Document emBoxeKBByRV2Gk5EKdJ1ZRBm

Attachments to Letter to C. Auer dated May 25, 2000 Toxicology Studies and Other Information on PFOA o H62. Teratology 1) Teratology Study of T-2998CoC in Rats a) Oral Rangefinder Study of T-2998CoC in Pregnant Rats, Riker Laboratories, Inc., Study No. 0680RR0018, February 25, 1981 b) Final Report, Oral Teratology Study of T-2998 CoC in Rats, Riker Laboratories, Inc., Study No. 0681TR0110, December 15,1981, with Amendment to Final Report, December 22,1981 and Protocol 2) Teratology Study of T-3141CoC in Rabbits a) Oral Rangefinder Study of T-3141 CoC in Pregnant Rabbits, Riker Laboratories, Inc., Study No. 0681RB0331, November 18, 1981 b) Final Report, Oral Teratology Study of T-3141CoC in Rabbits, Riker Laboratories, Inc., Study No. 0681TB0398, February 23, 1982 c) 3M Internal Correspondence re analytical analyses of T-3141CoC, from LD Winter to DR Ricker, dated February 5, 1982 3) Letter re further testing from E. Marshall Johnson, Jefferson Medical College to Dr. Franklin D. Griffith, dated November 19, 1982 4) 3M Memo re FC 95 and 143 Teratology, from Marv Case to Georjean Adams, dated May 26, 1998, enclosing an analysis of the eye lens defect 7 C0.7025 Oral Rangefinder Study of T-2998COC in Pregnant Rats Experiment No.: Conducted At: Dosing Period: Study Director: 0680RR0018 Riker Laboratories, Inc. St.'Paul, Minnesota January 20, 1980 to January 29, 1980 E. G. Gortner 3 / p y/f'/ E. G. Gortner Date Senior Research Technologist Animal Teratology Reproduction Study Director J lS juv i o M f r a j i A J / a v /tf E. G. Lamprecht, DVM, PhD Date Research Veterinary Pathologist M. T. Case, DVM, PhD Date Manager, Pathology-Toxicology Safety Evaluation Laboratory C-C3026 Introduction This oral rangefinder study^ was conducted to determine the upper dose level of T-2998CoC-- for a subsequent oral teratology study in rats. The study was sponsored by 3M Commercial Chemical Division, St. Paul, Minnnesota and was conducted by the Safety Evaluation Laboratory, Riker Laboratories, Inc., St. Paul, Minnesota. The study was conducted in accordance with the Safety Evaluation Laboratory's Standard Operating Procedures for such studies. The storage location for the raw data and a copy of the final report is maintained in the Safety Evaluation Laboratory's record archives. Methods Thirty-six time-mated Sprague-Dawley derived female rats from Charles River Breeding Laboratory were used in the study. The animals were indiscriminately removed from the shipping boxes by Animal Care personnel and placed in the rack of cages from the left to right starting at the top and working down. Later the Study Director assigned dose groups by vertical rows. The rats were housed individually in hanging stainless steel cages with wire mesh floors and fronts in a temperature and humidity controlled room. Purina Laboratory Chow and water were available ad libitum. The lights were on a 12 hour light/dark cycle. The animals were observed daily from day 3 through day 20 of gestation for abnormal clinical signs. Body weights were recorded on days 3, 6, 9, 12, 15 and 20 of gestation and the rats dosed accordingly using a constant dose volume of 5 ml/kg of body weight. T-2998CoC was suspended in corn oil and administered daily by oral intubation at doses of 150, 100, 75, 50 or 25 mg/kg/day to groups of 6 rats on days 6 through 15 of gestation. A control group of 6 rats received only corn oil by oral intubation on the same days. On day 20 of gestation the rats were killed by cervical dislocation and each uterus, including its contents, was examined immediately to determine if the animal was pregnant. Because two previous teratology studies (Riker Experiment Nos: 0680TR0008 and 0680TR0010) with chemically related compounds resulted in fetuses with teratogenic changes in the lens of the eye, a few fetuses were also taken at day 20 of gestation and examined for eye abnormalities. Blood samples from three rats in each dose group were taken before the first dose and at day 20 of gestation. Liver specimens were also taken from the same rats on day 20 of gestation. The plasma samples and liver specimens were frozen and submitted to the sponsor. Results and Discussion The oral administration of T-2998CoC at 150, 100, 75, 50 or 25 mg/kg/day to rats during the period of organogenesis (days 6 through 15 of gestation) did not result in any deaths. A toxic effect of reduced body weight gain occurred between days 6 and 9 of gestation in the 150 mg/kg/day dose group (Table 1). The two nonpregnant 150 mg/kg/day rats had a more severe effect on body Riker Experiment No. 0680RR0018 ^ PC-143 003027 2 weight on day 9 of the study than the pregnant high dose dams (Appendix I). They lost a considerable amount of weight and one was observed to have urinary incontinence on days 11, 12 and 13. The pregnant dams of the 100, 75, 50 and 25 mg/kg/day dose groups did not have abnormal clinical signs and gained weight at comparable levels to the 0 mg/kg/day group. Four fetuses were examined from each of four dams in the 150 and 25 mg/kg/day dose groups for eye changes. All of the readable fetuses sectioned had eye changes consisting of one or more of the following: large lens clefts, dark streak running one-half to three-quarters of the way through the lens or disorganized lens fibers (Table 2). The lens abnormalities occurred in the same location as those observed in the two previous teratology studies (Riker Experiment Nos: 0680TR0008 and 0680TR0010) on chemically related compounds. The abnormalities in this study appeared more pronounced than in the previous studies. Zn the previous studies, the teratogenic effect was a developmental eye abnormality which appeared to be an arrest in development of the primary lens fibers forming the embryonal lens nucleus,' followed by secondary aberrations of the secondary lens fiber of the fetal nucleus. The same general morphological changes occurred in this rangefinder study with T-2998COC. Conclusion The objective of determining an upper dose level for an oral rat teratology study was met in this study. The above results suggest that the 150 mg/kg/day dose level would be an appropriate high dose in a rat teratology study because of the toxic effect of reduced body weight gain. Zn addition to the toxic effect of reduced body weight gain, the teratogenic effect of lens abnormality was observed and is likely to be reproduced in a teratology study. 003028 K $ r copy M W ABU Table 1 Oral Rangefinder Study of T-2998CoC in Preqnant Rats Mean Body Weight Gains of Pregnant Rats With Standard Deviations (g) Control 150 m g A g / d a y 100 mg/kg/day 75 mg/kg/day 50 mg/kg/day 25 mg/kg/day Day 8 8 12 1 b If 21 22 *'6 4 2 ?. 4 ,V b 1. 6 lt>. ? 21. 2b 2. 12 84 b. b IV. 8 8. 8 12. 8 12. 1 22 10 1 V 18 84 4. i b 1 A . A 12. 8 12. b 2 11 21 18 74 f. 0. 1.0 0 2. V 10. b 12. 6 :0 it. 6. b 2. V L<. 6 ?\ 6 10. O 2 A 16 * `*'1 ' r. S-. ` Ir4 b. 8 3. -- Significantly higher them the control (Dunnett's t test p <0.05) C03029` Table 2 Oral Rangefinder Study of T-2998COC in Preqnant Rats Ratios of Fetuses with Eye Changes to Fetuses Examined^ High Dose Group (150 mgAg/day) 16/16 Low Dose Group (25 mgAg/day) 15/15- 4. Four fetuses examined from each of four dams One fetus not examined because eye architecture destroyed in sectioning |tr|o> 003020 Appendix I BEST COPY AVAU ABLE Oral Rangefinder Study of T-2998CoC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats 5 _______ Day________________ 6 S' 12 15 0 8 Mu.-'K G, '[-'HV Nik 216 1*4 221 244 26* 2 7*' ---c'2 Nik 217 186 214 L*-l*C* 262 2 k-' 2 ?b Nik 21V 1*2 21? w2'*1 ,''a'': 2*-'2 26 b Nik 11* 2L'>t' 21 2bb 25* 2bb 260 Nik 140. 1*5 211 -ir( 280 i n 262 NEh N 1*5 225 264 *"r*5 2;6 9 SI HN. d e v 7. 7 10. 1 11. b 10. 5 11 5 6. 2 n u n pkbGNHt-5 HNII-IHLS Nik 120 1*4 21v 22-1 215 22 222 Day________________ ? 12 1 5 2 0 1 5 0 MG.-'KG/DH 01k Oik GIF: Dlk 121 202 222 216 257 28? 267 124 1*1 218 21? 25? 261 344 125 '177 1*1 244 243 214 247 206 222 `26 378 NEHN 195 216 220 STEIN. DEV 12. * 1?. 5 4. 6 NUN PREGNHN'I HNIMHl S Oik 222 20? 228 I'-Db Glk 322 181 205 181 255 26? 7. ? 1*. 4 200 21* 1*6 215 351 246 221 003031 BEST COPY AVA llABL Appendix I (Continued) Oral Rangefinder Study of T-2998CoC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats 6 Da t* 12 16 2t 1U0 I'lb.'Kb. L'H PIP PIP PIP Pit: PIP PxP 226 227 226 226 220 246 164 21'1 262 26b 166 166 162 240 'felt 216 il 210 24 6 246 224 24 0 cl'* ! C* 117 266 24 6 2 -< 252 265 J-A v !~! 26*3 .2-<ii'r* 221 4 2 --*J-- j-1*~ S 271 MEHN 202 247 264 L C*l2 2 STH N . DEV 22. 6 21. 2 20 4 2 t* j 4. S* 46. 5 Day_________ Ee 1 2 1 75 MG/KCi/DRV U1P 221 162 221 242 265 266 246 CUP ---- 166 212 226 246 271 246 Q1P ,172 202 215 225 262 246 01P 224 211 241 226 261 2 11'O 226 01P --j-iT* 162 216 226 244 266 221 Q1P 24 6 200 221 246 265 262 262 MERf-l 164 221 222 252 272 24 6 STfiN. DEV 12. 6 14. 1 12. 2 12. 4 10 6 20. O' 003032 BEST COPY AVAI1ABLE Appendix I (Concluded) Oral Rangefinder Study of T-2998COC in Pregnant Rats Individual Body Weights (g) and Mean Body Weights with Standard Deviation for Pregnant Rats Day_________________ 9 12 5 20 50 MG/KG/L RV R1R R1R R1R R1R R1R R1R 226 192 219 .*26 252 276 3^:0 227 177 201 212 225 259 ----c* 228 226 251 2S2 214 3*7 229 170 19 S' 2IS 2 i'" 254 3tic: 240 IS 7 2'2'6 245 267 204 i``C1 250 192 229 242 276 208 282 MERN 191 221 II 3 259 286 259 STRN. DEV 19. 4 19. 6 18. 2 20. 1 26. 2 22. 0 Day___________ 9 12 15 25 MG/KG/DHV SIR 242 216 229 s 204 28: SIR 242 ' 207 224 249 279 204 28: SIR 244 185 20S ".* 252 ,,* SIR 245 2010 219 223 249 270 24: SIR 251 205 222 28 268 207 29 MERN 202 227 J- 266 295 27 STRN. DEV 11. 4 12. 8 15. 4 15. 2 15. 2 19. NON PREGNRN7 RNIMRLS SIR 241 IS?' 202 219 220 0 O'I /I'/I0 003033