Document reYOkbGYDYdb2VJ7KVD217k3v

Special lans Or&l Toratology Study of T-2999CoC in Rats Experiment No,: Conducted At: Dosing Period: Stu4y Director: 0680TROO20 Safety Evaluation Laboratory Riker Laboratories,, Inc. St. Paul, ml=esota February 9, 1981 through March 26, 1981 E. G. Gortner r tnttr senior Rpse4rch Technologist Date i,ni@@i ftpr'o-d'uction-Teratology Study Pirector G. Lamprecht, DVM, PhD Date Research Veterinary Pathologist &wt@n- :7r44.4) 14@e-o@wl M."T. q@se-I 'DV.F1F*-PW-''- - Date 14;nager, Pathology-@-Toxirology Safety Evaluation Laboratory 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 appe&rance 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 alrtifact 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. 2. T-2999Co(:La-was labeled a teratogen of the lens because -malities were observed at the 75, 37.5 and 25 mg/kg/day dose .atology study (Riker Experiment Number 0680TRO(ElO). The T-2999CoC studyb 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 .aboratories, Inc., St. Paul, Minnesota. Six sets of @tion 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 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 .alf 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 dissectingmicroscope. Fetal specimenswith visiblelens ided in paraffin, sectioned at 5-6 microns, stained with iin and examined histologically. The remaining females were il grade FM-3422) 0680TROO20) Chow, Ralston Purina Co., St. Louis, MO 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. 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 0680TROO10 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. 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 the 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 dam 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. Table I 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 82S 18 67 14 54 Fetuses with Lens Findings N t 41 14 55 241 59 22-a 41 16 -ESicjnificantlyhigher than the control (Chi-square with Yates correction p <0.05) Table 2 Special Lens Oral Teratology Study of T-2999CoC in Ratp Results of Ocular Examination Findings of Pups at Day 21 of Lactation Dose Group 0 mg/kg/day No. Total of Number Dams of Pups 29 291 25 mg/kg/day 30 263 2.5 mg/kg/day 28 266 0.25 mg/kg/day 26 211 No Abnorm. Found Abnorm. Found Findings 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 7. 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 DAY 6 9 12 :L5 20 --------------------------------------- MEFIN 29 STAN. DEV 10. 9 24 7. 9 2:L 26 70 S. 0 15. 5 29. 1 - MEFIN 31 2:L :LO1 27 70 STAN. DEV :L6.9 :L:L.5 :L3.9 16. 1 24.6 -MEAN 33 STAN. DEV 10. 0 23 14 30 65 4.5 :L3.3 13.7 30.2 MER14 31 22 15 31 64 STAN. DEV 9.4 7.4 :L2.3 :L7.9 29.9 Second Replicate 0 mg/kg/day 25 mg/kg/day 2.5 mg/kg/day 0.25 mg/kg/day DAY 6 9 :L2 :L5 20 ------------------------------------- i MEAt4 STAN. DEV 30 2:L 30 25 70 5. :1 6.6 6.3 6.9 22.4 iME19N 29 STAN. DEV li.8 1I MEFit4 29 STAN. ' DEV 5.8 MER14 32 STAN. DEV 7.8 :L9 8.3 21 5.7 20 6.0 22S 23 71 6.7 7.1 15. 3 26S 28 76 7.0 7.1 12. 4 28 23 68 6. 7 7.1 26.9 Significantly lower than the control (Dunnett's t test p < 0.05) 8. Appendix I TITLE: Protocol for a Special Lens Oral Teratology study of T-2999CoC2 in Rats OBJ'ECTIVE: 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 068OT-RODIO). 7ne objectives of the study are to deterrrdne 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 libitumo 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-2999Coc@E. 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) 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 48 2.5 mg/kg/day 48 0.25 mg/kg/day 48 0 mg/kg/day 48 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. will be divided among the dose groups as follows: The 96 new animals Dose Group High Kid Low Control Dose Level 25 mg/kg/day 2.5 mg/kg/day 0.25 mg/kg/day 0 mg/kg/day No. of Animals 24 24 24 24 The reason for this amendment is a reduced number of pregnant animals in the first two groups of animals. 10. Appendix Il 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 APPENDIX STATEMENT OF QUALITY ASSURANCE STUDY NUMBER: TITLE: 0680TROO20 SPECIAL LENS ORAL TERATOLOGY T 2999CoC in Rats STUDY OF 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 Compliance Audit Riker Laboratories, Inc. /,2IR D-aT-e- 12. APPENDIX IV Test aiid/or Control Article Characterization ,f-or T-2999CoC 1. The identity strength, uniformity, composition, purity or other pertinent characterizations of the test andio),co=ntrol 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 docuntented. yes no 3. The stability of the test and/or control substances have.be n deter- mined or will be determined as of 4:@dlieaodlj4he@,;zl The above cords. information and documentation are located in the sponsor's re- Sponsor Date *CCD Analytical Req. No. 16474 October 28, 1980 Form 19793 PWO 13. Appendix V special Lens Oral Teratology Study of T-2999COC in Rats individual Body Weights (g) with 14ean Body Weights and Standard Deviations for Pregnant Animals Replicate I 6 9 :12 :L5 20 ------------------------------------------------- 0 MG/KG/DAY NIR :L:L3O :185 220 247 275 298 341 NIR :L132 202 221 250 277 308 369 NIR 1:133 194 220 246 272 304 382 N:LR 1:134 230 251 264 291 317 377 NIR 1150 195 215 230 227 232 235 NIR 1.151 170 212 242 262 290 337 NIR il52 208 231 248 262 273 282 NiR 1153 206 226 242 268 295 376 NIR 1154 187 217 240 254 260 276 NIR 1179 192 218 244 269 303 396 NIR 1180 221 249 267 293 327 416 NIR :1181 184 211 226 247 283 345 NIR li82 224 246 266 289 324 407 NIR :1198 206 226 249 256 261 271 NIR 1199 206 229 255 284 317 392 NiR 1200 200 228 255 278 318 395 NiR 1201 207 225 265 284 318 407 NIR 1202 193 211 226 253 284 359 NIR 1218 197 216 243 264 302 393 NIR 1414 175 226 252 282 309 407 NIR 14l5 183 219 233 256 228 339 NiR 1416 201 240 274 298 330 422 NIR 1417 172 205 229 252 262 331 NIR 1433 174 224 245 251 307 403 NIR 1434 NIR 1435 NiR 1436 174 204 225 249 273 345 157 160 205 222 262 357 192 232 268 288 316 413 NIR 1453 178 223 248 275 301 397 NIR 1454 173 211 228 235 266 345 MEAN STFIN. DEV 193 221 245 266 292 362 17.4 16.7 :15.9 :19.6 27.5 47.9 NON PREGNANT RNIMALS NIR 1131 181 208 227 N:LR :1170 194 223. 240 NIR 1171 195 208 230 NIR 1178 209 235 248 NIR 1219 191 219 242 NIR 1413 184 219 233 NIR 1437 184 225 249 244 259 245 e250 232 228 240 263 249 o 252 241 251 248 273 270 0 266 279 258 Animal died 14. Appendix V (Continued) Special Lens oral Teratology Study of T-2999COC in Ratg Individual Body Weights (9) with Mean Body Weights and standard Deviations for Pregrtant Animals Replicate 2 DAY 3 6 9 12 :L5 20 -------------------------------------- --------- 0 MG/KG/DAY N:LR NIR NIR NiR N:LR NIP NIP NIR NiP NiF,: NIP NIR NIP NIR NIP NIP NIP NIP NIP NIP NIP NiR NIR NIR NIR NIP NiR NIR NIP NIP NIP NiR NiR 1461 :L462 :L463 :L464 1465 1481 1482 1483 1484 :L485 1501 1502 2374 2375 2376 2378 2394 2395 2396 2397 2398 2414 2415 2422 2423 2425 2426 2442 2443 2445 2446 2462 2463 MEAN STAN. DEV 2:L6 :LB5 :L79 :L93 :LS7 235 213 186 203 :L95 177 199 196 183 210 199 214 204 195 217 210 187 196 189 225 222 212 172 208 200 215 194 174 199 15.7 239 211 205 220 2:L9 260 235 211 231 224 203 224 237 206 241 230 244 232 221 249 245 213 226 220 259 252 250 207 246 231 238 230 205 229 16.4 259 230 232 24:L 240 296 265 237 252 249 229 249 2-62 235 269 253 259 258 240 273 268 233 244 235 280 267 256 221 265 240 251 243 215 250 17.7 278 253 267 274 268 320 293 262 277 288 253 271 299 266 297 284 287 290 265 305 303 275 284 261 314 299 285 235 298 271 288 277 238 280 19.9 302 274 285 299 298 345 318 286 298 317 278 293 339 296 331 307 312 319 296 330 332 298 307 285 341 325 311 233 327 298 311 310 251 370 340 -354 383 355 437 398 369 378 410 356 350 418 370 402 374 349 421 366 382 417 377 398 349 431 406 310 238 416 372 383 380 298 305 374 24.4 40.3 NON PREGNANT ANIMALS NiR NiR NiR 2377 2424 2444 184 196 197 208 236 223 231 253 227 236 283 238 248 315 248 256 394 262 Appendix V (Continued) is. Special Lane Oral TeratolOgY Study of T-2999COC in Rats Individual Body Weights (g) with Mean Body Weights and Standard Deviations for Prec-rnantAnimals Replicate I DAY 3 6 9 12 15 20 --------------------------------------------- 25 MG/KG/DAY OiR OiR O:LR OIR ILOIR O:LR O:LR .OiR OIR OIR OIR OIR OIR OiR OIR O:LR O:LR DIR OiR OIR OIR OIR OIR OIR OIR :L135 :LJL36 :1:137 1138 l156 l:158 :1172 t173 1194 li86 li87 1204 1206 1221 1418 1419 1420, 1421 1422 1438 1439 1440 1441 1442 1455 212 214 238 160 192 237 :162 201 214 199 198 179 212 235 186 160 :L95 164 167 170 192 190 191 181 191 MEAN 194 STAN. DEV 23.3 241 228 261 203 223 269 163 237 248 226 225 196 241 257 241 201 248 209 210 208 232 226 166 229 218 224 26. 1 265 238 278 216 238 290 200 251 261 239 246 207 263 267 260 213 278 226 233 229 246 254 231 258 242 245 22.9 275 234 28:1 214 251 3:L7. 214 257 272 254 268 222 os 281 279 216 297 233 255 263 261 266 250 228 223 317 243 307 222 264 348 253 265 288 276 301 246 0 294 314 261 321 266 275 278 283 290 259 296 286 255 281 27.4 21B. 6 392 258 388 241 305 429 33:1 277 381 366 369 308 0 375 400 331 389 42 352 357 3@,,., 372 367 362 374 352 45.8 . INON PREGNANT ANIMALS OIR 1139 224 237 246 OiR t155 224 250 260 OIR 1157 187 198 220 1159 192 223 236 OIR 1183 215 238 253 OIR 1185 219 236 235 OIR 1203 142 205 219 OIR 1205 210 226 230 OiR 1.207 219 233 240 O:LR 1220 208 222 236 :OIR 1456 156 185 199 i Animal died ---------------------------- -- ---- 252 270 247 256 220 214 220 230 254 272 240 246 238 246 235 253 240 249 OS 0 200 206 272 270 237 233 287 265 255 26:1 265 0 233 16. Appendix V (Continued) special Lens Oral Teratology Study of T-2999COC in Pats individual Body Weights (g) with mean Body Weights and Standard Deviations for Pregnant Animals Replicate 2 DA'T' 3 6 9 12 15 20 -------------------------------------------- 25 MG/KG/DAY OIR DIR O:LR O:LR ---O:LR OIR OIR OIR OIR OIR OiR OIR OIR OIR OIR OIR OIR OIR OiR OIR OIR OIR DIR OIR OIR OiR OiR OiR OiR OiR OIR OIR 1466 1468 :1469 :L470 1486 14S7 1488 1489 1490 1503 1504 2379 2380 2381 2382 2383 2399 2400 2401 2402 2403 2416 2417 2428 2430 2431 2447 2448 2449 2450 2464 2465 181 242 205 :LS6 :L58 200 199 203 207 204 192 189 214 202 195 199 183 195 194 188 199 233 222 219 203 208 191 213 206 189 193 196 MEAN 200 STAN. DEV 15.6 203 280 236 205 208 225 225 239 234 234 224 223 247 228 219 229 171 230 217 239 220 260 258 250 246 241 195 249 247 211 225 228 230 20.9 229 300 255 230 222 244 246 250 256 253 257 237 272 251 234 249 217 250 233 269 234 279 275 256 263 263 225 259 249 224 237 243 258 328 281 248 247 275 279 278 278 273 291 260 296 270 251-' 271 239 264 257 290 250 305 301 275 289 293 241 267 252 247 254 266 275 356 299 266 270 288 303 303 274 295 318 276 326 292 267 295 266 293 281 311 279 336 330 291 319 320 266 288 281 274 279 293 249 271 294 iS.5 20.8 23.0 343 442 381 323 362 366 381 405 358 361 414 338 390 343 294 352 332 360 343 385 354 415 412 334 383 399 348 342 349 343 353 371 365 31.5 NON PREGNANT ANIMALS DIR 1467 184 215 234 251 263 287 OIR 2427 196 226 228 229 240 255 OIR 2429 195 230 241 239 250 268 OiR 2451 192 228 234 225 237 255 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 I Ix DAY 3 6 9 :12 :L5 20 ------------------------------------------------ 2.5 MG/KG./DA P:LR P:LR PIR P:LR PIR PIR .P:LR PIR PIR PiR PIR P:LR PiR PiR PIR PIR PIR PIR PiR P:LR PIR P:LR PiR PIR PiR P:LR PiR P:LR :L:140 :L90 :L142 227 IL144 209 :1:160 201 1161 194 :L162 :L96 :1164 :182 liSS 229 1.189 177 1190 198 :1191 .205 il9'e*_* 214 1208 181 1209 225 1210 249 1211 205 1223 209 1423 166 1424 177 1425 178 1426 135 1443 157 1444 170 1445 197 1446 153 1447 182 1457 iSi 1458 152 2:15 246 238 232 224 223 207 258 196 230 230 243 200 250 287 228 240 215 223 223 196 195 205 238 199 215 215 190 234 270 267 255 252 249 225 272 217 253 251 261 221 268 314 247 261 243 252 242 218 217 230 274 221 236 236 211 MEAN STAN. DEV 191 26.0 224 246 22. :L 23.0 232 265 300 261 266 257 218 293 238 281 274 282 246 293 333 264 275 278 236 273 220 218 243 292 244 239 230 230 260 28.6 243 271 328 276 292 288 230 314 271 322 311 3i9 277 330 381 278 317 294 295 292 246 261 284 307 258 287 275 264 290 31.7 254 271 405 277 327 320 235 395 347 411 395 401 341 412 470 327 390 400 394 375 335 339 369 382 329 377 337 327 355 53.2 NON PREGNANT ANIMALS PiR PIR PiR PIR PiR P:LR PIR PIR 1141 l143 1163 1174 1175 1212 1222 1427 177 167 194 190 147 179 191 183 206 207 217 205 184 197 217 214 Animal died 219 239 239 215 196 227 226 232 223 246 241 227 211 a o;o@@ 234 245 256 252 237 213 0 o 239 252 273 260 246 223 0 o 258 18. Appendix V (Continued) Special Lens c)ral Teratology Study of T-2999CoC in Rats individual Body Weights (g) with Mean Body Weights and Standard Deviations for Pregnant Animals Replicate 2 DAY 3 6 9 12 15 20 -------------------------------------------------- 2.5 MG/KG/DA PiR P:LR PiR PIR PIR PIR PiR PIR PIR PIR PIR PIR PIR PiR PiR PIR PIR PIR PiR PIR PIR PIR PIR PIR PIR PIR PIR PIR PiR PIR PIR 147:1 :L472 1473 1474 1475 1491 1492 1493 1494 1495 1505 1506 2384 2385 2386 2387 2388 2404 2406 2407 2408 2418 2419 2433 2434 2453 2454 2455 2456 2466 2467 :L94 234 185 :L96 179 209 195 205 218 205 193 191 189 209 233 192 191 226 200 202 205 196 225 196 222 194 203 217 211 199 197 MEAN STAN. DEV 204 13.9 223 268 210 223 209 248 212 235 251 225 223 214 213 245 256 226 220 257 223 231 234 223 249 239 264 225 232 244 243 229 225 233 16.1 247 283 237 246 233 262 243 261 269 245 243 240 243 262 282 243 247 281 248 253 253 241 278 249 277 246 248 265 256 2-39 245 244 315 267 271 258 290 259 283 305 269 270 269 268 295 313 272 268 316 274 285 282 265 304 271 303 272 267 286 283 263 270 254 279 14.5 18.1 298 337 290 300 283 317 285 315 335 298 290 286 302 328 345 296 297 350 3e5 310 315 292 333 302 330 299 284 315 295 292 300 388 439 359 3186 35@ 398 348 400 410 380 361 369 361 404 434 358 356 432 373 398 392 356 412 390 406 373 335 413 348 371 394 307 384 :18.9 27.2 NON PREGNANT ANIMALS PIR 2405 192 220 242 245 256 272 PIR 2432 199 233 238 247 257 270 PIR 2435 202 240 262 277 304 336 PIR 2436 224 259 273 271 281 289 PIR 2452 L98 228 240 242 249 261 19. 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 I DAY 3 6 9 :12 15 20 ------------------------------------------- 0.25 MG/KG/D Q:LR Q:LR :Q:LR .QIR "QIR IQIR QiR QIR OIR QIR QIR QIR QIR OIR QIR QiR OIR QIR QIR QiR QiR QIR QIR GIR QIR QiR :L146 :LI.48 I.:L66 1168 I:L77 1193 :L:L94 :L195 :LI96 1197 1213 1214 1215 1216 1217 1224 1225 1428 1429 1430 1431 1432 1448 1449 1450 1451 1452 :L97 2:L5 210 199 222 213 185 215 200 215 208 197 212 207 185 2e5 218 175 176 206 208 170 196 211 187 204 196 2:16 249 235 226 243 236 202 239 225 247 227 224 238 233 212 237 251 218 199 242 251 203 236 244 237 257 228 MEAN 201 232 STAN. DEV 14. :L :L5.5 234 276 262 247 251 25 213 263 241 274 246 242 246 251 228 259 267 244 232 2-63 282 232 259 281 2-69 286 253 254 18.0 261 31D6 288 249 266 286 214 287 263 295 266 257 269 277 247 274 296 250 250 265 273 216 288 294 286 294 252 269 23.0 293 339 314 248 265 320 230 325 294 306 299 259 311 307 274 312 325 301 282 274 334 284 300 328 318 339 312 300 27.9 357 395 369 262 286 396 244 412 353 402 368 275 384 391 332 385 339 377 369 289 429 369 361 426 417 438 409 364 52.7 NON PREGNANT ANIMALS QIR 1145 176 203 234 251 260 266 QIR 1147 183 207 232 243 245 251 QIR IA49 172 187 194 217 228 242 OIR 1165 199 228 254 270 283 279 QIR :1167 196 241 257 264 272 278 OIR IA69 192 221 244 257 255 258 QIR 1176 192 220 246 263 es o ;Q:LR 1459 182 2:L3 242 246 255 277 'Ql.R -1460 :177 225 251 237 256 269 Animal died 20. Appendix V (Concluded) 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 DFIY 3 6 9 12 15 20 --------------------------------------------- 0.25 MG/KG/D OIR QIR QIR QiR QIR OIR GIR OIR QiR QIR QIR OIR QIR OIR OIR OIR QIR QIR QiR QIR QiR QIR QIR QIR GIR OIR QIR QIR QIR OIR QiR QIR QIR OIR 1476 1477 1478 1479 1480 1496 1497 1498 1500 1508 2389 2390 2391 2392 2393 2409 2410 2411 2412 2413 2420 2421 2437 2438 2439 2440 2441 2457 2458 2459 2460 2461 2468 2469 216 202 187 214 222 208 238 204 182 200 209 -184 208 187 200 193 206 213 212 205 190 189 185 208 192 206 208 196 193 212 173 187 236 190 248 227- 217 243 249 229 265 233 212 231 242 201 246 218 234 226 229 240 240 229 245 219 211 246 238 244 24:1 224 229 246 223 224 278 220 283 252 237 268 273 243 285 249 233 253 267 207 266 237 257 254 252 257 260 254 272 244 225 261 255 255 256 239 242 276 237 246 293 236 324 286 273 300 299 273 314 255 261 279 299 228 310 265 289 281 281 292 287 288 306 269 250 280 287 279 279 272 264 302 265 277 318 259 MEF114 STA14. DEV 202 234 254 282 :L4.6 15. 4 17. 8 20.6 345 303 296 331 318 308 332 263 294 304 332 252 334 290 313 310 307 321 298 313 332 282 270 281 313 301 302 300 290 324 284 300 340 288 305 22.0 454 386 369 408 387 383 389 278 357 378 410 261 413 362 383 394 376 429 351 397 425 316 322 300 398 351 363 382 363 396 285 379 459 368 373 45.8 NON PREGNANT ANIMALS GiR GIR 1499 1507 191 180 219 201 226 212 230 215 234 223 243 234