Document 0qYwRnKnk2vybOg15RxyjJMoJ

Spacial Lans Oral Teratology Study of T-2999COC in Rats Aftex-ozsa 5 __ ^ _ _ _ _ _ _ _ _ _ _ . . J ,.., f * Experiment So.: Conducted At: Dosing Period: Study Director: 0680TR0020 Safety Evaluation Laboratory Riker Laboratories/ Inc. St. Paul/ Minnesota February 9 , 1981 through March 26/ 1981 E. G. Gortner E. G.'(Sortner ~ Date Senior Research Technologist Animai Reproduction-Teratology Study director E. G. Lamprecht, DVM, PhD Date Research Veterinary Pathologist '//avtok * 3/P9/f/ cse; Date Manager, Pathology-Toxicology Safety Evaluation Laboratory 004260 1. Summary This special rat teratology study was conducted specifically to evaluate rat lenses exposed to T-2999CoC during the period of organogenesis. The objectives of the study were to determine a no-effect dose level of the lens abnormality reported in a previous teratology study and to describe the appearance of the lens abnormality in weanling rats. Groups of time mated female rats were orally dosed with T-2999CoC at 0, 25/ 2.5 or 0.25 mg/kg/day on days 6 through 15 of gestation. Approximately one-half of the females were killed on day 20 of gestation while the rest of the females were allowed to litter and raise their pups to weaning. Since this study was conducted, the lens findings have been found not to be abnormal. The lens findings observed are interpreted as a freehand sectioning artifact of a normal area of lens fiber degeneration. The lens artifact was observed in fetuses of all dose groups, including the control group. The 25 mg/kg/day dose group incidence of the artifact was significantly higher than the control group incidence. The histological appearance of the lens findings were the same in all dose groups including the control group. The differences among the dose group incidences were due to the manner and frequency in which the artifact was created and the limitations inherent in its visualization. T-2999CoC in utero exposed rat fetuses did not have compound-related lens changes. Weanling rat pups which had been exposed in utero to T-2999CoC did not have lens nucleus abnormalities. The finding of no lens nucleus abnormalities in weanlings supports the conclusion that the lens findings in the rat fetuses were an artifact and not a teratogenic change. The fetal lens findings observed under the dissecting microscope were artifact. T-2999CoC in utero exposed fetuses and weanlings did not have compound-related lens changes. 4261 2. T-2999CoC was labeled a teratogen of the lens because rmalities were observed at the 75, 37.5 and 25 mg/kg/day dose ratology study (Riker Experiment Number 0680TR0&10). The T-2999CoC studyii were to determine a no-effect dose level of :y and to describe the appearance of the lens abnormalility The study was sponsored by the 3M Commercial Chemical Minnesota and was conducted by the Safety Evaluation laboratories, Inc., St. Paul, Minnesota. Six sets of ition groups were dosed between February 9 and March 26, and list of the principal participants and supervisory >und in Appendices I and II respectively. s study were conducted according to the Good Laboratory lations and the Safety Evaluation Laboratory Standard s (see Appendix III for Quality Assurance Unit statement), n for specimens, raw data and a copy of the final report is afety Evaluation Laboratory's record archives. Dawley derived CD rats were obtained from Charles River , Wilmington, Massachusetts, and assigned cages according to d random numbers table. The rats, ranging in weight from ere then divided into four groups of 72 animals each. The l in six sets and the body weight data were interpreted in e rats were housed individually in hanging stainless steel h floors and fronts in a temperature and humidity controlled ter were available ad libitum. The lights were on a 12 hour >served daily from day 3 through 20 of gestation for abnormal >dy weights were recorded on days 3, 6, 9, 12, 15 and 20 of :r groups were dosed with T-2999COC suspended daily in corn .nd 0.25 mg/kg/day. The suspensions were administered daily se volume of 5 mg/kg by oral intubation with a syringe 1-tipped intubation needle to the rats on days 6 through 15 indicated by sperm-positive vaginal smear). T-2999CoC ed by 3M Commercial Chemical Division, St. Paul, Minnesota ialf of the females were killed on gestational day 20. All re fixed in Bouin's fixative and the heads were freehand Ison technique. The presence of lens findings were e dissecting microscope. Fetal specimens with visible lens Ided in paraffin, sectioned at 5-6 microns, stained with >in and examined histologically. The remaining females were al grade FM-3422) ar 0680TR0020)' / Chow, Ralston Purina Co., St. Louis, MO 004262 3. allowed to litter in plastic shoe box cages bedded with ground corn cobs. On day 21 of lactation the eyes of the weanlings were examined by slit lamp biomicroscopy or indirect ophthalmoscopy. The weanling rats were then killed and their eyes were fixed in 10% buffered formalin, imbedded in paraffin, sectioned at 5-6 microns, stained with hematoxylin and eosin and evaluated histologically. i Results and Discussion The first objective of this special lens teratology study was to determine a no-effect dose level of the lens abnormality reported in a previous teratology study. Since this study was conducted, the lens findings have been found not to be abnormal. The lens findings observed under the dissecting microscope are interpreted as a freehand sectioning artifact of a normal area of lens fiber degeneration. The fetal rat lens finding was incorrectly interpreted as a teratogenic change in Riker Experiment Number 0680TR0010 and, therefore, the first objective of this study was not valid. The fetal lens findings were observed to occur in individual fetuses of all dose groups including the control group. The lens findings were localized to the area of the embryonal nucleus, although a variety of morphological appearances were present within that location. The range of morphological appearances as observed under the dissecting microscope included: a discoloration of the lens near the anteriocentral region extending from beneath the lens epithelium to half-way through the lens posteriorly, a cleft at the anteriocentral lens region or a combination of lens discoloration and the presence of a cleft. Histologically, the cleft was a space opened up at the vestage of the lens vesicle remnant and consisted of a separation of primary lens fibers of the embryonal nucleus from the lens epithelial cells. The dark streak discoloration of the embryonal nucleus resulted from either the lens being freehand sectioned across the area of normal primary lens, fiber degeneration or an artifact being created in the lens during freehand sectioning accentuating the area of normal primary lens fiber degeneration. The differences in the appearance of the lens artifact in individual fetuses and differences among the dose group incidences were largely due to the manner and frequency in which the artifact was created and the limitations inherent in its visualization. Statistically significant differences occurred among the incidences of fetuses observed to have the lens artifact. The 25 mg/kg/day dose group incidence was significantly higher than the 0 mg/kg/day dose group incidence (Table 1). The artifact was the same in all dose groups regardless of the morphological appearance described under the dissecting microscope and regardless of the statistical comparisons among the group incidences of the artifact. T-2999CoC in utero exposed fetuses did not have compound-related changes in their lenses. 004263 4. The second objective of this special lens teratology study was to describe the appearance of the lens abnormality in weanling rats which had been exposed in utero to T-2999CoC. Again, since the fetal lens finding was an artifact, this objective also was not valid. All eyes of the weanling rats were observed by either slit lamp biomicroscopy or indirect ophthalmoscopy. Neither a lens cleft nor a fetal lens nuclear opacity were observed in any of tfce lenses of any of the weanlings in the control or compound-treated offspring. One high dose weanling did have a lens opacity, but the opacity did not involve the fetal nucleus (Table 2). The crystalline appearance of the centers of the weanling lenses in all dose groups made histologically sectioned and stained specimens unsuitable for evaluation of individual lens fibers. The finding of no lens nucleus abnormalities in weanlings supports the conclusion that the lens finding in the rat fetuses were an artifact and not a teratogenic change. T-2999CoC was maternally toxic to the pregnant dams of the 25 mg/kg/day dose level in both study replicates. The compound caused the toxicity of reduced mean body weight gain during the dosing interval. The mean weight gained between days 9 and 12 of gestation for the 25 mg/kg/day dose group was significantly lower than the weight gained by the 0 mg/kg/day dose group during that same interval (Table 3). No compound-related clinical signs were observed in any of the three compound treated groups. Six intubation deaths occurred during the study (Appendix V). One 25 mg/kg/day dose group dam died during parturition. 04264 Table 1 Special Lens Oral Teratology Study of T-2999CoC in Rats Results of Dissecting Microscopic Observations of Gestational Day 20 Fetal Lens ^ Dose Group 0 mg/g/day 25 mg/g/day 2.5 mg/g/day 0.25 mg/g/day Dams 28 22 27 26 Fetuses Examined 292 225 271 279 Dams Having Fetuses With Lens Findings N 13 46 18 82- 18 67 14 54 Fetuses with Lens Findings N% 41 14 55 24^ 59 22-- 41 16 -- Significantly higher than the control (Chi-square with Yates correction p <0.05) 004265 6. Table 2 Special Lens Oral Teratology Study of T-2999CoC in Ratjs Results of Ocular Examination Findings of Pups at Day 21 of Lactation Dose Group No. of Dams Total No Number Abnorm of Pups_____Found Abnorm. Found______Findings 0 mg/kg/day 29 291 25 mg/kg/day 30 2.5 mg/kg/day 28 0.25 mg/kg/day 26 263 266 211 288 3 Corneal Opacity Bilateral corneal ulcer with opacity Left eye grossly enlarged - 2 X normal size, lens may be absent 262 1 Opaque area of lens - 1 to 3 o'clock 263 3 Questionable cloudy area of cornea 209 2 Corneal opacity 004266 Table 3 Special Lens Oral Teratology Study of T-2999CoC in Rats Mean Body Weight Gain (g) of Pregnant Rats Between Weighings with Standard Deviations First Replicate 0 mg/kg/day 25 mg/kg/day 2.5 mg/kg/day 0.5 mg/kg/day DRV 6 9 12 15 28 ';MERN 29 24 21 26 70 STRN. DEV 10. 9 7. 9 8. 0 15. 5 29. 1 " ] MERN 31 21 10 - 2? 70 STRN. DEV 16. 9 11. 5 13. 9 16. 1 24. 6 -MERN 33 23 14 30 65 STRN. DEV 10. 0 4. 5 13. 3 13. 7 30. 2 MERN 31 22 15 31 64 STRN. DEV 9. 4 7. 4 12. 3 17. 9 29. 9 Second Replicate DRV 6 9 12 15 20 0 mg/kg/day 25 mg/kg/day 2.5 mg/kg/day 0.25 mg/kg/day ;MEAN 30 21 30 25 70 STRN. DEV 5. 1 6. 6 6. 3 6. 9 22. 4 i MEAN 29 19 2 2 - 23 71 STRN. DEV 11. 8 8. 3 6. 7 7. 1 15. 3 'MEAN 29 21 2 6 - 28 76 STRN. DEV 5. 8 5. 7 7. 0 7. 1 12. 4 MEAN 32 20 28 23 68 STRN. DEV 7. 8 6. 0 6. 7 7. 1 26. 9 -- Significantly lower than the control (Dunnett's t test p < 0.05) 004267 Appendix I 8. TITLE: Protocol for a Special Lens Oral Teratology Study of T-2999CoC^ in Rats OBJECTIVE: A purified grade of T-2999CoC was teratogenic to the eye and caused developmental lens abnormalities at 75, 37.5 and 25 mg/kg/day in a rat teratology study (Riker Experiment Number 068QTR0010). The objectives of the study are to determine a no-effect dose level of the lens abnormality and to describe the appearance of the lens abnormality in the weanling rats. The study will be conducted according to the 1978 Good Laboratory Practice Regulations and the Safety Evaluation Laboratory's Standard Operating Procedures. SPONSOR: 3M Commercial Chemical Division, St. Paul, Minnesota. TESTING FACILITY: Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. STUDY DIRECTOR: E. G. Gortner START OF DOSING: February, 1981. TEST SYSTEM: One hundred and ninety-two sexually mature, time mated Sprague-Dawley derived female rats from Charles River Breeding Laboratories will be housed in hanging stainless steel cages with wire mesh floors and fronts in a temperature and humidity controlled room. This strain of rat will be used because it was used in the previous teratology study and time mated females are readily available. Purina Laboratory Chow and water will be available ad libitum. The lights will be on a 12 hour light/dark cycle. TEST SYSTEM IDENTIFICATION: Each animal will be ear tagged and that number will be indicated on the outside of the cage. RANDOMIZATION: The animals will be assigned cages according to a computergenerated random numbers table. CONTROL ARTICLE: Corn oil. TEST ARTICLE: T-2999Co(. ANALYTICAL SPECIFICATIONS: The test article composition and purity will be determined by the Sponsor (3M Commercial Chemical group) prior to the start of the study and at the end of dosing. -- FM-3924 (technical grade FM-3422) 004268 9. DOSAGE LEVELS AND EXPERIMENT DESIGN: The test article will be suspended in corn oil daily. The test article suspension and the control articles will be administered by oral intubation to the rats on days 6 through 15 of gestation according to the following: Dose Group Dose Level Group Size High Mid Low Control 25 mg/kg/day 2.5 mg/kg/day 0.25 mg/kg/day 0 mg/kg/day 48 2 48 9 48 2 48 2 The oral route of administration will be used because teratogenicity resulted by this route in the previous teratology study. No dietary contaminants are known to interfere with the test article. The animals will be observed daily from day 3 through 20 of gestation for abnormal clinical signs. Body weights will be recorded on days 3, 6, 9, 12, 15 and 20 of pregnancy and the rats will be dosed accordingly using a constant dose volume of 5 ml/kg of body weight. Approximately one-half of the females will be killed on day 20 of gestation. All of their pups will be fixed in Bouin's solution and the heads will be free-hand sectioned by the Wilson technique. The presence of eye abnormalities will be determined using the dissecting microscope. Select eye sections can be sent to histopath for microscopid examination. The remaining females will be allowed to litter. On day 21 of lactation the eyes of neonates will be examined to determine the presence of lens abnormalities. DATA ANALYSIS AND FINAL REPORT: The proposed statistical method to be used for analysis of the data is the Chi-square for percent of abnormalities. The proposed date for the final report is 2-3 months after day 21 of lactation and the pup eye exam has been completed (approximately second quarter, 1981). Amendment to the Protocol for a Special Lens Oral Teratology Study of T-2999CoC in Rats An additional number of rats will be added to this study. The 96 new animals will be divided among the dose groups as follows: Dose Group Dose Level No. of Animals High Mid Low Control 25 mg/kg/day 2.5 mg/kg/day 0.25 mg/kg/day 0 mg/kg/day 24 24 24 24 The reason for this amendment is a reduced number of pregnant animals in the first two groups of animals. 004269 10. Appendix II List of Principal Participating Personnel NAME Edwin G. Gortner Elden G. Lamprecht Gary C. Pecore Vinkateswa Pothapragoda Loren 0. Wiseth FUNCTION Study Director Veterinary Pathologist Supervisor - Animal Care Commercial Chemical - Analytical Technician 004270 APPENDIX HI STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: 0680TR0020________________ TITLE: 'SPECIAL LENS ORAL TERATOLOGY STUDY QF T 2999CoC in Rats Audits and/or inspections were performed by the Riker Compliance Audit unit for the above titled study, and reported to the study director and to management as follows : Date Performed Date Reported 12 February 1981 23 February 1981 18 March 1981 18 March 1981 31 March 1981 25 & 27 April 1981 21 December 1981 12 February 1981 24 February 1981 23 March 1981 24 March 1981 6 April 1981 29 April 1981 21 December 1981 11. 004271 Compliance Audit Riker Laboratories, Inc. Date APPENDIX IV 12. Test and/or Control Article Characterization .for T-2999CoC 1. The identity strength, uniformity, composition, purity or other per tinent characterizations of the test and/or,control substances have been determined and documented as of ___ $ ' / __ * * 2. The method of synthesis or origin of the test and control substances, including their amount and the method of bioassay (if applicable) is documented. yes 3. The stability of the test and/or control substances have, been deter mined or will be determined as of The above information and documentation are located in the sponsor's re cords. Sponsor GBk st*./9S/ ' Date *CCD Analytical Req. No. 16474 October 28, 1980 F o rm 19793 PWO 004272 Appendix V Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals DRV Replicate 1 3 6 9 12 15 20 0 MG/KG/DRV N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R N1R NIP. N1R N1R N1R N1R N1R N1R N1R 1130 1132 1133 1134 1150 1151 1152 1153 1154 1179 1180 1181 1182 1198 1199 1200 1201 1202 1218 1414 1415 1416 1417 1433 1434 1435 1436 1453 1454 185 202 194 230 195 170 208 206 187 192 221 184 224 206 206 200 207 193 197 175 183 201 172 174 174 157 192 178 173 220 221 220 251 215 212 231 226 217 218 249 211 246 226 229 228 225 211 216 226 219 240 205 224 204 160 232 223 211 247 250 246 264 230 242 248 242 240 244 267 226 266 249 255 255 265 226 243 252 233 274 229 245 225 205 268 248 228 275 277 272 291 227 262 262 268 254 269 293 247 289 256 284 278 284 253 264 282 256 298 252 251 249 222 288 275 235 298 308 304 317 232 290 273 295 260 303 327 283 324 261 317 318 318 284 302 309 228 330 262 307 273 262 316 301 266 341 369 382 377 235 337 282 376 276 386 416 345 407 271 392 395 407 359 393 407 339 422 331 403 345 357 413 397 345 MERN 193 221 245 266 292 362 STRN. DEV 17. 4 16. 7 15. 9 19. 6 27. 5 47. 9 NON PREGNANT ANIMALS N1R 1131 181 208 227 244 240 248 N1R 1170 194 223 240 259 263 273 N1R 1171 195 208 230 245 249 270 N1R 1178 209 235 248 0* 0 0 N1R 1219 191 219 242 250 252 266 N1R 1413 184 219 233 232 241 279 N1R 1437 184 225 249 228 251 258 -- Animal died 13 Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Heights (g) with Mean Body Heights and Standard Deviations for Pregnant Animals Replicate 2 DAV 3 6 9 12 15 20 0 MG/KG/DAV N1R 1461 216 239 259 278 302 370 N1R 1462 185 211 230 253 274 340 N1R 1463 179 205 232 267 285 354 NlR 1464 193 220 241 274 299 383 N1R 1465 187 219 240 268 298 355 N1R 1481 235 260 296 32 345 437 N1R 1482 213 235 265 293 318 398 N1R 1483 186 211 237 262 286 369 N1R 1484 203 231 252 277 298 378 N1R 1485 195 224 249 288 317 410 N1R 1501 177 203 229 253 278 356 N1R 1502 199 224 249 271 293 350 N1R 2374 196 237 262 299 339 418 NlR 2375 183 206 235 266 296 378 N1R 2376 210 241 269 297 331 402 NlR 2378 199 230 253 284 307 374 NlR 2394 214 244 259 287 312 349 N1R 2395 204 232 258 290 319 421 N1R 2396 195 221 240 265 296 366 N1R 2397 217 249 273 305 330 382 NlR 2398 210 245 268 303 332 417 N1R 2414 187 213 233 275 298 377 N1R 2415 186 226 244 284 307 398 NlR 2422 189 220 235 261 285 349 NlR 2423 225 259 286 314 341 431 NlR 2425 222 252 267 299 325 406 N1R 2426 212 250 256 285 311 310 N1R 2442 172 207 221 235 233 238 N1R 2443 208 246 265 298 327 416 N1R 2445 200 231 240 271 298 372 NlR 2446 215 238 251 288 311 383 NlR 2462 194 230 243 277 310 380 NlR 2463 174 205 215 238 251 298 MEAN 199 229 250 280 305 374 STAN. DEV 15. 7 16. 4 17. 7 19. 9 24. 4 40. 3 04274 NON PREGNANT ANIMALS N1R 2377 184 208 231 236 248 256 N1R 2424 196 236 253 283 315 394 N1R 2444 197 223 227 238 248 262 14. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals Replicate 1 DRV 3 6 9 12 15 20 5 MG/KG/DFIY __ ;01R 1135 212 241 265 275 317 392 01R 1136 214 228 238 234 243 258 I01R 113? 238 261 278 281 307 388 i01R 1138 160 203 216 214 222 241 !01R 1156 192 223 238 251 264 305 i01R 1158 237 269 290 317 348 429 01R 1172 162 163 200 214 253 331 01R 1173 201 237 251 257 265 27? !01R 1184 214 248 261 272 288 381 01R 1186 199 226 239 254 276 366 01R 1187 198 225 246 268 301 369 01R 1204 179 196 207 222 246 308 01R 1206 212 241 263 0fL 0 0 01R 1221 235 257 267 281 294 375 01R 1418 186 241 260 279 314 400 01R 1419 160 201 213 216 261 331 01R 1420 . 195 248 278 297 321 389 01R 1421 164 209 226 233 266 342 01R 1422 167 210 233 255 275 352 01R 1438 170 208 229 263 278 357 01R 1439 192 232 246 261 283 355 01R 1440 190 226 254 266 290 372 01R 1441 191 166 231 250 259 367 01R 1442 181 229 258 228 296 382 01R 1455 191 218 242 223 286 374 MERN 194 224 245 255 281 352 STRN. DEV 23. 3 26. 1 22. 9 27. 4 28. 6 45. 8 ( NON PREGNfiNT RNIMRLS 01R 1139 224 23? 246 01R 1155 224 250 260 01R 1157 187 198 220 01R 1159 192 223 236 01R 1183 215 238 253 01R 1185 219 236 235 01R 1203 142 205 219 01R 1205 210 226 230 01R 1207 219 233 240 01R 1220 208 222 236 01R 1456 156 185 199 252 270 247 256 220 214 220 238 254 272 240 246 238 246 235 253 240 249 0- 0 200 206 272 270 237 233 287 265 255 261 265 0 233 Animal died 004275 15. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals DRV Replicate 2 3 6 9 12 15 26 25 MG/KG/DAV 01R 1466 181 203 229 253 275 343 01R 1468 242 280 308 328 356 442 01R 1469 205 236 255 281 299 381 01R 1470 186 205 230 248 266 323 01R 1486 158 208 222 247 270 362 01R 1487 200 225 244 275 288 366 01R 1488 199 225 246 279 303 381 01R 1489 203 239 250 273 303 405 01R 1490 207 234 256 278 274 358 01R 15G3 204 234 253 273 295 361 01R 1504 192 224 257 291 318 414 01R 2379 189 223 237 260 276 338 01R 2380 214 247 272 296 328 390 01R 2381 202 228 251 270 292 343 01R 2382 195 219 234 253 267 294 01R 2383 199 229 249 271 295 352 01R 2399 183 171 217 239 266 332 01R 2400 195 230 250 264 293 360 01R 2401 194 217 233 257 281 343 01R 2462 188 239 269 298 311 385 01R 2403 199 220 234 250 279 354 01R 2416 233 260 279 305 336 415 01R 2417 222 258 275 301 330 412 01R 2428 219 250 256 275 291 334 01R 2430 203 246 263 289 319 383 01R 2431 208 241 263 293 320 399 01R 2447 191 195 225 241 266 348 01R 2448 213 249 259 2 6 1** 288 342 01R 2449 206 247 249 252 281 349 01R 2450 189 211 224 247 274 343 01R 2464 193 225 237 254 279 353 01R 2465 196 228 243 266 293 371 MEAN 200 230 249 271 294 365 STflN. DEV 15. 6 20. 9 18. 5 20. 8 23. 0 31. 5 004276 NON PREGNANT ANIMALS 01R 1467 184 215 234 251 263 287 01R 2427 196 226 228 229 240 255 01R 2429 195 230 241 239 250 268 01R 2451 192 228 234 225 237 255 16. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals DRV Replicate 1 3 6 9 12 15 20 2. 5 MG/KG/DR P1R 1140 190 215 234 232 243 254 P1R 1142 227 246 270 265 271 271 P1R 1144 209 238 267 300 328 405 P1R 1160 201 232 255 261 276 277 P1R 1161 194 224 252 266 292 327 P1R 1162 196 223 249 257 288 320 P1R 1164 182 207 225 218 230 235 P1R 1188 229 258 272 293 314 385 P1R 1189 177 196 217 238 271 347 P1R 1190 198 230 253 281 322 411 P1R 1191 .205 230 251 274 311 395 P1R 1192 214 243 261 282 319 401 P1R 1208 181 200 221 246 277 341 P1R 1209 225 250 268 293 330 412 P1R 1210 249 287 314 333 381 470 P1R 1211 205 228 247 264 278 327 P1R 1223 209 240 261 275 317 390 P1R 1423 166 215 243 278 294 400 P1R 1424 177 223 252 236 295 394 P1R 1425 178 223 242 273 292 375 P1R 1426 135 196 218 220 246 335 P1R 1443 157 195 217 218 261 339 P1R 1444 170 205 230 243 284 369 P1R 1445 197 238 274 292 307 382 P1R 1446 153 199 221 244 258 329 P1R 1447 182 215 236 239 287 377 P1R 1457 181 215 236 230 275 337 P1R 1458 152 190 211 230 264 327 MEAN 191 224 246 260 290 355 STflN. DEV 26. 0 22. 1 23. 0 28. 6 31. 7 53. 2 NON PREQNRNT RNIMRLS P1R 1141 177 206 219 223 245 252 P1R 1143 167 207 239 246 256 273 P1R 1163 194 217 239 241 252 260 P1R 1174 190 205 215 227 237 246 P1R 1175 147 184 196 211 213 223 P1R 1212 179 197 227 00 P1R 1222 191 217 226 0s- 0 0 P1R 1427 183 214 232 234 239 258 004277 17. Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals Replicate 2 DRV 3 6 9 12 15 20 2. 5 MG/KG/DR P1R 1471 194 223 247 244 298 388 P1R 1472 234 268 283 315 337 439 P1R 1473 185 210 237 267 290 359 P1R 1474 196 223 246 271 300 386 P1R 1475 179 209 233 258 283 355 P1R 1491 209 248 262 290 317 398 P1R 1492 195 212 243 259 285 348 P1R 1493 205 235 261 283 315 400 P1R 1494 218 251 269 305 335 410 P1R 1495 205 225 245 269 298 380 P1R 1505 193 223 243 270 290 361 P1R 1586 191 214 240 269 286 369 P1R 2384 189 213 243 268 302 361 P1R 2385 209 245 262 295 328 404 P1R 2386 233 256 282 313 345 434 P1R 2387 192 226 243 272 296 358 P1R 2388 191 220 247 268 297 356 P1R 2404 226 257 281 316 350 432 P1R 2406 200 223 248 274 305 373 P1R 2407 202 231 253 285 310 398 P1R 2408 205 234 253 282 315 392 P1R 2418 196 223 241 265 292 356 P1R 2419 225 249 278 304 333 412 P1R 2433 196 239 249 271 302 390 P1R 2434 222 264 277 303 330 406 P1R 2453 194 225 246 272 299 373 P1R 2454 203 232 248 267 284 335 P1R 2455 217 244 265 286 315 413 P1R 2456 211 243 256 283 295 348 P1R 2466 199 229 239 263 292 371 P1R 2467 197 225 245 270 300 384 MERN 204 233 254 279 307 384 STRN. DEV 13. 9 16. 1 14. 5 18. 1 18. 9 27. 2 004278 NON PREGNANT RNIMRLS P1R 2405 192 220 242 245 256 272 P1R 2432 199 233 238 247 257 270 P1R 2435 202 240 262 277 304 336 P1R 2436 224 259 273 271 281 289 P1R 2452 198 228 240 242 249 261 18 Appendix V (Continued) Special Lens Oral Teratology Study of T-2999CoC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals DRV Replicate 1 3 6 9 12 15 20 0. 25 MG/KG/D Q1R 1146 197 216 234 261 293 35? Q1R 1148 215 249 276 306 339 395 Q1R 1166 210 235 262 288 314 369 Q1R 1168 199 226 247 248 248 262 Q1R 117? 222 243 251 266 265 286 Q1R 1193 213 236 259 286 320 396 Q1R 1194 185 202 213 214 230 244 Q1R 1195 215 239 263 287 325 412 Q1R 1196 200 225 241 263 294 353 Q1R 1197 215 247 274 295 306 402 Q1R 1212 208 22? 246 266 299 368 Q1R 1214 197 224 242 25? 259 275 Q1R 1215 212 238 246 269 311 384 Q1R 1216 20? 233 251 277 307 391 Q1R 1217 185 212 228 247 274 332 Q1R 1224 205 237 259 274 312 385 Q1R 1225 218 251 267 296 325 339 Q1R 1428 175 218 244 25 301 377 Q1R 1429 176 199 232 250 282 369 Q1R 1430 206 242 263 265 274 289 Q1R 1431 208 251 282 273 334 429 Q1R 1422 170 203 232 216 284 369 Q1R 1448 196 236 259 288 300 361 Q1R 1449 211 244 281 294 328 426 Q1R 1450 187 237 269 286 318 417 Q1R 1451 204 257 286 294 339 438 Q1R 1452 186 228 253 252 312 409 MERN 201 232 254 269 300 364 STRN. DEV 14. 1 15. 5 18. 0 23. O 27. 9 52. ? 004279 NON PREGNRNT RNIMRLS Q1R 1145 176 203 234 251 260 266 Q1R 1147 183 207 232 243 245 251 Q1R 1149 172 187 194 217 228 242 Q1R 1165 199 228 254 270 283 279 Q1R 1167 196 241 257 264 272 278 Q1R 1169 192 221 244 25? 255 258 Q1R 1176- 192 220 246 263 0-- 0 Q1R 1459 182 213 242 246 255 277 Q1R 1 4 6 6 177 225 251 237 256 269 -- Animal died 19 Appendix V (Concluded) Special Lens Oral Teratology Study of T-2999CoC in Hats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals DRV Replicate 2 3 6 9 12 15 20 6. 25 MG/KG/D Q1R 1476 216 248 283 324 345 454 Q1R 1477 202 227 252 286 303 386 Q1R 1478 187 217 237 273 296 369 Q1R 1479 214 243 268 300 331 408 Q1R 1480 222 249 273 299 318 387 Q1R 1496 208 229 243 273 308 383 Q1R 1497 238 265 285 314 332 389 Q1R 149S 204 233 249 255 263 278 Q1R 1500 182 212 233 261 294 357 Q1R 1508 200 231 253 279 304 378 Q1R 2389 289 242 267 299 332 410 Q1R 2390 184 201 207 228 252 261 Q1R 2391 288 246 266 310 334 413 Q1R 2392 187 218 237 265 290 362 Q1R 2393 200 234 257 289 313 383 Q1R 2409 193 226 254 281 310 394 G1R 2410 26 229 252 281 307 376 Q1R 2411 213 240 257 2>2 321 429 Q1R 2412 212 240 260 287 298 351 Q1R 2413 205 229 254 288 313 397 Q1R 2420 190 245 272 306 332 425 Q1R 2421 189 219 244 269 282 316 Q1R 2437 185 211 225 250 270 322 Q1R 2438 208 246 261 280 281 300 Q1R 2439 192 238 255 287 313 398 Q1R 2440 206 244 255 279 301 351 Q1R 2441 208 241 256 279 382 363 Q1R 2457 196 224 239 272 300 382 Q1R 2458 193 229 242 264 290 363 Q1R 2459 212 246 276 302 324 396 Q1R 2460 173 223 237 265 284 285 Q1R 2461 187 224 246 277 300 379 Q1R 2468 236 278 293 318 340 459 Q1R 2469 190 220 236 259 288 368 MEAN 282 234 254 282 305 373 STAN. DEV 14. 6 15. 4 17. 8 20. 6 22. 0 45. 8 NON PREGNANT ANIMALS Q1R 1499 191 219 226 230 234 243 Q1R 1507 180 201 212 215 223 234 04280