3 24.4 20.2 24.4 22.0 Day 63 26.5 16.9 23.2 21.9 26.4 21.4 22,7 24.9 25.1 22.4 20.7 25,7 20.3 22.8 22.8 24.0 21.3 20.6 22.3 27.1 19.2 22.6 26.2 26.1 19.5 21.9 26.1 23.8 20.7 23.7 23.5 27.3 20.1 28.1 22.2 ' Feeder misweighed. Data excluded from statistical analyses. 543 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL FOOD CONSUMPTION (g/day) BY FEMALE RATS Female, 641396 641369 641336 641355 641260 641312 641313 641311 641298 641361 641321 641391 641340 641247 641319 641378 641263 641297 641304 641274 641351 641272 641258 641276 641350 641376 641315 641286 641231 641338 641318 641373 641365 641348 641323 Day 70 Day 77 IV - 50 mg/kg/day 19 .0 21 .1 20 .7 22 .8 24 .9 20 .9 21.9 23 .0 25 .6 23.3 21 .3 24 .0 20 .6 22 .3 23 .1 24.2 21.6 19.7 21.5 24.9 25.7 21.3 24.6 24.1 24.8 20.0 22.4 21.4 22.4 24.1 Day 83 18.4 21.2 17.8 23.9 24.6 Day 84 21.4 22.5 20.6 22.1 24.9 20.1 23.7 22.6 23.0 21.7 Day 91 20.2 20.7 19.0 20.2 22.5 22.7 21.7 21.7 22.1 20.9 Day 99 Day 106 Day 112 Day 119 22. 4 18. 8 20. 5 25. 0 24. 2 23 .4 16 .3 19 .3 23 .4 21 .5 20 .6 17 .3 23 .5 26 .7 19 .6 23 .1 20 .0 22 .3 23 .9 19 .0 544 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Female, 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 Day 7 Day 14 VI - 250 ing/kg/day 20.2 17.1 23.7 18.3 22.2 19.3 17.9 19.8 21.4 24.4 20.1 19.0 21.4 19.7 17.0 18.5 18.8 21.1 19.8 22.4 19.4 19.9 16.6 23.1 17.6 22.4 19.6 21.2 22.5 19.5 23.2 20.4 19.9 22.9 21.6 22.8 19.0 22.9 18.8 23.8 19.4 17.0 19.0 23.4 24.6 20.2 22.1 17.6 20.1 19.0 20.1 22.8 22.8 21.8 23.1 21.0 23.4 14.9 25.6 19.2 25.1 24.3 23.2 23.4 21.4 23.2 22.9 20.5 24.6 21.6 INDIVIDUrALFOC)D'CONSUMFriON (g/da:/) BY FEM^\LERATS Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 23.8 19.5 26.6 20.0 24.7 20.1 17.9 18.7 23.5 25.0 22.1 22.2 23.9 21.1 19.6 20.6 22.5 23.6 20.1 25.1 21.2 23.3 19.0 24.0 19.1 24.8 25.4 23.9 23.8 20.3 23.9 23.8 19.3 26.0 21.2 24. 1 21. 1 22. 1 19. 5 25. 0 22. 6 20. 7 21. 3 25. 9 23. 5 31. 6 25. 5 21. 5 23. 8 20. 1 22. 6 21.4 23. 8 22. 0 26. 4 25. 2 26. 2 19. 9 26. 7 a - 22. 9 28. 2 24. 2 25. 6 a 23. 8 23. 1 22. 3 25. 4 22. 0 22.6 20.4 23.9 19.6 24.8 21.5 19.0 18.8 24.5 23.2 21.7 23.4 23.1 21.3 21.1 24.5 21.5 23.6 20.0 23.8 21.8 24.4 17.9 26.3 19.1 23.2 24.9 22.5 22.6 18.9 24.4 22.1 20.0 22.8 19.1 21.5 20.8 24.5 19.4 26.8 23.0 20.4 20.0 26.5 24.0 24.2 27.2 26.0 23.3 22.1 25.0 24.2 24.1 20.4 24.0 23.9 25.1 20.2 23.4 20.1 23.8 . 27.1 24.7 23.4 20.9 24.3 23.6 21.4 24.9 21.3 19.7 17.8 22.2 18.4 21.4 21.3 18.9 18.6 24.7 22.6 17.4 25.6 24.1 22.3 16.6 25.0 22.3 24.1 19.8 22.8 24.5 21.1 19.2 23.7 20.3 23.1 27.4 20.6 24.0 18.1 19.3 21.5 20.9 23.4 21.5 22.0 21.2 22.9 18.2 27.2 24.3 20.2 21.2 25.2 21.0 20.8 24.7 23.0 21.4 24.0 22.3 21.4 23.5 19.6 19.2 22.3 23.1 17.7 27.6 19.8 25.7 24.2 25.4 22.1 19.2 23.2 23.2 20.8 22.6 18.7 Day 63 22.0 21.5 21.3 19.3 26.0 24.5 21.4 20.9 27.5 23.4 19.8 23.4 23.4 22.7 21.3 21.9 22.8 25.7 20.3 21.2 22.7 22.9 17.6 19.1 18.4 25.0 24.8 23.4 20.1 19.4 21.6 21.6 19.5 23.1 19.5 ' Feeder misweighed. Data excluded from statistical analyses. 545 ' -g ^ J J Q g 3 , J S" -1 w ^ Q H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL POOD CONSUMPTION (g/day) BY FEMALE RATS Female, 641398 641251 641292 641269 641379 641302 641244 641362 641363 641375 641382 641262 641232 641305 641372 641271 641280 641252 641386 641277 641233 641238 641235 641392 641360 641381 641333 641239 641228 641334 641347 641367 641303 641339 641316 Day 70 Day 77 VI - 250 ing/kg/day 22. 8 21. 2 20. 8 19. 1 28. 1 24. 4 20. 0 18. 8 26. 7 24. 5 22. 4 23. 5 23. 0 23. 5 21. 1 21. 1 19. 2 22. 8 20. 2 25.4 24. 3 20. 5 20. 5 29. 5 23. 7 21. 9 24. 0 25. 2 24. 8 19. 4 Day 83 20.6 26.6 25.1 21.7 18.9 Day 84 18.5 20.1 25.5 19.2 25.3 22.7 19.2 19.8 27.6 22.6 Day 91 18.9 17.3 24.3 18.9 25.0 22.3 18.9 20.7 25.4 23.8 Day 99 Day 106 Day 112 Day 119 22 .9 20 .8 25 .7 23 .4 16 .9 22 .1 23 .0 24 .7 24 .8 21 .1 21 .9 25.3 25 .3 24 .3 22 .3 21 .9 26 .1 26 .5 23 .0 24 .5 546 I y Q ^ J S" Q, g 3 , R 3r 3" -J ^ ^ y -- "% H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations Female, 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 Day 7 VIII - 1000 20 .7 19 .1 18 .8 21 .3 21 .5 20 .8 19 .4 22 .5 22 .4 21 .5 23 .1 19 .0 21 .2 19 .0 19 .6 19 .7 18 .9 18 .4 18.1 20 .5 18 .5 20 .2 19 .3 20 .7 19 .1 18 .6 20 .0 22 .0 19 .7 19 .7 16 .3 23 .5 19 .7 23 .0 18 .9 17 .0 19 .5 23 .7 21 .0 17 .1 23 .8 19 .9 19 .8 21 .0 18 .9 Day 14 ing/kg/day 19.2 22.3 19.9 23.0 18.8 20.3 16.9 23.7 22.7 22.9 21.7 21.3 24.2 24.9 22.7 21.0 21.2 19.8 19.5 23.4 20.2 21.0 21.7 22.2 24.2 21.2 21.3 21.6 21.1 20.6 15.4 26.1 22.3 24.5 20.6 20.9 21.2 25.6 21.6 18.9 24.2 20.6 18.8 23.0 21.5 INDIVIDU ALPOODICONSUMPTION (g/da:^)BYFEM^\LERATS Day 21 Day 28 Day 35 Day 42 Day 49 Day 56 19.3 19.5 18.4 22.4 23.5 21.3 20.1 25.4 22.3 15.2 23.8 20.0 25.1 19.7 21.5 20.9 22.4 19.9 19.5 26.4 20.8 21.3 19.8 21.0 22.8 21.7 23.2 24.2 22.3 21.8 20.4 29.7 20.9 23.1 19.3 20.0 20.2 27.4 21.1 18.9 22.5 19.8 19.6 23.9 20.0 19.8 19.8 22.0 24.3 22.7 21.5 20.9 25.6 25.3 a 25.1 24.8 24.8 21.2 22.0 20.7 23.5 20.3 19.2 21.5 22.2 33.8 20.4 23.0 24.0 21.6 26.1 25.8 23.9 21.6 22.8 26.6 21.2 25.0 20.5 23.4 20.2 25.5 20.6 19.5 23.1 20.3 21.5 23.1 19.7 18.8 19.4 19.6 11.6 21.9 20.9 19.5 25.0 21.9 25.2 26.6 22.1 21.8 21.4 23.1 21.2 21.7 18.3 17.7 20.5 19.1 22.9 22.0 22.9 24.1 21.0 22.2 23.4 20.2 21.5 21.8 27.3 17.6 17.7 20.2 20.7 20.3 26.5 20.7 19.2 22.4 19.4 17.6 21.9 18.5 20.7 20.3 22.0 26.1 23.0 19.4 20.5 25.9 23.8 24.6 25.8 23.9 24.3 20.7 22.1 22.2 24.6 18.6 17.4 24.8 21.8 22.8 20.2 23.7 26.5 23.9 25.7 23.5 21.4 22.0 21.0 25.3 22.0 25.8 20.7 22.6 19.0 23.2 21.5 15.9 26.2 21.1 22.3 23.4 22.7 15.5 17.9 20.6 21.7 19.3 21.1 19.1 23.1 21.7 25.0 28.1 25.0 24.0 20.3 21.3 20.3 22.7 18.9 19.3 24.0 21.0 23.0 19.2 22.8 26.3 21.5 22.7 25.0 21.6 21.4 21.6 23.6 23.2 24.0 20.6 23.6 21.3 26.1 20.3 18.2 21.7 20.8 22.1 21.6 21.2 17.9 16.6 21.2 27.0 22.7 19.6 19.3 23.0 23.9 26.8 20.4 27.7 25.0 20.3 23.0 21.1 21.9 17.0 16.7 20.9 20.3 21.5 18.5 20.2 22.2 18.4 23.2 18.9 17.7 22.6 19.5 21.3 21.1 20.3 19.4 23.5 20.3 25.0 20.1 17.3 25.9 19.8 21.8 21.1 21.2 Day 63 18.0 19.7 19.9 52.8 21.6 21.2 21.6 24.1 24.3 26.5 25.4 25.8 24.2 21.0 21.2 20.7 22.0 18.5 17.4 19.9 20.1 20.3 15.8 21.0 22.3 18.4 19.3 24.5 18.5 20.8 20.6 22.7 22.2 24.4 18.8 20.0 19.1 23.9 20.6 18.2 25.5 19.1 25.0 21.5 21.0 " Feeder misweighed. Data excluded from statistical analyses. 547 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDU ALFOOD(CONSUMP'TION (g/day)BYEEMALE RATS Female, 641299 641275 641326 641380 641314 641237 641300 641279 641390 641327 641259 641264 641301 641395 641278 641265 641393 641402 641246 641320 641353 641401 641307 641368 641343 641254 641242 641284 641230 641273 641296 641248 641370 641243 641329 641385 641387 641282 641234 641256 641356 641352 641366 641399 641377 Day 70 VIII - 1000 19.0 21.0 19.1 26.8 22.6 21.5 19.6 24.6 22.1 24.8 25.5 25.7 20.4 21.0 22.5 21.9 19.6 25.1 21.8 18.6 27.9 21.0 25.0 23.1 22.7 Day 77 ing/kg/day 18.6 20.5 19.8 23.5 22.8 15.4 21.7 25.0 24.7 29.4 26.5 26.9 23.7 21.7 24.3 23.7 20.6 26.5 20.7 19.9 28.1 22.0 22.1 22.3 20.1 Day 83 24.6 22.8 23.2 20.7 20.6 Day 84 19.4 20.2 19.5 23.5 21.9 22.3 18.0 29.8 24.6 26.0 24.9 19.9 27.2 22.3 18.6 24.9 18.9 27.4 22.3 20.3 Day 91 18.3 21.4 21.1 22.8 24.1 22.8 20.0 22.7 22.9 27.5 24.3 20.5 25.6 21.1 18.5 23.5 19.1 21.8 21.9 19.7 Day 99 Day 106 Day 112 Day 119 28.0 26.6 24.0 21.2 23.1 27.9 26.7 23.0 21.0 22.8 25.2 26.5 24.7 21.6 22.1 27.4 26.4 24.7 22.7 21.7 25.1 21.0 29.0 22.4 20.5 27.9 22.2 26.8 30.6 21.7 26.0 20.4 30.7 21.6 20.4 28.4 23.5 24.0 22.5 22.3 25.2 20.6 33.2 21.5 20.6 9.3 20.9 23.2 21.2 21.2 27.1 20.0 33.0 21.7 19.7 18.5 21.3 21.8 21.1 22.1 548 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations __ DuPont-4739 APPENDIX D INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA 549 .CMBpanySanHfeed. Does mil obtain raCA CBI H-24616: Subchromc Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations DuPont-4739 INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA EXPLANATORY NOTES Critical Dates Day 69 Male and female rats designated for reproduction evaluations were co-housed. Clinical observations collected during the cohabitation and post-mating periods are reported in the Reproductive Toxicology section. Day 91 Male rats designated for the 90-day exposure period were sacrificed. Day 92 Female rats designated for the 90-day exposure period were sacrificed. Days 122 and 123 Male and female rats designated for the one-month recovery period were sacrificed, respectively. Day 182 Male and female rats designated for the 3-month recovery period were sacrificed. Any clinical sign observed on consecutive data collection days is assumed to have been present during the interim between observation days, and will be reported as having been observed over the period from the first-last day observed. Ophthalmology Evaluation observations and Clinical Pathology Evaluations are documented as Clinical Observations and interrupt the continuing clinical observations. All ophthalmology observations from test days 88 or 116 are those observed during the examination by the veterinary ophthalmologist. 550 Gmpsasy Sanitized. Does not contain TSCA CB! H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal Observation Days 641149 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for din Path, Left No Ophthalmological Abnormalities Detected 44,91 88 Sacrificed by design 91 641155 General observation, No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 44,-91 88 Sacrificed by design 91 641222 General observation, Mo Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Lett 44,91 No Ophthalmological Abnormalities Detected 88 641214 Sacrificed by design General observation, No Abnormality Detected 91 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 641069 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 641070 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 551 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M I 641147 641172 641206 641094. Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for din Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Face, Left Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Foreliirib, Bilateral Hair Loss,'Side, Right Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42,49-84,90-91 44,91 88 91 0-42,49-70,90-91 44,91 88 77-84 91 0-14,90-91 44,91 88 21-42,49-84 56-84 91 0-42,49-84,90-91 44,91 88 91 552 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days M I 641098 General observation. No Abnormality Detected 0,7,14-35,42-56,106,119,126-182 Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right 36,78,90,106,120,133,154,175 1-4,10,21,57,93-99 Discharge, Nose, Black 77,84,91,99 Discharge, Eye right. Black Wound, Superficial, Nose Sacrificed by design 63-77,84,91,99 112 182 M I 641066 General observation, No Abnormality Detected 0,7,14 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120,133,154,175 Eye Observations, Bled via Orbital for blood fluorine. Right Hair Loss, Forelimb, Right 1-4,10,57,93-99 175-182 Hair Loss, Forepaw, Bilateral 70-77,84,91,99-119.126-182 Hair Loss, Forepaw, Right 28-35,42-56,63 Wound, Superficial, Forepaw, Right 21 Sacrificed by design 182 M I 641115 General observation, No Abnormality Detected 0,7,14-35,42-56,63-77,84 Eye Observations, Partially Closed, Left 175-182 Eya Observations, Enophthalmus, Left 126-182 Eye Observations, Exophtbalmus, Left 91,99-119 Eye Observations, Bled via Orbital for blood fluorine, Left 21,36,78,90,106 Eye Observations, Bled via Orbital tor blood fluorine. Right 1-4,10,57,93-99,120,133,154,175 Eye Observations, Comeal Opacity, Lett 99-119,126-182 Discharge, Eye left. Black Sacrificed by design 91,99-119,126-140 182 553 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M I 641220 M I 641104 M I 641114 M I 641217 M I M I M I 641204 641158 641100 Observation General observation. No Abnormality Detected Eye Observations, Enophthalnnis, Right Eye Observations, Bled via Orbital for blood fluorine. Bilateral Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Eye Observations, Comeal Opacity, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for din Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Sacrificed by design General observation. No Abnormality Detected Hair Loss, Forepaw, Bilateral Removed from study General observation. No Abnormality Detected Vocalization Removed from study General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study Days 0,7,14-35,42-56,63-77,84,91,9 106-119,126-147 93 21,36,78,90,106,120,133,154,1 1-4,10,57,99 106-119,126-182 182 0,7,14-35,42-56,63-77,84,91,9 21,36,78,90,106,120,133,154,1 1-4,10,57,93-99 182 0-14 21-69 69 0-7,21-69 14 69 0-69 69 0-69 69 0-69 69 554 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days 641060 General observation. No Abnormality Detected 0-69 Removed from study 69 641188 General observation, Mo Abnormality Detected 0 Hair Loss, Forelimb, Bilateral 63-69 Hair Loss, Neck, Ventral 14-56 Wound, Superficial, Neck 7 Removed from study 69 641106 General observation, No Abnormality Detected 0-63 Wound, Deep, Tail 69 Removed from study 69 641175 General observation. No Abnormality Detected 0-69 Removed from study 69 641079 General observation, No Abnormality Detected 0-69 Removed from study 69 641125 General observation. No Abnormality Detected 0-69 Removed from study 69 641186 General observation. No Abnormality Detected 0-69 Removed from study 69 641052 General observation. No Abnormality Detected 0-69 Removed from study 69 641140 General observation. No Abnormality Detected 0-69 Removed from study 69 641135 General observation. No Abnormality Detected 0-69 Removed from study 69 555 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal 641174 641107 641072 641053 641168 641084 641154 641085 641105 Observation General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Retina, Retinal Degeneration Focal, Left Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88 116 122 0-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88,116 122 556 w H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M I 641215 M I 641123 M I 641101 M I 641165 M I 641083 M I 641159 Observation General observation. No Abnormality Detected Hyperreactive No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Ho Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42 49-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88,116 122 0-84,91-112,119-122 88,116 122 0-84.91-112,119-122 88,116 122 557 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M III 641146 M III 641218 M III 641073 M III 641056 M III 641178 Observation General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 558 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M III 641055 M III 641144 M III 641198 i M III 641081 M III 641224 Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Urine, Present Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Retina, Retinal Degeneration Focal, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-7,21-42,49-84,90-91 44,91 88 14 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 559 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M III 641194 M III 641059 M III 641160 M III 641113 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine. Right Water nipple not working well Missed Water Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design Days 0,7,14-35,42-56,63-77,84,91,99-1 126-147,161-182 21,36,78,90,106,120,133,154,175 1-4,10,57,93-99 154 154 182 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154,175 1-4,10,57,93-99 182 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154,175 1-4,10,57,93-99 182 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154,175 1-4,10,57,93-99 182 560 im--s" H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days M III 641225 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left 0,7,14 21,36,78,90,106,120,133,154,175 Eye Observations, Bled via Orbital for blood fluorine. Right 1-4,10,57,93-99 Hair Loss, Forelinib, Bilateral 140-182 Hair Loss, Forepaw, Bilateral 21-35,42-56,63-77,84,91,99-119,1 Hair Loss, Neck, Right 21-35,42-56,63-70 Sacrificed by design 182 M III 641087 General observation, No Abnormality Detected Removed from study 0-69 69 M III 641108 General observation, No Abnormality Detected Removed from study 0-69 69 M III 641118 General observation, No Abnormality Detected Removed from study 0-69 69 M III 641128 General observation, No Abnormality Detected Removed from study 0-69 69 M III 641091 General observation. No Abnormality Detected Removed from study 0-69 69 M III 641199 General observation. No Abnormality Detected Removed from study 0-69 69 M III 641209 General observation, Mo Abnormality Detected Hair Loss, Forepaw, Left 0-21,69 28-63 Removed from study 69 M III 641163 General observation. No Abnormality Detected Removed from study 0-69 69 561 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUALC'LINICAL AND OPHTHALMOLOGICAL OBSER;VATIONS AND MORTALITY DATA FO Sex Group Animal M III 641129 Observation General observation, No Abnormality Detected Removed from study Days 0-69 69 M III 641138 General observation, No Abnormality Detected Removed from study M III 641103 General observation. No Abnormality Detected Removed from study M III 641181 General observation. No Abnormality Detected Removed from study M 641171 General observation, No Abnormality Detected ? III Removed from study M III 641111 General observation. No Abnormality Detected 1 Hair Loss, Forelimb, Bilateral 1 Hair Loss, Forelimb, Right Removed from study 0 III M 641062 General observation. No Abnormality Detected w Removed from study III M 641156 General observation. No Abnormality Detected a & Hair Loss, Foreliirib, Right 3 a Removed from study III 5 .w M 641173 General observation, Mo Abnormality Detected 0 s, Removed from study M III 641121 General observation. No Abnormality Detected Removed from study 0-69 69 0-69 69 0-69 69 0-69 69 0-14 49-69 21-42 69 0-69 69 0-63 69 69 0-69 69 0-69 69 562 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations_____________________________ INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M III 641074 M III 641191 Observation General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study Days 0-69 69 0-69 69 563 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal Observation Days M V 641190 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 M V 641134 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 M V 641202 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 44,91 88 Sacrificed by design 91 M V 641197 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 M v 641200 General observation, Mo Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 M V 641061 General observation. No Abnormality Detected 0-42,49-84,90-91 Eye Observations, Bled via Orbital for Clin Path, Left 44,91 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 91 564 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M V 641162 M V 641089 M V 641137 M V 641102 M v 641076 Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design Days 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0,7,14-35,42-56,63-77,84,91,99-1 21,36,78,90,106,120,133,154 1-4,10,57,93-99,175 182 565 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M V 641090 M V 641141 M V 641187 Observation Days General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Bilateral Eye Observations, Bled via Orbital for blood fluorine, Left 0,7,14 21 36 Eye Observations, Bled via Orbital for blood fluorine, Right 1-4,10 Hair Loss, Forelimb, Bilateral Hair Loss, Forepaw, Bilateral Hair Loss, Neck, Ventral 21-35,42-51 21-35,42-51 49-51 Wound, Superficial, Neck Wound, Deep, Meek 21-35,42-49 51 Sacrificed in extremis 51 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine, Right 0,7,14,91,99 21,36,78,90,106,120,133,154 1-4,10,57,93-99,175 Discharge, Eye right. Black 63-77,84,168 Hair Loss. Porepaw, Right 21-35,42-56,63-77,84,106-119,1 Sacrificed by design 182 General observation. No Abnormality Detected 0,7,14-35,42-56,63-77,84,91,99 126-182 Eye Observations, Bled via Orbital for blood fluorine. Bilateral 10 Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design 21,36,78,90,106,120,133,154 1-4,57,93-99,175 182 566 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation M v 641148 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design M V 641170 General observation. No Abnormality Detected M V 641065 Removed from study General observation. No Abnormality Detected Removed from study M V 641126 General observation, No Abnormality Detected Removed from study M V 641058 General observation. No Abnormality Detected Urine, Present Removed from study M V 641131 General observation. No Abnormality Detected Removed from study M V 641176 . General observation. No Abnormality Detected Removed from study M V 641119 General observation, No Abnormality Detected Removed from study M V 641075 General observation. No Abnormality Detected Urine, Present Removed from study Days 0,7,14-35,42-56,63-77,84,91,99-1 21,36,78,90,106,120,133,154 1-4,10,57,93-99,175 182 0-69 69 0-69 69 0-69 69 0-7,21-69 14 69 0-69 69 0-69 69 0-69 69 0-7,21-69 14 69 567 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days M V 641180 General observation. No Abnormality Detected 0-69 Removed from study 69 M v 641117 General observation. No Abnormality Detected 0-69 Removed from study 69 M V 641124 General observation. No Abnormality Detected 0-21 Hair Loss, Forepaw, Left Removed from study 28-69 69 M V 641082 General observation. No Abnormality Detected 0-69 Removed from study 69 M V 641151 General observation, No Abnormality Detected 0-69 Removed from study 69 M V 641195 General observation, No Abnormality Detected 0-7 Hair Loss, Forelimb, Bilateral Removed from study 14-69 69 M V 641122 General observation. No Abnormality Detected 0-69 Removed from study 69 M V 641184 General observation. No Abnormality Detected 0-69 Removed from study 69 M V 641142 General observation, No Abnormality Detected 0-69 Removed from study 69 M V 641120 General observation. No Abnormality Detected 0-69 Removed from study 69 M V 641179 General observation, No Abnormality Detected 0-69 Removed from study 69 568 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M V 641164 M VII 641201 M VII 641095 M VII 641223 M VII 641157 M VII 641086 Observation General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital tor Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Forepaw, Bilateral Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Sacrificed by design Days 0-69 69 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-21 44,91 88 28-42,49-84,90-91 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 569 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal M VII 641067 M VII 641097 M VII 641132 M VII 641166 M VII 641077 Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthaimological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 0-42,49-84,90-91 44,91 88 91 570 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal Observation Days M VII 641130 General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Discharge, Nose, Black 0,7,14-35,42 21,36,78,90,106,120,133,154 1-4,10,57,93-99,175 99 Hair Loss, Poreliirib, Left 49-56,63-77,84,91,99-119,126- Sacrificed by design 182 M VII 641057 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Bilateral 0,7,14-35,42-49,140-182 57 Eye Observations, Bled via Orbital for blood fluorine, Left 21,36,78,90,106,120,133,154 Eye Observations, Bled via Orbital for blood fluorine. Right 1-4,10,93-99,175 M VII 641205 Hair Loss, Forepaw, Bilateral Sacrificed by design General observation, No Abnormality Detected 56,63-77,84,91,99-119,126-133 182 0,7,14-35,42-56,70-77,84,91,9 i Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right 21,36,78.90.106,120,133,154 1-4,10,57,93-99,175 . Discharge, Nose, Black 63 ^ Discharge, Eye right, Black 0 Misshapen Observations, Tail ) Ct Sacrificed by design 2- M VII 641196 General observation. No Abnormality Detected 112-119,140-182 106-119,126-182 182 0,7,14-35,42-56,63-77,84,91,99 Eye Observations, Bled via Orbital tor blood fluorine. Left 21,36,78,90,106,120,133,154 Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design , 1-4,10,57,93-99,175 182 ^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal M VII 641169 M VII 641110 M VII 641096 M VII 641212 M VII 641068 M VII 641093 M VII 641054 M VII 641208 Observation General observation, Ho Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Eye Observations, Bled via Orbital for Clin Path, Right Hair Loss, Forelinib, Bilateral Hair Loss, Forepaw, Bilateral Hair Loss, Forepaw, Right Sacrificed by design General observation. No Abnormality Detected Vocalization Removed from study General observation. No Abnormality Detected Compound evident on lips during dosing Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study Days 0,7,14-21,77,84,91,99-119,126 21,36,78,90,106,120,133,154 1-4,10,57,93-99,175 28-35,42-56,63-70 140-182 133 182 0-7,21-69 14 69 0-63,69 67 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 572 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal Observation Days M VXI 641193 General observation, No Abnormality Detected 0-14 Hair Loss, Foreliirib, Bilateral 21-69 Removed from study 69 M VII 641207 General observation. No Abnormality Detected 0-14 Hair Loss, Forepaw, Bilateral 21-69 Removed from study 69 M VII 641139 General observation. No Abnormality Detected 0-69 Removed from study 69 M VII 641080 General observation, No Abnormality Detected 0-69 Removed from study 69 M VII 641078 General observation, No Abnormality Detected 0-69 Removed from study 69 M VII 641177 General observation. No Abnormality Detected 0-69 Removed from study 69 M VII 641112 General observation, No Abnormality Detected 0-69 Removed from study 69 M VII 641210 General observation. No Abnormality Detected 0-69 Removed from study 69 M VII 641152 General observation, No Abnormality Detected 0-69 Removed from study 69 M VII 641182 General observation. No Abnormality Detected 0-69 Removed from study 69 M VII 641150 General observation. No Abnormality Detected 0-69 Removed from study 69 573 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days M VII 641211 General observation. No Abnormality Detected 0-69 Removed from study 69 M VII 641145 General observation, No Abnormality Detected 0-14 Hair Loss, Forepaw, Bilateral 49-69 Wound, Superficial, Lumbar 21-63 Wound, Superficial, Neck 21-49 Removed from study 69 M VII 641185 General observation, Mo Abnormality Detected 7-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88,116 Feces, Present 0 Sacrificed by design 122 M VII 641064 General observation, Mo Abnormality Detected 0-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 M VII 641216 General observation. No Abnormality Detected 0-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 M VII 641092 General observation. No Abnormality Detected 0-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 574 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FO Sex Group Animal Observation Days M VII 641167 General observation, Ho Abnormality Detected 0-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88 Retina, Retinal Degeneration Focal, Left 116 Sacrificed by design 122 M VII 641189 General observation, No Abnormality Detected 0-84 General Teeth Observations, Absent 85,91-112,119-122 Mo Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 M VII 641213 General observation, No Abnormality Detected 0-84,91-112,119-122 Mo Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 M VII 641153 General observation. No Abnormality Detected 0-84,91-112<119-122 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 122 M VII 641203 General observation, No Abnormality Detected 0-70,77 Hyperreactive 99-112,119-122 Breathing Observations, Noise 84,91-112 No Ophthalinological Abnormalities Detected 88,116 Compound evident on animal's lips 74 Sacrificed by design 122 M VII 641143 General observation. No Abnormality Detected 0-14,77-84,91-112,119-122 No Ophthalmological Abnormalities Detected 88,116 Hair Loss, Forepaw, Bilateral 21-70 Sacrificed by design 122 575 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F II 641257 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 0-42,49-84,91-92 44,92 88 Sacrificed by design 92 F II 641290 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-42,49,77 44,92 No Ophthalmological Abnormalities Detected 88 Hair Loss, Porelimb, Bilateral Sacrificed by design 56-70,84,91-92 92 F II 641283 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-14 44,92 No Ophthalmological Abnormalities Detected 88 Hair Loss, Forelinib, Bilateral 21-42,49-84,91-92 Hair Loss, Lumbar, Dorsal 21-42,49-84,91 Sacrificed by design 92 F II 641344 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-42,49-84,91-92 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 F II 641384 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-42,49-84,91-92 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 576 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days P II 641293 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-42,49-84,91-92 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 F II 641249 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-42,49-56,77-84,91-92 44,92 No Ophthalmological Abnormalities Detected 88 Hair Loss, Forelinib, Right 63-70 Accidentally killed 92 F II 641245 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-14 44,92 No Ophthalmological Abnormalities Detected 88 Hair Loss, Forelimb, Bilateral 49-84,91-92 Hair Loss, Forelimb,. Right 21-42 Sacrificed by design 92 F II 641240 General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 0-42,49-84,91-92 44,92 88 Sacrificed by design 92 F II 641335 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett 0-42,49-84,91-92 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 577 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F II 641309 General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Sacrificed by design 0,7,14-35,42-56,63-77,84,91,99 21,36,57,78,90,106,120,133,154 4,10,93-99 182 F II 641285 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine, Right 0,7,14-35,42-56,63-70 21', 36, 57,78,90,106,120,133,154 4,10,93-99 F II 641241 Discharge, Eye right, Black Hair Loss, Forepaw, Bilateral Sacrificed by design General observation, No Abnormality Detected 77,84,91,99-119,161-168 106-119,126-182 182 0,7,14-35,42-56,63-77,84,91,99 126-161,175-182 F II 641288 Eye Observations, Bled via Orbital for blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Discharge, Eye left, Black Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Bilateral Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,57,78,90,106,120,133,154 4,10,93-99 168 182 0,7,14-35,42-56,63-77,84,91,99 10 21,36,78,90,106,120,133,154,17 Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design 4,57,93-99 182 578 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F II 641394 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Bilateral 0,7,14-35,42-56,161-182 10,57 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120,133,154,17 Eye Observations, Bled via Orbital for blood fluorine. Right 4,93-99 Discharge, Eye left. Black Hair Loss, Side, Right 147-154 140 Wound, Superficial, Side, Right 99-119,126-133 Mass Side, Right, Mass #1, Not Ulcerated 63-77,84,91 Sacrificed by design 182 II 641345 General observation. No Abnormality Detected Removed from study 0-69 69 II 641236 General observation. No Abnormality Detected Removed from study 0-69 69 II 641337 General observation, No Abnormality Detected Removed from study II 0 641328 General observation. No Abnormality Detected Removed from study 0-69 69 0-69 69 II 641310 General observation. No Abnormality Detected Removed from study 0-69 69 II 641324 General observation. No Abnormality Detected > Removed from study II 0 641371 General observation. No Abnormality Detected Removed from study 0-69 69 0-69 69 579 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F II 641332 General observation. No Abnormality Detected Hair Loss, Forelimb, Bilateral 0-56 63-69 Removed from study 69 F II 641358 General observation, No Abnormality Detected Removed from study 0-69 69 F II 641389 General observation. Wo Abnormality Detected Hair Loss, Forelimb, Bilateral 0-56 63-69 Hair Loss, Hindlimb, Bilateral Removed from study 63-69 69 F II 641317 General observation. No Abnormality Detected Removed from study 0-69 69 F II 641255 General observation. No Abnormality Detected Hair Loss, Forepaw, Bilateral Removed from study 0-28 35-69 69 P II 641403 General observation. No Abnormality Detected Removed from study 0-69 69 F II 641388 General observation, No Abnormality Detected Removed from study 0-69 69 F II 641261 General observation, No Abnormality Detected Removed from study 0-69 69 F II 641306 General observation, No Abnormality Detected Removed from study 0-69 69 F II 641349 General observation. No Abnormality Detected Removed from study 0-69 69 580 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F II 641346 F II 641308 F II 641289 F II 641253 F II 641359 F II 641325 F II 641281 Observation General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed 'by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital tor Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-69 69 0-69 69 0-69 69 0-84,91-112,119-123 123 88,116 123 0-84,91-112,119-123 123 88,116 123 0-84,91-112,119-123 123 88,116 123 0-84,91-112,119-123 123 88,116 123 581 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F II 641294 General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for din Path, Left No Ophthalmological Abnormalities Detected 0-84,91-112,119-123 123 88,116 Sacrificed by design 123 F II 641383 General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett 0-84,91-112,119-123 123 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 123 F II 641364 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-84,91-112,119-123 123 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 123 F II 641331 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-84,91-112,119-123 123 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 123 F II 641400 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-84,91-112,119-123 123 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 123 P II 641266 General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left 0-84,91-112,119-123 123 No Ophthalmological Abnormalities Detected 88,116 Sacrificed by design 123 582 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F IV 641396 F IV 641369 F IV 641336 F IV 641355 F IV 641260 Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophtbalinological Abnormalities Detected Sacrificed by design Days 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 583 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F IV 641312 F IV 641313 P IV 641311 P IV 641298 P IV 641361 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Foreliirib, Bilateral Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Discharge, Nose, Black Discharge, Eye right. Black No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-28 44,92 88 35-42,49-84,91-92 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-77 44,92 84,91 92 88 92 0-42,49-84,91-92 44,92 88 92 584 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F IV 641321 F IV 641391 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Discharge, Eye right. Black Sacrificed by design General observation. No Abnormality Detected Eye Observations, Partially Closed, Bilateral Eye Observations, Enophthalmus, Bilateral Eye Observations, Eaophthalrnus, Right Eye Observations, Exophthalmus, Left Eye Observations, Bled via Orbital for blood fluorine. Bilateral Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Eye Observations, Corneal Opacity, Bilateral Eye Observations, Comeal Opacity, Right Discharge, Eye right. Black Hair Loss, Forepaw, Bilateral Hair Loss, Face, Right Fluorine bleed not done Bled by tail vein Sacrificed by design Days 0,7,14-35,42-56,70-77,84,91,9 21,36,78,90,106,120,133,154,1 4,10,57,93-99 63 182 0,7,14-35,77,84,91 168-182 140-182 119,126-133 99-112,126-133 93 21,36,78,90,99-106,120 4,10,57 154-182 106-119,126-147 99-119,126-133 42-56,63-70 106-119,126-140 133 154,175 182 585 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F IV 641340 P IV 641247 F IV 641319 F IV 641378 F IV 641263 F IV 641297 P IV 641304 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Bilateral Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine, Right Discharge, Eye left. Black Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design General observation. No Abnormality Detected Removed from study General observation, Mo Abnormality Detected Hair Loss, Forelimb, Bilateral Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study Days 0,7,14-35,42-56,63-77,84,91,9 112-119,126-182 133 21,36,78,90,106,120,154,175 4,10,57,93-99 106 182 0,7,14-35,42-56,63-77,84,91,99 21,36,78,90,106,120,133,154,17 4,10,57,93-99 182 0,7,14-35,42-56,63-77,84,91,99 21,36,78,90,106,120,133,154,17 4,10,57,93-99 182 0-69 69 0-49 56-69 69 0-69 69 0-69 69 586 fe^SSs^ia^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F IV 641274 General observation, No Abnormality Detected 0-69 Removed from study 69 F IV 641351 General observation. No Abnormality Detected 0-69 Removed from study 69 F IV 641272 General observation, No Abnormality Detected 0-7 Hair Loss, Forelinib, Bilateral 14-69 Hair Loss, Forepaw, Bilateral 35-69 Removed from study 69 F IV 641258 General observation. No Abnormality Detected 0-69 Removed from study 69 P IV 641276 General observation. No Abnormality Detected 0-14 Hair Loss, Forelimb. Right 21-69 Removed from study 69 F IV 641350 General observation. No Abnormality Detected 0-69 Removed from study 69 F IV 641376 General observation. No Abnormality Detected 0-69 Removed from study 69 F IV 641315 General observation. No Abnormality Detected 0-14 Misshapen Observations, Ear, Left 21-69 Removed from study 69 F IV 641286 General observation. No Abnormality Detected 0-69 Removed from study 69 P IV 641231 General observation. No Abnormality Detected 0-69 Removed from study 69 587 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F IV 641338 IV 641318 IV 641373 IV 641365 IV 641348 IV 641323 Observation General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study General observation. No Abnormality Detected Hair Loss, Abdomen, Bilateral Hair Loss, Base of tail Hair Loss, Forelimb, Bilateral Hair Loss, Hindlinib, Bilateral Removed from study General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Hair Loss, Forelimb, Bilateral Removed from study General observation, No Abnormality Detected Removed from study Days 0-69 69 0-69 69 0-14 42-69 42-69 21-69 42-69 69 0-69 69 0-28 35-69 69 0-69 69 588 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F VI 641398 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye Observations, Bled via Orbital for Clin Path, Left 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 F VI 641251 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye Observations, Bled via Orbital for Clin Path, Left 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 P VI 641292 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 44,92 88 Sacrificed by design 92 P VI 641269 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye observations. Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected 44,92 88 Sacrificed by design 92 F VI 641379 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye Observations, Bled via Orbital for Clin Path, Left 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 F VI 641302 General observation. No Abnormality Detected 0-42,49-84,91-92 Eye Observations, Bled via Orbital for Clin Path, Left 44,92 No Ophthalmological Abnormalities Detected 88 Sacrificed by design 92 589 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VI 641244 F VI 641362 F VI 641363 F VI 641375 F VI 641382 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for din Path, Left Ho Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Wo Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Exophthalmus, Left Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design Days 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0,7,14-35,42-56,63-77,84,91,99,1 106-119.126-133 21,36,78,90,106,120,133,154 4,10,57,93-99,175 182 590 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days P VI 641262 General observation. No Abnormality Detected 0,7,14-35,42-56,63-70,91,99-119 Eye Observations, Partially Closed, Left Eye Observations, Enophthalmus, Left 168-182 140-182 Eye Observations, Exophthalmus, Left 126-133 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120 Eye Observations, Bled via Orbital for blood fluorine. Right 4,10,57,93-99,133,154,175 Discharge, Eye left. Black Hair Loss, Forepaw, Bilateral 126-133 77,84 Hair Loss, Face, Left 133-140 Sacrificed by design 182 F VI 641232 General observation, No Abnormality Detected 0,7,35,42-56,63-77,84,91,99-119 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120,133,154 Eye Observations, Bled via Orbital for blood fluorine. Right Discharge, Eye right, Black 4,10,57,93-99,175 14 Hair Loss, Face, Right 21-28 Sacrificed by design 182 F VI 641305' General observation, No Abnormality Detected 0,7,14-35,42 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120,133,154 Eye Observations, Bled via Orbital for blood fluorine. Right 4,10,57,93-99,175 Hair Loss, Forelimb, Right 56,63-77,84,91,99-119,126-182 Wound, Superficial, Forelimb, Right 49-56,63-77,84,91,99-119,126-13 Sacrificed by design 182 591 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VI 641372 F VI 641271 F VI 641280 F VI 641252 P VI 641386 P VI 641277 P VI 641233. F VI 641238 Observation General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Bilateral Eye Observations, Bled via Orbital for blood fluorine. Left Eye Observations, Bled via Orbital for blood fluorine. Right Sacrificed by design General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Removed from study General observation. No Abnormality Detected Hair Loss, Forelimb, Bilateral Removed from study General observation. No Abnormality Detected Removed from study Days 0,7,14-35,42-56,63-77,84,91,99 175 21,36,78,90,106,120,133,154 4,10,57,93-99 182 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-14 21-69 69 0-69 69 F VI 641235 General observation. No Abnormality Detected Removed from study 0-69 69 592 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation F VI 641392 General observation. No Abnormality Detected Removed from study P VI 641360 General observation. No Abnormality Detected Hair Loss, Forelinib, Bilateral Removed from study P VI 641381 General observation, No Abnormality Detected Removed from study F VI 641333 General observation. No Abnormality Detected Hair Loss, Forelinib, Bilateral F VI 641239 Removed from study General observation. No Abnormality Detected F VI 641228 Removed from study General observation, No Abnormality Detected P VI 641334 Removed from study General observation. No Abnormality Detected Removed from study F VI 641347 General observation. No Abnormality Detected Removed from study F VI 641367 General observation. No Abnormality Detected Removed from study F VI 641303 General observation, No Abnormality Detected Removed from study Days 0-69 69 0-28 35-69 69 0-69 69 0-14 21-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 593 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VI 641339 F VI 641316 Observation General observation. No Abnormality Detected Removed from study General observation, No Abnormality Detected Removed from study Days 0-69 69 0-69 69 594 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VIII 641299 F VIII 641275 P VIII 641326 F VIII 641380 F VIII 641314 Observation General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations. Bled via Orbital for Clin Path, Left Breathing Observations, Noise No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-70,84,91-92 44,92 77 88 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 595 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VIII 641237 F VIII 641300 F VIII 641279 P VIII 641390 F VIII 641327 Observation General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Wound, Superficial, Keck Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation, Ho Abnormality Detected Eye Observations, Bled via Orbital tor Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 0,21-42,49-84,91-92 44,92 88 7-14 92 0-42,49-84,91-92 44,92 88 92 0-42,49-84,91-92 44,92 88 92 596 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR F Sex Group Animal F VIII 641259 F VIII 641264 F VIII 641301 F VIII 641395 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital tor blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Eye Observations, comeal Opacity, Left Hair Loss, Forelimb, Right Hair Loss, Forepaw, Right Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital tor blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for blood fluorine, Left Eye Observations, Bled via Orbital for blood fluorine, Right Sacrificed by design Days 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154 4,10,57,93-99,175 182 0,7,14-35,42-56,63-70,147-154 21,36,78,90,106,120,133,154 4,10,57,93-99,175 161-182 140 77,84,91,99-119,126-140 182 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154 4,10,57,93-99,175 182 0,7,14-35,42-56,63-77,84,91,99-11 21,36,78,90,106,120,133,154 4,10,57,93-99,175 182 597 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation Days F VIII 641278 General observation, Mo Abnormality Detected 0,7,21-35,42-56,63-77,84,91,99,1 Eye Observations, Bled via Orbital for blood fluorine. Left 21,36,78,90,106,120,133,154 Eye Observations, Bled via Orbital for blood fluorine. Right 4,10,57,93-99,175 Hair Loss, Forelimb, Bilateral 106-119,126-140 Urine, Present 14 Sacrificed by design 182- P VIII 641265 General observation. No Abnormality Detected 0-69 Removed from study 69 F VIII 641393 General observation. No Abnormality Detected 0-69 Removed from study 69 F VIII 641402 General observation. No Abnormality Detected Removed from study 0-69 69 F VIII 641246 General observation, No Abnormality Detected 0-14 Hair Loss, Forelimb, Bilateral 28-69 Hair Loss, Forelixrib, Left 21 Removed from study 69 F VIII 641320 General observation. No Abnormality Detected 0-14,56-69 Hair Loss, Forelimb, Bilateral 21-49 Removed from study 69 F VIII 641353 General observation. No Abnormality Detected 0-14 Hair Loss, Forelimb, Bilateral 21-69 Removed from study 69 F VIII 641401 General observation. No Abnormality Detected 0-69 Removed from study 69 598 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations________________________________ INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal Observation F VIII 641307 General observation, No Abnormality Detected Removed from study F VIII 641368 General observation, Mo Abnormality Detected Removed from study P VIII 641343 General observation, No Abnormality Detected Removed from study F VIII 641254 General observation. No Abnormality Detected Removed from study F VIII 641242 General observation. No Abnormality Detected Removed from study F VIII 641284 General observation. No Abnormality Detected Removed from study F VIII 641230 General observation. No Abnormality Detected Removed from study F VIII 641273 General observation, No Abnormality Detected Removed from study F VIII 641296 General observation. No Abnormality Detected Removed from study F VIII 641248 General observation, No Abnormality Detected s Removed from study F VIII 641370 General observation. No Abnormality Detected Removed from study ^ _________________________________________________59_9_ Days 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 0-69 69 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal P VIII 641243 F VIII 641329 F VIII 641385 P VIII 641387 P VIII 641282 Observation General observation. No Abnormality Detected Hair Loss, Forelinib, Bilateral Removed from study General observation. No Abnormality Detected Hair Loss, Forelinib, Left Wound, Superficial, Forelinib, Left Removed from study General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Lett No Ophthalmological Abnormalities Detected Hair Loss, Forelinb, Bilateral Sacrificed by design General observation, No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Forepaw, Bilateral Sacrificed by design Days 0-14 21-69 69 0-49 56-69 63 69 0-14 123 88,116 21-84,91-112,119-123 123 0-84,91-112,119-123 123 88,116 123 0-21 123 88,116 28-84,91-112,119-123 123 600 ,.*a3^^S^^J^fl^^^^^ ^^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VIII 641234 F VIII 641256 F VIII 641356 F VIII 641352 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Hair Loss, Forelimb, Bilateral Hair Loss, Forepaw, Bilateral Sacrificed by design General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Sacrificed by design General observation, Mo Abnormality Detected Discharge, Eye bilateral. Black Discharge, Mose, Black Mo Ophthalmological Abnormalities Detected Abnormal Gait, Hindlimb, Bilateral, Mild Found dead in cage. General observation, Mo Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left Mo Ophthalmological Abnormalities Detected Hair Loss, Forelimb, Bilateral Sacrificed by design Days 0-14 123 88.116 21-84,91-112,119-123 77-84,91-112,119-123 123 0-84,91-112,119-123 123 88,116 123 0-84,91-106 112,119-121 112,119-121 88,116 119-121 121 0-14 123 88,116 21-84,91-112,119-123 123 601 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproductive Evaluations INDIVIDUAL CLINICAL AND OPHTHALMOLOGICAL OBSERVATIONS AND MORTALITY DATA FOR Sex Group Animal F VIII 641366 F VIII 641399 F VIII 641377 Observation General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalaological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalaiological Abnormalities Detected Sacrificed by design General observation. No Abnormality Detected Eye Observations, Bled via Orbital for Clin Path, Left No Ophthalmological Abnormalities Detected Sacrificed by design Days 0-84,91-112,119-123 123 88,116 123 0-84,91-112,119-123 123 88,116 123 0-84,91-112,119-123 123 88,116 123 602 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations_____________DuPont-4739 APPENDIX E OPHTHALMOLOGICAL EXAMINATION REPORTS 603 H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations ___ OPHTHALMOLOGICAL EXAMINATION REPORTS ABBREVIATIONS: OD OS - right eye left eye EXPLANATORY NOTES DuPont-4739 NOTES: Only animals with ophthalmological findings were reported. All other animals had no abnormalities detected. 604 Company ganlHzed. Daes not eontain TSCA CB> H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations OPHTHALMOLOGICAL EXAMINATION REPORT (TEST DAY 88) DuPont-4739 NANCY M. BROMBERG, VJM.D., M.S. EYE CLINIC FOR ANIMALS 6119 MASSACHUSETTS AVE BETHESDA,MD 20816 STUDY INFORMATION: Study NCl||f|U|| Species: Rat Study Director: DOB DeBter OPHTHALMOLOGICAL EXAMINATION SUMMARY Examination Date: December 15,2000 METHODS: Indirect Ophtbatmoscopy following 1% Tropicamide mydriasis Sex Group # Animal # Observation Mafe m 641144 Focat retinal degeneration OD COMMENTS/DISCUSSION One (1) male animal wos identified with focal retinal degeneration, considered to be an incidentel finding. AH other animals had no Visible opathalraoscopic tegions. W> Nan^M.BrAnlfe4,YJ.D.,M.^J DiploBiate,A.C.V.O. r^)e^J^^/^D Date 605 Company SanMzeA Does no8 eonta?n TW^ ^ H-24616: Subchronic Toxicity 90-Day Gavage Study in Rats with One-Generation Reproduction Evaluations OPHTHALMOLOGICAL EXAMINATION REPORT (TEST DAY 116) DuPont-4739 NANCY M. BROMBERG, VJM.D, M.S. EYE CLINIC FOR ANIMALS 6119 MASSACHUSETTS AVE BETHESDA,MD 20816 STUDY INFORMATION: ^^^jSH^fffJt Speciefi:Rat Study Director: DOB Belter OPHTHALMOLOGICAL EXAMINATION SUMMARY Examination Date: January 12,2001 Test Day: 116 METHODS: Sex Male Indirect Ophthalmoscopy following 1% Tropieainide mydnris ABimal^ 641154 Observation Focal retinal degeneration OS 641167 Focal retinal degnaerarioB OS COMMENTS/DISCUSSION Two (2) msks were identified with focal retinal degeaeratwa, considered to be an iacideBtal Treding. All other aBimalg esaBained had na vislbteophthalmoaeopic lesions. No compound related abaonfflaBties were identified. aey I^fBrsitaberg, VMS., MS. DSploaate,A,C.V.O. U^O/ 606 Cwapsny SsmfSzeS. Does nn9 ennM, s-ss^s. ^