Document reXaJgK6eJYpMd3BjGGYzVmQG

Study Tite #R226_ 1092 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER `GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (APFO) IN RATS SPONSOR'S STUDY NUMBER: T-6889.6 Data Requirement U.S. Environmental Protection Agency (1998). Health Effects Test Guidelines; Reproduction and Fertility Effects. Office of Prevention, Pesticides and Toxic Substances (OPPTS) 870.3800, August, 1998. U.S. Environmental Protection Agency (1997). Toxic Substances Control Act (TSCA) `Test Guidelines; Final Rule. Reproduction and Fertility Effects, 799.9380 (crossreferenced to OPPTS 870.3800). Federal Register, August 15, 1997. Author Raymond G. York, Ph.D., DABT (Study Director) Study Completed On 26 March, 2002 (Final Report) Performing Laboratory Argus Research 905 Sheehy Drive, Building A Horsham, Pennsylvania 19044-1297 LaboratoryProjectID Argus Research Protocol Number: 418-020 = 8z ox 2 39 3 Z2Zg 2 ~ Page 1 of 1245 ARGUS 418-020 Confidentiality Page "This is ablank page to be inserted by the Sponsor. Page2 ARGUS 418-020 GOOD LABORATORY PRACTICE STATEMENT "This study was conducted according (0 U.S. Environmental Protection Agency (EPA FIFRA/TSCA) "Good Laboratory Practice Standards; Final Rule" (40 CFR Part and Development (OECD) 160/792) and the Organisation for Economic Co-operation Practice", with the exceptions in bulleted list below. "Principles of Good Laboratory `Exceptions to GLP compliance: TAhreguAsrSgtuusdSytDuidryepcrtootropcroilor41to8-t0h2e0i,niwtiaastiaopnporfoavneyd wboyrtkhepeSrpfoonrsmoerdafnodr stihgisnesdtubdyy.thTehe Sponsor's analytical group developed a separate protocol [3M FACT-TCX-164] and apCoosrrsteiisgoennnetdaesad aSistneupAdapyrpaDetinerdeisctxtuodLry.oforTthhtiheserSweppooornrkts)ocrwohniidscushucetadeddadraretesptsoherestirtohsriettefhoailsnldsoewviginmegewneatrdoeatfhstehoefannaslotyuntdiycal compliance: ThInveesatnigaaltyotri,cal protocol identified a second Study Director rather than aPrincipal Thtoeprdootosceoclo3nfMirFmAatCiTo-nTaCnXd-s1ta6b4ilibteyianngalaypspersovweedreancdonidsuscuetde.d by the Sponsor prior The purity and stability ofthe surrogate THPFOS standard is not included in the full study report, as it is not known at this time. Submitter: Studyy Director: Sponsor: VNera CKA. 2008 3000 RAarykiy)npRnedseGa.rYchork, fh.D.PABT Date omKliabeff 3M Corporate Toxicology 2 opal 2c Date Page3 ARGUS 418-020 Flagging Page This is a blank page to be supplied by the Sponsor Page 4 ARGUS 418-020 PROTOCOL 418-020: ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (APFO) IN RATS SPONSOR'S STUDY NUMBER: T-6889.6 TABLE OF CONTENTS SUBJECT PAGE IL SUMMARY AND CONCLUSION 15 A Methods 15 B. Results 18 C. Conclusion 2% IL DESCRIPTION OF TEST PROCEDURES 25 A. Conduct of Study 25 B. Test Substance Information 23 C. Vehicle Information 2 D. Test Substance Preparation and Storage Conditions 2 E. TestSysem 30 F. Husbandry 2 G. Methods 35 I. RESULTS - P GENERATION RATS 46 A. P Generation Male Rats 46 B. P Generation Female Rats 50 Page 5 ARGUS 418-020 SUBJECT PAGE IV. RESULTS - FI GENERATION RATS 55 A. Fl Generation Male Rats 55 B. Fl Generation Female Rats 62 REFERENCES 68 APPENDIX A - REPORT FIGURES 70 Figure 1. Body Weights - PGeneration Male Rats mn Figure2. Body Weights - P Generation Female Rats 7 Figure3. Body Weights - FI Generation Male Rats 7 Figured. Body Weights - FI Generation Female Rats 7 APPENDIX B - REPORT TABLES - P GENERATION MALE RATS 7s Table BI. Clinical Observations - Summary - P Generation Male Rats 76 Table B2. Body Weights - Summary - P Generation Male Rats 8 Table B3. Body Weight Changes - Summary - P Generation Male Rats 80 Table B4. Absolute Feed Consumption Values (g/day) - Summary - P Generation Male Rats 82 Table BS. Relative Feed Consumption Values (g/kg/day) - Summary - P Generation Male Rats 83 Table B6. Mating and Fertility - Summary - P Generation Male Rats 84 Table B7. Necropsy Observations - Summary - P Generation Male Rats 85 Table BS. Terminal Body Weights and Organ Weights - Summary - P Generation Male Rats 86 Table B9. Ratios (%) of Organ Weight to Terminal Body Weight - Summary - P Generation Male Rats 88 Table BIO. Ratios (%) of Organ Weight to Brain Weight - Summary - P Generation Male Rats 9% Page 6 ARGUS 418-020 SUBJECT PAGE Table BI1. Cauda Epididymal Sperm Motility, Count, Density and Spermatid Count - Summary - P Generation Male Rats 92 Table B12. Cauda Epididymal Sperm Morphology - Summary - P Generation Male Rats 9 Table BI3. Clinical Observations - Individual Data - P Generation Male Rats ~~ 95 Table B14. Body Weights - Individual Data - P Generation Male Rats 106 Table BIS. Feed Consumption Values - Individual Data - P Generation Male Rats nm Table BI6 Mating and Fertilit-y Individual Data - PGeneration Male Rats 116 Table BI7. Necropsy Observations - Individual Data - P Generation Male Rats 121 Table BIS. Terminal Body Weights and Organ Weights and Ratios (%) ofOrgan Weight to Terminal Body Weight - Individual Data - P Generation Male Rats 127 Table BI9. Brain Weights and Organ Weights and Ratios (%) ofOrgan Weight to Brain Weight - Individual Data - P Generation Male Rats 145 Table B20. Cauda Epididymal Sperm Motility, Count, Density and Spermatid `Count - Individual Data - P Generation Male Rats 163 Table B21. Cauda Epididymal Sperm Morphology - Individual Dat-a P Generation Male Rats 169 APPENDIXC - REPORT TABLES - P GENERATION FEMALE RATS 174 Table CI. Clinical Observations - Summary - P Generation Female Rats 175 Table C2. Body Weights- Precohabitation - Summary - P Generation Female Rats 178 Table C3. Body Weight Changes - Precohabitation - Summary - P Generation Female Rats 179 Table C4. Maternal Body Weights- Gestation - Summary - P Generation Female Rats 180 Table C5. Maternal Body Weight Changes - Gestation - Summary - P Generation Female Rats 181 Page? SUBJECT Table C6. Table C7. Table C8. Table C9. Table C10. Table Cl1. Table C12. Table C13. Table C14. Table C15. Table C16. Table C17. Table CI. Table C19. Table C20. ARGUS 418-020 PAGE Maternal Body Weights- Lactation - Summary - P Generation Female Rats 182 Maternal Body Weight Changes - Lactation - Summary - P Generation Female Rats 183 Absolute Feed Consumption Values (g/day) - Precohabitation - Summary - P Generation Female Rats 184 Relative Feed Consumption Values (g/kg/day) - Precohabitation - `Summary - P Generation Female Rats 185 Maternal Absolute Feed Consumption Values (g/day) - Gestation - `Summary - P Generation Female Rats 186 Matemal Relative Feed Consumption Values (g/kg/day) - Gestation - `Summary - P Generation Female Rats 187 Maternal Absolute Feed Consumption Values (g/day) - Lactation - `Summary - P Generation Female Rats 188 Maternal Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - P Generation Female Rats 189 Mating and Fertility, Estrous Cycling and Days in Cohabitation - `Summary - P Generation Female Rats 190 Necropsy Observations - Summary - P Generation Female Rats 192 Terminal Body Weights and Organ Weights - Summar-y P Generation Female Rats 193 Ratios (%) of Organ Weight to Terminal Body Weight - Summar-y P Generation Female Rats 194 Ratios (%)ofOrgan Weight to Brain Weight - Summary - PGeneration Female Rats 195 Natural Delivery Observations - Summary - PGeneration Female Rats. 196 Litter Observations (Naturally Delivered Pups) - Summary - P Generation Female Rats 197 Page 8 SUBJECT Table C21. Table C22. Table C23. Table C24. Table C25. Table C26. Table C27. Table C28. Table C29. Table C30. Table C31. Table C32. Table C33. Table C34. Table C35. ARGUS 418-020 PAGE Clinical Observations from Birth to Day 22 Postpartum - Summary - F1 Generation Pups 200 Necropsy Observations from Birth to Day 22 Postpartum - Summary - FI Generation Pups 201 Pup Organ Weights - Summary - FI Generation Pups 202 Clinical Observations - Individual Data-P Generation Female Rats 205 Body Weights - Precohabitation - Individual Data - P Generation Female Rats 215 Maternal Body Weights- Presumed Gestation - Individual Data - P Generation Female Rats 220 Matemal Body Weights - Lactation - Individual Data - P Generation Female Rats 225 Feed Consumption Values - Precohabitation - Individual Data - P Generation Female Rats 230 Maternal Feed Consumption Values - Presumed Gestation - Individual Data - PGeneration Female Rats 235 Maternal Feed Consumption Values - Lactation - Individual Data - P Generation Female Rats 240 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Individual Data - P Generation Female Rats 25 Necropsy Observations - Individual Data- P Generation Female Rats 250 Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - P Generation Female Rats 257 Brain Weights, Organ Weights, and Ratios (%) of Organ Weight 10 Brain Weight - Individual Data-PGeneration Female Rats 267 Natural Delivery, Implantation Sites, and Pup Viability and Sex - Individual Data- P Generation Female Rats am Page 9 SUBJECT Table C36. ARGUS 418-020 PAGE Pup Body Weight Litter Averages from Birth to Day 22 Postpartum - Individual Data-FI Generation Litters 282 Table C37. Pup Body Weighs from Birth to Day 22 Postpartum - Individual Data - FI Generation Pups 287 Table C38. Pup Vital Status and Sex from Birth to Day 22 Postpartum - Individual Data - F1 Generation Pups 312 Table C39. Clinical Observations from Birth to Day 22 Postpartum - Individual Data - F Generation Pups 317 Table C40. Necropsy Observations from Birth to Day 22 Postpartum - Individual Data - FI Generation Pups 320 Table C41. Pup Organ Weighs - Individual Data - FI Generation Pups 330 APPENDIX D - REPORT TABLES - FI GENERATION MALE RATS 35 Table D1. Clinical Observations - Summary - FI Generation Male Rats 336 Table D2. Body Weights - Summary - FI Generation Male Rats 339 Table D3. Body Weight Changes - Summary - FI Generation Male Rats 341 Table D4. Absolute Feed Consumption Values (g/day) - Summary - Fl Generation Male Rats 343 Table DS. Relative Feed Consumption Values (g/kg/day) - Summary - Fl Generation Male Rats 345 Table D6. Sexual Maturation - Summary - Fl Generation Male Rats 347 Table D7. Mating and Fertility - Summary - FI Generation Male Rats 348 Table DS. Necropsy Observations - Summary - FI Generation Male Rats 349 Table D9. Terminal Body Weights and Organ Weights - Summary - F1 Generation Male Rats 351 Table DIO. Ratios (%) ofOrgan Weight to Terminal Body Weight - Summary - FI Generation Male Rats 353 Table DI1. Ratios (%) of Organ Weight to Brain Weight - Summary - Fl Generation Male Rats 355 Page 10 ARGUS 418-020 SUBJECT PAGE Table DI2. Cauda Epididymal Sperm Motility, Count, Density and Spermatid `Count - Summary - FI Generation Male Rats 357 Table DI3. Cauda Epididymal Sperm Morphology - Summary - FI Generation Male Rats 359 Table DI4. Clinical Observations - Individual Data - FI Generation Male Rats 360 Table DIS. Body Weights- Individual Data - FI Generation Male Rats 378 Table DI6. Feed Consumption Values - Individual Data - FI Generation Male Rats 398 Table DI7. Sexual Maturation - Individual Data - FI Generation Male Rats 408 Table DIS. Mating And Fertility - Individual Data - FI Generation Male Rats~~ 410 Table D9. Necropsy Observations - Individual Data - FI Generation Male Rats 415 Table D20. Terminal Body Weights and Organ Weights and Ratios (%) of Organ WeighttoTerminal Body Weight - Individual Data - Fl Generation Male Rats 432 Table D21. Brain Weights, Organ Weights and Ratios (%)ofOrgan Weight to Brain Weight - Individual Data - FI Generation Male Rats 7 Table D22. Cauda Epididymal Sperm Motility, Count, Density and Spermatid Count - Individual Data - FI Generation Male Rats 462 Table D23. Cauda Epididymal Sperm Morphology - Individual Data - Fl Generation Male Rats 468 APPENDIX E - REPORT TABLES - FI GENERATION FEMALE RATS 473 Table EL. Clinical Observations - Summary - FI Generation Female Rats 474 Table E2. Body Weights- Precohabitation - Summary - FI Generation Female Rats 419 Table E3. Body Weight Changes - Precohabitation - Summary - Fl Generation Female Rats 481 Table E4. Maternal Body Weights - Gestation - Summary - F1 Generation Female Rats 483 Page 11 SUBJECT Table ES. Table 6. Table 7. Table ES. Table E9. Table E10. Table E11. Table E12. Table E13. Table E14. Table EIS. Table E16. Table E17. Table EIS. Table E19. Table E20. ARGUS 418-020 PAGE Maternal Body Weight Changes - Gestation - Summary- Fl Generation Female Rats 484 Maternal Body Weights - Lactation - Summary - FI Generation Female Rats 485 Maternal Body Weight Changes - Lactation - Summary - Fl Generation Female Rats 486 Absolute Feed Consumption Values (g/day) - Precohabitation - `Summary-FI Generation Female Rats 487 Relative Feed Consumption Values (g/kg/day) - Precohabitation `Summary - FI Generation Female Rats 488 Maternal Absolute Feed Consumption Values (g/day) - Gestation - `Summary - Fl Generation Female Rats 489 Maternal Relative Feed Consumption Values (g/kg/day-) Gestation - Summary - FI Generation Female Rats 490 Maternal Absolute Feed Consumption Values (g/day) Lactation - Summary - FI Generation Female Rats 91 Maternal Relative Feed Consumption Values (g/kg/day) - Lactation - Summary - FI Generation Female Rats 492 Sexual Maturation - Summary - Fl Generation Female Rats 493 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Summary - FI Generation Female Rats 494 Necropsy Observations - Summary - FI Generation Female Rats 496 Terminal Body Weights and Organ Weights - Summar-y FI Generation Female Rats 498 Ratios (%) of Organ Weight to Terminal Body Weight - `Summary- F1 Generation Female Rats 499 Ratios (%) of Organ Weight to Brain Weight - Summary - FI Generation Female Rats 500 Natural Delivery Observations - Summary - F1 Generation Female Rats s01 Page 12 SUBJECT Table E21. Table E22. Table E23. Table E24. Table E25. Table E26. Table E27. Table E28. Table E29. Table E30. Table E31. Table E32. Table E33. Table E34. Table E35. Table E36. ARGUS 418-020 PAGE Litter Observations (Naturally Delivered Pups) - Summary- F2 Generation Pups 502 Clinical Observations from Birth to Day 22 Postpartum - `Summary - F2 Generation Pups 505 Necropsy Observations - Summary - F2 Generation Pups 507 Pup Organ Weights - Summary - F2 Generation Pups 508 Anogenital Distance - Summary - F2 Generation Pups si Clinical Observations - Individual Data - FI Generation Female Rats 512 Body Weights - Precohabitation - Individual Data - FI Generation Female Rats 527 Maternal Body Weights - Presumed Gestation - Individual Data - FI Generation Female Rats 537 Maternal Body Weights- Lactation - Individual Data- Fl Generation Female Rats 542 Feed Consumption Values - Precohabitation - Individual Data - Fl Generation Female Rats 547 Maternal Feed Consumption Values - Presumed Gestation - Individual Data - FI Generation Female Rats 557 Maternal Feed Consumption Values - Lactation - Individual Data - FI Generation Female Rats 562 Sexual Maturation - Individual Data - FI Generation Female Rats~~ 567 Mating and Fertility, Estrous Cycling and Days in Cohabitation - Individual Data- F1 Generation Female Rats 569 Necropsy Observations - Individual Data - FI Generation Female Rats 574 Terminal Body Weights and Organ Weights and Ratios (%) of Organ Weight to Terminal Body Weight - Individual Data - FI Generation Female Rats 586 Page 13 ARGUS 418-020 SUBJECT PAGE Table E37. Brain Weights, Organ Weights and Ratios (%) of Organ Weight to Brain Weight - Individual Data-FI Generation Female Rats 596 Table E38. Natural Delivery, Implantation Sites, and Pup Viability and Sex Individual Data - F1 Generation Female Rats/F2 Generation Litters 606 Table E39. Pup Body Weight Litter Averages from Birth toDay 22 Postpartum - Individual Data - F2 Generation Pups 611 Table E40. Pup Body Weights from Birth to Day 22 Postpartum - Individual Data - F2 Generation Pups 616 Table EAL. Pup Vital Status and Sex from Birth to Day 22 Postpartum - Individual Data - F2 Generation Pups. 641 Table E42. Clinical Observations from Birth to Day 22 Postpartum - Individual Data - F2 Generation Pups. 646 Table E43. Necropsy Observations - Individual Data-F2 Generation Pups 648 Table E44. Pup Organ Weights - Individual Data - F2 Generation Pups 658 Table E45. Anogenital Distance - Individual Data - F2 Generation Pups 663 APPENDIX F - PROTOCOL AND AMENDMENTS 683 APPENDIX G - DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY 42 APPENDIXH - CERTIFICATES OF ANALYSIS 755 APPENDIX I- ANALYTICAL REPORT 758 APPENDIX J - ENVIRONMENTAL AND HUSBANDRY REPORTS 869 APPENDIX K - HISTOPATHOLOGY REPORT 924 APPENDIXL - HISTORICAL CONTROL DATA 1230 APPENDIX M -QUALITY ASSURANCE STATEMENT 1242 Page 14 ARGUS 418-020 TITLE: ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (APFO) IN RATS ARGUS RESEARCH PROTOCOL NUMBER: 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 I SUMMARY AND CONCLUSION A. Methods Crl:CD(SD)IGS BR VAF/Plus rats were used. The P generation consisted of 150 rats per sex assigned to five dosage groups (Groups I through V), 30 ratspersex per dosage group. Two FI generation pupsper sex per litter per group (60 male and 60 female pups per group) were selected for continued evaluation, resulting in 300 rats per sex assigned to five dosage groups (Groups I through V). Solutions of ammonium perfluorooctanoate: (APFO) in reverse osmosis membrane processed deionized water were administered to the P generation male and female rats, beginning at approximately six weeks of age and continuing until the day before sacrifice, at dosages of 0, 1, 3, 10 and 30 mg/kg/day. The dosage volume was 5 mL/kg, adjusted daily on the basis of the most recently recorded body weight. The F1 generation rats were given the same dosage level of the test substance as their respective P generation sires and dams. Dosages were given once daily, beginning at weaning and continuing until the day before sacrifice. Dosages were adjusted at least weekly for body weight changes and given at approximately the same time each day. F1 and F2 generation pups may have been exposed to the test substance during the maternal gestation (in utero exposure) or via maternal milk during the postpartum period. `The P and FI generation rats were observed for viability at least twice each day. The rats were also examinedforclinical observations of effects of the test substance, abortions, premature deliveries and deaths before dosage and 60 2 10 minutes after dosage during the dosage period. Body weightsofthe P generation male rats were recorded weekly during the dosage periods and on the day of sacrifice. Body weights of the F1 generation male rats were recorded weekly during the postweaning period and on the day of sacrifice. Body weights of the P generation female rats were recorded weekly during the a. Detailed descriptionsofall procedures used in the conduct of this study are provided in the appropriate sections ofthis report and in APPENDIX F (PROTOCOL AND AMENDMENTS). Page 15 ARGUS 418-020 precohabitation and cohabitation periods and on days of gestation (DG) 0, 7, 10, 14, 18, 21 and 25 (if necessary) and on DLs 1,5, 8, 11, 15 and 22 (terminal body weight). Body weights of the F1 generation female rats were recorded weekly during the postweaning period to cohabitation, and on DGs 0, 7, 10, 14, 18, 21 and 25 (if necessary) and on DLs 1,5,8, 11, 15 and 22. Feed consumption values for the P-and FI generation male rats were recorded weekly during the dosage period. Feed consumption values for the P generation female rats were recorded weekly during the precohabitation period, on DG 0,7, 10, 14, 18, 21 and 25 and on DLs 1,5, 8, 11 and 15. Feed consumption values for the FI generation female rats were recorded weekly during the postweaning period to cohabitation, on DGs 0,7, 10, 14, 18, 21 and 25 and on DLs 1, 5,8, 11 and 15. During `cohabitation, when two rats occupied the same cage with one feed jar, individual values were not recorded or tabulated. Because pups begin to consume maternal feed on or about DL 15, feed consumption values were not tabulatedafterDL 15. FI generation female rats were examined for age of vaginal patency,beginningon day 28 postpartum. F1 generation male rats were evaluated for ageofpreputial separation, beginning on day 39 postpartum. Body weights were recorded when rats reached sexual maturation. Estrous cycling was evaluated daily by examination of vaginal cytology beginning 21 days before the scheduled cohabitation period and continuing until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in sifu during the cohabitation period. On the dayofscheduled sacrifice, an examination of vaginal cytology was performed to determine the stageofestrous cycle. Within cach dosage group, consecutive order was use to assign P generation rats to cohabitatioone, `male rat per female rat. A tableofrandom units was used to assign F1 generation rats to cohabitation, one male rat per female rat. If random assignment to cohabitation resulted in the pairing of FI generation siblings, an altemate assignment was made. The cohabitation period consisted of a maximum of 14 days. "The P and Fl generation female rats were evaluated for duration of gestation, ertlity index, gestation index, number and sex of offspring per litter, numberof implantation sites, general conditionofthe dam and litter during the postpartum period, liter size and viability, viability index, lactation index and percent survival and sex ratio. Maternal behavior of the dams was recorded on DLs 1,5, 8, 15 and 22. Litters were examined after delivery to identify the number and sex of pups, stillbirths, liver births and gross alterations. Each litter was evaluated for viability at least twice ach dayofthe 22-day postpartum period.TheFI and F2 generation pups in cach litter were counted once daily. Physical signs were recorded for the pups each day. Pup body weights were recorded on DLs 1, 5,8, 15 and 22. On DL 12 all FI generation male pups were examined for the presence of nipples. Anogenital distance was measured for all live F2 generation pups on DLs I and 22. P and Flgeneration rats were sacrificed necropsied and examined for gross lesions Gross lesions were examined histologically. Tissue trimming and histopathology was performed under the supervision of or by a Board Certified Veterinary Pathologist. At Page 16 ARGUS 418-020 scheduled sacrifice, after completionofthe cohabitation period (male rats) and on DL 22 (female rats), blood samples were collected and centrifuged. The resulting serum was shipped to the Sponsor for analysis. The liver was excised, weighed, and a sample. section shipped to the Sponsor for analysis. The following organs were individually weighed and organ-to-body weight and organ-tobrain weight ratios were calculated: brain, kidneys, spleen, ovaries, testes, thymus, liver, adrenal glands, pituitary, uterus with oviducts and cervix, left epididymis (whole and cauda), right epididymis, prostate and seminal vesicles (with coagulating glands and with and without fluid). The following tissues were retained for possible histological evaluation: pituitary, adrenal glands, vagina, uterus with oviducts, cervix and ovaries, right testis, seminal vesicles (with coagulating gland), right epididymis and prostate. Histological examination was performed on tissues from 10 randomly selected rats per sex from the control and high dosage groups. All gross lesions were examined histologically. Reproductive organs of the low and intermediate dosage group rats. suspectedofreduced fertility were subjected to histological evaluation. Male rats were sacrificed after completion of the cohabitation period. A portion of the left cauda epididymis was used for evaluationofcauda epididymal sperm concentration and motility. The remaining left cauda epididymis was used to manually evaluate sperm morphology and to prepare a homogenate to determine sperm concentration. The left testis was used for evaluation of testicular spermatid concentration. Female rats were sacrificed on day ofday 22 of lactation (DL 22). The number and distribution of implantation sites were recorded. Pups that died before examination of the liter for pup viability on DL 1 were evaluated for vita status at birth. Pups found dead on DLs 2 to 22 were examined for gross lesions and for the cause of death. Al pups culled on DL 22 were sacrificed. Three pups per sex per litter were examined for gross lesions. Necropsy included a single cross-section of the head at the level of the. frontal-parietal suture and examination of the cross-sectioned brain for apparent hydrocephaly. The brain, spleen and thymus from oneofthe three selected pups per sex perlitter were weighed and the brain, spleen and thymus from the three selected pups per sex per litter were retained for possible histological evaluation. All remaining pups were discarded without further examination. AIF generation rats were weaned on DL 22 based on observed growth and viability of these pups. At weaning, two FI generation pupspersex per litter per group (60 male and 60 female pups per group), resulting in a totalof600 rats (300 rats per sex) were chosen for continued evaluation. At least two male pups and two female pups per liter, when possible, were selected. FI generation pups not selected for continued observation for sexual maturation were sacrificed and a limited necropsy was performed. The thoracic, `abdominal and pelvic cavities were examined for gross lesions. Gross lesions were preserved; all other tissues and the carcasses were discarded. Page 17 B. Results ARGUS 418-020 B.L. P Generation Male Rats One P generation male rat in the 30 mg/kg/day dosage group was moribund sacrificed on day 45 of the study (DS 45). The moribund condition was considered possibly related to the test substance because it occurred in the highest dosage group and this rat exhibited adverse clinical observations considered related to the test substance. Statistically significant increases in the incidencesofdehydration, urine-stained abdominal fur and ungroomed coat occurred in the 30 mg/kg/day dosage group. The number of male rats with chromorhinorrhea was increased in the 3 mg/kg/day and higher dosage groups; however these increases were not statistically significant; all other clinical observations were considered unrelated to the test substance. Body weight gains for the entire dosage period before cohabitation were significantly reduced in the 3, 10 and 30 mg/kg/day dosage groups. As aresult, body weight gains for the entire dosage period were significantly reduced in the 3, 10 and 30 mg/kg/day dosage groups. Body weights were significantly reduced in the 30 mg/kg/day dosage group on DS 8 through termination, in the 10 mg/kg/day dosage groupon DS 15 through termination and in the 3 mg/kg/day dosage group on DS 50 through termination. Absolute feed consumption values were significantly reduced in the 30 mg/kg/day dosage group for the entire dosage period before cohabitation and the entire study period and at most tabulated intervals within these periods. Relative feed consumption values were significantly increased in the 3, 10 and 30 mg/kg/day dosage groups for the entire dosage period before cohabitation and the entire study. All mating and fertility parameters were unaffected by dosages of the test substance as high as 30 mg/kg/day. All necropsy observations were considered unrelated to the test substance. Terminal body weights were significantly reduced in the 3, 10 and 30 mg/kg/day dosage groups. Absolute weights of the epididymides, left cauda epididymis, seminal vesicles, prostate, pituitary, adrenals, spleen and thymus were significantly reduced in the 30 mg/kg/day dosage group. The absolute weight of the liver was significantly increased in the 1,3, 10 and 30 mg/kg/day dosage groups. Weightsofthe kidneys were significantly increased in the 1, 3 and 10 mg/kg/day dosage groups, while these weights were significantly reduced in the 30 mg/kg/day dosage group. `The ratiosofthe organ weight to the terminal body weight were significantly increased in the 10 and 30 mg/kg/day dosage groups for the epididymides, left cauda epididymis (30 mg/kg/day only), testes and seminal vesicles. The ratio of the brain weight to the terminal body weight was significantly increased in the 3, 10 and 30 mg/kg/day dosage `groups. The ratiosofthe liver and left and right kidney weights t0 the terminal body weight were significantly increased in the 1, 3, 10 and 30 mg/kg/day dosage groups. The Page 18 ARGUS 418-020 ratio of the left adrenal weight to the terminal body weight was significantly increased in the 30 mg/kg/day dosage group. Ratios of the organ weight to the brain weight were significantly reduced in the 30 mg/kg/day dosage group for the epididymides, cauda epididymis, prostate, pituitary, spleen and thymus. The ratios of the liver weight to the brain weight were significantly increased in the 1,3, 10 and 30 mg/kg/day dosage groups. The ratios of the kidneys weights to the brain weight were significantly increased in the 1, 3 and 10 mg/kg/day dosage groups while the ratioofthe left kidney weight to the brain weight was significantly reduced in the 30 mg/kg/day dosage group. All sperm parameters evaluated were unaffected by dosages of the test substance as high as 30 mg/kg/day. No treatment-related microscopic changes were observed in the reproductive organs of anyofthe male rats in the Pgeneration. A treatment-related microscopic change was observed in the adrenal glands of the P generation male rats of the 10 and 30 mg/kg/day dosage groups. This change was characterized by hypertrophy and vacuolationofthe. cells of the zona glomerulosa of the adrenal cortex. All other microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. B2. PGeneration Female Rats `There were no P generation female rat deaths attributed 10 the test substance. All clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test substance. Body weights and body weight gains during the precohabitation, gestation and lactation periods were unaffected by dosagesofthe test substance as high as 30 mg/kg/day. Absolute and relative feed consumption values during the precohabitation, gestation and lactation periods were unaffected by dosages of the test substance as high as 30 mg/kg/day. `The average numbersof estrous stages per 21 days were comparable among the five dosage groups and did not significantly differ. Evaluationofestrous stages at sactifice did not reveal any differences among the five dosage groups. All mating and fertility parameters were unaffected by dosages of the test substance as high as 30 mg/kg/day. All necropsy observations were considered unrelated to the test substance. Terminal body weightsofthe P generation female rats were comparable among the five dosage `groups and did not significantly differ. The weightsofthe kidneys, the ratios of this organ weight to the terminal body weight and the ratioofthe left kidney weight to the brain weight were significantly reduced in the 30 mg/kg/day dosage group. Page 19 ARGUS 418-020 Pregnancy occurred in 27 to 29 rats in each dosage group. Natural delivery observations were unaffected by dosages of the test substance as high as 30 mg/kg/day. No clinical or necropsy observations were attributable to dosages of the test substance as high as 30 mg/kg/day. Terminal body weights of the F1 generation pups were. comparable among the five dosage groups and did not significantly differ. The weights ofthe brain, spleen and thymus and the ratios ofthese organ weights to the terminal body weight and brain weight were unaffected by dosages of the test substance as high as 30 mg/kg/day. No treatment-related microscopic changes were observed in the reproductive organs of any of the female rats in the P generation. All microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. B.3. Fl Generation Male Rats Three, three, three, two and seven FI generation male rats in the 0, 1,3, 10 and, 30 mg/kg/day dosage groups were moribund sacrificed or found dead. The increased incidence of mortality in the 30 mg/kg/day dosage group was considered treatmentrelated. Most deaths appeared to be related to a failure of the pups to thrive within a few days of weaning. This failure to thrive is common in this strain of rat when the weaning rats are small for weaning. `The incidences of annular constriction of the tail of male FI generation rats were increased in the 1, 3, 10 and 30 mg/kg/day dosage groups, reaching statistical significance in the 1, 10 and 30 mg/kg/day dosage groups. The number of male rats gorbosueprsv,edantdo bteheenmuamcbiaetresdowfamsalsiegnraitfsicwaintthlyuirnicner-esatsaeidniend tahbedo1m0iannadl 3fu0r,mgd/eckrge/adsaeyddmoostaogre adcotsiavgiteygarnodupa.bdTohmeinianlciddiesntceentoifonthweeorbesesirgvnaitfiiocnanotflycoilndcrteoatsoeudcihnwtahes3i0ncmrge/askegd/,daalybeit not significantly, in the 30 mg/kg/day dosage group. FBIodgyenweeriagthitosn amanldeboradtys bweefiogrhetagnadinasftweerrteherceodhuacbeidtaitniaondopseargioed-daetptehnede1n,3t,pa1t0tearnnd/foorr the 30 mg/kg/day dosages of the test substance, as compared 10 the control group. Absolute feed consumption values for the F1 generation male rats were significantly reduced and relative feed consumption values were significantly increased for the entire precohabitation period by dosages of APFO of 10 and 30 mg/kg/day. Page 20 ARGUS 418-020 dProespaugteiaglrsoeupparaantdioanboofvFe1thgeeTneesrtaitnigonFamcailleityrahtisswtoarsicsalligchotnltyrodlelaavyeerdagien tahned3r0anmgge/kfogr/tdhaiys parameter (see APPENDIX L). When this observation in the 30 mg/kg/day dosage group was covaried with the significantly reduced (<0.01) body weight at time ofacquisition to determine if the significantly reduced body weightswere a factor, the difference was ill significant, but at the p<0.05 level. When this observation in the 30 mg/kg/day dosage group was covaried with gestational age (calculated from the day of mating to the day of acquisition) at time of acquisition to determine if this group was younger and more immature than the control group, there was no significant difference in sexual maturation. Dosages of the test substance as high as 30 mg/kg/day did not affect anymatingand fertility parameters evaluated in the F1 generation male rats, of the mal rats assigned to cohabitation, 93.3%, 96.6%, 93.3%, 93.3% and 96.7% impregnated the cohort female rat in the five dosage groups, respectively. `Tan areas occurred in the left lateral and/or median lobesofthe liver in 6, 10 and 9 male rats in the 3, 10and 30 mg/kg/day dosage groups, respectively. One of these rats in the 30 mg/kg/day dosage group also had a small spleen. One 30 mg/kg/day dosage group rat had an enlarged liver. Moderatetoslight dilation of the pelvisof one or both kidneys occurred in 4 and 1 rats in the 10and 30 mg/kg/day dosage groups, respectively. A tan area in the parenchyma of the spleen occurred in one 10 mg/kg/day dosage group rat. Terminal body weightsofthe FI generation male rats were significantly reduced in a dosage-dependent manner in the 1, 3,10and 30 mg/kg/day dosage groups. The absolute: weights of the liver were significantly increased and the absolute weighs of te spleen were significantly decreased in the 1 mg/kg/day and higher dosage groups, compared to the control group values. The absolute weights of the left and/or right kidneys were significantly increased in the 1 and 3 mg/kg/day dosage groups and significantly decreased in the 30 mg/kg/day dosage group, compared to control group values. The absolute weight of the thymus was also significantly decreased in the 10 and 30 mg/kg/day dosage groups. The absolute weight of the prostate, brain and left adrenal gland were significantly decreased in the 30 mg/kg/day dosage group. "The ratiosofthe weights of the seminal vesicles, with and without fluid,liverand left and. ight kidneys to the terminal body weights were significantly increased in the 1 mg/kg/day and higher dosage groups, compared to the control group values. The ratios of the weights of the left testis, with and without the tunica albuginea and the right testis 10 the terminal body weight, were significantly increased in the 3 mg/kg/day and higher dosage groups. "The ratios of the weights of the left epididymis, left cauda epididymis, right epididymis and brain to the terminal body weight were significantly increased in the 10 mg/kg/day and higher dosage groups. "The ratios of the weightofthe seminal vesicles with fluid to the brain weight were increased in the 1 mg/kg/day and higher dosage groups, compared to the control group values. These ratios were significantly increased in the 1 and 10 mg/kg/day dosage groups. The ratios of the liver weight to the brain weight were significantly increased in the 1 mg/kg/day and higher dosage groups, and the ratios of the left and right kidney Page 21 ARGUS 418-020 weights to the brain weight were significantly increased in the 1, 3 and 10 mg/kg/day dosage groups. The ratios of the spleen weight to the brain weight were significantly decreased in the 1 mg/kg/day and higher dosage groups, and the ratios of the thymus weight to the brain weight were significantly decreased in the 10and 30 mg/kg/day dosage groups. The ratios of the left and right testes weight to the brain weight were increased in the 3 mg/kg/day and higher dosage groups. These ratios were significantly increased in the 10 mg/kg/day (right testis only) and 30 mg/kg/day dosage groups. No treatment.related microscopic changes were observed in the reproductive organs of anyof the male rats in the FI generation. A treatment-related microscopic change was observed in the adrenal glandsofthe F1 generation male rats of the 30 mg/kg/day dosage `groups. This change was characterized by hypertrophy and vacuolation of the cells of the zona glomerulosaofthe adrenal cortex. Microscopic examination of liver sectionsofthe Fl generation male rats which were observed grossly to be enlarged or have tan areas in the liver lobes showed up to marked diffuse hepatocellular hypertrophy. Single or lower incidences of hepatocellular necrosis also were observed in the male rats of these groups, All other microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. No statistically signoirdofsaige-cdeapenndetnt differences occurred in the numbers of `motile sperm, percentage of motile sperm, static count (nonmotile sperm), total count, sperm density, spermatid count or density. Sperm morphology was unaffected by dosages of the test substance as high as 30 mg/kg/day. BA. Fl Generation Female Rats Two, one, one and six FI generation female rats in the 1, 3, 10 and 30 mg/kg/day dosage groups were found dead. The increased incidence of mortality in the 30 mg/kg/day dosage group was considered treatment-related. Most deaths appeared to be related to a failureofthe pups to thrive within a few days of weaning. This failure to thrive is `common in this strain of rat when the weaning rats are small for weaning. All clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test substance. Body weights and body weight gains during the precohabitation period were significantly reduced by 30 mg/kg/day dosagesofthe test substance. Body weight gain for the entire precohabitation period was significantly reduced. Body weights during the gestation and lactation periods were significantly reduced in the 30 mg/kg/day dosage. Absolute feed consumption values were significantly reduced in the 30 mg/kg/day dosage group on DPs 1 (0 8,8 to 15 and 15 10 22 during the precohabitation period, on DGs7 to 10 during the gestation period and on DLs 1 to 15 during the lactation period. Relative feed consumption values were comparable among the 0, 1,3, 10 and 30 mg/kg/day dosage groups for the precohabitation, gestation and lactation periods and did not differ statistically. Page 22 ARGUS 418-020 `The 30 mg/kg/day dosage group F1 generation female rats had a small (approximately 1.7 days increase), but statistically significant delay in vaginal patency. The average day when vaginal patency was evident in the 30 mg/kg/day dosage group (36.6 days of age) significantly differed from the control group value (34.9 days of age) was above the: Testing Facility historical control average and range for this parameter. When this observation in the 30 mg/kg/day dosage group was covaried with the significantly reduced (p<0.01) body weight at time of acquisition, to determine ifth significantly reduced body weights were a factor, the difference was still significant, but at thep<0.05 level. When this observation in the 30 mg/kg/day dosage group was covaried with `gestational age at time of acquisition, to determine if this group was younger and more immature than the control group, there was no significant difference in sexual maturation. `The average numbers of estrous stages per 21 days were significantly increased in the 30 mg/kg/day dosage group. The Testing Facility historical control average and range for this parameter is 5.0 stages and 4.8 t0 5.2 stages, respectively. When this observation `was covaried with the day 64 body weight or age, the difference was still significant, but at the p<0.05 level. Evaluation of estrous stages at sacrifice did not reveal any differences among the five dosage groups. All mating and fertility parameters were unaffected by dosages of the test substance as high as 30 mg/kg/day. All necropsy observations for the F1 generation female rats were considered unrelated to the test substance. `Terminal body weights of the F1 generation female rats were comparable among the five dosage groups and did not differ significantly. The absolute weights of the pituitary and the ratios of the pituitary weight to the terminal body weight and to the brain weight were significantly decreased in the 3 mg/kg/day and higher dosage groups, as compared to the control group values. No treatment.-related microscopic changes were observed in the reproductive organs of any of the female rats in the F1 generation. All microscopic changes observed in the. various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. Pregnancy occurred in 28 to 29 rats in each dosage group. Natural delivery observations including viability and lactation indices were unaffected by dosages of the test substance as high as 30 mg/kg/day. Anogenital distances measured for male and female pups on DLs 1 and 22 were comparable among the five dosage groups and did not significantly differ. No clinical or necropsy observations were attributable to maternal dosages ofthe test substance as high as 30 mg/kg/day. F2 generation rats had comparable terminal body weights on DL 22; the values did not significantly differ from the control group values. Absolute weightsofthe brain, spleen and thymus and ratios of these organ weights to terminal body weight and to brain weight were comparable among the five dosage groups and did not significantly differ. Page 23 ARGUS 418.020 C. Conclusion O(nNOtAheELba)sifsorofamthmeosenidautma,ptehrefPluogreonoecrattainoonatpeatiserlneasls nthoa-nob1smegr/vkagb/ldea-ya(dtvheer|smeg-/ekfglf/eevdceatly wdeoisgahgte acnadusteodbsriaginnifwiecaingthinrcatrieoass)e.s TinhethmealtievrenraalnNdOkiAdEneLyiwse1i0ghmtgs/okg/tedramyin(atlhebody b3o0dmyg/wekigg/hdtayanddosoagberasiingnwiefiicgahnttlryatrieosd)u.ceTdhKeirdenperyodwuecitgihvteaNnOd AkiEdLneiynwtehiegmhatlteostaenrdminal effefmeaclteoPn gmeanteirnagt,ifoenrtrialtistyiosrgrmeaatteerrntahladne3li0vmergy/kpgar/admaeyte(rtsh)e.30 mg/kg/day dosage had no "pTehreflFu1orgoeoncetraantoiaotnepiastelrensalthnaon-o1bsmegr/vkagb/led-aaydv(etrhsee-| cmfgf/ecktg-/ldeavyela(ndNOhiAgEhLer)dfoosraagemsmocanuisuedm saingdnirfaitciaonsttdoetcerremaisneaslibnobdoydaynwdeibrgahitnswaenidghbtosdaynwdetihgeht30gamign/akngd/dcahyandgoessagien odreglaanyewdeights FseIxugaelnemraattuiroantmioantepmosaslibNlOy AduEeLtoisde1c0rmega/sekdg/gdeastyat(ithoena3l0amgge/aktgq/udiasyitdioosna)g.e iTnhcereased pcoonsstuwmepatniionng,mionrcarleiatsye,ddtehcerenausmebdeproosftwesetarnoiunsgcbycoldeyspweerig2h1t,dbaoydsyawnedidgehltagyaeidnsaenxudafleed mNaOtuArEatLioinn ptohsesmiabllyesduaendtofdeemcarleeaFs1edggeensetraattiioonnalraatgseisagracaqtueirsitthioann).30Tmhge/krge/prdoadyuc(tthieve "3T0hemgF/2kgee/ndearyatdioosnatgeermhiandalnoboefdfyecwteiognhmtastainngd,ofrgaeniweiogrhmtastierdnanlotdedliiffveerryampaornamgettehres). eroups. DilricnetMo.rofHRoebseermaarnchPh.D. DABT Dae |tome AA 24mtp-202 RAayaslolsockie GD.irYecotrokr,oPfResearthBT Date and Study Director Page 24 ARGUS 418-020 IL DESCRIPTION OF TEST PROCEDURES A. Conductof Study AL Sponsor 3M Corporate Toxicology, 3M Center, Building 220-2E-02, St. Paul, Minnesota 55144-1000 A2. Testing Facility Argus Research, 905 Sheehy Drive, Building A, Horsham, Pennsylvania 19044-1297 A3. Study Number 418-020 Ad. Sponsor's Study Number T-6889.6 AS. Purposeofthe Study "The purpose of this study was to provide information concerning the effects of Ammonium Perfluorooctanoate (APFO) on the male and female reproductive systems in C`mralt:inCgDbe(hSaDvi)oIrG,ScoBnRcepVtAiFo/n,Plpuarsturriattiso,n,inlcalcutadtiinogn,gowneaadnailngfuancntdiotnh,e egsrtorwotush cayncdles, development of offspring. This study was also designed to provide information about effects on neonatal morbidity, mortality and preliminary data on potential prenatal developmental toxicity, as well as to serve as a guide for use in the design of subsequent tests. AS6. Study Design `The requirements of the U.S. Environmental Protection Agency (EPA)? were used as the basis for study design. AT. Regulatory Compliance "The study was conducted in compliance with the Good Laboratory Practice (GLP) regulations of the U.S. Environmental Protection Agency (EPA)? and the Organisation for Economic Co-operation and Development (OECD). There were no deviations from the GLP regulations that affected the quality or integrity of the study. Quality Assurance Unit findings derived from the inspections during the conduct of this study are. documented and have been provided to the Study Director and the Testing Facility Management. Page 25 ARGUS 418-020 AS. Ownershipofthe Study `The Sponsor owns the study. All raw data, analyses, reports and preserved tissues are the property of the Sponsor. AS. Study Monitor John Butenhoff, Ph.D., DABT, CIH (3M Corporate Toxicology, St. Paul, Minnesota 55144) A10. Study Director Raymond G. York, Ph.D, DABT (Associate Director of Research, Argus Research, Horsham, Pennsylvania 19044) AL Technical Performance John F. Bamett, B.S. (Director of Laboratory Operations) Russell A. Gazzara, Ph.D. (Senior Research Associate) Joseph W. Lech, B.S. (Senior Research Associate) Alaine L. Casey, A.S. (Scheduling Coordinator/Blood Collection Coordinator) Allyson B. Hansell, B.S. (Laboratory Technician) Brian K. Kelsch (Necropsy Team Leader) Christopher K. Ruppert, B.S. (Formulation Laboratory Technician) A12. Report Preparation Raymond G. York, Ph.D., DABT Valerie A. Sharper, M.S. (Director of Study Management) Jo Ann Frazee, M.S. (Study Coordinator) Elizabeth M. Wiley, B.S. (Data Management Specialist) JoAnne M. Conklin, B.S. (Data Management Specialist) Cristina Petrescu (Report Administrator) A13. Report Review Alan M. Hoberman, Ph.D., DABT (Director of Research) Valerie A. Sharper, M.S. (Director of Study Management) A.14. Date Protocol Signed 7 November 2000 Page 26 A.15. Datesof Technical Performance Adl5.a. PGeneration Male Rats Rat Arrival `Test Substance Dosage Period Male Rats Sacrificed A15b. PGeneration Female Rats Rat Arrival Test Substance Dosage Period Precohabitation Estrous Cycle Evaluation Cohabitation Period Da0y of Presumed Gestation" (DG 0) Delivery Period" (Day 1 of lactation) DG 25 Sacrifice (Rats that did not deliver alitier) DL 22 Sacrifice (P generation dams and FI generation liters not selected for continued observation) Adl5.c. F1 Generation Male Rats Test Substance Dosage Period Male Ras Sacrificed - Interim (Rats not selected for continued observations following observations for sexual maturation) Male Ras Sacrificed - Scheduled ARGUS 418-020 07NOV 00 13NOV 00-01 MAR 01 26 FEB 01 - 02 MAR 01 07NOV 00 13NOV 00- 18 MAR 01 01 JAN 01 -21 JAN 01 21 JAN 01 PM -04 FEB 01 AM 22 JAN 01 - 04 FEB 01 12 FEB 01 - 26 FEB 01 16FEB01 - 18FEB01 05 MAR 01 - 19 MAR 01 06 MAR 01 - 05 JUL 01 13 APR 01 and 04 MAY 01 02 JUL 01-06 JUL 01 a Gestation day is defined as the day spermatozoa are observed in a smear of the vaginal contents and/or a copulatory plug observed in situ. b. The dayofbirth is designated postnatal day 0 (day 0 of lactation) in Addendum 10. to the Pesticide Assessment Guidelinesofthe U.S. Environmental Protection Agency (EPA). This same day is designated day 1 postpartum (day 1 of lactation) in the Standard Operating Procedures of the Testing Facility. Throughout this protocol, the dayofbirth will be designated day 1 postpartum (day 1 of lactation) and all subsequent ages of the F1 generation rats and days of the lactation period. will be determined and cited accordingly. c DLisan abbreviation used for day of lactation/postpartum. Page 27 ARGUS 418-020 A154. F1 Generation Female Rats Test Substance Dosage Period Precohabitation Estrous Cycle Evaluation Cohabitation Period Female Rats Sacrificed - Interim (Rats not selected for continued observation following observations for sexual DGO maturation) DL1 DG 25 Sacrifice (Rats that did not deliver alitter) DL 22 Sacrifice (F1 generation dams and F2generationpups) 06 MAR01 - 15 JUL 01 08 MAY01 - 28 MAY 01 28 MAY 01 PM - 11 JUN 01 AM . 06 APR 01 29 MAY01 -04 JUN 01 1901J-25UJUN N 01 23JUN 01-29 JUNO 10JUL 01 - 16 JUL 01 A16. Records Maintained `The original report, raw data and reserve samples of the test substance and vehicle are retained in the archives of Argus Research. Any preserved tissues are retained in the. archives of the Testing Facility for one year after the mailing of the draft final report, after `which time the Sponsor will decide their final disposition. All unused prepared formulations were discarded at the Testing Facility. Unused bulk test substance was retumed to the Sponsor. B. Test Substance Information B.L Description Ammonium Perfluorooctanoate (APFO) - white powder B2. Lot Number 332 B3. Date Received and Storage Conditions `The test substance was received on 7 November 2000 and stored at room temperature. BA. Special Handling Instructions `Standard safety precautions (use of protective clothing, gloves, dust-misVHEPA-filiered mask, safety goggles or safety glasses and a face-shield) were taken when handling the prepared solutions. Tyvek sleeves and a half-face respirator were worn when usingthe bulk test substance and preparation was conducted under a chemical fume hood. Page 28 ARGUS 418-020 B.S. Analysis of Purity Information to document or certify the identity, composition, method of synthesis, strength and purity of the test substance was provided by the Sponsor to the Testing Facility. A Certificate of Analysis is available in APPENDIX H. C. Vehicle Information C1. Description Reverse Osmosis Membrane Processed Deionized Water (R.O. deionized water). C2. Storage Conditions R.O. deionized water is available from a continuous source at the Testing Facility and was maintained at room temperature. C23. Special Handling Instructions Standard safety precautions (use of protective clothing, gloves, dust-misVHEPA-filtered mask, safety gogglesor safety glasses and a face-shield) were taken when handlingthe vehicle. C4. AnalysisofPurity Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the vehicle that would have interfered with the results of this study. D. Test Substance Preparation and Storage Conditions Solutions of the test substance were prepared weekly at the Testing Facility. Prepared formulations were stored refrigerated, protected from light. Page 29 D.1. Sample Information ARGUS 418-020 E E i A y R aAa . D.2. Analytical Results `The analyticalresultsare available in APPENDIXL E. TestSystem El. Species Rat E2. Strain Crl:CD(SD)IGS BR VAF/Plus E3. Supplier (Source) Charles River Laboratories, Inc., Kingston, New York (male rats) and Raleigh, North Carolina (female rats) Offspring were delivered at the Testing Facility by the pregnant P or F1 generation dams in this study. Ed. Sex Male and Female rats Page 30 ARGUS 418-020 ES. Rationale for Test System The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) this strainofrat has been demonstrated to be sensitive to reproductive and developmental toxins and has been widely used throughout industry for reproductive and developmental toxicity evaluations and 2) historical data and experience exist at the. Testing FacilityTM", E6. Test System Data Number of Rats Approximate Date of Birth Approximate Age at Arrival Weight (g) on Day after Arrival Weight g) at Study Assignment Male Rats 165 020CT 00 37 days 100-143 140-164 Female Rats 165 010CT00 38 days 88-132 120-144 E7. Method of Randomization E7.a. P Generation Rats Upon arrival, P generation rats were assigned to individual housing on the basis of computer-generated random units. After acclimation, rats were selected for study on the basis of physical appearance and body weight. Rats were assigned to five dosage groups (Groups I through V), 30 rats per sexper dosage group, using a computer-generated (weight-ordered) randomization procedure. E.7.b. FI Generation Pups/Rats Litters were not culled during the lactation period, because random selection of pups for culling could have resulted in potential biases in pup viabilities and body weight gains during this period. All FI generation rats were weaned on DL 22 based on observed growth and viability of these pups. At weaning,atable of random units was used to select two F1 generation `pupspersex per litter per group (60 male and 60 female pups per group), resulting in a total of600 rats (300 rats per sex) chosen for continued evaluation. At least two male pups and two female pups per litter, when possible, were selected. Following sexual maturation,a table of random units was used to select one male and one female FI generation rat per litter per group when possible for continuation through `mating to produce the F2 generation. Page 31 ARGUS 418-020 ES. System of Identification ES8.a. P Generation Rats Male and female rats were assigned temporary numbers at receipt and given unique `permanent identification numbers when assigned to the study before administration of the first dosage of the est substance or vehicle. Rats were permanently identified using Monel self-piercing ear tags (Gey Band and Tag Co, Inc., No. MSPT 20101) inscribed with the rat's designated unique permanent number. Cage tags were marked with the study number, permanent rat number, sex, test substance identification, generation and dosage level ES. F1 Generation Pups/Rats Pups were not individually identified during the postpartum period: all parameters were evaluated in terms of the iter. At weaning, each F1 generation rat selected for continued observation was identified with a Monel self-piercing ear tag. ES.c. F2Generation Pups Pups were not individually identified during the postpartum period; all parameters were evaluated in terms of the litter. F. Husbandry FL Research Facility Registration USDA Registration No. 14-R-0122 under the Animal Welfare Act, 7 U.S.C. 2131 et seg. F2. Study Rooms `The study rooms were maintained under conditionsofpositive airflow relativeto a hallway and independently supplied with a minimum of ten changes per hour of 100% freshairthat had been passed through 99.97% HEPA filters. Room temperature and humidity were monitored constantly throughout the study. Room temperature was targeted at 64F to 79F (18C to 26C); relative humidity was targeted at 30% to 70%". E3. Housing All cage sizes and housing conditions were in compliance with the Guidefor the Care and Use ofLaboratory AnimalsTM. a See APPENDIX J (ENVIRONMENTAL AND HUSBANDRY REPORTS). Page 32 ARGUS 418-020 F3a. P Generation Rats/F1 Generation Litters P generation rats were individually housed in stainless steel, wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair of rats `was housed in the male rat's cage. Beginning no later than DG 20, female rats were individually housed in nesting boxes. Each dam and delivered litter was housed in a common nesting box during the postpartum period. F3b. Fl Generation Rats/F2 Generation Litters After weaning, the F1 generation rats were individually housed before cohabitation, housed in pairs (one male rat per female rat) during cohabitation, and individually housed after cohabitation. The same type of caging was used as described for the P generation rats. Beginning no later than DG 20, female rats were individually housed in nesting boxes. Each dam and delivered litter was housed in a common nesting box during the postpartum period. Fd. Lighting An automatically-controlled fluorescent light cycle was maintained at 12-hours light: 12-hours dark, with each dark period beginning at 1900 hours EST. The lights were turned on one hour early on 13 April 2001 in order to accommodate the necropsy schedule. FS. Sanitization Cage pan liners were changed a minimum of three times weekly. Cages were changed approximately every other week. Bedding was changed as often as necessary to keep the. rats dry and clean. F6. Feed Rats were given ad libitum access to Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in individual feeders. FJ. Feed Analysis Analyses were routinely performed by the feed supplier. No contaminants at levels exceeding the maximum concentration limits for certified feed or deviations from expected nutritional requirements were detected by these analyses. Copies of the results of the feed analyses are available in the raw data and in APPENDIX J. Neither the Sponsor nor the Study Director was aware of any potential contaminants likely to have been present in the feed that would have interfered with the results of this study. Page 33 ARGUS 418-020 F8. Water Local water that had been processed by passage through a reverse osmosis membrane (RO. water) was available to the rats ad libitum from individual bottles attached to the cages andor from an automatic watering access system. Chlorine was added to the processed water as a bacteriostat. F9. Water Analysis `The processed water is analyzed twice annually for possible chemical contamination (Lancaster Laboratories, Lancaster, Pennsylvania) and monthly for possible bacterial contamination (Analytical Laboratories, Inc., Chalfont, Pennsylvania). Copies of the results of the water analyses are available intheraw data and in APPENDIX J. Neither the Sponsor nor the Study Director was awareofany potential contaminants likely to have been present in the water that would have interfered with the results of this study. F.10. Bedding Material Bed-o'cobs bedding (The Anderson's Industrial Products Group, Maumee, Ohio) was used as the nesting material. FIL. Bedding Analysis Analyses for possible contamination are conducted semi-annually. Copies of the results of the bedding analyses are available in the raw data and in APPENDIX J. Neither the Sponsor nor the Study Director was awareofany potential contaminants likely to have been present inthebedding that would have interfered with the results of this study. Page 34 G. Methods G.1. Dosage Administration G.la. P Generation Rats ARGUS 418-020 Cr T To 5TT oT[oomow[owewno]] Group| (mg/kg/d: ) Sex |MaleRais |FemaleRats | Irv=oT= w 5 To 0[[wwomm[[wwoowws]] rCto rd TT= 1 Tom mom] G.Lb. F1 Generation Rats Dosage | Dosage | Concentration'| Dosage Volume| NumbofeRatrs. Group_| (mg/kg/day " (mk) perSex* |MaleRots |Female Rais | TT Te Te oem|[oTom 6553 - 6555%, | 19779, 19780, CnvTToTo5 510 wo [wmenoo[wwoew]| DrCE bTo [5T 1 woe[hwsarw]wawrr] 0S T fed r e ea iieedeeeeoeh G.2. Rationale for Dosage Selection Dosages were secs on the bass ofprodietaryand gavage tis in rts erfomed by the Sponsor. The highest dosage was expected to produce some toxicity. The intermediate dosage levels were expected to produce minimal observable toxic effects, while the lowest dosage level was expected to produce no evidence of either systemic or reproductive toxicity [no-observable-adverse-effect level (NOAEL)). Page 35 ARGUS 418-020 G3. Routeof Administration and Rationale for Route of Administration `The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) it is one possible route of human exposure. Gad. Frequency of Administration Gd.a. PGeneration Rats Male and female rats were given the test substance or vehicle once daily, beginning at approximately six weeks of age (at least 70 days before cohabitation) and continuing until the day before sacrifice. The dosage volume was adjusted daily on the basisofthe most recently recorded body weight" and given at approximately the same time each day". Dams in the process of delivering pups were not intubated until completion of parturition, in order to preclude possible disruption of maternal behavior and/or cannibalizationofthe pups. Consequently, some dams were not administered one daily dosage during the delivery period. No dam missed more than one daily intubation. G.4b. FI Generation Rats FI generation pups may have been exposed to the test substance during maternal `gestation (in utero exposure) or via maternal milk during the postpartum period. Fl generation rats were given the same dosage level of the test substance as their respective P generation sires and dams. Dosages weregivenonce daily, beginning at weaning (approximately 70 days before cohabitation) and continuing until the day before: sacrifice". Dosages were adjusted at least weekly for body weight changes and given at approximately the same time each day'. G.d.c. F2 Generation Pups F2 generation pups may have been exposed to the test substance during maternal `gestation (in utero exposure) or via maternalmilk during the postpartum period. a See APPENDIX G (DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY), item 1. b. See APPENDIX G, item 2. c. See APPENDIX G, item 3. d. See APPENDIX G, items 4 and 5. Page 36 ARGUS 418-020 G5. Method of Study Performance G5. PGeneration Rats The P generation rats were observed for viability at least twice each dayofthe study and. for general appearance weekly during the acclimation period. The rats were also examined for clinical observations of effects of the test substance, abortions, premature deliveries and deaths before and 60+ 10 minutes after dosage during the dosage period". Body weights of the male rats were recorded weekly during the acclimation and dosage periods and on the day of sacrifice. Body weights of the female rats were recorded `weekly during the acclimation, precohabitation and cohabitation periods and on DGs 0, 7, 10, 14,18, 21 and 25(ifnecessary) and on DLs 1,5,8, 11, 15and 22 (terminal body weight). Feed consumption values for the male rats were recorded weeklyduringthe dosage period. Feed consumption values for the female rats were recorded weekly during the precohabitation period, on DGs 0, 7, 10, 14, 18, 21 and 25 (if necessary) andon DLs 1,58, 11 and 15. Because pups begintoconsume maternal feed onorabout DL 15, feed consumption values were not tabulated after DL 15. During cohabitation, when two rats occupied the same cage with one feed jar, replenishment of the feedjars was documented but individual values were not recordedor tabulated. Estrous cycling was evaluated daily by examination of vaginal cytology beginning 21 days before the scheduled cohabitation period and continuing until spermatozoa were observed in a smear of the vaginal contents and/or a copulatory plug was observed in sit dvuargiinnagltchyetcoolhoagbyitwaatsiopneprefroiromd"e.d tOondettheerdmaiyneofsthcehestdaugleoedfessatcrriofuiscec,yacnlee.xaWmiitnhaitnieoancohf dosage group, consecutive order was used to assign P generation rats to cohabitation, one. male rat per female rat. `The cohabitation period consisted ofa maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in situ were considered to be at DG 0 and assigned to individual housing. Ifa female rat had not been matedafter two weeks, the pair of rats was separated without further opportunity for mating. The P generation female rats were evaluated for duration of gestation (DG 010 the day the first pup was observed), fertility index (percentage of matings that result in pregnancy), gestation index (percentage of pregnancies that result in birth of lve litters), `number and sexofoffspring per litter (live and dead pups), number of implantation sites, general condition of the dam and litter during the postpartum period, litter size and viability (tabulated on DLs 1,5, 8, 1 and 22), viability indices (percentages of pups born that survive to DLs 1 and 5), lactation index (percentage of pups that survive from DLs 5 0.22) and percent survival and sex ratio (tabulated on DLs 1, 5,8, 15 and 22). Maternal behavior ofthe P generation dams was recorded on DLs 1, 5, 8, 15 and 22, a. See APPENDIX G, items 6 and 7. b. See APPENDIX G, item 8. c. See APPENDIX G,item 9. Page 37 ARGUS 418-020 Deviations from expected maternal behavior were recorded, ifand when observed, on all other days of the postpartum period. G.5b. F1 Generation Pups/Litters Litters were examined after delivery to identify the number and sex of pups, stillbirths, live births and gross alterations. Day 1 of lactation [(postpartum), DL 1] was defined as. the day of birth and was also the first day on which all pups in a liter were individually weighed (pup body weights were recordedafterall pups in a liter were delivered and `groomed by the dam). Each litter was evaluated for viability at least twice each dayofthe 22-day postpartum period. Dead pups observed at these times were removed from the nesting box. The Fl generation pups in each litter were counted once daily. Physical signs (including variations from expected lactation behavior and gross extemal physical anomalies) were recorded for the pups cach day". Pup body weights were recorded on DL 1,5, 8, 15 and 22. On DL 12, all male pups were examined for the presence of nipples. The criterion of passing was met when no nipples were present. G.c. F1 Generation Rats `The F1 generation rats were observed for viability at least twice each day of the study. `The rats were also examined for clinical observations of effects of the test substance, abortions, premature deliveries and deaths before and 60 10 minutes after dosage tdhueripnogstthweeadnoisnaggepepreiroidoda".ndBoondtyhewediagyhtosf soafcrtihfeicme.aleBoradtys wweeirgehrtesocfortdheed wfeeemaklley rdautrsiwnegre. recorded weekly during the postweaning periodtocohabitation, and on DG 0,7, 10, 14, 18,21 and 25 (if necessary) and on DL 1, 5, 8, 11, 15 and 22 (terminal body weigh)". Feed consumption values for the male rats were recorded weekly during the dosage period. Feed consumption values for the female rats were recorded weekly during the postweaning period to cohabitation, on DGs 0, 7, 10, 14, 18, 21 and 25 (if necessary) and onDLs 1,5, 8, 11 and 15. Because pups beginto consume maternal feed on or about DL 15, feed consumption values were not tabulated after DL 15. During cohabitation, when two rats occupied the same cage with one feed jar, replenishment of the feed jars was documented but individual values were not recorded or tabulated. a. See APPENDIX G, item 10. bh. See APPENDIX G, items 6,7, 11 and 12. See APPENDIX G, item 13. d. See APPENDIX G, items 14 and 15. Page 38 ARGUS 418-020 Female rats were examinedforage of vaginal patency, beginnionng day 28 postpartum. Male rats were evaluated for age of preputial separation, beginning on day 39 postpartum'. Body weights were recorded when rats reached sexual maturation. Estrous cycling was evaluated daily by examination of vaginal cytology beginning 21 days before the scheduled cohabitation period and continuing until spermatozoa were observed in a smearof the vaginal contents and/or a copulatory plug was observed in sifu during the cohabitation period. On the day of scheduled sacrifice, an examination of vaginal cytology was performed to determine the stage of estrous cycle. A table of random units was used to assign Fl generation rats to cohabitation, one male rat per female rat. If random assignment to cohabitation resulted in the pairing ofF1 generation siblings, an alternate assignment was made. The cohabitation period consisted of a `maximum of 14 days. Female rats with spermatozoa observed in a smear of the vaginal contents and/or a copulatory plug in sifu were considered to be at DG 0 and assigned to individual housing. Ifa female rat had not been mated after two weeks, the pair of rats was separated without further opportunity for mating. `The FI generation female rats were evaluated for duration of gestation (DG 0 to the day the fist pup was observed), fertility index (percentage of matings that result in pregnancy), gestation index (percentage of pregnancies that result in birth of live litters), number and sex of offspring per litter live and dead pups), number of implantation sites, `general condition of the dam and litter during the postpartum period, iter size and viability (tabulated on DLs 1,5, 8, 15 and 22), viability indices (percentages of pups born that survive to DLs 1 and 5), lactation index (percentageofpups that survive from DLs 5 10.22) and percent survival and sex ratio (tabulated on DLs 1, 5, 8, 15 and 22). Maternal behavior of the FI generation dams was recorded on DLs 1, 5,8, 15 and 22. Deviations from expected maternal behavior were recorded, if and when observed, on all other days of the postpartum period. G.5.d. F2 Generation Pups Litters were examined after delivery to identify the number and sex of pups, stillbirths, live births and gross alterations. Each litter was evaluated for viability at least twice cach day of the 22-day postpartum period. Dead pups observed at these times were removed from the nesting box. TheF1 generation pups in each litter were counted once daily. Physical signs (including variations from expected lactation behavior and gross external rpheycsoircdaeldaonnomDaLlsies1),5w,e8r,e1r5eacnordd2e2d.foArntohgeenpiutpasl edaicshtadnacye".waPsumpebaosduyrewdefiogrhtalslwleirvee F2 generation pups on DLs 1 and 22. a. See APPENDIX G, item 16. b. See APPENDIX G, items 17 and 18. c. See APPENDIX G, item 19. d. See APPENDIX G, item 20. e. See APPENDIX G, item 21 Page 39 ARGUS 418-020 G.6. Gross Necropsy G.6.a. P and F1 Generation Rats P and FI generation rats were sacrificed by carbon dioxide asphyxiation, necropsied and examined for gross lesions. Representative photographs of paternal and matemal gross lesions are available in the raw data. Gross lesions were retained in neutral buffered 10% formalin and examined histologically. Tissue trimming and histopathology were performed under the supervisionoforby a Board Certified Veterinary Pathologist. At scheduled sacrifice, after completion of the cohabitation period (male rats) and on DL 22 (female rats), blood samples (approximately 4 mL per rat) were collected from the inferior vena cava into serum separator tubes and centrifuged". The resulting serum was. immediately frozen on dry ice and maintained frozen (<-70C) until shipment to the `Sponsor for analysis. The liver was excised, weighed, and a sample section (lateral lobe) frozen and retained at <-70C until shipmentot the Sponsor for analysis. Gross necropsy included an initial physical examinationof extemal surfaces and all orifices, as well as an intemal examination of tissues and organs in stu. The following were examined: external and internal portions of all hollow organs; the external surfaces of the brain and spinal column, the nasal cavity and neck with associated organs and tissues; the thoracic, abdominal and pelvic cavities with associated organs and tissues; and the musculo/skeletal carcass". The lungs of the F1 generation male and female rats assigned to scheduled sacrifice were perfused with neutral buffered 10% formalin. The urinary bladderof F1 generation rats was perfused with neutral buffered 10% formalin. `The following organs were individually weighed and organ-to-body weight and organ-tobrain weight ratios were calculated: brain, kidneys, spleen, ovaries, testes, thymus, liver, adrenal glands, pituitary, uterus with oviducts and cervix, left epididymis (whole and cauda), right epididymis, prostate and seminal vesicles (with coagulating glands and with and without fluid). The following tissues were retained in neutral buffered 10% formalin for possible histological evaluation: pituitary, adrenal glands, vagina, uterus with oviducts, cervix and ovaries, right testis (initially fixed in Bouin's solutionfor48 to 96 hours), seminal vesicles (with coagulating gland), right epididymis and prostate". Histological examination was performed on tissues from 10 randomly selected rats per sex fromthe control and high dosage groups. All gross lesions were examined histologically. In addition to gross lesions such as atrophy or tumors, testicular histopathological examination was conducted to identify treatment-related effects such as retained spermatids, missing germ cell layers or types, multinucleated giant cells or sloughing of spermatogenic cells into the lumen. Examination of the intact epididymis included the caput, corpus and cauda (accomplished by evaluation of a longitudinal a. See APPENDIX G, item 22. b. See APPENDIX G, item 23. c. See APPENDIX G, items 24, 25 and 26. Page 40 ARGUS 418-020 section) and conducted in order to identify such lesions as sperm granulomas, leukocytic infiltration (inflammation), aberrant cell types within the lumen,or the absence of clear cells in the cauda epididymal epithelium. Reproductive organs of the low and intermediate dosage group rats suspected of reduced fertility (e.g., those rats that failed to mate, conceive, sre or deliver healthy offspring, or for which estrous eyclicity or sperm number, motility or morphology were affected) were subjected to histological evaluation". Rats that died or were sacrificed because of moribund condition were examined for the causeofdeath or moribund condition on the day the observation was made. The rats were examined for gross lesions. Representative photographs of gross lesions are available in the raw data. Tissues of the Pgeneration rats were weighed and retained and examined histologically as described for male rats sacrificed at the completion of the cohabitation period and female rats sacrificed on DL 22. G.6.a.1. Male Rats Male rats were sacrificed after completion of the cohabitation period [days of study (DSs) 106 to 110:and 109 to 120 for the Pand FI generation rats, respectively]. A portion of the left cauda epididymis was used for evaluationofcauda epididymal sperm concentration and motility using computer assisted sperm analysis (CASA). Motility was evaluated by the Hamilton Thorne IVOS by collectionof a sample from the left cauda epididymis. The remaining left cauda epididymis was used to manually evaluate sperm `morphology and to prepare a homogenate to be evaluated by the Hamilton Thorne IVOS for a determinationof sperm concentration (sperm per gram of tissue weight). Sperm `morphology evaluations included the following: 1) determination of the percentage of normal sperm in a sampleofat least 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail. The left testis was usedfor evaluation of testicular spermatid concentration using computer-assisted sperm analysis (CASA). The left testis was weighed (both before and after removalofthe tunica albuginea) and then homogenized. A sample from the resulting homogenate was stained with an IDENT Stain Kit from Hamilton Thorne Research and a slide was prepared for analysis by the Hamilton Thorne IVOS. Ten fields were analyzed to determine testicular spermatid concentration (spermatids per gram of tissue weight). All images produced during analysis were retained as raw data. G.6.0.2. Female Rats P generation female rat 13822 in the vehicle control group was sacrificed on DL 8 and dam 13852 in the | mg/kg/day dosage group was sacrificed on DL 11. The ltrs from these two dams were inadvertently mixed together. Both dams and liters were sacrificed because it was not possible to identify to whichliterthe pups belonged. a. Sec APPENDIX G, item 27. Page 41 ARGUS 418-020 All surviving P and F1 generation female rats were sacrificed on DL 22. The number and distribution of implantation sites were recorded. Rats that did not deliver a liter were. sacrificed on DG 25 and examined for pregnancy status. Uteriof apparently nonpregnant rats were examined while being pressed between glass plates to confirm the absence of implantation sites. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. Female rats without a confirmed mating date that did not deliver a liter were sacrificed onanestimated DG 25. The P generationdam with no surviving pups was sacrificed after the last pup was found dead. A gross necropsy of the thoracic, abdominal and pelvic viscera was performed. G.6b. Fl and F2 Generation Pups Pups that died before examination of the liter for pup viability on DL 1 were evaluated for vital status at birth. The lungs were removed and immersed in water. Pups with lungs that sank were identified as stillborn; pups with lungs that floated were identified as liveborn, and to have died shortly after birth. When postmortem autolysis precluded these evaluations, it was noted in the necropsy data. Pups found dead on DLs 2 to 22 were examined for gross lesions andforthe cause of death. When postmortem autolysis precluded these evaluations, it was noted in the necropsy data. Al pups culled on DL 22 were sacrificedbycarbon dioxide asphyxiation. Three pups per sex per liter, when possible, were randomly selected and examined for gross lesions. Necropsy included a single cross-section of the head at the levelofthe frontal-parietal suture and examinationofthe cross-sectioned brain for apparent hydrocephaly. The brain, spleen and thymus from one of the three selected pups per sex per liter were weighed and the brain, spleen and thymus from the three selected pups per sex per liter were retained in neutral buffered 109% formalin. Gross lesions from the three selected `pupspersexper liter were retained in neutral buffered 10% formalin. Representative photographs of gross lesions are available in the raw data. All remaining pups were discarded without further examination. F1 generation pups not selected for continued observation following continued observations for sexual maturation were sacrificed by carbon dioxide asphyxiation and a limited necropsy was performed. The thoracic, abdominal and pelvic cavities were examined for gross lesions. Gross lesions were preserved in neutral buffered 10% formalin. Representative photographs of gross lesions are available in the raw data. All other tissues and carcasses were discarded. Page 42 ARGUS 418-020 G7. Data Collection and Statistical Analyses Data generated during the course of this study were recorded either by handor using the Argus Automated Data Collection and Management System, the Vivarium Temperature `and Relative Humidity Monitoring System and the Hamilton Thorne IVOS. All data were tabulated, summarized and/or statistically analyzed using the Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). Page 43 ARGUS 418-020 "The following schematic represents the statistical analyses of the data: 1. Parametric Type of Test" IL. Nonparametric A. Bartlett's Test A. Kruskal-Wallis Test (ST5% ties) Significant at p<0.001 Not Sighificant Significant at p<0.05 Not Significant colame Analysis of Variance Dunn's Test Saitgpnsi0f.i0ca5nt Not shine B. Fish(er7's5E%xaticets)Test ks Test TIL. Test for Proportion Data Variance Test for Homogeneity ofthe Binomial Distribution a Statistically significant probabilities are reported as either p<0.05 or p<0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance. Page 44 ARGUS 418-020 All adult and pup incidence data were analyzed using the Variance Test for Homogeneity of the Binomial Distribution. Body weights, body weight changes, feed consumption data, durations of gestation and delivery, liter averages for pup body weights and percent male fetuses or pups and mortality, cumulative survival nd parameters involving continuous data ere analyzed using Bartlett's Test of Homogeneity of Variances" and the AnalysisofVariance", `when appropriate i.., Bartlett's Test was not significant (p>0.001]. If the Analysis of Variance was significant (p<0.05), Dunnett's Test"? was used to identify the statistical significance of the individual groups.If the Analysis of Variance was not appropriate `[iw.hc.e,nB7ar5tl%etot'rsfTeewsetrwtaiess swiegrniefipcraensten(tp;<0w.h0e0n1)]m,ortheetKhrauns7ka5l%-WtailelsiwseTreesptr"e?sewnta,sFuissehde,r's Exact Test") was used. In cases where the Kruskal-Wallis Test was statistically sstiagtniisftiiccaalntsi(gpn<i0f.i0c5a)n,cDeuonfn'thseMientdhivoidduoafl Mgurlotuippsl.e Comparisons" was used to identify the Al other natural delivery data involving discrete data were evaluated using the Kruskal Wallis Test" procedures previously described. Page 45 ARGUS 418-020 IL RESULTS - P GENERATION RATS A. P Generation Male Rats AL. Mortality and Clinical Observations - PGeneration Male Rats (Summary - Table BI; Individual Data - Table B13) Aa. Mortality One P generation male rat in the 30 mg/kg/day dosage group was moribund sacrificed on day 45ofthe study (DS 45). The moribund condition was considered possibly related to the test substance because it occurred in the highest dosage group and this rat exhibited adverse clinical observations considered related to the test substance. Observations in this rat are described below. All other P generation male rats survived to scheduled sacrifice. Male rat 13732 in the 30 mg/kg/day dosage group was moribund sacrificed on DS 45. `This rat was administered 44 daily dosages of the test substance. Adverse clinical observations before sacrifice included dehydration on DSs 8 and 9, emaciation on DS 18 to 34 and 41 t0 45, cold to touch and urine-stained abdominal fur on DSs 44 and 45 and decreased motor activity on DS 45. This rat lost weight on DSs 1108, 15 to 22 and 36 to 43 and feed consumption values were reduced on DSs 1 108, 15 t0 22 and 36 t0 43, compared to other rats in the dosage group. All lobesofthe liver were pale and tan and both testes were red at necropsy; all other tissues examined appeared normal. Ab. Clinical Observations Statistically significant increases (p<0.01) in the incidences of dehydration, urine-stained. abdominalfurand ungroomed coat occurred in the 30 mg/kg/day dosage group. The `number of male rats with chromorhinorrhea was increased in the 3 mg/kg/day and higher dosage groups; however these increases were not statistically significant, Al other clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only oneor two male rats in any dosage group. These observations included soft o liquid feces, emaciation, dried red or red perinasal substance, cold to touch, missing/broken and/or misaligned incisors, chromodacryorrhea, decreased motor activity, pale. extremities, dried red substance on fur, no feces, scant feces, rales, swollen ears, abrasion ona limb, red substance on the penis and vocalization. The significant increases (p0.05orp<0.01) in the incidences of scabbing in the 1 and 3 mg/kg/day dosage groups were considered unrelated to the test substance because they were not dosage dependent. The significantly reduced (p<0.01) incidences of localized alopecia (total and limbs) in the 1,3, 10 and 30 mg/kg/day dosage groups were related to the increased incidence of this observation in the vehicle control group and were not test substance related. Page 46 ARGUS 418-020 A2. Body Weights and Body Weight Changes - P Generation Male Rats (Figure 1; Summaries - Tables B2 and B3; Individual Data - Table B14) Body weight gains for the entire dosage period before cohabitation (DSs 1 10 70) were significantly reduced (p<0.05 or p<0.01) in the 3, 10 and 30 mg/kg/day dosage groups. Within this period, body weight gains were significantly reduced (p<0.05 or p<0.01) in the 30 mg/kg/day dosage group at almost all tabulated intervals before the cohabitation period, in the 10 mg/kg/day dosage group on DSs 8 1015, 29 to 36, 43to 50 and 57 to 64, and in the 3 mg/kg/day dosage group on DSs 29 t0 36 and 4310 50. As a result, body weight gains for the entire dosage period (DSs 1 to 106 and DS 1 to termination) were. significantly reduced (p<0.01) in the 3, 10 and 30 mg/kg/day dosage groups. Body weight gain was significantly reduced (p<0.05) in the 3 mg/kg/day dosage group on DSs851092. Body weights were significantly reduced (p<0.05 orp<0.01) in the 30 mg/kg/day dosage `group on DS through termination, in the 10 mg/kg/day dosage group on DS 15 through termination and in the 3 mg/kg/day dosage group on DS 50 through termination. Body. weight gain was significantly increased (p<0.05) in the 3 mg/kg/day dosage group on DS 1 10/8 but this increase was considered unrelated to the test substance because it did not persist. Body weights and body weight gains were unaffected by the | mg/kg/daydosage of the test substance. A3. Absolute (g/day) and Relative (g/kg/day) Feed Consumption - P Generation Male Rats (Summaries - Tables B4 and BS; Individual Data - Table B1S) Absolute (g/day) feed consumption values were significantly reduced (p<0.01) in the 30 mg/kg/day dosage group for the entire dosage period before cohabitation (DS 1 to 70) and the entire study period (DS 1 to 106) and at most tabulated intervals within these periods. Relative (g/kg/day) feed consumption values were significantly increased (p=0.05 orp<0.01) in the 3, 10 and 30 mg/kg/day dosage groups for the entire dosage period before cohabitation (DSs 1 to 70) and the entire study period (DS 1 to 106). Within these periods, relative (g/kg/day) feed consumption values were significantly increased (p<0.05 or p<0.01) in the 30 mg/kg/day dosage group at all tabulated intervals after DS 8, in the 10 mg/kg/day dosage group at all tabulated intervals after DS 15 and in the 3 mg/kg/day dosage group on DSs 29 to 36 and all tabulated intervals after DS 50. `The relative (g/kg/day) feed consumption value was significantly reduced (<0.01) on DSs 1108 in the 30 mg/kg/day dosage group. Absolute and relative feed consumption were unaffected by the 1 mg/kg/day dosage of the test substance. Page 47 ARGUS 418-020 Ad. Mating and Fertility - P Individual Data - Table Generation B16) Male Rats (Summary - Table B6; All mating and fertility parameters (numbers of days to inseminate, rats that mated, fertility index, rats with confirmed mating dates during the first and second week of cohabitation and rats pregnantperrats in cohabitation) were unaffected by dosages of the test substance as high as 30 mg/kg/day. The significant reduction (p<0.05) in the number of days in cohabitation in the I mg/kg/day dosage group was considered unrelated to the test substance because it was not dosage dependent. AS. Necropsy and Histopathology Observations - P Generation Male Rats (Summary - Table B7; Individual Data - Table B17; Histopathology APPENDIX K) All necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent and/or 2) the observation occurred in only one or two male rats in any dosage group. These observations included small and flaccid testes and/or epididymides, large or red testes, slight or moderate dilationofthe renal pelvis, dark red areas on the lung lobes and pale and tan areas on the liver. All male rats with gross lesions of the testes and/or epididymides impregnated the cohort female. No treatment-related microscopic changes were observed in the reproductive organs of any of the 10 male rats in the P generation selected for histopathologic evaluation that had been given up to 30 mg/kg/day of the test substance. A treatment-related `microscopic change was observed in the adrenal glands of 2/10 and 7/10 male rats of the 10 and 30 mg/kg/day dosage groups. This change consistedofincreased thickness and prominence of the zona glomerulosa due to cytoplasmic hypertrophy and vacuolation of the cells of the adrenal cortex. All other microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. There were a few microscopic changes observed in rats designated as "reduced fertility", but these changes occurred spontaneously and were of the type that occur spontaneously in male rats of the age and strain and were not compound-related. AS. Terminal Body Weights and Organ Weights and Ratios (o% fOr) gan Weightto Terminal Body Weight and Brain Weight- P Generation Male Rats (Summaries - Tables BS through B10; Individual Data - Tables BIS and B19) Terminal body weights were significantly reduced (p<0.01) in the 3, 10 and 30 mg/kg/day dosage groups. Absolute weights of the left epididymis, left cauda epididymis, seminal vesicles with and without fluid, right epididymis, prostate, pituitary, left and right adrenals, spleen and thymus were significantly reduced (p<0.05 orp<0.01) in the 30 mg/kg/day dosage group. The absolute weight of the seminal vesicles without fluid was significantly reduced (p<0.05) in the 10 mg/kg/day dosage group. The absolute weight of the liver was significantly increased (p<0.01) in the 1,3, 10and 30 mg/kg/day Page 48 ARGUS 418-020 dosage groups. Weights of the left and right kidneys were significantly increased (p<0.05 orp<0.01) in the 1, 3 and 10 mg/kg/day dosage groups, while these weights were significantly reduced (<0.5 or p<0.01) in the 30 mg/kg/day dosage group. The weight of the pituitary was significantly reduced (p<0.05) in the 3 mg/kg/day dosage group but this reduction was not considered related to the test substance because the reduction was not dosage dependent, The ratios of the organ weight tothe terminal body weight were significantly increased (pS0.01) in the 10 and 30 mg/kg/day dosage groups for the left epididymis, left cauda epididymis (30 mg/kg/day only), left tests, let testis minus tunica albuginea, scminal vesicles with and without fluid, right epididymis and right testis. The ratio of the seminal vesicles with fluid to the terminal body weight was also significantly increased (p<0.05) in the 3 mg/kg/day dosage group. The ratio of the brain weight to the terminal body weight was significantly increased (<0.05 orp<0.01) in the 3, 10 and 30 mg/kg/day dosage groups. The ratios of the liver and left and right kidney weights to the terminal body weight were significantly increased (p<0.01) in the 1, 3, 10 and 30 mg/kg/day dosage groups. The ratioofthe left adrenal weight to the terminal body weight was significantly increased (p<0.05) in the 30 mg/kg/day dosage group. Ratios of the organ weight to the brain weight were significantly reduced (p<0.01) in the. 30 mg/kg/day dosage group for the left epididymis, left cauda epididymis, right epididymis, prostate, pituitary, spleen and thymus. The ratio of the pituitary weight to the brain weight was significantly reduced (p<0.05) in the 3 mg/kg/day dosage group. The ratios of the liver weight to the brain weight were significantly increased (p<0.01) in the 1,3, 10and 30 mg/kg/day dosage groups. The ratios of the left and right kidney weights 10 the brain weight were significantly increased (<0.05 orp<0.01) in the 1, 3 and 10 mg/kg/day dosage groups while the ratioofthe left kidney weight to the brain weight was significantly reduced (p<0.05) in the 30 mg/kg/day dosage group. AJ. Sperm Evaluation (Summaries - Tables B11 and B12; Individual Data - `Tables B20 and B21) Al sperm parameters evaluated were unaffected by dosagesofthe test substance as high as 30 mg/kg/day. Valuesforpercent motile sperm, sperm density and spermatid density were comparable among the five dosage groups and did not significantly differ. The significant reduction (p<0.05) in the number of nonmotile sperm in the 10 mg/kg/day dosage group was considered unrelated to the test substance because it was not dosage dependent. The numbers of sperm with normal morphology and the percentages of sperm with abnormal morphology were comparable among the five dosage groups. Page 49 ARGUS 418-020 B. P Generation Female Rats B.L. Mortality and Clinical Observations - P Generation Female Rats (Summary - `Table C1; Individual Data - Table C24) B.La. Mortality No deaths related to the test substance occurred. One P generation female rat in each of the 0 and 1 mg/kg/day dosage groups were `moribund sacrificed. The moribund conditions of these rats were attributed to accidents resulting in a broken palate or a fractured limb, respectively. Observations in these rats are described below. All other P generation female rats survived to scheduled sacrifice. Pgeneration female rat 13804 in the vehicle control group was moribund sacrificed on DS 68. This rat was administered 67 daily dosages of the vehicle. Adverse clinical observations before sacrifice included chromorhinorrhea, chromodacryorrhea, swollen snout, misaligned upper incisors and broken palate on DS 68. This rat gained weight from DSs 1 10 64 and feed consumption values were unremarkable. Necropsy confirmed the clinical signs. All other tissues examined appeared normal at necropsy. P gencration female rat 13836 in the 1 mg/kg/day dosage group was moribund sacrificed on DS 59. This rat was administered 59 daily dosages of the test substance. Adverse clinical observations before sacrifice included a swollen left forelimb and paw on DSs 57 10 59 and fractured left forelimb on DS 59. This rat gained weight from DSs 1 to 57 and feed consumption values were unremarkable. Necropsy revealed a broken radius and ulna in the left forelimb. Al other tissues examined appeared normal a necropsy. P generation female rat 13822 in the vehicle control group was sacrificed on DL8 and dam 13852 in the | mg/kg/day dosage group was sacrificed on DL 11. The litters from these two dams were inadvertently mixed together. Both dams and litters were sacrificed because it was not possible to identify to which litter the pups belonged P generation female rat 13822 in the vehicle control group was sacrificed on DL 8. This rat was administered 101 daily dosages of the vehicle. Adverse clinical observations before sacrifice included a scab on a forelimb on DSs 15, 16 and 22 10 26. Body weight gains and feed consumption values throughout the precohabitation, gestation and lactation periods were unremarkable. All tissues examined appeared normal at necropsy. `This dam delivered 12 normal pups that appeared norma at necropsy. P generation female rat 13852 in the | mg/kg/day dosage group was sacrificed on DL 11. `This rat was administered 102 daily dosages of the test substance. There were no adverse clinical observations before death. Body weight gains and feed consumption values throughout the precohabitation, gestation and lactation periods were unremarkable. All tissues examined appeared normal at necropsy. This dam delivered 12 pups, one pup had amass on the forelimb on DLs 50 6. All pups appeared normal at necropsy. Page 50 ARGUS 418-020 B.Lb. Clinical Observations All clinical observations during the precohabitation, gestation and lactation periods were considered unrelated to the test substance because: 1) the incidences were not dosagedependent; and/or 2) the observation occurred in only one or two female rats in any dchorsoamgoerghrionuopr.rhTeah,esuengobrsoeormveatdioconast,inscclaubdbeidngm,iscshirnogm/obdraockreynorarnhd/eosr, mliocsaalliizgendedalionpceicsioras, (limbs, underside and head), swollen forelimb and paw, soft or liquid feces, fractured forelimb, broken palate, swollen snout, swollen ears, mass on the head or the axilla, dried red perinasal substance, dried red substance on paws, abrasion on the paw, traumatized cornea and swollen paw, eye or ear. B22. Body Weights and Body Weight Changes- P Generation Female Rats (Figure 2; Summaries - Tables C2 through C7; Individual Data - Tables C25 through C27) Body weights and body weight gains during the precohabitation, gestation and lactation periods were unaffected by dosages of the test substance as high as 30 mg/kg/day. Body weight gain was significantly reduced (p<0.05) during the precohabitation period on days 2910 36 of study, and body weights were significantly reduced (p<0.05) on days 7 and 14 of gestation in the 30 mg/kg/day dosage group but these significant reductions were. not considered toxicologically important because they did not persist. B.3. Absolute (g/day) and Relative (/kg/day) Feed Consumption - PGeneration Female Rats (Summaries - Tables C8 through C13; Individual Data Tables C28 through C30) Absolute (g/day) and relative (g/kg/day) feed consumption values during the. precohabitation, gestation and lactation periods were unaffected by dosages of the test substance as high as 30 mg/kg/day. Absolute feed consumption values were significantly reduced (p<0.05) during the precohabitation period on days 57 to 64 of study, and during the gestation period on days 10 to 14 and 0 t0 21 in the 30 mg/kg/day dosage group but these significant reductions were not considered toxicologically important because they did not persist. The significant reduction (50.05) in the absolute feed consumption value on gestation days 10 10 14 in the | mg/kg/day dosage group was considered unrelated to the test substance because it was not dosage dependent. Bd. Estrous Cycling, Mating and Fertility - P Generation Female Rats (Summary - Table C14; Individual Data - Table C31) The average numbersof estrous stages per 21 days were comparable among the five dosage groups and did not significantly differ. Evaluationofestrous stages at sacrifice. did not reveal any differences among the five dosage groups. All mating and fertility parameters (numbersofdays in cohabitation, rats that mated, fertility index, rats with confirmed mating dates during the first and second week of Page 51 ARGUS 418-020 cohabitation and rats pregnant per rats in cohabitation) were unaffected by dosages of the otefstdasyusbsitnacnocheabaisthaitgihonasin3t0hmeg1/kmgg//dkagy/.daTyhdeossiaggneifgircaonutprweaduscctoionnsi(d<e0re.d05u)nrienlattheedntuomtbheer test substance because it was not dosage dependent. BS. Necropsy and Histopathology Observations - P Generation Female Rats (Summary - Table C15; Individual Data -Table C32; Histopathology APPENDIX K) All necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one female rat in any dosage group. These observations included marked dilation of the renal pelvis and a broken ulna and radius. No treatment-related microscopic changes were observed in the reproductive organs of any of the 10 female rats in the P generation selected for histopathologic evaluation that had been given up to 30 mg/kg/dayofthe test substance. All microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelated to treatment. There were a few `microscopic changes observed in rats designated as "reduced fertility", but these changes occurred spontaneously and were ofthe type that occur spontaneously in female rats of the age and strain and were not compound-related. B.6. Terminal Body Weights, Organ Weights and Ratios (%)of OrganWeightto Terminal Body Weight and Brain Weight - PGeneration Female Rats (Summaries - Tables C16 through C18; Individual Data - Tables C33 and C34) Terminal body weights of the P generation female rats were comparable among the five dosage groups and did not significantly differ. The weights of the left and right kidney, the ratios of these organ weights to the terminal body weight and the ratoofthe left Kidney weight to the brain weight were significantly reduced (p<0.05 orp<0.01) in the 30 mg/kg/day dosage group. The ratios of the liver weight to the terminal body weight were significantly reduced (p<0.05 or p<0.01) in the 3 and 10mg/kg/day dosage groups. All other organ weights (pituitary, brain, left and right adrenals, spleen, cervix, left and right ovary and uterus) and the ratios of these organ weights to the terminal body weight and the brain weight were unaffected by dosages of the test substance as high as 30 mg/kg/day. BJ7. Natural Delivery and Litter Data - P Generation Female Rats (Summaries Tables C19 and C20; Individual Data - Tables C35 through C38) Pregnancy occurred in 27 10 29 rats in each dosage group. One pregnant dam (13862) in the 3 mg/kg/day dosage group did not deliver a litter by day 25 of presumed gestation. "The liter consisted of one implantation site (identified at necroposny day 25 of Page 52 ARGUS 418-020 gestation). Such events are relatively common in rats, and this nondosage-dependent event was unrelated to the test substance. One or more liveborn pups were delivered by every other pregnant dam assigned to natural delivery (there were 27 to 29 litters delivered in each dosage group). 3Na0tmurga/lkgd/edlaiyv.eryVaolbsueersvafotriotnhse wneurmebeurnsafoffecdtaemdsbydedloisvaergiensgolfitttehres,tetshtesduubrsattainocneoafs high as ``ogfedsatamtisonw,iatvheroangeeosrfmororimeplliavnetbaotrinonpsuiptses/npuemrbdeerloivfeprreedglniatenrt, rtahtes)g,etshteatniuomnbienrdsexof(nduammbser with stillborn pups, dams with all pups dying, liveborn and stillborn pups, viability index, pup sex ratios and body weights were comparable among the five dosage groups and did not significantly differ. `The lactation index was 98.1% and 96.3% in the 3 and 30 mg/kg/day dosage groups, respectively. These values were significantly reduced (p<0.05 and p<0.01, respectively) from the control group value of 99.7%. The TestingFacility historical control average `and range for this parameter is 98.8% and 94.4% 0 100.0%, respectively (77 studies; 1995 to 2000). The reductions in the lactation index in the 3 and 30 mg/kg/day dosage groups were not considered treatment-related because: 1) the reduction in the 3 mg/kg/day was not dosage-dependent; 2) this effect did not occur during lactation in the F2 pups; and 3) the reduction in the 30 mg/kg/day was within the historical control range for this facility. One dam in the 30 mg/kg/day dosage group delivered one pup that died on day I of lactation (DL 1. The numbers of pups found dead or presumed cannibalized were significantly increased in the 3 and 30 mg/kg/day dosage groups on days 6 to 8 of lactation. These increases were not considered related to the test substance because they did not affect any other measures of pup viability (surviving pups per litter, live liter size at weighing). Pup body weight per litter was significantly reduced (p<0.05 orp<0.01) in the 1 mg/kg/day dosage groupon DL 1 and in the 30 mg/kg/day dosage group on DLs 1, Sand 8. The pup body weight reduction in the | mg/kg/day dosage group on DL 1, however, was not considered treatment-related because it was not dosage-dependent. B.S. Clinical and Necropsy Observations - F1 Generation Litters (Summaries - Tables C21 and C22; Individual Data - Tables C39 and C40) No clinical or necropsy observations were attributable to dosagesofthe test substance as high as 30 mg/kg/day because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one or two litters. These clinical observations included cold touch, no milk in stomach, umbilical hernia, pale, mass on limb or mouth, not nesting, scab on the back, red perianal substance, not nursing, missing or black tip of tail, traumatized cornea, rotated hindlimbs and absent tail. All male pups met the criterion (no nipples present) at nipple examination on DL 12. Necropsy observations included no milk in stomach and moderate dilation of the renal pelvis. Page 53 ARGUS 418-020 B.9. Terminal Body Weights, Organ Weights and Ratios (%) of Organ Weight to `Terminal Body Weight and Brain Weight - F1 Generation Litters (Summary - Table C23; Individual Data - Table C41) `Terminal body weights of the F1 generation pups were comparable among the five dosage groups and did not significantly differ. The weightsofthe brain, spleen and thymus and the ratios of these organ weights to the terminal body weight and brain `weight were unaffected by dosagesofthe test substance as high as 30 mg/kg/day. The significant reduction (p<0.05) in the ratio of the thymus weight to the terminal body `weight in the 3 mg/kg/day dosage group was unrelated to the test substance because the value was not dosage dependent. B.10. PFOA Serum Levels (ug/mL) Data Summary (APPENDIX I) 0 mg/kg/day Group 1 0 mg/kg/day 10 mg/kg/day oe10 mg/kg/day fe30 mg/kg/day Lactation Day 22 Male End of Cohabitation LactationDay 22 = End of Cohabitation Lactation Day 22 N=3 0.0344 0.0148 N=3 N=10 N=10 N=10 30 mg/kg/day LOQ = Limit of Quantitation Endof Cohabitation N=10 Low levels of PFOA were detected in the sera of the control male rats. In general, PFOA levels found in sera of the female rats increased from 10 mg/kg/day dosage group to the 30 mg/kg/day dosage group. PFOA levels found in sera of the male rats remained the same between the 10.0 mg/kg/day dosage group and the 30 mg/kg/day dosage group. Page 54 ARGUS 418-020 IV. RESULTS - FI GENERATION RATS A. FI Generation Male Rats AL. Mortality and Clinical Observations - FI Generation Male Rats (Summary - Table D1; Individual Data - Table D14) Ala. Mortality 3Th0rmeeg,/ktghr/edea,ytdhroesea,gtewograonudpssewveerneFmIorgiebneurnadtisoancrmifailceedraotrsfionutnhde d0e,ad1., 3,Th10e ainndcreased incidence of mortality in the 30 mg/kg/day dosage group was considered treatmentrelated. Observations for these ratsaredescribed below. Al other F1 generation male rats survived to scheduled sacrifice. 0 mg/kg/day dosage group Rat 1024 was found dead on postweaning day (DP) 25, approximately one hour after the 25th daily dosage. There were no adverse clinical observations before death. This rat was one of the smallest in this group at weaning, weighing only 30 g. This rat gained weight on DPs 1 to 22. Feed consumption values were comparable to other rats in the. dosage group. Necropsy revealed all lobesof the lungs to be mottled and dark red; all other tissues appeared normal. The death of this rat was considered to be due to an intubation accident. Rat 1029 was moribund sacrificed on DP 4, after the 4th daily dosage. Clinical observations before death included chromorhinorrhoena DPs 2 through 4 and decreased `motor activity and cold to touch on DP 4. This rat weighed only 31 g at weaning. All tissues examined appeared normal at necropsy. The moribund condition was attributed to a failureto thrive postweaning. Rat 1039 was found dead on DP 42, approximately 33 minutes after the 42nd daily dosage. The only adverse clinical observation before death was vocalization on DP 34. Body weights and feed consumption were comparabletoother control group male rats. All tissues examined appeared normal at necropsy. The death of this rat was considered 10be due to an intubation accident because death occurred immediately after administration without any adverse clinical observations. 1 mg/kg/day dosage group Rat 1064 was found dead on the morning of DP 6. The rat was administered five daily dosages. Clinical observations before death included chromorhinorrhea and urine-stained abdominal fur on DP 5. This rat weighed 37 g at weaning. All tissues examined appeared normal at necropsy. No cause of death could be determined. Rat 1087 was found dead on DP 45 before administration of the 45th daily dosage. There were no adverse clinical observations before death. Body weights and feed consumption were comparable to other male rats in this dosage group." All tissues examined appeared normal at necropsy. No cause of death could be determined. Page 55 ARGUS 418-020 Rat 1104 was found dead on DP 2 before administration of the 2nddaily dosage. Clinical observations before death included decreased motor activity, cold to touch and `emaciation on DP 1. This rat was one of the smallest in this group at weaning, weighing only 23 g. All tissues examined appeared normal at necropsy. This death was attributed 10. failure to thrive postweaning. 3 mg/kg/day dosage group Rwaetre1n12o1adwvaesrsfeoucnlidnidceaaldobosnerDvPatiobnesfoobreseardvmeidnibsetfroarteiodneaotfh.theThSitsh draatilwyediogshaegde.35Tghearte weaning. All tissues examined appeared normal at necropsy. No cause of death could be determined. wRaetre1n1o30awdvaesrsfeouclnidnidceaaldobosnerDvPat2iobnesfobreefoardemidneaitsht.ratTihoinsorfatthwea2snodnedaoiflythdeossamgael.lesTtheirne this group at weaning, weighing only 24 g. All tissues examined appeared normal at necropsy. This death was attributed (0 a failure o thrive postweaning. Rat 1140 was found dead on DP9 before administration of the 9th daily dosage. The only adverse clinical observation before death was emaciation on DP 3. This rat weighed only 37 gat weaning and 55 g on DP 8. Feed consumption on DPS 1 to 8 was reduced as `compared to other rat in this group. All tissues examined appeared normal at necropsy. `This death was attributed to a failure to thrive postweaning. 10 mg/kg/day dosage group Rat 1200 was moribund sacrificed on DP 40 before administration of the 40th daily dosage. Clinical observations before death included chromodacryorrhea on DP 24, dehydration on DPs 24 to 40, abdominal distention on DPs 25 to 40, urine-stained abdominal fur on DPs 29 to 32 and 39 to 40, and emaciation and cold to touch on DPs 29 1040. This rat was eating and gaining weight through the frst three weeks of dosage administration and then lost body weight over the next two weeks. Feed consumption was reduced on DP 29 t0 36. Necropsy revealed the intestines distended with gas, a small (0.02 g) thymus and numerous ulcerations (pinpoint to 0.1 cm in diameter) in one cardiac region of the stomach and five ulcerations (pinpoint) in asecond cardiac region of the stomach; all other tissues examined appeared normal. Rat 1210 was found dead on DP 4 before administration of the 4th daily dosage. Clinical observations before death included decreased motor activity, cold to touch and emaciation on DP 3. This rat weighed 41 gatweaning. All tissues examined appeared normal at necropsy. No cause of death could be determined. 30 mg/kg/day dosage group Rat 1260 was found dead on the morning ofDP4. The rat was administered three daily dosages. Clinical observations before death included decreased motor activity, cold to. touch and urine-stained abdominal fur on DP 3. This rat was one of the smallest in this `group at weaning, weighing only 24 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. Page 56 ARGUS 418-020 dRoastag1e2.63ClwiansicfaoluonbdsedrevaadtioonnsthbeefmoorrendienagthofiDncPlu2d.edThdeecrraetasweads maodtmoinriasctteirvietdy,onceomdeaailly `opacity, emaciation and cold to touch on DP 1. This rat was one of the smallest in this `group at weaning, weighing only 25 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. Rat 1264 was found dead on the morning of DP 2. The rat was administered one daily dosage. Clinical obscrvations before death included decreased motor activity, comeal `ogpraocuiptya,tewmeaacniiantgi,owneaingdhicnogldotnolyto2u4chg.onAlDlPti1s.suTehsiesxraamtiwnaesd oanpepoeafrtehdensomramlalelsattin this necropsy. This death was attributed to a failure to thrive postweaning. Rat 1275 was moribund sacrificed on DP 39 before administration of the 39th daily ddoeshaygder.atiColinnoicnalDPobsse2r6vtaoti3o9n,sebmeafcoiraetidoenatohninDcPlsud2e9d tcoh3r9o,modrehcirneoarsrehdemaootnorDaPcsti2vi6tytoon33, DPs 32 to 39, urine-stained abdominal fur on DP 32 to 39, cold to touch on DPs 33 to 39 and chromodacryorrhea on DP 39. This rat was eating and gaining weight through the first three weeks of dosage administration and then lost body weight over the next two weeks. Feed consumption was reduced on DP 29 t0 36. Necropsy revealed numerous atlalnoatrheearst(ipsisnupeosianptpe0ar0.e1d cnmor)moaln.the median lobe of the liver and a small (0.04 g) spleen; Rat 1277 was found dead on the morning of DP 4. The rat was administered three daily dosages. Clinical observations before death included chromorhinorrhoeanDPs 2 and 3 and decreased motor activity, cold to touch, emaciation and urine-stained abdominal fur on DP 3. This rat was one of the smallest in this group at weaning, weighing only 25 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure: to thrive postweaning. Rat 1280 was found dead on DP3 before administrationofthe 3rd daily dosage. The only adverse clinical observation before death was chromorhinorehea on DP 2. This rat weighed 34 gat weaning. All tissues examined appeared normal at necropsy. No cause of death could be determined. Rat 1296 was found dead on DP 107 before administration of the 107th daily dosage. Clinical observations before death included rales on DP 100, chromorhinorrhea on DPs 100 to 101, chromodacryorrhea and misaligned incisors on DPs 100 t0 106, emaciation on DPs 103 to 106 and urine-stained abdominal fur on DPs 104 to 106. This rat gained weight similar to other rats in this group up to DP 99 after which it lost 130 g in body weight over the next week. Feed consumption values were unremarkable up to DP 70. All tissues examined appeared normal at necropsy. No cause of death couldbe: determined. A.Lb. Clinical Observations `The incidences of annular constriction of the tail of male F1 generation rats were increased in the 1, 3, 10 and 30 mg/kg/day dosage groups, reaching statistical significance (p<0.05 or p<0.01) in the 1, 10 and 30 mg/kg/day dosage groups. The number of male rats observed to be emaciated was significantly increased (p<0.05 or Page 57 ARGUS 418-020 PuSri0n.e0-1s)taiinnethdeab1d0oamnidna3l0 fmugr,/kdge/cdreaaysdeodsmaogteogrraocutpisv,itaynadntdheabnduommbienrasl odfismtaenlteiornatwsewriet:h significantly increased (p<0.01) in the 30 mg/kg/day dosage group. The incidence of the observationofcold to touch was increased, albeit not significantly, in the 30 mg/kg/day dosage group. All other clinical observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and/or 2) the observation occurred in only. one to three male rats in any dosage group. These observations included chromorhinorrhea, chromodacryorrhea, missing/broken and/or misaligned incisors, scab. tlhoecaltiemdbos,nbtahcekneocrkh,ehaeda,dc,obmaecakl, ompoauctithy,orraelaers,,sdoefhtyodrraltiiqouni,d fleaccersi,maltoicoanl,izsewdolalloepneecyiea,on ars or snout, red substance on the penis, excess salivation, dried and red perinasal ssuubbssttaannccee,, pvtoocsailsi,zaetnioopnh,tthiaplomfosta,ilambirsassiionng oonr btlhaechk,eaudlcaenrdateinonlaorngetdheeybea.ck, red perioral A2. Body Weights and Body Weight Changes - F1 Generation Male Rats (Figure 3; Summaries - Tables D2 and D3; Individual Data - Table D15) Body weights and body weight gains were reduced for the FI generation male rats before and after the cohabitation period at the 1, 3, 10 and/or 30 mg/kg/day dosages of the test substance, as compared to the control group. Body weight gains for the entire dosage period (DPs 1 to 113) were significantly reduced (p=0.01) in a dosage-dependent manner in the 1, 3, 10 and 30 mg/kg/day dosage groups. Body weight gains were also significantly reduced (p<0.01) in the 10 and 30 mg/kg/day dosage group forthe entire precohabitation period (DP 1 to precohabitation). `Within these periods, body weight gains were significantly reduced (p<0.05 orp<0.01) in the 1 and 3 mg/kg/day dosage groups on DPs 43 to 50, in the 3 mg/kg/day dosage group on DPs 57 to 64 and in the | mg/kg/day dosage group alone on DPs 15 (0.22. Body weight gains in the 10 and 30 mg/kg/day dosage groups were significantly reduced (p=0.05orp<0.01) on DPs 8 0 15,2210 29, 29 10 36, 43 to 50 and 5to057. Body weight gains in the 30 mg/kg/day dosage group were also significantly reduced (p<0.05 orp<0.01on) DPs 1108, 1510 22,36 10 43, 57 to64and64 0 70. B1o06dyanwdei1g1h3tsinwtehree1simggn/ikfigc/adnatlyydroesdaugceedgr(opu<p0,.0o5n oDrPps<01.0061)anodn1D1P3sin50t,he573,m6g4/,k7g0/,d9a9y, dosage group and at all weekly intervals after DP 36 in the 10 mg/kg/day dosage group and DP 8 in the 30 mg/kg/day dosage group. A3 Absolute (g/day) and Relative (g/kg/day) Feed Consumption - FI Generation Male Rats (Summaries - Tables D4 and DS; Individual Data - Table D16) Absolute (g/day) feed consumption values for the F1 generation male rats were significantly reduced (p<0.01) and relative (g/kg/day) feed consumption values were significantly increased (<0.05 or p<0.01) for the entire precohabitation period (DPs 1 to 70) by dosages of APFO of 10 (absolute only) and 30 mg/kg/day. Page 58 ARGUS 418-020 Absolute feed consumption values for the 30 mg/kg/day dosage group were significantly reduced(p<o0rp<.0.001)5on DPs 1 10.8, 8to 15, 1510 22, 22 10.299t,o 36, 43 10 50 and the 5010 57. Relative feed consumption 30 mg/kg/day dosage groupon DPs 1 values were significantly reduced (p<0.05) in 10 8. Relativefeed consumption values were significantly increased (p<0.05) in the 10 mg/kg/day dosage group on DPs 29 to 36 and significantly increased (p<0.01) in the 30 mg/kg/day dosage group on DP 22 10 29, 29 to 36,36 10.43, 43 10 50, 50 10 57, 57 10 64 and 64 to 70. Relative feed consumption values were significantly increased (p<0.01) in the DP5 9910 106, 106 to 113 and 99 to 13. 10 and 30 mg/kg/day dosage groups on `The significant reduction (p=0.05 or p<0.01) in the absolute feed consumptionvalueon DPs 221029, 2910 36,43 10.50 and 1 to 70 in the 1 mg/kg/day dosage group were considered unrelated to the test substance because they were not dosage dependent. Ad. Sexual Maturation - F1 Generation Male Rats (Summary - Table D6; Individual Data - Table D17) Preputial separation of FI generation male rats was slightly delayed (approximately three: and a half days later than the control group value) in the 30 mg/kg/day dosage group, compared to the control group. The Testing Facility historical control average and range for this parameter is46.1 days and 43.9 t0 47.7 days, respectively (42 studies; 1995 to 2000). The average day when preputial separation was evident in the 30 mg/kg/day dosage group (52.2 daysofage) significantly differed (p<0.01) from the control group. value (48.5 days of age). When this observation in the 30 mg/kg/day dosage group was covaried with the significantly reduced (p=0.01) body weight at timeofacquisition, to determine if the significantly reduced body weights were a factor, the difference was still significant, but at the p<0.05 level. When this observation in the 30 mg/kg/day dosage group was covaried with gestational age at ime of acquisition to determine if this group was younger and more immature than the control group, there was no significant difference in sexual maturation. AS. Mating and Fertility - FI Generation Male Rats (Summary - Table D7; Individual Data - Table D18) Dosages of the test substance as high as 30 mg/kg/day did not affect any mating and fertility parameters evaluated in the F1 generation male rats. Values for the fertility and pregnancy indices (number of pregnancies per number of rats that mated and rats in cohabitation, respectively), the number of days to inseminate, the number of rats that mated and the number of rats with confirmed mating dates during the first week of cohabitation were comparable among the five dosage groups.Of the male rats assigned to cohabitation, 93.3%, 96.6%, 93.3%, 93.3% and 96.7% impregnated the cohort female rat in the five dosage groups, respectively. A6. Necropsy Observations - FI Generation Male Rats (Summary - Table D Individual Data - Table D19) `The numberofFI generation males that appeared normal at necropsy was significantly reduced (p<0.01) in the 10and 30 mg/kg/day dosage groups, compared to the control group. Page 59 ARGUS 418-020 `mTaalnearraetassionctchuerr3e,d10inanthde 3le0ftmlga/tekrga/ldaanyd/doorsamgeedigarnoulposb,esreosfpetchteivleilvye.r iOnn6e%,of10t*h*esaenrda9s%i*n the 30 mg/kg/day dosage group also had a small spleen. One 30 mg/kg/day dosage group rat had an enlarged liver. Moderate to slight dilationof the pelvis of one or both kidneys occurred in 4** and 1 rats in the 10 and 30 mg/kg/day dosage groups, respectively. A tan area in the parenchymaofthe spleen occurred in one 10 mg/kg/day dosage group rat. All other necropsy observations were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one: male rat in any dosage group. These observations included small prostate for one a1nmogth/ekrg/|dmagy/dkogs/adgaeygdroosuapgeratg,rsomuaplrlata,nldarfgleaclceifdt tleesfttitsefsotrsoanned3smmagl/lklge/ftdaeypiddoisdaygmeidgersoufpor rat, ulceration of the cardiac region of the stomach, intestines distended with gas and small thymus for one rat that was moribund sacrificed in the 10 mg/kg/day dosage group. Mottled dead. dark red lung lobes occurred in one 0 mg/kg/day dosage group rat that was found AZ. Terminal Body Weights, Organ Weights and Ratios (%)of Organ Weights to `Terminal Body Weight and Brain Weight - F1 Generation Male Rats (Summaries - Tables D9 through D11; Individual Data - Tables D20 and p21) `Terminal body weights of the FI generation male rats were significantly reduced (p<0.05 orpS0.01) ina dosage-dependent manner in the 1, 3, 10 and 30 mg/kg/day dosage groups. `The absolute weights ofthe liver were significantly increased (p<0.01) and the absolute: weights of the spleen were significantly decreased (p<0.05 orp<0.01) inthe 1 mg/kg/day and higher dosage groups, compared to the control group values. The absolute weighs of the left and/or right kidneys were significantly increased (p<0.05 orp<0.01) in the 1 and 3 mg/kg/day dosage groups and significantly decreased (p<0.01) in the 30 mg/kg/day dosage group, compared to control group values. The absolute weight of the thymus was also significantly decreased (p<0.01) in the 10and 30 mg/kg/day dosage groups. The absolute weight of the prostate, brain and left adrenal gland were significantly decreased (p=0.05 or pS0.01) in the 30 mg/kg/day dosage group. `The ratios of the weights of the seminal vesicles, with and without fluid, liver and left and right kidneys to the terminal body weights were significantly increased (pS0.05 or PS0.01) in the 1 mg/kg/day and higher dosage groups, compared to the control group values. The ratios of the weightsofthe left tests, with and without the tunica albuginea and the right testis tothe terminal body weight, were significantly increased (p<0.05 or p<0.01) in the 3 mg/kg/day and higher dosage groups. The ratios of the weighs of the Teft epididymis, left cauda epididymis, right epididymis and brain to the terminal body weight were significantly increased (7<0.05 orp<0.01) in the 10 mg/kg/day and higher dosage groups. * Significantly different from the Group I value (p<0.05). ** Significantly different from the Group I value (p<0.01). Page 60 ARGUS 418-020 `The ratios of the weight of the seminal vesicles with fluid to the brain weight were increased in the 1 mg/kg/day and higher dosage groups, compared to the control group values. These ratios were significantly increased (p<0.05) in the 1 and 10 mg/kg/day dosage groups. The ratios of the liver weight to the brain weight were significantly increased (p<0.01) in the 1 mg/kg/day and higher dosage groups, and the ratios of the left and right kidney weights to the brain weight were significantly increased (p<0.05 or S001) in the 1,3 and 10 mg/kg/day dosage groups. The ratios of the spleen weight to the brain weight were significantly decreased (p<0.05 or p<0.01) in the | mg/kg/day and higher dosage groups, and the ratios of the thymus weight to the brain weight were significantly decreased (p<0.05 orp<0.01) in the 10 and 30 mg/kg/day dosage groups. `The ratios of the left and right testes weight to the brain weight were increased in the 3 mg/kg/day and higher dosage groups. These ratios were significantly increased (p<0.05 orp<0.01) in the 10 mg/kg/day (right testis only) and 30 mg/kg/day dosage groups. AS. Histopathology (APPENDIX K) No treatment-related microscopic changes were observed in the reproductive organs of any of the 10 male rats in the F1 generation selected for histopathologic evaluation that had been given up to 30 mg/kg/dayof the test substance. A treatment-related microscopic change was observed in the adrenal glands of 7/10 male ratsofthe 30 mg/kg/day dosage group. This change consisted of increased thickness and prominence of the zona glomerulosa due to cytoplasmic hypertrophy and vacuolation of the cellsofthe adrenal cortex. Treatment-related microscopic changes also were observed in the liver sections of the F1 generation male rats in the 3, 10 and 30 mg/kg/day dosage groups. Microscopically, these gross changes were due to diffuse hypertrophy of the hepatocytes. Hepatocytes in all areas (diffuse) ofthe hepatic lobules were enlarged due to an increased dense, eosinophilic cytoplasm. A very low incidences of single-cell or focal/multifocal hepatocellular necrosis also was observed in a few rats. of these groups. Hepatic tissue was available for micropic examination only from rats with gross observations in the liver. All other microscopic changes observed in the various organs and tissues were considered (0 have occurred spontaneously and to be: incidental and unrelated to treatment. There were a few microscopic changes observed in rats designated as "reduced fertility", but these changes occurred spontancously and were of the type that occur spontaneously in male rats of the age and strain and were not compound-related. AS. Cauda Epididymal Sperm Motility, Count, Density and Spermatid Count - F1 Generation Male Rats (Summary - Table D12; Individual Data - Table D22) A9.a. Cauda Epididymal Sperm Motility No statistically significant or dosage-dependent differences occurred in the numbers of motile sperm, percentage of motile sperm, static count (nonmotile sperm), total count or sperm density. Page 61 ARGUS 418-020 A9b. Cauda Epididymal Spermatid Count and Concentration `Cauda epididymal spermatid count and density were unaffected by dosages of the test substance as high as 30 mg/kg/day. No statistically significant differences occurred. A10. Cauda Epididymal Sperm Morphology - F1 Generation Male Rats (Summary -Table D13; Individual Data - Table D23) Sperm morphology was unaffected by dosagesofthe test substance as high as 30 mg/kg/day. The number of sperm with a broken flagellum was significantly reduced (p=0.05) in the 1 mg/kg/day dosage group, compared t0the control group. This finding `was not considered treatment-related because it was not dosage-dependent. B. Fl Generation Female Rats BL. Mortalityand Clinical Observations - F1 Generation Female Rats (Summary - Table E1; Individual Data - Table E26) B.La. Mortality `Two, one, one and six+* F1 generation female rats in the 1,3, 10 and 30 mg/kg/day dosage groups were found dead during the post-lactation period. All the deaths, except onc in the 1 mg/kg/day dosage group, occurred postweaning days 2 10 8. This increased incidence of mortality in the 30 mg/kg/day dosage group was considered treatmenrelated and may have been related to their small size (5 ofthe 7 founddead pups were 28 gor less at weaning). Observations for these rats are described below. All other FI generation female rats survived to scheduled sacrifice. 1 mg/kg/day dosage group Rat 1365 was found dead on postweaning day (DP) 4 before administration of the fourth daily dosage. Clinical observations before death included tip of ail missing on DPs 1 to 3 and decreased motor activity, chromorhinorrhea and cold to touch on DP3. This rat was oneofthe smallest in this group at weaning, weighing only 31 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. Rat 1373 was found dead on DP 51 before administration of the 51st daily dosage. Clinical observations before death included chromorhinorrhea on DPs 28 to 35, dehydration on DPs 29 to 50, urine-stained abdominalfuron DPs 32 to 50, chromodacryorrhea on DP 35, emaciation on DP 35 to 50 and decreased motor activity on DPs 45 10 50. This rat lost weight after DP 29. Feed consumption values were unremarkable. Necropsy revealed distended stomach and intestines and a depressed white area on the dorsal surfaceofthe right apical lobe of the lungs. All other tissues appeared normal. No cause of death could be determined. + Significantly different from the control group value (<0.01). Page 62 ARGUS 418-020 3 mg/kg/day dosage group Rat 1432 was found dead on the morning of DP 7 before administration of the 7th daily dosage. Clinical observations before death included urine-stained abdominal fur and chromorhinorrhea on DPs 4 0 6 and emaciation on DP6. This rat was oneofthe. smallest in this group at weaning, weighing 31 g. All tissues examined appeared normal at necropsy. This death was tributed to a failure to thrive postweaning. 10 mg/kg/day dosage group dRoastag1e4.84ClwiansicfaoluonbdsedrevaadtioonnsthbeefmoorrendienagthofiDncPlu3debdefuorrienea-dsmtianiinsetdraatbidoonmiofnatlhefutrhiornd daily DPs 1 and 2 and decreased motor activity, cold to touch and labored breathing on DP 2. Tehxiasmirantewdaasppoenaereodf tnhoersmmaalllaetsntecinrotphsiys.grTohuipsadtewaetahnwiangs,awtteriigbhutiendgtoonalyfa2i8lurge. tAoltlhtriisvesues postweaning. 30 mg/kg/day dosage group Rat 1549 was found dead on DP 8 before administration of the eighth daily dosage. Clinical observations before death included decreased motor activity on DPs 2 and 3, chromorhinorrhea on DPs 2 t0 7, cold to touch on DPS 3 to 7 and urine-stained abdominal fur on DPs 5 to 7. This rat was oneofthe smallest in this group at weaning, weighing only 28 g and feed consumption was severely reduced on DPs 1 to 8. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. Rat 1559 was found dead on DP 6 before administration of the sixth daily dosage. Clinical observations before death included urine-stained abdominal fur on DPs 3 to 5 `and cold to touch and emaciation on DP 5. "Thisrat was oneofthe smallest in this group at weaning, weighing only 22 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. Rat 1562 was found dead on the morning of DP 2. The rat was not administeredthe test substance. No clinical observations, body weightor feed consumption values were recorded. All tissues examined appeared normal at necropsy. No causeofdeath could be determined. Rat 1563 was found dead on the morning of DP2. The rat was not administered the est substance. No clinical observations, body weight or feed consumption values were recorded. All tissues examined appeared normal at necropsy. No cause of death could be. determined. Rat 1574 was found dead on DP 3, approximately one hour after the third daily dosage. Clinical observations before death included cold to touch and urine-stained abdominal fur on DPs 2.and 3. This rat was one of the smallest in this group at weaning, weighing only 23g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning, Page 63 ARGUS 418-020 Rat 1575 was found dead on the morning of DP 3 before administration of the third daily dosage. There were no adverse clinical observations before death. This rat was one of the smallest in this group at weaning, weighing only 23 g. All tissues examined appeared normal at necropsy. This death was attributed to a failure to thrive postweaning. B.Lb. Clinical Observations All clinical observations during the precohabitation, gestation and lactation periods were considered unrelated 10 the test substance because: 1) the incidences were increased to statistically observation significant levels; 2) occurred in only one the to incidences two female were not dosage-dependent; and/or rats in any dosage group. These 3) the ocbhsreormvoatthiionnosrrihnecal,udreadleas,bdtopmionfatlaildimsitsesnitniogn,,sucraibneo-nsttahienehdeaadbdoormbiancakl, fluorc,acloilzdedtaoltoopuecchi,a on the limbs, neck or head, decreased motor activity, emaciation, bent tail, missing/broken and/or misaligned incisors, lacrimation, swollen eye, labored breathing, soft or liquid feces, chromodacryorrhea, swollen ear, dehydration, annular constriction of the tail, swollen head or snout, ptosis, mass in the right axilla and red perivaginal substance. A significant increase (<0.01) in the incidenceofred perivaginal substance in the 3 mg/kg/day dosage group during the lactation period was not considered treatmentrelated because it was not dosage-dependent. B2. Body Weights and Body Weight Changes - F1 Generation Female Rats (Figure 4; Summaries - Tables E2 through E7; Individual Data - Tables E27 through E29) B.2a. Precohabitation Body weights and body weight gains during the precohabitation period were significantly reduced (p<0.05 orp<0.01) by 30 mg/kg/day dosagesofthe test substance. Body weight gain for the entire precohabitation period (DP 1 to precohabitation) was significantly reduced (p<0.05). Within this period, body weight gains were significantly reduced (p=0.01) on DPs 1 to 8 and to 15. Body weights in this group were significantly reduced (p<0.05 orp<0.01) on DP 8, 15, 22, 29, 50, 57 and precohabitation. Body weights and body weight gains during the precohabitation period were unaffected by dosages of the test substance as high as 10 mg/kg/day. Body weight gains in the 1 mg/kg/day dosage group were significantly reduced (p<0.05orp<0.01) on DPs 1 to and to 15 and in the 10 mg/kg/day dosage group were significantly reduced (p<0.01) on DPs 8 to15. Body weights in the 1 mg/kg/day dosage group were aiso significantly reduced (p<0.05 orp<0.01o)n DP 8, 15, 22 and 29. These reductions in the 1 and 10 mg/kg/day dosage groups were not considered treatment-related because: were not dosage-dependent; and 2) they did not persist. 1) they. Page 64 ARGUS 418-020 B.2b. Gestation Body weights during the gestation period were significantly reduced (p<0.05) in the 30 mg/kg/day dosage group on gestation days (DGs) 0, 7, 10 and 14, compared to the control group. Body weights and body weight gains during the gestation period were unaffected by dosages of the test substance as high as 10 mg/kg/day. B.2.. Lactation Body weights during the lactation period were significantly reduced (p<0.05 orp<0.01) in the 30 mg/kg/day dosage group on lactation days (DLs) 5,8, 11 and 15, compared to the control group. Body weights and body weight gains during the lactation period were unaffected by dosages of the test substanacse high as 10 mg/kg/day. B3. Absolute (/day) and Relative (g/kg/day) Feed Consumption - F1 Generation Female Rats (Summaries- Tables ES through E13; Individual Data -Tables E30 through E32) Ainbstohleu3t0em(gg//dkagy/)dafeyeddocsoangseumgprtouipononvaDluPess w11e0r.e8,si8gntiofi1c5anatnldy r1e5dtuoc2e2dd(upr<in0g.0t5hoerp<0.01) precohabitation period, on DGs 7 to 10 during the gestation period and on DLs 1 to 15 during the lactation period. Relative (g/kg/day) feed consumption values were. comparable among the 0, 1, 3, 10 and 30 mg/kg/day dosage groups for the precohabitation, gestation and lactation periods and did not differ statistically. Absolute and relative feed consumption values during the precohabitation, gestation and lactation periods were unaffected by dosages of the test substance as high as 10 mg/kg/day. Absolute feed consumption valueswere significantly reduced (<0.01) in the 1 mg/kg/day dosage group on DPs 1 to 8 and to 15 during the precohabitation period. These significant reductions in the absolute feed consumption in the 1 mg/kg/day dosage group were considered unrelated to the test substance because they were not dosage dependent and did not persist. BA. Sexual Maturation - F1 Generation Female Rats (Summary - Table E14; Individual Data - Table E33) `The 30 mg/kg/day dosage group F1 generation female rats had a small (approximately 1.7 days increase from the control group value), statistically significant (p<0.01) delay in vaginal patency. The Testing Facility historical control average and range for this `parameter is 32.1 days and 30.1 to 34.0 days, respectively (42 studies; 1995 t0 2000). The average day when vaginal patency was evident in the 30 mg/kg/day dosage group (36.6 daysofage) significantly differed (<0.01) from the control group value (34.9 days of age). When this observation in the 30 mg/kg/day dosage group was covaried with the significantly reduced (p<0.01) body weight at time of acquisition, to determineifthe significantly reduced body weights were a factor, the difference was still significant, but at the p<0.05 level. When this observation in the 30 mg/kg/day dosage group was Page 65 ARGUS 418-020 covaried with gestational age at timeofacquisition, to determine if this group was `youngerand more immature than the control group, there was no significant difference in Sexual maturation. BS. Estrous Cycling, Matingand Fertility - F1 Generation Female Rats (Summary - Table E15; Individual Data - Table E34) `The average numbersof estrous stages per 21 days were significantly increased (p<0.01) in the 30 mg/kg/day dosage group (4.7 versus 5.4 stages). The Testing Facility historical control average and range for this parameter is 5.0 stages and 4.8 to 5.2 stages, respectively (7 studies; 1992 10 2002). When this observation in the 30 mg/kg/day dosage group was covaried with the day 64 body weightorage, the difference was still significant, but at the p<0.05 level. Evaluation of the number of rats with 6 or more consecutive days of diestrus or estrus and estrous stages at sacrifice did not reveal any differences among the five dosage groups. fAelrltimlaittyiinngdeaxn,drfaetrstiwliittyhpcaornafmiertmeerds m(antuimnbgerdsatoefs ddauyrsinigntchoehafbiirsttatwieoen,kroaftscothhaatbimtaatteido,n and ats pregnant per rats in cohabitation) were unaffected by dosagesofthe test substance as high as 30 mg/kg/day. B.6. Necropsy Observations - FI Generation Female Rats (Summary - Table E16; Individual Data - Table E35) All necropsy observations for the F1 generation female rats were considered unrelated to the test substance because: 1) the incidences were not dosage-dependent; and 2) the observation occurred in only one female rat in any dosage group. The observations included a small spleen foar0 mg/kg/day dosage group rat, a mass on the left lateral lobe: of the liverwith adhesion of the caudate lobe foar | mg/kg/day dosage group rat; slight dilation of the pelvis of both kidneys foar 3 mg/kg/day dosage group rat; moderate: dilation of the pelvisofthe right kidney, thickened urinary bladder walls and moderate dilationofboth ureters with one calculi atthecaudal end foar 30 mg/kg/day dosage `group rat. One rat in the 1 mg/kg/day dosage group that was found dead had distended stomach and intestines with a depressed white area on the lungs, as previously described BJ7. Terminal Body Weights, Organ Weights and Ratios (%)ofOrgan Weights to `Terminal Body Weight and Brain Weight- F1 Generation Female Rats (Summaries - Tables E17 through E19; Individual Data - Tables E36 and E37) Terminal body weights of the FI generation female rats were comparable among the five dosage groups and did not differ significantly. `The absolute weight of the pituitary and the ratios of the pituitary weight to the terminal body weight and to the brain weight were significantly (p<0.05 orp<0.01) decreased in the 3 mg/kg/day and higher dosage groups, as compared to the control group values. Page 66 ARGUS 418-020 `The absolute weights of the brain, liver, kidneys, adrenals, spleen, thymus, ovaries and wuteeirguhstawnedrtehuenraaftfieocstoefdtbhyesdeoosraggaens woefitghhetstesttostuhbesttearnmcienaals hbiogdhyawse3ig0hmtga/nkdg/tdhaey.brain Primordial follicle count for ten FI generation female rats in the vehicle control and 30 mg/kg/day dosage groups were comparable and did not significantly differ. BS. Histopathology (APPENDIX K) No treatment-related microscopic changes were observed in the reproductive organs of any of the 10 female rats in the FI generation selected for histopathologic evaluation that had been given up to 30 mg/kg/dayofthe test substance. All microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be incidental and unrelatedto treatment. There were a few `microscopic changes observed in rats designated as "reduced fertility", but these changes occurred spontancously and wereof the type that occur spontaneously in female rats of the age and strain and were not compound-related. B.9. Natural Delivery and Litter Data - FI Generation Female Rats (Summaries - `Tables E20, E21 and E25 ; Individual Data - Tables E38 through E41 and E45) Pregnancy occurred in 28 to 29 rats in each dosage group. Natural delivery observations were unaffected by dosages of the test substance as high as 30 mg/kg/day. Valuesforthe `numbersofdams delivering liters,the duration of gestation, averages for implantation sitesperdelivered litter, the gestation index (numberofdams with one or more liveborm pups/number of pregnant rats), the numbers of dams with stillborn pups, dams with all pups dying and liveborn and stillborn pups were comparable among the five dosage groups and did not significantly differ. `The viability index (number of live pups on day 5 postweaning per number of liveborn `pups on day 1 postweaning) and lactation index (number oflive pupson day 22 postweaning per numberof live pups on day 5 postweaning) were comparable and did not differ significantly. "The numbers of pups found dead or presumed cannibalized were significantly increased (p=0.01) in the 3 and 10 mg/kg/day dosage groups on day 1 of lactation. These increases were not considered related to the fest substance because: 1) they were not dosagedependent; and 2) they did not affect any other measuresof pup viability (surviving pups per litter, live liter size at weighing). `The number of pups surviving per litter, the percentage male pups, litter size and average pup body weight per litter were comparable and did not differ significantly on DLs 1,5, 8, 15 or 22 for any of the dosage groups when compared to the control group. Anogenital distances measured for male and female pups on DLs 1 and 22 were comparable among the five dosage groups and did not significantly differ. Page 67 ARGUS 418-020 B.10. Clinical and Necropsy Observations -F2 Generation Pups (Summaries - Tables E22 and E23 ; Individual Data - Tables E42 and E43) No clinical or necropsy observations were atributable to maternal dosages of the test substance as high as 30 mg/kg/day because: 1) the incidences were not dosagedependent; and 2) the observation occurred in only one or two litters. These clinical observations included cold to touch, absent tail or eye, tp of tail missing, scab on tail or back, pale in appearance, abrasion at the base of the tail, mass on the mouth, abrasion on the back or ail, emaciation, domed head, dehydration, ail bent or thread-like, no anal `opening present, ungroomed coat and no milk present in the stomach. Necropsy observations were limited to no milk in stomach in pups that were found dead. In the `pups examined at necropsy on DL 22, dilated kidneys occurred in the 0 mg/kg/day (1 pup dinosoangeelgitreoru),ps1 amngd/kmga/rdkaeyd(d1ilpautpioninoofntehelitthteirr)daanndd3lamtger/aklgv/ednatryic(l2epsuopfstihne 2brlaiittnerosc)curred in the 10 mg/kg/day dosage group (1 pup in 1 liter). BIL F2 Generation Terminal Body Weights and Selected Organ Weights and Ratios (%) of Organ Weightsto Terminal Body Weights and Brain Weights (Table E24; Individual Data - Table E44) F2 generation rats had comparable terminal body weights on DL 22; the values did not significantly differ from the control group values. Absolute weights of the brain, spleen and thymus and ratios of these organ weights to terminal body weight and to brain weight were comparable among the five dosage groups and did not significantly differ. REFERENCES 1. U.S. Environmental Protection Agency (1998). Health Effects Test Guidelines; Reproduction and Fertility Effects. Office of Prevention, Pesticides and Toxic Substances (OPPTS) 870.3800, August, 1998. 2. US. Environmental Protection Agency (1997). Toxic Substances Control Act (TSCA) Test Guidelines; Final Rule. Reproduction and Fertility Effects, 799.9380 (cross-referenced to OPPTS 870.3800). Federal Register, August 15, 1997. 3. US. Environmental Protection Agency. Federal Insecticide, Fungicide and Rodenticide Act/Toxic Substances Control Act (FIFRA/TSCA); Good Laboratory Practice Standards; Final Rule. 40 CFR Part 160/Part 792. 4. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principlesof Good Laboratory Practices [C(97)186/Final]. Page 68 ARGUS 418-020 S. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington, D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 6. Christian, MS. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium, New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 7. Lang, PL. (1988). Embryo and Fetal Developmental Toxicity (Teratology) Control Data in the Charles River Crl:CDBR Rat. Charles River Laboratories, Inc., Wilmington, MA 01887-0630. (Database provided by Argus Research Laboratories, Inc.) 8. Institute of Laboratory Animal Resources (1996). Guidefor the Care and Use of LaboratoryAnimals. National Academy Press, Washingion, D.C. 9. Snedecor, G.W. and Cochran, W.G. (1967). Variance test for homogeneity ofthe binomial distribution. Staristical Methods, 6th Edition, lowa State University Press, Ames, pp. 240-241. 10. Sokal, RR. and Rohlf, F.J. (1969). Bartlett' test of homogeneity of variances. Biometry, WH. Freeman and Co., San Francisco, pp. 370-371. 11. Snedecor, G:W. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, Towa State University Press, Ames, pp. 258-275. 12. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121 13. Sokal, RR. and Rohlf, FJ. (1969). Kruskal-Wallis Test. Biometry, WH. Freeman and Co., San Francisco, pp. 388-389. 14. Siegel, S. (1956). Nonparametric Statisticsfor the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. 15. Dunn, OJ. (1964). Multiple comparisons using rank sums. Technometrics 6(3):241-252. Page 69 ARGUS 418-020 APPENDIX A REPORT FIGURES Page 70 ARGUS 418-020 ol iPo h5d5d5d JPEH] li 5 A 5 i 142 : Ck 8 yg: 2 ! iq: 3 2 g iq: i 8 Be Wzoe gg : RH sg sh : ' ! Ck : EE TT TTT . g Soro # Page 71 ARGUS 418-020 ; dedfg 8 x x x z x fg] ] 3 3 i5 f] e "5E3Z 5 Sa -8 g Ph "3 Hi ] 5 < =i py "= SoaUn 5i3E EBBE oazzbiy. 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Fi ii if 38 | : :HH ii IssRssRxaNsResEanIsIssIesIsoEsEseNnsEeNnaRnaGs AEs BB essmsssrasevsssneBLsE A i [RnR ENE if Poel feastassniursssassssnanese nae Dig 8 i, B3 E BEaEa (EiRcReREmFaRncEaZsImGcErEEsInIsRmnEsIRIeIsZeERrRsIInEeDIsIEcAaSRs|aazoBNsOal}F Si fHEo E lst glhh #0 ii z | gf i.ig999935595gnavansananssaazanayistig? it i Jr 3 8 | 8 aensfasansssnanscsazesiong adil Page275 ARGUS 418-020 : i gh RR ss i : Lh mmm | gH iy i : Dog mmmEmmmEIImIIINILNE | Ee THREEL] l0s3s5e0se3s3u0s0sa0s0z0edvi0s0a0sadsdsdsazadniedianiiiiipEih i : 5 gE| EssEcsmsIesEnm:gNeRscIosEeEsnEeRssgIaaIssBeasd 0 [HA 2 s{asdmsmdasssansinassesdniianssnsnaasananiaiananaeiining HEN = FE fifs & }0 g; E} {IsIrRuUsRnLeuIsAiIaNnAeUaiIzEaRnNnIeiaaaiaedaisg;sdaisgeiabEety fer Fel Inn Bai #1 fini HRI gf #5 i it 8 BE i iidisi[SEIIIATIIANORNNNINCsIeIeIzCeNsNeNsNyNnielsy 5 oi gf iisuzaansazzacassaanazataatzssssiniyl Pr8oglg mmpsanai: agnaapnasnsacsnanrpysatnegsagtiaagated i i i if HRT Page 276 ARGUS 418-020 Hilw ihEi (Eg | ax a552an Araninzissdzassan ly Fie 5EF B8 i i8%fena"niicne TcuoEveTe A auggeesT emenvenA saner] 8 BbyrBiip mi e a2 e Blei ta ki i [, [gElniaspannans aRnaRaananneannag 3s 220 iSifigleecgecenen coconcococaencacanl Eis LESr g iiSEEecaafananaz sanasmamanacasaanan fog iPloon 1 | iJ i f LE ARGUS 418-020 PE Ei E"E ener aes senssnens sasssesas Ph EEN N eB, evens wae wrugeerene reergendd Bl hres ae copes creeped Pop meee oo meeenaan mage] ha Freee ere meinen mpzeeenend BE de 1 rE Bi Teer ome meee mmr i i files fnanavnass sasssnnan} Eo BEE cece cocoooroon cosonnenel FEY Poon 2 i : EE ESE LTT Eff Fil eis : i i8 i anaes Sasnazenns sasdranen) i 18Eg ii ggigeg hts J enena 002 EERE Page 278 bo $1] ARGUS 418-020 | fii it "jn mererernssmneoraesnesesngger] fs i | 8 "i sermeeranseesnen sg ess i Bo SE BE ome Bd bess sssnsnreanasnsasasa) 8 ff Br ee-------- gf Ege feeerenee : fram igii Fag : i pe Le Brame ssssadacansnbeonnane i I1 sressERaRaRasanaan sania ARGUS 418-020 PE ihi | BE sensnana Atma y Ran] Pl ee| Eo. if, eeereenn cogmaneranvreacavacs : { : iH Tiennegeens sroseegnesstennnee] ; Be Bl en BEL ; iy ks EL lm ee TH i 8 08 EH E iE4n oocoooebocienonoosessssosenosl1] PrAEon iHiH 4 i {HE sennssncdesnsnrnsmnzanee san) ; 3 HL LL ni ARGUS 418-020 BEE EER : il Boi Pa PBELg,sn Po ius |Bi iEEefxiTieeravers ,Pd coat reengr:resresemreirns'Ld eveonngAeursnB enAnLAN Pd ARG] EJfERisp ieeravers cvorergeerengenenionPHlH he Booomommmnn g gg" By 8 Lo gg oo eed 88 ee ae TTT An | agt yo i Bef leBEeamananas azanaazazanzacazacanz| BEE i20` spd HIBiceei enioe dig ig cononeconnonocooocaaLntEBEE sm i i {THER anananax sasassnansnseeansiany| Hi gE [A Bl HT i8 Es i2ii3agfesn ai nnannan BRuEnAaRger"aRsRiRaInAaAnAaIRnAaAnRaInNaNsA|itiis Hl 3 nmnssenaaaniananaaaaasastang BAA Page281 ARGUS 418-020 ih | Hn RIE PE omens somes connie 5 Po PEE di3sad Jeddansads aman fg 00 Teije? saa: aammamnazc nusmanid : N [1 eifER ARAE M LEIEENBIeReRsIN Bi p-iRE3 FERRER GEAGINNIRARRAEAEANCLY ; : ii aE Fianad -- Bi AH EEE Hinaha n i gemma mms li ms mn, i Hi J so grmmnpannih een Egtbi - repensfnannia) { i g i ig E =LHaBFaRrNeHPEORNRNRNIRNENRN R ii 33 a ba s HERR m ERAss na 1h Page282 ARGUS 418-020 8 mmm ann nn Pli i = jeu a 26% desdddides graces BE hom mn sis yd i : i mid IN ma IREy T sgdn ssm n su i st BE {REI TRAIN, NINE1s gi mnhmnanmnrmnun ARGUS 418-020 i | Pr | 5irSL.ee]| R[ H pmsrl bo ST PL SA gE wns k fo EE h111 1 0 srme s am I i 5 ml Ed: h if s La tr n34n 0a9333a 233330i 48 HEE TRE ti ; | | fn 0 ms PER TT Page 284 ARGUS 418-020 ph i pl elmmng nmmmmunng 211 a lmmress sesvrsrasmrnensss Pp umm mnEnnanEn 11 pio ne Por mmm mamanaanaBn BE. iriieaeianiaEsE Bfogy acnsilEile SsHmAaNNENi LE ERE i ai =izsarszazensoaasysgsassssanacid dr $a 8 imi ih] ; eee LiIRICNIECIUSIINIIIIAIIIIINN: sms ={SRIERIRINEGSININNRAIIGINEG : 3 di nanan ARGUS 418-020 IR Po Commun mammmungn pe 5 i i | yvin's4usaR AMARASRsAfAfsIse wail i i 11 awn mmm al Ey liienuane ssnnananianazenne cunis BdEp is r naT de fs pi CR RL HE 02 iE enn emmmnkgiadnigs THLF CE a TH TI ESFEEEB iEniL wilcveedvdedndadedaddaecducodnnsdriaiciadaciaacdnaadneaBaicnadlind io mg gb jTeEnsssanan nnnnedanity ARGUS 418-020 ola ns 3 i PLE om oro smog : ol i 33 303330 selrENiNa sl : TPE] l $a |r smn mama nny 3% | 3% www sma mun | EH ee ` Bg i-] -iney 303330 IIIRIII0IMITINITAeLl 4 i Emme sms A di ite sms EE PE feel somnnpannnvsnasoaisd H i. |EO Ei a srsvinmasraseasies ANUED #0. fad naa ] HH og ie it iserBIaNISEOANIINSUNINRNRNNNNIET OR Page 287 ARGUS 418-020 Ff. iol en my FECL Ln moe i | Een memes 5s fi iE" I Ea] josiad 23 ame 29AdSNN43 7 i iei iraaadeas el amano snmmmi)d : el mmmoa es smnm sez ! i is i a} MEE 232 Janne szamnaans t B: a8 i~i T133e3335337 353% SL SRIRIIGER CEL of Eu ie 333330333 sso: He BEL pansion snennenas smamsmas gdh od giant snes sumedG B i : eL mp ann pL 0 fonmpalranafu Bil EIN jl gin {27330 BI0aaTIINIII ARIAL, Page 288 ARGUS 418-020 BoeoelfloG REE Ne 3 gg fai 3m EEN I = Piel | ozonmzommam za osamifdy i: jai oH 3 I3pGI SII MINN sami : i gf 8 io] alan somne cnonosdennan maneip if 5 io i fi fi io fi #e i og ei 3 gpaTITIEIOSERNNCIR I3sRiNLES sfesmmmn nan Sa |a Ci------e -- wz a0l J ---- cRanaBIIIIIIIIRRRIIRDNGNNNRIESD Bf ARGUS 418-020 fR1r0o]gsF,Eiim mae fa fhm on osm oan sassy amis d g i i wevanen CLBERGE WHEW RNGY civiE : i ai jase seas sumaaaa said | | i fms ss sy Jog ep seme um sani az] sf 5 oi FiSNA03GIEE GIITeR SUSAN Adie B I}i ; ied By biel i Pd i:8 H og iol mssas p rissa sezzzzzzazzs jan Elesssnaongannannnanniucaiaaatis de | ea: Hassan fH i nzmanarazEIIOIIIaI;aORCIRIGNST OR ARGUS 418-020 Hipoznze, : Ean ny ] i mvs on seb Bo Biel pi% DIDI IIIIEIIENSN sagan : gb i-0 Eimvazens mamnmannanvg cnalnuip iB 8 iu Hlannanans sssgerireanes saifanalf g fi Bl ererrs pm wn | So E p enenenseneebaen iBIEL gh Evi gis anIlIInIIIIIIIaIenNiY ds. Bi ivan sresssssasssesehans AAE EE fannie J) lo il og ie mmssmmnmnuaniEmg ARGUS 418-020 Hoge mm faivig 30H isg 3 33 ; Pi oon fEia rEamm Eame m : i A py 333333 snnssiaag as i] Lic Emm Bi fle Sion sna pnmenmnmgnnine fd diE; EFRR feecE gas ag s p = Iigi iasd H i | a AA PogA o-l DBpbmmppmanmnsiintg ARGUS 418-020 fnA T piL rm Phofagr: oan omme i Pl fits 2 I Fell masmam 2, : g a gi $13 faite svg | : i ia} [33733 ep sn 32RgEI ImIMINIIY ! : Biel fnmass ng er aaorges ampeniid ! i i: fla mm om amp maa] : t pon 0 cfm en e mmmg aman | hE ; : - rep sasned: pez Hl i i Li er 13333083 separ HEE fhIe ie ta a 1 8g ii RREINRINEIINRZIZICEIRIZLARNIE Pak 4 23mm pang % wt [10 ERED ELE L0 io rm || 0 Lhe 2 ol posh -- 00 Fegmenniganiaanninns nn gpd EE {ihn sannipded g0 i a p i ! C0 ia i| i fin: Tommy HH i t aon igen ay ogoi s3tie 5 [{- |mo mm on I TE RN vp fy of EEE 1 frm Poo Em Page 295 ARGUS 418-020 Dis geoms mp: 5 fia a an a5 ! 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Ei g inigl EEE meme Eofofofafnfofy sfelelelsisdel eee Mt CT NN CM B SofafafafriSafcdrifal elafalelelsistaiedi 3 i i=i"i sdsfsjsjsgeisl slalalelatsid sielind af Eid ialsislslelsels] slalelelelels'elal isl. i Tiel isdsdsislslisdsisl snslelsld sislisle it 1 sdeeisieisie snsjsislsisseisipehl fo8 cl lespeeieeisie sisjelsisieisisiosi;d i{IEREcEigiDfEaEeasasieiIeEin E sjelsieisE ieisieielEHE| F i yee saan CdE inifA isisisR isislsS isisid S seE iS nsSBy [1 Hh I BH IEREEEREE PaaEa Eat An Piiprssrassrasaaanasg id Page 675 ARGUS 418-020 g f NjaEi i IE fai r Poo de PooH ot PgooonssE ii Iii ]i iiE iPdf E ; Ei seena Bfidg sisd 8? aE i Eis sdsl sielelalal g ! ee sldnigaa | ef in ied sisleleledelelelsl) g gf i=iEisfedslaieislalalalelal' i il | 1 dedsasana BiBo ivEieliee deel.elNaa dshtal0alaaalalu ats alm ; ]o o ini jejeleleieiaiaieieietel gn HH Pei leislsieieledsleledadsl ff Ho lgeseisienstageoosf Leena BEL iganaaanaanan1s6 pBide sdiesdadsaiaasdeasainnBsel Plgpsessisiniiam fg pE RRL RrES REEE RE Page 676 ARGUS 418-020 gai Hl PPo on iig io LE LI CHE 3 0 Lisiidge oo oa iL]g B Lila ad aif 8 al 3 iniBielal slelelsl al {=i jsfed sistedsl sl i Ld jeselalalelalel 23 Lo ommmnniNEE EN i: 22 LE 8 sls Ed ; so slslelsl fog 8 EERE i el spenanena shell sl slsfelal | { Es i fieasjeladealejadalegel sf slelelad ig 3 g i=i"isisislelslslensisiel sg sfeld 3 af gE ini isisjsgefelsisisisnedelsi 9 sdsif | i. i Tiel jedsisisisisisleisisiedsi sielegd <j i { ivi isisisisisislsisislelecs seteisiediaih A a sisisisisd shi Lis gaaanaganaany gaa ERS PENATAEEEALPE RIE 3 hn sisfelsieniiel 3 eigirizieg nye e rear aeiilg g Pipidiacsscadadzana a EE Pi PE Ep itd wm 0 iI ff 3X HE 8233s TTEIRILORO OAR IS IIINIIIIIINILI g Page 677 ARGUS 418-020 PoPiel Poa Pon ion Psoi e z PA i fn2g afc ia 8? slslsl { g 17] {ost sdsdal fini fof isl | 88 =if] Bp tiE ef sfelalsl slejelelelel spedeledalelds) OF sjelslelelel i# g iiTi side sislsiel bu] Fini sasdeledelsisl i Tiel elsgelessdensd Hil gaaaans Bt ames BE o-pgosisna i! LH speieisianein fil samen gg frig Tame 1if i8 ereSreEz 112 fafa : 3 sal ig sisisdi g slsfeli eRelel) gn edeled} | elelel| gg s3tigl sjeier fig sjagelifffy goooh gel aan siete see a SLE i PiiEipirresyresdirigiHfE Page 678 ARGUS 418-020 Po = i fai i8 i= isigie : PlalEEl,E | xi oied EB in jer f io {sf Bo bial lel i : Lie g HE 5 ioiTied LE ini fe HH Pei isi BD oy ivipigd i | inigied Bch 3 LL 3ToPiiglif:lgs eT reEoe, adel sled slsl efelel sil PR FE &F sds SIF Ref ated slelsl slelslelel sled stelelelelelslelsd See ER sisfsdefegedelsialetagsl sislefelsleislslelslsiel s sisist islsie elslsl felsie slel sisislsdedelsisisielsiel DE, asissieiseieiieiseitedsaisinsist]] d sadiardid id iiaidiaisd ed FE adid g 8% |g slelelgl sesest | slslsdi g rater ] $3838 g sisis7igd sieisiiiE. sieied fit oago seis 2 sgeied fiz wseiieel1in5gg ididddim 1:4 Hh Page 679 ARGUS 418-020 |goco fhfail Poca Posh 1i edi 8 Eo oa oe i ii edad 89 seed alslgl 8 ini jel? 8 sled sal} [A isi {staislal 2 slalstatal] i i imi jsdslefel BF slsdelsleld] g of & i2i8iatslalal gasladelateafali i [ [SHEEN sisly slsfsisdl if g ini jeleisld fetedelelae nd of i io} lslelsisl fre leeleed Ho edd Bloc neal Biogen slelsnelslelslifE Seiad oF deddaadoef asdafi mao i asassaddan1n if glee aaieeiesieist S$E ligirsiiiriraiiiaaiycgCyoaiEe iE Hy Page 680 ARGUS 418-020 HS pi 1 Po iF iiE Poilke B i i rp f 5 IH 23s2 Eafe sl i f : i=i isle slsle slsl sled 2 ig FOE ini elf selsl elelelelelel 3s3l g fF eecddadadadaan | icf jaf isdefefelelelelatalelataladalad] i gt = {2ifiedelataletadadalalelalatalalaly : {oigielelsdalelalatalaleadadaladatal! o it 3 [7 stelegeeiedeteneladetetaTetal id of ini fefefsfefelelsdedslegt siedstelifh. i Coie stella 1 HE in llepelsieeleieieneneleleieiel igo ff lesjeeiesisesieisisesSihe Bl Gicaagaaaaaagadgs1d at oy sess icf sssanssdos 1 Fleas beJfERE RE3R ZX ART AER th uN Page 681 ARGUS 418-020 Po He Po ia E | F TY if i8 B HE HE) E tad} i { Ci i so go E Po on m. s a cHEed bi aie 0 a ame an! Fe sieisl ened er snets ce Bo fia lslelsl sled elelededel 38 0g ge faifistalsl 2782 sdsltalslse] sted { bi oinigiedeled sled elelelelsf efsdf g Sf g iniTiedsl siel eledslalsy sis]iad 50 lemme epeleneisl ened dh BR seta ae Setsteneien Hf Hidde 1 sagoacecpdl Ef else elslsislsiensieloisioehr Baa gaaaaaafai 2 i gles siejedeaaneieienae : ie sasneangas i EI BH HE 8d dd 4 aig Page 682 ARGUS 418-020 APPENDIX F PROTOCOL AND AMENDMENTS Page 683 ARGUS 418-020 rI J (A Argu9s05ReSsheeacrhcyh DLraibvoer.atBouriiledsi.nIgn:A Horsham PA. 19054 TelTeeplheofnaex::((221155))444433..88758170 STUDY TITLE: PURPOSE: TESTING FACILITY: STUDY DIRECTOR: SPONSOR: PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 ROreaplro(dGuacvtaigoen)STtwuod-yGoefneArmamtoionniu(mOnPeLeirtftleurcrpoeroGcteanneoraatteion) (APFO) in Rats cTohnecpeumripnogsethoefetfhfiescsttsuodfyAims mtoopnriouvimdePeirnfflourmoartoioocntanoate C(rAP:FCOD)(oSnDt)hIeGmSaBleR aVnAdF/fePmlaulse rreatpsr,odiuncctliuvdeinsgygsotneamdsalin function, estrous cycles, mating behavior, conception, dpaervtuerliotipomne,nltacotfatoifofns,prwinega.niTnhgeanstdutdhyeisgraolwsothdeasnidgned to provide information about effects on neonatal morbidity, dmoervtealloitpymeanntdalprteolxiimciitnya,raysdawetlal on as potential to serve prenatal as a guide for use. in the design of subsequent tests. dFoervefluorpthmeerntin,faodrdmiattiioonnalonstfuudnyctsieongamlendetfsicciaenncibees and dinecvoerlpooprmaetnetdailnttooxtihceitpyraontodcodlevbealsoepdmeonntatlheneguuriodteolxiicnietsy.for 9Ar0g5uSshReeesheyarDcrihveL,abBourialtdoirnigesA, Inc. THeolresphhaomn,e:Pen(n2s1y5l)va4n4i3a-817910044-1297 Telefax: (215) 443-8587 RAsasyomcioantde GD.irYeocrtko,r oPfh.RDe.s,eDarAcBhT raymond.york@primedica.com 3M 3M CCeonrtpeorr,atBeuiTlodxiincgo2l2o0g-y2E-02 St. Paul, Minnesota 55144-1000 Page 684 ARGUS 418-020 STUDY MONITOR: John Butenhoff, Ph.D., DABT, CIH 3M Corporate Toxicology 3M Medical Telephone: Department (651) 733-1962 Telefax: (651) 733-1773 Protocol 41P8a.g0e220 REGULATORY CITATIONS: UR.eSp.roEdnuvcitrioonnmeanntdalFePrrtoiltteyctEifofnecAtsg.enOcfyfic(e19o9f8)P.revHeenatlitohn,EfPfeescttiscTiedsets aGuniddeTloixince:s; Substances (OPPTS) 870.3800, August, 1998. U.S. Test EGunivdierloinnmeesn;taFilnaPlroRtuelcet.ioRneApgreodnuccyt(i1o9n97a)n.d TFoerxtiicitSyuEbfsftecatnsc,e7s9C9o.n9t3r8o0l Act (TSCA) (cross- referenced to OPPTS 870.3800). Federal Register, August 15, 1997. UAc.tSi.TEonxivcirSounbmsetnatnaclePsroCtoencttrioolnAAcgte(nFcyI.FRAF/eTdSeCraAl);InGsoecotdiciLdaeb,orFautnogriyciPdreacatnidceRSotdaenntdiacriddse; Final Rule. 40 CFR Part 160/Part 792. OPrrignacniipzlaetsioofnGfooroEdcoLanboomriactoCroyopPerracattiicoens a[nCd(9D7e)1v8e6l/oFipnmaeln]t. (1998). The Revised OECD REGULATORY COMPLIANCE: This study will be conducted in compliance with the Good Laboratory Practice (GLP) regulations cited above. All changes Director and or revisions of the Sponsor, this protocol shall be dated and maintained documented, signed with the protocol. by the Study Tahnde tTheestrienpgorFta,cailnitdy'wsilQluianlsipteycAtscsruiircaanlcpehUansiets(oQfAtUh)oswiellpoarudtiitontsheofptrhoteoscotlu,dythceonrdauwcdtaetda at the Testing Facility in accordance with the Standard Operating Procedures of Argus Research Laboratories, Inc. SQhAoUulfdoratnhyatpofractiilointyowfiltlhceosntduudcytbceritciocanldpuhcatesde biynsapescutbicoonnstarancdtoaurdoirt bryestpheectSipvoenrseosru,lttshe apnhdasreepionrstpsecftoirotnhartepsotrutdsyapnordtiroenpoarctcaourddiitnsgwitloltbhee sSubOmPittoefdthbayttfhaactilftayc.iliStuyctohtchrietiSctaludy DairQeActUor.StTatheemedanttegseonfertaheteidnsbpyectthaitonfsacailnidty raenpdorptrsouvbimdiesdstioonthsewTielsbtienignFcaocriploitryatfoerd into inclusion in the final report. Tthheerfeipnoarltraecpocrutrawtilellyinrcelfuldeectas tchoemprlaiwadnacteasotbattaeimneendtdsuirginnegdtbhye ptheerfSotrumdaynDciereocfttohrethsattudy. Page 685 ARGUS 418-020 Protocol 418-020 Page3 aSnhodutlhdatsialglniafpipclainctadbelveiaGtLioPnsrefgruolmatGioLnPs wreegruelaftoilolnosweodcciunr,theeaccohndwiulcltbeofdtehsecrsitbudeyd.in detail, together with how the deviation might affect the quality or integrity of the study. SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE: See ATTACHMENT1 to the protocol. TEST SUBSTANCE AND VEHICLE identification: Test Substance: Ammonium Perfiuorooctancate (APFO), Lot 332. TidheentiStpy,oncsomoproswiiltliporno,vimdeetthootdheofTseysnttihnegsiFsa,cilsittryendgotchumaenndtaputriiotnyoorfctehretitfeisctatsiuobnstofantchee. Vehicle: Reverse Osmosis Membrane Processed Deionized Water (R.0. deionized water). tNoeibteheprrtehseenStpionntshoervneohirctlheetShattudwyouDlidreicnttoerrfiseraewwairteh tohfearneysptotsenotfiathliscosnttuadym.inTahnetrselfiokreel,y no analyses other than those mentioned in this protocol will be conducted. Safety Precautions: Gtolobveesw,odmusdtu-rmiinsgyfHoErPmAu-lfaittioenrepdrempaasrka,tiaopnparnopdridaotseageey.e protection and uniform/tab In addition, Tyvek sleeves coat and ahohoadlfw-fhaecenruessipnigratthoer wbiulllkbteeswtosrumbastnadncpree.paTrhaetioMantweirlilableScafoentdyucDtaetda iSnhaeecthe(mMiScDalS)fuisme attached to the protocol (ATTACHMENT 2). Storage: Bulk Test Substance: Vehicle: Room temperature. Room temperature. Prepared Formulations: Refrigerated, protected from light. MAlalntaesgtesruobfstFaonrmcuelsahtiiopnmse,ntatstshheouprledvbioeuasldydrceitsesdeTdestotitnhge FaatctielnttyioandodfreJuslsiaannGdultbeilnespkhio,ne. number. Shipments should include information concerning storage conditions and shipping Page 686 ARGUS 418-020 Protocol 4P18a-g0e2s0 cartons should shipment. be labeled appropriately. The recipient should be notified in advance of FORMULATION: Erequency of Preparation: Formulations (solutions) are prepared weekly at the Testing Facilty. Detailed preparation procedures are attached to this protocol (ATTACHMENT 3). Adjustment for Purity: `The test substance calculations, will be considered 100% pure for the purpose of dosage Testing Facility Reserve Samples: `5ThmeLTessatmipnlgeFaocfilviethyicwillel urseseedrvdeurain1g gthseacmopulreseofofeatchhe slottudoyf.buSlakmtpesltessuwbislltabnecsetaornedda under the previously cited conditions. ANALYSES: Results of required study report. analyses will be provided to the Testing Facility for inclusion in the Samples additional to those the course of the study. described below may be taken if deemed necessary during Bulk Test Substance Sampling: A sample (1g) of the (ambient conditions) test substance to the Sponsor fwiolrl abnealtyaskise.n on the last day of treatment and sent Page 687 ARGUS 418-020 Protocol 41P8a.g0e2s0 `This sample will be sent to: Kris J. Hansen, Ph.D. aM Environmental Technology & Safety Services 935 Bush Avenue Building 2-3-09 St. Paul, Minnesota 55133-3331 TTeelleefpaxh:one: (651) (651) 777788--66011786 `The recipient wil be notified in advance of sample shipment. Analyses of Prepared Formulations: Concentration: Cstoundcye.ntDruaptliiocnatoef tshaempplreepsawrielldbfeortmaukleantifornosmwielalcbhecvoenrcifeinetdradtuiroinngotnhethceoufirrssteaonfdthliasst dreamyasionfinpgrespaarmaptlioens.wiOlnbee sraetmapilneedofaseabcahckduupplsicaamtpelesse.t wiBlal cbkeusphispapmepdlefsorwainlalbyesisst;otrheed under the request of ptrheeviSopuosnlsyorci.ted conditions and discarded at the Testing Facilty upon the Stabilty: Stability of the prepared formulations wil be documented during this study. Two sets of dpurpelpiacraatteiosna.mpOlneess(a2mmpLleeoafche)acfhrodmupelaicchatcesonectewnitlrabtieosnhwiipllpebde otnaktehneodnaythoeffirst day of pprreeppaarraattiioonn. asThpeossseibslaempalnedstweinlldbaeysanaaftleyrztehdeaftirtshteanfaollylsoiwsi.ngTthiemerpeomianitsn:ingassasmopolneasfter will be retained at the Testing Facilfty as backup samples. Backup samples will be storedunder the request otfhteheprSepvoinosuosrl.y cited conditions and discarded at the Testing Facilty upon `Shipping Instructions: `Samples to be analyzed will be shipped (on cold packs, protected from light) to Kris J. Hansen, Ph.D.. at the previously cited address. The recipient will be notified in advance of sample shipment. Page 688 ARGUS 418-020 Protocol 1P8a.g0e206 DISPOSITION: Prepared formulations will be discarded at the Testing Facility. All remaining bulk test `substance will be retumed to: Nelda Marecki, Ph.D. 3M SMMG EHS&R 3M Center Building 236-1B-10 St. Paul, MN 55144-1000 EST SYSTEM: Species/Strain and Reason for Selection: The Crl:CD(SD)IGS BR VAF/Plus rat was selected as the Test System because: 1) this strain of developmental rat has been demonstrated toxins and has been widely to be used sensitive to throughout reproductive and industry for reproductive and dev Testing elopmental Facility"); toxicity evaluations; 2 and 3) the test article ) historical is phamaco data and logically experience exist at the active in the species a nd strain Number: P Generation: Initial population acclimated: Population selected for study: 165 virgin male rats and 165 virgin female rats. s1e5x0 pvierrgignromuapl).e rats and 150 virgin female rats (30 per F1 Generation: 150 male rats and 150 female rats, 30 rats per sex per group, will be selected for coovnert-irneuperdeseevnatlauattiioonn.of AannyaPttgeemnpetrwaitlliobnepmaraednetatlopsaeilreicnttoF1thgeeFne2rgaetnieornatriatosn.to avoid Body Weight and Age: P generation rats will be ordered to weigh from 100 g to 125 g each at receipt, at which time they will be expected to be at least 35 days of age. Actual body weights recorded will be recorded the day after receipt and will be documented in the raw data. The weight range will be included in the final report. Page 689 ARGUS 418-020 Protocol 41P8a-g0e2?0 Sex: Both male and female rats wil be evaluated. Source: P Generation: Charles River Laboratories, Inc. `The rats will be shipped in filtered cartons by air freight andor truck from Charles River Laboratories, Inc.. to the Testing Facilty. F1 and F2 Generations: Offspring will be delivered at the Testing Facilityby the pregnant P or F1 generation dams in this study. Identification: P Generation: Rats are permanently identified using Monel selt-piercingear tags (Gey Band and Tag Co., Inc. No. MSPT 20101). Male and female rats will be assigned temporary numbers. at receipt and given unique permanent identification numbers when assigned to the study before administration of the first dosage of the test substance. 1 and F2 Generations: Pups will not be individually identified during the postpartum period: all parameters will be evaluated in terms of the liter. At weaning, each F1 generation rat selected for continued observation will be identified with a Monel self-piercing ear tag, ANIMAL HUSBANDRY: All cage sizes and housing conditions are in compliance with the Guide for the Care and Use ofLaboratory Animals. Page 690 ARGUS 418-020 Protocol 41P8a.g0e2s0 Housing; P Generation Rats/F1 Generation Litters: P generation rats will be individually housed in stainless steel, wire-bottomed cages except during the cohabitation and postpartum periods. During cohabitation, each pair of rats will be housed in the male rat's cage. Beginning no later than day 20 of dpraemsuamndeddegleisvteartieodlni,ttfeerwmialllebreathsowuilslebdeininadicviodmuamlolynhnoeussteidnginbonxesdtuirnignbgotxhees.posEtapcahrtum period. 1 Generation Rats/F2 Generation Litters: After weaning, the F1 generation rats will be individually housed before cohabitation, housed in pairs (one male rat per female rat) during cohabitation, and individually housed after cohabitation. The same type of caging will be used as described for the P generation rats. Beginning no later than day 20 of presumed gestation, female rats will be individually housed in nesting boxes. Each dam and delivered litter will be housed in a common nesting box during the postpartum period. Nesting Material: Nesting material (bed-0'cobs) will be provided. Bedding will be changed as often as necessary to keep the animals dry and clean. Analyses for possible contamination are conducted semi-annually and documented in the raw data. Room Air, Temperature and Humidity: The animal room is independently supplied with at least ten changes per hour of 100% fresh air that has been passed through 99.97% HEPA filers. Room temperature will be maintained at 64F to 79F (18C to 26C) and monitored constantly. Room humidity wil also be monitored constantly and maintained at 30% to 70%. Light: An automatically controlled 12-hourlight: 12-hour dark fluorescent light cycle will be maintained. Each dark period will begin at 1900 hours EST. Diet: Rats will be given Certified Rodent Diet #5002 (PMI Nutrition Intemational), available ad libitum from individual feeders. Page 691 ARGUS 418-020 Protocol 41P8a.g0e2s0 Water: Waantaeurtowimlaltbiec wavaatielraibnlge aacdcelisbsitsuymsftreomm. iAnldlivwiadtuearl wbioltltlbeesfartotmacaheldoctaol tshoeurccaegeasndorpfarsosmed tphrroocuegshseadrweavteerrseaossamobsacitsermieosmtbatr;apnreocbeefsosreed uwsaet.erCihsloerxipneectwieldl btoecaodndtaeidntnoothmeore than 1.2 bacterial ppm chlorine at the contamination and time twice of analysis. annually for Water is possible analyzed chemical monthly for possible contamination. Contaminants: NtoeibteheprrtehseenStpionntshoercnerotriftiheed Sditeutd,ythDeirdercitnokrinigs awwataerreoorf tahneynpeostteinntgiamlatceornitaalmaitnalnevteslslitkhealyt wroouutlidneilnytperefrefroerwmietdh tbhyetrheesufletesdosfutphpilsisetruodry.thTohseeremfeonrtei,onnoedaninalthyissesprootthoecroltwhialnl btehose conducted. DAY NUMBERING SYSTEM: Gestation day O vaginal contents is defined as the day spermatozoa andor a copulatory plug observed are observed in sit in a smear of the TTehsetdGauyidoeflibinretsh i-sRdeepsriogdnuactteidonlaacntadtiFoenrdtiatyyOEf(fpeocsttsp(aOrftfuimcedoafyP0r)evienntthieonH,eaPletshtiEcfifdeecsts aponsdtTpoaxritcumSu(bdsatya1ncofesla8c7t0a.ti3o8n0)0,in tAhueguSstta,n1d9a9r6d).OpeTrhaitsisngamPerodcaeyduisredsesoifgtnhaeteTdesdtaiyng1 (Fadcaiylit1y.ofTlharctoautgihono)utantdhiasllprsoutobcsoel,qutehnetdaagyesofobfitthhewFil1l bgeendeersatiigonnatreadtsdaanyd1dpaoysstpoafrtthuem lactation period will be determined and cited accordingly. RANDOMIZATION AND COHABITATION: Ucopmopnutaerrri-vagle,nPergaetneedrartainodnormatusniwtisl. bAeftaesrsaicgcnleidmattoioinnd,ivriadtsuawlilhlobuesisnegleocntetdhefobrasstiusdoyfon tghreoubpassibsaosfepdhyosniccaolmpauptpeera-rgaennceeraatneddb(owdeyigwheti-gohrtd.ereTdh)erraantdsowmiillzabteioansspirgonceeddutroesd.osage tWoitchoihnabeiatcathiodno,soangee mgraoluep,ractopnesrecfuetmiavleeorratd.erAwicllombpeutuesre-dgteonearsasitgend Pragnednoemriaztaitoinonrats procedure or cohabitation, a table of one male rraatnpdeormfeunmiatlsewirlalt.beIf used to random assign F1 generation rats to assignment to cohabitation results in the pairing of F1 generation siblings, an altemate assignment will be made. T1h4edacyosh.abiFteamtiaolnepreartisowdit(hP sapnedrFm1atgoeznoearaotbisoenrrvaetds)iwnilal scomnesaisrtooffthaemvaaxgiinmaulmcoonftents andlor a copulatory plug observed in situ will be considered to be at day 0 of presumed Page 692 ARGUS 418-020 Protocol 4P1a8g-e01200 gestation and assigned to individual housing. If a female rat has not been mated after two weeks, thepair of rats will be separated without further opportunity formating. Day 1 of lactation (postpartum) is defined as the day of birth and is also the first day on which all pups in a liter are individually weighed (pup body weights will be recorded after all pups in a liter are delivered and groomed by the dam). Litters will not be culled during the lactation period, because random selection of pups for culling could result in potential biases in pup viabilties and body weight gains during this period. All F1 generation rats will be weaned at the same age, based on observed growth and viability of these pups, on either day 22 postpartum, or if required, day 29 postpartum. Should it be necessary to extend the lactation period to day 29 postpartum, al affected observational intervals will be adjusted accordingly. At weaning, a table of random unitsor a computer-generated randomization procedure will be used to select 30 male and 30 female F1 generation pups per group, resulting in a total of 300 rats (150 rats per sex) chosen for continued evaluation. At least one male pup and one female pup per litter, when possible, wil be selected. If results warrant that the study be extended to includea third generation, the procedures previously described for the F1 generation will be used for selection of F2 generation pups continued on study. If study results should warrant (e.g., poor reproduction performance in the control group or treatment-related aherations in liter size), parental pairs may be remated to produce. F1b or F2b litters. If production of a second litter is deemed necessary, the second cohabitation period will be scheduled approximately one to two weeks following weaning of the F1a or F2a liters. ADMINISTRATION: Route and Reason for Choice: `The oral (gavage) route was selected for use because: 1) in comparison with the dietary route, the exact dosage can be accurately administered; and 2) tis one possible route of human exposure. Method and Frequency: P Generation: `Maaplperoaxnidmafteelmyalseix rwaetsekwisll obfeaggieve(nattlheeasttes7t0sduabystsabnecfeoroenccoehadbaiyt,atiboeng)inannidngcoanttinuing until the day before sacrifice. Dosages will be adjusted based on the most recently recorded body weight and given at approximately the same time each day. Page 693 ARGUS 418-020 Pc psroeczs F1 Generation: F1 generation pups may be exposed to the test substance during matemal gestation (in utero exposure) will be given the or via same mdaotseamgaellemviellkodfutrhiengtetshtespuobssttpaanrcteumaspetrhieoidr.reFs1pegcetnievreaPtion rats (geanpeprraotxiiomnatseilryes7a0nddadyasmbse.foDroescaohgaebsitwailtliobne) gainvdencoonntcienudianiglyu.ntbielgtihnenidnagyabtewfeoraening Jro-- ma ne aime ns ach day sacrifice. Dosages will be adjusted at least weekly for body weight changes and given pPuopsrmay be exposed in utero during gestation or via matemal milk during the lactation Rationale for Dosage Selection: Dosages were selected on the basis of prior dietary and gavage studies in rats performed by the Sponsor. Concentrations may be adjusted if toxicity observed in the P or F1 generation rats indicates that it is required. The highest dosage is expected to produce some toxicity. The intermediate dosage level is expected to produce minimal observable toxic effects, while the lowest dosage level is expected to produce no evidence of either systemic or reproductive toxicity [noobservable-adverse-effect level (NOAEL)]. Dosage Levels, Concentrations and Volumes: FC o TT TeT Te e oTTeommmsmmamonne]|| voTTo oT [w +[+ =Teemmomocoommmmmmm]] CrToTo--T-- o--|+ --[emamcommmm] Page 694 ARGUS 418-020 Protocol 4P1a8g.e02102 TESTS, ANALYSES AND MEASUREMENTS - P GENERATION: Viability - Male and Female Rats: All Periods: Atleast twice daily. Clinical Observations and/or General Appearance - Male and Female Rats: Acclimation Period: Weekly Dosage/Exposure Period: Daily before dosage. Postdosage observations will be recorded approximately 60 =10 minutes after administration. Matemal Behavior: Days 1,5,8, 15 and 22 postpartum. Observed abnormal behavior recorded day. Clinical observations may be recorded more frequently than cited above if deemed appropriatebythe Study Director and/or Study Monitor. Body Weights - Male Rats: Acclimation Period: Weekly. Dosage/Exposure Period: Weekly Day of Sacrifice: Prior to sacrifice. Body Weights - Female Rats: Acclimation Period: Weekly. Precohabitation Period: Weekly. Cohabitation Period: Weekly. Gestation Period: Days 0,7, 10, 14, 18, 21 and 25 (if required) Postpartum Period: rDeacyosrd1ed,)5.8, 11, 15 and 22 (terminal body weight Feed Consumption Values - Male Rats (recorded and tabulated): Dosage/Exposure Period: Weekly. Page 695 ARGUS 418-020 Feed Consumption Values - Female Rats (recorded and tabulated): Protocol P4a18g-e02103 Precohabitation Period: Weekly. Gestation Period: Days 0,7, 10, 14, 18, 21 and 25 (if necessary). Postpartum Period: Days 1,5,8, 11 and 15. wFiellebdecgoinnstuomcpotniosnumneotmtaatbeulmaatledfeaefdt.er day 15 postpartum, when it is expected that pups Feed Consumption Values - Male and Female Rats: nFeeceedsscaornysutmoprteipolnenviashlutehsemfeaeyd.beDurreicnogrdceodhamboitraetiforne,quwehnetlny ttwhoanractisteodcacbuopvyethifeistiasme `cage with one values will not fbeeedreacro,rdreedpolrentiasbhumleanttedo.f the feed jars will be documented. Individual Estrous Cycling and Mating: Estrous 21 days cycling before will the sbceheevdaullueadtecdohdaabiiltyatbiyonexpaemriinoadtiaonnd ocfonvtaigniunianlgcyunttoillosgpyebremgaitnonzionga are doubrsienrgvtehdeicnoahasbmietaatrioonf ptehreiovda.ginal contents and/or a copulatory plug is observed in situ tOondethteerdmaiyneofthsechsetdaugleeodfseasctrirfoiucse,cyacnlee.xamination of vaginal cytology will be performed Duration of Gestation: `The first pduurpatisioonbsoefrgveesdt.ation is calculated from day 0 of presumed gestation to the day the Litter Observations: Litters will live births abnedegxraomsisnaeldtearfatteirondse.livery to identify the number and sex of pups, stilbirths, Fertility Parameters: Fertiity sex. Index (percentage of matings that result in pregnancies). Reported for each Gestation Index (percentage of pregnancies that result in birth of live litters). Number and sex of offspring per litter (live and dead pups). Page 696 ARGUS 418-020 Protocol 4P1a8g.e02104 Number of implantation sites. General condition of dam and litter during the postpartum period. Litter Data: Litter size and viabily [tabulated at birth (day 1) and on days 5, 8, 15 and 22 postpartum]. Viability Indices (percentages of pups bom that survive to days 1 and 5 postpartum. Lactation Index (percentage of pups that survive from day 8 to day 22 postpartum). Percent Survival and Sex Ratio [tabulated at birth (day 1) and on days 5. 8, 15 and 22 postpartum). TESTS. ANALYSES AND MEASUREMENTS - F1 GENERATION: Viability: Preweaning Period: dLaiitltye.rs Twihllebpeuposbsienrevaecdhfolritdereawidllpbuepscoautnlteeadstotnwciece daily. Postweaning Period: Twice daly. Clinical Observations and/or General Appearance - Male and Female Rats: Preweaning Period: Postweaning Period: Daily. bDaeilryecboerfdoerde daopsparogxei.maPtoesltyd6o0sag1e0ombisneurtveastiaofntesrwill administration. Matemal Behavior: aDbanyosrm1,a5l,b8e,ha1v5iaonrdre2c2orpdoesdtpdaariltyu.m. Observed CalpipnriocparlioabtseerbvyatthieonSstumdayyDbireecrteocroarndde/domroSrteudfyreMqouneinttolry.than cited above if deemed Body Weights - Male and Female Rats: Preweaning Period: Days 1 (livebom pups), 5, 8, 15 and 22 postpartum. Postweaning Period: Weekly. Page 697 ARGUS 418-020 Protocol 4P1a8g.e02105 Presumed Gestation Period (Female Rats): Days 0,7, 10, 14, 18, 21 and 25 (if required). L(aFcetmaatlieonRaPtesr)i:od Days 1,5,8, 11, 15 and 22. Day of Sacrifice: Prior to sacrifice. Feed Consumption Values - Male and Female Rats Postweaning to Cohabitation: Weekly. P(oMsatlceohRaabtist)ation Period Weekly until sacrifice. G(eFsetmaatlieonRaPtes)r;iod Days 0.7, 10, 14, 18, 21 and 25 (if required). Lactation Period (Female Rats) Dnoatytsab1u,l5a,t8e,da1f1tearndda1y5.15Fpeoesdtpcaorntsuumm,pwtihoenn vitalisues efexepde.cted that pups will begin to consume matemal nFeeceedsscaornysutmoprteipolnenviaslhutehse mfaeeyd.beDruercinogrdceodhamboitraetiforne,quwehnetlny ttwhoanractisteodcacbuopvyethifeitsias me cage with will not be one feed recorded jar, or traebupllaetneid.shment of the feed will be documented. Individual values Postweaning Developmental Observations: `Sexual Maturation: Fpoesmtaplaertruamt.s wMiallbeereavtsalwuilaltbede feovratlhueataegdefoorf tvhaegiangale poaftpernecpyu,tibaelgsienpnairnagtioonn,dabyeg2i8nning on day 39 postpartum. Estrous Cycling and Mating: 2E1stdraoyuss cbyecfloirneg twihlel sbceheevdaullueadtecdohdaabiiltyatbiyonexpaemriinoadtiaonndocfonvtaigniunianlgcyunttoillosgpyebremgaitnonzinoga are observed in a smear of the vaginal contents and/oar copulatory plug is observed in situ during the cohabitation period. On the day of scheduled sacrifice, an examination of vaginal cytology will be performed Page 698 ARGUS 418-020 to determine the stage of estrous cycle. Protocol 4P1a8g.e02106 Duration of Gestation: As cited above for P generation rats. Litter Observations: As cited above for P generation rats. Eertility Parameters: As cited above for P generation rats. Litter Data: As cited above for P generation rats. TESTS, ANALYSES AND MEASUREMENTS - F2 GENERATION: Viability: Preweaning Period: Litters will be observed for dead pups at least twice daily. The pups in each litter will be counted once daily. Clinical Observations and/or General Appearance: Preweaning Period: Daily. Body Weights: Preweaning Period: Days 1,5,8, 15and 22. Preweaning Developmental Observations: IFf1trgeeantemreantti-orne,laatneodgeenfifteacltsdairsetaonbcseewrivllebdeinmseeaxsurarteiodafnodr/aollrisveexuFa2l gmeanteurraattiioonn poufptsheon days 1 and 22 postpartum METHOD OF SACRIFICE: Rats and pups will be sacrificed by carbon dioxide asphyxiation. Page 699 ARGUS 418-020 Protocol 4P1a8g-e02107 GROSS NECROPSY AND HISTOPATHOLOGY: AGdruolstsPleasnidonFs1wigllenbeerarteitoaninreadtsinwinlelubteranlebcurfofpesrieedd1a0n%d feoxrammaliinnedanfdoregxraomsisnleedsions. histologically. Tissue supervision ofor by a tBroiamrmdinCgeratnifdiehdisVteotpeartihnoalroygPyatwhilollobgeispt.erformed under the A`dtaysc2h2edpuolsetdpasratcurimfi(cfeemafatleer rcaotmsp)lbeltoioodnsoafmtphleecsoh(aabpiptraotxiiomnatpeelryio4d m(mLalpeerrartast)) awinlldboen croelsluletcitnegdsferromumthweillinbfeeriiomrmveedniaatcealvyafriontzoensoernudmryseipcearaantdormtauibnetsaiannedd cfernotzreinfu(gse-d.70TCh)e u`nstaimlpslheispemcetnitonto(ltahteeraSlploonbseo)rfrfoorzeannaalynsdisr.etaTihneedliavtersw-i7ll0beC eunxtciilssehd,ipwmeeingthetdo,thaend a Sponsor for analysis. A(tftreorzecnomopnledrtyioinceo)ftsoaKmrpislJe.cHolalnescteino,n,Pshe.Dr.u,maat ntdhelipvreervsieocutsiloyncsitaemdpaldedsrweislsl.beBosthhiptpheed recipient and the Study Monitor will be notified in advance of sample shipment. Gorriofiscsesn,eacsroweplslyawsillainncilnutdeemaalneixnaimtailnpahtyisoincaolf teixsasmuiensaatinodnoorfgeaxntseimnaslitsuu.rfTahceesfoalnlodwialnlg swiulrl fbaeceesxaofmitnheedb:raienxtaenmdalspainnadlicnotleummanl,potrhteinoanssaolf caallvihtoylalonwd onregcaknsw;itthheasesxotceimaatled o`arngdafnisssauneds;tiasnsduetsh;etmhuestchuolroa/csikce,laetbadlomcianrcaalssa.ndTpheelvilcuncgasviwtiilelsbweitpherafsussoecdiawtietdh onreugtarnasl buffered 10% formalin. For all postweaning rats, the urinary bladder and lungs will be inflated with neutral buffered 10% formalin ShiesetoAloTgiTcaAlCeHvaMlEuaNtTio4nsfotroabdedictoionndaulctteisds;uaelsl toothbeerwteisisguheesdwialnl dberedtiasicnaerd,deadn.d Adult Rats Found Dead or Moribund - P and F1 Generation Rats: Rdealtisvetrhyatwidlliebeoreaxraemsianceridfifcoerdthbeeccaauussee ooff mdoeraithbuonrdmcoornidbituinodn,coanbdoirttiioonn oonr pthreemdaatyurtehe oabnsderuvtaertiinoen ciosnmtaednet.s oTfhfeemraaltes wrialtlsbweillexbaemrienceodrdfeordg(rwohsesnleaspipornosp.riaPtre)e.gnaAnbocrytsetdatus fUetteruiseosf,adpeplairveenrteldypnuopnspraengdnoarntcornatcsepwitllibnueteerxiawmililnebde wehxialmeibneeidngtoptrheesseexdtebnettpwoesesinble. glass plates to confirm the absence of implantation sites. e`SveaeluAaTtiToAnsCtHoMbEeNcTon4dufcotretdi;ssaulelsotthoebretiwsesiugehsewdillanbde retained. and discarded. histological Page 700 ARGUS 418-020 Protocol 4Pa1g8e02108 Should postmortem autolysis preclude these evaluations, it will be noted in the necropsy data. `Scheduled Sacrifice and Sperm Evaluations - P and F1 Generation Male Rats: Agfrtoesrscnoemcprloeptsioynofofthtehethcoorhaacbiict,ataibodnompeirniaold,anaddulptelmvaiclevirsactesrwailwlilblebseacpreirffiocredm,eda.ndTao assess the potential toxicity of the test substance on the male reproductive system, the following endpoints wil be evaluated: `Sperm Evaluations: A`sppeorrtmicoonnocfentthrealteifotncaaunddameotpiildiitydyumsiisngwicllombpeutuesre-dasfsorisetveadlusaptieornmoafncaalyusdias e(pCiAdSiAdy)mal tMhoteilletfyt cwialludbae eepviadliudaytmeids.byTthhee rHeammaiilntionngTlhefot mcaeuIdaVOeSpibdyidcyomlilescwtiilolnboef uasseadmtpolemafnruoamlly evaluate Hamilton sTpheormmemoIrVpOhSolfoogary and to prepare a determination of shpoemromgecnoancteenttroabtieoenv(aslupaetremdpbeyr the gram of tissue weight). determination Sperm morphology of the percentage of neovarlmuaaltisopnesrwmilliniancslaudmeplteheoffoaltlolweiansgt: 1) 200; and 2) qualitative evaluation of abnormal sperm, including such categories as abnormal head, abnormal tail, and abnormal head and tail. Organ Weights: T(whheolfoelalonwdincgauodrag)a,nsriwgihltl ebpeidiinddyimviidsu,alsleymwieniaglhveeds:iclreigsht(wtietshtias,ndlefwtittehsotuist,flleufitd)epainddidymis prostate. Histopathology: Tvehseicrleemsawiinlinbge pfoirxteidoninonfetuhterallefbtuefpfiedrieddym1i0s,%tfhoermrailgihtn efpoirdpiodsysmiibsl,ephriossttoaptaethaonldogsiecmalinal evaluation. retained in The testes will neutral buffered b1e0f%ixfeodrimnalBionuifno'rspossolsuitbiloenfhoirst4o8patthoo9lo6gihcoaulrsevaanlduatthioenn (see ATTACHMENT 4). tShheouclohdaabistaetcioonndpleirtieordbfeordteheemseedconnecdelsisttaerr,y,exmtaelndeirnagtsthwiellstnuodtybbeysaapcrpirfoixciemdautnetlilyafter 14 weeks. Scheduled Sacrifice - P and F1 Generation Female Rats: Faesmeacloendraltistewrilnlobtebseacrreiqfuiicreedd)a.fteTrhceomnpulmebteiornaonfdtdhiest2r2i-budtaiyonpoofstipmaprlatnutmatpieorniosdit(esshwoiulld be recorded. Rats that do not delivera litter will be sacrificed on day 25 of presumed Page 701 ARGUS 418-020 Protocol P4a18g-e02109 gbeesteaxtaimoinnaenddwehxilaemibneeindgforprpersesgendabnectywesteantugsl.asUsteprliatoefsatpopacroennftilym ntohneparbesgennacnet orfats will ibmeplpaenrtfaotrimoends.iteFs.emaAlgerorastss nweitchroauptsya ocfontfhiertmheodramciact,inagbddoamtientahlatadnod npoeltvdicelviisvceaerraliwtitlelr will be sacrificed on an estimated day 25 of presumed gestation. Dams with No Surviving Pups - P and F1 Generation Female Rats: Dams with no surviving pups or presumed cannibalized. A wil be gross sacrificed necropsy after of the the last pup is found thoracic, abdominal dead, missing and pelvic viscera will be performed. F1/F2 Generation Pups Found Dead on Day 1 Postpartum: Pstuaptsustahtatbidrithe. beTfhoereleuxnagmsiwnialltiboenroefmtohveelditaerndforimpmueprvsieadbilitnywwaitlelrb.e Peuvpalsuawittehdflournvgistatlhat sainndk twoillhabveeiddeinetdifsiheodrtalsysatfitlelroobmir;thp.upPsuwpisthwiltuhnggrsotshsatleflsoiaotnswiwlillbebeidpernteisfeirevdeadsilniBvoeubionm',s solution for possible future evaluations, it will be noted evaluation. Should postmortem in the necropsy data. autolysis preclude these F1/F2 Generation Pups Found Dead or Moribund on Days 2 to 22 Postpartum: Pups found lesions and fdoeratdheorcasaucsreifoifcetdhedumeortiobmuonrdibcounndditcioonndiotridoenawtihl.l bPeuepxsamwiitnhedgrfoosrsglreossisons feovaulnudatoinond;agyrso2sstole5sipoonsstopfarptuupmswfiollunbde opnredsaeyrsve6dtion 2B2oupions'tspsaorltuutimonwifllorbepopssriebsleervfeutduirne neutral buffered 10% formalin. Should postmortem autolysis preclude these evaluations it will be noted in the necropsy data F1/F2 Generation Pups Not Selected for Continued Observation: Awillllpbuepsracnudlloemdlyonsedlaeyct2e2d aponsdtpeaxratmuimnewidllfboregsraocsrisfilceesdi,onasn;dgrtohsrseelepsuiposnspweirllsbeex per liter spercetsieornveofd tihn enehuetaradlabtutfhfeerleedvel10of%tfhoermfarolnitna.l-Npaerciretoaplssyuwtiulrleinacnldudeexaamsiinnagtlieocnroosfst-he cthreostsh-rseeectsieolneecdtebdrapiunpfsorpearppsaerxenpterhylidtrteorcweilplhabley.weiTigshseudesan(dsereetAaTinTedACinHnMeuEtNraTl 4) from buffered 10% formalin for possible histological evaluation. All remaining pups will be discarded without further examination. Page 702 ARGUS 418-020 ProtocoPl a41g8e.02200 PROPOSED STATISTICAL METHODS": Averages and percentages `appropriate. Additional pro will be calculated.Litter cedures and/or analyses values will be used may be performed, where if appropriate. Type of Test" I. Parametric Il. Nonparametric A. Bartlett's Test' A. Kruskal-Wallis Test (75% ties) Significant at p<0.001 Not Significant~ Significant at p<0.05 Not Significant Nonparametric Analysis of Variance Dunn's Test Significant at ps0.05 | Dunnett's Test Not Significant B. Fisher's Exact Test (>75% ties) III. Test for Proportion Data Variance Test for Homogeneity of the Binomial Distribution a. Statistically significant probabilities are reported as. either p<0.05 or p<0.01. b. Proportion data are not included in this category. c. Test for homogeneity of variance. Page 703 ARGUS 418-020 DATA ACQUISITION, VERIFICATION AND STORAGE: Protocol 4P1a8g.e02210 Data generated during the course of this study will be recorded either by hand or using the Primedica Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System and the Hamilton Thome IVOS. Al data will be tabulated, summarized and/or statistically analyzed using the Primedica Argus Automated Data Collection and Management System, the Vivarium Temperature and Relative Humidity Monitoring System, Microsoft Excel [part of Microsoft Office 97 (version SR-2)] and/or The SAS System (version 6.12). Records wil be reviewed by the Study Director and/or appropriate management personnel within 21 days after generation. All original records will be stored in the. archives of the Testing Facility. All original data will be bound and indexed. A copy of all raw data will be supplied to the Sponsor upon request. Preserved tissues will be stored at the Testing Facility at no charge for one year after mailing of the draft final report,afterwhich time the Sponsor will be contacted to determine the disposition of these materials. RECORDS TO BE MAINTAINED: Protocol and Amendments. Test Substance, Vehicle and/or Reagent Receipt, Preparation and Use. Animal Acquisition. Randomization Schedules. Mating History. Treatment (if prescribed by Staff Veterinarian). GCleinneicraallOCbosemrmveanttiso.ns and/or General Appearance. Blood Sample Collection, Processing and Shipment. Body Weights. Feed Consumption Values. Gestation Length. Litter Observations. Gross Necropsy Observations. `Sperm Evaluation (motility, concentration and morphology). Organ Weights. Histological Observations. Study Maintenance (room and environmental records) Feed and Water Analyses. Packing and/or Shipment Lists. Page 704 ARGUS 418-020 Protocol 4P1a8g-e02220 KEY PERSONNEL: Executive Director of Director of Research: RAelsaenarMc.h:HoMbielrdmreadn,S.PhCh.rDi.s,tiDaAn,BPTh.D., Fellow, ATS Associate Director of DOipreerctaotrioonf sRaesnedaCrocmhplainadncSet:udByaDribraerctaoJr.: Raymond Patterson, G. York, B.A. Ph.D., DABT Director of Director of Laboratory Operations: John Study Management: Valerie F. A. Bamett, Sharper, BM..SS.. Manager of Animal Operations and Chairperson, Institutional Animal Care and Use CCoonmsmuiltttaenet,: VDeteenrainCa.ryLePbaot,hoVl.ogMy.:D. W. Ray Brown, D.V.M., Ph.., ACVP REPORTS: TDrhaeftSstuudmymaDirryecttaobrlweisllofpruonvaiuddeipteerdiocdoimcpuutpedra-treescoofrdsetduddyaptraomgraeyssactocothmepaSnpoynsthoers.e. updates. Statistical analyses will not be performed on these interim data. AbecfoimnpalriezheednfsoilvloewidnrgafctofnisnualltraetpioorntwwiiltlhbteheprSeppoansroerd.onThcoemrpelpeotritowniolfitnhcelusdteutdhyeand will following: `Summary and Conclusion. Experimental Design and Method. Evaluation of Appendices: Test Results. Figures, Summary and Individual Tables Summarizing the Above DGaLtPa,CPormoptloicoalncaendStAastseomceinatt,edReApmoertnsdmofenSutpspoarntdinDgevDiaattiao(nisf,apSptruodpyriDaitree)ctaonrd's QAU Statement An interim summary report through weaning of the F1 covering the period generation will also from initiation of be issued. This test diet exposure report will be identical in format to the final report with the exception of inclusion of histopathological findings. The Sponsor will receive one copy of the draft report and two copies of the final report. INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE STATEMENT: TInhsetitpurtoiocneadluArneismdaelsCcarirbeedanidn tUhsisepCroomtmociotltehea.veAbleepnrorceevdiuerweesddbeysctrhiebTeedsitnitnhgisFapcriolittoyc'osl that involve study animals will be conducted in a manner to avoid or minimize discomfort, distress or pain to the animals. Page 705 ARGUS 418-020 Protocol 4P1a8g-e02203. The Sponsors signature below documents the fact that information concerning the nduepcleiscsaittiyvefosrtcuodnydmucatyinbgetohbistasitnueddyfarnodm tthhee fSapcotntshoart.thiNsoisanlottemaantiuvnene(icnesvistarro)ily procedures were available for meeting the stated purposes of the study. REFERENCES: 1. Christian, M.S. and Voytek, P.E. (1982). In Vivo Reproductive and Mutagenicity Tests. Environmental Protection Agency, Washington. D.C. National Technical Information Service, U.S. Department of Commerce, Springfield, VA 22161. 2. Christian, M.S. (1984). Reproductive toxicity and teratology evaluations of naltrexone (Proceedings of Naltrexone Symposium. New York Academy of Sciences, November 7, 1983), J. Clin. Psychiat. 45(9):7-10. 3. LCoanntgr,oPl.DLa.t(a19i8n8t)h.e EChmabrrlyeos aRinvdeFreCtrali:DCevDelBoRpmRaetn.taClhaTorxliecsitRyi(vTeerrLaatboolroagtyo)ries, Inc., Wilmington, MA 01887-0630. (Data base provided by Argus Research Laboratories, Inc.) 4. Institute of Laboratory Animal Resources (1996). Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, D.C. 5. Snedecor, GW. and Cochran, W.G. (1967). Variance test for homogeneity of the binomial distribution. Statistical Methods, 6th Edition, lowa State University Press, Ames, pp. 240-241 6. Sokal, R.R. and Rohlf, F.J. (1969). Barlettstest of homogeneity of variances. Biometry, W.H. Freeman and Co., San Francisco, pp. 370-371. 7. Snedecor, GW. and Cochran, W.G. (1967). Analysis of Variance. Statistical Methods, 6th Edition, lowa State University Press. Ames, pp. 256-275. 8. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Amer. Stat. Assoc. 50:1096-1121. 9. Sokal, RR. and Rohlf, F.J. (1969). Kruskal-Wallis Test. Biometry, W.H. Freeman and Co., San Francisco, pp. 388-389. 10. Dunn, OJ. (1964). Multiple comparisons using rank sums. Technomelrics. 6(3):241-252. 11. Siegel, S. (1956). Nonparametric Statistics for the Behavioral Sciences, McGraw-Hill, New York, pp. 96-104. Page 706 PROTOCOL APPROVAL: FOR THE TESTING FACILITY ARGUS 418-020 Protocol P61a8g.0e2t0 Alan M. Hoberman, Ph.D., DABT Director of Research (tome, fas RASestusdoyihDtirdeeGcDt.iorYreocrtko,rofPhR.eD.s,darPcABhT pls limba L dana C. Lebo, V.M.D. Chairperson, Institutional Animal Care and Use Committee FOR THE SPONSOR Glin Zailatellf John Butenhoff, Ph.D., DABT, CIH ``SStpuodnysoMro'nsitRoerpresentative Date 27 NE ce Date 27 MymC Date og NOV - 00 Date Page 707 ARGUS 418-020 ATTACHMENT 1 SCHEMATIC OF STUDY DESIGN AND STUDY SCHEDULE Page 708 ARGUS 418-020 ATTACHMENT 1 Protocol 418-020 Page 10f3 TWO-GENERATION REPRODUCTION STUDY* FirsStuDbsatyaonfceTest #EGxepnoesruarteionPramating ? aGleneerRaattison 10 weeks PPaGmeanlearaRtaitosn 10 weoks #1 GeRnaeirsation posentins| Towesks | | Conabtation LasStuDbasytaonfceTest EGxapnoasruarteion- t 2 weeks Naural GePsrteastuimoang Delivery Lactation 3 weeks 3wesks #1 Generation Postpartum Rats 3 weeks Poostspyar2t2um Weaning: LasSEtuxDbpasoytsaounfrc-Teeost conan| pmreosumneg|| aciF!oGnensration weeks | 3wesks | weeks Postpartum #2 Generation Fans weeks Pos0tapyar2t2um' mm. Dosage Period a. For additional details see `Tests, Analyses and Measurements" section of the b. Mpraolteocroalt.s sacrificed after determination of sufficient number of pregnancies; sperm evaluation. cP generation female rats and F1 generation rats not selected for continuation on d. sFitudgyensearcartifiiocnedd.ams and F2 generation litters sacrificed. Page 709 ARGUS 418-020 ATTACHMENT 1 ProtocPoalg4e182.00l230 SCHEDULETM 07 NOV 00 BPeGgeinnesration Animal Receipt - Acclimation 13 NOV 00 Start of Test Substance Exposure P Generation Rats 21 JAN 01 PM - 04 FEB 01 AM P Generation Cohabitation Period (After at least 70 days of test substance exposure). 22 JAN 01 04 FEB 01 12 FEB 01 01 MAR 01 16 FEB O1 01 MAR O1 First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation. First Possible Deliver-y F1 Generation Litters. {ay21 `of presumed gestation). (Daisyt P2o5ssoifbplereDseulimveedryge- sFt1atGioenn)e.ration Litters First Possible Day 25 of Presumed Gestation FLaesmtaPloessRiabtleSacDraiyfic2e5. of Presumed Gestation Female Rat Sacrifice. 12FEBO1 Scheduled Sacrifice - P Generation Male Rats (Earliest possible date). 05 MAR 01 22 MAR 01 First Possible Day-22 Postpartum Weaning (Sacrifice of P generation dams and F1 generation pups not selected for continued observation). Last Possible Day-22 Postpartum Weaning. 06 MAR 01 F1 Generation Postweaning Observations Begin (Details of tests cited in protocol). a. The study inilation date is the day the Study Director signs the protocol. b. The day of birth is designated postnatal day 0 (day 0 of octane). in APrdodteecntdiuonmA1g0entocyth(eEPPeAs)t.icTihdiesAssasemsesdmaeyntisGdueisdieglnianteesdofsatyhe1Up.So. stpEanrvtiurmonm(ednatya1l of lactation) Throughout tihnisthperoSttoacnold,a rtdheOpdearyaotfinbgir tPhrowiclledbueredsesoifgtnhaetedTedsta y Facility. 1 postpartum day 1 of lactation) and all subsequent ages of the F1 generation rats and days c. owTfahtrehreainntld,aifctethaiptsoirostntiupodneyroimfoadthyweilblsetbueedxydteweitnleldrermdeiqtnuoeirdienacanlpudpdrceoaixteitdmhaiatrcdeclogyredn4ie2nrgawltyei.eokns;.suIcf hreasuslttsudy extension would be conducted according to the procedures described previously forthe F1 and F2 generations. Page 710 ARGUS 418-020 ATTACHMENT 1 ProtocPoal g4e183.a0l230 31JuL0t Interim Status Report - Draft Mail Date. Estimated Dates 06 MAR 01 Start of Test Substance Exposure F1 Generation Rats 28MAY 01 PM- 18 JUNOT AM F1 Generation Cohabitation Period (After at least 70 days of test substance exposure). 29 MAY 01 18JUN O01 First Possible Day 0 of Presumed Gestation. Last Possible Day 0 of Presumed Gestation. 19. JUN 01 13JUL 01 First Possible Delivery - F2 Generation Litters (Day Last 21 of presumed gestation). Possible Delivery - F2 Generation Litters (Day 25 of presumed gestation). 23JUNO1 13JUL 01 First Possible Day 25 of Presumed Gestation Female Rat Sacrifice. Last Possible Day 25 of Presumed Gestation Female Rat Sacrifice. 26 JUN O1 DF1ayGe2n1erofatCioohnabMiatlaetiRoantPseSraicordi-fiEcaerdliaefstter Approximate Date. 10JUL 01 03AUG 01 (FiFr1stgPeonsesraitbiloenDdaaym2s2 Postpartum and F2 generation liters sacrificed). Last Possible Day 22 Postpartum. 12 DEC 01 Draft Final Report (Including histopathology). a Adlelpoefntdheensteudpaotnesthaeretinmoitnpgoosfsimbalteintog aocfctuhreatPelgyensecrhaetdiuolneabnedcatuhesetitmheesy lairteers are delivered and weaned. Page 711 ARGUS 418-020 ATTACHMENT 2 MATERIAL SAFETY DATA SHEET Page 712 ARGUS 418-020 31-0cT-2000 09:14 au Pax Message page 2/17 DMAATTAERISAHLEETSAFETY 3EMd center S5t5. 14P4a-u1l0,00Minnesota 1-800-364-3577 or (651) 737-6501 (24 hours) ACilonlpfyorrriimggahhttti,sonr20ef0so0er,rvteMhdie.nnpeusrCpoootpsayeinMgiofniannpgdr/oaopernrdldyMoawnnuultfoiaalcidztiinungrginofg3MtCohpmirpsoadnuyc.ts 11)S athlelowiendfoprrmoavtiiodneditshacto:pied in full with no changes unless 2) pQheriiistothrreirabgurtteheeedmewcniottphyitnshoerobttiahnietneeondrtiigfoirnnoaomlf34ei,asrnarinendsgolda porrofoitthetrhweirseeon DTIRVAIDSEIONNA:ME: 3M SPECIALTY MATERIALS IDFCN-U1M4B3ER/FUL.UPO.RCAD '98-0211-0008-0 Brand Fluorochemical Surfactant 00-51135-09138-8 98-0211-0891-9 9588--00221111--57438994--77 0000--5511113355--0120974612--11 92Z8F--00201012--60538718--08 SIUSPSEUERDS:EDEASu:gusJtuly25,28,20020000 DOCUMENT: 10-3808-2 0000--5511113355--0190346055--87 ==- 1. INGREDIENT C.A.S. No. PERCENT AAMMMMOONNIIUUMM PPEERRFFLLUUOORROOOHCETXAANNOOAATTEE............. 32812651-52-64-71-a AMMONIUM PERFLUOROHEPTANOATE............ 6130-43-4 96.5 =Si10s0 -1 HESPTAADLETCAFLUon ORnOoNtOiNnAtNuOnInCitAiCaIaDi,iiAiMiMaOnNnIeU.M. 4149-60-84 -2 TnIhonetgirfceiodcmiapetonintoesnntisrneoqtfhuiistrhemimesanttepsrrioadolufctTaSrCaeAr.eliisAntlelcdoamoppnpllitiahcneacbeEluewriotpcehhaenmtihceIanlcvheenmtiocraylof Emxoinsotmienrgs CahreemilciaslteSduobnstaEnIcNeEsCS (EINECS), or are exempt polymers whose 2. PHYSICAL DATA BVAOPIOLRINPGREPSOSIUNRTE:: .....................l..l.l.l.lll VEAVPAOPRORADTENISOTNTYR:AT.E...l..llllll: IlIL0 SSPOELCUIBFIILCITYGRAIVNITWYA:T.E.R.:...................... oPHE:RCENT VOLATILE: .........: ..... VISCOSITY: ..................... NN//AA NN//AA 0ap.p4re-c.0.5 Weter=l N/(ABulk) r(e2% aqueous solution) N/A Abbreviations: N/D - Net Determined N/A - Not Applicable CA - Approximately Page 713 331-007-2000 09:14 au Pax Message ARGUS 418-020 rage 3/17 AMSuDgSu:stFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant Pace 2 2. PHYSICAL DATA (continued) MELTING POINT:................. N/A APSPoElAiRdA,NCELigAhNtD OcDoOlRo:red powder; slight odor 3. FIRE AND EXPLOSION HAZARD DATA FFLLAAMSMHABPOLIENTL:DVITS - LEL.................. NN/oAn-flammable FALUATMOMIAGBNLIETIOLINMITTESMP-ERUATEULR:E.....] .. NN//AA EXWTaItNeGrU,ISHcIaNrGbonMEDdIiAo:xide, Dry chemical, Foam SPHEpaCoaIsrAiLtifvuFleIlREpprreFoIstGseHuTcrIteNiGvoerPRpcOlrCoeEtsDhsUiuRnrEgeS,.deimnacnldudibnrgeathhelimnegt,appsaerlaft-ucso,ntabiunnekde,r coat 2pnrdotpeacnttisv,e cbaonvdesrianrgoufnodr earxmpso,sedWaiasrteasandoflteghse, hefaadc.e mask, and UNUSSeeUALHaFzIaRrEdouAsNDDEeXcPoLmOpSoIsOiNtioHnAZASReDcSt:ion for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INNCoOtM.PAApTpIlBiIcLaIbTlYe- MATERTALS/CONDITIONS TO AVOID: HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur HAZ`CAaRrDbOoUnSMoDnEoCxOiMdPaOSIaTnIdONCarPbROoDnUCDTiSo:xide, Oxides of Nitrogen, Hydrogen Fluoride, Ammonia 5. ENVIRONMENTAL INFORMATION SPIOULsbLeserRvEveSetPOpsNrwSeeEce:apuitnigoncsompforuonmdootrherwatseerctitoonsa.voidColdulsetcitngs.pilClleedamnatueprial. residue. Place ina closed container. Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 714 31-07-2000 09:24 3u Fax Message ARGUS 418-020 rage a/27 MASuDgSu:stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant 5. ENVIRONMENTAL INFORMATION (continued) PAGE 3 RECaOcMciMonEmaNbrDuaEstDteibDlIiSenPOmaSanAtLeir:nidauls.triaClomborustcioomnmerpcrioadluctfsaciwliiltly iinncltuhdee Siiposa of in a sanitary landfill. Disposal altarnative: HpFr.esenDocenooft Dispose of Sacto product in a facility permitted to accept chemical waste EN`VSIURPOPNOMRETNITNAGLDADTAAT:A: BIO`CTDhhEeeGmoRirAceDatAliTcIaOlONx:yOgexnygenDeDmeamnadnd(CO(DT)O:D):0.000.03720g/gg/g 20-Day Biocheaical Oxygen Demand (B0D20): Nil AQUBWFAlaaTuttIeehCgreialdTflOlXemIaisCnuInn(TofDYwia:sphh(nPii(amLeemppaohgmanilase)snp4ar8co-rshoerclhaiECsr5)u0s:)96-9h66r-32hrLCmSgEO/C:SLO: 7665629g/mLg/L G5r1e0e0n0 Almgga/eL (Selenastrum Hicrotox (Photobacterius capricornutum) 14-Day ECSO: phosphoreus) 30-min ECS: 730 mg/L BIOBNCCEON=CE1N.T8RATION: REVGoUlLaAtTOiRlYe Voc Less OHIzrNogFaORn&MiAcETxIeCOmoNpm:ptouSnodlsv:entNs/:A N/A. Saifnocreerealgsuploastailo.ns vU.aSr.y, EcPoAnsHualztardaopupsliHcaasbtlee rNuemgbuelrati=onsNoonre a(uNtothorU.iSt.ies EPA Hazardous) TThaegisctormaptoinoenntsreqofuitrheimsentprsodoufctTSCaAr,e EiInNEcCoSm,pliCaDSnLc,e wAIiCtSh, tMheITIc,heKmEicCaTland Pcs. OTHLTEohRwiassEtNsVuIbLGRsSOt0aN,nMcEeNETCAhS0aL,sImoNirFnOiRImMCAaSTl0IOt<No:xoirci=ty10T0o0 Bagq/uLa)t.ic organisms (100 ag/L < NVoasdtaatvaatearretarveaaitlmaebnltesoynsttehmeotrogxainciistuys effects of this substance on TaFhioitsshiesrtprotddheurgcortuagdhactaindoinpsostoaecnnidtaitpaielorlsnyisotfgenmieenrtaatbthoeeliePsnemvr,ifrlouwnohimrceohnotcthaasnoatthee apnoitoenn,tial to EPCRA HAZARD CLASS: Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 715 31-0c7-2000 09:14 34 Fax Message ARGUS 418-020 rage 5/17 MASuDgSu:stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant PAGE 4 5. ENVIRONMENTAL INFORMATION (continued) or FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes CHRONIC: Yes 6. SUGGESTED FIRST AID EYEIacmoendTiAaCtTe:ly flush eyes with large amounts of water for at least 15 minutes. Gat immediate medical attention. SKIFNluCsOhNTsAkCiTn: with large amounts of water. If irritation persists, get medical attention INHIAfLAsTiIgOnNs:/symptoms occur, remove person to fresh air. If Signs/symplons continue, call a physician. IFDoSWAnLoLtOWiEnDd:uce vomiting. Drink two glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYEAvPoRiOdTEeCyTeIOcNo:ntact. Wear vented goggles. SKIANvoiPRdOTsEkCiTnIOcNo:ntact. material. A pair of gWleoavresappmraodperifartoem gthleovefsollwohewninghamnadtleirnigslt(hsi)s are rpeecrosmomneanldepdr:otec`btuitoynl riutbebmesr.as Unseecesosnaeryortomorperevoefnttheskfinollcoonwtiancgt: head bZoeveBraidneg,of`ceoivtehrearllso.f tPhreotfaocltliovweinggarmmateenrtisal(so:ther than gloves) should polyathyilene/polyvinylidene chioride (Saranex) Use%odriasfpaorsaabblleefosrhoea/ilbooptrotceocvteirvienggoarrmernutbsb.er boots. Disposable fabric REUvCseOenMtMiwEliNatDthEiDoanVpEpNrtTooIpLrmAiaTaiItnOetNa:ilnocaelaiesxshiaounsstbevlenotwilraetcioomnm.endePdroevxidpeosusrueffilciimeitnst. pIrfoteexchtaiuosnt. ventilation is not adequate, use appropriate respiratory RESANPvIoOIiSRdHATObaRprYperaotPvhReiOdTnEgCrTeoIfsOpNai:irratboorrsnebamsateedrioanl.airbSeolrencetcoonnceenoftratthieonfoloflowing contaminants and in accordance with OSHA regulations: full-face high- Abbreviations: N/D - Not Datarmined N/A - Not Applicable GA - Approximately Page 716 31-07-2000 09:14 sn rax message ARGUS 418-020 rage vsis MASuDgSu:stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant PAGE 5 7. PRECAUTIONARY INFORMATION (continued) efficiency filter respirator, full-face supplied air respirator. PRDEoVENnToItONeatO,F AdCrCiInDkENorTALsmoIkNeGESwThIeOnN:Using this product. Wash exposed abreefaosretheoatrionugg.hly with soap and water: Wash hands after handling and RE`CSOtMoMrEeNDaEwDaySTfOrRoAmGEa:reas where product may come into contact with food oCrlopzhaadrmwahceenutnioctalsi.n useS.tora at room temperature. Keep container **PREVENT MOISTURE CONTAMINATION TO KEEP POWDER FREE FLOWING. = FINRoEnfAlNaDmmEaXbPlLeO.SION AVOIDANCE: OTNHoERsPmoRkEiCnAgU:TIOSNmAoRkYingINFwOhRiMlAeTIuOsNi:ng this product can result in Gcfon`ttahmeinhaatziaorndouosf dtheecomtpoobsaictcioonanpdr/oodrucstmsokemeanntdionleedaditnothteheRefaocrtmiavtiitoyn DcSlahototarhoiusngeghc,ltyiofnboaodofforanetdhirste-ouMbsSaeDc.Sc.oDiprSsotcdoaurrcedtswc.oornktWaamcslihontahtceeosdntsalemepiaantraheatrteedcllycoltofhtrihonimgn.gother Decontaminate work surfaces frequently to avoid exposure by contact. HMIS HAZARD RATINGS: HPEEARLSTOHN:AL3PROFTLEACMTMIAOBNI:LITXY:(SOee RpErAeCcTaIuVtIiToYn:s, Osection 7.) EXPOSURE LIMITS INGREDIENT VALUE UNIT TYPE AUTH SKIN AAMMMMOONNIIUUMMPPEERRFFLLUUOORROOHOECXTAANNOOAATTEE................... AMMONIUM PERFLUOROHEPTANOATE 00..101 MMGG//MM33 01 mam3 TTaHnA A3Mcem x A 3M HEAPMTMAODNEICUAMFLSUAOLRTO.N.O.N.A.N.O.I.C...A.C.ID.,........ NONE NONE NONE NONE h= aSKIpoNteNnOTtAiTaIlONc:ontLriisbtuteidonsutbostatnhceesoveirnadlilcaetxepdoswuirteh b'yY' tuhnedecrutSaKnIeNousrefreoruteto biyncdliurdeicntg cmuocnotuasctmWeimtbhratnheeansudbsaytea,ncee.itheVrehibycleasircbaonrnealtore,r smokrien apbasrotripctuiloanr.ly, SZO"3UMR:CE OF3EMXPROeScUoRmEmenLdIMeIdTEDxApToAs:ure Guidelines Z AcGmm: American Conference of Governmental Industrial Hygienists - NONE: Nome Established Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 717 31-07-2000 09:14 34 Fax message ARGUS 418-020 wage 1100 MASuDgSu:stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant . HEALTH HAZARD DATA PAGE or BYEpoadiconor,naTtAtCaeTa:rBiyneg,Irarintdathiaozny: vissiigonns./sysptoms can include redness, swelling, skMSi1g6_ncsoS/wksTiyAnmCTptIornrsitacatnioninc(laufdteerrpedrnoelsosn,gedswoerllirnegp,eaatnedd ciotncthaicntg).: Mtahyosebecaabussoerdbebdy tihnrhoaulgahtiotnheasnkdi/onranidngpersotdiuonce effects similiar to INHlbAyiLnAiaTnsIhOeaNl:raetqiuoinritnogmomdeedriactael aqtutaennttiitioensmaoyf rtheissultmatferroimala. single exposure May be absorbed by inhalation and persist in the body for an extonded tise Single overaxposure, above recommended guidelines, may cause: ISorrreinteastsionof (tuhpepernosreespainrdattohrryo)a:t, sciogungsh/isnygmptaonmdsscneaenziinngc.lude Prolonged or repeated overaxposura, above recommended guidelines, may cause: LainvdertenEfdfeercntess:s sofignusp/pseyrmpatbodmosmecnan include yellow skin(jaundice) IFTTohnSiiWmAcPeLerLprOreWotiEdhuDuro:cortuogohccatndainpscosatotecenitaaitnaiiloolnnyoifgnednmieectraaatbteoeleiPfsafmre.fctlsuAonriicmnaoclcltuasdnticunadgtieelsiavnceioronnd,ucted SSSiiasftteeuurib"oTahnec"riaensa,abreawneiinogghntktnuolmwoonssr,shuomlfaonssthhoeefalltaiphvapenreei,tfoifntepecaw,tnhscerandefraruesosnmeaadlnadnasattniedcisinthpteeaesmtnaedtdoeofdlomaganildce Sixnpsotrsuucrteedc.o this perfluorooctancate Illness may result from a single swallowing of a moderate quantity of this material canApceErmRfi:lxutourroeheopftaanmcmaotnei,umampmeorfnliuuomrcpoecrtfalnucoartoep,anatamnmcoantieumand ammonium Bcea3rr6fc2li5u-no2o6rg-oe1nn)eixcawinatcsyatfweaa,sd fttohoautnaldbwiainsnot93hreattosstuf9do7yr%.A2MTMhyOeeaNrrIesU,MwenrPoeERFcsLotUmaOptRoiOusOntCdiTcAaiNlnOldAyuTcEed _tSwidgyniefaircansttudcyomptohuenrde vreerleatesdtabteinsitgincaltleystisciuglnairfictuasnotrsc.ompIonunadserceolnadted Abbreviations: N/D - Not Datarmined N/A - Not Applicable CA - Approximately Page 718 321-007-2000 09:14 3# Fax Message ARGUS 418-020 rage u/1s MASuDgSu:stFC25-,143200F0LUORAD Brand Fluorochemical Surfactant PAGE 7 8. HEALTH HAZARD DATA (continued) bTeinbiigtnuntuamnodrspaiirn-tfheed cloinvterro,lsp.ancBraesaesd,onandthetecsutrirsenwthenknocwolmepdagree,d tthoasaed f1i9n9d3insgtsudiheavseconondhuucmtaend hjoeianlttlhyibmypli3catainodnsD.uPo(n3t8)2.5-26-1) (1963 and MUTNtAorGtaEnNmsIufCtoIarTgmYea:ntiiconininianvmiatmromalmiuatnagecneillcittyranasssfaoyrsm.atiDoind nasostayc.ause cell REPNRoOtDUtCeTrIaVtEo/gDenEiVcELOiPnMErNaTbAbLitsTOXbIyNSo:ral administration. Not teratogenic to rats by gavage or inhalation exposures. OTHAERProHdEuAcLtTHToHxAiZcAiRtDyISNFuOmRmMaArTyIOSNh:eet is available. Tpohpeulparteisoennceandofsourbgpaopnuilcatfilounosr,ochsuecmhicaalsswoirnketrhse, blhoasodbeoefntpheublgiensehreadl Gvaotriknegrsbaicnkditcoatetsheno197a0dvse.rse3'esffeecptisd.emiological study of its own ThehaiistshetrhperotpdhourtcoetungthciaandlipssotootcebineattiiaaolbnlsyoorrbgeedmneetaraanbtdoelriePsmeaar.ifnluPoeirrnoftolhcuetoarbnoocodacytteanfcoarnaitoelno,nagnion pfoerikondoswnofhustaimneheaanldthmayaffaeccctusmulfartoem waintthicrieppaetaetdedexepxopsousrueretso. tThhiesre are Parfluorooctancate anion when used as intended and instructed. SECTION CHANGE DATES INGREDIENTS SECTION CHANGED SINCE July 28, 2000 1ssUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 719 331-007-2000 09:14 au pax message ARGUS 418-020 -- MASuDgSu.stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant PAGE 8 TbIheMePcLIoiErnDrf,eocrtmIaNtaCisLoUnoDfINiGtn,hethBdiUasTteMNOaTtiessLruiIeaMdlI.TESDaf3eMTOt,yMAAKDNEaYStaNDOSMhPWeLAeIRtERDA(NWMTASIRDESRS)A,NTiYsEXPbOFReElSiSeEvDedORto WMPhEEeRRtCFhHOeARrNMTAANtBChIEeLIO3TRMYUpSrOAoRGdEuFcItTONFEiSTsRSAfDFiEtO.RfAorUsPeaArRpTaIirsCtUiLrcAeuRslpaPorUnRsFipObuSlrEeposfORoerCaOdnUedRtSesErumiitOnaFibnlge for GQCnasinaqruaseflfymecettwhiottdhheinoufstehueseanudosrerapaspppllkiinccoaawttliieoodnng.eofanGadiv3ecMnonpttrrohodelu,cvta,riitestoiysmeoefosfsefnwathciitacolhrsatrtheahtat tphaertiucsuerlarevapluuraptoesethaend3Msupirtoadbluectftoro duseetre'rsminmeethwohdethoefrusiet oirs afpiptlifcoartiaon. D3iuMne'perrtoroovritsdh,eesromeiimnsofstoieromnpasotisoosrnibiaillnitteeyrlaetctithoartnosniecliencfttorhroimsniacsinatfrorasmnessrtfvieiorcne,matoy3himatavskaecsursetnsooumletresd fiiennpffrooerrsmmaaantttiiaootnniooinbnstatiahsneetdMoSDfSritosmavcaaoimldpaalbtelatebeandseiesrsemcatyolrynoatcfcruobrmeaca3ys. curIrnenatddiatsiotnh,e Page 720 31-0CT-2000 09:14 3u Pax Message ARGUS418-020 rage 10/11 MDAATTEARSIHAELETSAFETY a3N center St. Paul, Minnesota 55144-1060 1-800-364-3577 or (651) 737-6501 (24 hours) CAIoLnpifyorrriimggahhttti,sonr20ef0so0er,rvteMhdie.nnpeusCrooptpoaysienMgiofniannpgdr/ooaprnedrdlMyoawnnuultfoiaalcditiznuigrnignofg3MCtohpmirpsoadnuyc.ts i1)c aptrhlieloorwiendafgorprermeaomtveiinodtnediitsshaoctbo:tpaiiendedinffruolml3w4,ithanndo changes unless 2) hQefistthreirbuttheed cwoiptyh ntohre tihneteonrtiigoinnaolf eiasrnriensgolda oprroofitthertwhiesreeon TDIRVAIDSEIONNA:ME: 3M SPECIALTY MATERIALS FC-143 FLUORAD Brand Fluorochemical Surfactant ID'9N8U-M0B2E1R1/-U0.0P0.8C-.0: 98-0711-5489-7 0000--5511113355--0029914318--18 9988--00221111--06859811--90 ISS3U8E-D0:711A-u7g3u9s4t-725,002-05001135-10762-1 2ZF-0002-0378-4 SDOUCPUEMRESNETD:ES:10-J3u8l0y8-228, 2000 0000--- 5511113355--= 1009430655---78 1. INGREDIENT C.A.S. NO. PERCENT AAMMMMOONNIIUUMM PPEERRFFLLUUOORROOOHCETXAANNOOAATTEE..........:... AMMONIUM PERFLUOROHEPTANORTE.......... 32812651-52-64-71-a 6130-43-a 96.5 E- 1e00 Sa HESPATLAT.DECAFLUORONONANOIC ACID, AMMONIUM a145-60-8 -1 Tf[honetgirfceiodcmiapetonintoeenntisnreoqtfuhiistrehmmieasnttepsrrioadolufctTaSrCeaAr.eiisiAntleldcoomanpppllitiehcneacbeEluewriotpchehaetmnhiecIanlcvheenmtiocrayl of nmoinonmegrs CahreemilciaslteSdubosntaEnINcEeCsS.(EINECS), or are exempt polymers whose 2. PHYSICAL DATA VBAOPIOLRINGPREPSOSIUNTR:E. ................. VAPOR DENSITY: ..........l..... NN//AA N/A ESOVLAUPBOIRLAITTIYONINRATWEA:TER: ... ...... . 1. SPECIFIC GRAVITY:.............. aNp/pArec. 0.4 - 0.5 Water=i PBHE.RCoENeTvuVnOnLAnTnInLnEn: .............. N/(ABulk) iii A= 7 VISCOSITY:.............cooc.... N/(A2% aqueous solution) Abbreviations: N/D - Not Determined N/A - Not Applicable Page 721 CA - Approximately 321-007-2000 09:14 34 Fax Message ARGUS 418-020 rage 11/11 AMSuDgSu:stFC25-,143200F0LUORAD Brand Fluorochemical Surfactant PAGE 2 2. PHYSICAL DATA (continued) MELTINGPOINT:................. N/A APSPoElAiRdA,NCELigAhNtD cODoOlRo:red powder; slight odor. 3. FIRE AND EXPLOSION HAZARD DATA FFLLAASGHMBPLOEINTLDNTS - LiEiiL.I.D.DI1111D NN/oAm-flammable AFULTAOMIMGANBILETIOLNDMITETMSPE-RAuTEULR:E(:Dl1ll.]. NN//AA EXHTaItNeGrU,ISHCIaNrGboMnEDdIiAo:xide, Dry chemical, Foam SPWEeCaIrALfuFlIlREprFoItGeHcTItNiGvePRcOlCoEtDhUiRnEgS,. including helmet, self-contained, ipnodsiptainvtes,prbeasnsdusrearorounpdreasrsmusr,e wdaeimsatndanbdrealteghsi,ngfaacpeparmaatsku,s,anbdunker coat protective covering for exposed areas of the head. UNUSSeUeALHazFaIrRdEouAsNDDEeXcPoLmOpoSsIiOtNioHnAZAsReDcSt:ion for products of combustion. 4. REACTIVITY DATA STABILITY: Stable INNCoOtM.PAApTpIlBiIcLaIbTlYe- MATERIALS/CONDITIONS TO AVOID: HAZARDOUS POLYMERIZATION: Hazardous polymerization will not occur HAZCAaRrDbOoUnSMoDnEoCxOiMdPeOSIaTnIdONCaPrRbOoDnUCDTiSo:xide, Oxides of Nitrogen, Hydrogen Fluoride, Ammonia 5. ENVIRONMENTAL INFORMATION SPOIbLsLerRvESePOpNrSeEc:autions from other sections. Collect spilled material. rUesseidwueet. SwPeleapciengincoampcoulnodseodrcownattaeirnetro. avoid dusting. Clean up Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 722 31-0cr-2000 09:14 3 pax Message ARGUS 418-020 rage 12/17 MASuDgSu:stFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant 5. ENVIRONMENTAL INFORMATION (continued) PaGE 3 `REnCcOcMioMnmEabNruDasEttDiebDlIiSenPOmaSanAtLei:rnidauls.triaClomobrustcioomnserpcrioadluctfsaciwlililtyiinncltuhdee pHEr.esenDcoenootf 3va1s5t0e06proofducitn ainasaniftaacrilyitlyanapfeirlmli.tteDdistpoosaaclcepatltecrhneamtiicvael: wasDties.pose of ENV`SIURPOPNOMRETNITNAGLDADTAAT:A: `BITCOhhDeeEmoGirRceAatDliAcTaIOlONx:ygOexnygenDeDmeamnadnd(CO(DT)R:OD):0.000.03720gg//gg G0Day Biochemical Oxygen Demand (B0D20): Nil AQUFVAaaTtteIhrCeadTfOlXmeIaiCnIn(ToDYwa:ph(nPiiamempahganlae)s p4r6o-mheelaEsC)S0:96-h6r32LCmSgO/:L 766 3g/L GBlrueoegnilAllgaseunf(iSSehlen(aLsetproumiascmaapcrrioccohrinruutsu)s) 9164--hDayECESC:SO: 569 Bg/L H5i1c0r0o0tox"mg/(LPhotobacteriua phosphorous) 30-min ECSO: 730 3g/L BIOBNFCON=CE1N.T8RATION: RE`GVUoLlAaTtOiRlYe Voc Tess o2IrN0gFaOnR&iMAcETxIeCOmoNpm:ptouSnodlsv:entNs/:A N/A. bSienfcoereredgisuploastailo.ns vU.aSr.y, EcFonsHualztardaopupslicWaabsltee rNueagbuolrati-onsNoomre a(uNtothorU.iSt.ies EPA Hazardous) TahgeisctormaptoinoenntsreqofuirtehmisentpsrodoufctTSCaAr,e EiInNEcCoSm,pliCDaSnLc,e AwIiCtSh,thMeITIc,heKmEicCaIland Piccs. OTTHThEoiRusasEtNsVuIbLRossOt0Na,MnEcNeETcSAh0La,sImoNirFnOiR1mM0aA5lT0IOt<Noxoirci=ty10t0o0 a3gq/uLa)tic organisms (100 3g/L < NVoasdtaetvaataerretraavaatisleanbtlesoynstethmeortgoaxniicsimtsy effects of this substance on TGhiitsherprotdhurcotughcandispsootceinattiiaolnlyofgemneetraabtoeliPsear,fluwohriocohcthaanscatthee panoitoenn,tial to Fosist degradation and persist in the environment. EPCRA HAZARD CLASS: Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 723 31-00T-2000 03:14 3 pax Message ARGUS 418-020 rage 13/1; MASuDgSu:stFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant =. ENVIRONMENTAL INFORMATION (continued) FIRE HAZARD: No PRESSURE: No REACTIVITY: No ACUTE: Yes PAGE 4 TT CHRONIC: Yes 6. SUGGESTED FIRST AID EYETamCOaNdTiAaCtTe:ly flush ayes minutes. Get immediate mweidtihcallargaetteanmtoiuonnt.s of water for at least 15 SKIFlNuCsOhNTsAkCiTn: with large amounts of water. If irritation persists, get medical attention INH1A2LAsTiIgnOsN:symptoms occur, Signs/synptons continue, rcaelmlovea ppheyrssiocniatno. fresh air. If IFDSoWAnLoLtOWiEnDd:ice vomiting. Drink two glasses of water. Call a physician. 7. PRECAUTIONARY INFORMATION EYEAvPoRiOdTEeCyTeIOcNo:ntact. Wear vented goggles. SKAIBNWaoteiPrRaiOaTslEk.CiTnIOAcNo:nptaaicrt.of gWleoavresapmpardoeprifartoem tghleovefsolwlhoewninghamnadtleirnigalt(hsi)s are SFpooevcraoermoimnnoagnl,depdcr:oovtaerbcautltilyoeln. riutbPebrmesort.aesctinUvseeeceosgnsaaerrmyeornttomsorp(eroetvohefenrtthteshkanfionlgllcooovwnetisanc)gt:shohueladd bPeolydeadcehyoifeneei/tphoelryvoifnytlhiedenfaollcohwlionrgidemat(eSrairaalnse:x) Uis=epdriesfpeorasbalbelefsorhoeai/lbooptrotceovcetriivneggaorrmernutbsb.er boots. Disposable fabric REvCUTestOenMteMixEwlhNiaatDuhtEsiDtoaVpnEpvNretToonIptLrimAilaTaaiIttnOeitNoa:nilnociaeslmniosatsxihaoaundssetqubaveteleno,twiluraseteciooamnpe.pnrdoePprdroiveaixtdpeeosruesrsuepfifirlcaiitmeiotnrsty. protection. RESANPvIoOIiSRdHATOabRrpYepartoPhRvOieTndEgCrToeIfsOpNai:irrabtoorrnsebmaasteedrioanl.airSbeolrenectcoonnecenotfratthieonfoolflowing __contaninants and in accordance with OSHA regulations: full-face high Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 724 321-007-2000 09:14 3# Fax Message ARGUS 418-020 Page 14/1 MASuDgSu:stFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant PAGE 5 7. PRECAUTIONARY INFORMATION (continued) - efficiency filter respirator, full-face supplied air respirator. PREDoVENnToItONeatO,F AdCrCiInDkENorTALsmoIkNeGESwThIeOnN:using this product. Wash exposed bareefaosretehaotrionugg.hly with soap and water: Wash hands after handling and RECSOtMoMreENaDwEaDySTfOrRoAmGEa:reas where product may come into contact with food ocrlospehdarmwhaecneuntoitcalisn useS.tore at room temperature. Keep container **PREVENT MOISTURE CONTAMINATION TO KEEP POWDER FREE FLOWING*.~ FIRNoEnfAlNaDzmEaXbPlLeO.SION AVOIDANCE: OTNHoERsPmoRkEiCnAgU:TIOSNmAoRkYingINFwOhRiMlAeTIuOsNi:ng this product can result in ocfonttaheminhaatziaorndooufs tdheecotmopboascitcioonandp/roorducstmsokemenatnidonleedaditnothteheRefaocrtmiavtiitoyn CDlaottahisnegc,tiofnoodofantdhistobHSaDcSc.o prSotdourcets.workWacslhothceosntasmeipnaartaetdelylfortohmingothar tDheocroonutgahmliynabteefowroerkres-uursfea.cesDisfcraerqduenctolnytamtoinaatvoeidd leexaptohesrureclobtyhicnogn.tact. HMIS HAZARD RATINGS: HPEEARLSTOHN:AL3PROFTLEACMTMIAOBNI:LITXY:(SOee pRErAeCcTaIuVtIiToYn:s, Osection 7.) EXPOSURE LINITS INGREDIENT VALUE UNIT TYPE AUTH SK AAMMMMOONNIIUUMM PPEERRFFLLUUOORROOOHCETXAANNOOAATTEE................... AHMEMPOTNATDUEMCAFPLEUROFRLOUNOORNOAHNEOPITCANOACAITDE, AMMONIUM SALT...................... 00..101 MMGG//MM33 01 mam3 NONE NONE TAHA AacMomH x TMA 3M NONE NONE t*heSKpIoNteNnOtTiAaTIlONc:ontrLiibsutteidonsubtostatnhceesoveirnadlilcaetxepdowsuirteh b'yY'thuendecrutSaKnIeNousrefreoruteto biyncdliurdeicntg cmounctoaucstmewmitbhranteheasnudbsetyaen,cee.itheVrehibcyleasirbcoarnnealtore,r smkoirne apbasrotripctuiloanr.ly, SZOU3MR:CE OF3MEXPROeScUoRmEmenLdIMeIdTExDApToAs:ure Guidelines - ACGIH: American Conference of Governmental Industrial Hygienists - NONE: None Established Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 725 31-07-2000 09:14 3n pax Message ARGUS 418-020 page 15/1: RMSuDgSu:stFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant 5. HEALTH HAZARD DATA PAGE oT EYENodCOaNrTaAtCeT:Eye Irritation: signs/symptoms can include redness, swelling, pain, tearing, and hazy vision. SKIMSNiilgCdnOsNS/TksAiyCmnTptIormrsitcaatnioninc(laufdteerrpedrnoelsosn,gedsweolrlirnegp,eataendd ciotncthaicntg).: Mtahyosebecaaubsseodrbbeyd tihnrhoaulgahtitohneansdk/inoranidngpersotdiuocne effects similiar to INHTAlILiAnnTeIseOsN:reTqouniritonganmdeedircaatle aqtutaennttiitoinesmaoyf rtehsiusltmatferroimala. single exposure Mtaiynebe absorbed by inhalation and parsist in the body for an axtended Single overexposure, above recommended guidelines, may cause: SIorrreinteastsionof (tuhpepernosreespainrdattohrryo)a:t, sciogungs/hsiynmgptaonmds snceaenziinngc.lude cParuosleo:nged or repeated overexposure, above recommended guidelines, may LainvderteEnfdfeercntess:s osfigunpsp/esrympatbdoommsenc.an include yellow skin(jaundice) IFSTShiWitAshLeLrpOrWotEdhDur:cotughcandipssootceinattiiaolnlyogfenmeetraabtoeliPsemr.fluAonriomaolctasntcuadtieesancioonnd,ictod GSoflnfsatPcuetrrsbf,alnucoaernsod,obcetwnaeiniggchnattetulamoonssri,sonolfoisnstdhieocfatleaipvpeeerf,tfietcpeta,sncraiednarcselnuaadlnidngatnedlsithveeesrmatofolomgailce GCaxtpso.surTahetroe tarhaisnoPerkfnlouwnorohoucmatnanchaetaelthaneifofnecwthsanfursoemdaansticiinptaetnedded and Snscructed. tIhlilsnemsastemraiyalr.esult from a single swallowing of a moderate quantity of capnAocrEmRti:xltuuorreohoofptaanmcsaotnei,usapaemrofnliuuosropoecrtfalnuccartoep,antaamnsooantieusand ammonium D7o3c8l25u-o2r6o-n1e)xawnacsatfeo,d carcinogenicity was ttfohoautanldwbaiisnno9t3rhaettsostuf9do7yr%. A2MTMhyOeeaNrrIesU,MwenProeERFscLtoUamOtpRioOsuOtnCidTcAaiNlnOldAyuTcEed Suidg-nyiefaircansttudcyomtphoeurned wraerleatesdtatbiesntiigcnaltleystisciuglnairfictuasnotrs.compInouandsreeclonadted Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 726 31-07-2000 09:14 3u Fax nessage ARGUS 418-020 rage 10/17 AKuSDgSu:stFC2-5,14320F0L0UORAD Brand Fluorochemical Surfactant PacE 7 5. HEALTH WAZARD DATA (continued) nn bTeinbiig%nuntaumnodrspaiirn-tfhaed cloinvterro,lsp.ancBraesaesd,onantdhetesctuirsrenwthenKnocwolmepdagree,d ttohesaed f19i8n3dinsgtsudiheasveconondhuucmtaend hjeoailnttlhyibmypli3cHatainodnsD.uPo(n3t8)2.5-26-1) (1983 and MUTNtAroGatEnNsmIfuCotIraTmgYae:ntiiconininianvimtarmomalmiuatnagecenlilcittyranasssfaoyrsm.atiDoind nasostayc.ause cell REPNRoOtD_UtCeTrIaVtEog/eDnEiVcELOiPnMErNaTbAbLitsTOXbIyNSo:ral administration. Not teratogenic to rats by gavage or inhalation exposures. OTAHEPRroHdEuAcLtTHToHxAiZcAiRtDyISNuFOaRmMaArTyIOSNh:eet is available Tpohpeulparteisoennceandofsourbgpaonpiuclatfilounosr,ochseumcihcaalsswoirnketrhse, blhoasodboeefnthpeubgleinsehreadl aWotriknegrsbaicnkdictaotetshano197a0dvse.rseH'esffeepcitsdemiological study of its own eTihtihserprotdhurcotughcandispsootceinattiiaolnlyofgemneetraabtoeliPsemr.fluPoerrcfolcutoarnocoactteancanaitoen,anion Fphoearsikontodhwsenopfohtueatnaitmnieahleaanldtothmbaeyaffaaebccsctousrmbuelfdartoeamnawdinttrhiecmirapeiapnteeaidtneedtxhpeeoxspbuoosrdueyreftsoo.rthTlihosenrge are Parfluorooctancate anton when used as intended and inStructed. SECTION CHANGE DATES INGREDIENTS SECTION CHANGED SINCE July 28, 2000 1ssUE Abbreviations: N/D - Not Determined N/A - Not Applicable CA - Approximately Page 727 32-07-2000 09:14 3 pax Message AugustFC25-,14320F0L0UORAD Brand Fluorochemical Surfactant ARGUS 418-020 rage 11/17 PAGE 8 bTheecoirnrfeocrtmaatsionofitnhethidsatMeatiesrsiuaedl. Saf3eMtMyAKDEaStaNOSheWaAtRRA(NMTSIDESS), iEsXbPeRElSiSeEvDedORto PMIEEMRRPFLCIOHERADMN,ATNACBIEINLCOILRUTDYIUNSOGAR,GEFIBOTUFTNESTNROSATDFEO.LRIMAITUEsPeDArRTTOIi,CsUALrNAeYRspoPInUMsRPiPLbOIlSEeED OHRARRCAONUTRSYEOFOF for determining cuwashneert'hasefrfemctethtehothd3eKofupsreoudseuacntodraipaspplpfliiictcaatftioioronna.ofpaaGrtiiv3ceMunlpartrohdeupcvutar,rpiosesetoymeaonfdoffsauwcihttioacrbhsleartehfaotr tuhneiquuesleyr ewivtahliunatethteheus3eMr'prokdnuocwtledtgoedeatnedrmcionnterowlh,ethietr isitesissenftiitalforthaat particular purpose and suitable for user's method of use or application. D3us'prtoovithdeesreimnoftoermpatoisosnibiilniteylatchtraotnieclecftorromniacs tarasnesrfveircematyo hiatvsecursetsoumletresd rienpreerrsoernst,atioomnisssiasonstooritsaltceormaptlieotnesnesisn otrhisacciunrfaocrym.atioInn,ad3d4itBiaokne,s no iinnffoorrmmaattiioonn oinbttahieneMdSDfSroamvaaildaabtlaebasdeiremacytlynotfrboem a3sM current as the Page 728 ARGUS 418-020 ATTACHMENT 3 TEST SUBSTANCE PREPARATION PROCEDURE Page 729 ATTACHMENT 4 ARGUS 418-020 Version: 418:P0r2o0to(c0o4lN4O1V8.00020) Page of 2 TEST SUBSTANCE PREPARATION PROCEDURE Test Substance: Vehicle : Ammonium Perfluorooctancate (APFO) R.O. deionized water A. Purpose: Tdohseapguerpsoolsuetioofntshiosf pArPoFceOdufroreoirsalto(pgraovvaigdee) aadmmeitnihsotdraftoirotnhteoprraetpsaornatiPornimoefdica Argus Research Laboratories, Inc., Study number 418-020. B. General Information: 1. Aslplecsiolfuyttihoen pcroonttoacionlernsumwiblel rb,etleasbtesluebdsatnadncceoliodrenctoifdiecda.tioEna,cAhrglaubselbawtilclh number, concentration, dosage level, preparation date, expiration date and storage conditions. 2. Solutions will __ Daily be prepared: X_Weekly ~~ _For_days of use Once prior to dosing By Sponsor 3. Solutions wil be administered at a final dosage volume of 5. miikg/day. 4. Safety: X_ XC DGluosvte-sM,isutnRiefsoprimr/altaobrco(afotr, sgoolgugtiloens porrepsaarfeattyiognlaasnsdesdoasnidngf)aceshield ~~ Half-Face Full-Face Respirator Respirator/Positive Pressure Hood X_ TX TWyovrekkinslaeecvheesmi(cwahlefnuumseinhgotohde abnuldkumsaetearihaall)f-face respirator when using the bulk TA/S only 5. DosaYgeessolutions adjustXedfNoor %(CaAlcctuilvaittyi/oPnusribtaysoerdCoornre1c0t0io%n)Factor: Activity ~~__ %Puity __ Comection Factor 6. Sampling requirements: Cited in protocol. 7. Storage: Cited in protocol. Page 730 ATTACHMENT 4 ARGUS 418-020 Version: 41P8ro0nP2oaNs40Oe1zV80.0o004i21?0 TEST SUBSTANCE PREPARATION PROCEDURE C. Dosage Solution Preparation: 1. Wsieziegd,hloaubteltehdecroenqtuaiirneedra(msoeuenPtRoEfPthAeRtAeTstIsOuNbsCtAaLnCcUeLiAn TaInOaNpSpr)o.priately 2. Aanddd maipxpriotxihmaastteilryba8r0%anodf tmhaegnreetqiuicrsetdirapmloatuent(soefevPehRiEclPeAtRoAtTheIOcoNntainer CALCULATIONS). 3. aOnncaepptrhoeprtieastteslyubssitzaedncgeraisducaomtpeldectyelliyndderi.ssoQlvSeda,dtwriatnhsfveerhtihcleestoolutthieon to required volume (see PREPARATION CALCULATIONS). 4. SSetvoeprpaelrttihmeesgrtaodeunastuerdecpylrionpdeerrmoirxcinogv.erRweitthupmartahfeislomlautnidonmoixtbhyeilnavbeerlseidon tcoonatanidnedrurwiintgh atlhiqeuostitribnagr,.doPslaagcee oadnmianimsatgrnaettiionc astnidr/polratseaampnldianggitate prior 5. Repeat steps (1) through (4) for each concentration. Can Witten By: "2a ( Coder. Approved oA / 27-000 Clarification: _//No _ Yes (See attached clarification form.) witiasiate: (LZlele K Pppfe oy Page 731 ARGUS 418-020 ATTACHMENT 4 NECROPSY, ORGAN WEIGHTS AND HISTOPATHOLOGICAL EVALUATION Page 732 ATTACHMENT ARGUS 418-020 ProtocPoalg4e181.001220 NECROPSY, ORGAN WEIGHTS AND HISTOPATHOLOGICAL EVALUATION `Organ Weights TwheeifgohtllroawtiionsgwoirlglabenscawlilclublaeteidndfiovridaulallPlyawnedigFh1epdaarenndtaolrgaatns.-to-body weight and organ-to-brain bKriadinneys sopvlaereines tetshtyemsu.s ta(rigeitdeontrigfaiendsby amendment) avderrenal glands pUitteirtuasrywith oviducts and cervix epproisdtiadtyemides se(mwiitnhalcovaegsuilcalteisng glands and fluid) sFeolreFc1tedanpdupF2pegrenseerxatpieornlwiteear:nlings, the following organs will be weighed from one randomly brsaplienen thymus. Tissue Retention Tahtse aftolnleocwirnogpstiysasunedsrweiltlaibneedcoilnlneecutterdaflrboumffalelrPeda1n0d%F1fogremanleirnatfioornpopsasrienbtlaelhimsatloelogaincdalfemale evaluation: pittairgteatryorgans (if dentified by amendment) agdrroesnsallegsiloannsds (including tissue masses) Female Rats vagina uterus with oviducts, cervix and ovaries Male Rats tseesmtiisna(lrivghets)icles (with coagulating gland) epididymis (right) prostate Note: Testes will be fixed in Bouin's Solution for48 to 96 hours before being retained in neutral buffered 10% formalin. Page 733 ARGUS 418-020 ATTACHMENT 4 ProtocPolag41e82.o0t220 iTnhneeuftorlallowbiunfgfteirsesdue1s0w%illfobremacloilnlefcotrepdofsrsoibmlaellhiFs1toalongdicFa2l egveanleurataitoino:n weanling rats and retained ta(rigfeitdeonrigfaiendsby amendment) gr(oinscsluldeisnigontsissue masses) Histological Evaluation fHrisotmoltohgeiccaolnterxoalmainnadthiiognhwidlolsbaegepegrrfoourpmse.d Iofnletsiisosnusesatftrroibmut1e0d rtaontdhoemtleystsesluebcstteadncraetsarpeer sex `hoisbtsoelrovgeidcailnlythfoerrtahtes frermoamitnhienghirgahtsdionstahgeecgorntoruopls,antdhehisgahmdeoosraggaensgrwoilulpbseaenxdafmoirntehde rats in the low and intermediate groups. All gross lesions willbe examined histologically'. sInhoaudldditbioenctoongdruocstsedletsoioindsenstiufcyhtraesatamternotp.h-ryeolfatteudmeofrfse.cttsesstuiccuhlaarshriesttaopiantehdoslpoegircmaaltiedxsa,mimniastsiionng `lguemremnc.allElxaaymeirnsaotriotnypoefs.thmeulitniancutcleepaitdeiddygmiiasntshceolullsdoirnscllouudgehtihnegcoafpustp,ercmoartpougseannicd Ccealuisdainto the (accomplished by evaluation of a longitudinal section) and conducted in order to identify such lleusmieonn,s oarstshpeearbmsegnrcaneuolfomcalesa,rlceeulklosciyntitcheincfailutdraatieonpi(diindflyammamlateipiotnh)e,liaubme.rrant cell types within the. Tcohrepoproasttiaectaioonfallaocvtaatriyons.hoHuilsdtocpoantthaoilnogpirciamloredxiaalmiannadtigornoswhionuglfdoldiectleecstaqsuawleiltlataisvethdeepllaertgieon of tchoendpuricmtoerddifaolr fFo1lifcleemaploepurlaattsi;ont.heAnuqmuabnetritoaftirvaetse,voavlauraitiaonnsoefctpiroinmosredlieacltifoonliacnledsssehcotuilodn bseample isinzcelusdheoeunldumbeerasttaitoinsotifcatlhlyeanppurmobperriaotfepfroirmtohredieavlafloulalticiloens,pwrhoiccehducraen ubseedc.omEbxianmeidnawtiitohnsmsahloluld growing folicles, for comparison of ovaries of ats assigned to treated and control groups. `rAedddiutcieondalfleyr.tirteypr(o.du.cttihvoesoerrgaatnssthoafttfhaeilleodwtaonmdatien,tecromnecdeiiavtee,dsoisreagore dgerloivuepryrahtesasluthsypeocfftsepdrionfg, osrubfjoercwtheidcthoehsitsrtooluosgiccyacliceivtayluoartisopn"e.rm number, motity or morphology were affected, should be a aSnhdoutlhderreastusltisn wthaerrlaonwtaenxdamiinntaetrimoendioafttehdeorseamgaeingirnogucposntarnodl aconnddhuicgthodfotshaegqeuagnrtiotuaptivrea.ts evaluation, or addtional evaluations of low and intermediate dosage groups rats `sAudsdpiteicotnaeldcoofsrtesdwuilclebdefeirntciutryr,esdcshheoduulldedthreespeoretvadlautaetsiwoinls bbeeraedqjuuisrteedd.Naoccvoermdbiengrly7., 2000 Page 734 ZPRIMEDICA ARGUS 418-020 AA rsTResaearpRch Laoboratoriesa, Itnc. PROTOCOL s18.020 (oN EA ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) (APFO) IN RATS `SP Admit 1. 18 Dar ONSOR'S STUDY NUMBER: 200T-6889.6 1. BWodey iganhdAtge (page 6ofthe protocol): Actual body weights will be recorded the day after receipt and will be documented in the raw data. Tie hang mets Rea forsCho angne: a pagan er 2. RandomainzdCaohatbiitaotinon (page 9 ofthe protocol): a een or oestps osory At weaning, a table ofrandom units or a computer-generated randomization (60 male and 60 female pups per group), resulting in a total of 600 rats (300 rats per speexr)licthteors)eFn1fgoernceornattiinounepduepvsapleuartgiroon,upr,atrheesrutlhtianng3i0n maatloetalaonfd33000feramtasl(e1(510preartsspeexr sex) chosen for continued evaluation. At least two male pups and two female pups, rather than one male pup and one female pup, per litter when possible, will be selected. Thebody weightswillbe recorded whenratsreach sexual maturation. FB lowing esh l mara,ebcletofecndoomnieloer smcoomepefrgeenre FI generation rat per litter per group for continuation through mating to produce the EE rani seceasnatteoromenP gm mratone w+il bed or `selection ofF2 generation pups continued on study. AT NY REVIm SIONSTO, THIS FINALIZED AMENDMENT MUSTBE MADE BY Page 735 Reason for Change ARGUS 418-020 Prot"oAcmoeln4d1m8e.n0t20| Page? "The Sponsor requested that sexual maturation be measured for two pups per sex per lite per group. 3. RationaleforDosageSelection (pege 11ofthe protocol): The intermediate dosage levels are expected to produce minima observable toxic: effect, ratherthanthe intermediate dosage level is expected to produce minimal observable toxic effects. ReaforsChoangne: "This change corrects the protocol because thereare two intermediate dosage levels rather than one intermediate dosage level 4. PostweaningDevelopmentalObservations(page 15ofte protocol): NippleExamination: cOrnitderaiyon1i2spmoesttpwahretunm,thaelrepiuspasnwiiplpllbeepreexsaemnti.ned for th presence ofnipples. The ReaforsChoangne: "The addition was requested by the Sponsor. 5. SEpevrmaluatio(pnagse 18oftheprotocol): "`Tchoempluetfr-teasstssiswtieldl sbpeeursmedanfaolryseivsal(uCaAtSioAn)o.fteTshteicluelftartessptiesrmwailtlidbecowneciegnthreadti(obnotuhsing bferfoomrethaenrdesaufltetrinrgehmoovmaolgoefnatthee wtiulnlicbaeasltbauigniendewai)tahnadntIheDnEhNoTmoSgteaniinzKeidt.frAomsample. THahmoimleioInVTOhS.omTeeRnesfieealrdcshwialnldbae aslniadleywziedltboedperteepramriendeftoerstaincaullyasrisspbeyrmtahteidHamilton canoanlcyesnitsrawtiilonb(esrpeetramianteiddassprerawgrdaatmao.ftissue weight). All images produced during ReaforsChoangne: "ATgheisncchyaHnegaelwthasEfafdedctesdTiensotrGdueirdteolicnoemsp(lOyPwPitThSU8.7S.0.3E8n0v0i)r,oAnumgeunstta,l P1r9o98t.ection ANY REVISIONS TO THIS FINALIZED AMENDMENT MUST BE MADE BY SUBSEQUENT AMENDMENT. Page 736 ARGUS 418-020 ProtAomceolnd4m15e.n0t20| Pages 6. EpLr/otEo2coGle)n:erationPups NotSelectedforContinuedObservation (page 19 of the. Tthirseseuesselfercotemdopnueopsftpheretsehxrepeesrellietctetre, dwiplulpbsepweerisghxedp.erTliitstseru.esrafthreormtthhaentfhrroeem saelllected pupspersex per litter will histological evaluation. be retained in neutral buffered 10% formalin for possible. Reafosr Choangne: `This change clarifies the protocol. 7. EpLrIotEo2coGle)neration PupsNotSelectedforContinuedObservation (page19of the Aslelxupaulpmsantuortasteiloenctweidllfobrecsoanctiifniuceeddoabseranvlaitmid iotnedfonlelcorwoinpgsycowniltlinbueedpeorbfsoerrmveadt.ioTnshefor tlheosriaocniscw,iallbbdoempirneasleravneddpienlvniecutcraavlitbiuefsfewirleldb1e0e%xafmorimnaelidn.forAglrloostshleersitoinsss:uegsraonsds the carcass will be discarded. ReafosrChoangne: `This addition provides observation following cfoonrttihneuesdacoribfsiecrevaatnidonnsecfroorpsseyxoufarlamtastunroattisoenl.ected for continued 8. TissueRetention (pages | and 2 ofATTACHMENT 4 to the protocol): w`Tehaenlfiolnlgorwaitnsgpteirsssueexspweirlllibteterc,orlaltehcetredthfarnofmrtohme atlhlreFe1saenledctFe2dgFe1nearnadtiFo2n gweenaenrlaitnigon rats, and retained evaluation: in neutral buffered 10% formalin for possible histological (itafrigdeetntorigfainesd.by amendment) gross lesions (including tissue masses) ASUNBYSREEQVUIESNITONASMTEONDTHMIESNFTI.NALIZED AMENDMENT MUST BE MADE BY Page 737 Reason for Change: This chang clarifies he proto. APRcGa aUS148108-0020 el ABliarnctMo.r oHfobReersmeaarnc.hPh.D., DABT ~~ Date ARSuausybtofiDiereDGci.troYeroctrokr,oPhfD.fen\BT Date 24 i Hus [soe Fr 2 Bebibc enC. Lebo, VAD. Date John Buenhort. PhD. DABT, CIH Die Chairperson, Institutional Animal Care Study Monitor and Use Committee Sponsor's Representative ANY REVISIONS TO THIS FINALIZED AMENDMENT MUST BE MADE BY SUBSEQUENT AMENDMENT. Page 738 ARGUS 418-020 P "2 RPRIMEDICA AgSsisReSsheeaercnhrLvab,oBruaatnoItrciA. TellepihHo:noesn(G2i113.3))4P45A533.1889575814708 -------------------------------- PROTOCOL 418.020 GOERNAELRA(TGIAOVNA)GER)EPTRWOOD-UGCETNIEORNATSITOUNDY(OONFEALMITMTOENRIPUERM PERFLUOROOCTANOATE (APFO) IN RATS SPONSOR'S STUDY NUMBER: T-6889.6 Amendment 2 - February 2001 I. NEinxplae minat(ipaogen2ofAmendment 1: e{Exfafmeictnievde fDoartet:he 1prFeesbernucaeroyf2n0ip0p1l]eOs.ndTahey c1r2itperoisotnpoafrptuams,saillnmiaslmeetpuwphsewnilnlobneipples are present. ReaforsChoangne: Ths change clarifies the criterion and sex ofpups to be examined Yl 0 Co 2i Netra Pun DiArleacntMo.r oHfobReersemaarnc,hPhD, DABT Date ARsasyomdcgilattGe.DirYeoctrokr,ofPh.Rpes.eshcAh BTand Study Director ctame Date MUtetra llondoad otfiner Fh z. Znlacit] 2% fle for CThhaeirrepsearsHo.nW,oIondstairtdut,ioDn.aVl.AMn.imal Care Date JSothundyBuMtoenniltoofrf,anudDS,ponDsoArB'Ts,ReCpIreHse_ntaDtaitvee and Use Comminee Any revisions o this finalized amendment must be made by subsequent amendment. Page 730 p7aPRIMEDICA ARGUS 418-020 mii csi eLemssin, moTocoL 41802 SE SE ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM Amendment 3-20 hy 201 SPONSOR'S STUDY NUMBER: T-6889.6 1. Gross Necropsy and Histopathology (page 17 of the protocol): Tissues will be shipped (ambient conditions) for embedding 1: MckoRaysBraosi, DcVM, oD. ACVE Veterinary Pathologist `Telephone: (215) 345-7070 ne recite nie nai Fax: (215) 345-4326 ofape siren. I Tteatenge tte tale oreprops lei eaidl sors Mis Aihitsp zo 501 7 Kian M. Hoberman. PhD. DABT Date ValerieA. SharperM.,S. Dae _ "Director of Research e SDirenctorioe frStudy Manoageememnatsfor OY pirellbatedses"buus.nGToea.s2t. BFDe.iaDAaBi,iCt1? rDate m a SrC i e eet `Any revisions to this finalized amendment must be made by subsequent amendment. "Page 740 ARGUS 418-020 05Sheshy Drive Sco A re14438710 Telefox: (215)443-8587 ~~ ARGUS RESEARCH Charles River Labordtories Disanc dDeo velov pmee ntSr erviy ces PROTOCOL 418-020 `ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM 'PERFLUOROOCTANOATE (APFO) IN RATS SPONSOR'S STUDY NUMBER: T-6889.6 Amendment 4 - 19 November 2001 ) LitterData (page 14oftheprotocol): o[fEfpfuecptsitvheaDtsautrev:iv6eAfurgoumsdta2y001]toLdaacyt2at2ipoonsItnpdaerxtuwmil,lrbaethcearltchualantdeadyasttohedapeyr2c2entage `postpartum. `RefoarCshaongne: Tchailscuclhaatinogneofwavisabmialidteytionadexc(pcetfcooeartsuaugrneviovftaploupfspbuopsmfotrheanstuirrvepieveritooddfaoylslo1wainndgt5he postpartum). Ltd on Vanni Ua 191002001 ADliraenctMo.r oHfobReersmeaanr, Ph.D, DABT Date `RoMapndeud DG.iYeodrk,oPfhRDe.yPeAsBaTnd Date Suly Directo \ U6 ei llWienked30 a 200) \ `Theresa H. Woodard, D.V.M. Date John Butenhoff, Ph.D., DABT,CIH Date Chairperson, Institutional Animal Care `Study Monitor ` and Use Committee Any revisions to this finalized amendment must be made by subsequent amendment. : Page 741 ARGUS 418-020 APPENDIX G DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY Page 742 ARGUS 418-020 DEVIATIONS FROM THE PROTOCOL AND THE STANDARD OPERATING PROCEDURES OF THE TESTING FACILITY EEeE n 1. On 22 February 2001, the following P generation female rats were not weighed and potentially received the incorrect dosage volumes based on the previous body weight. p | (play) | Sud [ous TT Rat Numbers i38i413817. 13818,13830 | [ous 1 Ll -- mas | sae EC ee be v [V v 0 30 [ [oa bsn[ ionm hhi e Lon Ion.s 6. 90 | DL 1s used as an abbre[ viatio onfoi rday| ofl--actat-- ion. DUG s used amanoabbsreviation for day of seston. `These deviations did not adversely affect the outcome or interpretation of the study because it was asingle event and all rats were administered adosage very similar to the dosage they should have received. 2. Onl December 2000, DS 19, the P generation male and female rats in all dosage `groups were administered the appropriate vehicleortest article approximately two hours and fifteen minutes late and three hours early, respectively. This deviation did not adversely affect the outcome or interpretationofthe study because it was a single event and all rats received the appropriate vehicle or test article. 3. Body weights were not recorded and predosage and postdosage observations were not recorded for the following ras. It s presumed that the rats were not dosed. [ons [ Docsaget|iDoosagne | pe [3Dayar [so [imRale| EE Lr [osMAROI| DST | Female | i563 | These deviations did not adversely affect the outcome or interpretation of the study because it was a single event of a missed dosage and sufficient data were available to evaluate these parameters. Page 743 ARGUS 418-020 4. On 13 April 2001, day 35 of study (DS 35), FI generation male rat 1166 in the 3 mg/kg/day dosage group received 0.94 mL of the test substance rather than 0.86 mL. This deviation did not adversely affect the outcome or interpretation of the study because it was a single event and the amount of overage was small (0.08 mL). 5. On 15 April 2001, FI generation female rats in the 30 mg/kg/day dosage group received the incorrect dosage volume. nl) (nL) (nL) [Dosa 1" sar 1 ok 1 13 Toa | [DossTse100 1 ie Tes] [oss Teas 0Te ee | [sd 1 isae 0Te ea [--Dss0 |"ise 1087 | ii 02 | [pss 1 usso 1"ora 1 hr Tos] [oss Tiss oss[2 om) [Doss 1" "usss 1 oor Tui Tome] [Ds 1 wssrThi 1 14 Ted] [CossTse[ooTia 70s | [oss 1 seo | 00s 1 ur oar | [CosseTse oss[ha osm | [oss 1 ses Tos | 13 1 oa | [Coss 1s[1 ha oa [Coss Tse [ii [0s 04 | [oss Tis [oss | 12 1 om | [Toss Ts aa 1 aa 03] [oss 17isse os2 [ose |om | [ossTs; [093 [13 Tom | [Coss Tse[1 11 7 03] [Coss7[iss oo1 3 os [ossT seaTose [Tha os | [os37 1 isse Tosa | ur 1 oa | [oss7[user oss[ha om | [oss7Tiss [007 |" ia oa] [oss7[see 1 ses) [Ds wor[097 | ia | oa | Cossr sos[ur 3 1 02] `These deviations did not adversely affect the outcome or interpretationof the study because it was a single event for each of the rat; they receivedmorerather than lessofthe test substance and the amount and the overage was small. Page 74 ARGUS 418-020 6. Postdosage observations were performed out of the rangeof60+ 10minutes on the following dates. [2 p | (nghgiiinay[|mNpoveeo[[[| iM1elT |eFRo opnsilaohr[ ass]| (a mineutels || CCasC peco [ ESEE2[ 0 a T=--| [is7msSoTr[I 5 | 0 | wea--| F(iGswwaarror[00 [1 1[i wu]| [NCiosNvovoor[ [10[1 0| | 0 slwwws0 || FCorCpeCcor[0 1 ----ww=--| [I ope[2 ES0[ -- a --| [CFiossNpoEvcoo0r|i 0[ [3 0 | vtieeew || [o7 msBoT r[B0 STSS |5 nYeYaS|| WV To [srNomvseo |0 i 0 1 st1em || FFoosrbmescooro[ [a 0[ 2[ 0 1 +t 1| FFiizeesssoorr[ 0 01 w a w]| [Feasmsoo [2 2 0 0 | wetess 1| v [bFoerecsor[00 1 2 i i 1| [C Foarse7 pseocro |7 0 -- 2| [ 0 -- v1 ie-- s || [ CmY o[I00 |--0--[s --te--ad| [[aDserssor|0 0 1 >ir[di ea || [rma 011 a] Page 745 ARGUS 418020 EE[SE],[EEE mr | Group | (myrgiay)[OMAR [ [h3is1 |eT0 ehmieaRuss| (a mine C[MswaaRkOo [[34 % 0 0 | T ssiteeam || [CilsoaApPrRoOrL[ 2 0 0. 1 loss || CE oapror 1 PS 0 T T SE w SO | [aCamsoonor[0 4[ 0 1 wwwra || [MCoaekwtoo[ [0 0 2 1 1wi || [[sGmMaaRkoo[0 0[ [1 da > || [CZrivvaarroorr 0 0 T-->5Ta i--|1 CFoosaapmoolr[ [210 0[1 "ios |1 [[ooavasmoolr[ --d0 # 0[|S 0 l0 oa1|1 Coeanmmoorr[00[1 3 4wi 1| MChoouvnoe[ o 0[ > 3Tw "ton |1 [[MoAvRoOT[ 0 05[ | sieaww|] M[hCeaisaroor[ 5 1 01 0 so1us || [Cooaavmoor[ [ 0 0 1 2[ Tw ii es| C[aowvaeo[--0o1 [1 5T Ta a|| [Culonwoor[ [0 0[ 12 1Tw a || hg Tare [oto |o 0 3T o i a|| [wCoazarrreor[to0 1 0 1[ [ de a s|| [[oCoaammoo [ [4&02 11 0 | s+ eas || [[CCosairneo[[ 15 o 0 | t st4em || [ono [0 1 5 sles | Page 746 ARGUS 418-020 [nt | mtgion| owe hem Pm en | Group | (mg/kg/day) (minucs) v [osmarROL| 2 11Totes [Csmaror 110 var] [rmaROU 76 0Ties| [CoMAROLT7355 170T6709| [omaror 0 177 a0 [Carol[2 0TT Teviz | [CosaprOU se or [Cosapror 310 51] [Coapror 1 1701 1] [aROr se 170 1 Swe | [20APROL[0 TsTT es | [eMavor 0 0Tow| [CoomnorT077 awe3 d | [CewoNo T171+171] [ommoror 06 TT +iwss | `These deviations did not adversely affect the outcome or interpretation of the study because, except for fifteen incidents,the extent of the deviation was ten minutes or less. 7. Postdosage observations were not recorded for the following rats [cen|Bo [ction | ae | So | see | ime| p oid Sud Number [CmT+TeJANOL|"DS67 | Male |13656 | [CIV 10 [i8JANolL| DSe7 | Male | 1372 | [Vv 30 TiSDECO0| DS33| Male | 13741 | FI [1 | 0 [oMAROI|DSI4 [Male | 103 | [26MAROI| DS19 | Male | s | [2imMAYOI| DS76 |Male |" 1132 | [[0SJULOL| DLIS | Female | 1448 | wv [3IMAROI| DS2s| Male | 1186 | [12APROI| DS3| Male | 124 | [(12APROI| DS34| Male | 1225 | [(12APROI| DS3| Male | 1236 | [[12APROI[DS34| Male | 1237 | [12APROI[DS34 | Male | i238 | [Tv130 [oaApror| ps3 | wale | 1246] `These deviations did not adversely affect the outcome of interpretation of the study because sufficient data were available to evaluate this parameter. Page 747 ARGUS 418-020 8. The estrous cycle evaluation was not recorded for the following rat. CrTw TT 3 Ti9JANOL| DS68 | Female | 13882 | `This deviation did not adversely affect the outcome or interpretationofthe study because sufficient data were available to evaluate this parameter. Page 748 ARGUS 418-020 9. Observations for matemal behavior were not recorded for the following P generation female rats. Dayar Crncutm | ovamonss | SPs Number oP Behavior | Number Group| (mghkg/day) | Sua, Female Rats | Recorded' | Affected [DLi [ i1 6F1E 23.B 45|OffeL male| [DL22[osmaROr[271 45 | an | [DLz2 | 3 [os 1M 45 AR [aOlL| [DL22[o7mMAROL[3Tas an | [DL22[osMAROL[4 as Tan | [DL22[oomAROL[7 as Tan | [DL2z[omar [TEa S [DL smARo Es a [DL22 iomaRor[7 45 1 1 al | [DLT[14FEBOL[1123.|4 lfem5 ale| [DL22[osmAROr[a as Tan | [DL TosMAROI[91 45 [al | [DL Tormaror[sa|s ail | [DL22[osmAROL[a as Tan | [DL22[ooMAROI[414 |s ail | 3 [DL22[TosmAROL [as Tan | [DL22TosMAROL[9145 [an | [Dro[ormaror[7 as an | [DL22[osMAROL[4Tas a| [DL22[oomAROL[6Tas Tan | [DL22[omMAROL [GST a | [DL [3MAROL[1| 4s [al | wv [DLT[aFEBOL[ 1 52 .2.3,45 |ime| [Li[isFEBOL| 1 T1234 |ifemale| Poploirn | 4 a Loa [DL22[ormaror 7 1 as] [DL22[osMAROI[8[a [s an | [DL22[ooMAROL[70 [4|5 an | v 30 |DLI| 14FEBOL[1 | 1.2345 | female] [CoL[ i[ 1ieF 023E .4B 5|OmaL le| [DL22[osmAROL [T as T an | [DL22[o6MAROI[5 as an | [DL22[formar [0 as Tan | [DL22[osmaror[3 as [ar | [Dr22[oomaRor[7 as an | [DL22[omAROr[1Tas an | a Behavior observati[onpotLrecor[derdimaror[Tas an 21. proesmtopvaarltoufmpgurpooamminniogtic sac 43.nroermmoavlaleosftipnugpapcltaicveintyta/umbilical cord 5 normal nursing activity `These deviations did not adversely affect the outcome of interpretation of the study because sufficient data were collected to evaluate this parameter. Page 749 ARGUS 418-020 10. Observations for pups were not recorded for the following liters. [cmon GDorsaage||pDiosoagne | poe | SDiayo | Titer[|SeNumyber| NENT [TV T7730 TiomARor| DL22|ia0 | 15 | `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. XZ = 11. Predosage observations and dosage volume were not recorded for the following rat. [co|nony [copii |poe| So |sor| imi CETT 1 o TJ2TMaRoi] Dsi4 | Female | i030 J This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. 12. Predosage observations, dosage volumes and postdosage observations were not recorded for the following rats [conning| pigion| poe |Sa | ser | mer| Dosage| Dose Dayo Rar [Cor 73 TTAPROL| DS34| Male | 1166 | Vv [zAPRO1IMT aleD|S " 13 225d| [1zAPROITT DS3 1Male | 7227-1235| [ZAPROI|DS3d TT "Male | 1239 | [12DSA 34 P |"R MaleO |I 12] 40] `These deviations did not adversely affect the outcome or interpretation of the study because sufficient observations were available to evaluate theses parameters. There was no discrepancy in the chemistry data, therefore it is presumed that the rats were dosed appropriately. 13. Terminal body weights were not recorded for the following rat. PN r PR Iv I I Dosage CF[Vv TT Day of 30 TO6APROI| DS28 | Female | 1506 | "This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. Page 750 ARGUS 418-020 14. On29 May 2001, DG 0, Fl generation female rat 1486 in the 10 mg/kg/day dosage group was not removed from cohabitation and remained in cohabitation until DG 1. As a result of not being removed from cohabitation until DG 1, the feed consumption value for the interval DG 0 to DG 7 was not recorded. This deviation did not adversely affect the outcome or interpretation ofthe study because sufficient data were available to evaluate feed consumption. ee TET=TG] 15. Feed left values were not recorded for the following rats. eer | Gop | pao |poe| Sy | so | ime [0]7[[2o6APoROrL| DeSsSiT_1| FRemealme | | n131s3 || Tee Ei v [OM0ASARPROOLI| DDSS2?0 | | FFeemmaale || 11556020 || [CoO6IMaApRROOLL|| DD5S228| |FFeemmaailee|| 11559663 || `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. SET | 16. Vaginal patency was not evaluated until observed for the following ras. [crn|Sy|cpp |Bn| St | ser |me| FLO 1 [2MAROI| DSis |Tema | 100| [or 5 mAROr| DSW |Female | lass| [C1V 0 [23MAROI | DS16 | Female | 1489 | These deviations did not adversely affect the outcome or interpretationofthe study because sufficient data were available to evaluate this parameter. 17. Preputial separation was not evaluated until observed for the following rats. [cot |BDoosage||coDopsaigei||DaeoftLias|| SDaryo | sc| aRmalr | [CA oOsAPP ROLR | DO 525I| |TMMaaD lee| S | 2 li0o40s|| QAPROI | DS25| Mae | es: | `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. Page 751 ARGUS 418-020 18. Observations for sexual maturation were not recorded for the following rats [cn|Gy|otption|ose |Sa | sec | me| Dosage| Dosage Dayo Tar FI [[OSAPROI| DS39 |Male | 1059 | [[0CO8SAAPPRROOLI[|DSDS3390 | | MMaallee || G150560 || [V1] OTAPROL | DS20[Ma |l 122e 2 | OSAPROI |DS[|3 Mal0 e| 1222 `These deviations did not adversely affect the outcome or interpretation of the study because these sufficient data were available to evaluate this parameter. [crn[ GA y[om|_epaen| So" |te |" 19. Matemal observations were not recorded for the following rats. [Cr1 o TiajuLor| bLaa Tiss|ar | [Vv [paulnsIls I di v 30 2000NOL | pL iss 1] [235uNoi| pri 1 ises 1] [2sioNor[pLs ss TT 28JUNOI | DL | asst |1] `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. = 20. Clinical observations were not recorded for the following pups. cons | Gry| opin|pwc| Sy | mer | "um Fl v 25JUNOL | DL3| ises | 12 | `These deviations did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. AR ANTEEEE 21. Anogenital distance measurements were not recorded for the following rat. Grow | (mgd Stud Number CmToT 3Tower[ola | Femle | 1474] "This deviation did not adverselyaffectthe outcome or interpretation of the study because sufficient data were available to evaluate this parameter. Page 752 ARGUS 418-020 22. The terminal blood sample was not taken forthe following rat. [ccncre || Gy | opopppoor ||pac| Soa |s|c an | CpTTT0TIOMAROI] DL22 | Female | 13809 | "This deviation did not adversely affect the outcome or interpretation of the study because this was a control group rat and sufficient data were available to evaluate: this parameter. [ome] E 23. Necropsy observations were not recorded forthe following rat. concn|Gry| pgs |poe| Soy | se |ime| CmTwTvTuer] pL | Female | i362 | "This deviation did not adversely affect the outcome or interpretation of the study because it was a single event. EHP 24. The pituitary was not retained for the following rat. [comin [o|t poe| So |soc [ime| CeT1071 0TOMAROI[DL22 | Female | 13807 | "This deviation did not adversely affect the outcome or interpretation of the study because this was a control group rat and sufficient data were available to evaluate this parameter. [omg] 25. The right adrenal was lost during processing and therefore not saved in neutral buffered 10% formalin for the following rat. corgi| Gs |wi|gpose | Sa |so| ir me| CrTv 30 TT ooueor[Dsus| Mae | 1252 | "This deviation did not adversely affect the outcome or interpretation of the study because sufficient data were available to evaluate this parameter. Page 753 ARGUS 418-020 26. The organ weights for brain, kidneys, spleen, ovaries, thymus, liver, adrenal `glands, pituitary and uterus with oviductsandcervix were not weighed and the. pituitary and adrenal glands were not retained for the following rats. I I Generation| Group gid Study sen "1 O8MAROI | DS1 |Female| 1319 |08MAROL| DST |Female | 1320 | Ch ei Mame [o5r Tis MAROL [Ov Tio ooMAROI v 30 [[09MA|RFeO malI e |D1S 5632| 11 MAR O1 [14M1 ARO3 L |MDA ST R | |OFFeeL mmaalleT e | |D 151S 565096]| `These deviations did not adversely affect the outcomeor interpretation of the study because sufficient data were available to evaluate these parameters. 27. Reproductive organs (uterus, ovaries, oviducts, cervix and vagina) were not retained for the following rats. [ccscion| SDoywge[|comDpostagoen |_oae |SDaoy of [ser | imRare| O06JULOI | DGS| Female | 1358 | [ T2ST JUNOI|"DG25 |T Female | i378"| 3 23JUNOL | DG25| Female | 1458 | ww [a26iJUaNO[L]D|GD2G52s5| | FFeemmaallee || 11444863 | | [T297UNOI[DG25 |Female | iS1T__| a U[ terusv and co1 rvix wer3e re0 taine]d. 25JoNor These deviations did not adversely affect the outcomeor interpretation of the study because sufficient data were available to evaluate these parameters. All deviations are documented in the raw data. 4-4 eee TES jnd G. York, PD., PABT Assotfate Directorof Ressdich and Study Director 26Mbk2pe Date Page 754 ARGUS 418-020 APPENDIX H CERTIFICATE OF ANALYSIS Page 755 ARGUS 418-020 eo CentP3hr0oe4n8e:RAe(s8ne1a4ar)cl2h3Dy1t8r0ie02calFaxL:(a81b4)o2r31a-S1ta2o5o3rCorio(e3t16s)i.P23Ag11-Is61n888.0c01. INTERIM CERTIFICATE OF ANALYSIS CenTterset3ACMnoanlPtyrrtooidlcuaRcletf.LearbAeomnrcmaetoon#r:iieuTsCmCRP9Oe9Ar1f3lRu1eof-re3or7oe,cntcLaeonto#:a#t:0e2333-2033 a Purity: 9S5p2%eci Rew omy 1 wm Teenifcanon Viel 1. (CPCalcium 2 Magnesium 2L0000001wwmians 33 SPooadsusmum 5. Nickel +3 0000005wmisn 5 <0001 we 7. IMannnganese 6700000011 wwianns [TouloeImpurity COMS) || i@wmn [[RPeasydblSyolDvSenCts_(T_G_A) [e | Nm oweDetemned 21organic CFAhulonoririoidndees (IC) 21 00001055wweinnns 35. NBriomeide 5. Nimwe +5 00.000809wwmna 5 0006 mms 57. PShuoslpehate Orga Acid1s0 7 0000060mmsm 2TTEAa 2L <<00w1wnmnss 5 HNeBaA FemailAral? +500a51wimmimse 231.. CHNaiyrvdborogonegnen TT"hhTheeeooorrreeetttiiicccaaalllVVVaaalllueee ===23022..9533%%5% 251. 37118593ww0mwam% pd mo45.n_iFSiuvlofAunrnem? T"hTeheoorreettiiccaallVVaalluuee ==06%6.1% 456a32amwmm% | Ton Selective Electrode Theoretical Value =4.18% 349 wisn. % CON 37doc Page 756 Page 102 ARGUS 418-020 : \ eo "P3h0o4n3eR:Ae(sn6e1aa6r)cl2h3y1O-tv8ie03c2 alFaLx a(8b14)o2r3aS1tat-oe1orCo2(it3o5e1g4e3s).,5P0A11Is6no5c0y7. CeIntNrTe3AEMnaRlPyIrtoiMdcuacCltE:LaRbAoTmrmIatoFonrIiieCusmACTPOeEArflORueofFreorAoecaNtcaAeno#La:Yte0S23I-0S33 `Test Control Referenc#e: TCR-99131-37, Lot #: 332 Date ofLastAnalysis: 12/15/00 Expiration Date: 12/15/01 Storage Conditions: <-10C Reassessment Date: 12/15/01 `"TPoutrailtLy C=/1M0S0i-m%pu(rTiottiaels,M4e.ta4l9%i)mpurities, 0.006% + Total NMR impurities, 0.34% + TotPaulriimtpyur=it10y0f%rom- 4all.es8=s94=5.4%3.%84% TNHFFFAPBAA NToHreinpfatlfaulfoulrouoroaorcopebteuinrctyaarnciiocdiaccaicdid PFPA Pemafluoropropanoic acid Theoretical value calculations basedonthe empirical formals,CyFysONH, (MW=431.1) LC/MS Purity Profile: [W Te| won Cee Tamer] wow] "This work was conducted under EPA Good Laboratory Practice Standards (40 CFR. 160) Prepared By: ied 5.zBellrtee Scippist, alyicef Laboratories Baautelerhr Reviewed By: LoahbSiknoraFlta1ohreyrtMyanagHeafrl,er)Centre Analytical LaboratoriesBa2te4 CONO203337.406 Page2012 Page 757 ARGUS 418-020 APPENDIX I ANALYTICAL REPORT Page 758 3M Medical Department Study: T-6889.6 `3M MedicalDepartmentStudy: T-6689.6 = crzrmeens or ---- ARGUS 418-020 Analytical Report: FACT TOX-164 LIMS E00-2738 `AnalyticalReport: LFIAMCSTTE0O0X--2713684. Study Title Oral (Gavage)`TAwmom-oGneinuemraPteirofniu(oOrnoeocLiiatneoratpear(GAePnFsOraItPiFoOnA))ReinprRoadtusctiHoniSgtu-Wdoy eofe Analytical Laboratory Report Title Determination ofthePresenceand ConcSeenmtprlaetsi.onof PFOAFiuorochemicalinRatSera Data Requirement January 7,2002 Author 3M Environmental Laboratory Study Completion Date Atsigning Performing Laboratories Sora Analyses. Sera Extractions 3M Environmental Laboratory Pace Anaiysca Services, Inc--Tio2 Facity Building 2-36-09, 935Bush Avenue 1700Ei StreetSE.Suite 100 St.Pau, MN 55108 MinneapMoNl5i54s1,4 Project Identification `3M Medical Deparment Study: T-6889.6. Argus In-Lie Study: 418-020 Analyt`iIcaMlLRIeMpSorNto:. FEA0C0-T2T7O8X3-164 Total Numberof Pages. 110 3M EnvironmAenFtravlimLnambeonrtaatior|ayhovsiory Page 759 Pare t Page! 3M Medical Deparument Study: T-6889.6 3M Medial Doparmen: Stuy: T6885. = mee `Anal--yti--cal RAepRorGtU: SFA4C1T8T.O0X0-0164 LIMS E00-2738 Anaytcal Report LFAvCsTTEO0X2-17654 Tris page has been reserved for specific country requirements. IM EnvironmentalLaboratory Page2 Page 760 3M Medical Department Study: T-6889.6 Anatyica Rp PLAiCvHF00E-R276348 aMMatic Deparment Su 9995 oo Avaya Roper jFArCT TOK164 GLP Compliance Statement Araiyica Labortory Report Tite: _ Detarmiaton of the Presence and Concatatn of Stay entati"oPnFONAuFmlbuoerroschTe-m6i8c8a0l.6i,n RFaAtCSTerTaOXS-a1m6p4l,esIVS EQ02738 Ta ehiosstnucsnywsanshcSoooodlanemsdoi8nrcuoepmocpFol:ritaeniceee v(diGtLhPn)iSetdSatnatdes4aE0rnCidFrsRonmPeantt7a92P,rwoittehchioan Exceptions 0 GLP compliance: + TTooamrawarertmetoewsoxsdTshhdioIrmeicatenorpofhiasnstpeies(scAuscu.,#T4h1ho8i.s0ns2u0h)cywwceasscddonyessd(riOeWgdFa0nAsCweoTnd-odTaOtXacaoocviargraonwdcsssoprraaor5Siucserypcffpooroaferh,cosnoesffsporaoehoacnhapssaoeswreeasnfaeresisr,eamThes + STDoooemspasuctro,tnynlamnaadtsooanbainlydxopftaahcbeiisdusHtaaomgmpailtneesTwHeexPrcFaOpnRoSEtsnat.naanldyazreddisacncotrdiinncgludetdhnGiLsP, Topon. snot Know a tis me, Fh 2 Taibel/ TornBurhf, Pn...Su Director Gunes 7,200 Bae Dav SaniddA r.PhD. SponsarAapreseniaive ioleefor ehmen. PincaAvail vestgaror Wikan aa an 1.5.--Laboratory Management gBlate ee [BeeI 3M EnvirPonmTentalLaborator-- y ] Page 761 Pace Page3 3M Medical Department Study: T-6889.6 Sera porwennere = ills: == ARGUS 418-020 Analytical Report: FACT TOX-164 GLPStudy--QualltyAssurance Statement AT ET eI iCar UCoS arse TioesvSanys bvonr eapsteoesta3o0e 8EE8ve,enAlt T LTevrsLcGNo uGultEyy Sn Darree a EE [wom [eee |wm | osm| |om |wes | wow | oem E ootT se |Dm| two | eon sahoalider iofrz Eis 3M EnvironmentalLaboratory Page 762 pons Paged 3MMedic.alDepartmentStudy: T-6889.6 SM Medical Dapartment Study: T-6880.6 = messesAnalymtic=al ReApRorGi:UFSA4C1T8T-O0X2-0164 LIMS E00-2738 Anaitcal Report: LFAMCSTT0O2X-713648 Table of Contents GLPCOMPHANCE SIBEMENL....c.corrrmsssssmmnnnd GLPStudy -QualityASSUTBNGESIBIOMEN rvs ES -------------------- StudyPersanodCOnNIaOLIlOS cv A.| I -------------------- FS Chemical Characotfthee RrefierzencaeStUBiSIIoNGnS -------- rcv: 10. S`HDoEseCPonIfiOrmPatAioIBnNaBnAIdARSIBtaIObViINlStyAnalyses... mrm-------- 11" S ADBYIGEIe MOO eA sos Ee -------- --2 mmimm--r DataQualtyOblectivesand DEA NGQHHY DaStueSmmUaarryyo,fQAuTaBIlYS0C8o,ntArNodlRAnEaSlUySS.e.s. vv -- RBSURS........rrcrire 1145 FA oem r er A ---- SitcalMEthO0S ad CAIGUBNONS ....rrssnn SH OfCOO NGOE rrr AT `AAppppeenndidxiBAx::PCrhoetomciocla,lACMhnardamcaentdanenDOdVrCtIoBinIstOzNr(o,Sla)MtBiIon...evn 8 19 EATSp-p8-e4.n1C,d:ExE tractXionoa faPAeACNrBIuYHIoCEr!O MooBNcNtaOnoUeOtsShuer.lFifo.roo.cnhea.mticrsalvComrpousndss 36 rom Serum forAnalysisUsing HPLC-ElecrosprayiMess Spectrometry, (14 pages)... 37 EHTS.P8-L4.G2,E-xtrEactlioneocfFtSlpueorcrtoorcohmesemliprcya,lr(C1oa5mppyBogueMnsd)as rsomsSerumforArnalym sis Us sing: 51 E`TSSe-r8u.m5E.x1t,raAcntaslUyssiisnogfPHotPasLsCiu-m PEelrefclturSoopersctoproormceatotryyra,O(/tn9hMaerasFlsuuoslrofchpoeagmemnsi).ca.a.ltsien 88 ET`SSe.r8u.m5.Ex2t,rAancatlsyUssiisongfHPPoLtCa-sEslieucmiProesprrafyluMaossrSpoecotrcomtetorayr,Ont(1eh1esrpFulaulogrfoechosemn)icaa.lts.ie.n 18 AppendiDx: DoseConfirmation Analysesand Data SUmMAry Tables... ADDE:DEalNSPIOGRUSNIOISX rrr: 87 90 3MEnvironmSenMtEanlvLiarboomreanttoarlyLaboratory Page 763 Pages Pages 3M Medical Department Study: T-6859.6 3M ModicalDoparimantStudy:T-6889.6 ~ meen er ---- ARGUS 418-020 `Agalyical Report: FACT TOX-164 LIMS E00-2738 AnaRlepoyrt:tFLAMiCSTEcT0O0Xa2-71l3684 APPENGiFX:EXBMPICAICUIBIONS. ..ccvvvvvsssmmsrssssmssmsssssssssssssmssssssssss 108 Appendix G:InterimCertificofaAtNBeIY(SIsS) ...........wummmwssssssssssssssssssssssnonss 107 AppendiHx: Report Signature Page... ---- | ] List of Tables Table1. S1p4eNcoivmeemnbesrre,c2e0i0v0e.d.f.r..omArgus Researc----h--LaberetoryStu.dy(418.020) on s Tabl2e. Specimens recefriomvAreguds Research Laboratory Study (418-020) on Table 3F.ESpecimens received fomArgus Research LaboratA ory Sty (418.020) on Tabl4e. Specimens received fromArgusResearch LaboStruya(6t18.o02r0)oyn Table L5.ECharacterizaotfitohneAnalytical Reference Substs ance in Study n10 Table6. PGenerationRatSamplesAnalyzedinStudy FACT-TOX-164 v1 Table 7. Target lons Monitoredin 3M LabOTR(0ryARYSES......vvvvvt Tabel8. DeterminationoftheLOG intheAnalysesofRat SeraEXIACtS ...........15 Table 9. MatrixSpike RecoveriienstheAnalyseosf Rat Sra EXIGE... 16 Table 10.RCOhRaratctneroiftizheartCoinetoronelMatrricresmUseedfoerSemraeAnarlysmesimnSt--ud--y --t Table 11. CharaofcTestt SuebstrancieinzStuadyFtACTion TOX-164...cvv 18 Table 12.DoseConfimation Analyses ~Extracted 11/17/00, Analyzed 1/270..... 87 TTaabbllee1134..DDoosseeCoCnofnifirmmaattiioonnAAnanlaylsyesse-s~EExXtaracctteedd 1011//1277//0010,,AAnTaalYy2z6edd 01/2301 ......1/28/0..... 88 89 Table 15. TOX 164Data SummofaPrFOyA Conceniration--Rat Serum (gL)... 89 3MEnvironmUendtEarliLoambmoarnattaolr|ya.horaons __ Page 764 [2 Page 3M Medical Deparment Study: T-6889.6 3M Medical Dopartmant Study: T-6889.6 = cmos orAna--lyt--ical AReRpoGr:USFA4C18T-T0O2X0-164 LIS E00-273%8 Anayical Report: FUAMCST0T0O.X2-713684 `Study Personnel and Contributors JStoundyBDuilreecnttor, Ph.D. 33BuMMilCMdeoindrgipco2ar2la0tD.ee2Tp5oa0xri2cmoelnotgy St.Paul, MN 55144 `Analytical Chemistry Laboratories S2o0raEnAvniarioynsmoesntal Laboratory (9M Lab) Lisa Clomen, PrincipalAnayical investigator 3SpMoCnosroprorate Toxicology 3SBuTMi.lMdPeiadnugilc,2a2Ml0ND-e25p65a10r42t4ment DReapvriedsSeanntdaetrisv,e Ph.D.. Sponsor SPoarcaeEAxnsaicytsioanlsServices, Inc --Tiar2 Facity 3M Lab Contributing Personnel KiRihsotenndaJ.DiHcakn"sen, Ph.D. MHaarroilednO.M.JoHnisnogn" Corman ressavo eaons KolJl. Kuehiwein BSoabllWAy.. LWiynndnae"" Locationof Archives. EAnlvoirriogninmaelntraalwLdaabtoar,aptroortyo.colT,heantdesatnsaluybtsitcaalncreepaorntdhaanavleytbiecaelnraerfcehrievnecdeatsttahneda3rMd reserve asracmhpilveesd. aat twheell3aM5tEnhvoisrpoencmeinmteanlspLeabrotraaitnoirnyg. otheanalytical phaseof thisstudyare IMEnvironmentalLaboratory + ___ Page? Page 765 SH Dept STR acornsu pdr a E EE = rere =~-- ARGUS 418-020 A ---- Introduction and Purpose SF foiuroroichnempe i(ca iaClnainstraeytsegsraSseaa Pemorptlsheesonnt)LaF kPienboforoprmtmhoies ns3McsStudyoy "OrAauln(bGTaevaCgeA)BTwo-OTte 2 i etSioooor)sereslMenEeSr Las aT S Spe1cirmeen RaecleipEte anLd MaTinteMne anHcr e TAT ironsnot aae eresa e a ee TTeatee,.SSppeeiennanevs ormArg ReeartyShey(162)on [iSo mam|Dwo orn[|s ou5w r || [[C(oDmwmi| o|sw5 ] oiy| 3M Environm3eMntEanlviLraobnomraanttaolrLyaboratory Page 766 Pace 8 Page 8 Mts Dope Sd T6H9 DamaTorst ~ iemeees wr ---- ARGUSa418-0. 20 61 J rp c FBCTTE O 184 Talo,Sparsesa vsets apySty 5m 18 April,2001 [v= | T T--s e ----] ] -- C TTo | C v v = Yi. vanera AG LESHYS SE [omen 13July,2001 | ren| tour| [mrss | Goorin|] A maton ------ [oom ow |ome | wows | on =| v V1T T Ce T] s 3M Environmsenttaml Ltaboratory a Page 767 rans Page9 3M Medical Deparemen Sud: T-6889.6 MoccaDeparmentSuey: T6885. ~ imeees erAssyial AReRpoGrU: SFA41C8T-T0O2X0.16 Lvs E00-2738 Arata Rep(ACoTTeiOrnKz1rta6s4 {rEoonnmvticooonmmmmeaenrttcilicasLl uSasouebcneossavroniadlabanrsao6lry0s1ee6ss0epaeneddrminaoAmdLadEnueNndTgoAF.AeGST-ucTmOrKeo-e1ra6n4lyeveceeordreiconbgseined GLP equrements. Chemical Characterizationofthe Reference Substance "CHG Nuno: 3025.28 `Ammonium perfluorooctanoate pChaaGrhmoeirnciaaccaclchaaFroanrcatmeusrliauz:saetGidoFnnf(hoCsrOumOaNytHo:1sopnetsherreefdernenacebsusbsttaon[ mcebaomomm.a-- rium -- Table. CharofathecAnsitytclrRefzerenaceSutbstainceoinStnudy FACTTOX-164 Tonepso0n000|0| rSeoormraoonss. ) [E | m meme| SE cre= epermsw Tw] 3M EnironAmeMnFanlvLiambnomraanttoalryLaboratory Page 768 Pace 10 Page 10 3M Medical Department Sud: T-6889.6 = meen wAnaolyrticeal ReApoRrtG:UFSAC4T18T.O0X2-0164 LIMS E00-2738 MModiclDopaimantSuc: -63606 rE emer `Sample Preparation and Analysis AnaReptort:iF[ACcTrTaOXe1l84 ---- Dose Confirmation and Stability Analyses uD(conosnecgecniotnrofatinimoaint,eiDpoanhyaans0deSosatfabbtiihtlys,taanynad:lyDhsaeeysrw1es0eurSlaetbsiaplrteype)rceosrlelneoctfnteeddeiosontnAsp1rup0besNntmodavinecxeronDd.boedsrDeo2s0s0ea0mples Co`ncumraetdioponrtaonsdtsutadbyilnyastaimopnl)eswerenot alyzedaccording 0 he GLP (analyses hD2e7ossNeeoscvoaenmmfpbilermrea,stwi2io0in0ha0M,niadlnsdtaowbnaeltyree-,sexthireraancceltoinoxsnwpteerrerfpotrechmreefsdioarommnnpel1deg7osnJaun17uaNsroyv,hiee2m0b0onen1prba,gy2i0d0iu0t.ing procedure, ETS-8-4.1. For onedosesolutionconcentrasatmiploen, a matrix spikewas. pGHErTiPeSLpg.aCa6r-:es.Ed1oS(wtMaeSorpA.oSpu.sIrneoldTlhxfecoiar1isdmne0ossats0,retnusgmseae/monlmptuLiya)olebsnpyaawdnreaarmyi eestaenel sart.lshyu Daezenectt ddoanvaicnei learelnsydtun trdsiacaiaeglnonscuos ncnedxrita irioaocnftipsm hetdedtheneCssp imcpuerioitkel bihnenoudgsdstie isnnhge. used are located in Appendix C. oSAqenupraoalGrrmAtonhumaplsyotsuwdeoaysftpmeraaolnteoacaloynlz,doendalmiyasliaasrrupamthsasasemeapstsluaedmsypr(iSeosemewtheTeraoPblrGeaenndefororarnmtyioornelGierncfotouerpdmaf1,toirGoranno)a.ulpyAsVne,. `npSeerraiaosmmmaanecfemoulwreiporuydolcehxartetroamhcastt(eoVdgIBrgEa)ip.nhnySi-anegmlopelncer1oe4sxpJarucantyeas,nw2d0ee0rm1emauasnisanlsgyaszpenedcoutnsrpioanmgierthiriynggh(:HrePaLgCe:nt EweSreSqNua)niinttheedbmyaelxitemraelacctailobnrmaotodna.versus anexactedsera cue.PFOAlevels Table. PGenerationRatSamplesAnalyzedinStudy FACT-TOX-164 [Cosmo | ooier |Toms | I-- a Gov |[MFeo [ |ms 0 e|| BL -- 3M Environmental Laboratory Page 769 Pace 11 Page 11 3M Medical Department Study: T-6889.6 30Medial DeparStty:mTe68n89t ~ errno rm ARGUS 418-020 Analytical Report: FACT TOX-164 LIMS E00-2738 AnaRlepoyrt:tFLAMiCSTcTEO0Xa-713l684 Method Summaries FEonlvliorwoinnmgeinstaablriLaebfodrateorsy. cDerotfailtehdpedmeiasctorihpntsiounsseodftdhuerimnegtthhiosdasnaulsyeidcanlstthiusdystbuydtyhaereIM located in Appendix C. 3 Environmental Laboratory PrepanaToRYMETHOD + FElTuSo-ro6c4h1e,riEcxatlraCcotmiopnouofndPsotfarsosmiuSmerPuermffuoorrAonoaclaynseissuuisfionngatHePLoCr-OEtlheecrtrosprayMass Spectromeny" + HEPTLSC--8E4l2e,ctErxotsrpacrtaiyoMnasofs FlorochemicalCompounds Spectrometry" fom Serum for Analysis using Apaniarliyntgicral seampalweagsswaederdeenedxttioraactleadboursaitnograysnaimopnl-epaainfndgtehxetarnaacltyion pornopceaduirew.asAn onipnatortioninterdogiennoemvetahpy-oterrubanuttiyoc-eyrt.hEersc(VhIeBxEt)r.acTtheedlMaIboBrEatpohraysseamwpalserweamso.ved and put reconstituted in1.0mLofmethanol andfiteredusinga 3 mLplasticsyringeatached 1080.um2nylon filterinto glassautovials. Anavyrca, Memon + EiTnSS.8e:r5u.m1,Ex"tArnaacltyssUissoifnPgoHtPaLsGs-iEulmePcterrofsuproaryoMoascsiaSpneecstruolmoferotrnOyathteer Fluorochermicals + EinTSSe-r8u5m2,Ex"tArnaacltyssUissionfgPHoPtLaGss-iEulmctPerrofsuporraooycMteasnsesSupiefcotnraotmeetoryO"ther Fuorochericals Analyses wereperformedbymonitoringaneofmoreproductionsselectedfrom a raFnoae rleyxsoatm,pawlaen,s mfiorolanegccmhueainratarcetideorfnius4rtt1ih3ce,rostfeoalpeprcaotrdetudiccaueslaitrohnfel1pu6or9riom(caChraeyFm)iio.cnalfTourhsePinFcghOaHrAPacL(tGCe//rFiE1sSt1IiCcM0oS0/n)MS. 169 was monitored for quantitative analysis. 3M EnvironmtenttEarliLranbmoararttoarty ahs Page 770 bana 12 Page 12 3M Medical Department Study: T-6889.6 WMMedical DoparmentStudy: 6889.6 ~ meen orAna--lyt--ical RAeRpoGrU:SFA4C18T-T0O2X0-164 LIMS E00-2738 Analytical Report UFANCST0T0O.X3.713684 ANALYTICAL EQUPMENT Tshtuedfy.olowingisrepreseonftthaestetitivnges used dutrheainalnytigcal phaofstheis LAniaqluyitdicCalhrcoolmuamtno:grKeaypsht:onHeewiBeett-aPsaicTMkaCryds2S6e6ri0emsm11(050uLmi)quid Chromatograph system MCoobliulmenptheamspeercaotmuproen:en3t0s:C `CompConeont AmB :2epmtMhaaomnm!nonieumancettate IFnljoewctriaotne:vo3l0u0meu:Li1m0inuL Solvent Gradient: 8.0 minutes Time (m0i0nes) %108% 5150 e10w% 7850 e10n% MsyasstsemSpectrometer:~McromassAPIMass Spectrometer Quatro I" Triple Quadrupole SCoofntewaVroel:taMgaes:s15Ly-n6c0TMV 3.4 GNooldies:ioEnlGeactsoEsnperragyyN:e2g0a-ti5v0e0V E`lSeocutrrcoedBe:lo2c-ksTpermapyerature: 150C +10C `Analysis Type: Multile Reacion Monitoring (MRM) Table7. TargetlonsMonitoredIn 3M LaboratoryAnalyses PFOA | a0 1690 THPFOS | aro | 200 3M EnvironSmMenEtnavliLoanbmoreantaolrLyaboratory 3 Page 771 Page 13 Page 13 3M Medical Deparment Study: T-68896 0 Maal Dopartment Stuy: T6869 ~ omens r Analy= tical ReApRorGt:UFSA4C1T8T.O0X0-0164 LIMS E00-2738 Ansiytcal Report: LFASCTET0O0X.-2176348 DevistionsiAmendments "There werethreedeviationsandoneamendmentfromthe originalprotocol. ADepvpieantidoxns8.and amendments from the original protocol and methods ar included i the Data Quality Objectives and Data Integrity The folowing data qualty objectives (DGOs) were indicated i the protocol for ths study: + Linearity:Thecoeffofidecteirmeinantiton(1%) equaltoorgreater than0.990using 1/x + Lhiweamigichattlilnogrf.aQtuiaonnctiutravtei,odnef(iLnOeGda):sTthheelLoOweQsstSeaqnudaalrtdo tthhaetlobwoetshta2ctceipmteasbltehsemtaatnrdiaxrd in blankand iscalcuwlhtahnt3e0d%ofthe expactedconcentration. + pArcocveipdteadtbhleeyAacrceurqaucaynt:itQauteadlwitchoinnttohlassaemlpelcteesdacraslbrreaqtuiiornedatnogmee.et 225% accuracy, + CpornoftiorcmaawtiolrbyeMietthno.ds: I aconfirmatorymethod is sed,an amendmentfo the + Demonstration ofSpecific: chromatographic retention time PFOA ideiiication il besubstantiatedby (approximately 7 minutes),by the characteristic primaryion (613)andthecharacteristicproducton (169). FDEata Summary, Analyses, and Results ---- DEartvairqauamaeymoabljeLcatbiovreastoorrytphreoatnoacleyltfiocralFAphCaTsTeoOfX-th1i6ss4t(usdeyooAutpipneendadbBo)vewearnedmien tthwoihSM the exceptions noted in this report. 3MEnvironmAeWntEarluLiambmoroanttoary.ahoors Page 772 pana 14 Page 14 SO, SP rorr nnS, eIvLiAeS = emmeses wr o-- ARGUS 418-020 SummaryofGuntyControlAnsytesRests +Linearity: Ce alplrrtona Sangrev : uaaae ofa moto reasowas baEte on or Thecoefficientofdetermination (1%) ofthestandardcurvewas20.990. on ee esate ovisLot, oe Or re raa ar c areoenSvaalrSt)staLyraeiPd.oeOracaACrSn,aygee thatoftheextraction blanksweredeactivatedtodisqualify adata rangethatmayhave forsale eer + LimbactGusstaion (L0G) The LOoGInaa q. 0lovstfEsreotpelavlsaaslra T Tia t#ib8.bl eDltoe wr).inatons atheLOG nthAyesof Srxcs [oomosnon|| wroonr|srmovmroommt|| + LBloannka 3 Sarkmre ctr var tron rcp of . dT emure RS A Ma Soken:Aho pre matea ereertS e ra satyh R cntSoaacrsomSnairetsioa aotoor Sr Toiics anisecooned os shovedrt `completetodetermineextractionefficieaston aficiny ncyandrecovery. vrs saci Toescott ound mt pk ectvari 28% `theoreticalconcentrationversusextractedmatrixcurves.(see Ta#b 9bel lowe). were 3MEnvironmentalLaboratory Page 773 rants Page 15 iDepry 705 Stes Orriy Ta ~ meen A orm ARGUS418-020 eraaHRTr Table 9. Matrix Spike Recoveries intheAnalysesofRatSeraExtracts me Tmraen|| ShemEa, Prorto Zogm. [| ex ow Ses _songm.|_emm | ~ Toryiree oT = EEC oon ST -- + SSr aSFelurlcecmB soooentpineuisngecsalibrrtationen vesr(i(ofEicEr7atoi0on0ms)sr e pmBeikesedtio nttheesconttrolergmI aptrsisxy. p osrstSusaeerl, KS A ElgsHTm omh etDi",sy S wt oe y8N pesSrUar pIeoSnUiLseesSoIsSA SR Teor e mse R ocotanA nttnrasrse sa uumoittteoysn: PEOOe ANs00ro0t .0ro0y1,0.. 1 "PFOAresults(thoseobtainedusinglot #332)havebeencorrectedforpurityofthe om SSo erSpepntoeenmoSerotkmot ermt:eetngnorrtagPAEFOOeELGrToweti eriinrnSneupiea dt BR maleandfemale PFOAlevelswereobservedinthesedata. Detailedsampledata Wm 3MEnvironmantalLaboratory Pana 18 _ 3M Medical Department Study: T-6889.6 ~ mens Analoytriceal RAepRorGt:UFSA4C1T8-T0O2X0-164 LIMS 00-2738 aM Medical Department Study: T6689.6 Analytica Report: FLAMCSTETO0X0-17634 Statistical Methods and Calculations `StAaptpiesntidciaxlmFfeotrheoxdasmwpelreecemlictueatioontsh ucsaeldcutloagteinoneoraftmeethaenssearnudmsstaanmdpalredcadetvaiaitnioFnAs.CTSes Tox 64. Statement of Conclusion SeUrndaeorftahiecroantsdditoisoensdowfitthhetphreetseestnstusbusctianec,edhuerfinlgortohcehenm-ifceaplhPaFsOeAowfathseosbtusdeyr.vedinthe References None 3MEnvironmAenhtFalrLiaboarantotry.aportons . Page 775 bana 17 Page 17 MeinDeparment Sty: Ts Sas CorSvmar avenrs = emeAerrieABRGAUSSL4i1E8s-0E2Dc0 o,ese Arn opropdaTe sc00 AppendiAx: Chemical Characterization, and Control Matrices Ty al10,Craa racaizntonofthContr MaticUsdforSrsAnsaes [Same 1Someaen| [Epmi| onandamwe e| |C Swoago e nd |e Frezn en20s_| [[Crom| caioreireosesrr y| [Prysicai|DesRcarrspensmo|n T4al1. Carsten ofTsSutaceinSat FACTO: pfeye n ra [twep coatiors|ese [[Corromsicaotisoete| |r|| EEREE Emi atEntommaasy ) Page 776 rows ro1e8 3M Medical Deparment Study: T-6889.6 3M Medical Department Study: T-6885.6. = mess `Ana--lyti--cal ReApoRrtG:UFSAC4T18T-OX0-0164 LIMS E00-2738 AnalyticalReport:FUANCSTT0O0X.-2176348 Appendix B: Protocol, Amendments, and Deviation(s) 3M EnvironmuetntEarlwLiambmoarnattoar|yahortons Page 777 Paon 19 Page 19 3M Metical Deparment Study: T-6889.6 TT nav Ro HALBre ProtocolFACT-TOX-L1I6M3S E00-2738 Oral (Gavage) Two-Generation (One LitePrhpaesreGeTnietrlaetion) Reproduction Study of Ammonium Perfluorooctanoate (APFOIPFOA) in Rats PHASE PROTOCOL Performing Laboratories 3M Environmental Technology & Safety Services `3M Env9i3r5oBnmuesnhtAalveLnabuoeratory St. Paul, MN 55106 1P7a0c0e EAnmalySttirceaelt SSeEr,viScueist,eIn1c0.0 Minneapolis, MN 55414 LabFoArCatTo-rTyOPXroNjuemcbteIrdTenOtXi-f1ic6a4tion 3M Toxicology StudyNumberT-6889.6 `Argus In-liLfIeMStSud0y0N-u2m7b3e8r 418-020 `3M EnvironmentalLaboratory 3MEnvironmental Laboratory Page 778 Page 10/90 Page 20 3M Metical Deparment Study: T-6889.6 TT RenHep EAE 1a ProtocolFACT-TOX-L1I6M4S E00-2738 Study Identification OArmamlo(nGiavuamgeP)erTfwlouo-rGoeoncetarnaoiaotne ((AOPeFLiOt/tPeFrpOeAr)GiennReartastion) Reproduction Study of Sponsor `Sponsor Representative Study Director Phase Locations PrincipalAnalytical Investigator (PA) Analytical Tasting Laboratories Proposed Phase Timetable Analyses Start Date Analyses Termination Date 33MM CMoerdpiocraaltDeeTpoaxritcmoelnotgy BSuti.lPdaiunlg, 2M2N0-52E5-10424 David Sanders, PhD. 33MM CMoerdpiocraaltDeeTpoaxrimcoelnotgy BStu.ilPdaiunlg, 2M2N0-25E5-1042.4 Telephone: (51) 733-5226 John Buterhoft, Ph.D. 33MM CMoerdpiocraaltDeepTaorxtimceonlto.gy Buikling 2202E-02 STte.lePpahulo,neM:N(65551)147437-1962 Lisa Clemen 3BuMilEdninvgir2o3n6me-n0t9al Laboratory 9St3.5PaBuuls,hMANven5u5e106 Telephone: (631) 778-6176 P1a7c0e0EAlnamlyStitcraleSSeeErtv.icSeusi,teIn1.00 Minneapolis, MN 53414 May 28,2001 November 30, 2001 SM EnvironmentalLaboratory 3M Environmental Laboratory Page 779 Pagezotdp | Page 21 3M Medical Department Study: T-6889.6. TT aie ARGLYIMRS EA00O-271R3684 Protocol FACT-TOX.164 1. Stor AOrmamlo(nGaivuamgeP)erTfwlou-oGreooncetraantoiaotne ((AOPeFLOi/tPeFrpOeAr)GiennReartastion) Reproduction Study of 2. Pumpose o"fThFeOangaelnyetircaatliopnhamsaeleoftahnidsfsetmuadlyeraitsdeesxipgonsededtoaenvdalFu1atgeelneeverlastoiforPanFpOuApsinpsotreantsiaplelcyimens e`AxnpaolysteidcatloSAerPvFicOesinInAcr.gTuiserInII-lffaeciSlittuy.dyS4e1r8a-s0a2m0p.leSserwailsabempainsalwyzieldbleat extracted the 3M au Pace Environmental Laboratory. Data quality objectives for this study are indicated in section 1 3. REGULATORY CoMPLANCE "`TAhgiesnsctyudGyowoidllLbaebocroantdourcytePdraicntiaccecoStradnadnacredst:heFiUnnailtReudlSet,a4te0sCEnFvRirPoanrmte1n6t0a/lPaPrrtot7e9c2t.ion 4. Quaury Assurance "rTahwe d3aMta,EnavnidrofinnmalenrteaplorLtatboordaettoerrymiQnuealciotmyplAisasnucreanwciethUrGioowdilLaabuodriattohreysPtruadcyticcoenduct, regulations, this protocol, and 3M Environmental Laboratory Standard Operating Procedures. 5. REFERENCE SUBSTANCE FOR FACT-TOX-164 Ammonium Perfluorooctanoate (APFO/PFOA), CFisCOONHC"AS, 3825-26-1 "The target analytei perfluorooctanoate (PFOA), C/F1sCO0 6. TesrSussTance Ammonium Perflurooctancste (APFO/PFOA), C1FisCOONHLY, CAS 3825-26-1 7. Testsvstem Fwievreedgoisveengrtohuptses(t3s0uibssetxagnrceoubpyforoaal (tgoatavlaogfe)30r0o)uto.fAmfaleeracnohdafbeimtaatlieornaotsf(tPheGPeneration) iSGeevlneeencrtaettdhieofnrs,oammfieFv1edogGsreaongueeprsalteovifeolmnaoplfuetphasefndtoefscteomsnautlbiesntauatensdce(e3avsa0l/tushaextii/rognrr.eosuFppIecfGtoiervnaeePrtaottGaielononefrra3at0si0o)wniwlsililbleesbea: nd 2Ga2msp. Aou scshedfutolrefdepmsaaclraeisf)i,crebl(oaftoedrancuodmipmvleertiosn ofathwemecorbpeacbiotllaltciteoendpasenridodshfioprpmeadle0s3anMd day Environmental Laboratory. SM EnvionmantalLaboratory 3MEnvironmental Laboratory i Page 780 Page3otdie, 11 Page 22 3M Metical Deparment Study: T-689.6 TT Anion RR EAH 16a ProtocolFACT-TOX-L1I6M4.S E00-2738 Number of Specimens per Dosage group and Dosage Levels eTwT Ho To | [Cw[o +T [o | [e 15o | oe | [ww oo Tw| | CvT To wTs | Fo(3r0 tmhgi/skpgh/adsaeys)tufdryo,m4t0he--1P0Ge0nseerraatsiaomnpolnelsyfwriolmlbGeraonualpyIzeVd.(1A0nmge/qkugal/dnauym)bearndofGrmoaluep V. thanednufemmbaelerosafmspalmepslewislalnbaelyrzaenddmomalyybseeiemcptleedmfernotmetdhae ttwhoeddiossceregtrioounposf.thMeodPifAiIcaantidontsheto Study Director. 8. SPECIMENRecErT ISieerpa shpecaoimnseAnpsreiwler1e8,r2e0ce0i1v.edSefrraosmpAercgiumsenRsewseearrecshhLiapbpoerdabtoyrioevse,rInnicg.hat ctohuerieenradonfdtwheerienrneucmebievredsfrorozneunmobnerdsryascsci.gnSepdebcyimAerngsusweRerseeiadrecnhtifLiaebdorwaittohriscasm,plnec.n) uupomn r(be1caebierpte,rquesst rAlelgisspteerceidmewnisthsetnhte t3otMhEenv3iMroEnnmveinrtoanlmLenatbaolraLtaobroyraatnodrtyrwanesrfeerreedcetioveadfraenedzetrrafcokresdtorage. sapcecocridmienngionsptehcetSioanmpfolredTarmaacgkei,ngreScyeisptte,mstSotraangdea,riddeOnpteirfiactaitnigon,Prcohcaeidnuorfec.usDettoadiyl.s of protocolsanddatawillbepresentedinthephase report. 9. PREPARATORY METHODS E'HTPSL-C8-4El,ec"tExrtorsapcrtaiyo/noMafsFslSupoercotcrhoemmeitcrayl"Compounds from Serum for Analysis using. Arneaalgyetnitcailsaadmdpeldestoaraeleabxoarcattoerydsuasimnpglaenanfdont-hpaeiarnianglyetxetriaonctpiaoinrpiropcaerdtiutrieo.nAednionno-pmeatihryiln-g etevra-pbourtaytlo-retuhnetirl(dMryB.EE)a.chTheextMraIcBteEdelxatbroraactsortyhseanmrpleemoiveredcoannsdtiptuutteodntion a1.n0imtrLogoefn `methanoland iteredthrough a 3cm"plasicsyringeattachedt0 a0.2um nylonfilter nto. glass autovials. 10. ANALYTICAL METHODS ESTeSr-u8m:5Ex,t"rAancatlsyussiisnogfHPPoLtCa-sEslieumctPreorfslpuroaryoMocatsasncSspuelcftornoamteetorry"other Fluorochemicals in `3MEnvironmentalLaboratory 3M Environmental Laboratory Page 781 Pagesor|gilg, Page 23 3M Medical Department Study: T-6889.6 ~ meen oArnal--yti--cal ReApoRrtG:UFSAC41T8T.O0X2-0164 Protocol FACT-TOXL-I16M4S 00-2738 ApnrailmyasriysiiosnpcehrafroacrtmeerdisbtiycmoofniatpoarritnigcuolnarefouromroocrheempirocdaulcutsiiongnsHsPelLeCct-eEdSfMroSmMaS.sinFgoler: example, molecular ion 413, lected as the primary ion for PFOA (C;F15CO0) analysis, isfragmentedfurtherto produce ion 169 (CFy). Thecharacteristic ion 169 is monitored for quantitative analysis. dMiisncorertimoondioffitchaetiPonAsLt the preparatory and analytical methods may be implemented at the 11. DATA QUALITY OBJECTIVES 11.1 Linearity `The coefficientofdetermination (r) of the standard curve must be equal to or greater than 0.990 using 1/x weighting. 11.2 Limits of Quantitation (LOG) de"fTiheneLdOaQstwhilellbooweesqtusaltatnodtahredltohwaetstsbaoctcehpt2tabilmeessttahnedamradtriinxtbhleacnaklaibnrdatiison curve, calculated within 30%ofthe expected concentration. 11.3 Acceptable Accuracy `qQuuaalnittiytactoendtrwoiltshianmptlheessaerleecrteeqduciarleibdrattoiomn rean=gee2.5t% accuracy,providedtheyare 11.4 Use of Confirmatory Methods Ifaconfirmatory method is used, an amendment to this protocol will be writen. 11.5 DemonstrationofSpecificity, etc. c(PhaFaprOparcAotxeiridimesantttiiecfliypcra7otidmouincntwuitilelonsb,e(b1s6yu9bt)sh.teancthiaartacetdebriysctihcropmraitmoagrryafpohnic(4r1e3t)enatnidonthteime Minor modifications to the Data Quality Objectives may be implemented at the discretionofthe PAL 12. SUB-CONTRACTED ANALYSIS sPpaecceiAmneanlsyftoicraalnaSleyrsveisc.eA,lIlnec.xtTriacetredIsaamcpilteys)wiwlilllbebse pherifoprtpmoitenghdethe3MexEtnrvacitrioonnmoefntsaelrum LEnavbiorroantmoernytfaolr aLnaabloyrsiast.orPyacSetaAnndaalrytdiOcaplerSaetrivnigcsP,roIcnce.duwriellsfandothaellflolalplopowiicnagwblPeac3eM Analytical Inc. Standard Operating Procedures. PSS-Admin-01 Quality System PPSSSS--AAddnmiinn--0064 LTraabionriantgoRryecFoacridliFtiielss Maintained by QAU PSS-ARC-02 DispositionofArchive Materials 3M EnvironmentalLaboratory 3M EnvironmentalLaboratory . Page 782 Pagesolgy Page 24 3M Medial Deparment Stuy: T-6889.6 `AnaicaRS PAC1H64 Protocol FACT-TOXL1I6M3S E00-2738 PSS-ARC-04 PSS-DC.05 ALracbhiNvoitnegboDoatkas,, SLpoegcbiomoeknsa,nadnLdoPghboonoekLsogs PPSSSS..0DPMS--0031 UStsaetisatnidcalMaEivnatleuantainocneooffDUalttraa Turrax T25 Homogenizer PPSSSS-OOPPSS..0032 HRaazwarDdaotuas Waste Disposal PPSSSS-OOPPSS-.0054 UUsseeoafndCoMmapirnteesnsaendcGeoafseNs-iEnvtahpe LAanbaolyrtaitcoarlyEvaporator PPSSSS..0OPPSS-.0076 CUlseeanainndgMNaoinn-tdeinsapnocseabolfeNVAolNuOmpeutrriecIPIipWeattteesr. Purification System PSS-OPS-08 PSS-OPS-09 LDeavbioartaitoonrsyfCraolcmuElsattaibolnisshed Procedures PPSSSS--OOPPSS--1110 UAnsaelyatnidcaClaDleifoirnaittioonnosf a Bottke-Top Dispenser PPSSSS-.OOPPSS--1143 UUssee aanndd CMaaliinbtreantiaonncoefoSfyLraibngReesfrwiigtehraatoHrasm,iFlrteoenzeCrhsa,naenydAOdvaepntser PPSSSS-.OOPPSS--1156 PSS.OPS-17 UGsieaasnswdarMeaClienantinegnaofntche Fisher Scientific Isotemp Freezer Use and MaintenanceofUrasoric Water Baths (Soricators) PPSSSS..OOPPSS--1284 UUssee aanndd MMaaiinntteennaanncceeooffVaoDretseixccSahtaokrers PPSSSS.-OOPPSS-3312 PSS.OPS.37 OOUppseeerraaattniidooMnna,,iMMnaatiiennnttaeennncaaennccoeef,aSanhndadkCeCaralsliibbrraattiioononfofLapbHorMaettoerrys and pH Electrodes PPSSSSMMCC..0012 RPeucrecihpatsionfLgoabfoLraabtoorratyoSruyppSluipepslies PPSSSS--MMTTRR-0012 CCaalliibbrraattiioonnooffCCeerrttiiffiieeddTWheeirgmhotrmSeetters/Thermocouples PPSSSS-.MMTTRR.-0056 VCearliifbircaattiioonnooffECgaplebnrdaotrifoPniopfetttheesEppendorf Pipetior PPSSSS--MMTTRR.0078 PSS.MTR09 NVeeriwfiEcqautiiopnmoefnCtalQuiablriaftiicoantiaonnd(U1s0.ePoQf.An0aQly)tical Balances Use and Maintenance of Fisher Scientific Electronic Temperature PSS-Safety-01 GMeonneirtaolriLnagboDreavtiocreysSafety PPSSSS..SSaaffeettyy--0024 UEsmeeragnedncMayiEnvtaecnuaantcieoonfBPiroolcoegdiucraels Safety Cabinets PSS-Safety-05 PSSTS01 Use and MaintenanceofLaboratory Fume Hoods Training Procedures 13. SSTtaAtTiIstSiTcaIlCAmLetAhNoAdLsYwSiIlSlbe limited to the calculationofmeans and standard deviations. Examples ofthecalculationsusedintheanalyseswillbeincludedinthephase report. `aM EnvironmentalLaboratory 3MEnvironmental Laboratory Page 783 PageBolFR Piaige 25 3M MedicalDepartmentStudy:T-6889.6 ~ meses Aonalrytmical RAeRpoGr:USFA4C1T8-T0O2X0-164 Protocol FACT-TOX-L1I6M5S E00-2738 14. RepoRT A report ofthe analyte resus wil be prepared by 3M Environmental Laboratory. The report will include, but not be limited to, the folowing, when applicable: 74.1 Name andaddressofth facilityperformingthephase. 14.2 Datesuponwhichthephasewas itatedandcompleted. 14.3 ALabsotraattemoernytoPrfacctoimcpelSitaanncdeardbsy.the PAI addressing any exceptions to Good 14.4 aObmjeencdtmiveenstsantdoptrhocoerdiugrienaslapshsatsaeepdroitnotchoel.approved phase protocol, including any. 14.5 Icodnednitti,onpsoufrusie.stabilty and the solubility ofthe reference standard under the 14.6 A descriptionofthe methods used to conduct the est(). 14.7 A description ofthe specimens. 14.8 iAntdeegsrcirtiyoptfitohnoefdaatnay. circumstances that may have affected the quality or the 14.9. TsuhpeernvaimsoeoryfptehresoPnAneIlainndvotlhveendaimnetshoefpohtashee.r scientist, professionals, and 14.10daAtad,escarsiupmtimoanorfytahnedatnraalnyssfiosromaftitohnesa,naclalyctuilcaatliocnhse,miosrtorpyedraattai,oannsdpearsftoartmeemdenotnotfhe the conclusions drawn from the analyses. 78.71 Statistical methods used to evaltuheadatte,if applicate 14.12Tpreofseisgsnioendaalsndinvdoaltveeddrin ethepophfaoesae,rcihfotafptpshliecianbdlei.vidualsiemtists orother 74.13Thelocationwhererawdataan thephasereportare obe stored. 14.14inAsspteactteimoennsatpnrdeapuadrietdsbwyetrheemQaudaleiatnydAtshseurdaatnecseoUfniatnylifsitnindgitnhgsrdeaptoersttehdattosttuhdey Study Director and Management. 14.15Iacfceiptende,cetshseacrhyantogmeaswkielclobrreemcatdioenisntorhaeddfiotrimoonfsatno aamfiennadlmeeponrttsasfuecrdibhyatshbeeen isSbteuidnygDiarmeecntodre.dT,thheearmeeansodnmsefnotrtwihlleaclmeeanrldymiednentt,iafyndthweiplalrbteofstihgneedfbinyal trheepSotrtudthyat Director. `3M EnvionmentalLaboratory 3M Environmental Laboratory Page 784 Pago 701912. Page26 5M MeticalDeparment Stuy: T65896 = camoens eKraotiee RAeRpGoUFSA4C18T.O)A 164 ProtocolFACT-TOX-L1I6M4.S E00-2738 15. LOCAOFTRAIWDOATNA, RECORDS, ANDFINAL REPORT faOcriilgiitnaatleaduadtiatsorocftophieessttuhderyedoufr,iwniglil sbepavarilbolaenatdgb3eMfroErneveaicrcoesnpmteansntcaeloLfabtohreapthoarsyetoreport. `bWehleonw twhilelpbheasreetraeipnoerdtiinstchoemparlcehtievde,saolfo3riMgiEnnavlipraopnemrednattaal,Lianbcolruadtionrgyt.hoAslle ciotrermseslpiostnedding tprraoicneidnugrreesc.oredqsu,ipcamleinbtraptriooncerdeucroersd,sa,nidnsmtreumtenthmwoaiildnltbseenarnecteailnoegds,instthaendaarrcdhiovpeesroaftintgh.e 3M. Environmental Laboratory. 15.1 Tarhcehifvoelsloawcicnogrrdainwgdatota3aMndEnrveicroorndmsenwtiallblLearbeotraaitnoerdyiSntthaensdtaurddyOfpoelrdaetrinign the Procedures 15.1.1 Approved proatndaomecndmoenlts 15.1.2 Study correspondence 15.1.3 Shipping records 15.1.4 Raw daa 15.1.5 Approvedfinalreport (original signed copy) 15.1.6 Electronic copiesofdata 16.2 Tinhethefoalrlcohwiivnegssaucpcpoorrdtiinnggtroec3oMrdsEnwviillrobnemernettaailneLdabsoepraartaotreylyStfarnodmartdheOspteurdaytifnoglder Procedures: 15.2.1 Training records 15.22 Calibration records 15.2.3 Instrument maintenance logs 16.2.4 Standard Operating Procedures, Equipment Procedures, and Methods 16. DATA/SAMPLERETENTION Allseraspecimensremainingafter theanalyticalphaseis completedwillbesent10and `maintained by: L3iMsaECnlveirmoennmental Laboratory B9u3i5kdBiunsgh2-A3v6e-n0u9e TSte.lePpahuol,neM:N(S6S11)07618-6478S54 HC along, SMEnvironmentalLaboratory 3M Environmental Laboratory Page 785 PageBotglo Page 27 3M Medical Department Study: T-6889.6 TT rye RSS EAB16a Protocol FACT-TOX-L1I6M4S E00-2738 17. PROTOCOL AMENDMENTS AND DEVIATIONS PSltaundnyeDdircehcatnogreasntd tthhee Sprpootnoscoorl'swiRlelpbreeisenntthatifvoer.mAomfewnrditmteenntsawmienldbmeecnotnssisdigenreeddbyas tphaert obfetihnedpircoatteodcoinltahnedpwhialslebreepaotrtt.achAendytootthheercfihnaalngperostowciolll.beAlil cthhaenfgoersmtoofthweriptrtoetnocol will deviation, signed by the Study Director and filed with the aw data. 18. ATTACHMENTS 18.1 AttachmenAt: Material Safety Data Sheets (MSDS) for Reference Standard 3M EnvironmentalLaboratory 3M EnvironmentalLaboratory Page 786 Page 901910. Page28 IMMetical Department Sty: T8896 19. SIGNATURES RoeiysrTtee e re rFoo? Tmulanptrlf-- ~ ummeees AcorPor=ai--ARCAeTpRoTGUOESTChN4Ts18-ET0Or2R0e16s4 lnTfoeey C/oTrufrer L I . .. Ob) naa 3MEnvironmentalLaboratory Page 787 f-- Page29 3M MedicalDeparment Study: T65856 ~ mension"r--i--c RAoRpeGrUSACT418.OR164 LIMS E00-2738 Ls Oral (Gavage) Two-Generation (One LiteSrtpurdyGeTnietrlaetion) Reproduction Study of Ammonium Perlluorooctancate (APFO/PFOA) in Rats PROTOCOL AMENDMENT NO. 1 ANmoevnemdbmeern1t7, D2a0t0e0: 3MEnvironPmeenrttaolrTmeicnhgnoLlaobgoyr&atSoarfyety Services 3M En9vi3r5oBnmuesnhtaAlveLnaubeoratory St Paul, MN 55106 3LMabMoodriactaolrDyepParrotjmeecnttiSdteundtyi:fTi-c6a8ti8o9n.6 Ana`lAyrtgiucsalInRceLpiofret:StFudAyC:T4T1O8-X0-21064 3M LIMS No. E00-2738 3M EnviraonmEennvtiamlnmLaarbtoarlaLtaobroyratory Page 788 Pace 1013 Page 30 3M Medical Department Sudy: T-6889.6 TTT paiva REG RAU1B6 LIMS 00-2738 Protoco`lAmFeAniCdTmeTnOtXN-o0.011 `This amendment modifies the following portion(s) of the protocol: D1.osePRcoOnTfOirCmOaLtiRoEnAwDaSs:not discussed in the Environmental Laboratory analytical phase protocol. 2. ThAeMdEoNsDeTcOonRfEirAmDa:tionandsabiltysampleswerepreparedandanalyzedprior 0thestartof thGLeaPs.nMaethlopdhysasEetToS-fi8t-h4ci.1sataundldy.ETTSh-e8s-e5s.a1mwpelrees lwoeorseelnyoftoplrleowpeadr.eTdohreanraesluylztesdwaiclclboredrienpgorttetdhein the fRiEnaAlSaOnaNl:ytical report. From the protocol for the Primedica study: `AnofPareplareyd Fosrmuelasosns: Concentration: DCuopnlciecnattreastaiomnploefstwhielprbeepatraekdenfforrmoumleataicohnscowniclelnbteatvieroinfioedndtuhrifnigrsttahencdoluarsstedoafystiosfpsrteupdayr.ation rOenteaisnaedmpalseboafckcuacphsdaumpplliecsa.teBsatckwuilplsbaempslheipspweidllfobreasntaolryesdisu;ntdheerrtehmeapirneivnigoussalmyplcietsedwciolndbietions and discarded at the Testing Facility upon th request of the Sponsor. `stability: dSutpalbiicliattyesoafmtphleepsre(p2amreLdcfaocrhmu)lfartoimoncsawcihlclobnecednotcrautmieonntweidldlubreitnagktehinsosntutdhy.fiTrswtdoasyeotsfof saprmepplaerastwiionl.lObenaensaalmypzeldeoafttchaecfholdlupolwiicnagtetsimtepwoiillnsbe:sahsispopoendoafnetrhpedrayeofppraepaarsrapatoistosni.bileTohaensned. tebnacdkauypssaafmtpelretsh. fBrsatckanuaplyssaimsp.lTeshweirlelmbaeinstionrgedsuanmdpleerstwhielplrbeeviroeutsaliynecdiattetdhcoenTdeisttiionngsFaancidlityas discardedattheTestingFacility uponthe reqofutheeSposnsotr. `bSetsatbitloiptyermfeoarsmurtehimsepnrtisordetomtohnestarnaatleyttihcaatlthpehapsreesptaurdeyd tiesnartiiclet0weinilsubreoestthnaabtlepfroerptaerneddadyoss.intgis `dmaiyx.turAelsswo,ilnoraepmparionvsetdabvlaeliadnadttehdusmeatvhooiddsthweecreositnapnldacpeoftoerndaolsee xcoonfoifrpmraetpioanrianngaldyossiess.cach 3M EnviraonmEennvtiamlomLaanbioarta|taohroyratons Page 789 Paca20l3 Page31 3M Medical Deparment Say: T-6889.6 = einen oHraa--tyi--ea RAepRosG:UFSLAv4C1sE8-TE0O00R70 31684 Protocol FACT TOX-001 `Amendment No. 1 Amendment Approval DKiniedSanhderrsSp.on Re--presents whlDaeey Clr bility John L. Butenhoff, Ph.D., Study Director z iroer Date MEmirswomEeminoanmLanoaoLsavoro [Se rag2e Page 790 3M MedicalDeparmentStudy: T-6889.6 TET RaineRope PLAIMHS ET00o-27s38 Record of Deviation I. Identification Study/ Project No. FACT-TOX-164 Argus 418.020 LIMS 00-2738 Deviation Type (Check one) gsop OProtocol XMethod [] Equipment Procedure [J Other: Document Number(s): ETS-8-4.2, ETS-8-5.2 Date(s)ofoccurrence: 06/14/01, 06/15/01 i. Description: Required Procedureprocess: i hMeetshaomd Method EmETTaSS--r884-.5a2.tdhsoeteastseansmopftlvelissptiLmena.strr,iaxtastsepriiukmemscuaalsmiab,QraCtaiioepna1r0caubmreevteueseriadnfdttrohaegtcesuenrrvruemeisstapemrpeclpaaelrsfe)rdatiin on || | curveandthecurve * mustbe > 0.990. |- dAcettuearlmiPnreoceexdturraect/ipornoceefsfsi:cienc(y06an1d40to1)determinehthesenodofgeenoums evpellofteargeot annalyrtee prresent | w{etrheebceolmomwer1c.i0a0lplpybafvoratlhaeblasregreutma.naFloyrtet.hTihsicsosmmeerrucmiawlalsytahveaniulsabeldetsoerpum,reentdhopgeeenaxoturrsaclteeevdels trix calibration curve and continuing calibration verifications for this sudy. wTheerseefsolalmopwleed.extOrnalcytsfwoeurrepoainnatlsywzeedreouns0e/d1f5to/0h1.eFcoarlibtrhaitsiaonnalcyusrivse,innosttelaldosftatGeed QpCoctrsitearnida tadhdeit7ivonaallumeawtarsi0x.sp9i8k3e1siwnisltleabdeeoxfa0c.9t9e0d0.aStitnhceetnhdeosefdtahteasatruedsyctrheeesneidnagtqauaarleitOyKoanlyenatnedred. These sample extrscts were not reanalyzi ed.Actions Taken: i "oTuhcshadaemveinatdimoennwtassuwdr,iteSnO.Prevision, ec) LiRsecaorA.deCdlBemyen hon Oth No adverse impact on the outcToVm.eIoftmipsasctountdy.Study/ Project 0D8a/e1001 08Jle, | Authorized a. By(Stufdyo;Director2/7ProjAecnt gLeeadw) ! 227! Date ErIc ah 7 220 STpooilEonmeER1megr5eta40b-oDroownd Sanders (ard StyDic oeoigatLoenno4.n__yL_)_ 3M EnvironmentalLaboratory Page 791 Page 33 3M Medical Deparment Src: T-68096 TT en RASA LIMS E00-2738 Record of Deviation T Tdentication Study / Project No. FACT-TOX-164 Argus 418020 LIMS E00-2738 D(eCvhieactkioonneT)ype XSPrOotPocol [[JMOtehetr:hod Equipment Procedure Document Number(s): FACT-TOX-164 Datofeocc(urrsenc)e: Ti Descri0p6t1i9o/n0:1 RSeecqtuiiorned7 Pstraotcese:duAren/perqoucaelssn:umberofmale and female samples will be randomly selected from the two P generation dose groups (group IV -- 10 mg/kg/day and group V - 30 mg/kg/day) grog | `An cqual numberofmale and female samples were randomly selected from the two P gInenaedrdaittiioonn,d3osmeaglreoaunpds (3gfreomuaplIeVsa-m1p0lemsg/wkegr/edaryanadnodmlgyrosuepleVcte-d30frmoemkgth/edaPyg.e)neration control group (group 1 - 0 mgkg/day) (uchasamensudedmSOePrenvistion, eTc)i Actions Taken: i "This deviation was writen. RLeicaorAd.eCdlBmyen 1, [) - - Doavteiomy, These samples' results will ddIVu.sIefmulpaincftoromantioSn ctonc/uePrrndoinjgeycetndogenous levels present i the control group. No adverse impact on ths study. Authori2zedBdy (StRudyuDirector [Proje2ct7Lepade)t? 2001 Dae i Say SrctOr QSoFn rGullenihee 5 Spr 20 Spd Ronee ted Senders 3M EFnvoimronEmTeSn.ta4l4L0aboratory apdby StyDrorDervieatsiL on No. e_3. dyo ro) 3M Environmental Laboratory Page 792 Page 34 3M Medical Department Study: T-6889.6 ~ meee oArnal--yti--cal RAepRorGt:USFA4C1T8-T0O2X0-164 LIMS E0738 Record of Deviation T Tdentication St/PurojdectNyo. FACT-TOX-168 Argis 418020 LIMS EQ02738 Deviation Type (Check one) SOP X Method Equipment Procedure Protocol Other: Dociment Number(s: ETSI, ETS-6:5.1 DoTa,ofi0o1cG2li3m0e1n)ce:" TT Description: ReMqeutihroedsdPsrtoacreedA:urmelaptroecesssp:iad atx spike dpliate will be exacted and analyzed per | fortysamples,with a minimumof 2per batch. 1 ES | O `Acttuhaeln dPorsoecedcure/oprocnesse:fxtracitionmperafaoitned o1/1n701 no mati siorkmateix spike || duplicatewere preparedan subsequewenrteloyt analyzed on 012301 (sTuicshadsevaimaetnidomnewnas werditeSnO.Previsionll). Actions Taken: LRiescaoAr.deCdlBeymen OaA Comin D1a0t0e51h01os | | "aniaslysmiisswseiroeniwniclllundoetdh(abvlan5IksV,a,cdovnetIrimsnepuaiincgctmaolinbporSattaihtoinscsvueu/rPdtfrydco,tjoieytochnters)quwalhiitcyhcmoneitromleatshpoedctcsriotfetrihae. Te 5 io 7Project ead), Date Gobuflinr Td Tua cks heSa ds 0 /if2e0r 34 EnFveirmoEnm5en0ta8l0Laboratory petby tyDitDevrioatioondNo.5_A _3__) __ 3MEnvironmental Laboratory Page3s Page 793 3M Medical Depart Stuy: T8896 wt ittpaAvnteicsa RAoBpe SAyTCOR.H164 LIMS E00-2738 aM MedicalDepartmentStudy: T6569. Anayical Report:LFAMCST 0T0O.X2-713684 errors `Appendix C: Extraction and Analytical Methods "Tis appendix includes the following methods: ETS-8-4.1,ExtracionofPotassium PerfuorooctansuiofroOtnhtere FSlpueocrtorcohmeemtriyc,al(C14ompapgoeusn)ds fromSerumforAnalysis using HPLC-ElectrosprayiMass EHTPSL-C8-4E.la2c,tErxovsapcratyoinMoafssFuSopreoccthreommiectayl,C(o1m5ppoaguensd)sfomSerumforAnalysis Using IEnTSS-e8r:u5m.1E,xAtrnaacytssiUsoifnPgoHtaPssLiCum-PEelercfruoosrpoSrpoaeccyttMamaaoerstnOyste,h(se9rpuFaigiueofsr)aocnheamitales EiTnSS-e8r.5u.m2E,xAtnraalcytssiUssoifnPgotHaPsLsCi-uEmlePcteosrpfrauyMoasrs oSpoecctoimoaatOnyt.ho(e1sr1Fuipaufgoerosa)cnhaamitcaee 3M Environ3mMentEanvliLraobnmoernattaolrLyaboratory Page 794 Pace 20 Page 36 3M Medical Deparment Study: T-6889.6 = meee `Ana--lyt--ical RAeRpoGr:USFA4C1T8.T0O2X0-164 : _ LIMS E00-2738 3EMNVIRONMENTALLABORATORY ' METHOD FLEUXOTRROACCHTEIMOINCOAFLPCOOTMAPSOSIUUNMDSPEFRRFOLMUOSREOROUCMTFAONRESAUNLALFYOSNIASTUESOIRNGOTHHPELRCELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-3-4.1 Adoption Date: 03/0199 Author: Lisa Clemen, Glenn Langenburg Approved By: 1 15. Laboratory Manager Va fe Group Leader Revision Date: 4/27/77 "fortis Date 4/2/39 Dae TechniincalARevCihreowner oDtu/eau]e -- : Ll ital Dats / 1S 0 coreawpApucamon 11 Scope: This method is for the extraofcpottaissoiunm perfluorooctanesulfonate (PFOS) `or other fluorochemical compoundsfromserum. 12 Applicable compounds: Fluorochemical surfactants or other fluorinated compounds. 13 Matrices: Rabbit,rat,bovine, monkey,andhumanserumor otherfluidsasdesignatedin the validation report. Vierd 695 3M EnvironmentalLaboratory ETSeat rT Page 795 Page Lof14 Page 37 3M Medical Department Study: T-6889.6 ~ semen `Aorna--lyti--cal ReApoRrtG:UFSA4C1T8T.O0X0-0164 ~ LIMS E00-2738 2.0 SUMMARY OF METHOD. 2.1 (PThFiOsSm)eotrhoodthdeerscfrliuboersocthheempircoaclesduurrfeacftoarnetxtfrraocmtisnegrpuomt,aossoiutmheprerfflluuicdsr,oouctsaneaisnunlfigoonnate pAauiorrioncghreemaigceanltsawnedrmeetehxtyrlatcetretd-:bPutFyOlSe,tPheFrO(SMAI,BEP)F.OISnAtAhi,s EmeFtOhSodE,-OseHv,enPFOSEA, thM5e5s6a,mpalnedasnudrrtohgeaatneasltyatnedairodnp(asiere3i.sp0aDretfiitniiotnieodnisn).toAMnBoEn.pTahireiMngBreEageexattraiscatidsded to mrLemoovfemdeathnadnpoult,tohnteonfainlitterreodgtehnreovuagpohraat3ocrcuplnasitdircys.yEriancgheaetxatcrahcedits oreac0o.n2sptintnuytileondn1.0 Sterno glass autovials. 22 T`hmeetsheosdsa.mple extractsareanalyzedfollowingmethodETS-8-5.1 or otherappropriate 3.0 31 DeEnvTIONS PFOS: perfluorooctanesulfonate m(a-- nimonof-- potas-- sium-- salt)C-- iSOs-- ;eme-- n es 32 PFOSA: perfluorooctane sulfonylamideCF,SONH, 33 PFOSAA: perfluorooctane sulfonylamido (ethylacetate C,F,,SO;N(CH,CH,)CH,CO; 34 BFOSE-OH: 2(N-ethylperfluorooctane sulfonamido)-cthy! alcohol 35 CFPF1O,SSEOA;:Np(erCfHl,sCorHo,o)cCtaHn,eCsHu,l0foHny! ethylamideCF,SON(CH,CE)H 3.6 37 MsSS6: CF,,SON(H)(CH,COOH) Sumogate standard: 1H-1H-2H-2H perfluorooctane sulfonic acid 40 WamnnesawCavmows 41 Health and safety warnings 41.1 Useuniversalprecautions,espesiallylaboratorycoats,goggles, sndgloves whea - sO51lvTmhemreeearmeenvoicsnterfkneowrneatnthicsteimse. 6OFoueweNr 61 Thefollowing equipmenits usedwhileperfotrhimsmietnhogd.Equivalent equipmentis acceptable. 611 Vortexmixer, VWR, VortexGenie2 612 Centrifuge, Mistral 1000 or [EC 61.3 Shaker, Ebecbachor VWR 3M EnvironmentalLaboratory ETS ome Page 796 Page2014 Page 38 3M MedicalDeparmentStudy: T-6889.6 TTT eaRot n Pi AHn164 _ LIMS E00-2738 6.1.4 Nitrogen evaporator, Organomation 615 Balance (01005) 2s 0 ueeuesavoMa 000t 000a 000s 0 71 Gloves 72 Eppendororf disposable pipetes 73 Nalgene bots, capable ofholding 250 mL and 1 L 74 Volumetric flasks, glas, type A 75 L-CHEMvials,glass, 40mLglass 76 Ceanifuge tubes, polypropylene, 1S mL 77 Labels 78 Oxford Dispenser~3.0t0 100mL. 79 Syringes, capableof measuring $ uL to 50 bL. 7.10 Graduated pipettes 7.11 Syringes, disposable plastic, 3 co 7.12 Syringe filers, nylon, 02ym,25mm 713 Timer 7.14 Crimp cap autovials and caps 715 Crimpers Note:Prior tousingglasswareandbottles, rinse 3timeswithmethanoland 3 imeswith `sMeiplalria-tQeviaatlesr.. Rinsesyringes aminimumof9timeswithmethanol, 3rinsesfom 3 8R0 EAGENISANDSTANOMARDS 81 T`ybepMeil!lrie-aQgPenwtagtreardaenwadtmeary, bMeiplrio-vQiTMdoerdbeqyuiavMaillelnit-;QalTlwOaCtePluusseTMdsiynsthtiesmmethodshould 82 Sodium hydroxide (NaOH), J.T Bakerorequivalent - 83 Temabuhtydroygenlsulfaae(mTBAm),Koodankoriequuivalnent 84 Sodium carbonate (Na:CO,), J.T. Bakerorequivaleat 85 Sodium bicarbonate (NaHCO), J.T. Bakeror equivaleat 86 Methyl-T-Butyl Ether, Ommnisolv, glassdistilled or HPLC grade 87 Methanol, Omuisoly, glass distilledorHPLC grade 88 Serum or blood, frozen from supplier 89 Fluorochemical standards 89.1 PFOS (3M Specialty Chemical Division),molecularweight= 538 892 PFOSA (3M Specialty Chemical Division), molecular weight= 499 3MEnvironmental Laboratory FmcioEfTPoSR8On4S1fiom Son Page alld Page 39 Page 797 3M Medical Department Study: T-6889.6 ~ menos or `Analytical ReApoRrtG:UFSA4C1T8T-O0X2-0164 _ LIMS 00-2738 893 PFOSAA (3M Specilty Chemical Division), molecular weight = 585 89.4 EFOSE-OH (3M Specialty Chemical Division),molecularweight = 570 . 89.5 PFOSEA (3M Specialty Chemical Division), molecular weig=h52t7 : 8.9.6 MSS6 (3M Specialty Chemical Division), molecularweight = 557 89.7 CS.uFmoSgOa,teHs)tamnodlaercdu:l4a-rHw,epiegrhftl=uo4ro2o8ctane sulfonic acid (1-H,1-H, 2-H, 2-H 89.8 Other fluorochemicals, as sppropriste 810 Reagent preparation NOTE: Wprheepanraptrieopna,riadnjgluastrgaeccovrodliungmleys.than listed in reageat, standard,orsurrogate 810.110100N0msoLdbieuamkheyrdcroonxtiadieni(nNgaO5H0)0:mWLeMiiglhlia-pQprowxaitmeart,emlyix20un0tgilNaallOsHo.liPdsoaurreinto a dissolved.Storeina 1 LNalgenebottle. 8102 N1 NNsaoOdHiusmoluhtyidornornitdoe(aN1a0O0Hm)L: vDoilluumteetr1i0cNflNasakOaHnd1d:1i0.teMeoavsoulruem1e0usinogf10 Milli-Q water. Store in 2 125 mL Nalgenebottle. 8103 o0f5TBMtAeirnstbouat1ylL amvomlounmieutmrihcycdornotagienninsuglf5i0t0em(TLBMA)i:llW-eQigTMwhaatpeprr.oxAidmjautsetltyo1p6H9 g "NaO10uHsi,ngaadpdprsolxowilmyatbeelcya4us4etoth5e4pmHl.cohafng1e0sNabNruapOtlHy()W. hDiilleuateddtio nvgotlhuemleawsittmhLof Mill-QTM water. Storeina 1 L Nalgenebottle. 8103.1 TnBeeAderedquusiirnegs 1acNheNcakpOrHiosorltuotcioanc.huse toensurepH = 10. Adjusats 8.10.4 a0.p2p5roMximsaotdeiluym2c6a.r5bgonoaftseo/dsioudmiucmarbibcoanrabtoena(tNe&b,uCfOf,e)r(aNnda,2C1O.,0/3NoafHsCoOd,i)u:mWeigh bQicarwabtoenra.te (StNoarHeCiOn,)a1inLtoNaalg1eLnveoblotutmleet.ricflask andbringtovolume with Milli- 811 Standards preparation 811.1PreparePFOSstandardsfo th standardcurve. - 8.11.2 Pfrleuopraorceheomtihcearlfsltuaonrdocahredmsiacraelacsctaenpdtaarbdlse,(afsorapepxroapmrpilaet,ea.nMeuwlotrikcionmgpsotnaenndtard s1o.l1u0tpiponmcoEnttFaOinSiEn-gO1H.L0)0 ppm PFO, 1.02 ppm PFOSA, 0.957ppmPFOSAA, and. 8.113 Wtheeiagchtuaaplprwoeixgihmta.tely 100mgofPFOS intao100mLvolumflaeskatndrreicocrd 8.11.4 (Bug/rmlt)o.violunmewgithmethanolfor stockstandardofspproximately 1000 ppm 8115 Dilutethestocksolution withmethanolfo aworkingstandard |solution of approximately 50 ppm. 8.11.6 Daiplpurtoex.wo5r.0kipnpgm.standard 1 with methanol for a working standard 2 solution of . ETS 841 Pagedarte 3M Environmental Laboratory rT TT Page 40 Page 798 SM MedicalDeparment Sty: T6589 ~ mmissioan = a ReARGEhTACs LIMS E00-2738 8.11.7 Daiplpurotxe.wo0r.5k0inpgpmst.andard 1 with methanol for a working standard 3solution of 812 Surrogatestock standard preparation + 8.12.1 WCeJiFgShOa,H npto pa 50rm5L0-ov6o0lmuxmgetorifiscufmmloagskaataensdttraencdoaerrddth1le-Hac,ty-uHal,w2e-iHg,ht2.-H, 8.12.2 Bring to volumewithmethanol for a surogate stock ofapproximately 1000-1200 8.123 ppm. sPtroe0pkarte a81s0urmroLgavtoe lwuormkeing Sstaasnkdaarndd,brTirnagntsfoevroalpuprmoexiwmiatthemlyet1hamnLool ffosruarrogate workingstandardof 100ppm. Recordtheactualvolumetransferred: 9s 1 o AlsaS mplesaa rerecw eivedfm rozenp andmuE stbekA eptfrN ozenunO tilthL eextracI tionisN perfoG rmed. 92 Allowsamplestothawtoroomtemperaturepriofto extraction. 110010QuSoalvrevntCBolawnRksO,MLethod blanks and matrix blanks 1100..112EAxntraalcitqutowtoo1f.10.m0LmaL mlethianooqflMiisuluise-odQPstswastsoelrvefntbolanlk.thlisporocwedurieanndugse 10.13 Eaxstmreatchtotdwobl1a.a0kms.Laliquotsoftheserumfollowingthisprocedureanduse35 `matrix blanks. See 11.14. 102 M10a.t2r.i1xPrseppikaerseandanalyzematrixspikeand matrix spikeduplicatesamplestodetermine 10:22 Ptrheepaacrceuraacchyospfitkheeuesxitnragctaisoan.mplechosenbytheanalyst,usuallytecontrol 102.3E``xmAadprdeiicttireoendcaceloisnvpceiedknetwsriamttahiyoenabscewhisilancmlpaulldeeisdnaetnthdemmiady-fralnlgenothfethleionwi-traalngcaeloifbtrahteiionnitciuarlve. 10.2.4PCraelpiabrraeoionnecmuartvrei.xspikeandmatrixspikeduplicateper40samples,with 2 `minimumof 2 matrixspikesperbatch. 103 C1o0n:t3i1nPurienpgarceacloibnrtaitniuoinngcchaelcikbsrationchecksamplestoensuretheaccuracyoftheinal 103.2Percxeaalpmiabprrleaet,ia,otinfcaamusriavnem.ipmluemse,to=ne3c4o,nftoiunrucihnegcckhseacekpperrepgarroeudpaonfd1ex0tsraamcptleed.s. For 10:33 Prepare each contisuing calibration check rom thesamematix used to prepare the initial curve. 3M Environmental Laboratory ETS841 or net Page 799 Pagesofi Page 41 3M Medical Department Study: T-6889.6 ~ "mmeess wrAna= lytical RAepRorGt:USFA4C1T8.T0O2X0-164 LIMS 00-2738 103.4 cTahleiberxaptieocntecdurcvoe.nceAndtdriattiioonnaslwislplikfeaslmwaiythbien tihneclmuidde-drathnagtefaolftl ihn tihneitlioalw-range of . otnhleyitnihteiallocwaleinbrdaotifotnhceurcvalei.brTahtiiosn icsunrevcees(sfaorryiefxatmhpelaen,alypsptbmu~s1t0q0upapnbt,itartaethuesring ` t5hpanpb-- 1000 ppb). 1C10ALIBRATIONANDSTANDARDIZATION 111 Prepare matrix calibration standards 11.1.1 Transfer 1mLofserumto a 15mlcentrifugetube. 11.1.2 `Ivfomlousmetsseaqmupalletvootlhuemseasmaprleelveossltuhmaens.1D.0oTLno,texetxrtaracctstletssathnanwd0i.at5h0rmmaLdtrosifx `matrix. Recordeachsamplevolumeontheextraction sheet. 11.13Wbheitlweeperneaplairquiontgs.atotaloftwentyaliquotsin 15mL.centrifugetubes,mixofshake 11.1.4 `TTywpoica1mllLy usleitquhoersst,aonrdaotrhdecroanpcpernotprraitaitoenvsoalnudmsep,iskeirnvgeaamosumnattsrilxibsltaendiksn.Table1, caitgthhteeeenndstoafntdhairsdss,ecttwioonm,attorpiixkbel,ainnkdsu,palnidcattweo,mtewtohstoadnbdlaarndkcsu.rves,for atotal of 11.15raRnefgeerstaonvadltihdeaLtiionneraerpCoarlitbErTaSt-i8o-n4R.a0n&gEeT(SL-C8R-)5f.or0-ca-l1ib,rwahtiiocnhcluirsvtsets.he working 11.16 UstsaenAdatrtdasc.hmSeeentSeDcatsiaonn1a3i.d0itnoccaallccuullaattienagctthueaclocnocnecnetnrtartaitoinosnosfotfhPeFwOoSrkiinng calibration standards. 112 woTorekaicnhgssttaannddaarrdd,fbolratnhke,coornccoennttirnautiinogncthoefclkl,waidtdhaipnprtohepcrailaitberaatmioonucnutrovfesruamnoggeat5pepb - 1000 ppb. 113 EtxotersatcatblsipsihkceadcmhaitnriitixasltaCnudrvaerodnstfholelmoawisnsgs1p2e.c6a-1O2C.I1e6orfthismethod. Use thesestandards 3M Environmental Laboratory ETS841 me - Page 800 Pagebo1e Pages 3M Medical Deparment Su: 6559.6 = simone o`rAn--syi--ca ReApRorGtUFSLAMC4S1E8ET-00O02R30A7G3S8 llTobie T $ Approximate spi`ksiinngga1m.0omunLtosffmoratstrainxdards and spikes T (apTpSr0ox0.pceonnc.| ) 1T 0 O `anamlytemip nxmatrix | 50000mpomm|520 | |0o0m0wma m|| I ---- [50 | 10 5 [m 0mm m | 120 ProcppuRE 12.1 Vater Obtainfrozensamplesandallowtothawatroomtemperatureorin a lukewarm 12:2 Vpoolrvtperxompiyxiefnosrc1e5astcaofungdesb,teh.en ansfer 1.0mLo thes approprsevolume0315 123 Retumunusedsamplestofreezerafteextractionamountsavebeenremoved. 12.4 Recthoe nriadlvolumeontheextractionworksheet. 12.5 LwaobreklshteheettfuobredwoictuhmtehnetsitnugdyhenurmebmerR,eisnagmpElPeSI.D, date and analyst initials. See attached 12.6 SSphiokdearaldlas dseoed 112. samples, including blanks and standards, ready forextraction with surrogate - 127 CSopTniitkiencaitaacsgehccmtliaobtnatfiowoitnthehtcahaenaldpfpaortroip.orniactueravmeSouanntdeofrsst.aAnldsaordpsrsepdaersecmriaberdisap1i1k1e,saonrdTable 12.8 VSoarmtpelxemfxorh13esseacnodnadsr.d curve samples, mati spike sample, and contnsing calibration 129 Checktoensurethe 0.5 MTBAreagentisatpH 10. Ifnot,adjustaccordingly. 12.10 Toeachsample, add 1 mL 0.5 M TBAand 2mLof 0.25Msodiumcarbonate/sodium `bicarbonate buffer. 12.11 Using anOxfordDispenser,add mLmethyl-tert-beuttheyrl. 12.12 Cap eachsampleandputontheshakerat asettingof 300 rpm,for 20 minutes. 12.13 Cseepnatrraitfeusg.efor20 to 25 minutesat asetoft35i00nrpgm,oruntillayersarewell Essar Perot 3M Environmental Laboratory Page 43 Page 801 3MMedicalDeparment Sudy: T-6889.6 = mess eArns--lyi--cal RAepRorGtUSPA4C1T8.T0O0X0.164 3 LIMS E00-2738 1122.1154 LRaebmeolvaefr4e0shm1L5mofLtcheentorrigfanuigcetluabyeerwto i thtihst ecsleah amne15inmfoLrmcaatiiionfausgientu1b2e..5. . 1216 Pbuotwse.ach sample on the analytical nitrogen evaporator until dry, approximately 1 to 2 12.07 Ade 1.0mofmethanol to exch cenifige tube usingagraduatedpipette. 12.18 Vortex mix for 30 seconds. 12.19 ASytrtiancghe.a0Fi2lteurm innyoloan1m.5eashLflilatsers at3o3vicaelsoyrriInogwe-vaonldutmraensafuetrovtihalswahmepnlenetcoeshsiasry 1220 Label the autovial with the study number, animalnumberand gender,sampletimepoint, 1221 C`maaptrimx,dfsionarlsseoxlvaecntt,sexsttrarcotoimontdeamtpee,raatnudraenoalaystta(psp)rpoexrifmoartmeilnyg theCeuxtnralctainoanl.ysis. 12.22. Cormpleetheextractionworksheet,atachedtothisdocument, andtap i thestudy `notebook or include in study binder, as appropriate. 131.310 DACTaAlcAuNlAatLiYoSnsISANDCALCULATIONS 13.1.1 Calculate actual concentrationsofPFOS, or other applicable fluorochemical, in calibration standards using the following equation: mELLofosftsatnadnadradr+dxrclonocfenstaraotpioaneosftsatnadnadradr+d n(utgl/mml)axvolume (aL) = `Final Concentration (ug/mL) of PFOS inmatrix 14.0METHODPERFORMANCE 141 142 TTohhreemfeotlhloowdidNngDeqTutalaiaetdyclctoinmittitrtio(olfMsoDqmuLnpa)laiiesasa taironn ex(tLraa OanGcd)tml eavdtwuriy eitxshs(et psaeeccsihe fbAiatct.ncchR homf ee saattmospf MlBeDsaLe n0rdepr o)r.t `evaluatethequalityoftheextractionand analysis. 14.2.1 Method blanks and matrix blanks. precisionofhe extraction. - 14.2.2Matrixspike andmatrixspikeduplicatesamplestodetermineaccuracyand 14.2.3 Continuing calibration checksamples to determine the continued accuracy ofthe initial calibration curve. 143 Retf oseectiron 14 ofETS-8-5.1 for method performance criteria. 50 m w 151 Sample waste is disposed inbiohazard containers, flammable solvent waste is disposed in high BTU containers, and used glass pipette waste is disposed in broken glass containers, located in the laboratory. EPrasgeaa8102 Fugesorie 3MEnvironmental Laboratory - Page d4 3M Medical Department Study: T-6889.6 ~ "mens or ---- ARGUS 418-020 Analytical Report: FACTTOX-164 LIMS E00-2738 16.0 Recorps ` 16.1 CRompolettetoerhienbecxltuoradcetioinotnkhweor3k-srhinegetstautdaycbhienddtero,tah5iasppmreotphroida,taen.dtapeinthestudy U0 SArac0 wwens0000000 17. Antachment A, Extraction worksheet 172 AttachmenBt,MDLvalIuesaLndsOummQ ary 173 AdtachmentC, Calibration standardconcentration worksheet 1BORemeRewces 0000000000 18.1 Thevalidationreportassociatedwiththismethodis ETS-8-40 &S0-V-1. 182 'FAHCPTL-CM--E3l.e1,ct"rAnoaslMpyasrisasoysfSpSeecrturmomoertOrtyh"erFluidExtracts for Fuorochemicals using 190 AepcrsoDocomnrs 0 19.1 EHTPSL-8C--5E.1l,cc"AtnraolysspMisraoasfysSeSpreucmtorormOetthrey"rFluidExtractsforFluorochemicals using woRpevisos 00 Revision Revision Numb1 er Section 12.21ChangedtoRienaclsuodnesFaomrpRleevsitsoiroangeatroom temperature. 04D/0u2c/99 SSeecattiioonn1122..1173FAidndalevdothleusmheaikser1s.0pmeLed;.notadjustedforinitialvolumes less than 10m. 3MEnvironmental Laboratory FactionETofFSO$4S1from Serra Page 803 Page9otte Pages 3M Medical Department Study: T-6889.6 ~ smenes Extraction Worksheet ETS-8-4.1 eAnarlytimcal RAepRorGi:USFA4C1T8-T0O2X0-164 LIMS E00-2738 MaHcTs, Sspperoox. ppaom||approFx.C0M5pm|apprFoxo.Sxppm |approFxO.N5E0pm Comes BW ors b s| mal pe pm |scmad Tpplm|ea Tnpe pma|al coal 7ppm . DuSpiciia ewsw --w ---- rrrT e r r e t r r ----t---- r r rr r r r r r r r r r r r r r r rr r T r r r r rr r T r r rr r r r r 1 r r rr T r r r r r r r r r r 1 tr EMormmie --| F [ eF ma e nm nwm r i on in a e| SSasa mime e ea------------Sk --ed----------------| TF-- AT EE -- ----e-- rs "Cionet.sGaml rVecrhteoaioonmssnemdsammermattoaesrforei a rv.tes 3M EnvironmentalLaboratory or Page 804 TT pagess 5M Medical Deparamens Sudys T6589.6 = smmeees oAr n=a=--y--a RAepRorGtUFSLAI4C1MT8-ET00O02X-0-2176348 'MDL/LOQ values for rabbit serum ` `Compound| MPD|L| @L6ObQ)||LASitpnapenradorasriCdamClaaitlbeirbactroianoctneinoRtnarCnaatgireovn(esLCtoR)be used for prepara the [[PE PFFOOSAAR[|135416[[2a0m35[[EssppmEob-ott00000Z ppe || [[EMFsOSsEOR[|6101s4 [[3T6o2a[[ssppo-oit00pp (ProSER [71[162[spo-tobopp ||| DLTOq ales in, oni,andis,deyPa wer okSaal opdreettenrymisnterde.isTpwononsceuc,rvqrevsoiienrnea,ccehh,oRefetsMhpeDosLnem,saeetsrdicLeOsrwGetwr,ielbelxbotriao,ctseHdmOaeNnKdvYain,all0ey4zDeddwivetehtmehreesrdaebqbaitasbertum0 Plssec LOQ Summary ndMDLsayin BTS-$-40 & 50-1forferinformation. chenB:MDLLOGQSumi 3MEnvironmentalLaboratory Essar Page 805 Pettis Page 47 3M Medical Deparment Study: T-6859.6 ~ mean cr---- ARGUS 418-020 Analytical Report: FLAICMST TE0O0X--2176348 7 Compound: PFPOrSepared ngs| LOREom| Recovery| RSD- ` RabbitSerum| ofsundarts | oo) eel) curve |G) Range | Range [ome[n ||wwe | [x em [oem|snr |sows| Compound:PFOPrSeAparedrage| LCRfom | Recovery| RSD RabbitSerum| oofosanmdad)s || Gcavae | Range | Range [[[[FoirixertmmeL|[ommrmmes|[|en emmonoe||m ooew|m]]|awsw|||| Compound: PROFSreApaArsd range| LCRAom | Recovery| ESD RabbitSerum| Oorfs)aGndoarls)|| GgcGuorbv)e Range | Range [[moione[| mommar[[oaonn||wm||owns|| [m[o oon|r wow |s aw | AaBcMDh LLOQeSwmnmiy 3MEnvironmental Laboratory | ETS841 Page 806 Page12014 Page48 Sisstve ~ summons i or =---- ARR ARGUS 418-020 rs ET RabbitSerum| ofstandards | curve Range Range. * Rvacmes ||owwoe|| weaws|_ on | wsms|| (ppb)(ng/ml) (ppb) (ng/ml) [-- xen[|owomm[[owmne||oowmn ||wovnee|| =SBSe| |1 [[rFeeree [[w(opponb)m(angn/ml[)[reo aoy nn ||wwre ||wwwre || [[oBFroroeTm|o--omme [[aomorn ||oewr ||wwooews|| CESTT TT [Fee| womms [ (ppb) (ng/ml) 2a(pob,)s |we|oo| [[[ iRmno[[oow onne[[[rwoaro eee|||wwmoenwm ||| owwowes||| wa 3MEnvironmentalLaboratory Page 807 on Pagde9 3M Medical Deparment Sudy: T-6889.6 omens porer ARGUSoT LIVS E00-2738 AnPraelp ydatte:(s: + Samplematrix: Methodrevision: Ion Pair StandSEatqraundidpaCmruednrstvuemnubsmeb--re:Frl:uids FBilnaaaksfuaidvidaeenntaniTfetNr:: F`CTarmgietxantadlyate(ps):p0r.5o00spp.m: FFSCCmumiirxxrssttdodatadgpapapppptrorr5ex5..o00o1000ppsx0ppp..mmp::m: Acta ualconceofnstatndrardasintthieFoCmnix Som: Suc Scone Seon Swen: Sweme| Am Faslwl [[Coossoo0 T--oosso07[Taass [TsossaTTossaarT[oossoo ||"oomon[Toonrss]] [[ST30e00[[ssomr[[ssomT[ssaorrTTssaarr[[ssoorToooom i1oonn]] [OSE00[sor[E soJ Tsar sa [sC or om om]| I IE 0W X BW BCC M7 E [m0[sr|w2TsuTs 1sor | ooo | wos] CaFlTicOunlSiastedFcFoOloiSnnFFciRlOSieAooAnfnstPaBtnOidSarroEdsianFFRtOthSaEeAsoiampoFleaWEmniatarsixSSadmoes AniApTsel ww -x : ts [C4o Te s TT h sa0e "T74n96TosonrT513w5e |1100 T0005 | I C2 c WC m LE 3 9 E NNS J 2 CN NC TO1 CE J AJ | - Validatedranges -spprozimateconcentrations [_Senm | Pros PrOSA___PROSAA EWOSEOW_FROSEA WN [Rabb A ---------------- 1300-100]_SO0-1000_]_S00-1000 |S00-1000|S00-100 |300-1000 | Rar Evinsonly Usevaluasformbon [Monkey & Plasma| Eimates only.Use valves formbot Aeachmes C: onPi Sadar Curves 3M Environmental Laboratory ETS Page 808 Page 14014 Page $0 3M Medical Deparment Study: T-6889.6 ~ ermine`Ana--lyti--cal ReApRorGt:UFSA4C1T8-T0O2X0-164 LIMS E00-2738 3M ENVIRONMENTAL LABORATORY ' MeTsOD EXTRACTION OF FLUOROCHEMICAL COMPOUNDS FROM SERUM FOR ANALYSIS USING HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-8-4.2 Adoption Date: 03/01/59 Effective Date: 3/2101 Approved By: Labor2atory Mc anageL r LbHe Group Leader o/b fey Dae ox0x/e1 Dae LO SCOPE AND APPLICATION 11 Scope: This method is for the extraction of fuorochemical compounds from serum. 12 Applicable compounds: Fuorochemical surfactantsor other fuorinaed compounds. 13 tMhaetrviacliedsa:tioRnabrbepio,rta.t, bovine monkey, and human serumo other fa o Ledne)i yTFigisast 20 SUMMARYoF METHOD 21 Tshulifsonpaetrefo(rPmFaOnSc)e-obrasoetdhemreftlhuoordodcehsecmriicbaelssuthrefparcotcanetdsurferfoomrseexrturma,ctoirngotpheerrflluiodrso,ocutsainncg-an tfhoen spaaimrpilneg arenadgtehnet aannadlymteet-hjyoln-fpearitr-ibutpyalrteitthieorne(dMiBntEo)M.BAEn.oTnhpeaiMriBngEreeaxgternatctisisadded to r1e.0momvLedofanmedtphuatnooln,tothaennifterorgeedn etvharpoourgahtaor0.un2tiulmdrnyy.lEoancfhieexrtsraicntgias r3e-cmonLstpiltausttiecd in Word 695 3M Environmental Laboratory Extractionof FEsTcaSch8e4mi2cals from Serum Page 809 Page 1ar1s Page 51 3M MedicalDeparmentSudy: T-6889.6 TE anon RRSLIMVS ES00-21B763s8 syringe into glass autovials. (Applicationof this method to seven fluorochemicals was demonstrated: PFOS, PFOSA, PFOSAA, EtFOSE-OH, PFOSEA, M556, and a surrogate {22 `standa These rd (see sample 3.0 Definitions). extracts are analyze d folowing met hod ETS-5-5.2 or ther app ropri ate method. 30 Demons 31 PFOS: perfluorooctanesulfonate (anionofpotassium salt) CsFiSOy 32 PFOSA: perfluorooctane sulfonylamide CiFirSO:NH; 33 34 PFOSAA: perfluorooctane sulfonylamido (ethylacetate CsFinSO,N(CH:CHy)COH., E(FOSE-OH: 2(N-ethylperiorooctanesulfonamido)-thylalcohol CaF 12SO;N(CH:CH;)CH;CH:0H 35 PFOSEA: perfluorooctane sulfonyl ethylamide CoFinSO;N(CH;CHy)H 36 37 M556:CFnSO;N(H)(CH:COOH) Sumogate standard THPFOS: 1H-1H-2 H.2H p e rf ls or o oe ia ne sulfonic ac id 44.10WARHNeaIlNtGhSaAnNdDsCafAeUtTy IwaOrNnSings 4.1.1 hUasneeluinnigvearnsialmaplreicsasuutei,onwsh,iceshpemcaiyalclyonltaabionraptaotrhyogceonast.s, goggles, and gloves when 55..01 INTTEhRFaeErRerEnNoeCESinterknfoewnraet tniscteimse. 6O1FoTuheenfoelwlorwing equipment s used while perfothrismmeithnodg. Equivalent equipment is `accep 611 t able. Vortex mixer, VWR , Vortex G e ni e 2 . 612 Centrifuge, Mistral 1000 or [EC 6.3 Shaker, berbach or VWR 61.4 Nitrogen evaporator, Organomation 615 Balance(0.1009) Z0SumwMammas 71 Gloves 7.2 Eppendorf or disposable pipettes, plastic or glass (or equivalent) 73 Polypropylene bottles, capableofholding 250 mL and 1 L (Nalgene or equivalent) . 3M Environmental Laboratory Erssa2 Tr Page2of15 Pages2 Page 810 3M Medical Deparment Study: T-6889.6 ~ emeens oAnarlytmical RAepRorGt:USFA4C1T8.T0O2X0-164 LIMS 00-2738 74 Volumetric flasks, glass, type A 75 40 mL glass vials (-CHEM or equivalent) . 76 Cenifuge tbes, polypropylene, 15 mL t 27 Labels 78 Botle-top Dispenser ~3.0 to 100 mL or a 5-10 mL graduated pipete, ghiss 7.9 Syringes, capableofmeasuring5 WL to 50 pL 710 Graduated pipettes 7.11 Syringes, disposable plastic, 3 mL. (B&D or equivalent) 72 Syringe fiers, nylon, 0.2 pm, 25 mm 733 Timer 7.24 Crimp cap glass atovials and caps 7.15 Crimpers Note: Priotorusing glasasnwdbaotrtese, rinse 3timeswithmethanoland3 timeswith water.Rinsesyringes aminimumof 9timeswithmethanol, 3rinsesfrom 3separatevias. 8R 0 escersaoSmaamns 81 Reagent grade water, Mill-QTM, NanopurIe or equivalent 82 Sodium hydroxide (NaOH), LT Baker or equivalent 83 Tetrabutylammoniam hydrogen sufate(TBA), Kodak or equivalent 84 Sodiumcarbonate (N&:COy), J.T. Baker or equivalent 85 Sodium bicarbonate (NaHCO), J.T. Baker or equivalent 86 MethyhT-Butyl Ether, Ommisol, glass distilled or HPLC grade 87 Methanol, Ommisolv, glass distilled or HPLC grade 88 Serum or blood, frozen from supplier 89 Fluorochemical standards 89.1 KPFOS (PFOS) (3M SpecialtyChemicalDivision), molecular weight = 538 892 PFOSA (3M Specialty Chemical Divison), molecular weight = 499 893 P58F5OSAA+H (PFOSAA) (3M Specialty Chemical Division), molecular weight = 89.4 EFOSE-OH (3M Specialty Chemical Division), molecular weight = 570 89.5 PFOSEA (3M Specialty Chemical Division), molecular weight = 527 89.6 MS56 (3M Specialty Chemical Divison), molecular weight = 357 897 CSuirFroygSaOteH,sta[nTdHaPrdF:OS4]-H),, pmeorlfelcuuolraorocwteaingehtsu=lf4o2ni8c acid(1-H, 1-H, 2-H, 2-H 8.9.8 Other fluorochemicals, as appropriate 3MEnvironmental Laboratory ETS842 Page 811 Page 3011S Page 53 3M Medical Department Study: T-6889.6 ~ meee orAna= lytical RAepRorGt:USFA4C1T8-T0O2X0-164 LIMS E00-2738 8.10 Reagent preparation NOTE: Wphreepnarparteipoanr,iandgjduisftfarcecnotrdvinoglluym.es than std i reagen, standard, of surrogate * 8.10.1 11000N0 ina 1 msLoLdpiobuleymapkhreyordprycoloxneitndaeie(no(irnNgeaqO5uH0i)0v:amlLWe.netiw)agbtheora,tpmp.iroxxiumnatteallyl s2o0l0ic sNraeOdHis.soPloveudr. inSttooare 8.10.2 w11a0NteNrs,oNdaSitOuomHrhsyoidlnruaotix1oi2nd5eimt(LoNap2Oo1Hl0y)p0:rmoDpLiyllvuetoneleu1mo0etrNrieNcquafilvOaasHlkena1t:n)1d0b.boriMtne.gats0urveol1u0mmeLusoinfg 8.103 o0.f5TBMAtienrtaob:ur1yLlavmomlourmieutmrihcycodnrtoagienninsuglfSa0te0m(TLBwAa)t:eWre.iAgGhjapsptrtooxpiHmat1e0luysi1n6g.9 & Spproximtely 44 to 54 mL of 10 N NaOH. (Add the fast 10 mLofNaOH slowly, ``asptohlyeprpoHpcylheanneg(eosraebqruuipvtallye.n)tD)ibloutttleet. o volumewithwater. Storeina lL 8.10:3.1TBArequires checkpriortoeachuseto ensure pi = 10. Adjusats needed using 1 N NaOH solution. 8.10.4 0.25 M sodium carbonate/sodium bicarbonate buffer (NayCOYNaHCOy): Weigh `baipcparrobxoinmaatteel(yN26a.H5CgoOfnstoodiu|mLcarvbolounmaetteri(cN8fl;aCsOkya)nadnbdri2n1g.0ogvooflsuomdeiwuimth water. 811 StandarSdtosrperienpaar1aLtipoonlypropylene (or equivalent) bottle. 8.11.1 Prepare PFOS standardsfo the standard curve. 8.11.2 uProerpoacrheeomtihcearlflsutoarnodcahredmsicaarle asctcaenpdtaarbdlse, (afsosrpepxraomprpilset,e.onMeowlotrckoimnpgosnteanntdard solution containing approximately 1.0 pg/mL of PFOS, PFOSA, PFOSAA, PFOSEA, M556 and EtFOSE-OH). 8.11.3 hWeeiAgchtaupspwreoxiigmha.teFloy 1s0ta0nmdagrodfsPwiFtOhSKCinotfo oat1h0e0smtLs,vmoluulmieptlryicbyflasCkorarnedctrieocnord ewfaqcutaeotri.oiFnoo:f rgPeFxhOamSpl=e,439t.heCamlocluelcautlearthweeciogrhrtecotfioKnPFaOcStor=by53u8s,inagndthtehefmoolloewciunlgar "mreotlecadrr w. KPPFROOS(C53)8) (onc 8.11.4 Bring t volume with methanol for a stock standard of spproximatly 1000 g/mL. 8.11.5Dilutethe stocksolution with methanolfor a workingstandard 1 solution of `approximately 50 pg/mL. 100s /mixsnL) 8.11.6 Diluteb workinl g stan] dard 1 SY with methanolfor a working standar2d solution of approx. 5.0 pg/mL. 3MEnvironmentalLaboratory Ersaaz Tr Pageaotis Page s4 Page 812 3M MedicalDeparment Study: T-6889.6 = meee on na-- viesRAepo FACEyB14 LIMS E00-2738 (Soeu itmLxniont)) _ sou : 8.11.7 Daiplpurotxe.wo0r.k5i0nuggs/tLa.ndard1 with methanol for a working standard 3 solution of Sougiiminxiont) ) _,0500s nL 812 Surrogate THPFOS stock standard preparation 8.12.1 W(CeuiFgyhySaOp;pHro(xTiHmaPtFeOlSy)50i-t6o0amg5o0 mfLsuvroolguamtetersitcafnldaasrkda1n-dH,r1e-cHo,rd2-thHe,a2c-tHu,al weight 8.12.2 B1r2i0n0gptogvao.lume with methanol for a surrogate stockofapproximately 10008.12.3StPocrkteoapas1ua0momrgLaevtoelwuomrektirincgsfltaasnkdaanrdd.brTirnagnsofervoalpupmreowxiimtahtmeeltyh1amnLolofforsuarrogate working standard of 100 pg/mL. Recordth actual volume transferred. sosamEHMOINe 91 Allsumplesarereceivedfrozenandmustbekeptfrozenunitheextraction iperformed. 92 Allowsamples tothawat room temperatureorin lukewarm water rir toextraction. MwooQuumvCowmoL 101 Solvent Blanks,Method Blanks and Matrix Blanks 10.1.1 Solvent Blanks: An aliquot of 1.0 mL methanol i useda asolvent blank. 10.1.2 aMnedthuosedaBslamnektsh:oFdolblloanwkisn.g this procedure, extract two 1.0 mi aliquots of water 10.1.3 MCoanttrrioxlmBaltarnikxs:frMoamtestbluadnykcsonatrreolpraenpiamraedrfercoemivoendweoifthteraecehssoaumrcpelse: s1t):a2s)tuady cSoumrmteorgcaitealmlaytorbixt,aaisnoeodsbatmapinleeodfctohmemsearmcieasple,cibuetsaosftahedisfteurdeyntansipmeaciless;tohran3t)he `Smtoundkyeanyiormarlat(es.5e.raifsrtaubdbyi)t.Tihuesemda1xgentoeursaetdesptaennddasrodcnurwvheastamnatdrCixCVsufsoerdfaor the curve. 10.1:3.1cSutruvdey,pcroenptraorletmawtroi(x:2)cmuartrviexb--ltIahnfekssutsuidyngctonhtrsotlumdaytcroinxtirsoulsmeadtroirx.the 10.132pCroempmaerrecdiuaslilnygobctoamimneerdci(aslalmyoebstpaeicineesd)mamtatrriixxicntuesramvetsehpeecciuersv2sisthe Savtauidaybalneimmaalt,ipxr.epare two matrix blanks using this same commercially 3MEnvironmental Laboratory ExiacionofFoEreTcShe8m4i2cals rom Seu Page 813 Page sors Page 55. 3M Medical Department Study: T-6889.6 ~ "means o`Arna= lytical ReApRorGt:UFSAC41T8T.O0X2-0164 LIMS 00-2738 10.133 cSounrtrionguaitnegmcaatlribirxactiuornvveer--ifIiafcastiuornosgaamtpelemsa:trix is used for the curve and : a) preparetwo (2) matixblanksusingthesurrogate matrix. b) Al`msaotr,ipxrseppiakree/maamtartirisxpbikleandukpwliitcahtceaacthosnetloefvmea)truisxinsgpaikceosm(maesrectiaisllay. availablematrix ofthesamespeciesas thestudyanimals. 102 Matrix spikes 10.2.1 Study Control Matrix Curve No matrix spikes are prepared. 102.2 Commercially obtained matrix curve (same species) No matrix spikes are prepared. 102.3 Surrogate matrix curve stMuadtyiaxnsipimkaelsaanrdenaescuersrsoagartyeifmmatartiix.iissnsoetdafvoaritlhbleecuirnvteheasnadmCeCspVesciaemsplaesst(he5.. troabmbeiassuerraabmlaeylebveelusosefdetnodgoegneenroauts satnaanlydtaerdicnuthrevemsofnokr eaymsoenrak)e. yPsreerpaasrteudayn,ddue atnhaeleyxztermaacttiroinxsfpoirktearagnetdmanaatlryitexss.pikeduplicatesamples toverifytheaccuracyof 10.2.4Pcroenpcaerntercaatciohn)MSsianngdaMsSaDmpaletcthwoos(e2n)blyevtelhse a(nuasluyasltl,ytaylpiocwaallnydsemriad-frraomngaecontrol group animal received with cach sample set. 1024.1`Imfatthreirxsepiiskneostussuifnfigccioemntmesrecraiaalvlaiylavaabielfarbolemmtahtericxontrroolmtghroeuspa,mperseppeacreies25 the study animal. : 10.25 pPerre2pa0resaomnpelemsa,twiitxshpi8mkeanidmantorfiix2smpamitkreiudxuspplimikceastpeeartleeavcehlpleevreblaittcehd.Iifna1b0a.t2c4h `Tioncwl,udoershmiogrhertahnagen2le0vselasm.ples, additionalspikesmaybe preparedatthesame, 10.2.61aftmaoprpertoxhiamna2te5l%yo2-f5thteismaesmptlheeesxapreect<eLdOLQO,Qt.womatrixspikes should be prepared 10.2.7 1afddtihteiomnaajlormiattyroifxtshpiekseasmsphloeusldarbeae proerpaarbeodvetotahpphriogxhirmaantgeesoaftmhpleeccuornvcee,ntrations. 103 Continuing calibration verifications (CCVs) 10.31 vPerreipfaicraeticoonntdiunruiinnggacnaalllybsriast.ioPnrevpearrifeicaantdioannsalaymzpeleCsCfoVr ifnosrtreuvmeernytasstsaabyilirtuyn, regardlessofthematrixtypeused topreparethestandard curve. 10.32pPrreeppaarreeethachinciotinatlicnuurivneg(cial.ibratthiorntvhereisfticuadtyicoonnftrroomltmhaetrsiaxm,ecmoamtmreirxcuisaledmattorixof same specie, or surmogate matrix) 3M Environmental Laboratory ETS842 or Page 814 Page6of15 Page s6 3M Medical Department Study: T-6889.6 = meee Aornal= ytical ReApRorGt:UFSA4C1T8.T0O2X0-164 LIMS E00-2738 10.3.3 Tcahleiberaxtpieocntecudrcvoen;cteynptircaatliloynstohfetlhoew CtoCmVisd-wrialngfeaollftwihtehincutrhvee.rangeofthe initial 1 103.4 Pcreoparne,catea mnpientrigmruromu,aptotwfo1ic0onostaimnnpuli,ensg.cFaloirbreatioxn veariiffimcaastiapomnps,lleesaeceht=at3,a4d,ieffiegrhetnt c(8o)nccehnetcraktsiaorne. prepared; four (4) at & low range and four (4) at a mid-range 1035 `Amdidditoirohnailghcroantnigneuicnongcceanltbrraattiioonn. verificationsmaybe includedatthe same, low, 1C10ALBRATIONANDSTANDARDIZATION 111 Prepare matrix calibration standards 11.1.1 aTvarialnasbfleesr|emrLa,isoufsapepdr,opprreipaatreestewroummatoriax b1l5amniksc,eunstirnigftuhgeetvuoble.uImfeocfomsmeerracially `available for most study animals 11.1.1.1aDvaeipleanbldei,ng suuproongsatluedmyagtorailxsmoariyfbaenuasleytdefforresgecnoemrmateirocnioalfethreacsalnbortation staatndstaurddi.eFsiofrqueaxnatmiptlaet,iornaobbfitesxetrreammealyybloewusleedvaelsoftshuerraongaaltyetmeaitsrriexqfuiorred. 11.1.2 vIof mloumsetsseaqmupallevtootlhuemseasmapreleevsoslutmheasn1..D0omLn,oetxetxrtraaccttstasnsdtahradnsw0i.t5h0mmaitroifxmatrix. Recordcachsamplevolumeon teh xtractsiheoetn. 11.1.3 Wsehrialbeeptrweepearnianlgiquottost.alof thirteen aliquots in 15-mL centrifuge tubes, mix or shake 11.1.4`TTywpioca1ll-ymuLsealtihquesott,anodaortdhceorncaepnprtorpartiiaotnesavonldusmpei,kisnrgvaemoa5unctursvleismtaetdirinxTbalbalneks.| at tthweoemnadtroiftxhblsasnekcs,tiaonndtotswpoikmeeotnheosdtbalnadnaksrdcurve,foa totalofnine standards, ILLS rRaengfeestraonvdtaheLlinieraderpCoaarlitbtErTaSit-i8oon-4R.na0ng&e(ELTSC-R-)5.fo0r-cVa-l1r,atwihoincchulrivstesst.he working 11.16 SSteaendSaercdtsi,on 13.0 to calculate actual concentrationsofPROS in calibration 112 Tsuorcraocgahtestwaonrdkaridn,gbsltaannkd,caorndttionuaicnhigcevheecakc,onasntdasnatmcpolneceandtdraatnioanpptrhoatprailastewaimthoiunnttheof ccaolnisbtraanttiocnonccuernvterartainogne oinf2a.ll5snamgp/lmeLsa~t10a0p0 npg/rmoL.xUsiu5am0ll0ayn,tgs/aemmpLlloeyrs aortehesrpickoendcefnotrraation as determined by the analyst. 113 EtoxtersatcatblsipsihkeeadcmhaitnriiaxlsctaunrdvaerdosnftohlelToawisnsgs1p2e.c6t-r1o2m.e1t6ero.fthis method. Use these standards 3M Environmental Laboratory ETS842 Crm Page 815 Page ols Page 57 3M MedialDeparment Stuy: 6889.6 TE pain ARSELAMSHE0R03173a8 ,` Approximate spiUksiinngg aLm`0oTumanlblt.esof1fomrsattanedards and spikes Waorpkpirnog.scioanndeard "Apipreox. faa lcon. of ES-- -------- ------ 112210PRObOtCaEiDnfUrRoEzensamplesandslow tothawat room empraarso fn akewarm we, 122 iSLabeesl a15mmLipeSlryepetrioinponynlgeedSnwecoepmnartfegse(tuAbenwaihctmhe stoufdsymauntbewr,orsahmepsle)Do,xdate and 123 V1or5temxmpioyfporop15insescconodsgthsenuaen.te1.0mL rotor appropriatevohame(0 the 124 Returnunusedsamples tofreezerafter extractionamountshavebeenremoved. 125 12:6 RSSepcmoersdaht!hseaminpilteisal,vboalnumkesoanndtsheanexdtaradcstitohnatwoarvkesrheeaedty(fAotrteaxchrmceinotnAiorhsismuilraorgse 127 SEpikaemeeaschnadleLbrreoaordnTnasba1ln1ed2a,1rmd mtaiiecwoitnh,thoeraphpercouprriaatiimoonuinrtoefasnadnard.asAlso 125 oVoriteex mnittheosetasndardcuorressaamapldesc,ommiiingspeiakle saaimpolnes,maandrcson.tinuing calibration 125 CShuepclkstofocru1r3esetchoend0s.,5 M TBA esgen sa pH 10. 1 or, dustaccordingly. 1210 SToeasbcohsnaamtpbluetea.dd 1mL0.5 MBA and 2 mi of025Msodiumcarbonated 12.11 Ubsoiyngreanebrottle top dispenser or 5-10 mL graduated glass pipette, add mL methy-tert- 12.12 Cap each sample and put on the shaker at asetting of 300 rpmfor 20 minutes. . Eras Paeborts 3M Environmental Laboratory mm ------ Page 58 Page 816 3M Medical Deparment Sudy: T-6889.6 ~ meee oArna= lytical RAepRorGt:USFA4C1T8-T0O2X0-164 LIMS E00-2738 1213 Centrifuge for 2010 25 minutesa a setting of 3500 rpm or unc layers re well separated. 1214. Labaferelsh 15mL centrifugetube withth sameinformationas in 12.5. , 1215 Remove 4.0 mLofth organic (top) layer to this clean 15 mL centrifuge tube. "12.16 Phuoutresa.ch sampleonthe analytical nitrogen evaporator until dry, approximately 1 to 2 1217 Add1.0mLofmethanol t cachcentrifuge ubeusing graduatedpipette. 1218 Vortex mix for 30 seconds, or longer if needed. 1219 Lnuarbaeblera,1a5nmimLalgulmasbsearutaovnidalge(nodrerl,ows-avmoplluemiemaeutpoovita,l mwahtee,neGcoeaslsasroyl)vewnit,thextthreascttuidony date, and analys() performing the extraction. 1220 Aeutpac1h2.21285tmotmhi,s0s.y2riangme.nyFliolnemresthotfhieerla1b0e.le3dmaLwt.osvyirali.ngeandtransfee thesamplefrom 1221Capandstoreextractsat oomtermopraearppraoxuimarteley4 Cun analysis. 1222 Cthoempstluedtyebtihnedeerx.traction worksheet (AttachmentA or similar worksheet) and include in 13.0 DATA ANALYSIS AND CALCULATIONS 131 Calculations 13.1.1 CcaallicburlaattieonacsttuaanldacrodnsceunstinrgattihoenofofloPwFiOnSg,eoqruaottihoenr:applicable lorochemicl, in a7 in+kmoLf osfe sucroogntceedr+niofisildmiagc/mviol)ane(nD) oTeo HRALIst 2503 in 140 MeTop PERFORMANCE 141 TfohresmpeectihfoidcdMeDteLcatinonlliimmiitt(ofMqDuLan)tiasatniaonl(yLaOnGd)mvaatlruiexssp(escecifAitct.aRcehfmeernttosMBDaLnredpCo)r.tAt thediscretion ofthe PAL,MDLmayno bedefine forsomestudies. 142 Tthheeqfuolaloywoifngtqhueaelixciyrccotnitornolansdamapnalleyssiasr.e extracted with cach batchofsamples 10 evalu: 14.2.1 Method blanks and mat. blanks. 14:22IdfuspulrircoageatseammaptlreisxiosuvesreifdyfoexrtcruarcvtieoannedffQicCie,ncmya.trix spke andmatrixspike 14.233 Cinotnitailncuailnibgractailoinbrcautriovnec.hecksamples to determine the continued accuracyofthe 143 Refer to section 14ofETS-8-5. for method performance criteria. 3M EnvironmentalLaboratory Furaion ofEEnoTrSme8m4ie2als fom Sorm Page 817 Page9otts Page 59 3M Medic} al Deparment Study: T-6859.6 ~ mess wrAna--lyt--ical RAepRorG:USFA4C1T8-T0O2X0-164 LIMS 00-2738 ,: 1W 515..01 PA ODLiLsUpS oTsIeOoNfT PsRaEmpVlE EeNwaTsItM Oe,NAfNlaA DrumablN esolveA nt waG ste anE d usedM glassE pipetN e wastT e using proper roethodsandby pacingcach ntheir designawtasetde container. 160 Recorps pe--r ------------------ee-- e -- 16.1 Cioncmlpuldeetien tthhee sextturdaycbtiinodnewr.orksheet attached to this method (or a similar worksheet), and v17o.1AmAtctamchmeenat sA, Extraction worksheet (a similar worksheet may be substited for `Autachment A) 172 Attachment B, MDL/LOQ values and summary 17.3 sAutbtsatcihvmuteendtfCo, AItotnaPcahimreSnttanCd)ard Curves worksheet (a similar worksheet may be 180ReFpmeNces 18.1 The validation report ass oc iated with this method s ETS-84.0 & 5.0-V-1. 182 F'HAPCLTC--ME-le3c.t1r,os"pArnaaylyMsaisssofSSpeercutrmomoertOrtyh"erFluid Extracts for Fuorochemicals using 183 `ESTeSr-u8m-5E.x2t,ra"cAtnsaUlyssiinsgoHfPPLoCt-aBslsciturmoPseprrfalyuo/rMoaoscstaSnpeesucltfroonmaetteryo"rOtherFluorochemicals in 1A 199.01 r ETS-E 8-5.2,c"AnaT lysisoE f PotaD ssiumD PecfuoO rooctC anesalU fonatM e or OtB her FN lorochT emicaS ls in `Serum Extracts Using HPLC-Elecrospray/Mass Spectrometry" 200 Revisions --_-- Revision Revision NumTb er Secon1221Conga oincodesRaemaplseosnFaoorRervoismionpers [Da=te SSceieonn 112..1137FAiddsevd ioesmr1.0m spdottdforflvoles ssa LOL 2 Sc5i1onAUL1K201PEFOmSin pss'fromprcrocanentnsc 1502311A0H24I, P14F2.O2SAAddRnos sbout in roemai,clsycorrme 0d s1p0i3kiCnlgshteyp curv, ce hoifngnst ipski0lvbtryni20osnecmhpelckess: 10.1 Aed rinshotcontro siasa, ing nd cksin comcElyavaible nrpbcn,mbakee msysbpeeii.oreqipmendspSloibca. waer o MQ, Nalgee 3MEnvironmentalLaboratory Frainof FETrSe84r2e fre Som. Page 10015 Page 60 Page 818 3MMedicalDepartmentStudy: T-6889.6 Extraction WorksheT etETE S6-42 en eR Livis E00-21738 BSV ooee n :S[soasgae|| oFrCo0Ms|| on | pFootvs ml || | sFpOoVn|T ms Com| V=ee DuWeoSmpied SS pews J ----r---- rr TT --wT TT woTT rrTT A em me fCr---- te---- ee He}eer}et--e---- fo,mrmmm esserp e taem------------ rrrTTT eefmeererasmeet---- ]-- ------ ---- -- rrrT rr Semmes ---------------------------------- a Dr rr TT Fe i----------------------------r-- --rT TrTT rT TT rrr rT ------ rr rT -- Tr rrrrT oe m -- I aT----s--l----r--------r---- rrrrr rrrTT eI Le--r-- -- r----dda rrr t I eat et ) rT TT e [m oee asumsi e nse| [p PoemH imi= oro_ smA_ H_ I __________[ _s| ae [Pioene 2mi of025 NaCOVOISMNaiCOnBuller___ swe | CCCoromm mmeme.sprswemr Foam Comme EE [DAhdiimmebtoanas vVoowwme Eh ns whsa i mL x ce Cwoeemweeesss wweea 1 { T | ] || AopenA:Exasion Wishes 3MEnvironmental Laboratory Essa or = Page 819 Pagetot1s Page 61 3M Medical Deparment Suds T-6589.6 ~ cme w`rAnamlytiecal ReApoRrtG:UFSA4C1T8T.0O2.0164 LMS E00-2738 'MDL/LOQ values for rabbit serum `Compound | MDL LLOQ | Linear Calibration Range (LCR) (ng/mL)| (ng/mL)| Approximate concentrations to be used for preparing [0 Fos | 17a | 555 t[5nhegS/tmalnd1a0r0d0Cnalmibration Curve [[PPFFOOSSAAR [|135416||427095 ||SSooggmmiiitoooooomnggmmee | [EFOSEGR| 114|362 |Sngmitooongmt [PMroDSLEIALlO|iG5in1ut,|bov1is8mo2nk[s,Sanndgnhiaiosoeonrganndt eyPAS weemo sical deine,Tw curveinchof(se ice weeexacted ndrly with he eb sem `acubrvestopdoertetrsm,ineequoivra,leencet.MRDesLp3on7sesLiOnthweiralt,bbeotvhinse,umeonvkaelyo,sanaddheucmmainoweedre1esqubivalesnettrovt.he Pleasese LOQ SummarysndMDL sy in TS-8-4.0 & 50-V- fo fer information Appenix 5:MDLVaIlessLdSOummQarycrlETmS8a42o om 3MEnvironmental Laboratory Page 820 Page 20115 Page 62 3M MedicalDeparmentStudy: T-6889.6 TE cn RRRALB16s eseTEEr [| TTSi [[ imam [wm om[[oaso mm|wwmmn |o[osme| [[rxene[[mroanm[woomn|[wn[|oswosn|| [orsas [rime ToFmvEipne[[|Taoms[|TwRIm | Svou|| [[rieenee[|osram ||somem|| owms[|soww || fr [om [mre[oom |ss| [[rpomssse[| eEPm|oEsoSinne[|o7[Swr]|wwe|| [[raarntes[| omaen ||saoom[owrmo||ocosr|| [oe om [om | wn[wm | J. omTE 3MEnvironmentalLaboratory ~ Page 821 ---- Page63 3MMedicalDeparment Sud: T-6889.6 TE RaRAv R e3l 0, 0 LIMS E00-2738 -- , = J----=| `Prepared range Recovery|| =RSD [[roeree[| aooon[[owmomme||wwoo|| wisan || [ sreen )i T = [|mr=To oEr[wT[m|Rw [wan]| [[pmaermee[eoonm [oowsnm[[womn[|weena|| [ L --L Pe S Towm [wwo [mr| [[Fireree[[rooomme[[ommn[|mwemr||oooon|| [[opee[ormse[[woowms[|oomn |amwoosm|| esAmy 3M EnvironmentalLaboratory . Page 822 eres Page64. 3M Medical Deparment Sudy: T-6889.6 ~ meen Arnalywtical RAeRpoGrUt SF4A1CT8T0O2X0-163 LIMS E00-2738 ExampLs Asabsts) Ton Pair StandSatruddyCnumuberr:-vFleuisds [AnaR lysey): FiBlnaanklsBoidldevanneldeTnrNt:: nReen d ms wsere `Study AnimalMatrix Se TMaertgheodainreavlsyisone:: FC misstdapp0r500opr.: Fes POE STOP FCmixstdapprox. 5.00ppm: (hodthe saesac$useddiotopr ga hethe extractedcarves. ) Surrogatestd appro. 100 pp: SAFcotOmaS]econcSRenoOtrSmaAetionsSoPfaRsoOtSamAnedAardsSBonImOtSheeEFCPSmRuiOemSienEmethSaMnesolsc.|| AAIm FaANv [[sCooossootoToosssooorrT[ [oos5 ssasTToossosorr[Tasosaseisr[Toosssooi |||oooooomnnT[|tfooosnss||] [sSoow isome[r ssoxny[so soorra|w sarKswor||oooomn[tioons]] [[ssooooHfsbr B srkEobI irKK olflB BNeoa T|oooonn[1r0on5]| ([ssooooT[ssooirT| a2[|ssoorr[Tssaair[[ssori||oooosw |ttoosws|] Fr0S CalculatedTcFOo SKncFOeSAn oAft |star BnIdFaaOrSdt EsiintPoRhOeSnsEeAs ra mMaStrSix: RaSbabrivtpsn AT E = e ue: enn [aes ~gr--a12631248 252W258 | Surroms A7 | [ors f &o MNTNof WowNLok| nmi [oe W259 /R ONE & JRF Fos,| so [aon SR2 ACI SeS 7 Bod 2S| ome os | joss | om | os | dow | La Validated ranges - spprosimate concentrations [Seum | PFOS__PFOSA__PROSAA EWFOSE-OH_PFOSEA _Msse | [ ho EmmT aalyUGeewwehmamh e---------- ------m ----------| [Monkey& Plasma | Esumstesonly.Usevaluesforrabbit | [Fuman |Etimaesonly.Usevalvesformbbi | AchmetC: onPicSuntrdCurEvesesofcFErToiSheeom4c2anls romSerum 3M Environmental Laboratory - Page 823 Page 150115 Pages SM Medial Deparmens Sed: 68896 TT te Repo FACTOR164 _ LIMS E00-2738 3EMNVIRONMENTALLABORATORY ` METHOD ANALYSIS OFPOTASSIUM PERFLUOROOCTANESULFONATE OR OTHER 'FLUOROCHEMICALS IN SERUM EXTRACTS USING 'HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-8:5.1 Author: Lisa Clemen, Robert Wynne Approved By: g1 lV3ee Taboratory Manager| Voto flo Group Leader `Adoption Date: 03/01/99 Revision Date: 4/26/71 000 "jZace, Dae 9/2095 Date TecHhnuicdalRevDiomeewser 04}Da2:t0e/91 a Ow = BactCopy of y22 l0ScomaArucsnon 1.1 Scope: Thismethod describes the analysisofserum extracts for fluorochemical surfactants `using HPLC-electrospray/mass spectrometry. 1.2 Applicable Compounds: Fluorochemical surfactants or other fluorinated compounds, or `other ionizable compounds. 1.3 Mthaetrviacliedsa:tiRoanbrbeipto,rtr.at, bovine, monkey, and human serum, or other fluids as designated in ord695 Asay ofSEeTamSEsxs1cUsiogESMS Page 069 3M Environmental Laboratory Page 66 Page 824 3M Medical Department Study: T-6859.6 ~ crmeens `orAnal= ytical ReApoRrtG:UFSA4C1T8T-O0X2-0164 _ LIMS E00-2738 20 SUMMARY OFMETHOD {o21thTehirs mfelutihdos,dudseisncgriHbPeLsCt-heelaencatlryossipsorafyf/lmuaosrsocshpemeiccatl rsuorfmaocertsatintmrsiyleax,rtsryasctteedmraosmapsperrouprmiaotre. "fTlhueoraancahleymsiicsails,pseurcfhoramsetdhebypemrofnliutorooroicntgaanseisnuglfloenaitoen (chPaFrOacSt)erainsitiocno,fmiazp=ar4t9i9c.ular `tAhdediitdieonntailtlyyo, fsaamcpolmepsomuanyd bbeyadneatlecytziendgudsaiungghtaetrafnodnesomfmtashspsapreecattroomne.ter to further verify sopeewmos 3.1 AsytsmtoesmpshaelrliocwfPorrevsasruiroeuLsomnieztahtoidosno(fAioPnDi:zaTthieonMbiycruotimlaiszisngQuvaartiroousIswoiuprlceesq,upardorbuepso,lea.nd iPnrteesrsfuarceesc.heTmhiecsaeliInocnliuzdaetibount(aArPCm)ot,Tlhimeirtmeodstpor:aEyl,ecettrc.osTprhaeyiIoonniizzaattiioonnpr(oEcSes,sAitnmotshepsheeric techniques occurs atatmosphericpressure (i. notunderavacuum). 3.2 Eprleescsturreo,spwrhaeyrIeobnyiziaotusioinn(sEoSlu,tEioSnDa:reatmreantshfoedrorefd itoontihzeatgiaosnpphearsfeovrimaedtiantyacthmaorspgheedrdirco.plets. These charged droplets are produced by the applicationof astrong elecrical field. 3.3`MTahesAsPSIpQeucatrtotmreotIrtyr,ipMlaesqsuaSdpreucptorloemseytsetrem(sMaSr)e,eTqauinpdpeemdwMiatshsqSupadercutproolmeemtaesrs(sMeSle/cMtSi)ve: ddeetteeccttoerds.. ATosnisngalreeMseSlemcatiyvebley deimspcrliomyiendatfeodrbiyonmdaestsetcotciohnarorgesreartiieos((mMzS)/aMnSd)fsoubrsemqoureeatly specific fragmentation information. 3.4 tCroinplveeqnutaidornuaplolvse.sZy-sstpermasy(pporsotb1e99in8t)erutfialciez:e aT"hZe-slpatreasyt"mocodneflosromfatMiiocnr.oTmahsesspQruaatyteruoniItied fdirroemctl2ypartotbheecisoorntehaopgeorntuarlet,atfheercpoansesaipnegrtthurroeu.Ighnathteocrotunovuesnptaitohnwaalycionnftohrmeactoiuonntetri.s aimed emlaeicnttreodnea.ncTehaoruegthhethseamceon.fiHgouwreatvieorn,isZ-dsipffrearyencto,mtphoenmeeatihsodasnodfcoopnevreanttiioonn,alclceoamnpinogn,eanntds are ncootmpcaotmipbalteibwlietwhistohmoeontehaenrotZh-esrp,rbauytsoynsltyemWsi,thcSiicm)ilar syste (i. Z-5pray components are 3.5 MIatsrisplLeyqnuxadSroufptowlaersey:stSeymss.teCumrsroefnttwlayreMdaesssiLgynendxfhoarsthWeisnpdeociwfsic9o5pearnadtiWoinonfdtohwessNeTQu4a.t0tro * v(eMrisciornosm.aAslslQvuaetiroIsatrireispiolmeinqluaasrd.rFupoorlmeoMraesdseLtayinlxssoereMtahsesmLaynnuxalNsTpeUcsiefri'csoGtuhideei)n.strument 4W 401 a Healtm h andn Safetyn WarnG ings:savCavmons 4.11 Uemspelcoayustiaonvowlittahgtehoefvoalptpraogxeicmaabtleelsyf5o0r0t0heVporlotb,e. When engaged, the probe. 412 Wanhdecnlohtahnidngl.ing samples or solvents wear appropriate protective gloves, eyewear, 3MEnvironmental Laboratory ETS mm Page 825 Page20f9 Page 67 3MMedicalDepartment Study: T-6889.6 = mens ore ARGUS 418-020 Analytical Report: FACTTOX-164 . LIMS E00-2738 42 Cautions: 42.1 DIfotxhoetboapcekrparetsssuorleveenxtcpeuedmsp4s0a0bboavre,ctahpeaHciPt1y1o0f04w0i0llbairni(ti5a8t0e0apustio)mbaaticckshpruetsdsouwren.. 422 Doxsolo ventt pumprstoudrynness. souegeemeses 00000 5.1 STtoomriagneiomrizaenyinptaerrtfeofreinncsetsrwumheenntatainoanlyzthiantgcsoammepslesi,tceofnltoancsthwoiutlhdtnhoestbamepulseeodrfeoxrtsraamcptl.e: e6o1BoEquumipemewartlistedbelowtaybemodifiedinorder 0optimizethesystem.Documentany `modiinthferaiwdacta aasmtethioddoevinatiosns. 6.1.1 MeilcecrtormosapsrsayQuioantiziaotiIontsroipulrecqeuadrupoleMassSpectrometerequippedwithan 612 H`PLc1o00mlopwapuralnsdteasmuotleovsenaamttpplu,emrpingsystem,solvent degasser,column 1S 701 Sup pplies rEsaoMaTRS 711 igh pity deison platto proimacly 007s ows ie 712 HiPLnCrtaanwahldyatteiacalcolumn,specificstobedeterminedbytheanalystanddocumented 713 Cappedautovialsorcapped15mLcentrifugetubes SR 8O1 eReagaentsceMsawpSTAMNOMRDS 8.1.1 MetHPhLCagradneooequlival,ent | 8.1.2 Meiqluilvia-lQentw,attoedr,malylwbaetperrouvsieddeidnbythaisMmieltlh-oQdTshOoCuPlldubsesMyisltlem-oQrPwoathteerrvoerndor 8.13 Ammoniumacetate,reagentgradeorequivalent 82 Standards 82.1 T`yppriecpaalreldydturwionmgettheheoxdtrbalacntkiso,npwroocmeadturriex.SbleancksE,TaSn-8d-e4i.g1h.teen matrixstandardsare s9o.1 SFarevsphHmaAtrOiMxsItaNndGardsarepreparedwitheachanalysis.Extractedstandardsandsamples arestoredincappedautovilsorcapped15mL centrifugetubesuntil analysis. 3M EnvironmentalLaborato... Asay ofSeEruTmSE8x5a1ctUsiogESMS =... ~ Page 826 Page3ofd Page68 3MMedicalDepartment Study: T-6889.6 = sree rm ARGUS 418.020 _ Aulytical Report;LFIAMCSTTEO0X0--2176348 92 Iafpparnoaxliyosinsawtiellyl4bedCe,laoryaetd,reoxotrmactetmepdesrtaatnudraer,dusaatnldasnaamlpysliessccaannbbeeperreffoigremreadt.edat i 100 QuALITYConTROL pe-- t ---------- 10.1 Solvent Blanks, MethBloandksandMatrixBlauks 10.11 S`eoalcvhebnattbclhatsokdse,tmeertmhiondebclaonnksteandmmaitorniFxabcaltrarniykosovaenrr.epreparedandanalyzedwith 10.12Analyze a methodblankand amatrixblankprior toeachcalibrationcurve. 102 MatrixSpikes 10.2.1reMcatorviexrspyeifkiecsiaernecpyr.eparedandanalyzedtodeterminethematrixeffect onthe 10.22Mrateixscpfiookreedvaucplheiacnaratleysytaer.eprepared andanalyzedtomeasuretheprecisionandthe 10.2.3A`nalmyzeiaomafnt2rsipixiskpeimskpeeaunbdamtmacthr.ixspikeduplicate prfortysamples,witha 10.2.4Mtahetiinixtsiaplickaealnidbmratarctiuxirsvoepn. kAddduiptliiocnaatlescpoinkceenctroatnioncsweilnllmtiarynftaahletlminitd-horealnnogswe-of rangeoftheinitial calibractuirvoe.n 103ContinuingCalibration Verifications 103.1Coofnttihnecuailnigbcraaltiibornactuirovnev.erificationsareanalyzedtoverifythecontinuedaccuracy 1032 Aonfaalnyezpeerabmaitdc-hr.angecalibrationstandardaferevery tenthsample,with 8minimum 1C1L1.01aAanvuaelryamzgeeotmhfetsewxotsrTtaacntOdeadrmdNacturrAivxesstNwaindlDalrbdeSspplroTitotretAdobayNnldinfDeoalrlrAoewgirRnegsesDaiocnhIs(yet=ZofmeyAxtr+abTc)t,sw.IeiTgOhheteNd Ux,motforcedthroughzero,usingMassLynx orothersuitablesoftware. 1122 Isfttahnedacrudrcvuerdvoecsinf ontemceesesatrrye)qaunirdermeeanntasl,ypzee.rformroutine maintenance of reextactthe 113uFsEoxerapmfuperllpeo:oswwecshoedfaaoafcceutrcactyewihetomonqnuqapuncatnuitrtitvateatrteianihpgplrsoontxwiamlanegtvetelhlyesolf10alnaplpgbyteeo,foaintbmalsayytsebn,edgnaeenrcedreastsearv8yet.o c"aalnigberatoifotnheccuurrvveeco(n5spipstbitnog o1ft00h0epspabn)d,aTrhdissfvoalme5pdpubtion1a0cc0uprpabcryaatbhaerttehadntthoelfinlelar Tegression weightingofhighconcentration standards. Anni f SoEmaTnSF8e5a1rThine EMS 3MEnvironmentalLaboratosirn. =. - -=-=r.. ~ Page 827 Pagesofs Page69 `3M Medical Department Study: T-6889.6 ~ mes wr = ARGUS418-020 B Asalytical Report: FLAiCnTs TE0O0X--3176348 RO12P.1RoAccqEuipsiUtRioEnSSetup . 12.11Clickon startbuttonintheAcquisition ControlPanel.Setup a samplliset. Assign " a filename using MO-DAY-lastdigitofyear-sample number, assaimegthnod (MS) for acquiring, and type in sample descriptions. 12.1.2Tocreate amethodclick onscanbuttonintheAcquisitioncontrol panelandselect SIR (Single Ion Recording)or MRM. Set Ionization Modeas appropriate and mass 10 499orotherapproprmiasastese. Afullscanisusuallycollectedalongwiththe SSiTuRs.ySnvxeGsUcIuDsEtiToOnmDeAtThaAd.A1CfQMUSIS/TMHSIiOaNsrfomresndtdsifwieonpalionfyoemda,tiaogndniodnsl product ion fragmentation information may be collected. See Micromass MRM(MultipleReactionMonitoring). SRdards 12.1.3 Typically mo ad wih theanalytical b tof atchrun sreaqcueendcmebaetginsSwaitnhaatsetofextractedmatrix 12.1.4 S`saammppllee.s Saorlevaennatlybzleadnkwsisthhoauclodnbteinaunianlgyzcealdipberraitoiodniccahlelycktoinmjoencitteodrafptoesresivbelreytaneanltyht.e 12:2 Using the Autosampler carryoverandarenotconsideredsamplesbutmaybe includedassuch. 12.2.1 Set up sample tray according to the sample list prepared in Section 12.1.1. 122.2 `SteSate-muapettnhcetoH nlsoeP gronp1 :ro1pr0e0 forato/ tphtea ifmolu lsopwot innsgceo o.ndRis etciooa rndsosm reautlp cocnodl nidtiite oinosnsr thiethe 12.221 Semple size = 10 iL iecion 12.222 Inject/sample = 1 11222..22234 CSoylcvleenttiamem=p =13.5 minutes AmmoTnioummsects : [[Ec5o0mmian|| oaoon[|twon n|| [(L2o0mma||aoon% || oimon || 12.2.2.5 Press the "Start" button. 123 Instrument Set-up 1122.:33.12RhefeecrktothETsSo-l9v-en2t4.e0veflorimnorreesedrevtoaiilrs.ad reiffnieslsal. 3MEnvironmentalLaboratory. . ArenETtS-8e-5e.1 hie ES -- Page 828 Page Sof Page 70 `3MMedicalDepartment Study: T-6889.6 = mess or = ARGUS 418-020 . Analytical Report:LFIAMCSTET0O0X--2176348 12.33 Check thestainlesssteelcapillary attheendof theprobe. Useaneyeptioechcecek tuhnestaitpi.sfTahcteotryi,psdhiousldabsesflteahtmewpibrtolhbneeoajnadgrgeepdeladcgeest.heIsfttahienlteispsisstfeelocauptinollbadery.. i 12.3.4 OSebtseHrPvLeCdroppulmetpstcoo"mOinn"g.oSuettotfhethfeltoiwptoof1th0ep- r$o0b0eu.LA/lmlionwotraoseqauppirloiprbiraftaeto.er `approximately10minutes. 12.3.5 Tumon thenitrogen. Afinemistshouldbeexpelled with noritrogen leaking. `aroundthetipofthe probe. Readjustthetipof theprobeifnomistisobserved. 12.3.6Theinstrumentusestheseparametersatthefollowingsetings. Thesesetingsmay change in order to optimize the response: ` 12361 Dryinggas250-400liters/bour 123.62ESInebulizignags 10-15 liters/hour 11223.3..66.43HPrPeLssCucroen<s4t0a0nbtafrl(owTimsodpea,rafmloewterraitsen1o0ts--et5,0i0tuisL/agmuiinde fo ensure the HPLCis operatingcorrectly.) 12.3.7Carefullyguidethe probeintotheopening.Insertprobeuntilitwillnotgoany further. Connectthevoltagecablestotheprobe. 12.3.8tParipnetdtnhettoutnheeipangse,twriutmhetonsgpt.arameters,andstoreitinthestudy binderwith acopy 12.39 Usingthecross-flowcounter clectrodeintheES/MSsource i recommendedfor theanalysis ofbiologicalmatrices. 12.3.10`CMlaiscskLoynnsxtavretrbsuitotnosn,sienethaepApcrqoupriisaitteiMoansCosnLtyrnoxlPUaSnEeRl('tShiGsUmIaDyEv)a.rPyraemssotnhgestart `button.Ensurestart and end sample numberincludes allsamples to be analyzed. 130DATAANALGSADCALCULATIONS 13.1 Calculations: 13.14 Calculate matrixspikepercent recoveries using thefollowingequation: - %Recovery= OBbsearvecdR`eEkmxupletgc-tedrResoultuRnesuldtx 100 13.1.5Calculate percentdifference using thefollowingequation: %Differenc=e ECxpeasteldCo`cEnxep.euc-teld Coanc.tCeoncd.x 100 13.1.6Ca(lucgu/lmalt)e:actualconcentroaftPiFOoSn,or otherfliunoar)ochemi*inmcaatrli,x (initalVolumeofmatrix (mL)+ mLofSurrogateStandard) 10002g `Final Volume (mL) AnaisofSeEruTmSeFasc1tUsion EMS 3MEnvironmental Laboratormp--. +=. ~ Page 829 Page6ofs Pag7e! 3M Medical Deparment Study: T-6889.6 = meee or = ARGUS 418-020 Analytical Report: FACT TOX-164 - LIMSE00-2738 1M 40 eTHODPERFORMANGE {m14.a1 MuetihodsDpeectiefcitc.ioPnlLeiamseistc(eMDETLS)-a8-n4d.L1i,mAitttoafcQhumaennttitBa,tfioonra(LiOQs) aotrfeicmuerntrheognd,avnaalliydtaet,edand MDLand LOQvalues. 142Solvent Blanks,Method Blanks,aad MatrixBlanks 142.1loSowlevsetntsbtlaanndkasr,dimnetthheocdabllainbksr,aauctudirmoavtenr:ixblanksvaluesare mustbebelow the 143 CalibrationCurves 143.1 The valueforthecalibrationcurvemustbe0.980 o beter, 14.4 MatrixSpikes 14.4.1Mcaotnrcienxtrsaptiikoepn.ercentrecoveriesaremustbewithin 2 30%ofthe spiked 145 Continuing CalibrationVerifications 14:51Coconntciennutriantgicoanl.ibrationverificationpercentrecoveriesmistbe + 30%ofthespiked 14.6 `Ipfecrriftoerrmiealdiosntetdhienstyhsitsemmeatnhdosdpaemrpfloersmraeanncaelsyeczteidoonrostuh'etrmaectt,imoanisnatsedneatnecremminaeydbbeythe Snalyst. Documeatallactionsintheappropriselogbook. 14.7 IfFodoammtoataerdeotnobtaebrleepsoarntdeddiwshceusnspeedrifnorhmeatnecxetcroifttehreirahepaovretn.otbeen et, thedatamustbe 1155.01PSOaLmLpUlTeIexOtNrPacRtEwVasEtNeTaInOdNfAlNamDmWaAbSleTsEolMvANAiGsdEiMsEpoNsTedinhigh BTUcontainers,andglass pipettewaste is disposed in brokenglasscontainerslocatedinthelaboratory. 6oRecows 16.1 Each page generated for astudymust ave th following information includedeitherinthe A ihneeagdreestoirobnamnetdhwordi,tesnaomnpltehneapmaeg,e:esxttruadcytoiornpdraotj,ecdtinluumtiboenra,ctoqrui(sfiatpipolnimceabtlhe)o,da,nd 16: 2 analyst. Paripn pthretounpsetpruadigyefa,osltdaemerp.lCeolipsyt,tahnedsaecpqaugiessi tainodnmteatpehiontdoftrhoemiMnasstrsuLmyennxttrounilnocgl.udeinth e 163 sPtloortethaectahleisbtruadtiyofnocludrerv.ebylinearregression, weigted1/,thenprint these graphs and 16.4Parnidnsttdoarteaiinnttehgersattuiodnysfoulmdmear.ry integrationmethod,and chromatograms,fomMassLyx, Assy ofSeEruTmsE8xa5c1tUsingESNS 3MEnvironmental LaboraiGgy_ -. .-v.vcn.. ~ Page 830 Page7019 Pega 3M Medical Deparment Study: T-6889.6 < cesrmeens or ---- ARGUS 418.020 _ `Analyical Report: FLAMCST TEO00X--2176348 165 S`AutmtmaacrhimzeentdaAtafoursisnngesxuaitmapbllee sooffatswuarmem(aErxyceslp5r.e0a)dsahnedett.oe in th study folder, see i 16.6 Banadckloucpateiloenoctfobnaicckduatpaetloecstprpornoipcrdsate.medium. Recordinsatuddy notebook the fle mene 1A 717.01TN AAtBtaLcD EhSmeDnItV AAG:RAEA MTSS-.8F-U L5.O1WCDI HaAtaRTsD Sum.maA ry sprTeadshI eet. ONDATA s0 18o.1RFe0 AmCTm-Met0 o.1s, "E0 xtracti0 onofPo0 tassiu0 m Peflo0 roocta0 neslfn0 ate orO0 theFl0 orocber0 sical compoundsSomSemfo AnalysisUsing PLC,Eleczospray/baseSpecromery 182 EToTnSi.z9a:t2o4n0/,Ma"sOspSepraetcitornomaentdeMraQiunattenraonIcreiopftehequMaidcrruopomlaessyAattmeoss"pheci Pressure 183The validationreportassociatedwiththismethodis ETS-84.0 & S.0V-1. 1A 199.01 Em TS-84.m 1, "Exte ractioT nof Poo tassiuD m Pefuoo rooctac nesulfw onat on r Othere Fluoror chemics al Compounds from Serum forAnalysis UsingHPLC ElecrospreyMass Spectrometry" w0 Reovismio0 en ns0000000000Re0 vision `Numbe= r, SSeeccttiioonn61.11..12AvCerlageaoftrReooaifcsuHorfPvne1Fs1io,0rn0Rocseyvssialtsaeinmodtnacrodmipvaolnoueeas,tnasr.eusedfor 0D2at9e9 pSleoctttiionngl1i2n2e.24rCegrlessrionincdaodafdseotdltvheinetro1xpnwe.ighting oftecurve: Section17.1Changedfrom tischmentB toA. AntsofSEemmEs xsigc ESNES 3MEvironment Laboratory... -- Page 831 Pagesord id 3M Medical Department Study: T-6889.6 = enrmeens - or ARGUS 418-020 Analytical Report: FACT TOX-164 LIMS E00-2738 Laboratory Study # {sn MTaeitnhaerSova AsMeatyiiodaRlevEiqsuoinp:mentSystem Nbr: sFiucmamee:: SofwareVers: R.Squred Va: Stlonpe:cepe DDaaeeooffEAuxaalcsiioAns/aAlsyaty:st = 5 [fe |Tez e| SGhroopupefDToaske:efToakenofeomrheesgaryefsoludiaetroi:onn. CSoanmtpelnotkr:atTiaoknen(fsgoimmLye:Tesnfordloemsm.theMasLyas o tegrationsumsay. LDFliuolstaoCnoVnoFela.ucmt(oeor(:fmlLT))a:k:eTCnafkrloeuftrheoedmsbtahyeydifdvoliydnsfo.lhdeern. tlvolun rrth concestnion =chines A:SummarySpreadsbes"tAsay ofSEerTumSE8x5ac1tUsigESMS 3MEnvironmental Laboraiary__ .. ce. ~ Page 832 Page9of9 " Page 3M Medical Deparment Sudy: T-6889.6 = cmmeens or ---- ARGUS 418-020 `Analyical Report: FLAICMTST0O0X.2-713684 MethodModification MeSetchtoidons:modified: Method reads: a EaTdSd-s8e-c7t.i0o,nE1T4S-382-5.1, ETS-897.0 Modify method to read: 1432 TThoesfectoindv(ebrsacdkec ting)cale ibrationp curvemht acybesdhei aalctbivcatho edisfsstn lruments driftaffectsthedata. EEffffeeccttiivvee ddaatteeooffmmooddiiffiiccaattiioonn EETTSS-88:.75..01:: 47/2262//9999 `Effective dateofmodificationETS-8-97.0: 7/28/99 2 sl Votoei .f[ PAIw5 dt te feijeqe(oev. Ect Conyof origi 3MEnvironmentalLaboratary__ . .. . -e.asn.. ~ Page 833 Pag7eS 3M Medical Department Study: T-6889.6 = emcee er ---- ARGUS 418-020 Analytical Report: FLAICMTS TE0O0X--2176348 3M ENVIRONMENTAL LABORATORY ' MeTHOD ANALYSIS'OFFLPUOOTRAOSCHSEIMUIMCPAELRSFLINUOSREOROUCMTEAXNTERSAUCLTFSONUASTIENGOR OTHER 'HPLC-ELECTROSPRAY/MASS SPECTROMETRY Method Number: ETS-8-52 `Adoption Date: 03/01/99 Author: Lisa Clemen, Kes Hansen Revision Date: 2] 1/01 Approved By: Ya p> Taboratory Manager 02Du[e1/01 A on Ae = Group Leader oz/Deaiefe] Aa sale Technical Reviewer 27 -ot-ol Date 2 BactCopyof ea Da 10Scop AMpAPRICATIN 1.1Scope: Thismethoddescribestheanalysisofserumextractsfor fluorochemicalsurfactants `using HPLC-lectrospray/mass spectrometry. 1.2 Applicable Compounds: Fluorochemical surfactants or otherfluorinated compounds, or other ionizable compounds. 1.3 vMaaltirdiacteiosn:reRpaobrbti.t,rat, bovine,monkey, and human serum, or other fluidsasdesignatedinthe. Word 695 3M Environmental Laborato + -=rmr.. ETS-$-52 ie menee ~ Page 834 Page lof11. Page 76 3MMedicalDepartmentStudy: T-6889.6 = cmmeees rm ARGUS418-020 Analytical Report:LFIAMCST ET0O0X--2176348 +2S 201 pAeu lrtfhoorumgM ahnscuepbpv aosreteddmba eythavoadR l.iCdaatrioev nlfoatrtmeO notsitocnsoF hmomuolndlM byeupsaeidE dmtaotmriectT ehso,dthQiH sCiassathO er sD great Saerxitraabcitleydifnrosemrsae.Trhuimsomreotthhoedrdfelusicdrsi,buessitnhgeHaPnLaCl-ylsescotfifousoprroacyh/emmaiscsalSpseucrftarcotmaenstys, or SCihmairlaacrtseyrisstteimc aofsaappaprrtoipcruilaatre,flTuhoreocahneamliycsails,isspucehcfaostoheedpbeyrfmlounoirtooorcitnagneasuilnfgolneaitoe n(PFOS) `i{too fnur,thmeirzv=er4i9f9y.thAeddiidetnitointaylolfy,ascaommplpeosumnadybbyedaentaelctyiznegdduasuignhgteatriaonndsemofmtahsespsapreecnttrioomne.ter o3p1qeuaAwdtrmumoposelpehsesyrssitceiPnrseaslsluorwefIoonviazraitoiuosn(mAePtDb)o:dTsohfeiMoniiczraotimoansbsyQuutaitltizriongIvfaarnidoUulstsiomuarcweisl,e iAPnttmrhoesspsohtaeenrcbdihicnnePitrqeerussfesasucO.reCseC.cuThrheSmeaistceaaitlnmcIolosnupidhzeaebtruiiotcnaPr(reAenPsCosDut)r,lei(Tmihi<te.er,dmBtooFs:puErnladeyce,trertoacvs.paTrcahuyueiImoo)nn.iizzaatitoinon(EpSrDo)c,ess 32TphreesEssleuecrceht,arwrohgseeprdredarbyoypIilooenntisziaatesiolnpt(rioEodSnu,caEerdSebtDry:atnhasmefeearptrphelodidtcoaottfihoieonnoigazfsatsipothnraposneegrvfieolaetrcimtnreyidccaahltafariteglmedod.sdprhopelreitcs. 33(M`SM/qaMsSu)s:SapTmehacdsetsrsAroemPleIeutcQrtuyiap,vtetdMoreaotseIlcstaSonpresed.cUtlrTkooinmmseaatrteerrisp(elMleeSqc)tui,avdTerlauypndodlieesmysMstacesmrssaiSrbpemeyecqmituarisnopsmpteaetodcetwrhiaetrhgde Setriieos((1MsS)/aMnSd)fsuobrsmeqoureenstpleydceitfeicctferda.gmeAnstiantgiloeniMnSfomramaytiboene.mployedforiondetectionof a 34qPuraoCdboreunpviooelnetsriyosttneamlhsvs(.opotoZs-hgtspc1ro9oan9y8ep)naupreloraibtzeueirlneat.e"IrZfn-atscphere:acTyo"nhcveoennlftaoitroemsnatamtloicodneo.lsnThofefoMsiprcrrmaioyameiamtisatsittmoeredinpdlreom a SoiereicetlnoaitstehTehancoroueatnghheenastphuecermcteeou.nrfei,Hgoauwfretarvtpeiaorsn,siZid-nisgfptfrhearryeocnuo,gmthphaoenmteeornttthusooadunsspodacftonohpvweearnyattiiinootnnha,elcclceooamunpniontgne,erantnsd ars TCootmpcaotmipbalteiwbiltehwsiothmoenoetahneortZh-esrp,rbauytSyosntleywmis,tehxsc.m) asystems (c., spraycomponentsare 35Qu2a0Mtvtaerrsossio1nLtsiy,pnAlxelSqouvfatdewruarproesl:aersiSyyssosittmeenimlmasssro..fCFtuworarrremenodterlseyidMgeantseasdlLfyosnrexthhtaehssepemWcaiinnfudiacolwosspp9ece5ifarincadottoWftitihhneoedsnoewsNT istrament(MicromassQuatro IorUltimatriple quadrupoleMassLynx or MassLyuxNT User'sGuide). 4W 0 imnpesANpCAvmoNs 41 HealthandSafety Warnings: 4.1.1 Usecautionwiththevoliagecablesforthe probe. When engatgheeprdob,e employs a voltageofapproximately S000 Volts. ord 695 Analysisof SEerTumSE8xt5ra2ctUsingESMS 3MEnvironmentalLaborato. . .. veins. =~ Page 835 Page20f11 Page77 3M Medical Department Study: T-6889.6 ~ vmmee wor = ARGUS 418-020 Analytical Report: FACT TOX-164 LIMSE00-2738 4.12 aWnhdecnlohtahnidnlgi.ngsamples or solventswearappropriate protective gloves, eyewear, 42 Cautions: 421 DIoftnhoebtaocpkeprraetsessoulrveeexnctepeudmsp4sa0bboavre,ctahpeaHciPtLyoCfw4i0l0lnbtaart(e5a8u0t0posmia)tbiacschkuptrdesoswunr.e. 422 Donotrunsolventpumpstodryness. SO5.I1vETmomeiRniemvizceientserferenceswhenanalyzingsamples,Teflonshouldno beusedforsample storageorany pastof instrumentationthatcomesincontactwiththesample oFextract. S6O.1FoEquupipemsenrt listedbelowmay bemodified inordertooptimizethesystem.Documentany `modiinthferaiwdactaaasmtethioddoevinaiosns. 6.11 MwiictrhoamnaeslsecQturaotstprraoyiIoonirzUaltitoinmsatoruirpcleequadrupoleMass Spectrometerequipped 6.1.2 HcP1o10m0poraAgrialntednatmulteoowsnpaumltpsle,esrolventpumpingsystem,solventdegasser,column 7S 7.01 u Supplp ies pupsaNpMaTERILS 7.11 nHiitgrhogpuernistyysgtreamd)enitrogengasregulatedtoapproximately 100psi(Hous aifor 7.12iHnPtLheCaanwaldyattiac.alcolumn, speifis obedeterminedbytheanalystanddocumented 7.13 Cappedautovialsandcapped 15mLcentrifugetubes 80 REAGENTSANDSTANDARDS 81 Reagents 8.11 MetHhPLCagrandeoorequlival,ent 812 Meqiulilva-lQeTMntw,aatnedrm,aayllbweateprruosvieddedibythiasMmieltlh-oQdTshOoCulPdlbusesMyisltelm-oQrTMotwhateerroverndor 8.13 Ammoniumacetate,reagentgradeorequivalent 82 Standards 8.2.1 pTryeppiacarleldydturwionmgetthheoedxbtlraacntkiso,ntpwroocmeadturriex.blSaeneksE,TaSn-d8e4i.g2ht.eenmatrixstandardsare ETS852 3M Environmental Laboratay___. cron Page 836 Page3ornt Page78 3M Medical Department Study: T-6889.6 ~ srmeees or = ARGUS418-020 Analytical Report:LFIAMCST TE0O0X--2176348 sosaepEANLNG 9.1 Farreessthomraetdriinxcsatapnpdeadradustaoveiaplreopracraedpwpietdhe1a5cmhLancaelnyusiifs.uEgxettruabcetseudnsttilanadnaalrydssias.ndsamples % 92 aIpfparnoalxyismiastweillylb4edCe,laoyFeadt,erxotormatcetmepdesrtaatnudraer,dusannldsaanamlpylsiessccaannbbeepreerffroirgmereadt.edat 1100.01 QSoulavernvtBCloawnkrsm,oMrethodBlanksandMatrixBlanks 10.1.1 `Soonlcveednutrbilnagntkhs,emceoutrhsoedobfltahnekssatnuddymtaotdreitxebrlmainnkesaifrceopnrteapmairneadtaionndaoncacluryrzeedddautrilenagst sample prep. 10.12Analyzeatlast onesolventblankprior toeachcalibrationcurve. 10.1.3Meaxttriacxtbs.lanksshouldbeanalyzedwitheachsamplels thatincludesundiluted 102Matrix Spikes 10.2.1sIefrcau,rsvaemspalnesdmaertemhoondkQeCyaserreap)r,empaatrreidxisnpiakseusrarnodgamtaetmraitxrsipxik(ee.dg.ucpluircvaetse narreabbit pexrterpaacrteidoinnebflfiacnikenscaym.plematrix (.5.,monkeysera) ndanalyzed tovery 10.22I`mfacturrivxsesapndmaieretkrheoqdeuiQrCseda.reprepared i th samematrixassamples,noadditonal 103ContinuingCalibration Verifications (CCVs) 10:31Ctohnetcianliubirnagtciaolnicburartvieo.n verificationsareanalyzedtoverifythecontinuedaccuracy of 10.32A`nSaalmpylzees,twwiotchalaimbirantiimonusmtoafndtawrodpse(robnaeaictheaancdhoaflw2alyesvfeilnsi)sahfitnegraenvienrjyeocntieotnoten Sequencewithat least twocalibrationstandards: 1C111.01A`AinUlallybPzeepltRohtetAeexdbtTryaclitIneedarmOartergNirxe.scAsailoiNnb,rawtDeioingsShttaenTdda1r/A5d,spnNroitoDfrtorocAeedacRthhrsoDeugohIfezxetZror,acAstis.nTgThMIeascsuOLryvNenx orothersuitablesoftwar. 112. Irftheecuartvnehdeosaetaslnndoatyrmdeczeurtreveeq.uirements,perform routine maintenance,reextractsamples,of 113rFaonrgpeu,riptomsaeysobefnaeccceusrsaacrywy hoeunsqeuaintthietatthinegloewveelnsodfofatnhaleyhtegaht tehnedofmitthse coaftlihbercatuirovnec.urve. 2fcpaoptnhrseoirxsttihimanagntotefhltyehf1el0slptparnabdnoagfreodsaffntarlhoytmes,.taipnmpdaabrydtboce1urb0ev0nee.pfpiEbcxriaaamtltpheolregt:ehnwaenhrtaethneeafaltclaltrlarenatgimeootnfpoctuhqtrueavicneutrintvaegte(5 ob to 1000ppb). This will reduc inaccuracy attributedto linearregression weighting of Anaisof SEeTmSF8t5r2ct sine ESS 3MEnvironmental Laboratosi--. .-.. vse. ~ Page 837 Pagedoitl Page79 3M Medical Department Study: T-6889.6 ~ swmmeens r= ARGUS 418-020 Aualytical Repor:LFIAMCST ET0O0X--2176348 haingdh2choingchecnutrrvaet.ioInfstthainsidasrddosn.Ie,inaolsmooreacthcaneopnetpoaobibnetlasekhtohueldlbineeuaserdaingneciontmomaonlobwetcuwreveen . t`hpepcbaanrvdetsh,ehFiogrhecxaumrpvleem,atyhienlcolwucduetrhveempoaiyntsi:n2cl5u0d,e5t0h0e,fo7l5l0o,wi1n0g0p0o,i1n2is5:0p1,p5b,.25, 100, 250 1122.01 PARcOCqEuDiUsRiEStSeitounp. 12.1.1 OdtehpsritoghuuegaMhttaohrseesatLleyprhn,axlbmaesattiw2nidptaihggeesa,coshfcatduedsipttiyaosenaaarml-plmlsoet-fldosarty,tnaahnmaded.aaye.Staevretthhaetlwsialinmcsrterausmeent `Example SampleList:IYYMoMrDDO10D71a23. YI=i=noyfsetneastatm(e0rr(1)Dufomr "eDavneyt") aD`=fiMDrsMts=a=omfdpmloeesoflaitts(ntey1t(2tr()u0hn7))oftheday (thenex:samplelstwilendwith 'b" thenextc'an80odn) 12:12 dAasys,iagnnad fai3l-einagmietusseqiunegntthiaelinfslternaummebnetdrtesaitgnsattarotrlsewtittehr,t1haenldasitnc2rdeiagsietssboyfoyneafro-mroeach iename. `ExampleFileName: TYYMMoDrDDOI#071#20#01 YIei=noyftsenesatatm(e0rr(1D)ufomr"eDavneyt") #``##M=D3M-Ddiio=g=fttsdomeefsqotatu(ee1nnsy2tt)ti(a0lh7f)lenumberstaring with 1through999 (001) bAoltslo,easnpumabrero,ftanhiensjaecmtpiloenlvso,luamsseaignndasmaemtphloedde(sMcSri)pftoiroancsq.uiring,aninlet ie, a 12.13sTJeoolnicezrcaettSaiTtoenR aM(moSeidntgehloaedsT,aopcnlpRirceokcpoorrinadMtieentga)hnoodrdmEaMdsRisttMoo(rMb4uu9lt9ttoiornplnetRhteeharecaMtpiSproSontpMraoitnaiuttseomPraaisnnsege)as.n.dSeAtlso S`ceiotnlslttehrceutmecedqn,utSsiaesrieieMoenimcsptrlaoormytaeasdns,daMdsadositpsiLtoiynmanlexpsGr.oUSdIauvDcetEaicToqnuOifsriDatAgimoTenmAnetaAtthCioQodnU.iInSfIofIrMTmSIat/OiNMoSnfmoraybe: `additonalinformationandMRM. 12.1.4eTxytpriaccatlelydtmhaetarniaxlysttiacndaalrbdast.ch unsequenceb3 eginswithsolvent blanksand aset of 12.15 `aSSnaodmlvpaelrneetenbxotltraanccktossnssahirodeuealrneddabsleayamznpealdlewyeizxtethdrtpaewcrtoisoCbdiuCctValmlayiytnbjoeemciotnencdieltvourederpdyoasossnsiebutlcoehat.neanlystaemcpalrersy.over 3MEnvironmental Laboratary Anata ofSeEruTms8r5a2e Using FSMS ------a Page 838 Pagesofll Page 80 3M Medical Department Study: T-6889.6 ~ simmer ARGUS418-020 Analytical Report:LiFvAiCTBToOoX--3176348 12.2 U1s2i:n2g1theetHupPsLamCple rayaccording (0the sample is prepared n Secon 12.1 i 12.2.2S`eatpp-ruopptrihaeteHfPorLCopttoimtahlerfeoslploonwsien.gRceocndoirtdiaocntsuoarlactoncdointdiiotnisoinnstthheeiannsaltyrsutmeconntsiders logbook: 12.2.2.1Samplesize = 10pLinjection 12.222Inject/sample = | Err 1 12.2.22.3CFylc2 olwertie2me==3. 0100.0um4 ilniutnes 12.225MoPhbase riogrsam) [[0o0om0imne| ttoonx oaco ewtate(sim nH;0)]| [[1S5300mmnn|| oossm% 5s%u ]| [so0maTim sox] 12.3Instrument Set-up 1212:.33.21RCehfeecrktthoeEsoT lvenStl- fevoerl9 mionr- eedse2 rtvaoi4 rlss.ndrfl cesar. 12.3.3 Chheeicpk.thTehsetaGipnlseshsostueeblecapialtlwariyhatntohjeaegngdeodefdtgheesp.roIbe.heUGspeaneoyuetnp0dti0oechcecek probesholdbe checked weekly. `unsatisfactory,disassembletheprobeandreplacethestainlesssteelcapillary.The 12:34 OSiutHsPeLCopupmipstco"mOinn"go.Suteotfhteefloiwp o0f1h0e-p5ro0b0e in or55sppropeite. 12:35TruroonthheeUunpoofgn tene.prdoAvfei.eRmeisatdshsoulhdeUbepeoxfpelhleepdrwoibtehi 0n0iirosgein evsskeivnegd. 12:36Theinstrumentussthes parametersatthefolowingstings.Thesesettingsmay changeinordertooptimizetheresponse: 123.61Drying gas250-400liters/hour 11232.63.EHSP3ILnC. ecbouln6iszti. anngtg2falsow1m0o-1d5e,liteorwshoiutre 10-00Wma 12.3.6 Presare<400bar(Thisparameteris notsti 8guide 0 ensure the HPLCis operatingcorrectly.) 12.3.7 Carefullyguidetheprobeintotheopening. Insertprobe until itwillno goatny further. Connectthe voltagecablestotheprobe. 3M Environmental Laborato. AnisofSEcrrusnEsvsaasUng ESS -e-me. Page 839 Psartt Pages 3MMedicalDepartment Study: T-6889.6. = rman rm ARGUS418-020 AnalyticalReport: FACTTOX-164 LIMS E00-2738 12.38sPruimnethetpuangeepsagne, MrSsflne,eHPsLlCyparnamdeeteirsh,sacmpolyelaspadndtohesMicrrosonft dWord 8 4 12:39CVleriscikonosn,sstearztabutptopn irthoMeaMpsassrLsyLiynnUaxSmEatiRn'epSagGUeI(DtEhi)sm.aEynvsaurryeastmaortnagnMdeansdsLsyanmxple `numberinchudesallsamples tobeanalyzed. BODACAm LCULAA TIONSMMYSSAN 131 Calcalations: 13.1.1 Calculatematrixspikepercent recoveris usingthefolowingequation: Recoivery = Observed Resp uls ~Ml aris BankRest x 10 1342 Calculatepercentdifferenceusingthefollowingequation: Dirence = Sp CroeomeCole eslugd Gong, 10 13.4 Calculatesctualconcentrationof BFOS, orotherflvorochermical, inmatrix (ug/ml): (Conc{.noiflPVFoOlSuCmaeloef.MfraormiSde.nC)urv_+nlofeng Suro/gmla)_txe_DSilatinodnaFradc)io]r~) ~ 101040815 -- Feavemwmetnt) | 1M 4140.1 M`E meatichioxT dspDeectieH fcitc,ioPnlO eLaismeisD te(eMEDTP LS)-a8-nE 4d.L2i,mAiR tttoafcQhF umaentnitO taB,tifoonR (a LlOsQM i)ngaorefA mceutrhreoN ndt,avnaalC lidyattee,dE and MDL nd LOQvalues. 142SolventBlanks,MethodBlanks, and MatrixBlanks 14:21S`oacltvievensttbalnadnakrsd,imnetthheocdabllainbksr,aacntudirmvoaetn.rix blanksvalues mustbebelowthelowest 143CalibrationCurves 14.3.1Tbheettecro.efficientofdeterminationvalueforthecalibrationcurvemustbe 0.990or : AnseofSerEuTmS8Fsr5a2s TineFSMS 3MEnvironmental Laboraiom--. +.+-=nzn. ~ Page 840 PageToll Page82 3M Medical Department Study: T-6889.6 ~ "memes orm ARGUS 418-020 Analytical Report:LFIAMCST TE0O0X--2176348 14:32Ahlelesexticveecaplitborifattoihonen cLuOrQveppoionitn,twsmhuiscthmbaeywidtevhiiant2e5u%po1f0t3h0t%h.eoreticalvaluewith ` 1433`Cualsibtrbateidoenascttainvadtaerddtsowdiitshqpueaalikfayraedaastaesasntgheantthawtomtaiymebsetahfefccutrevdebmaytbraicxkbglraonuknd leovtheeanlalyste. 143.4tLootwhoerdahtiag.h curvepointsmaybedeactivatedtooptimize alinearrange appropriate: 14:35 Not including low or high points dropped to opttih lmineiarrzangee, curve points t`mhaeycbuervdeeiascteivvaaltueadtiefdtohveeyrdaevliianetaermroarnegtehaappnr2o5pr%iaftreomtotthheetdhaetoar.etical value When 1436dOheanfsienpaeopdienaakttbaehrleeloawolwteeshssettLhpaoOniQnttmwwaoiyttihrmaeecmscateiphnteaamcbatltiervdieeexvbvileaatnniikof;ni.htodewveivaetre,stmhoerLeOthQanwi2l3lb0e%.or 1437 hAevaLlOiQdc.albrationcurvemustcontain aleast activepointssboveandincluding 144Matrix Spikes 1441 Tchoencaevnetrraatgieomn.aRtercioxvseprikieespoeurtcseindteroefcotvhiesrriaenssgheosuhlodubledbwietdhiisncu+s3s0ed%ionfthtehreesppoirkte.d 145ContinuingCalibrationVerifications (CCVs) 145.1`TCehorinsetrinentcuroivenecgrocyva,leisrbuyrbwasiteikqouinesnnatm4dp2al5te%asoswhfiottuhhliesdntnphioekeblidencaeocanrccerepantntegrdeaot.ifAoctnch.eeLpfrtuanbCmlCeudVsattisahroouutswstiadbeeof bracketedbythecurve andpassing CCV. 14.6 Iefrcrtiotrermiealdiosntetdhienstyhsitsmemetahnodsdpaemrpfloersmraenacnealsyezcteidoonfiostn'htrmaectt,imoanisnatsedneatnecremmianyedbbeythe 1471afnoadoltayntsotat.aeDfdooctnuotbmaeberlneetpsaoalrnltdaecddtiiwsohcnuessinspneetdrhfieoartphmparnotecpxerticaorftitetlehroigrabheopaoovrket..hot becnmet, hedata mustbe . 151.5.01 SPDaOimpLepLtlUeeTweIaxOisrNtaPeciRtsEwdVaiEssNtpToasIenOddNinfAblNarmoDmkaWebAnlgeSsaToslEsvMcenoAtnNtiaAsidGniEesrpMsoElsoNecdTiaendhiinghthBelTaUbocroanttoariyn.ers,andglass l166O.1RTehfcoerofmimaststispoangienoclfucdaecdehditahteapianctkheetgheenaederra,tiendtfhoerfoaostteurdyomrhuasntdhwarviettehneofonltohweinpagge: study orproject numbes,instrument,sample matrix andtiepoint, date,andanalyst. 162 `A{cadoramgtopsaopuaanncdaksleuytmi(mnccaulrruvydere)e,stmpoehrtethffoooldlroerwaeipcnohgrtt:,daraWgtoeartradendavoliycetuwem,seuqnumtamnlatiisrftyyifncgoalsriemb-,rauMtpaiosPnsArrLeapyIonErxLtEfqTuoa,rncttiafecyh 3MEnvironmentalLaboratony..... . AaaysisofSEerTumSE8xtsa2c Using ESMS em Page 841 Pagesorl Page83 3M Medical Department Study: T-6889.6 ~ cmon or = ARGUS 418-020 Asalytical Report: FLAICMTSTEO0X0--2176348 `method report, MassLynxscanningmethod report, HPLCmethod report,samplelst, and. quantity sample report (chromatogram). 16:3 For cach analysis, after printing the tune method report, Word document listing, set-up 4 `parameters,MassLynxscanningmethodreport,andsamplelst, copyandtapeintothe instrumentrunlog.Theoriginalismaintainedinthedatapacker. 16.4 On each pageofthe quantify compound report, quantify calibration report (curve), and. i`nqtuahnetihfeyadsearm,plteh rfeopootretr(,cohrhoamantdowgrriatm)e,nothnetfhoelplaogwien:gsitnufdoyrmoaftpiroonjmeucsttnubmebienrc,liundsetdreuimtehnert, `method,calibration(the methodandcalibrationare usuallyassignedthesamename), analyst, and date. 16.5 aTrheeealneacltryosntimcualsltydiantcelaudneddonnicaalcthhpafgier.stIpagietiianls apnacdkdeattasalxonngoatstlehcetiroinniictailallysainncdlduadteed:, they mustdate and initial each page. 16.6 `SAutmtmaacrhimzeendtatAfauosrianngseuxiatambplleesoofftawsaurmem(ac.rg.ysEpxrceeald)shfeocti.nclusioninthefinal report. See 167 Bbaacckkuuppeclleeccttrroonniiccddaattaaitoinasptprruompernitatleomgebdoiouk.m.Recordtheflenameandlocation of 17A 1.7.01 TN AAuBaLcEhD Sm,eDnItV AAG:RDAA aMtSa.sL uFmLmOaWrI CyHsAprReD TadSsheA et. TIONDATA 1818..01REFcoAFmCEpTRo-EuMNn4dC.sE1fS,fo"mESxterrauctmifonoorfAPnoatlyassissiUusmiPnergfluPoLroCoEctlaneescultfornaotesporrOSatpheyecrt/rFMolmuaeotrsrosychemical 18.2 EToTnSi.z9a-t2i4o.n0/,Ma"sOspeSrpaetcitornomaentderMaQiunatternaonIcIeotrfitpheequMaidcrruopmoalsesSyAsttmeomssp"heric Pressure 183 The validationreportassociatedwiththismethodis ETS-8-40 & 50-1. . 1A 109.1 ETm S-8+.2,m "Extracc tionofPw otassiub mPerfluoo roociancc sulfonaw te or Otm her Fluoy rochemis cal CompoundsfromSerumfor AnalysisUsingHPLC-ElectrospSrpeacytr/oMmeatsrys" 3MEnvironmental Laboraiary__ .- .-Av.a-n..aofhS~eEriTuSm-Ex8t:r5ic2tUsing ESAMS Page 842 Pageof 11 Pagess 3MMedicalDeparment Study:T-6889.6 = meses rm ARGUS 418.020 Analytical Report:LFIAMCST ET0O0X--2176348 womevigons Revision Revision 4 Memb7er, Section 6.12 ClarRoeifssHoPfnIF1io0r0sRcyesvtiaesmitocnomiponoentns. 04D10u2e759 pSleocttiionngl1i1n.e1arArveegrreasgseioofn atnwdocaudrdveeds,hneot1sxtwanediagrhdivnalguoesf,thaerceuusrevd.for SSeeccttiioonn 1172..12C.2h4anClgaerdiffircoatmiaonotfasoclvhenmtBertaonmpAt.. 2 1100.12ACdldiefd nwshceibonaosrwwehraaa.rog maiswed. 1101.31SRpecitryselysacleaornCtCcuVr.vec thesamples. 111123CAlllaorwytworhtacodeothecucravrevde.osni steines. 1122.1413CClaa srapmiipclaeff riyuD.. 114232CChhaannggesstocmpail iphiatse.ArdaddsieaiSnidcsspfoercscewpraene.of alaincre. 114432..35WWhheennttooddaacivvieteccaalilbiradonssaannddaerrdssbwsienoeblaneka spognes.e. 1144.45DeosctriitessecrlluunaiioonnasnoddwseeooffCCiVx. ks. 1164.501AdEdvraelpureaostfCsiVfoosrne.rt nd cummin. AuschmenA:SummarySprsish"cAtsay ofSEerTumSE8x52cUsingESS 3MEnvironmental Laboratary__. I Page 843 Page 00011 Pag8e5 3M Medical Department Study: T-6889.6 ~ meen rm ARGUS 418.020 Analytical Report; FACT TOX-164 LIMS E00-2738 Laboratory Study # 4 nay MeaMrtauFritoa:Seber: AMebbotiReaviEsqiuoinp:ment System Number: Foinsane: SofvareVersion: RSSpqeu:aredValse: DYaienorefeEpxeactomAsayst: Dat ofAnivishsalic SGtroovue:nDToasek:e rTaokmenofarormoeress dsafollod.n. TiCSodancmaeplnlteVr:oatlTiuaomkneen((marbof:mlT:haekTseaukfeoofmrdohme.sheyMafsolsdy. tsa sur. PDiinlaltoCnoFna.ct(oar:hTaak.eCarloamiehedsbaddifvoilddiern. he ilvolumefromteconcaion NuachAt:Summary Spresdsbest"Assiof SEeTrusmEsxs2t sag ESIMS 3M Environmental Laborator_y_ ---- Page 844 Page rtartl Page86 remnants `3MMedicalDepartment Study:T-6889.6 ~ ermmenes wr = ARGUS 418-020 rm mmmRs Analytical Report: FACT TOX-164 Appendix D: Dose Confirmation Analyses and Data Summary Tables So [STae pra Table 12. DoseConfirmationAnalyses -Extracted mmm 11/17/00,Analyzed 11/27/00 E meCmrE =y EeeTA =E Ee]SE|TTs A =E ET TTTTEEESE :: E TrTw E EeaTeCre Il]E | ous 20 Fe A eE1N EYCY san = mn EET TER ere J B41802000102 ms = T 84102000101 | = ao 0 Ten | =] 200 T om[on [=| | esnussaammeeooenrs wuoe a-o | oe EE me[E eeZBEEEmEeEieT nE tesTEE TE E E E Ee toA eTEtT E IEE T-T T -e] 3MEnvironmentalLaboraiagy. .-. . .e.nsr. ~ Page87 3MMedicalDeparmentStudy: T-6889.6 aMMeccaDepartmen:Susy.T6009. = cmos wr ---- ARGUS 418-020 Analytical ReportL: FMACST ET0O0X--2176348 An Fora FACT Ts OR104 Table 13. DoseConfiAr nalmysa es t --Exitro actned 11/27/00,Analyzed 11/28/00 oo Sampo ConomnreaetsoennoatsFOA| PFOA" - Merot|s mymoowwesss || <<ooaarovnmgmy) Crono cs [oe [2] wo [secmaciomoous| ome [B:418.020-4.C-100p00MSO, 00888 1 Sunita' of | B4s1ao8t0no2c0pzAoCsa0oOrSasmsmLm|| 400 (10ngmL) w0saon(iOonnom EET rT] | son coor Go [=Tw =] 000m rpESEeTe TETE TTEeTw=]n]] a To EzTon sano: suse oo CI E = TTTe wiTE] usaoe00z | 187 afi 2TFTR =l7] Wo _sosmooos | a rE EYE emoows | me 00 wo iy po [T Em =TE Eee TY[eE =] sass pe = ConTcenetreation| |B_4_1sa8s0a0scCo1s | "" . |1 "o0w = = b [= =| saecoeot susamece so woonn | wmoen EI Samp r-xton1o25d01 cf caver. coreywes ofCreedconsidsn tna wascin om cnofcustodyforms csoparyogais. 3M EnvironmewnttaElLaiborratao Lo+rton +=... ~ Page 846 oz age i 3MMedical Department Study: T-6889.6 ~ meas ------ ARGUS 413-020 Analytical Report: FACT TOX-164 p[SE E rTsE ]imnn egTirnoat E mEpA Aee mamne:EoAfwwErmoITm N00 | pasomens 8000. = =S=yn ==ET == pm r em w5 = C| aEe ] =: WO, 3M EnvironmentalLaborato..-. =. w=. ~ Page 847 pos Page89 ~ rman rr = ARGUS 418-020 3M MedicalDepartmentStudy: T-6889.6 3MMedicalDepartmen Study: 6889.6 Analytical Report: FLAICMTS TEO00X--2176348 AnalRopoyrttFUAMiCSTcTEO00Xa--217l6348 Appendix E: Data Spreadsheets 2M Environmental Laboratory 3M Environmental Laboratogy___ ,. cr. ~ Page 848 Pace24 Page90 traiwt m ~ cmmeees ti ore---- pARnGUSARC4T1i8T-o0x2e06 EE. = Tr|oem [Eelilelmm=e 1eTsU] T] CEE + ESI +: [mee Te[eee = ES I= J- -P oT=1% [alm] I NP cs TeTeTaree = = T = Talal EETTe oe[mmm =mnlela] 5S 0 4A = PN PN rece oe TE Telmem =T= 1 = Tein] 3MEnvironmental Laboratary.... ------- Page91 3M Medical Department Study: T-6889.6 ~ comes or ARGUS 418-020 ---- esr Analytical Report: FACT TOX-164 LIMS E00-2738 [CTr ose e Tos TnTs alal [r Too msTm eTws Tele] IH SE res TatasTeTm nla] umes To amT=T5Tela] 3M EnvironmentalLaborato... SR Page 850 Page 92 3M Medical Deparment Study: 6889.6 ~ esmees I oe asa er = ARGUS 418-020 Analytical Report:LFIAMCSTET0OX2-71364 oe er -- I mm [= am xIEe E aeE Fr [TelelileEzs [e.m[sLTT.] [EleliEEse e .mTLs 1] Ess TTRTETEE Te em ala] [hmmses Tw[aToTaasar wToTw Tale] k me | ImoTelom2e Tr we Tel] a] Cammse TreTeTeTaslams @To| on Tela] Come TreroTal wrs TaT Te ws Tar lal mms TrTeeTeeleel mTER[ela] IM EnvironmentalLaboratory... cv. ~ Page93 Page 851 hedDm Tes mt apr BATOC1T6 ~ eeormeees or ee ARGUS418-020 Arye 15.030 LIMS E00-2738 Ere Ter fie: - mo 1Taal men ns rrr [aonmmgom [m =o ow s Te a] TmT= =Teaf TeTa 1 = 1 Twol I oe | ao[ a T = 1 wm [mlm] I I - -- - Le teTo| Tout) 3MEnvironmentalLaboratory... ------------ Page 852 Page94 3MMedicalDepartmentStudy: T-6889.6 ~ mews or = ARGUS 418-020 -- a ans Analytical Report: FACT TOX-164 LIMS 00-2738 3MEnvironmentalLaboraiagi-- =n. -- Page 853 Page 95 3MMedicalDepartmenSud: T6896 ~ "means wr == ARGUS 418-020 onan AssyicalReport: FLAMCTS TEO00X--2176348 ee semToirro eeeT r &T T] 3M EnvironmentalLaborato .-. cv. Page96 Page 854 - amee on Ares aisots ----ARGUS418-020 LIMS E00-2738 Sor fre? verre = E== re E EF . T VEINEENN -- Com |meme |ow [wlwl ow lwlwl ww [wl] menToToll =TalalwTulul EEE ramsToTell =TalalwTule CEmrememssTon w Touflael]l 2 woTlwwllawl|w ol[uwllul] Creme TaTalal Cree To Tela mw Talal wo Tule] Toll wTulwl eeeToTaleo Tell Tul] CrestToTell = Tolal ow Tull] Page 855 Pd DSTE A Rri FACTTt - psa. ~---- ARGUS418-020 wm Erm. = = tmnt ent 780m Em =E=E Engm.. hmm rami [T= = 1E-- mme1%[Em=m EEErm]er [Ek] FOP IA ve or OB [1g [rreresme[osyr| Emme CTE TEE laS la ( ans dime Tmeesa ery HEE ever | Poivsmaion uTmcambmLo8 | E ERo E| [|irEEiEcmEe| EE hmosens| E=or SEBEeR EEE men pee| BEE i % | aw [aa] |\ Ppar |e mE : | S ||e=De]| E EE5|2EE E==S Clean EB EES | |CECIZ BEE 2 om i BL| | 2 OH |. 3M EnvironmentalLaboratary.. ennit, Page 856 Page 98 3M MedicalDepartment Study:T-6889.6 pp He = evra ore ARGUS 418020 Analytical Report: FACT TOX-164 na LIS E00-2738 recor Ot Gr oR1 Eigen Seoarmomvaebrsa naan a |= [EEE Eels]Fl. ol TfTrieanrcneioess|| 2 i Firi aasnsioan|] Loranon| 1 CL Tmotodd ro FTerniearrso e itor a Tm TToovmoore pisme aasnn atioenn fitted icassy anton f ren esrea a sadaro]n ffm rreemmrrcee eeriioadd tmitmy, ommEan 3M EnvironmentalLaborators__ -. ----.ie. Pag9e Page 857 ~ ermine or mee. ARGUS 418-020 3M Medical Department Study: T-6889.6 FAArCeTsT4O1X8102604 Adalytical Report: FACT TOX-164 | LIMSE00-2738 so oe Ge OmGo r nm t 0 R=ViimeEee Sptreonitooun = paSrr= h. apneton narsmon _ CEslS eee bomen |+] tn|W|0(aoe Sn Te]ow] i Sma 3MEnvironmentalLaborato. ..-.v.. ~ Page 858 Tugs 100 3M Medical Department Study: T-6889.6 pn ET ~ meen =ARGUS 418-020 fcro--n Analytical Report: FLAiCeTs En 75s TOX-164 fete A a EET Dramamine: por SdEoDme a so J [=== E-- mmT TEEo[Ea lan = EERTEE L IE 3M EnvironmentalLaboratory. ---- Page 859 Page 101 SM MedicalDeparment Sey T6589 ~ mero Anyi immer meee RAeRpGosUSFLoA4uC1sT8-TE0Oo2.0017634n nn tremens etmron mm = En te rg ] E ml 0EE ET R 435 || Ce EES TTST Tras ] EET ETRE CT Dvr Semen 3MEnvironmental Laboratosy--. .-.. .e.min.. ~ Page 860 Page 102 tres ----ARGUS 418-020 Med DeparmeTntS ios AnReosn:FfAe CiTTOdl N:1e64 sr n-- finamtnnan --_-- Eprsmarrm Eu = BIER. HEE worsen i [[ E=mEEm R EREEETL EEEEE a E eTT l.) TE EeEveRnE ETT. SM ErsroLmabomraen we ~ Page861 he 103 ~ meas wor =e ARGUS 418-020 wpm mm se rem m at Lis Eo02rss 3M Medical Department Study: T-6889.6 Analytical Report: FACT TOX-164 Er Ea ED ExEEn s= EeEm Temi Comme TmToone alma] nm T=| %[2(oelmen = Tal.| Tolo| oo memeTi |[wlalees Twlw| ma, Te 3MEnvironmental Laborato... . --.i. ~ Page 862 Page 104 3M Medical DepartmentStudy: T-6889.6 EHom ~ wwmeee wo wee ARGUS418-020 e~ r Analytical Report:LvsFACT arse TOX-164 m Bauon EEE. =E srs = eEErE E EEE[ET LE I T 1Te eFS] M EvironmentLabora... age 05 Page 863 5M Medical Deparment Study: T-6889.6 SMModica DeparmentSucy.T-6969.6 - amas ~--ARGUS 418-020 Analytical Report: FACT TOX-164 LIMS E00-2738 AnRelport:yFfACiTaTrOXel -1s64 `Appendix F: Example Calculations FormulaUsedforSeraAnalysesIn Study FACT TOX-164 AR (ng/mL) x DFX FV (mL) x 10yg_ = Reported Concentration (4gmL) EV (mL) T00ng Calculation UsforeGrodup 4, LD2, Anil ID P131F 6s14ngmLxsx inl x _10ug =0326 pgiml "TmL T000ng ADFR--DiAlnaultyitoincaflacrteosrult fromMassys summary FEVL V----FiVnoall uexmotrefactsevi soleuxmtrea(c1t.e0dmLunleb ss otherwise notei d) s 3M EnvironmenJtal Lab-- orat-- o. --.+- = Page 864 Pans Page 106 3M Medical Deparment Study: T-6889.6 0MealDeparmentStay:T-6869.8 - arenes =~ ARGUS 418-020 Analyical Report FLAICMTS TE0O0X--2176348 AnaRepiortt(FAMGcSTTEavOoKz1lr0s4a `Appendix G: Interim Certificate(s) of Analysis 3M Environ[meIntal Lab--ora--to.-- ~ +. ~ Page 865 pamnn Page 107 5M Medical Deparment Study: T-6889.6 CT mee oy ARGUS 418-020 Analytical Report: FACT TOX-164 TIMS E00-2738 Centre fe Prone (16)23100%2 LFaarb6oT1r0ea31ts.o12or80iorres0a1.0)20I1n-c15.80 INTERIM CERTIFICATE OFANALYSIS Revi2s(10i17o/0n1) CentreAnalyticalLaboraCtOAoRrefiereencse #: 023-034 Te3sMtPCroondturcotl:RPePufrFeiOtryAe:,nP9cre5i:0m%aTrCyRS9t9a0n3d0a-r3d0 Nee [Seams Twas) Sie21. GM(alCgenPaeSsmium 335. SPNooinlkeuamman 7. oMunnganes 231 <0o0o00o1 wwwnnsss 35. 00000010wwanemts 7 001wns Ton27 geGFooAorrdsee 555. NiBrooommeiede &7 Psouommepae CAr c3EemYAr 5PEmNa =2I CHayrdeonpn 335.. NsPiuthfrorgeen onSelective Electrode 131 0SS0oo1sswwwwnmmss 45& S0De9owmsnmw 7 Sows 231 D QSaiw wka 4 awn Comms] 2L TThhoaiollVVaabween0s92335%%|| 21 118297wvm0%% | 335. TTThhheeeoswoesrcVVeVaalathubeei=e=3co02%oa5i%lh | p 35. 3w 7v6 ws r w TherstcalVale = 418% Connon REVISION2460 3M Environmental Laboratogs---- ox ~ Page 866 Pact ot2 Page 108 3M Medical Deparment Study: T-6889.6 --_-- - anne ~~ ARGUS 418-020 Analytical Report: FACT TOX-164 SEI eo CCeePnrnontte rr1e6e)2A3n18a0lytical LLaaabcbo3oTror1aat4too2rr3ivie1e1a(ss811n..9)2Ic3I1nn51ecc5.8.3s0 CeIntNrTeAEnaRlyItMicaClELRReavTibsIiFoonI2rC1A0aC1TO7tEA0o1ROe)frFeriAenNecAesL:Y0S23I-S034 T3esMt PCroondturcotl:RePfFeOreAn,cePr:imTaCryRISt%a0n3d0ar3d0 DaoftLaest Analysis: 1031/00 Expiration Date: 1031/06 Stomge Conditions: <-10C Reassessment Dat: 1031/06 "LPCuIrMiSt=yim1p0u0ri%tie-s(,to4ta6l8me%t)alimpurities, 0.002% +Total NMR impurities,0.36 +Total TotPaulriitmypu=ri1t0y0f%rom5ll.te0sts=49=525.00%%42% TFA HNPFFFBPPAAA "Trifluoroacetic acid `PNHoeennpaatlaffoilrouoroprpoerbmouiptayarnniocciiaccciaadcciidd orm Theoreticalvaluecalculationsbased ontheempirical formula, CyF150;"NHL ThisworkwasconductedunderEPAGoodLaboratoryPractice Standards (40 CFR 160). LerPurityProfle: Peale | RrieationTime(ols) |Mass)| Waemtiy| Ares |%Area| N [I 3 S wesw |131%1.1I[P1FOA7 [mewewl 1 Crem [| - Joos3&8] PreparedBy: Charis fle ReviewedBy: i dea Laboratories wb Flaherty bas "Laboratory Manager,Centre AnalyticalLaboratories CoAR034REVISION24x IM EnvironmentalLaboratory. +- Page 867 Pu 2002 Page 109 = 3M Medical Department Study: T-6889.6 ncnSt Tot008 Appendix H: Report Signature Page cvmmeess ET wr wee ARGUS 418-020 Analytical Report: FsACeT iTOXk-1o64 Dr Sloan Bellon fy "John Butenhoff, Ph.D., StudyDirector Bivoter Ta Jessy 7, 2202. Date (7=57e-0r2 Oe A Moma Lisa Clemen,PrincipalAnalytical Investigator OYoyloa Date H Oe Lr oyb%r yla wma ie 3MEnvironmentalLaboratory. mmm = Page 868 rant Page 110 ARGUS 418-020 APPENDIX J ENVIRONMENTAL AND HUSBANDRY REPORTS Page 869 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu0m5idity Report Protocol Number: 418-020 Range of Dates: 07-Nov-2000 14:11 to 13-Nov-2000 08:50 STparegceitesR:aRnagre: TTToootttaaalll NNNuuummmbbbeeerrrooofff bHDoaautyrass:P:oints: TCemEpRerIatSuEre 1b378ys RelaOtivoe HuTmiOdity 1f37e8ys Mean (25D): MMMeiadnxiiiammnu:om:: NNNumibuiermooomfffbPPPiooeinibntnrttsssieLHnioRgwahrn(G0g1ey(%): 85 (19 519 ean) 7581 59083 weos G(G0y0oowT s e (91000 Report Generated: 16-4u-2001 1 1107 commENTs: revieweosy: [0 By om ATE: 7 2400 Page 870 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHum1i7dity Report Protocol Number: 418-020 Range of Dates: 13-Nov-2000 08:00 to 21-Mar-2001 16:59 STpaercgieetsR:aRnagte: TToottaall NNuummbbeerr ooff HDaoyusr:s: Total Number of Data Points: TSemTpelraa7t9urFe 301820975 3078 Rela3t0i%vetHou7m0i%dity 308102.975 3078 Mean (5D): MeMdaixaimnu:m: Minimum: NNumubemroobff PPeooinnrttss HinigRhan(3g)e:(4): Number of Points Low (%): e408) 458 (62) 760713 702s 63 08 708 (1000) 30078 (10000)0) 0 0) 0 0) Report Generated: 181-2001 at 14:06 COMMENTS: [------Y DATE: 7 240, Page 871 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHum16idity Report Protocol Number: 418-020 Range of Dates: 09-Feb-2001 14:30 to 02-Mar-2001 12:59 STpaercgieets:RanRogte: TTToootttaaall NNNuuummmbbbeeerrrooofff HDDoaauytrsas:P:oints: TFemlpeora9tu7re 502o2r25 RelatE ive Hua mic 50S22t25 Mean (2 SD): MMMeaidxniiiammnuu:mm:: NmuumembooobefffpaPPeoainrorntrtess LHfnooRwn(aAn0g))o (4: 73 (208 465 (56) 87720312 87613 S0501 (G`0v0yo') 430m (o9o4) Report Generated: 18-1201 at 14:11 COMMENTS: REVIEWED BY: (Dlrex DATE: 77401 Page 872 ARGUS 418-020 ARGUS Relative LHoucmaitdiiotny: DReovioamti1o6ns Report Protocol Number: 418-020 Rangeof Dates: 09-Feb-2001 14:30 to 02-Mar-2001 12:59 Humidity Target Range: Species: Rat 30% to 70% FBD2rat0ee1a T00i67m00e00 R22H07.LL Brea0r oso0 zmsL Date Time RH. H=Vaolle ueoOuu tooffrEaRngEe R-elatiighv_e HLum=iVdailtuy(eo0u)t of range Report Generated: 18-Jul-2001 a1 14:16 _Thesedeviations id notadverselyaffectheoutcome or interpretationof the study. "Thefollowing deviaton(s) impactedontheoutcomeofth studyasdescribed: oo oF : A : vue _064040) Page 873 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu0m1idity Report Protocol Number: 418-020 Range of Dates: 05-Mar-2001 11:30 to 21-Mar-2001 16:59 STpaortgieetsR:aRnagte: TTToootttaaal NNNuuummbbmeebrr ooofff DHboaautyrass:P:oints: TEempTeratEura 0512705 RelativeeHuTmic 28i0325 Mean (50): MMMaeixdniiiammnu:om:: NNNuuummmbbbeeerrr ooofff PPPoooiiinnntttsss LnHiogRwh(an(g1e:(%): 0 wos sz (20) 0a319 0555233 50 (Go0gn0 350 (Gl10oo0n) Report Generated: 18-40-2001 at 11:13 CommeNTs: _ _ REVIEWED BY: __ (0 (By an DATE: 7 240/ Page 874 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu4m0idity Report Protocol Number: 418-020 Range of Dates: 21-Mar-2001 16:00 to 24-Mar-2001 08:59 T`aSrpegceitesR:anRgate: TToottaall NNuummbbeerr ooff DHoauyrss:: Total Number of Data Points: TSemFpe0ra7t9ure 6745 65 Rel3at0i%ve10Hu7m0i%dity 674 5 65 Mean ( SD): MMeadxiiamnu:m: Minimum: NNumubemroobffPPieonintrtss iHniRgahnge(3%):(%): Number of Points Low (%}: 05 (33) 514 67) 772421 68799 64% 30 60 (1000)) 605 (1000)0) 0 0) 0 0) Report Generated: 18-Jul-2001 at 14:01 COMMENTS: [------ AY DATE: 7 24-2/ Page 875 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu4m1idity Report Protocol Number: 418-020 RangeofDates: 21-Mar-2001 16:00 to 24-Mar-2001 08:59 TSapregceitesR:aRnagte: TTToootttaaalll NNNuuummmbbbeeerrrooofffDHDaoayutsra:sP:oints: TP empy ers 647545 Rotate0Hu0mi%dity 64.75 a Mean (25D): MMeiMdnaiixaimnmu:umm:: NNNumiubemroomobfffPPoPbeoioinnnrtttesssiLHnrioRgwahnG(g4o:e: (4): Report Generated: 18-10-2001 at 11:32 0 win 7276%2 6LTI O%(B0wE0 ste 28 55673884 eT s G (110)00) comments: reviewensy: (1 0B on ATE: _7 2401 Page 876 ARGUS 418-020 ARGUS Temperature and Relative Humidity Report Location: Room 01 Protocol Number: 418-020 Range of Dates: 24-Mar-2001 08:30 to 25-Mar-200115:59 TSaprogteitesR:aRnogte: TTToootttaaal NNNuuummmbbbeeerrr ooofff HDDaoayutsra:sP:oints: Temperature 64F 10 79F a32z Relative Humic 30% to 70% i 32zs Mean (2 SD): MMMeaidxniiaimnmu:om:: NNNimuubemmrooobbfffPpPoeeioininntrrttsss fHLniogRwha(n(0g51e:(4: 07 os 20 (17) 0n582 5B58e7 2?6 o`oyooooo (`1o0o0o) Report Generated: 18-Jul-2001 1 14:08 CommENTS: SE revieweosy: 0 (Bn en DATE: _7 240] Page 877 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu0m4i.dity Report Protocol Number: 418-020 RangeofDates: 24-Mar-2001 08:30 to 25-Mar-2001 15:59 TSahregveitesR:aRnegxe: TTToootttaaal NNNuuummmbbbeeerrr ooofff DDHaoayutsra:sP:oints: TFelmope9rat%ure 3322 RelaptiveoHumiid 3322 Mean (2 SD): MMMeaidxniiaimnmu:om:: NiNuummmpbboearr ooff PFBooiionnttsss LionohRwa(Cn4g01e (%): 607 205) a1 (16) 7s80e5 a8%372 2o ofow9o 2To(ywo oo (9 Report Generated: 18-4u-2001 at 14:09 COMMENTS: RevieweosY: (1 for on DATE: 7 2%8/ Page 878 ARGUS ARGUS 418-020 Temperature and Relative Humidity Report Location: Room 40 Protocol Number: 418-020 Range of Dates: 25-Mar-2001 15:35 to 15-Apr-2001 16:59 TSapragceetsR:aRnogte: ToTTooittalal NNNiuummmbbbeeerrrooofffbHDaoatuyrss:P:oints: Pray Temperature sS2hoo Wo To Relative Humidity si2t5o Mean (50): MMeMidanixiaimnmuu:mm:: NNNuiummmbbeabrreooorfff PPPoooiiinnntttsss iLHniogRwha(n(4g1)e)(*%): 26 @10) 505 (50 7##5374 3n2s3 se6et (6K0gy0 SW08F3 (99m) - Report Generated: 15-Aug-2001 at 09:30 commenTs: } ) REVIEWED BY: L TL Ln DATE: _ -/5 01 Page $79 ARGUS 418.020 ARGUS Relative HLoucmaitdiiotny:DReovioamti4o0ns Report Protocol Number: 418-020 Range of Dates: 25-Mar-2001 15:35 to 15-Apr-2001 15:59 HSpuemciideist:y RTaatrget Range: sADma0te01 T0i60m0e R7Hi.SH 30% 0 70% Date Time RH. H=Valaueeoouttoofrange RHeilgaht_e HLu=mVaildueGo0) uoftrange Report Generated: 15-Aug-2001 at 09:34 These deviations did not adversely affect the outcome or interpretationothe study. "The folowing deviaton(s) impacted on the outcome of the study as described: Suy tls = one 1S? Page 850 ARGUS 418-020 ARGUS TemperatureLoacnadtiRoenl:atRioveomHu4m1idity Report Protocol Number: 418-020 "Range of Dates: 25-Mar-2001 15:35 to 15-Apr-2001 15:59 Ta argety Range: TTToootttaaalll NNNuuummmbbbeeerrr ooofff HDDaoayutsra:sP:oints: TSemEpeRrature S50201 RelativeeHuemnic 50E28H01 Mean (50): MiMMneadixiimamunu:mm:: NNNuiimmmbbbeeerrrooofffbPPoooiiinnnttsss HiLniogRwha(nC4gh)e:(%): nz 09) 3 (en) 7E75x38 78&90 so e e 6 y 08 0 54T s d (6828) Report Generated: 16-4u-2001 at 1:15 COMMENTS: a REVIEWED BY: (0 Bri zn DATE: _7 244i Page 881 ARGUS ARGUS 418-020 Relative LHoucmaitdiiotny: DReovioamti4o1ns Report Protocol Number: 418-020 TT Rangeof Dates: 25-Mar-2001 15:35 to 15-Apr-2001 15:59 Humidity Target Range: Species: Rat o0ArbDAaamt0e001i T0oi5g0om00e R77H22.83Mm 0Sahaonbgg0oo0:i o013r00o00 7rr2iaaenmn hBBabAwoIa 00056000000 or7oiroenmh Awan oo osm 30% to 70% Date Time RH. H=Valusout ofrEaRnCge RHeilgihv_e_HLum=iVdailtuye(o0u)tofrange -Low Report Generated: 164-2001 at 1129 These doiations i not aersly afc the outcome or interpretation of th study. The follwing dviaton(s) impacted onth autcomeofth sidy as described: ---- it tp -- ate: _07Av gor Page 882 oo" ~ ~~ -- raaeIt wON ARGUS418-020 Page 102 SaNmo:pLOOl2228e5:3 RReepceoirvteed,: 0088/01360000 LSioec:orR:iSt002 Projet CERT. LCEORTTNIFUIMEBDERRODAENTU01DI0E9GT26.meAL Asn Lapa Protin, PKjeelndahl (vx 629) Rea une Pri FFiuber, fcruude Fier, Crude FERIA 0s " Fir sor " ACradnmieuAmrne ase as " cor 0200 oom Cacim Catan Catium car 00s wm LeMesrscurLyet vn oss " Hose op wom PhosphorMusercy Phosphorus or was jr SeleniumSelenium se a0s36o2 o"om F@0o)))r AdFFlooilrrioaNtosahsneryrlimqoieunnetfsshotIromindaooetnilpsoorngR,eyipac-lihCeomusnsaetn-oc,mDreoI.rNDSnaeo:rmmvunifccce,aHr3ia14ns.g9h8i23.1134103684362 ETR eLeTso sdttybconosisrteaeorhetnvSop 7r0c5ssep e hserses! contrT tes Tott sbui5 onofRanAm bo Asier ) TTeo tere oo B | . Page= 883 ETRY EX ACT Cli 2st... & ARGUS 418-020 PMI NUTRITIQM: sox CLEORTTNIUFMIBEDERRODAEUNGTOIDI0E0T2MTEEALNT RAN AT ow CERT. Assav/Amalvte Organophpoespihate pesticides DEiiselntnen Mey PVpaairristiooonnn TTThrhiiimooetntn OrganochHoreinpgpaesE&pPoCidBe's HeBaBsEhor EUrinidanne MKiiowxa DRiiadiBnHC Dic0d1in CrMieotdhaonnyehlor jBeya dic AatosiPncsaere `Aflatoxins. Result Units orar p02r0 oooomm wS0o0o2m00 ooomm Sum pom Rsen p"Sr0.o02m00 pooponmm 0SS00o20m0 wo-omm S00m0 oomm SDSoo0om0 ojoooomm pSr0e0 o=m SS0o3m0 oomo pSr0e0 =om aFtc iosmm om <5.00 pb F(1o)rFaodrisiaonylmineforhmataiond-pllCesoeoncogsnsSt:ecs, 314-982-1310 ((@3))FAolrl Ntuhwetriqonus!eIser-tpRriiceohamiononnds-,DrI.NDMoarnuafnactuHraiungghtP,a31,4-776658.-946326.29561 eimma oLesTe Th orasestypmitty niovfeoryaeBueYsrinh.toPfSeamrosinheoRadmiAEeMYnpelLedaa. Trsh rem a aps ond bonAn iort ot ofem tn e oEs T m C ono s --] Page 884 EXACT COF 1 ( Centified Papers Retneval ARGUS 418-020 LabDiet 1 swreno PPrroodduucctt DCeosdce:: CLoatocNoasmeo:er: Enwes Return toCertifiedAnalysis Retrieval C5E0R2TMIFIED RODENT DIET MEAL OLCOT02O5362030-13A 10500 ---- EF] eo oso 1 oem] a Em x r Ess Ta or] an boo [Molson oe [bEoszs Tom oe 00s Ess TAN por e e J(EPEsLs Tra F=ESeAeJ F[eEaSToos A [--|] _ ee pa _orJ n LESS THAN 002 e[LESSaTHANe0.02 Engin| [LEsSTraNooz Jpce Jiessthanois Naps abdietcomicertiiedipua_sped02asp pmo Page sss |EXACT CU | 23/0 w= 5 &a =wl = = 1212012000 ARGUS 418-020 Foe Toews Jiesstawsers| No tes. 2oT)yriaedhtBaiaeorJlnaaMnfuorHrpmhaytaioonou,3(1l43g)e1a3)se61co2na6.ct2o8r3fso8s.sn3ayo4mnetho3mdoalro6ogyta2ion 3 Rona. Nataincg Pant of (159) 52.9581 ol oer estos y su nr , eb wes,eduo alr e REVIEWED BY: DATE Page 856|E4RBACTZiCslUo: ARGUS 418-020 oto SmplNos LOOMIS? RRaepvoerises111340000 Losinv,ewro3002 Fro CER. CCEORTTNIUNAEBDERRO.DEBNETCODI1E0T10BMEAL Away/Analve rPruoms,Kedah (629 Fiberserheatee ce JAric cCuatcmuiCe,nation po Cun Lt MPehroocpuhroyraesry [I opti Soni oe Fran rum TM or ar Hose " = --Remit ns = 3 am oon osm ans ams ass aise . Unis " " I a " i wa " Ee @iForFFoiorrcNtioeeny miteolrdantioopgns,epliCeanosooDmraSDer:reviecse,H3a1n4g98,1134170644362 (3)Allotherquestions -Richmond,INManufacturingPlant, 765-962-9561. poE e bo lem Ao a Aerr etaegheearrsohhraa fBoegreL.aem 02 h Lo oo REVIEWED BY: 2\s\ov DATE : EXACT Ci. . fet.. Page 887 =. CCaxeEDnBoDpRoNcToDT15MEAL AmaviAsaive mony Organophosphatepesticides etoDPFBisaiiultniwn fooean OrpacaHiTeripmoantpe rAoPsCss Er5iele NNFoomyean BBaaotmnae fBS oor w iiaSme pr.-- p-- ---- ARGUS 418-020 Remit Units ORGP mo - pS<Sr0o.i0mm20o0 p===p pSSrimt =E=S nsen Er <0 = we pSSriimee === SpSoio]mw =Ez pprrSom === SSSoioamo === SPSoiomm =7Ee arc Pp eo ecnme erm, r 4Dmoviesfotm Fi147186-5463065261 Forsdditionalinformation,pleasecontact: (1)Forassymethodology + CustomerServioss, 314-982-1310 Se ren a pe tSi e re kltteseeeed leeo Tmt me. et o odoo llas REVIEWED BY: DATE L|2E2XA1CZT s& so: Page 888 CL CL SU ARGUS 418-020 Jp Lancaster Laboratories Where quail s aiscitencye. ctor sien Aamasarios Sepia de, WH SHNED cotter by passin. wisn 98183 sfYormommseisvipg0y67te0y/2t0i01 h1613m0 cranoisamte espe SEE 2 eT Page 889 Lim2 e Retr EL -- 7/00 2 Leas Jp LancasterLaboratories IV' Wherequality s ascience. Lancaster Laboratories Supe No. WH 3634413 ARGUS 418-020 ANQalysis Repori FE Dee bid 7s/e BEo. o 24/1 Page890 smn ] y5 Jp LancasterLaboratories y Wherequaltyis ascience. Sroseaten bSFILITIS Hapth Fo. 0 SAHA ARGUS 418-020 LIT rion Enarin sisenrse BE Sen WE. oh i ie. En oa Zz Sm, EXROTCE AB 7/12/32)... Page 891 TR Jp LancasterLaboratories IV" Wh quale ity isr ascee nce. Sanesetes Taborstostes supe vo. Ww S034e2e ARGUS 418-020 Laborssasy Ghvoniae -- i Page 892 Dear hr fs fer EXACT COPY | hz ANALYTICAPL.0.LABBOoRxAT3O1R9IES, INC. CHA(L2F1O5)NT,723P-A641686914 ARGUS 418-020 SAMPLE ANALYSISREPORT Customer: AH9or0r3gsuhsSahmeR,eesheyPaArDcr1h.9,,044BIunci.lding A AFtAeXn:#: A22t11t55n--.444433D--e88n75a280Lebo Sample source: Formalation L.iborhury 05 F Shey Drive. 15/700 ANALYTICAL TDSiaamtmeeplessaanmmuppmllbeeeddr::: DSaatmeplerdecebiyved:: RESULTS 1182110/90276-/0000A EM11/28/00 Wwaatteerr Ssaufppeltyy, Claatsstihfeictaitmieono:f NsaompCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefwoartee,r the Standards for this parameter. `Parameter MCL Result TNCoootnlacilofloiCrhfmloorBranicntBeea,rcitaem,rgi/alc,ounctosu/n1t0s0/10m0l ml <1 l<1o1 a sW 2faEr0) uALnLderrestuhlets"SwafheicDhrianrkeinogutsWiadteerthAect""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl"(++()C.L) established <Sy7mboltkeeeys: than NIC - too numerous to count (> 200) mg/l - milligram/liter PA DEP #09-332 losEi D ln e Mazgann E. Fedock/ President ~ Page8o3 EXACT C. i3/e 1 AKALYTCIaCAALBEL.O0R-LTA,BBOaRxPAAT3O21R98I9E1S4, TNC. (315) 723-166 ARGUS 418-020 Customer: AH5r0og8rushs`aSmhRe,eesheByaArbcr1h.5,,044BI_uncSi.iAdMiPnLgEAANALYSISREPOTSDRaiamTmtpeelessaammmuppsllbeeeddr::: 811141/092076-/00008 Aten: A2t1t5a-.44D3e-8n7a10Lebo DSaatmepleredcebivyed:: E1M1/28/00 FAX h: 215-443-858 Sample source: Rm. 39 SVaro 408Sheehy Drive ANALYTICAL RESULTS aHteer SSafeety ClCaesstihfeictaavmieono:f NsoampCloilnigf,ormmebeatcstetrheiaEwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Stindaras for this parameter. `Parametex MCL TCNoootlnaiclfooyCrinmfloorBranicntBeea,rcitaem,rai/alc,ounctosu/n1t0s0/1m0l0 ml <1 Result <ia0.1 Dt suf) AALL EreesultscawtheicbhrairneinogutsWiadteerthAect"MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl(++()CL) established Susrymeboletkoeeoty:ntuhmaenrous to count (> 200) mg/l - milligram/liter ea DEP #09-332 Zt ; Li= Fg edock/o presin dent Page 894 EXACT CL. /8/or ARGUS 418-020 ANALYTICA?L.0.LABBOoRxAT3O1R9IES, INC. CEA(L2F1O5)RT,723P-A641686914 SAMPLEANALYSISREPORT Customer: A9r05gusShReeesheyarDcrh.,, BIunic.lding A Dsaatmeplesamnupmlbeedr:: AHtotrns.hamD,enaPALe1b50o44 Attn: 215-443-8720 DTaitnee rseacmepilveedd:: sampled by : FAX #: 215-443-858 sample source: Rm. 15 D8 Shechy dive 13ar)o0 ANALYTICAL RESULTS 8111/9276-/0000C 11410/026/00 EM wWsaatttaeenrrdarsSduapsfpeltfyyo,rCltaathsisstihfpeiacrtaaitmmieeotneo:rf.NsoampCloilnigf,ormmebeatcstetrheiaEwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Parameter Hen Result CNoonlciofloirfmorBanctBearcitae,riac,ounctosu/n1t0s0/10m0l ml <1 <<11 Total Chlorine, m/l `oa 2 Ll rafaz/oo AuLnLderrestuhelts"SwahfiechDriarnekinogutsWiadteertAhcet""MaarxeimmuamrkCoendtabmyinaasntteriLsekvsel(+()C.L) establishec <Symbollkeesys: than nTsN/T1C - mtiololingurmaemr/oiuistetro count ( 200) PA DEP #09-332 Hogalr ik, WarE.yFedook/ President Page 895 EXACTCz ~ / 13/01| ARGUS 418-020 ANALYTCIHCALAF.L0O.RLTA,BBOaRxPNAT3O11R98I9E1S4, INC. (215) 723-6466 _SAMPLE ANALYSIS REPORT Customer: Argus Research, nc. Sample number: 8197-000 H9o0r5shSahme,ehyPADr1.9,044Building A TDiamtee ssaammpplleedd :: 11410/028/00 AFcAtXn:4: A22t11t55n--.44443D3-e-88n75a180Lebo DSaatmeplerdecebiyved:i BM11/28/00 Sample source: Analytical Laboratory @ ress Shecky drive 5ar)er ANALYTICAL RESULTS Woaeterr saaptpelcyy, Claatsstihfeictaitmieono:f NsoampCloilnigf,ormmebeatcstetrhieaEwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Standards for this parameter. Parameter MCL CNToootlnaiclfooyCrihmflooBrranicntBeea,rcitaem,rai/alc,ounctosu/n1t0s0/1m0l0 ml <1 Result l<i1oa Dt fa 7/00 AALnLderrestuhelts"swahfeicDhrianrkeinogutWsaidteertAhet""MaarxeimmuamrCkoendtabmyinaasntteriLsekvesl(+7)(.MCL) established TSTSTyCmbolctkoeeoty:nutmheanrous to count (> 200) 7/1 milligram/liter PA DEP #09-332 Hee B, Maryann E. Fedock/ President Page 896 EXACT ZT, 8/0! 5 ANALYTcIaCnLAiL.o0-NLTA,BBOoRxBNAT3O11R98T9E1S4, INC. (219) 723-6466 ARGUS 418-020 Customer: A5r0g8usShReeesheyarbcrh.,, BI_nuSci.AidMiPnLgEAANALYSISREPODSTRaaitmmTspelessaanmmuppmllbeeeddr:|: 1823/3118-/0000A 1315 HAotrtsnh,amD,enaBALe1b90o44 Aten: 215-443-8710 DSaatmeplreedcebivyed:: 1B2M/18/00 hx k: 215-443-858 Sample source: Analytical faboratory BJ ANALYTICAL RESULTS wHateer SSafeety ClCasseifictaatmieono:f NsoampCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteadr.inkThienrgefaotree,r the Seinards for this parameter. `Parameter MCL CSoolnicfoovrimfoBranctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 Total cniorine, mg/l Result <i1x loa Dr flr infor AAL1rreeesults whaichbrairneinogutsWiadteertAhcet""MaarxeimmuamrkCeodncabmyinaasntteriLsekvesl(**()M.CL) established SSusryeEmbola tkoeoy:nunmaenrous to count (> 200) mg/l - milligram/liter oA DEP #09-332 ys Taryang/s. Fedock/ President Page 897 EXACT CE, 1 ANALYTIC0AL.LABBOoRxAT3O1R9IES, INC. CHA(L1F5O)NT,72P3A-641869614 ARGUS 418-020 _SAMPLEANALYSISREPORT Customer: A5r0g3usSheReesheyarDcrh.,, BIunci.lding A Horsham, PA 19044 SDaatmeplesanmupmlbeedr: : 1823/3118-/00008 Tine sampled : 1315 FAtAeXn:#: A22t11t55n--.4444D33e--8n85a7810Lebo DSaatmeplerdecebiyved:: 1E2M/18/00 sample source: Chem. Lab ANALYTICAL RESULTS VWaatteerr Ssuapfpeltyy, Caltasstihfeictaitmieono:f NsoampCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefwoartee,r the Standards for this parameter. Parameter MCL CNoolnicfoolrimfoBramctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 Totas Chlorine, mg/l Result <11 PREY =2/ra lot AULnLderrestuhletssSwahfeicDhrianrkeinogutsWiadteertAhcet""MaarxeimmuamrkCeodntabmyinaasntterLiesvkesl'(**()M.CL) established <S<ymlboel skesy: than Tre coo numerous to count (> 200) mg/l - milligran/liter PA DEP #09-332 Faryany/&. Fedock/ President Page 898 EXACT Co 7/ sl ARGUS 418-020 ANALYTCIHACLAFL.O0N.LTA,BBOoRxPAAT3O11R98I9E1S4, TNC. (315) 723-6466 _SAMPLEANALYSIS REPORT Customer: AH5ro0gr%suhsSahmRe,eesheyPaArbcr1h.5,,044BIunci.iding A TDSiaantmeeplessaanmmuppmllbeeeddr: :: Aten: A2t1t5n-.44D3e-8n7a10Lebo DSaatmeplreedcebiyved:i FRx h: 215-443-858 Sample source: Em. 38 1823/3118-/0000C 11321/518/00 EM ANALYTICAL RESULTS aateer SSaefeyty,Cl"aatsstihfeicraitmieono:f NsoampCloilnigf,ormnebeatcstetrhieaEwPeAreanddetDeEcPteddr.inTkhienrgefvoartee,r the Standards for this parameter. Paranster re Resule CSToootlnaielfsoicrfhmloorBrnaicntBeea,rcitaem,rgi/alc,ounctosu/n1t0s0/1m0d0 ml <1 <i1a loa =/12 Jos 211 reshueltsTowahteicDhrianrekinogutsaitdeerthAect""MaarxeimmuamrCkoendtabmyinaasntteriLsekvesl'(*%()MCL) established fSYuSymmebol. tckoeoetynutmhaenrous to count (> 200) 6/1 miniigran/liter oA DEP #09-332 Taryang/t. Fedock/ president Page 899 EXACTC( .~ 28h75 . ARGUS 418-020 ANALYTICAPL.0.LABBOoRxAT3O1R9IES, INC. CHA(L2F1O5N)T,723P-A641686914 _SAMPLEANALYSISREPORT Customer: A5Hr0o5grsuhsSahmRe,eesheyPaArDcr1h.9,,044BIunci.lding A DTSaiatmmeeplessaanmmuppmllbeeeddr::: 81323/11-80/0000 1315 Date received: 12/18/00 Actn: A2t1e5n-.44D3e-8n7a10Lebo Sampled by i EM FAX #: 215-443-858 sample source: Rm. 20 ANALYTICAL RESULTS aoteer SSaupfpeltyy. Claatsstihfeictaitmieono:f NsoampCloilnigf,ormmebeatcstetrhieaEwPeAreanddetDeEcPteddr,inTkhienrgefwoartee,r the Standards for this parameter. Paxameter MeL Resulc CNoolnicfoolrimfoBramctBearcitae,riac,ounctosu/n1t0s0/1a0l0 ml <1 <11 0.4 Total Chlorine, mg/l 20a for AALbLerrestuhelts"swahfiechDrairnekinougtsWiadteertAhcet""MaarxeimmuamrkCoendtabmyinaasntterilsekvesl!(*()M.CL) established <Sy2mboltkeesys: than INTC too numerous to count (> 200) mg/l - milligram/liter A DEP #09-332 Waryann 2. Fedock/ President Page 900 EXACT GZ: 3/0! ARGUS 418-020 Analysis Report . (pLancaster Laboratories \ I' Wherequality s ascence. naetorz Lancaseas Laboratories duple do. Ww 3843350 J rosaries 92423 peurteedeevsasnes 10s0a8 m i -- So -- mBnL t an potne 13 ara Waar same oe meen HEIN 2 EnXACDT sCOfPc)Y Page 901 D. Riob i/tf-or ARGUS 418-020 Analysis Report Jp Lancaster Laboratories 0 Whquale ty 5r asciee nce. aezorz Samoastar taborstostas sungle Wa. Wo THIS cotter ww opm FE i Ha I r Lirdmi tro poi tvs J mLeLa, EL noe ie Bom o&= 3 D Ate helo SER, Page 902 aN COPY mPsliste! nen ARGUS 418-020 Analysis Report Jp LancasterLaboratories Bh V Wherequayisascence. waerorz Lxnastar Laberscorien sample We. W354 cotteceetion/aeraon owe by BA pain ws sous SBtoLU on veers #1 coun wasen seein oon in ssdanye Stes ame Soe aoa wenn cn SrET ER EE Tn EXACPTolCisOPloYs * Page 903 DSh hor ri ARGUS 418-020 Analysis Report Jp LancasterLaboratories ND Where quaityisascence f-- enosmter rstssssson siren 7or 0 rpasia ce, accom mbes. e233 r-- glmsasshhSe n 0 FRoaetlirs remy || n 5 Ern a im an on ih B oi 2| menaepn SiER Page 904 st wn ARGUS 418-020 ANALYTICA.L0.LABBOoRxAT3O1R9IES, INC. CHA(L3F1O5N)T,723P-A641686914 _SAMPLEANALYSISREPORT Customer: A5r0g5usShReeesheyarDcrh.,, IBnlcd.g. A Horsham, PA 19044 TDSiaantmeeplessaanmmuppmllbeeeddr::: Atta: A2t1t5n-.443D-e6n7a20Lebo DSaatmeplreedcebiyved:: FAX #: sample source: Velo Chem-Lab 708 F Sheehy Drive ANALYTICAL RESULTS 0210/1083-/0011 10413/003/03 EM aeteTr aSapfpeltyy. Claatsstihfeictaitmieono:f NsoamCploilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr,inTkhienrgefwoartee,r the Standards for this parameter. `Parameter ew Result CNoelnicfoolrimfoBramctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 <<a1 Soa Total Cnlorine, ma/l Je)or AALiLerrestuhelts"swahfiechDrairnekionugtsWiadteerthAect""MaarxeimmuamrkCeodntabmyinaasntterLiesvkeslr(**()MCL) established <<Symbol1keesys: than TTC - too numerous to count (> 200) mg/l - milligram/liter PA DEP #09-332 2 e =r eeCo Page 905 EEXXAACCTT COLEEY7- fol ARGUS 418-020 ANALYTICA0L.LABBOoRxKT3O1R9IES, INC. CHA(L2F1O5N)T,72P3A-641689614 _SAMPLEANALYSISREPORT Customer: A9r0g5usShReeesheyarDcrh.,, BIlndc.g. A Horsham, PA 19044 DSaacmeplesanmupmlbeedr:: Tine sampled : Attn: A2t1t5n-.44D3e-n6a720Lebo DSaatmeplerdecebiyved:: FAX #: sample source: Rm. 38 YEyzlPo 505 Shehy7 DriAvNeALYTICAL RESULTS 0210/1083-/00118 10413/003/01 EM Waattoerr Ssaupfpeltyy, Claatsstihfeictaitmieono:f NsoampCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefwoartee,r the Standards for this parameter. Parameter MCL Result CNoolnicfoolrimfoBramctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 Total Chlorine, mg/l b<E 111 py /e/ot ASLiLderrestuhelts"swahfiechDrianrkeinogutsWiadteertAhcet""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl"(*%()M.CL) established <ISymbol1keeeys: than Tre too numerous to count (> 200) mg/l - milligram/liter PA DEP 409-332 7 ea= Page 906 Er = EXACTCZ 3/0! ARGUS 418-020 ANALYTICAPL.0.LABBOaRxAT3O1R9IES, INC. CHA(L2F1O5N)T,723P-A641686914 _SAMPLEANALYSISREPORT Customer: A9r0g5usShReeesheyarDcrh.,, IBnlca.. A Horsham, PA 19044 sDaamcpelesanmupmlbeedr:: Tine sampled : Acen: A2t1t5n-.44D3e-8n7a10Lebo DSaatmeplreedcebiyved:: FRX # Sample source: or A0n5a.l8ytSihceaelhyLDarbiovreatory ANALYTICAL RESULTS 20011/80-30/10C1 01413/003/01 BM Weaeterr SSaufppeltyy.Claatsstihfeictaitmieono:f NsoamCploilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr,inTkhienrgefwoartee,r the Standards for this parameter. Parameter un Result CNoolnicfoolrimfoBramctBearcitae,riac,ounctosu/n1t0s0/10m0l ml <1 Total Cnlorine, mg/l <11 `oa /e/ol AiLeL rrestuhelts"swahfeicDhrianrekinougtsWiadteerthAect""MaarxeimmuamrkCeodntabmyinaasntteriLsekvsel(**()M.CL) established <Sym2bol.ekseys: than TTC too numerous to count (> 200) mg/l - milligram/liter PA DEP #09-332 Hogan Elie ace .FedockP/resident Page 907 EErXrA--C--T.S ' ARGUS 418-020 ANALYTICA2.L0.LABBOaRxAT3O1R9IES, INC. CHA(L3F1O5N)T,72P3A-641686914 _SAMPLE ANALYSISREPORT Customer: A5r0g5usShReeesheyarDcrh.,, BIlndc.g. A Horsham, PA 19044 sDaamceplesamnupmlbeedr:: Tine sampled : Attn: A2t1t5n-.14D3e-n87a10Lebo DSaatmeplerdecebiyved:: FAX #: sample source: Rm. 14 fo 905Sheahydrive,ANALYTICAL RESULTS 0210/1083-/00110 10413/003/01 BM aateer SSearfoeltyy, Claatsstihfeictaitmieono:f NsoampCloilnigf,ormmebeatcstetrhieaEwPeAreanddetDeEcPteddr.inTkhienrgefvoartee,r the Standards for this parameter. Parameter mew Result CNoolnicfoolrimfoBranctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 a<10.6 Total Chlorine, mg/l 1-7-0! AALeL rrestuhlets"swahfeicDhrianrekinogutWsaidteertAhcet""MaarxeimmumarkCoendtabmyinaasntteriLsekvesl'(**()M.CL) established Symbo2l eksesy: than TTC too numerous to count (> 200) ST meniTeran/titer PA DEP #09-332 pegl a ice ere TFedook/ President Page 908 EXACT CTT ol. ANALYTcIaCnAPtL.0o.LnA,BBOoRPxAAT3O11R98I9E1S4, INC. (225) 523-6466 ARGUS 418-020 _SAMPLE ANALYSIS REPORT Customer: HA9or0rg3suhs`aSmhRe,eesheByaArbcr1h.9,,044BIlndcg.. A STDiaanmtepelessaanmmuppmllbeeeddr::: ABteXn:: A2t1t5n-.44D3-e8n7a10Lebo DSaatmeplerdecebiyved: sample source: Chem. Lab Os 905 F Sheehy Drive foasfor ANALYTICAL RESULTS 0223/3174-/0011 1515 EM02/14/01 WVaatteerr Ssaapfpeltyy, Claacsstihfeictaitmieono:f NsoampCloilnigf,ormneebtasctetrhieaSwPeAreanddetDeEcPteddr.inTkhienrgefaotree,r the Standards for this parameter. [Parameter MCL Result TCNoootlnaiclfoolriChmflooBrramicntBeea,rcitaem,rai/alc,ounctosu/n1t0s0/1m0l0 ml <1 <il1oa 2Loo/o AAdLerrestuhelts"swaheichDrairnekionugtsRiadceerthAect""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl(++()M.CL) established V SymbolE . key: than TTC tos numerous to cout (> 200) 5/1 - midligran/liter oA DEP #09-332 El r ll, Faryahn E. Fedook/ President Page 909 {EXACT C277 tH 7013/01 ANALYTcIanCLAiL.o0-RLTA,BBOoRxBAAT3O11R98I9E1S4, INC. B15) 723-6466 ARGUS 418-020 _SAMPLE ANALYSIS REPORT Customer: AH5ro0gr%suhs`aSmhRe,eesheEyaArDcr1h.9,,044BIlndcg.. A TDSiaatmmeeplessaanmmuppmllbeeeddr::: cxen:4: A2t1t5n-.44D3e-8n7a10Lebo SDaatmeplerdecebivyed:: sample source: mm. 1-2 (4) g.. 705Sheahy DrivAeNAL"YSTuIeCsA!L RESULTS 20323/71-40/1081 1515 EM02/14/01 WaatteeTr sSuapfpeltyy. Claatsstihfeiccaitmieono:f NsoamCploilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefwoartee,r the Standards for this parameter. `Parameter MCL CNoolnicfootrimfoBranctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 Total Cniorine, mg/l Result <p1y os =Jets Jor AiLtLerrestuhlets"swahfeicDhrianrekinogutsWiadteerthAect""MaarxeimmuamrCkoendtabmyinaasntteriLsekvesl'(+%()M.CL) established SSyemboal ktey: than Time coo numerous to count (> 200) J1 matligran/liter he 2 DEP 409-3382 loga s. Fedock/ president Page 910 E#X5ACT CO-ot 1| It 7)3/>0 ANALYTCIanCLAbFL.o0N.LTA,BBOoRxPAAT3O11R98I9E1S4, INC. (215) 723-6466 ARGUS 418-020 Customer: A5r0g%usSnReeesneyarDcrh.,, BI_lndcS.gA.MPALEANALYSISREPODTSRaaitmTmepelessaanmmuppmllbeeeddr::: Horsham, PA 15044 Attn: A2t1t5n-.44D3e-n8a720Lebo DSaatmeplreedcebiyved:|: RX #: Sample source: Rm0.55SheatyDrivDe ono ANALYTICAL RESULTS 2023/3174-/0011 1515 EM02/14/01 aHatteerr S SafeetyCOClassithfeicLaitmieono:f NsoamCploilnigf,ormmebtasctetrhieaSwPeAreanddetDeEcPteddr.inTkhienrgefaotree,r the Stomdards for this parameter. `azaneter wn Result CNoolnicfsotrimforBanctBearcitae,riac,ounctosu/n1t0s0/1m0l0 ml <1 <PE 10.1 Total Chlorine, mg/l =z0)or AAL1 EreesultscawfheichDrairnekionugtsWiadteerthAect""MaarxeimmuamrCkoendtabmyinaasntteriLsekvesls(+()N.CL) established aSYsmyembol tckoeeony:nutmhearnous to count (> 200) mg/l - milligram/liter oA DEP #09-332 2 Dsl Di E. Ft edock/t Presio dent {EXACTCE ow ' Page911 LABY 2/301 -- ANALYTICA0L.LABBOaRxAT3O1R9IES, INC. CHA(L3F1O5)RT,723P-A641686914 ARGUS 418-020 _SAMPLEANALYSISREPORT Customer: A9r0g3usShReeesheyarDcrh.,, BIlndc.g. A Horsham, PA 19044 DSaatmeplesanmupmlbeedr:: Tine sampled: AFtAtXn:#: A2t1t5n-.44D3e-8n7a10Lebo DSaatmepleredcebiyved:: Sample source: Analytical oy 725 Shear dine @ info, ANALYTICAL RESULTS 2023/3174-/0011 1515 E0M2/14/01 WVaatteerr Ssuapfpeltyy, Caltasstihfeictaitmieono:f NsoampCloilnigf,ormmebeatcstetrhieaEwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Standards for this parameter. `Parameter MCL NCoonlciofloirfmoBramctBearcitae,riac,ounctosu/n1t0s0/10m0l ml <1 Total Chlorine, mg/l Result <11 `oa =/20/0/ IAlnlderrestuhlets"swahfeicDhrianrekinogutWsaitdeertAhcet"MaarxeimmuamrkCeodntaDmyinaasntteriLsekvesl(+()M.CL) established <Sy7mbolykeesys: than mNgT/Cl -- mtiololingurmaemr/oulsitetro count (> 200) PA DEP #09-332 In Ma Sul E. Fedock/ President Page 912 [TExRacE t CECEY 247/8/o ANALYTCIHCALAF.LO0R.LTA,BBOoRxPAAT3O11R98I9E1S4, INC. (219) 723-6466 ARGUS 413-020 Customer: A5r0g3usShReeesneyarDcrh., SAMPLE ANALYSIS REPORT BIlncd.g. A SDaamtpelesamnupmlbeedr:: 40133/507-/0011A RAtotzna.hamD,enFaALe1b90o44 Aven: 215-443-8720 DTaitmee rseacmepilveedd:: Sampled by: 01433/008/01 FO xb: Sample source: Room #39 ANALYTICAL RESULTS eWateer SSuapfpeltyy. Claarsstihfeicraitmieono:f NsoampCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefaotree,r the Standards for this parameter. `Parameter MCL Result CNToootlnaiclfootCrihmfloorBranicntBeea,rcitaem,rgi/alc,ounctosu/n1t0s0/1m0l0 ml <1 <bE 10.6 2hk Sass) AdLeL rrestuhlets"swafheicDhrianrkeinougtsWiadteertAhcet""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl'(+()M.CL) established STSTyCembo-altkoteoy:nutmhearnous to count (> 200) 79/1 milligran/liter PA DEP 409-332 aly? Fedotx/ president Page 913 EXACT COBY | ft of ARGUS 418-020 ANALYTCIaCnLAPzLoooRLTA,BBOoRxPAAT3O21R98I9E1S4, INC. (315) 723-caee _SaMPLEANALYSIS REPORT Customer: AHSro0gr8suhsSahnRe,eesheyPaArDcr1h.9,,044BIlndc.g. A DTSaiatnmeeplessaanmmuppmllbeeeddr::: Das received: ABtXtn:4 A2c1t5a-,44D3e-n8a710Lebo Sampled by : Sample source: C0he5m. FLaSbheehy Dove EH ANALYTICAL RESULTS 41014333/050-70/1081 0F3O/08/01 aHatteerr SSafeetyy ClCasseificfaitnieono:f NsoampCloilnigf,ormmebaatcstetrhieaEvPeAreanddeDtEePctderdinTkhienrgefaotree,r the Standards for this parameter. araneter new Result CSToootlnaielfootricnmftooBrranicntBeea,rcitaem,rgi/alc,ounctosu/n1t0s0/10m0l ml <1 <i1a loa Saofos AALL EreesultscawtheichDriarnekionugtsWiadteertAhect""MaarxeimmuamrkCeodntabmyinaasntterLiesvkesl(*()C.L) established SSSryYcmbRol.tokoeRoy:nutmhearnous to count (> 200) 6/1 mliigram/licer ea DER #09-332 on >) rama Page 914 EEXArCTmCavs EN ANALYTcIaCnAbtLooo.LnA,BBOoRxEKnT3O11R98I9E1S4, INC. (213) 723-6466 ARGUS 418-020 Customer: _SAMPLEANALYSISREPORT A9Hr0o%grsuhs`aSmhRe,eesneByaArDcr1h.5,,044BIlndc.g. A DTSaiatnmeeplessaanmmuppmllbeeeddr::: 401341/330057-/0011 ABtxen:4: A2t1t5n-.44D3e-n8a710Lebo DSaatmeplreedcebiyved:|: FO03/08/01 Sample source: Analytical L_oborat1orySafBer ANALYTICAL RESULTS Water Safety Classification: No Coliforn bacteria were detected. Therefore, the wStaatnedrarsdupsplfyo,r atthisthpeartaimmeeteorf. sampling, meets the EPA. and DEP drinking water `Parameter MCL CNToootlnaiclfootriChmflooBrranicntBeea,rcitaem,rgi/alc,ounctosu/n1t0s0/10m0l ml <2 Result <l1aoa 2 ft Sasfor ATLaLnerrestuheltsSswahfiechDrianrekinogutsMiadceertAhcect"MaarxeimmuamrCkoendtabmyinaasntterLiesvkesl!(+7()MCL) established uSVsryemboletkoetoy:nunmaenrous to count (> 200) R95 - mitiigram/liter PA DEP #09-332 p Posa i r Elc e,a Maryann E. Fedock/ President Page915 [Exact Ci oF 2s ANALYTCIHBCLAbFL.O0.NLTA,BBOaRxPAAT3O11R98I9E1S4, INC. B18) 723-6466 ARGUS 418-020 Customer: A5r0g%usShReeesneyarDcrh., BI_lndcS.gA.MPALEANALYSISREPODTsRaiaTtmmeeplessaanmmuppmllbeeeddr::: 041314/330057-/00110 Thootzas.hamD,enPaALe1b90o44 Acen: 215-443-8720 DSaatmeplreedcebivyed:: 0F3O/08/01 xb: sample source: Room #5 ANALYTICAL RESULTS wHaeterr SSafaetyy ClCasseificCaitnieono:f NsoamCpioilsigf,ormmebeatcstetrheiaEwPeArsanddetDeEcPteddr,inTkhienrgefwoartee,r the SeimGards for this parameter. `Parameter MCL SCeonlcifoorfmorBamctBearcitae,riac,ounctosu/n3t0s0/1m0l0 ml <a Total Chlorine, mg/1%> O Jn- hovse valve for room S or Hfor as 0-3 PPM. Di h2e)ol Result <i1 1.5 2 ftw Sao/o) AALi reesoultscawfheichDrairnekionugtsWiadteerthAect"MaaxreimmnarCkoendtabmyinaasntteriLsekvesl!(*%()M.CL) established aSTsryembol tekoeeoty:nutmhaenrous to count (> 200) mg/l - milligram/liter oa DEP 409-332 Zt SrA >) L 4 Tease preside Page 916 [Eacressy ) galtZs/e ARGUS 418-020 ANALYTCIHCAALFL.0O.NLTA,BBOoRxPAAT3O11R98I9E1S4, INC. (219) 725-6466 SAMPLEANALYSISREPORT Customer: A9r0g3us`ShReeesneyarDcrh., BIlncd.g. A Horsham, PA 19044 STDiaantmeeplessaammnuppmllbeeeddr::: 40246/602-/0011A 1400 Acca: A2c1t5a-.44D3e-n8a710Lebo DSaatmeplerdecebiyved:i 0B4O/02/01 Ch Sample source: Analytical ANALYTICAL RESULTS WVaatteerr Ssaufppeltyy, Claacsstihfeictaitmieono:f NsoampCloilnigf,ormmebeatcstetrheiaEwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Standards. for this parameter. `Parameter MCL. TCNoootlnaiclfoolriChmflooBrramicntBeea,rcitaem,rai/alc,ounctosu/n1t0s0/1m0l0 ml <1 Result <i1: loa #-9-0/ AAdLerrestuhlets"swahfeichDrairnekionugtWsaidteerthAect""MaarxeimmanrkCeodntabmyinaasntteriLsekvesl'(++()CL) established T SymboE l key: nan rc - too mumerous to count (> 200) mg/l - milligram/liter oA DEP #09332 FLL arya 5. Fedock/ President EXACT CU 17/00 Page 917 ARGUS 418-020 ANALYTICAL.0.LABBOoRxAT3O1R9IES, INC. CHA(L2F1O5N)T,72P3A-641869614 SAMPLEANALYSISREPORT Customer: A9r0g5usSheReesheyarDcrh.,, BIlndcg.. A HAtotrns.hamD,enaPALe1b90o44 AFtAtXn:#: 215-443-8710 SDaatmeplesanmupmlbeedr:: DTaitmee sreacmepilveedd:: Sampled by : Sample source: Rm. 16 Rack 027 40246/60-20/1081 10440/002/01 FO ANALYTICAL RESULTS Wwaatteerr Ssuapfpeltyy, Caltasstihfeictaitmieono:f sNaompCloilnigf,ormmeebtasctetrhieaEwPeAreanddetDeEcPteddr.inkThienrgefwoartee,r the Standards for this parameter. Parameter MCL Resulc NCoolnicfoolrimfoBractBearcitae,riac,ounctosu/n1t0s0/10m0l ml <1 <a1 Total Chlorine, mg/l 0.6 4-9-0/ AuLnLderrestuhelts"SwahfiechDrairnekinogutWsaidteertAhcet""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl"(++()N.CL) established <Symbo"lleksesy: than mNgT/C1 -- mtioollniugmrearmo/ulsitetro count (> 200) PA DEP 409-332 "2% 2. Wasfann . Fedock/ President Page 918 EXACT Clit Info! ; ARGUS 418-020 ANALYTICA2L.0.LABBoORxAT3O1R9IES, INC. CHA(L2F1O5N)T,72P3A-641686914 SAMPLEANALYSISREPORT Customer: A9r0g5usShReeesheyarDcrh.,, BIlndcg.. A Horsham, PA 19044 SDaatmeplesanmupmlbeedr:: Time sampled : Attn: A2t1t5n-.143D-e8n7a10Lebo DSaatmeplreedcebiyved:: FAX #: Sample source: Rm. 39 Rack 121 4042/6062-/0011 10440/002/01 FO ANALYTICAL RESULTS WVaatteerr sSuapfpeltyy, Claatsstihfeictaitmieono:f NsoampCloilnigf,ormmeebtasctetrheiaSwPeAreanddetDeEcPteddr.inTkhienrgefwoartee,r the Standards for this parameter. Parameter MCL Resulc NCoonlciofloirmforBmactBearcitae,riac,ounctosu/n1t0s0/10m0l ml <1 Total Chlorine, mg/l <11 0.3 #-9-0/ UAnLderrestuhelts"SwahfiecDhrianrkeinogutWsaidteertAhcet""MaarxeimmuamrkCeodntabmyinaasntteriLsekvesl'(++()MCL) established <Symbo"lleksesy: than TmgN/TlC - mtioollniugmrearmo/ulsitetro count (> 200) A DEP #09-332 yr fa EP Page 919 Ey U[7EplXiACzT/Cerrd! ANALYTcIaCmAEbLiLoAR,BORxA)TO1R8I9E1S4, TNC. 52 che ARGUS 418-020 Customer: Argus Research, Inc. sample SAMPLEANALYSISREPORT number: 4266-010 ace: r9RB0oio5bssnaaSinhaaaes:echeyinAiDorsT.5,048Bldg. A DRDS aaorteee s SSseaacmmtppillveeedda!|: 01o444/0/00022//0011 Ei sample source: Pormilations AALYTIAL RESULTS Vaantear EsC aTtetEyLCE lBaislsitSiacrFaaitmnieaotnne:r:-NsoanpCtoilnigf.ormmesbeasc.tetrhieaEwoenreanddetDeEcYteGde,inTthienrgefwoerbee,r the Rarametexr MCL Result SCPoolmiefRsorEmoEBmactSSeernitaSa,ricsounttesn/1i0a0 1a010 mi <a bfi i1 a 4-9-1 tALeL rresEuhltsTewhtichBearnenoyutshiadteerthheetn"MaarxeimmuamrkCeodntabmyinsasnrterLiekvsel'(+4()M.CL) established TSisymmebLol,LYKoey:munmaenrous to count ( 200) mg/l - milligram/liter Ze. 7 lod PA DEP #09-332 yan E. Fedock/ President EXACT CL LY 7/17/ - Page 920 ARGUS 418-020 ANaQlysis Repol JpLancaster Laboratories Where quailsaiscitencye. J atv SEEnrLanSTe ner s,ee nt pL itaimEnes fg mE OG wpm sa Ae weo mooomoomon a go oF HE Sion mepachics Spexide mow mye cen oHnW 7 Chom maomion sutace BTaerlLyon Bioe ia. ESEYE mBmE eomasoa ro<onio sao8.k I SR bye aEoe an yy Stns Tm Re PIE So in ESXnAiClTisClOsPY Page 921 Eo uml ane 1 Bo aEm L a3no aZm= eoz!i sts 228 we 21100 ARGUS 418-020 JpLancaster Laboratories 7' Wherequalityis ascence. Lancaster Laboratories Same No. G3 3415 cottestassar/aerion aso by Br ffsRumEirrcIcadea: LooyEu/zne/wzo0s0esen16s.a00me Le Accouns wher 03033 fpeprri--gee ET)3 Page20f2 ars opt x icon in srk 2 hatolr EXACT COPY FEE Page 922 man ARGUS 418-020 Explanation of Symbols and Abbreviations Thefollwingdefinescommonsymbolsandabbreviationsusedin oporingtechnicaldate TNNTODC. nToonoeNdeutemcteedTrooCouunst 10 iniematonalUnis BMMPQNL BMeolsotPwrMovianbmluemNQuumabneirtaton Level CPUnits cobaltchroplatuntnes shosiemC demgircereosmCneoslisaimus NTUF. dneegprheeleosmFealnnvcewnhretit unis mCeaql (meitli)ecqauloirlieensts ktog. kpoiuongdr(asm)s) wm9ig gmmriealrmtoesgr)rsa)ms) mg| rmiilsgr)amis) ul mroiterts) m3 cubicmeteis) fb >5umm fersgreaterthan micronsinlength perml leasnsbtehaenla-Ttlhyedneutmebremirnfeodlulswiinnggt1hess5p9e0ciisthteksti.tofqaiation,thesmallest amount of anaytewhich > oreaertran ppm `poGanrraetHmssep.erFroomfrwiaatqneureh-oOuansseiawapeuodimsgi,hpeoqveumriyviaullseounstatltotanaKekleomngir1garmba.e FeqpounrvGaKaliseonegtsroaofmmVia(bpMooXrrsa).mO.snpoeeorGnPeMrg5r(eanqmgup)iev.arlbeienlctia1eu0nse ne mcrofgaos pelrHetr ofrgs. ppb Oryweight parts perbilon Resutspriedunderthisheacinghavebeenadjusiedformoisturecontent.This increthaasnaelyste `basis weightconcentrationtoapproximate hevaluepresent in a SiarsameWNOutmoisture. Us. EPAdataqualfrs: Organic Qualifiers AB TAInCaiissawpoasssiisodseitdeicctoenddienthseabtaornpkroduct CPoesmtpcoiduenrdesquuatnciioatendofnbaiydGmiEeeMddSsamvle E Cronacnegnetorfatthieoinnesxtcruemeednsttecaibraton JN (EPTsCtsrmoanteye)dvsaebveuidenmceopfaicomvpouend P cCoonnficremnartaitonocnodlfuemrnesn>c2e5b%etweenprimary XYZ DCefionedmincpwaasseonnaorturdaetntveec.dted Inorganic Quaiifers E8 ValEuess<CtvROemL0,abnutrttf2o0erLendce MN DSpikuesapmnpjleelnctootinwiptrcheicnscaioonntntooltmmeeits 5 Mecatlhcuoldatoiofnstandardaddtons (SA)usedor W PCostodigmestipwonasosnpokutedoeuntetocdtfceodntol its: += DGuoplrieclaatteonacnaoleyfsiicsineonttwoirtMiSncAont<r0o8l8k5is Thneesatseysrtersieutsthsuersecwliaotlelbonellmyeeaotnofticthnegetlsseaisamsmo.ppllnIeefyeosUutnheidae.vCsel(qihueeensstatssimophnloseuraengbaaelrydaziwneagdtrihesetphuraltoypra ceeprtrceeacslheinsaatetupveiesn ooaffcchhoeelmbeuiclctkanlogfsorammamitpcelrreoisbai.loplnlovegoiavcseaeld. comntaectmuosfb,oWuoer sctraanfn.oTtibsarheepoirtrsehsaplonnoctbeefroersparomdpulceendelxecgeyp.thowfeulv,er, uhroiuessheswarmiptienngh3psrobveeelnofpteeroambeodrbiyo.a WsAEuXRbmPRiRAtEeNdS.TSYETDAHOENRDFLOIIMRPWELIGITOESDIO.NFWGELEIXADPBIRLIEITSSYS W-CIAAnNRLacRYcAAeTNpIHTinYEgMaR1SnEWaXAcCRLeRUAlSNwIToVIkEE,AS,wNeEDwXaP5RnGEtVSEShNEeDaIcNOLcRuIrEaIUcMOyPLFoIfAEDLe.sLIOrTeNsHuECsRoLWrAtAURhRWsDAaANmRITpRlIAeENsNSsTGY COFA"BTFOIERTDANTTEOOSRS,IDFEAOSMRSAPEGAELRISTAIFBCOLUERLFALORORPSUSNRDOIPFROPESRCEOTA,FNISTDPOWERCAIRGAROLAOCDNOWTNIYSLEOLQFUREMENEGTRAGIRHADALNL,TEOASBRSIOILFNIC(TIY4D.)ETNHITNEANLNODEEAGVMLEIANGGTEENSSCHIEA(NLGELLILUTDAHINENCRGSA,OSBTLUEETRONROT THEPCUORRSENTS)OIFOFLBASNUICCAHLSTDEIAMRLATAGBEYSO.RAWTeORaIccEeSpANnoDe(3g)aWeHsEpTonHiEbRifLyAfNoCrAnSeTpuErRpLoAsBeORfoArTwOiRcIhEShHe cAeSnBEuEseNstIhNFOesRMrEeDsOusF. inNoeuStracnhiaesredTaormsranideCronddeorfnoowfoLaknschasatlebreLaasocrpationebs LnadnwcaeshtrereLascaradtocre1swahnycchonncilcadsaayrsccoonridaoinsed(naalvnyayfom Sccofacedapraaonebcy heet. Page 923 ARGUS 418-020 APPENDIX K HISTOPATHOLOGY REPORT Page 924 ARGUS 418-020 RESEARCH PATHOLOGY SERVICES, INC. 438 EPcrotneB.utl2er1A6v.e5n4t,5.N7o0wF7Ba0rci2,18.P3A451.34530918 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (APFO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: 7-6889.6 HISTOPATHOLOGY REPORT SUBMITTED TO: Raymond G. York, Ph.D., DAB.T. Argus Research 905 Sheehy Drive Horsham, PA 19044 SUBMITTED BY: W Rey Brow man. 28, 100 'W. Ray Brown, D.V.M., Ph.D. Veterinary Pathologist March 25, 2002 Page 925 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT TAOFB CONL TENE TS Page REPORT Results " " " SUMMENY rss QualityAssurance UnitStatement 8 TABLES 1. Incidence and Degree of Severity of Histomorphologic Observations PB CRTRHII nsmmmpgimimspumisimparmpseigapmosnggommnd 2. Incidence and Degree of Severity of Histomorphologic Observations - PGeneration Reduced Fertiity ANIMAS... 13 3. Incidence and DegofrSeveeriety of Histomorphologic Observations PY GUTRIRI csp mms pamosins 16 4. Incidence and DegofrSeveeriety ofHistomorphologic Observations - F1 Generation Reduced Fertiity Animals sneak APPENDICES I. HiStomorphologicODSEIVations - PGENration..........................l-1 to 118 KeytoHistomorphologic Observations. p-------- JH Tables 1-1. Histomorphologic Observ-aGrtouipo|Mnalse RatS ..............12 1-2. Histomorphologic Observations - Group Il Male Rats 4 1-3. HistomorphologicObservations - Group Ill Male Rats .....................18 1-4. HistoObmsero vatironsp-Gh roupoIVlMaloe gic Rats.......................18 1-5. Histomorphologic Observ-aGrtouipVoMnalse Rats............ 10 16. Histomorphologic Observ-Garotupi|Foemnalse Rats... 12 1-7. Histomorphologic Observat-iGoronusp Il Female Rats....................-14 1-8. Histomorphologic Observat-iGoronusp lll Female Rats...................15 119. Histomorphologic Observat-iGoronusp IV Female Rats pon 1-10. _Histomorphologic Observations - Group V Female Rats ..................17 Page 926 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT TABLE OF CONTENTS (Continued) Page I. Histomorphologic Observations-F1 Generation... conn 0 11:20 Key 0HistomorpholOgic ObSENVations.....................rr. 1 1 114. Histomorphologic Observation-s Group | Male Rats....... ll2 112. Histomorphologic Observat-iGroonusp II Male Rats........................I14 11-3. Histomorphologic Observat-iGroonusp ll Male Rats.............. 16 114. Histomorphologic Observat-iGoronuspIV Male Rats.......................I18 116. Histomorphologic Observations - Group V Male Rats............ 1-11 118. Histomorphologic Observ-Garotupi|oFemnalse Rats..................I1-14 117. Histomorphologic Observat-iGroonups ll Female Rats...................I1-16 11-8. Histomorphologic Observat-iGoronusp lll Female Ras..................I17 116. Histomorphologic Observat-iGroonups IV Female Rats ................. [1-18 11-10. Histomorphologic Obser-vGarotupiFoemnalse Rats on l19 Hil. Individual Animal Gross and Histomorphology Data - PGeneration ..... csmmrmrssssnss110 1108 IV. Individual Animal Gross and Histomorphology Dat-a BY CONTE Misamis 10 N30 V. Individual Animal Gross and Histomorphology Data G108SLESIONS = F1AF2NPUPAS..ccoecsssrssrsssssssmsmsssssssssssses Ve Page 927 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT METHOD: Microscopic examination was made of the specified tissues from male and female Cr:CD*(SD)IGS BR VAF/Plus ratsof the P and F1 generations divided into five groups used in a two-generation reproduction study of ammonium perfluorooctanoate (AFPO). A brief outline of the study design is shown below. NupemrbSeeoxrfpRearts| Dosage | Concentration | DVoosleugme | Ganeraton_| TO)| (mom) (mk) [| v + ew a | 5 | (wv [0[nw | 2 | 5 | Lv[so | wo | oo | 5s | "The Tost substance was Considered T00% pure fr he Puropfdoossagee calculations. TheP generation male and female rats were given the test substance once daily, beginning at approximately six weeks of age (at least 70 days before cohabitation) and continuing until the day before sacrifice. The F1 generation adult rats were given the same dosage levels of the test substances as their respective P generation sires and dams (once daily, beginning at weaning [approximately 70 days before cohabitation] and continuing until the day before sacrifice). F1 and F2 pups have been exposed to the test substance in utero during matemal gestation and via maternal milk during the lactation period. The in-ife portion of the study, necropsies, and recording of the gross necropsy observations were performed by the staff of Argus Research. The preserved tissues were then submitted to Research Pathology Services, Inc. for tissue processing, microscopic slide preparation and histopathologic evaluation. The protocol-specified sectioned, and stained tissues were routinely processed, embedded in paraffin, with hematoxylin and eosin for microscopic evaluation with Tearoomsee 1 Page 928 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT the exceptionofthe testes sections which were stained with the periodic acid-Schiff technique. The tissues specified for microscopic evaluation from the P and F1 generation adult rats of Groups | and V included adrenal glands, pituitary and tests, epididymis, prostate, seminal vesicles and coagulating gland (male rats) or ovaries, oviducts, uterus, cervix and vagina (female rats). In addition, the reproductive tissues were examined from male and female rats of the P generation and male rats of the F1 generation suspected of reduced fertiity. Gross lesions were examined from all P and F1 generation rats and F1 and F2 pups of all groups. Upon completion of the project, all raw data (remaining wet tissue, paraffin blocks, microscopic slides and histology records) will be returned to Argus Research for archiving. Research Pathology Services, Inc. 2 Page 929 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT RESULTS: The type, incidence, and degree of severity of all histomorphologic observations in the P and F1 generation adult rats are summarized in Tables 1 and 3, respectively. Tables 2 and 4 summarize the histomorphologic observations in the rats suspected of reduced fertiity in the P and F1 generations, respectively. Individual microscopic findings from the P and F1 generation adult rats are presented in tabular form in Appendices | and I, respectively. A key to the individual microscopic observations precedes Table I-1 and Table Il-1. The gross necropsy observations, microscopic findings, and a correlation of the gross and microscopic changes, when applicable, are included in Appendices Ill andIVfor the P and F1 generation parental adult rats, respectively. Macroscopic observations and corresponding microscopic findings in the tissues with grossly observed changes for the F1 and F2 pups are listed in Appendix V. P Generation Adult Rats (Tables 1and 2, 1-1 to I-10, Appendix Ill: No treatment-related microscopic changes were observed in the reproductive organs of any of the 10 male and 10 female rats P generation rats selected for histopathologic evaluation that had been given 30 mg/kg/day of the test substance. A treatment-related microscopic change was observed in the adrenal glands of 2/10 and 7/10 male rats of Groups IV and V, respectively, designated for examination (Table 1). The change in the adrenal glands consisted of increased thickness and prominence of the zona glomerulosa due to cytoplasmic hypertrophy and vacuolation of the cells of this zone of the adrenal cortex. A similar adrenal effect was not observed in the male rats of Groups Il and ll or in any of the Group Vfemale rats. Male and female rats described as showing `reduced fertiity" were those male rats which failed to sire healthy offspring orfor which sperm or spermatid number, sperm motity or morphology were affected or female rats that failed to mate, conceive or deliver healthy offspring. The rats characterized as "reduced fertility" of the P generation are identified in the individual tables of microscopic findings in Research Pathology Services. Inc 3 _ Page930 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT Appendix | as "SSRF". The type, incidence and degree of severity of these findings are summarized in Table 2. There were a few changes observed in these "reduced fertility" rats, but these changes occurred sporadically and areof the type that occur spontaneously in male and female ratsof this age and strain (Table 2) and were not compound-related. All other microscopic changes observed in the male and female rats designated for microscopic evaluation were considered to have occurred spontaneously and to be unrelated to treatment. The type, incidence, or severity of these spontaneously occurring changes was not influenced by administration of the test substance. In general, these changes occurred at single, low, or similar frequencies among the control and compound-treatment groups. These changes are listed and summarized in the attached histomorphology tables. F1 Generation Adult Rats (Tables 3 and 4, 11-1 to 11-10, Appendix IV): No treatment.related microscopic changes were observed in the reproductive organs of any of the 10 male and 10 female F1 generation rats selected for histopathologic examination that had been given 30 mg/kg/day of the test substance. Microscopic examination of the adrenal glands revealed a treatment-related effect similar to that seen in the P generation male rats, consisting of an increased tahnidckvnaecsusolaantdiopnroofmicnelelnsceofotfhitshezoznoenaofgltohmeeardurleonsaaldcuoertteox ciynto7p/l1a0smhiicghhydpoesretrmoaplhey ratsof the F1 generation (Table 3). This adrenal gland change was not observed in the F1 generation male rats of Groups Il, lll and IV or in any of the F1 generation GroupVfemale rats. Treatment-related microscopic changes also were observed in the liver of male rats of Groups Ill, IV and V. These livers were grossly observed to be enlarged or to have tan areas in the liver lobes. Microscopically, these gross changes were due to diffuse hypertrophy of hepatocytes (Table 3). Hepatocytes in all areas (diffuse) of the hepatic lobules were enlarged due to an increased dense, Research Pathology Services, Inc. + Page 931 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT eosinophilic cytoplasm. A very low incidence of single-cell or focalimultfocal necrosis of hepatocytes also was observed in a few rats of these groups. Hepatic tissue was available for microscopic examination only from rats with gross observations in the liver. `There were no compound-related microscopic changes observed in anyof the male rats identified as having "reduced fertiity" (Table 4). The few changes in the male reproductive tissues were typical of those that occur spontaneously and their type, incidence or severity was not affected by administration of the test substance. None of the changes that were observed in these male rats were of sufficient degree to have resufted in reproductive insufficiency. These rats are identified in the individual tables of microscopic findings as "SSRF". All other microscopic changes observed in the various organs and tissues were considered to have occurred spontaneously and to be unrelated to treatment. These changes were typical of those of which occur in male and female rats used in multigeneration reproduction studies. The type, incidence or severity of these changes were not influenced by APFO administration. These changes are listed and summarized in the attached histomorphology tables. Research Pathology Services, Inc. s Page 932 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT SUMMARY: Microscopic examination was made of the specified tissues from selected parental male and female rats of the P and F1 generations and F1 and F2 generation pups of an oral (gavage) two-generation (one litter per generation) reproduction study of ammonium perfluorooctanoate (APFO). The concentrations used in the study were 0 (vehicle control), 1, 3, 10, or 30 mg/kg/day of the test substance. No treatment-related microscopic changes were observed in the reproductive organs of any of the male or female ratsof theP and F1 generations designated for microscopic examination that were given any of the dosage levelsof APFO. A treatment-related microscopic change was observed in the adrenal glands of the P generation male ratsof the 10 and 30 mg/kg/day APFO-treatment groups and F1 generation male rats exposed to 30 mg/kg/day of APFO. This change was characterized by hypertrophy and vacuolation of cells of the zona glomerulosa of the adrenal cortex. A similar effect in the adrenal glands was not observed in male rats of the lower dosage groups or in female rats of the 30 mg/kg/day dosage group of either generation. Microscopic examination of liver sections of F1 generation male rats which were observed grossly to be enlarged or have tan areas in the liver lobes showed up to marked diffuse hepatocellular hypertrophy. Single or lower incidences of hepatocellular necrosis also were observed in the male rats rats of these groups. There were a few male and female rats in each of the P and F1 generations that were classified as demonstrating "reduced fertility". Microscopic examination of the reproductive organs of the male and female rats of the P generation and male rats of the F1 generation designated as `reduced fertiity" animals showed no consistent microscopic changes and the changes that were seen were not considered to be treatment-related. Research Pathology Services, Inc s Page 933 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT All other microscopic changes observed in the various organs and tissues of the P and F1 generation adult male and female rats and F1 and F2 generation pups were considered to have occurred spontaneously and to be incidental and unrelated to treatment with APFO. Research Pathology Services, Inc. 7 Page 934 ARGUS 418-020 (ONE LIOTRTAELR (PGEARVAGGEEN)ERTAWTOI-OGNE)NREERPARTOIDONUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS SPONSOR'PSROSTTOUCDOYLN4U1M8B.E0R20: T-6889.6 HISTOPATHOLOGY REPORT QUALITY ASSURANCE UNIT STATEMENT repoArlt apsrpeepcatrsatoifonthefotristshuee processing, study fisted micoscopi side preparation, histopathologic above have been performed according to evaluation and the Standard Operating Procedures of Research Pathology Servis, Inc. and were audited in accordance withthe procedures established by the Quality Assurance Unit of Research Pathology Services, Inc. in compliance with the Good Laboratory Practice regulations specified in the protocol. Qualty Assurance inspections were performed as show below. There were no deviations from the protocol, Standard Operating Procedures and/or appropriate Good Laboratory Practice regulations noted during the conductofthe study that had any impact on study integrity. A summary report of QA inspections was submitted to the Study Directonr March 25, 2002. pOuosnt sPurpe oHzesoonoottasz TEiemsiinngg Ton E02 omy oon, avn ovz2 sang oooulniaaenne:: HcooDtapvaoertnioeygayon ovoCailamaiee:z: PGGpuoarPsrregeasin ozosiese DFosareor Olsionpert w1500o1.ooise A300001G1,,i22z33100011, Woridisi aoairsdaiin: aaoiisaies: ds Oosutebsrsee camewoo,ncto:on Gore ane cccoourreee: 1W1e0a1io0t1oc62eo0o1r0:2 a[n7i Research Pavlogy Secs. ne. Sh Ahn. 8.8 Kren W. Harkins, BS Date Quality Assurance Unit 3 Page 935 ARGUS 418-020 REPROGDRIALCTI(OGNAVASGTEU)DYTOUFD-AGMEINPOERNROITAOLTCNIOOLNPE4A(1OF8NL-EU0O2RL0OIOTCTETRAVPGEARTEGE(NAEPROA)TIOTNh)RATS SPONSOR'S STUOY WAGER: T-6899.6 mele 1 Incidence and Degree of SevFereityarofoHnistamorshologic Observations sNeumxberoGefeanntasla/eroup: FTmE3 3s boWosVTEp EE5Wm ELmFTh No0O..soDNuORmMcnAuLeDes; oPo.EoSd 0 @1095 00 00s1 ~dSeigennaeration, cystic, cortex w ? 9 o 0 n 0 nveonReey0 "hRyFpeienrnatrraospthoyn/vacuslation, zona Meo ooEf EFbn 0Po0o o9 noooo maoidiedrate eo5 oa b0 42 55 59 99 05 00 "uimaicnduilmaatlion, cortex B 2Toe0e21n10 08 OCOeo O9 oA0 oo 00 Roderate 50 1 5 0 o 5 0 0 e00..uhGomamwi.iaileo o0o8 05 0a ooww 105 00 00 11 --erat(s),pars intermedia 0 a 0 0 10 0 0 0 30e0s..ths:otane Bosio:oz 2ionos "Pamatorreokrpehadyt/edegereration, mitifocsl UoT1 ooo(1 0a o0 @11 dilatation, rete testis 101 "hmyaprokpeladsia, diffuse O w1 ooTno T0.otkoma, pastriroed d moderste exRatiionilidmaated spermatogentc cells moderate Boo4o2o1oizoomu Oooc ow1 eo0 no1 00 eo 5 oo 0 1 O00 w51 n00 o00 e0I 0101 TT = TomT Trerdence of specified Tester, grea - Page 936 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DY TOVFD-AGPMERINOOETVRIAOUTCNIOOLNFE4(R1OF8NLE-U0RL2OI0OTCTTEARNGEARTEGE(NPEFROA)TIOINN) TATS SPONSOR'S STUOY MMGER: T-6899.6. THBLE 1 (Continued) Incidence and Dogroa of Sev7eGrainteyraotfioHnistamorshologic Ghservations sMoexborotwelyGon EPIOIOMIS(Continued E"Pharyrpkoesepdernia "iminifndiilmtarlation, mononscleor-cell, focal 1F3 E1s DD 0s e w1oY1 oe2s [5o1 f2) (o00 oh001 (2) 5 EELEy Fa F D434h 10s0m.osTJtaotoee, S BosF2 01 ow "aiitrnotpehy, focal B ZPz eo9 owoonooo e "damiiilinaidtmaatlion, olandular, focal Beio owooo0 n90 eH1 modirate 1s oo 00 "aiininftleamna)tion, chronic $: 1B10o0w%12o0w "piminiftnilaaation, spprative, foal)fPooo[@ o0 oooo 0 0 f 0. ovoaul c BBo3s 2oz 1oomm 1B 0.NowE iTiAng L Acua BBo0s3:oz 1ronow 0.NOiRnMAeL "eyst(s). intracvarian "eysticbursa(e) Nn0O..eNroosvi)al;e 00r..eaGos.ve TT Tou Trerdgewe of peed Toten, a grades Page 937 enozzo11 o00 o1nB 20001 to 00 0 vwooz: 1 o1o9o mon nzloo r ooon EY ARGUS 418-020 REFROODRALLETI(OGNAVASGTEL)OYTGWFD-AGEWNPOERMROIATUTONICOONLPE4R(1OF8NL-EO0OL2SI0OTOTCETRANPOENRT.GE(NAEPRFA)TIODNh)AATSSPONSOR'S STUOY WAGER: T-6099.6 TALE 1 (Continued) Incidence and Degree of Sev7eGreinteyraotfiHoinstamorshologic Observations SNeixm:berof Aniasls/roun; TERS(Continued): dniaisintiiednstailon, lumen fmeodeertate ~sland(s), endenntrial, cystic "nmiiactnrteopehlages, pigmented moodeyrate s00.:uToenRe "dmioldaetraattieon NvOi. sN,ORMAeLn mmeiotdteircaatteion CFUMROIANLLICCORPAORAELuTSen: absence of corpora Tuten "presence of corpora utes "presence of orawing/antral follicles [ b 3s a Bohol EL3aE&E3 F4aFdh woiwoo o 0o 00e11 0e10 89 00 1 0001 w2i0we mo0o o0vo a 2 1905 00 00 ios BHooz: 1o1o00 8ow w9% o0 o0 1 w oz0:1100 o1w [ iTosC e Co0o I 90 ]0 0001 nozo1 0 ow moz o1 0 ou o. Jolne ~cmahoiodtnedrraotpaethy, auricular reed 0e82000 10 00 C0O Eon 201 0 @5000 d 50a0s0 02 B eTo9oL 00ooE111 ror f NO. Nod RkAL fracture 0e0050 00 00 00 oo 0 0 0 0e01 00 00 00 1000 TT Tou Tred of eed Teen. Age EY Page 938 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTUOFO-AGMEINPOERNROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OICTCTETRANIPAETREGE(NAEPROA)TIOTNh)RATS srousoR'S STioY WAGER: 1-6089.6 THLE 1 (Contin) Incidence and Degree of SevFeGreinteyroaftiHoinstomorshologic Observations seNxim:ber of Aninals/6roup: W3 ONds KK Tos [ 3 4a3 A 4h e0NO.s:NBOoRwMAmLen "cataract. amroadteirtattse, chronic 0e00 00 00 00 000 O o9 o9 o0 En 05 00 10 03 00 0100 o9%on1%no0 0o50..urKisow,nale diamliiatntiamtailon, pelvis Roderate 0 012a o1 i2 [eOoCeCo I0nCIg1 e010 59 59 00 00 00 R5vC 0B0C I09C bI0 CC0 S88 0 "hhieypphieitrhpellaisvina,,peflocvailc/papi lary OeoE oownE Ov0oo9 gWho n1NO0. eNnovael 1eo 95 09 a0 0 e0 0059 00 00 99 "hpemiotrriheadge, multifocal WPE eeE oewE O@ OoOo o0 O "indfelraamatteion, fnterstitial, mitifosl 1Pe0 Ye w 0 v0 9% p0XO..urNBoeiwuiAnlen fracture "hremioerrdhage 0 00 0a 00 00 0000 BCEIE EE 100 0a 00 00 to 0 0 0 WTo olo owos TT Tort Trerdenee of weed Teton. Aga EY Page 939 ARGUS 418-020 REPROORDAILKTI(OGNAVASGTEU)DYTVOOF-GAEANPAREOOANTAIOTUCINOOLFNE4R(1OFN8LE-U0RL2OI0ITCTTEARNGPAETREGE(NAEPRFAOT)IOINN) RATS SPONSOR'S STIOY OER: T-6800.6 hae 2 Incidence and Degree of Severity of Hista7mGoernpehroaltoigoinc Observations - Reduced Fertility Animals Nsoox:rEoefeAntesls/roun; 3NT oH3o 7 WIm wViv E TTzEIm TT AN0oO.n. oOBRUaANlLaDs: 0 59 11 00 0 5oe 59 99 05 00 E 0. Noe RMAL "aotcroeprhayt/edegeneration, mitiforsl "dilatation, rete testis g6NO..enNtOuRiMsAtL;o `"ratordoeorhayt.e "eBxinfoilimated spermatagenic calls Soderate "hRiyaproksepdaraia inmafiiinilidtmraation, mnonsclear-ceflocla,l eRNoO..saoRcmai,lne "amitriodpnhye. focal "iainifnilidanmamation, chronic 3: 33 Foz o1nd (1T) o[0 0 0 01 0001 ssoso 2101 mCI emo Oeo0wo10w0 ob0 fo 0101 w00 w01 o00Rs2 (e0 (1F1 0E[0 R[00 (E0) sost:2 o1o 4os B2Poow0 oo0 oo0 nH0 [TIoCT1IC0I0 01sI0O] SN0O.p. mNBOuRmvMiAenLseiDcles: 530053 d2 a1as S00..oRcsEsmALTeIN0G: ssss zoz a1 TT Tout Trerdence of speeTied Teen Mga n Page 940 ARGUS 413-020 REPRGOEA I(oAnVASGHEA)YTOIFO-MGNeTERORATHOIODNPE1(RO0PN-LE5I2RL0IIOTTCETRAN3ATEGEFNGSOA)TIOTNh)BATS SrontR'S STUB NBER: T-o088.6 THLE 2 (conti) Incidence and Degree of Severity of HistFgmmraprbaoltoigolnc Observations - facedFert ity nfasls so Eee E TTETT EVTETEmETT Maberofnieals/Growp: qTou. eWisa:nle 3 32 1 4 121 11 dDoEra 0 ~opt(a), travian EEE E 3: NoR mat E HE EE O To oomnare 1 P2E 1 s 0a diwrsetieadntaitoen, Tumen s$emoee a m e m rQm setmmq LEooos V6.AGInNNAo:eao DsooFrab0t =e mcification ouFs occou mmsLs es: absence of corr Tuten presence of carsos Tuten presence of groing/antral falcles m Pmemeomlmo 0001 Lea 0 Leon o0 oa ionnale oSe o1ap0 00 08 0380 h1 08 0 p~cehoontdiryopathy, auricular p5. rnoome R GaWewe0gm 0om0 Teo os10o0 00 2i g ooome wi e ooma 80 80 ooobs0 TT Tome rere of sptfied Toran, sl grader a Page 941 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DYTNOFO-GAEMPNIREOOTMTAIOLTCMIOOLNPE1R(OF6RL-EU0O2RL0OICTCTETRANIPAETSEGE(NAEPMFA0)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-688.6 THBLE 2 (Contec) Incidence nd Degree of Sevarity of Hista7mGoernpehroaltoigolnc Gsservations ~ Reduced Fertility Animals SeB xb:erof ansests/6roun: E H1Om 8W W E oN WV: [TT ETE: Imm TT KIDNEYS (Continued): "dmiiilnatitmaatlion, pelvis [FE C5CC0 ICI 0% I8E C B0C I0E C I0 CC)|0 Tou Teraoof eee Teton "is Page942 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DYTHOOF-ASWEPINROEONRTIAOLTCWIOOLNPE1R(6FOLN-EU0O2RL0OICTCTETRANIPTEER.GE(NAEFRFA0)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6809.6. ee 3 Incidence and Oegros of SeHverGietnyeroaftiWointamorshologic Observations Mseexe: rotmm. lyeon A00g..eeGoRaisaaLeuDas: "hyoperrmstasta,cortical,focal "hypRTeirotnnroiepnhryaaltorsvacuslation, zona nid "vmaicnuiolsation, cortex UW1 oW lK e2K2 0008s1 08:9 O CER ooo oe Ooe Eo0 oOooLoNb ewHNReEyE EEE FLU E gps 1 1 hh 0woso 90 00 9ow e 5 FeFe0 OooO5 D990 E5 on0QF O o0 o0 o0 9 NO. NOnRMAoL sc 50 08 a9 0ow "hemisitoepcoaletsts, extramedullary. Sinim R OR0 C1 IC1I 1 "pheyrpterrotsrhyo,phhyhe,epatocellular,diffe D[0 O(0 E E wG0 RPoadrekreadte 0 00 a4 8o ois "infarct, iver lobe 0a0 "imaniifnilidammaaltion, chron, foeal/mitifocnl0oee) 50 1n1T BM 0 "niiecnrtosets, focalmultifocal Oo0c o00 N91 Eo1z E02 neicrotsts, single-cell PRMeeYwRE fNo1O8.81 ORAL 2H3s:2 zof wow -sitrotphiy/ldegeneration, mitifocsl (1A ) ( E0NO..eolOvsma:eln 2wo3s 2ozo:zw7 0 01 00 00 00 RC B5 RC0 B0ORO) O0 o(0 oo 59 59 00 00 00 1000 95 0a 00 B@G0oooo5 o00os0 W9o 99n EQyo TT = ToT Trerdenes of speed Teen, Mga 6 Page943 ARGUS 418-020 REFROORDALLCTI(OGNAVSAGTEU)DYTOHFO-AGREARGORNoAITUtIKOaNFE4R(1OF8NL-EU0R2LO0IITCTTEARIGPAETREGE(NAEFRFAOT)IOTNN) RATS SPONSOR'S STIOY NBER: T-6889.6 THBLE 3 (Contec) Incidence and Degree of SeGveernietyraotfiHoinstamorphologic Observations Esoxe: Ges E TTEE WW VT[0 E WTET Meberofmmlofrom: 1 13 de 28 25 51 1 nu IDIOMS(Continuad): "innfiiltmration, mnoclear--ceflolca,l (21 @0 [00 0 (33 Rp0oo.sEuRirAeh,Le atiirnotphey, focal dailiaitdation, slandalar, focal "ii=nfnlatmmlation. chronic "iinfnltaemmation, suppurative 2wo3: 2iizw O 5 59m0oTn0 ow 1 nPeeoeeo mT ioewo o1or ow0eon0 o w9 o9 obnh s00:.oENmORMvAaELsIags: 2233:2 oozz ooww Sao0.ssGLMAioTtaINieG Guo: B0.ageiMsa:uel ~epst(s). tntraovarion 233d2:oz ooww wooo oo 00 8ow 0001 NO. NuORMAeL daiisinteintion, lumen moderate 2 5o 00 00 10 O P10RO9ROOY0ksa o 00 0 2 TT Tour meres of eed Teen Page94 ARGUS 418-020 on SRoo FE pap -- SE ets rn of-- sTrs-- Uort tion Mmberof Antmels/Growp: UTERUS(Continved): macrophages, pigmented J=y 17 13 19 26 25 or VAIN oorenin s riece coms e ur peon)ee go he 12 5 1 1 I m [og ti 8 i byes ow v wo ey n bheeee eeww Ppiaou w9S9es ewee mye ~edema/inflammation, submucosa mo Fle dee ue TR Ta wWsYoreweew asses Page 945 ARGUS 418-020 h3E sS on cop ue opin oioFS weres tend re of SGtyERnits rion Meberofnimslo/Grove: brCOLON(Continued): distention En EaRIS) hondropathy. PEyl wppeyry atrophy, retinal, focal nm neuropathy, opticnerve(s) o- Bane :distention 13 Je 26 26 Pe mm Tr Qa o w wye wm a TIL wowOEwEww mw POT EY @ o 00 1 0 Om jp 51}on Yu u@ wg iri 9@aaQ ore gow9 wooo om 9999 y 1 0 00 moe oo ~dilatation, pelvis Eo mw oO mw urothel jum' minimal 0) (0 m [ 9 9 wp 0 Om @ oo 0 0 0 Page 946 ARGUS 418-020 REPROORDACLTI(OGNAVASGTEU)DYTVOOF-GAEMNPOERMROIATUTONICOONLPE4R(1FO8NL-EU0OL2RI0OOTCTTEARNGPAETRE GE(NAEFRPA0T)IOINN) RATS SPONSOR'S STUDY MIMBER: T-6809.6. TABLE 3 (Continved) Incidence and Degree of SevFierGietnyeorfatHiiosntamorphologic Observations SEoex ew E1 EmT WN 7 1FOE T WFW ToF MmberofpmlafGrops 1 13 le 62 2s 1 1 nu KIDS (Continued): "amiinneirmaalltzation, pelvis "sppyeloonneepphritis o0 oonT oe W ee E ED ocooo0 o0 n ome o o moo S00K.. EovwoaislsnLesion: ~dareeartaitteis, chronic daoerramtse, wicerative S1000 01 00 00 a0 [CROR0E hw ICRC [POPRCRI ewICR @ 59 09 00 90 I9NORG0 BORO] B9OR CGR 9ORO) B30. uWoeL amtraorpkheyd --naeccrroosstss 8eo 95 00 10 1os E9O 9%L Nu B0 oEWWWEY 5195 95 98 oeoo WToen9 E0 n0 w e Oo w B 0. Noe RMAL eFrionstiimon]s). glandlar mucosa --piarniitoonn)sess, focal "ulrccearr(ts). alaslnaandatar ares oee 0050 00 01 9 OG5WOEe0 HooEw M oEENHSE ICI@ BERR e0 o1 0a 05 0 oa!n0 o9o no9 oo O@ L9 o0n 9%o ICRC CR 0) B10.ifooomle --ebscess constriction, focal 0 9009 0132 0010 00001 0 3198 90 1 0000 0000 TT ToT dene of ee Tee Ae Page 947 ARGUS 418-020 A A or BAA T-- ns Bos A iTran es T(ACILontinued): -- Lb AELlTTD 0G GWG Ww ww Ww wow wuowoo necrosis, focal Tos: Co~atrophy Ewrw distention mE owe om PPPTY Momo mo 1133838 22omTToYo PUY 1111; TRmm YDOYw u ea gne inflammation, chronic Oo om om EEREEEERERE TT=Totalincidence ofspecified Testom, 11 grades. Page 948 ARGUS 418-020 REFROOBRLALCTI(OGNAVASGTEL)OYTVGFO-AGENPVERROATITOICOONLPE4R(1OF8NL-EG0O2RL0OICTCTETRANPOEARTEGE(NNEROA)TIOINh)AATS SPONSOR'S STUOY NUMBER: T-6889.6 ae+ Incidence and Degree of Severity of Hista1moGresnheorlaotgiiocnObservations - Reduced Fertility Animals bSeex:rEowf Anieala/troun: zHToymH Wm 7 w7wwT A00g..mchEuouRmiaAnLeuDs: NEoS. TsNH:oRuiALe Seo050 00 1100 i2 s3 f 2 2a1 p00.. shBao;io "innfi1ntar)ation, mononuclesr-cell, focal sR0m.osomOaRrtAe,Le "amtirnoipehay, focal "pIminifnliasmation, chronic diss oFz ioz s1 [ ICI0 9 RWChI] :io:3 oi z 2q O@ o5 oGo 01 o Oosnom oh1 wono5 oo 0 SN0O.p. oomvviaelsdicles: i 233Foz o2 1 S0NOO..ULooATmlINeGG0: P2 d3 :2 2 TT Tou Tredof peered Town, Agden 2 Page 949 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION STU(DOYNEOFLIATMTEMRONPIERUMGEPNEERRFALTUIOONR)OORCETPARNOODAUTCETI(OANFPO) IN RATS PROTOCOL 418-020 HISTOPATHOLOGY REPORT APPENDIX | HISTOMORPHOLOGIC OBSERVATIONS P GENERATION Page 950 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION STU(DOYNEOFLIATMTEMRONPIERUMGEPNEERRFALTUIOONR)OORCETPARNOODAUTCETI(OANFPO) IN RATS PROTOCOL 418-020 e HIeSTr OPATHOLm OGY REPORT em-- KEY TO HISTOMORPHOLOGIC OBSERVATIONS -= *= <> = <> = () = A= Nocchhaannggeen(ontotprreesmeantr)k.able, within normal histologic limits or indicated Tissueplnaonteavoafisleacbtlieon(,spaerctiiffiaectd ptrisesculeudmeissseivnagl,uaitnisounf,ficoiresntpetciisfsiueed in Microstciospsiuce fniontdipnrge(sse)nitn tinisssecuteiso)n)w.ith gross observations). Within normal limits [no microscopic change(s) to correlate with the gross observation(s)]. Only oneof a pair of organs available for processing/evaluation. Advanced autolysis precludes evaluation. P= 1= 2= 3= 4= Indicated change or lesion present. MMiindimdaelgrdeeegroereaomroaumnotuonftinodfiicnadtiecdactehdancgheanogreleosriolne.sion. Moderate degree or amount of indicated change or lesion. Marked degree or amount of indicated change or lesion. SS = SD = SM = SSRF = Sacrifice-Scheduled Spontaneous Death Sacifice-Moribund Scheduled (Reduced Fertlty) 1 Page 951 ARGUS418-020 REFROIRDAILCTI(OGNAVASGTEL)OYTOVFD-MGPERONOEVTRIAOTCNIOOLNPE4R(1OP8NL-EU0GL2RI0OTOTCETRANPOEARTEGE(N1E9R7A0)TIOIN)ATS SPONSOR'S STUOY WAGER: T6289. LE 1-1 HistomorphFoolaangaircatOibosnervations ATnimaleNbr: Sex: R 1T_ 362E136E 08 13610 1T 3611 dTsE6Ei2T13814 1Lseis DashTie: S Sw Sw Sw & 0% 0& ASlRaEcAuLalatGiuoann,es:cortex - - 2 "S1tersonps,hy/degeneration,multifocal fo SA -- ZsZSaaigirsToaTptanaTyte.i:onf,ooclalandatar,focal Ciinnftliaammmmaattitoonn,, csuhprpounriactive.focal FE FR DiSoozFl robo -- i: 2 2% wSiaemmeiiarmrmraotgieo,n,mtiinftoercsat)itial, miltifocal s@ 2 Page 952 ARGUS 418-020 SAGeneitemsa)GrNaober: Dstnnes REPROORDAILCTI(OGNAVSAGTEU)DYTWOOF-GAEWNPOERNROIATLTOINCOONLDEA4(F1O8LNE-U0O2RL0OICTCTETRANAPTEER.GE(NPEFROA)TIOINN) RATS SPONSOR'S STUY NBER: T-6069.6 THBLE 1-1 (Continued) HistonTorRphtoleongeircatOibosnervations W 15616 T 1E 321TIE sT e 3E 4 T1362T5 13626 50s 0%oso %o0s oo--. So. - sa eSiioTesrat,ion, mononuclear, focal mEZifnoaftlaaatmeiaotni.on.stacnhdraotnairc, focal Sinfamation, suppurative, focal - == T cSoor.o o rrio 5) Page 953 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEU)OYTVOOF-GAEFBNROEOAMTAIOTGNIOOLNP4C1A(8AONL-EU0O2LR0IOTXTLETRANPAETREGE(NAE5R7A0TIOIN) ATS SPONSOR'S STIOY NBER: T-6800.6 ate 1-2 HistamorshoGleongetrcatOibosnervations ASenxi:mEalteWner: I FiN de LN es aiss 1T 369 LasT LT ewT Lases T Lis Dsthige 0%5 sw swoss sss aSmaceuo,tatgiuonn,s:cortex - - o. oa sTynphoptEast,e,rotrferutseenis w soo "i"aoxmtistt:ed spermtogentc cells "SIpneRspeerraatiioan,mononclear-call,focal minfolamemation,chronic @wCoo.rl p: -2 CORULATING Lang: aSShson.diopaty, auricular a~deatsat:ion, pelvis @ a Page 954 ARGUS 418-020 SAenxi:malTheus: bthee REPRGOBRLALETI(GGNAVASGTEL)OYTGWFO-AGENNPERIROOATTONICOONLPE4A(1OP8NL-EU0O2RL0OIOTCTETRANPOENRTEGE(NE0RA)TIOIN)ATS SPONSOR'S STUOY NUMBER: 1-689. THBLE 1-2 (Continued) HistamorTpFhoGleongefreaOtbisoenrvations EDTo36_0 T13651 a1T 36sz a196T 59 13654 T 1965S 1366 swess sossos A - --= Ions: - iSfiHmet.ion, mononctear-cell, focal 2 Ein, arom SELVESICLES: COMUATING GUND: eScheon)dropathy, auricular 1 - > 5 Page 955 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTUOFO-AGMEINPOERMROIATLTOMICOONLPE4(R1OF6NL-EU0O2LR0IOTOTCETRAGPAETREGE(NAEPROA)TIOTNh)RATE SPONSOR'S STUOY WNGER: T-6089.6 Le 1-3 HistamorphFoGleongeircatOibosnervations SrGeixe:naehnar: a TseeWnIsTee aTisseTs T13570 13671 1T38T2 T13673 DthToe 5 sw os ss os oss ASgimaccuuotagtuioano,sc:ortex Tr - - - ens: . seis: - saosTArE; - PLvesIgs: COAUATINGG00: aSaersat, petvis - > a 6 Page 956 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERMROIATUTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(NAEPROA)TIOINh)RATS SPONSOR'S STUDY NIMBER: T-6829.6. TLE 1-3 (Continued) HistonTorRphtoleongeirctOibosnervations SoAEnximEal Nor: iHILsT1I36L75I13T67E6 13662 13688 13684 Pthvee sw ss sss5 ASVaacuoTatuiopn,s,cortex : 13 Ins: - lexfmolsiat:ed Tressermia spermatogentc cells 3z state: = sm vesilgs: - CORSUATING Gua: - Page 957 ARGUS 418-020 Smei:nalGENmEber: Death Tipe: REPROODRUACLTI(OGNAVSAGTEL)0YTWOOF-GAENPPEREOATITOICOONLPE(4RO1FN8LE-L0O2LR0IGTTCETRIGPAETREGE(NNEFRTAO)TIOINN) AATS SPONSOR'S STUOY NUMBER: T-6889.6 hae 1-4 HistamorTpFhoGleongetreaOtbisoenrvations W W 13653WE1369E 5 W 136E 89 W1370W 0 13705 1W5708W13706 SS 0% Sw SS 0% AqSmacLioafawtiosn,:cortex - FE mZTauTpmaotpsattaisotna,, arreftreusteestis -: P&e "aetrosphy: ionpeitpeerraattiaon, sononuctear-cell, focal sormusamatrei.on, chronic SOL estes: coRsuLATING GLa: -:: @&& z - --e-- ee ------------------------ re Page 958 ARGUS 418-020 ASenxi:malBtNmnber: btnmee REPROODRAULCTI(OGNAVASGTEU)DYTUOOF-AGWEINFOERMROIATLTOMIcOoNPE4R(1FOL5NU-EO0R2LO0IOTCTTEARNGPAETRE.GE(NAEPROA)TIOINh) RATS SPONSOR'S STUOY MMBER: T-6009.6. TABLE 1-4 (Continued) HistonorphFoGleongeircatOibosnervations WINsIWE10 WtmWWtmee Etn n tans ss soso%5 fR o I ---- s"chson)dropathy, auricalar pSpaeeirraptslaat:tsotns,.ppeetlvviisc/pupi lary epithelium, focal - roa - @ a@ I] Page 959 ARGUS 418-020 SeenixnGa)oNbr: re REPROODRUACLTI(OGNAVASGTEU)DYTOHFO-AGOEPEMRRIOATLTONICOONLPER(4FO1LN8UE-O0R2LO0ICTCTTEARNAPAETRE.GE(NAEPRFA0)TIOTNh)RATS SPONSOR'S TIO NUMBER: T-6889.6 hae 1-5 HistomorFpGheonlesriatOibosnervations iA VyVLe dVesVlas T dss lT e dT ss le e "vacuoa lation,cNoarctueixaton, tom glosartess F1E 3 3 :2 -i "imiruopshy/degeneration,multifocal "esaxtofroollpiohayste;dspermatogentc cells TSipnefsipTeErranttiaon, nononuclear-cell,focal Ze"idniotlaistaam;taitoino,n,glacnhdruolnairc, focal "inflammation, suppurative, focal See T - os oe i Sonr o ons S:F o L Eo=l. a we $@ c F:E -IFI := BKiohnean poss wo @ 10 Page 960 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTUOFD-AGWEPINROEONRTIAOLTCWIOOLNPE4(R1OF8NL-EU0R2LO0IOTCTTEARVGPAETREGE(NPEFROA)TITOhNRATS SPONSOR'S STIOY NUMBER: T-6889.6 THBLE 1-5 (Continued) HistonorphFoGleangeircatOibosnervations SeAG nxi:mal Naber: e w 1s T 1 T 1T a V LT e 1 TE T1T13950 Dahvee 50% Sw swsw e iacu"otata ion, c.ocrteix attoimsloomanrlo,ss T= ol3 :io3 "mi"atirTsoapthayt/idoen,gerneetreattieosnt,imsultifocal Tapoisprer-- nia ------ SCiEnfiEam:atifoono,tchronic SEAL VESICLE: IE&EII 3 " Doenw e ro eoe. FdE o... -a es a. oe os tn Page 961 ARGUS 418-020 ASenxi:oalToEmber: Death Tipe: REPROODBILCTI(OGNAVSAGTEU)DYTWOOF-GAEe"IKFGORRNOAITTUoICKOoNLPE4R(1OF6NLE-U0D2LR0IOTCTTEARNGPAETREGE(NAEPRFAOT)IOINN) RATS SPONSORS STUDY NBER: T-6800.6 ete 1-5 HistomorphFoGleangeircaOtbisoenrvations TIFs_snpT1304 p1360ps T1811 1pT e3612TLpe eT13015 Sow Swe & 0&5 & fy --, SEB, imrasuarian eS"Geiassctr:eonpthiaoens,., TuBnreanmented seiitnicgation QF""UpprrReeOAsseeNnncLcee ooLff csorIropuoiCCrnoagm/apTLnuottreanELluTfSEoRl:licles s"chson)dropathy, auricular H"haetnctrirhease ' - - - - Se - iz iso-c -3 3 -e - - v; p[EoEre .; o> ie Page 962 ARGUS 418.020 ou (ave)JTOESNERaCIToIONL s(ON=EoLITe TER PR GECNrEA)TION)urs aL 1-6 (Contin) Wstemrto(logtcIoberations WE oe r: T pToeousTpso orTpfe eTpDet ee TeassTLes Meee 5% Wo bs rR aea S r,tscicorsern stcmrass [iA 3 2 2 SA U, imrsoarin Eingen. pomented CHEeLA ves ee sa a s Prceseunce of grom vina/antral follicles aBst:n, rice pPoore rohrooohn? w a ws Page 963 ARGUS 418-020 SAEonimtal eNaber: DeathTie: REPROGDRAULCTI(OGNAVASGTEU)DYTUODF-AGWEINPOERNROIATLTOWICOONLPE1R(O8FNL-EU0O2RL0OICTCTETRAVIPAETREGE(NPEFROA)TIOTNh)RATS SPONSOR'S STUOY WAGER: T-6289.6 ewe 1-7 MistonorphFaoleongatrcatOibosnervations p1me 389T1pn3840 SM Sw 1pT38e5_1 gT13056 Gwe fs ion, ven x C"prersencee oofftgCroosueiina/nanTtareaglLsfoAllicles rSehoonndropathy, auricular DSimraoctuuEres: So -- vPoer w ru Page 964 ARGUS 418-020 REPROGDRAILCTI(OGNAVASGTEU)DYTWODF-GAEMNIFEORRMOAITLTOMIcOoNPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NPE7R0A)TIOTNh)RATS SPONSOR'S STUOY NBER: T-6829.6 mele 1-8 HistanorsholGoegntecratOibosnervations SeAnximalEENbGr: Ii[ sa I1a 386T9 1388s pn0 ve0 e 000000000 sw0 so0 s ous: . omens): - wens: - = - rr N C rpreetseencea oR f groving/aI ntral follicles oSesho)nd:iopaty., auricular mSeeraasttiiratctts, chronic .' w P=s 115 Page 965 . ARGUS418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOOF-GAEMNIEORMAITLIMONPER(OFVLEUOLRIOTITCETRAMPGEARTEGE(NKEPRFAO)TIOINh)RATS. SPONSOR'SPROSTTOUCDYOLN4N1E8R-:020T-6889.6 BLE 1-9 HistosorpFhoGleongecraOtbisoenrvations STeW AnxRi:maGl Nonber: W [ 13898 a13900a139a 01 13608 Dthees 0s swos0s ousies: . oupucr(s): . wes: . co . vem: . `OVARIANFOLLICLES/CORPORALUTER:. + sScahosnd)ropathy, auricular w @a 1-18 Page 966 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DY TOVFO-AGMEPKNREOROVATITOUICNOONLP4E1R(F6OLN-EU0D2RL0OIXTCTETRANGPAETREGE(NAEFRFAOT)IOINh) 7ATS SPONSORS STUDY MBER: T-6880.6 Le1-10 HistamorphFoGleonpeircatOibosnervations E SAenxi:eal Nmber: V FIA an Le V 1V 7 a19V s a199T a1999T 19% bmn sw0% woswos8 aGSglgeugenaereatison:, cystic,cortex - - r- errumey. - - - f-- - Seo Saw"agtlsaenn:dt(si)o,n,anclounmsetnrial, cystic Ralrophages. pigmented .o :13;. - FI : rs H "pprreesseenancceeooffa grcoouriponrga/alr nuttreaalfoTlEl:icles rSchoonndropathy, auricular :[F3a S PPoothe roopo oh w =Y Page 967 TnSeeixo:all aRober: Dwthee ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-SAEMPNIREOORTMAOITCNIOOLPNER4(F1OUN6EU-R0GL2OI0OTCTETRANGPAETREGE(NPEFROA)TIOINN) TATS SPONSOR'S STUDY WAGER: T-6899.6. TALE 1-10 (Continued) HistamormshoelogtacObtservations VIsssVs 1a 9% VLAsseVz 1393 VLiouV13 sssssos Su"Gmiassctreosnphtaigoens,, pliumgemnented Siwartaxtion QZUorReIseMnFcOeoLLfIcCoLrEpSocroaRpuotReAsLUTEA: preosf aerownns/canteral follicles sSeahosnd)ropathy, auricular TSoLs.s sosy :3=== [p2 oe Aop p op o re Page 968 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 HISTOPATHOLOGY REPORT APPENDIX II HISTOMORPHOLOGIC OBSERVATIONS F1 GENERATION Page 969 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) INRATS PROTOCOL 418-020 HISTOPATHOLOGY REPORT KEY TO HISTOMORPHOLOGIC OBSERVATIONS == Nochange (not remarkable, change not present). within normal histologic limits or indicated * = Tissue not available (specified tissue missing, insufficient tissue in plane of section, artifact precludes evaluation, or specified tissue not present in section). <> = Microscopic finding(s) in tissue(s) with gross observations). <> = Within normal limits [no microscopic change(s) to correlate with the gross observation(s)]. () = Only one of a pair of organs available for processing/evaluation. A = Advanced autolysis precludes evaluation. P= Indicated change or lesion present. 1 2 = = Minimal degree or amount of indicated change or lesion. Mild degree or amount of indicated change or lesion. 3 4 = = Moderate degree or amount of indicated change or lesion. Marked degree or amountof indicated change or lesion. SS = SD = SM = SSRF = Sacrifice-Scheduled Spontaneous Death Sacrifice-Moribund Scheduled (Reduced Fertiity) I Page 970 ARGUS 418-020 SAenxiEmal wNaber: Desthree REPROODRUACLTI(OGNAVSAGTEU)DYTHOOF-GAEW"NIFEORRNOAITLToMICOoNLPE4R(1OF8NL-EU0O2LR0IITCTCETRANPIETREGE(NAEFRFA)TIOTNh) RATS SPONSOR'S TOY NBER: T-6809.6 Tate 1-1 HistamorgFihoGleongeircaOtbisoenrvations T ios T foie T lor T Ado T lois T dooT lo T dues T loos 5 swesow wo wos 8 or. - 1 1 Hon, mromctenr-cfolc,al 1 + - - EROSTATE Se . eine. mS"sattsrraopphhyy,.frreit/icnil.ifaorcyablody Si"nrafulracmpaatthiyo.n,spcthrorneircv,ei(rsi)s Eoi wm: - - - >Io>eleao w&* S83 : @ 2 Page 971 ARGUS 418-020 SeBHncinoal mNrber: Dthloe: REFROODRLALKTI(OGNAVASGTEU)DYTOWOF-AGPEWRNIOEOTRVAOITCNIOOLNFE4(R1OF8VL-EU0RL2OI0ITCTTEARNGPAETREGE(NAEFRPA0)TIOINN)RATS SPONSOR'S STUOY WAGER: T-6209.6 TABLE 11-1 (Continued) HistonorFpHtsoeleogriactiObosnervations w i1 o le oss dT_ o wlTe wTTa dus 10sT t dose T lose Ss 5s sw ss oss sss os REen "imtruopshy/degeneration,multifocal - - oa - eee ea. FE "Einiflanmma,tion:taarhartoanrte, toca SSosno=orf aano.n 1s Page 972 GASenxiE:malGRsber: Death Tipe: ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DYTWOOF-AGEMPNOREMORITAOLTCNIOOLNPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRRAO)TIO1Nh)RATS SPONSOR'S STUOY NABER: T-6809.6 hate 11-2 HistamorgFhiolGoegntecraOtbisoenrvations HlIosas e1T 066 107 T los losT lose loo S Sw Sw 8 Sw ss % S EROSTRAT io, crane Sa - soSNnagcuoTaatrpons, ;cortex - ' a i Page 973 ARGUS 418-020 EAimE e) Naber: Sbexa: tes A REPROGDRAULCTI(OGNAVASGTEU)RYTOUFO-AGMEONREVROIALTTNIOCNPE4A(1OT3NL-EU0O2RL0OICTCTETRANGPAETREGE(ANFEPR0A)TIIOhNRATS SPONSORS STUOY NBER: T-6889.6 THBLE 1-2 (Continued) HistomorpFploleangeircatOibosnervations T lo olwW e os olw o T wlt s m elt s 20 ss sososos ro- 1 - = 1s Page 974 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEL)DY THOOF-GHEPNRNEORTALOTCIOOLNF4E1(RO8FN-LE0I2OL0RIOTTCECRTAPAETREGE(NNEFROA)TIO1Nh) 7ATS SPONSOR'S STUOY NUMBER: T-6009.6 Tale 1-3 HistamoTrEghonloegrisctObisoenrvations soATnciemaltNeaber: WwHsIoTwMTae ElMasLeNles elTCeeuIae elTe Ta ewasenITTe nTLe Dathwe 505ssm55% tw 8 Ens: - lms - sipHaarmea:tion, chronic z sewvesiags: - CORUATING GLa: - i"nvemyiofpooctaeslis, extramedullary, "ihnyifpilaatrmutmsraeotsihoyn,, hecphraotnoicce,llular, "nTeeccraotsrimsu,teftofcoaclomnltifocal SSdKGearrmm(aatgtiritoeitssss,.uscwshircioeonrianct:ive wo. > > > ow aTe Ta - @S ns Page 975 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHODF-SACMNPOERMROIATLTOIMCOONLPCR4(F1OL6NUE-O0R2LO0ICTCTTEARNGPAETRE.GE(NAEFRRAO)TIOTNh) RATS SPONSOR'S STIOY MIGER: T-6889.6 THBLE 1-3 (Continued) HistomoFrlpGheonlercatOibosnervations sT AonimalGNbr: HTHsoIwTLs TleTsetLWe TWleswLe w WTTs whnmwTLe Dtnvee ssSs55 sw ss ws msn - selooms: - SAT - som vests: - COMUATING GLa: a smSaceuetatsiouns, ,cortex - - Sa LSpRroirtuonpehy, hepatocellular, @ @ LS Page976 ARGUS 418-020 ST Aenxi:ealGNmber: Dwthee Kens ms: EEROoSTA:TE focal somvesIags: CORUATING GLa: REPROODBILCTI(OGNAVSAGTEU)DYTOHFO-ASEWPNNREOIATLTOINCOONLPER4(F1O8LNE-U0O2RL0OICTCTETRANIPAETREGE(NAEFRFA)TIOINh) RATS SPONSORS STO NUMBER: T-6880.6 Thee 11-4 HistomorFpihoGleangeircatOibosnervations W WHeNW Tne T 1s lWWe dE W s LeW s nE se LWe Tuse 55S 55s Sw os 8% S50 - 1 - LS""nhiainecpfreloraatmtrmsoa,sthiyos.ni,nahlecephcracotenoliclce,llufloacr,fdmiftfufsoecal mZibustess "huperpiast/myperkeratosts pF pri r @7: => ne Page 977 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTWOFO-AGWEPINROEONRTIAOLTCWIOOLNPE4R(1OF8NL-EU0O2RL0OICTCTETRANIPAETREGE(NAEPROA)TIOINn)RATS SPONSOR'S STUDY NUMBER: T-6809.6 TLE 11-4 (Continued) HistonorpFplalsoegetrcatOibosnervations ASenxi:mtaloNummber: FFWW OEC A WW WW WAW Dtw hlme s sw ss 8%0% 0% mus - selon; - BoOSTAIE: - SDLvESIaES: - COAUATINGLv: - Re cS"deiadsetonentiinofnlammation, subucosa =w Sawieotenntion w gw w - 2 Siitmifoacanl , axtraseitlry, ""nheycpreorstirso,phyf,ohcealpamtioecielflouelsar,diffuse >=-a spSeeorroiustioo;nni(tsi)s.,glfaocnadlular mucosa a "licer(s). siandutar area = "matsro,phy ww F &@ a7 1s Page 978 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTHOOF-SAEMNKREOORVAITTUCIKONPE4R(1FO6LN-EL0D2RL0OIDTCTETRAKGPAETREGE(NAEFRFAOT)IOINN) RATS SPONSOR'S STIOY NIGER: T-6889.6 THBLE 11-4 (Continued) HistonorpFtialGoegntecratOibosnervations SATenxi:ealGKmper: W W 124 W E12sW EdwE s iWze WE 1 iWzE W1% 10 Dthrge 5sSs0% sows [SVacruofaetionr, cortex 1 - eSehson)diopathy, auricular w E""ehlyanpeerrnastlia,zsattsioppnee,rivvpiseci/vpiaspi lary urothaltm @-: gS"yipneeFratmraotpihayn,, hecphartooncee,llufloacra,l mduilftfiufsoecal "necronts, focalmntfoes! @2: &@ x >& sSeocronsts w 110 Page 979 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DYTOVFO-AGPEMRNKOEOTRHAOITCNIOOLNPE4R(1FO8NL-EU0RL2RI0OXTCTTEARIGPEART.EGE(NFEPROA)TIOTNN)RATS" SPONSOR'S STUDY NUMBER: 1-689. . TLE 11-5 HistamorFpcheomlearcatOibosnervations SeT Anximal Nrber: G ViwlVlE eV s dwT lsE V ds T loseT E dss T lw T Lm Death Te: SS 0% 8 0% S506 S mEianasmaation, chronic - - 1 ASmiSpHpeormterroaasthuoynlssua:cusiation, zone 2 ~vacustation, cortex : EE es arstanss - erat, repstocallatfaurs,e iCniRitriction, focal 11 ' > P 2z e > ow =n Page 980 ARGUS 418-020 REPROODRILCTI(OGNAVSAGTEU)DYTVOOF-AGMEPINROEOMRTIAOLTCMIOOLNPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRPA)TIO1Nh)RATS SPONSOR'S STUOY WAGER: 1-00.56 TABLE 11-5 (Continued) HistenorpFtsaolongrtactOibosnervations SeAG nxi:mal Naber: G Hio s V Go V les T TGV z T Ln E lm wTV nE dus Vlos Dthtee 0 ss5ssosowog aSFafaiTerpation, mononuctesr-cent, focal - - 1. FCSiesntTraaompTaneyt.:iofonc,al suppurative -i :. :E A"hyGpsheorntaerroapnthoys/:svacustation, zane ~vicialation, cortex EEars ntaredta L""Ihryupeemrotrtoipohyn.,hepcahtraocnetle lufloasra, /dmitfiffuosecsl "necrosis. focalfmtfocal eSSeroophy 2: :- ' - w@: SSoaa - >@HRY7 w mn Page 981 ARGUS 418-020 SeAnxi:mal TNEaEber: DsthTee REPROORNACLTI(OGNAVSAGTEU)DYTHOOF-AGEMNPOERNROITALOTNCIOOLNPE4A(1OF8NL-EU0O2RL0OICTCTETRANGPAETREGE(NAEFRPA)TIIOhNRATS SPONSOR'S STUOY NUMBER: 7-689. TABLE 11-5 (Continued) HistamorgFihoGleongeircatOibosnervations WTwsRVTlo lE ms lV aw lT E s iT ms sT s sw ossSsososos EHR, mnonuctesr-cofonet, 1 ro. saosTaTe. - - AygpSehorotmreorGpauhtayo/nnvsessc:ustation. zona elmer. wheimestiopfootceaslts, extramedullary. "hypertrophy, hepatocellular, diffuse [a - >- @aw >_> 1s Page 982 ARGUS 418-020 SeAEnxiemal Number: Dthroe REPROORDAULCTI(OGNAVASGTEU)DYTWOOF-GAEWNIPEORRNOAITLTOWICOONLPE4R(1FO8LN-EU0O2RL0OICTCTETRAIAPTEER.GE(NAEFRFA0)TIOINn)RATS SPONSOR'S STUOY NUMBER: T-6020.6 ele 11-6 HistonorpFtHalSoegnircatOibosnervations [T BA iz TwaTGwe aTLsTTdw 1a 0s sososo85 w"dsicssrtoe:pnhtaigoens,. lpuimgemnented CossEsEs Elation QF"rpeUrseIOesenNnccLee ooLff coroIorupiocnCroaam/apuLnotterasEL)uftSoell;icles unum: echoend;ropathy, auricular - er. a Ppooerooprhp ooph .=2aa w 1 Page 983 ARGUS 418-020 ASeox:iTbNaeber: bathe REPROODBILCTI(OGNAVSAGTEU)DYTHOOF-ASCWNPOERNROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OICTCTETRANIPAETREGE(NAEFRPA0)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6809.6. TABLE 11-6 (Continued) HistemorpHiroGleongetreaOtbisoenrvations TIePTTtius P1R s 1oT pe85 TpLe sTle 0s sososww s""dsicsrstoepnhtaigoens,. lpuimgemnented S eo.IG: "mBcoiftietaotinon, croc, toon) r "presencee aopf grost wlina/antre al follicles Srorao. nona Ppoorroerorppor e"Csho)nd;iopathy, auricolar SSEtrorphy w w 11s Page 984 ARGUS 418-020 SeAmnxi:maEl Nrber: Dente REFROORDALLCTI(OGNAVASGTEU)DYTVOOF-GAPEeNRKEOORNTAIOTUCINOONPLE4R(1OFV8LE-U0RL2OI0XTCITEARIGPAETREGE(NAEFRFAOT)IOTNN) RATS SPONSOR'S STUDY NMGER: 1-6999.6 Le 11-7 MistomorgHhlolsoogmircatOibosnervations IiEesERWTs_TdEeEWTor Tdas 0 wowsw Litiien w Hie, ver tose @* Rie. andar meoss @ B"rieHcraomaatts,iofno,caclhronic @- oT 11s Page 985 ARGUS 418-020 REPROODUULCTI(OGNAVSAGTEU)DYTOHFO-AGWEONFGMRRIoATLToWIcOoNPE4R(1FOL5NU-EO0R2LO0ICTCTTEARNGPAETRE.GE(NAEFRFA)TIOINh)RAT* S SPONSOR'S STUY IMBER: T-6209.6. Tee 11-5 HistomorpFhHocleamgaircatOibosnervations SEAenxie:mal War: F1mra pSaeartast:ion. pelvis @ ny Page 986 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEL)OYTVOOF-SAEMNPOERRVOATITOYICOOPNLER4(F1OLN8EU-O0RL2O0IOTCTTEARVOPNETREGE(NE0R)ATIOINh) AATS SPONSOR'S STUOY MINBER: T-6889.6. TLE 11-5 HistamorgFhioGleongeircaOtbisoenrvations T ASenxi:mal Nber: T F155 Death Te: Ss mSibsscess, pertocular > 1s Page 987 ARGUS 418-020 SeAnximal ENamber: Dante REPROODRUACLTI(OGNAVSAGTEU)DYTWOOF-GAERPNGREONATIAOLTCINOONLP4E1R(P8OLN-EU0O2RL0OICTCTETRANIPTEER.GE(NAEFRFAO)TIOINN) RATS SPONSOR'S STIOY NUMBER: T-6889.6 LE 11-10 HistemorFpioGleongeircatOibosnervations Vise Iope se dpe ss pT Iess TlEm sT15 50s sosomos "ewSsGcissrto:epnhtsaoens,.pTiugmemnented cau "arieiirfieeation SprUreeLsFesOoonLffcLecgoLerrEonp5voi/rmcaaco/TaumnttemeranLlTfAol:licles A"ohnypoersTaausatwae,sc:ortical. focal EenRue. ars stats wSCsha)na:topathy, auricular nT"nienuctraomatast,iofno,calchronic F5P43 35- . eo. ME - -. Ss PpoorpoeE Ppooee ro. - - Poe . w @= 1s Page 988 ARGUS 418-020 ASEneiExmal Naber: Death Te: REPROODBLLCTI(OGNAVSAGTEL)OYTHGOF-AGEPNRNEORTAIOTCIOOLNPE4R(1FO8LN-EI0O2RL0OIGTCTETRANGPAETREGE(NNEFROA)TIO(Nh)AATS SPONSOR'S STUOY NUMBER: T-6009.6. TABLE 11-10 (Continued) HistonorpHhlaleotgriacratOibosnervations V 10 93 dV e iER se v1ev s 1s 5 Ko o& ZB,tntraonrian w"esscr:aghages. pignented - eae sos sa Elation "ipa roefgsroewSiLnna/acntrea) follicles Ss 2. Pporrovop rp oohp pSoarefeiriaostnae:tpihorni,thpselvis 3= wS"apeiersrtepe:intaisotna, mucosa 3w Cinfiammation, chronic 2 R"eopytst,anhecrep;lastic w 1 Page 989 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 HISTOPATHOLOGY REPORT APPENDIX il INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA P Generation KEY TO CORRELATION OF HISTOMORPHOLOGIC OBSERVATIONS Not applicable = Microscopic evaluation/correlation not appropriate or not required by protocol Page 990 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTOWFO-AGMEINPOERMROIATLTOWICOONLPE4A(1FO5LF-U0O2RL0OIOTCTETRANPGEATEGE(NAEPRFA)TIO1Nh)RATS SPONSOR'S STUDY NABER: T-6099.6 Individual Anim AGroopBseasnndeiranantdi1oH1n1istcmorphology Data Asex:a ween: 13602 DoEoAsTeHGToIwPE:. S1ucr Fice-Schadulad 80S ORSCRUTIONS): SENERAL: ho gross changes. HISTOMEPHOLOGIC OBSERVATIONS): Not applicable HISTONRP0\051C pStavATIONS: ePRpOtSToArToE:ms: iinnffltarmaattiioonn,, cmhornoonniuccle(amri-nciem1la,) focal (minima) THEFOLLOUINGTISSUE(S)VERSWITHINNORAL LIMITS: ATeRsEtiAsL GLANDS COUNTING GLAND PrruTRY End of Racord- 13602 Son vesicies 1 Page 991 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)DYTHOOF-SAEM"IFOGRNSOIATLToIMCOoNLPE4R(1OF8NL-EU0O2LR0IITCTCETRAIPAETREGE(NPEFROA)TIOTNh)RATS SPONSOR'S STO NBER: T-6809.6 Individual imal AGFrpaopasemsnadraianxtdi1oH1n1istonorshelosy Data SAex:L Nr: W13609 oDuEsAtTHGToYwP:E: S1cheduled (Reduced Ferti1ity) GROSSOBSERVATIONS): SEUEBAL: No gross changes HISTORPHOLGGICOBSERVATIONS): Not applicable HIsToMsBiOL0GIC QRsERvATIONS: pTreossttiast:e: Sattrroopphhyy,idefgoecnalera(taiio1n6,)mit facal (moderate) THE EOULGHINGTISSUE(S)VEREWITHINNORMAL LIMITS: COASUATING GLAND Epinions sou estes End of Record 13600 1m Page 992 ARGUS 418-020 REPROODRULCTI(OGNAVASGTEU)DYTVOOF-SAEENPNERROTATLTONICOONLFEA6(FO-LN0ELO2RL0IIGTGTETRANGPAETREGE(NAEPRFAO)TIOINn) AATS srouson'S STLoY WAGER: 1-6009.6 Individual fea] GAForepoaemsnrdaianetdi1oi1n1atamorsnotosy Data aSaxeL wees: W13610 DcoEsNeTHGToYvPEe,: S1cheduled (Reduced Fertiity) S055 OBSERUATIONS): SEMBAL Ko gross changes. HISTORPHIGSICOBSERVATIONS): Not app cable HISTO08R1 RopsPEaHvaTOINLs: rrasTaTe: atrophy, focal (winimal) HEFOLLOUINGTISSUE(S)VERSWITHINbolLIMITS: CORULATING GLAND erioioms sounmaL vsicues Testis End of Rncord- 13610 ma Page 993 ARGUS 418-020 REPROODRLALCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERMROIATLTONICOONLPE4A(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(N1ER0A)TIO1Nh)RATS SPONSOR'S STUY MMGER: T-6209.6 Individual Ana) AGrpGopesensnedraianxtdi1oH11nistomorphalosy Data MsexA:L BER: 13611 oDoEsAeTHcToYvPeE:, S1cheduled (Reduced Fertility) S055 ORSERUATIONS): SEAEBAL: No gross changes HISTONRPHOLOSICOBSERVATIONS): Not applicable HISTOMRPHOLOGICOBSERUATIONS: FosTATE: aitnrfolpahmya.tifoone,s ch(rmoinniicmal()ainieel) THEFOLLOMING TISSUC(S)VERE WITHINNORMALLINITS: COASUATING GLAND eprooms seuImAL vestcLes Testis 03 of Record 13611 " mt Page 994 ARGUS 418-020 REPROGDRUACLTI(OGNAVASGTEU)DYTUODF-GAEWNIPEORRNOAITLTOMICOONLPE(4RO1FN8LE-U0O2LR0IOTCTCETRAIPAETREGE(NAEPROA)TIOTNh)RATS SPONSOR'S STO NBER: T-6809.6 Individual Anima) fGFrioompsmesanrtaaentdi1o1Hn1istomorphelosy Data sAaiw:a we: W13612 oDEoAsTeHcaToYuPrE:: S1acrifice-Scheduled 80S GBSERVATION(S): SEHEBAL: Wo gross changes. HISTONRPHOLGGICOBSERUATION(S): Not applable HEFOLLOUINGTISSUES)WERE WITHINbo LIMITS: APRROESTAALTEGuANDS SCEOMRIURLAALTIVNEGSICGLLEASND Teesotisns End of Record 13612 puma 1s Page 995 ARGUS 418-020 REPROGDRUACLTI(OGNAVASGTEU)DYTVOOF-GAEWNIPEORRMOAITLTOWICOONLPE4R(1OF6NL-EU0O2RL0OICTCTETRANIPAETREGE(NAEPROA)TIOTNh)RATSSPONSOR'S STUOY NUMBER: T-6880.6 Indivicusl Animal GA7rpoGpseesnnedarinaxdti1Ho11instororphalesy Data Alya wees: W13614 DoEsAeTHcaToYuPrE:, S1acrFice-Schadaled SAOSSOBSERVATIONS). UGGtNoaGtn:attMerr1.angTionbges-indasrikzerefdroamreIansoItonotn1m0er0c.u4smtoIn HISTOMEPHOLOGIC ORSCRUATIONS): Ihenmfolrarmhmaagtei,onm,ulinttfeorcsatlitial, multifocal HIsToMRPHOLOGIC OBSERVATIONS: wre: PROSTATE: hInenFmflolaramrmahaattgtieoo,nn.:mictIhinrftoeanrcisactli(t(3im1ao4td)meroatei)focal (sodarate) TEFOLLOVINGTISSUES)VERE WITHINNORMAL LINITS: ASmHeAn sVEusIacsLes TCeOsRtUisATING GLAND epioioms Ed of Record 13614 prrurmaRy oT urs Page 996 ARGUS 418-020 HEPROODRLACLTI(OGNAVSAGTEL)DYTWOOF-GAEMNROENROIAITTINOCNFE4R(1OF6NLE-I0O2LR0IOTGTCETRNGPAETREGE(NAEPRFAO)TIO1Nh) AATS SPONSOR'S STIOY NAGE: 1-6889.6 Tndividunt Anis) srFgeopaamesenriaacntdi1oM1n1stomorsraloay Data A sox: wees: W13615 oDEsAeTHoIuVrE:. S1ucriice-Schdiled SassopsERUTIONS): SENERAL: No gross changes HISIOHRPOLOGIC GRSERATIONS): ot apcable HISTOMRPHOLGSICCRSERATIONS: PARROSETAALTE:Gua: avitnafacltaaamttmiiaootnin,o,n,Sctosarirtpaesuxrtae(trxiv1fe0o,)lfoc(aelade(raaitnem)al) HEFOLLONINGTISSUE(S) VEREWITHINNolLIMITS: cTeasrtsiusATING ou erooms Pinu End of Record 13615 - oT SomAL VesIcLss TT mer Page 997 ARGUS 418-020 REFROGORLLCTI(OGNAVASGTEL)OYTVOOF-SAEONFERNROIATTONICOONLPER4(A1O6LNE-U0O2RL0OI0TCTETRANOPAETREGE(NAEPRFA)TIOINh) ATS SPONSOR'S STUDY NBER: T-5089.6 indviiduvalical Anima)heat GFroemeGrosraaanntdrhoHsniston i Osta MseAx:L wsER: W13616 DoEsAeTHrToYvPeE:: S1 orifice-Schaduled 8055 OBSCRIATIONS): RE): Swallen, both. HISTOMRPHOLOGIC.OBSERUATION(S): Tissue rot available HEFOLLOUINGTISSUE(S)VEREWITHINNORMAL LIMITS: PRAORSETAATLEGLANDS CSOOUNNATLIVNEGSICGLLEASND Teepsrnosomis pry TA ISSUEA (S)MOL T LA FOREB VALATE ION: exis) ns Page 998 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGMEKFXROEONRTIAOUTCKIOOLPNER4(F1O6LNE-U0R2RL0OIOTCTETRANGPAETREGE(NAEeRroA)TIOINh) RATS SPONSORS STUY OBER: T-6088.6 Individual Anima GAroeGpseesnnedraiantdi1oH1n1istmorpholosy Data Asex:C wer: W13621 oDEsAeTHcToYuEr,: S1acrice-Schaduled SROSS QRSCRUATION(S): SEERA Ho gross changes. HISTOAORPHOLOGICOBSERUATIONS):| ot applicable TEEOLLOUINGTISSUR(S)VEREWITHIN noms,LIMITS: APRROESTAALTEGLANDS CSEOARIUMAALTIVNEGSIGCLLEASND eTpetsotisomus End of Record 13621 Pry 1s Page 999 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTVOOF-SAEMNKFEROROVATITOUIGKOONLPER4(F1OLN8EU-R0RL2OI0DTCTETRANGPAETREGE(NPEFROA)TIOINh) 7ATS SPONSORS STUDY NIGER: T-6889.6 Individual nm) PAGrpeopasensnedriaaxntdi1oH1n1istonorphelosy Dota Sa ei: wen: W13622 oDuEsAtTHcaToYuPrE:: Sa1 crifice-Schadaled 8055 GRSERVATIONSS): SEAERAL: No gross changes HISTORORPH0\GGICOBSTRATIONSS): Not applicabie HISTOMRPHOLOGIC OBSERVATIONS: PROSTATE: inflammation, chronic (sf1d) TAC FOLLQUINGTISSUE(S)VEREWITHIN NORMALLIMITS: SAEMRINEAL GVeuSuTesies CToERSUTSATING GLAND eptooms Piru Ed of Reeara- Bez TTI 1-10 Page 1000 ARGUS 418-020 REPROGDRIALCTI(OGNAVASGTEU)DYTUODF-SAEMNPOERNROIATLTOWICOONLPE(1RO6FNL-EU0O2LR0IOTCTCETRANPIETREGE(NPEFROA)TIOINh) RATS SPONSOR'S STUY NBER: T-6800.6 Irtviidcihnal Anosae)t SFhoeSeaems+raa5tnrhodsnstoner 1 outa ft nL eR: W13626 oDEsAeTHsToYuPrE:: S1acrice-Scheduled S055opsERATIONIS): SEMEBAL ho gross changes. HISTOMRPHOLOGICOBSERVATIONS): atappl cable HISTONRPHOL0GIC opsTRIATIONS: ePRpOiSoTiAoTmEs:s: aIitnnfaftl1aattmriaaottinio,onn;,stamcnhodrnsootnnaiurcc,le(afaroi-cncailemla)l(.}a11fdo)cal (minima) AEFOLLOWINGTISSUE(S)VEREWITHIN og,LTS: sou cos COASUATING GLAND Piru Sou vesicles dof Record liseTTmmmmmmm-- mn Page 1001 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTUODF-AGEM"NOPEMRRIAOLTTMIOO.NPE4(RO1FN8LE-U0O2LR0IOTCTCETRAIPAETREGE(NAEPRFA0)TIOTNh) RATS, SPONSOR'S STUOY NUMBER: T-6289.6 ngviduvailda Animalaim) G#GrGoesonseaarnndadntMiointHiastanrotoloy Onto saA:L re: W13625 oDoEsAeTH sToYuPrE:: S1acrifice-Scheduled 805s GRSERVATIONS): EAEBALS Mo gross changes. HISTIRPHIGSIC OBSERVATIONS): Not applicable HISTOMRPHOLOGIC OBSERVATIONS: PRAOoSRTeAmTAEL:auanos: vTancfuloalmaattiioonn,,cosrutpepxura(tmivien,if)ocal (eile) HEFOLLOVINGTISSUE(S)VERE VCTHINNORMALLIMITS: TCeOsRtUsATING GLAND epiooms pray seINAL VestcLes Ed of Rocore- 13525 J 1-12 Page 1002 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTWOOF-GAEONPNERRTOATLTONICOONFLESR(OFiNLeELgGLReIGTGTCETROG7AET%EGE(NAEFRFAOT)IOTNN) SATS SPONSOR'S STUY MBER: T-6809.6 Individual Anima) GA#roGopesensnedraiantdi1Ho11nitomorshology ata AsaNAL NOR: W13625 sDEeATHgToYwPrE:. S1acr Fice-Schadsled Sa0ssopsERuTIONS): SENERALS Mo gross changes. HISIOMORPHOLGEICCOSERVATION(S): Not applicable HISTORRPHOLOOIC OBSTRIATION: AEPRiEoAIoLmiGsu:ns: vTancfuisiltartaitoino,n,csoorntoexma(tsata1rdc)all, focal (minimal) HEFOLLONINGTISSUES)VEREWITHINNOLLINITS: CTeOsAtTsING LD prrumaRy mosTATE soumaL vesicLes sy Page 1003 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)DYTHOOF-SAEWNPOERMROIATLTOIMCOONLPER1(FO6LN-UE0O2RLO0ICTCTTEARNGPNETRE.GE(NAEPRFAO)TIOINh) RATS sponson'S STIOY NMG: 1-6089.6 Individual Anima) AGPrpGopesnseenardnadti1Ho11instonorphalasy Data MseAx:L weER: 1W3632 DoEsAeTHcaToYuEe:: S1a1crice-Schadaled ROSS ORSCRIATIONS): SEMEL ho gross changes. HISTONOEPHOL061C OBSERVATIONS): Not applicable HEFOLLOWINGTISSUE(S) WERE WITHIN ORALLIMITS: AREAL Laws End of Record 13632 mee Page 1004 ARGUS 418-020 Scr SUL i(oGnAGSE)HsrToOonFcsBEonnOpESST1IHi0O0NPEWrA(ARoGLnEeRILIRTT-IO8R0Oa0P.eeE6 ceenrEaA)TIONars ndtv) ors sFSopeaaondn1i11samroteloy tuts Mkyv wea: 13658 wSHeRsInNrE: H11erinco-scheated S505OBSERATIONS): CELDIOMIBS: Right salt and acer IESIES: Right ma and Facets STOOL oss): AEattrosepehyrr.aeeo.pitorooemmiosmlisaar-cell sions focal riatniaon:, treunet,osiTsE:STITSris ostsowsstuTIN: enntonus: Tests of aor 980 r H y i eare ed -- SMelpattaosni,a Froieevteejkerked nts Page 1005 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DYTHOOF-GAEWNIPEORRNOAITLTOWICOONLPER1(FO6LN-UE0O2RLO0ICTCTTEARNIPAETRE.GE(NAEFRFA0)TIOINh)RATS srousoR'S STIoY WAGER: 1-6009.6 Indivicus) Anima) AGPrpoopesemsnedraianxtdi1oH1n1istomorshalsy Data sex:nL eR: W13638 DoEsAeTHsrToYuPrE:: S11cheduled (Raced Fort1ity) A058opsERATIONS): RS): Sellen, right. HISTORRPHOLOSIC OBSERVATIONS): chondropatry, auricular. HISTONRP0\G61C BSTRVATIONS: eExPitsd)io:MS: cehxofnodlrioaptaetdhys.pearumrsitcougleanrtc(cmooldler.at(en)i1d) HEFOLLOWING TISSUES) WERE WITHINNORMALLINITS: COASUATING GLAND rRosTATE SEMINAL VESICLES Testis Ed of Record 1369 : nr Page 1006 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTOUFD-AGWEINPOERNROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPEART.EGE(NAErRFA0)TIO1Nh)RATS SPONSOR'S STUOY WAGER: T-5999.6 Individual ma) GAFrpeopasensnedraianxtdi1oH1n1istomorphalosy Date feAstL eR: W13639 oDEsAeTHcToYvPEe,: S11cheduled (Reduced Fertility) 805 GRSERIATIONS): KIDNEYS: Right- pelvis, slight dilation HISTONRPrOUGGIC BsERUATIONS): artatation, pelvis HISTOORPI0\GGIConstavaTIONS: PKRieOopSvtTeAorTisEo::ms: diIinnlffalitatamrtaaittioiononn.,sercmvhoirnsoonniu(ccmlian(aiarmr-atcla)e)1l, focal (minima) HEFOLLOWINGTISSUE(S)WEREWITHIN ORAL LIMITS: CORUATING GLAND sou estes Tesnis 03 of Record. 136% - ny Page 1007 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTHOOF-SAEMNHPEORRVOAITTUOIYCOONFLE4R(1OFN8LE-U0RL2RI0OTCTTEARNGPAETREGE(NFEROA)TIOINN) RATS SPONSOR'S STUDY WAGER: T-6899.6. Int"vicn temal SFlm5erosraoa4nndtdieonHistonestmt= Onto A Sait eR: W13502 oDoEsAeTHhoTYwPeE.: S11ucr ce-Schecdsled 80S GBSERVATION(S): SEUEBAL: No gross changes. HISTOMAPHOLOSICOBSERVATIONS): Not applcasle HEFOLLOUINGTISSUE(S)VEREWITHINbolLIMITS: AOREMAL GLANDS Endo Ragone 3s -- =) Page 1008 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTHODF-GAEWNIPEORRMOAITLTOWICOONLPEA(4FO1LN5UE-O0R2LO0ICTCTTEARNGPNETRE.GE(NAEPROA)TIOINh) RATS SPONSOR'S STUOY NUMBER: T-6889.6 nda im) G# Goeneanrxnadti1Mo11ntamrsholony Buta MseAx:L NBER: 1"3544 oDEsAeTHcToYuPrE:, Sa11crifice-Schedaled R053 QRSCRIATIONS): SEERA No gross changes. HISTOMRPHOLOS1C.OBSERUATIONS): hot applicable IH FOLLOUINGTISSUE(S)WERE WITHIN ORAL LikITs: AREAL GLANS 1-19 Page 1009 ARGUS 418-020 REPROODRLACLTI(OGNAVSAGTEL)DYTOWFO-AGMEPONRNEOAITTUOINCOONLPER4(F1O8LNE-I0O2RL0OIGTETETRANGPAETREGE(NAEPRFA)TIO1Nh) AATS SPONSOR'S STO NDBER: T-6880.6. Individual Anima) sG#roGopesensnedraiantdi1Ho11nistosorshalagy Data Asex:a wees: W1365 DoEsAeTHcToYvPeE:: S11arifice-Scheduled S055 OBSERVATIONS): SEERA: Wo gross changes HISTOHRPHOLOSIC OBSERVATIONS): Not applicable HE FOLLONINGTISSUE(S)VEREWITHINsomalLIMITS: AREAL GLANDS 12 Page 1010 ARGUS 418-020 ACPROORDALLETI(OGNAVASGTEL)QYTWOFO-GAEWNRGENROIALTTYIOCNPE4R(1OF8VL-EI0O2RL0OIGTCTETRANOPAETREGE(NAEFRFAO)TIOINh)AATS srousoR'S STIOY WAGER: T-6889.6 Tnvidunt Anim) ASFpeapmaemnnadraianxtdi1oM1n1tamorpraloay Ota Sa o woes: 13645 oDEsAeTHoTwIP:E, S11ucr ice-Scheduled 053oBsTRATIONS): SERA Yo gross charges. HISTOHORPHLOSICQBSERATIONS): ot apcable HsToowIoL001c costavaTIons AREAL cL: vacolation, cortex (ainima1) End of Record 13646 - wa Page 1011 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTOWFD-AGMEINPOERMROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STUOY NABER: T-6209.6. Individual Anima AGFreooapnmesanrdaaintdi1oW1n1istmorpholosy Data seA x: WrgER: W13650 DoEuAsTtHcrToYuPpE:: S1c1heduled (Reduced Fertiity) 80SGRSCRVATION(S): SEERA: Wo gross changes. HISTONRPHOLGSICOBSERVATIONS): Not applicable HISTONRBHOLOG1C aseRvATIONS: PeROpStToAtToE:ms: iinnffillatmraattiioonn;, mchornoonniuccle(amri-ncieslell,} focal (afl) `HEFOLLOUINGTISSUE(S)VERSVITHINNORMAL LIMITS: CORUATING GLO spun Vestas Testis End of Record 13650 TTT ize Page 1012 ARGUS 418-020 RESROODRAILCTI(OGNAVASGTEU)DYTOWFO-AGWEINPOERVROIATUTONICOONLPE4R(1FO6NL-EU0OL2RI0OTOCTTEARNGPEART.EGE(NAEFRTAO)TIO1Nh)RATS SPONSOR'S STUY NNER: T-6869.6 Individual ormies) G#FGreoasnsaearnadtiMHosintsotmoarroprepthoaylosy Data AEyna ech: W13651 oDoEsAeTHrToYvPeE:: S11acrifice-Schaduled 8085 GBSERATIONS): SEHERAL: No gross changes HISTORPHOAGGICOBSERVATIONS): ot applicable HISTORRPHOLOGICOBsERUATIONS: AREAL GLANS: vacuslation, cortex (minimal) End of Record T3651 TT ------ zs Page 1013 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEL)OYTHOOF-GMENROERONATTIIOCNFE4(R1OF6NLE-L0O2LR0IITTCECRTAPNETREGE(NAEFRFAO)TIOINh) 7ATS * SPONSOR'S STIOY NUMBER: 1-6689.6 InvitcueAnteses)SrFSeaaonan+raan3tdtosntor Histomrshatosy Onto SAex:a wae: 13652 oDuEsAtTHcoTYuPrE:. S11acrifice-Schedsled 805 GRSCRIATIONS): SEUERAL: No gross changes. HISTONRPIOLGSICOBSERVATIONS): Not applicable TH FOLLGMINGTISSUE(S)VEREWITHINsomuAL LIMITS: AREAL GLANDS End of Record Bagg m2 Page 1014 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTVOOF-GAENPGERRONATTOIICOONLPES4(F1O6LNE-U0O2RL0OICTCTTEARNI7TEER.GE(NAEPROA)TIOINh)RATS SPONSOR'S STIOY NMG: 1-6889.6 Individual Anima] AG#roGopesensnedarinadti1Ho11instomorshalogy Data Asx:L ER: W13653 OooEsNeTHhoTYwPeE:, So11rifice-Scheduled S058 BSTRIATIONS): LAGE): Swollen, riot. HISTONRPHOAGGICOBSERVATIONS): chandropathy, auricular HisTouRpHOL081CopsEmvaTIONs: es): End of Record T3688 chondropathy, auricular (saderate) mez Page 1015 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTHOOF-SAEMIKPEORANOAITTUOIKCOOPNLER4(F1OLN8EU-R0RL2OI0DTCTETRANGPAETREGE(NAEPRFAOT)IOTNN) TATS SPONSOR'S STIBY NBER: T-6880.6 Individual Anim AGFroeepnseesnrdaaintdi1oH1n1istmorpholosy ota sAeL BER: W13654 oDoEsAeTHcoTYvPeE:. S1a1crice-Scheduled A058 QBSERUATIONS): SEERA Yo gross changes. HISTORRPHOLOGICOBSERVATION(S): hot. applicable THEFOLLGHINGTISSUES)WERE WITHINNORMALLINITS: AREAL GLANS nd of Record 13654 CT was Page 1016 ARGUS 418-020 REPROCROALLCTI(OGNAVASGTEL)OYTVOOF-GAEBNROEROMAITTNIOCPNEA4(R1OL6NUE-O02RL0IOT0TCETRANFAETREGE(NAEPRFA)TIOIN) TS SPONSORS STIOY NBER: T-6800.6 Individual ira) fGFraooapsmesanriaaentdi1o1Hn1istomorpholosy Data sAaNiI:MAL BER: 13655 DoEuAsTeHGrTYoPwE:. S11ucr ice-Scheduled 68055 OBSERVATION(S):. SEUERAL: No gross changes. THE0LLCUINGTISSUE(S)VEREWITHIN nom,LIMITS: AOREMAL GLANDS HISTOMORPHOLOGIC OBSERVATIONS): Not spp fcable ma Page 1017 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEU)DY TOVFO-ASMEFKNROEOMRTIAOUTCKIOOLPNER4(F1O6LNE-L0R2RL0OIOTCTETRANGPAETREGE(NAEPRFA)TIO1Nh) RATS SPONSOR'S TOY NBER: T-6029.6 Individual Animal AG#roGoespnseearnnadti1Ho11instomorphalasy Data Asex:L BER: 13656 oDEsAeTHcToYvPeE:: S11ocifice-Schadulad R053 QRSERIATIONS): SEMERAL Yo gross changes. HISTOMORPHOLOSIC OBSERVATIONS): hot applicable HEFOLLOWING TISSUES)WERE WITHINNOBUAL LINITS: AREAL GLANS ize Page 1018 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGEW"NIPERORoNATIToNIcOoNLPE4(R1OF8NL-EU0R2LO0ICTCTTEARIGPAETREGE(NFEROA)TIO1NX)RATS SPONSOR'S STUOY NABER: T-6889.6. Individual Animal GA#roGopesensnedraiantdi1Ho11instomorpholosy Data ASex:L BER: W13661 DooEsAeTHcTrIoPwE:: Sa1o11rifice-Schaduled R058 ORSERATIONS): SENERAL ho gross changes. HISTONOREHOLOGICOBSERVATIONS): Not applicable HISTOMRPHOLOGIC OBSERVATIONS: AOREMAL GLANDS: End of Record 13681 vacuolation, cortex (minima) ms Page 1019 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOWFO-AGMEINPOERMROIATUTONICOONLPE4R(1OT8NL-EU0O2LR0IOTOTCETRANPGEART,EGE(NAEFRFA0)TIO1Nh)RATS SPONSOR'S STUDY NMGER: T-6889.5 Individual imal APGrpGopesnesenradantdi1oH11nistonorphalosy Data Asex:a wees: W13662 DoEsAeTHsToYwPE:, S1c11heduled (Reduced Ferti11ty) 8085 GESERATIONS): GENERAL: No gross changes HISTORRPHAGSICOBSERUATION(S): Not applicable THEFOLLOMINGTISSUE(S)VEREWITHINNORMAL LIMITS: ASEnNeIAwL cVEuSIecsLEs TCEOSATSTING GLAND epioioms prosTare End of Racord- 13662 11-30 Page 1020 ARGUS 418-020 REPROODRUALCTI(OGNAVASGTEU)DYTVOFD-AGWEINPOERNROIATLTOWICOONLPE4R(1OF8NL-EU0O2RL0OICTCTETRAIAPTEER.GE(NAEPRFA0)TIOTNh)RATS SPONSOR'S STUY WAGER: T-3009.6 nndthviccuun)n asAnmim)a S PGeraonssearao nandtioMnatstomp> ate Asex:L eER: 13668 DoEoAsTeHcToYeE:: S1a1c1rice-Schadsled R053 ORSCRIATIONS): SEMBALL No gross changes. HISTOMRPHOLOGICOBSERVATIONS): Not applicable THEFOLLOMINGTISSUC(S)WEREWITHIN NORMALLIMITS: AREAL Suave mes Page 1021 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERNROIATLTOMICOONLPE1(RO8FN-LEU0R2LO0ICTCTTEARNGEART.EGE(NAEPRFA0)TIOTNh)RATS SPONSOR'S STUY MMGER: 1-699. Individual eal AGrpopsesndainxd1i11stomorsholosy Data # Generation Asex:L ER: W13670 oDEoAsTeHGToYwPE:: S1a1c1rice-Schadsled 8053 GRSCRUATIONS): KIDIESS: Right- pelvis, moderate dilation. HISTONRPHOLGGIC BSCRUATION(S): aitatation, pelvis HSToMRPrOL0GIC opsERUATIONS: xiowers: End of Record 13670 dilatation. pelvis (moderate) Crm mies Page 1022 ARGUS 418-020 REFROORDAILCTI(OGNAVASGTEU)DYTVOOF-ASMEHKNOERVROIATUTCNICOOPNER4(F1OL8NEL-R0G2LOI0OTCTETRANGPAETREGE(NAE0RFA0)TIOINh) AATS SPONSOR'S STIOY NIGER: T-6800.6 Individual ima] APGroGoespnseeranantdi1o1H1nistonorphalosy Data sAoMx:AL wpe: W13671 ooDEsAeTHcoTuYPrE:: S1a1c1rifice-Schadaled R053 QRSCRATIONS): GENERAL Mo gross changes. HISTOMEPHOLOSIC OBSERVATIONS): tt applicable THEFOLLGMINGTISSUES)VEREWITHINNORMALLIMITS: ARO GLANS ofRecora-WoT ss Page 1023 ARGUS 418-020 KeOrRALo(nGAVASGEH) TOHFO-HSEp NOEAHTIiONFEA(TO)UKTRLOIOTLTTERIACT3 GE(N1G0A)TIOIN)RATS Srovsan'S STUY NABER: T-6888.6 ndivicn) Antal oGFeopnneeradandt1iM1n1stcmorpolony Oa biis wren: 13672 wSoEsIGTarE, b1i11tiice-scrdited `6E80s5S ;QBSERRiVgAhTItONp(eS)w:s, stig itation. 'HaIiStTaOaMtORiPoHnOLpOeGlIvCiOsBSERVATION(S): HISTORICOBsEiATION: xaoers: ren aatation, pelvis (minal) ea Page 1024 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTHOOF-SAEWNPEGRRNAOTITIOONFE4R(1OF5NLE-L0O2LR0IITCTCETRIGPAETREGE(NNEFROA)TIOINh) AATS SPONSOR'S STIOY NUMBER: T-6889.6 Individual Animal GsFroeopasemsnadraianxtdi1oH1n1istomorpholosy Data sMix:L BER: W13673 cDoEsAeTHGiToYuPrE:: Sa11c1rice-Schaduled S058opsERUATIONS): SEMBAL:No grosschanges. HISTONRPHOLOGICOBSERVATIONS): Not applicable HEFOLLOUINGTISSUE(S) VERE WITHIN ORAL Limits: AREAL GLANDS End of Record- 13673 TT BE Tr ies Page 1025 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNKFREOORVTAIOTUGINOOLNPER4(F1OLN8EU-R0RL2OI0OTCTTEARNGPAETREGE(NPEFROA)TIOINh)RATS SPousoR'S STI MME: T-6069.6 Individual Anima) oGPFrpeoeasrnsaetraeantdi1io1n1stonorphalosy Date Asax:L NER: "13674 DnEoAsTeHcTaYoPE:, S1c11heduled (Reduced Ferti1ity) R053 ORSCRIATIONS): SEERA Yo gross changes. HISTOMORPHOL0GIC BSCRIATIONS): Net applicable HISTOMRPHOLGSICOBSERATIONS: eptooms. htupoolspteartaeidasp(enrim1ad)togentc cells (soderate) `THE EOLLOMINGTISSUE(S)VEREWITHINbORUAL LIMITS: CORSUATING GLAND PROSTATE se Vestas Tesnis End of Record 13674 oT " = Page 1026 ARGUS 418-020 REFROGBRLLCTI(OGNAVSATGLEOYTOVFO-AGEWIROEVIOAITTNIOCNFE4(R1OP6NL-EU0OL2RI0TCTTEARNOPNETREGE(A0ER)ATIIONATS SPONSOR'S STUOY WAGER: T6289. Individual Ana) AGFrpiopmsemsnadraianxtdi1o1Hn1istomorsholosy Data ssoua woes: 13675 cSoEsTeHcTaIeP:E, S11o1ri ice-Schaduled saossosEmvATIONS): SEB o ross chamses. HISTOMRPHOLOSICOBSERATION(S): tat apicatle sTouReHOL01CoostavATION: AREAL Gua: rd of Rosana 13675 vacwlation, corte nile) Tr o-- my Page 1027 ARGUS 418-020 REPROODAULCTI(OGNAVSAGTEU)DYTHOOF-SAEWNPOERMROIATLTOIMCOONLPER1(FO-LNU0EO2RL0OIOTCTTEARNAPAETRE.GE(NAEPRFAO)TIOINh) RATS SPONSOR'S STUOY MMGER: 1-6089.6 Individual Anima) sGFroaopesemsnedraianxtdi1oH1n1istomorphalagy Data MsexA:L BER: W13676 oDoEsAeTHcTrYoPwE:: S1o11crifice-Schaduled R055 OISERATIONS): SENERAL Yogrosschanges. HISTOMORPHOLOSIC OBSERVATIONS): ot appl cable TIE EOLLGUINGTISSUR(S)VEREWITHIN NoRHALLIMITS: AREAL GLANDS End of Record- 13875 or 13s Page 1028 ARGUS 418-020 REPROGDRIACLTI(OGNAVASGTEU)DYTWOOF-GAEMNFOERMROIATLToMIcOoNPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NPEFROA)TIOTNh)RATS SPONSORS STUOY NBER: T-6889.6 Individual Aiea) AGPFprGpoaesnnsedraianxtdi1Ho11instonorpholosy Data sAxw:a een: W13682 oDoEsAeTHGrToWvEe,: S11a1i fic-Scheduled 8085 GESERATIONSS): SEUEBAL: No gross changes. HISTONRPHOLGSIC OBSERVATIONS): Not ppicable HISTOMEPIOLOGIC OBSERVATIONS: AREAL GLAM: vacuslation, cortex (aininal) End of Record. 13082 TTT 1-3 Page 1029 ARGUS 418-020 REPRGORDAULCTI(OGNAVASGTEI)OYTUGOF-GAEONPNERRIOATLTONICOONLFER(4OF1NL-EI0O2RL0OICTCTETRANOPNETREGE(NPEFROA)TIOINh)ATS SPONSOR'S STO NBER: T-6809.6 Individual nm AGFroaopasemsnadraianxtdi1o1Hn1istomorphalosy Date ASuL nsER: W13683 oDoEsAeTHoTwYePE:. S1a11cece-Schaduled GR05S OBSERVATIONS): SEERA ho gross changes. HISTOMRPHOLOGICOBSERVATIONS): Not applicable HISTOMORPHOLOGICOBSERVATIONS: AREAL GLANDS: vacuolation, cortex (soderate) ta Page 1030 ARGUS 418-020 REPROORDAXLTI(OGNAVASGTEL)0YTOHFO-JGENRAERoAITICOPNEA1(P8OL-KU0K2IL0GIETTTREIRGN6T3E.GE(NAErRA)TIOINh)WATS srouson'S STUDY Mn: T-oae. Tnvidun) Anias) zoeneserasntdt1oMnstomorsrato_ny-- data pAia wre: i13684 GoEsNeTGToIvEe,: Sa11r1i ce-Schaduled `6805S OBSERVATION(S): GENERAL No gross changes 'HNIoStTaOpMpORtPcHaObLlOeGIC QBSERVATION(S): HEFOLLOWINGTISSUG(S) WERE WITHINMgoALLTS: AREAL Las End of Record- 13684 I CTT ma Page 1031 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-GAEWNIPERORONATITOLICWOONLPE4(RO1FN-LE0U2OL0RIITTCECRTAPAETREGE(NPEFROA)TIOTNh)RATS SPONSOR'S STO NUMBER: T-6889.6 Individun) Anima) GA7rpGopesnseenradantdi1Ho11nistomorphalaay Data a ey wees: 13699 DoEsAeTHcTrYoPwE:: SIavcrice-Schedsled R053 OBSERIATIONS): SEAL Yo gross changes. HISTORPHOLOSIC OBSERVATIONS): ot applicable HEFOLLOUINGTISSUES) WERE WITHINNOBUAL LINITS: AREAL GLANDS Ed of Recora- 19899 " Tr 1 Page 1032 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTHOOF-SACWNIPERGROMATITOLICNOONLPEA4(F1O8LNE-U0O2RL0OICTCTETRAVIPTEER.GE(NAEFRFAO)TIOINn) RATS SPONSOR'S TOY OBER: T-6889.6 Indivicun) Anima) GA#roGopesensnedraiantdi1Ho11instororphalosy Data MseAx:L BER: W13695 sDEeATHoTuYrPE:. Sa1vcrfice-Scheduled S058oBSERUATIONIS): SEUEBALL No gross changes. HISTOMORPHOLOSICOBSERIATIONS): Not applicable `THEEOLLOUINGTISSUR(S)VERE THIN NoRuALLikTS: AREAL GLANDS ie Page 1033 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)DYTHOOF-AGWEINPOERMROIATLTOWICOONLPE4R(1FO8LN-EU0O2RL0OICTCTETRANGPAETREGE(NAEPROA)TIOINh)RATS sPousoR'S STLOY WAGER: T-6809.6 Individusl Anima] AGroGopesensnedraiantdi1oH1n1istosorphalagy Data a5L wees: W13699 DooEsAeTHrToYPwE,: S1vacr ce-Schadulod 8085 GESERATIONSS): SEMERAL: No gross changes. HISTORPIOUGSICOBSERUATION(S): Not appicatle HEFOLLOUINGTISSUE(S)WERE WITHIN ORAL LIMITS: AREAL Guavos Ed of Record Ta TTT ta Page 1034 ARGUS 418-020 REPROGDRUALCTI(OGNAVASGTEU)DYTOUFO-AGMEINPOERMROIATLTOMICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(NAEPRFA0)TIOINh)RATS SPONSOR'S STUDY MBER: T-689.6 Individual Animal sGroopsesndainxd1H11istonorpbalosy Data # Generation Asex:L EER: N13700 . oDEsAeTHcToYwPE:: SIcvheduled (Reduced Fertility) R03 ORSERIATIONS): GENERALS No gross changes. HISTOMEPHOLOGIC OBSERVATIONS): Not applicable HISToRPIOLOGICopsEnvATIONs: PROSTATE: inflammation, chronic (si1d) HEFOLLOWINGTISSUES) WERE WITHINNORUAL LINITS: CORSUATING GLAND eprooms SeumAL VEsTeLeS Testis Ed of Record 13700 11s Page 1035 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTONFO-AGMEINPOERMEOIATLTONICOONLPE4A(1FO0LK-U0O2RL0OIOTCTETRAN8GATEGE(NEARA)TIOINh)SATS SPONSOR'S STUOY NABER: T-6299.6. Individual Anim PAGrpepeseasnndeiraxantdi1oi1n1stamorpholosy Data sAoMx AL wc: "13703 mDEsAeTHgToYwE:, S1avcrice-Schaduled R053 QBSERIATIONS); SEMEL Yo gross changes. HISTOMRPHOLOGICOBSERVATIONS):| at appl cable TEFOLLOUINGTISSUES)WARE WITHINbom LTS: AoRL suwos End of Record 13708 CTT . ies Page 1036 ARGUS 418-020 REPROOBDCLTI(OGNAVSAGTEU)DYTHOOF-SAEWXIPEORRNOAITLTOWICOONLPE1R(F6OLN-UE0O2RLO0ICTCTTEARNIPAETRE.GE(NAEPROA)TIOINh)RATS SPONSOR'S STUDY NUMBER: T-6009.6. Individual Animal Gs#roGopesensnedraiantdi1oH1n1istomorsholgy Data si AL BER: W13704 oDoEsAeTHhToYwPeE:. SIuvcrce-Schedsled SA05S oBSERATIONS): SEERA: Yo gross changes. HISTOMRPHOLOGIC OBSERVATIONS): Not applicable HEFOLLOUINGTISSUES)WERE WITHIN ORAL LIMITS: AREAL GLANS End ofRecord-13704 1a Page 1037 ARGUS 418-020 RCPRGOBRLAELTI(OGNAVASGTE)OTOWFO-AGEONPNERIROATUTONICOONLPE4A(1OR6NL-EC0O2RL0OI0TCTTEMROPNERT.EGE(NAEFRFA)TIOTNh)ATSSPONSOR'S STUOY MMGER: T-6099.6 Indivicun] Anima) sG#roGopasensnedratanetdi1Ho11nistomorpholasy Data MseAx:L ser: W13708 oDoEsAeTHhToYwPeE:. SIuvcrce-Scheduled A058OBSERVATIONS): EPIDIOIOES: Right- small and flaccid. TESTES: Right- smal) and flaccid HISTORPHLOSIC ORSCRUATIONS): aPTtnorfpoiopishtpyre.artaitEoapn,I,DEIrPOoIMnOIoInSOuMcIleSar-cell, focal, hcyiEpfPaoitpoalitaoismoiina;,s iretfeustee,stiTsE,STTIESSTIS HISTOMORPHOLOSIC BSERATIONS: AEPRiEbAioLmiGsL:AS: Tesnis: End of Record 13706 svIaytcpruooosplpnaeytria(otanet,ia()cmoarrkteesx) (ainisel) aTTafnpeiottparltaaistoiinao,,n,dreistfeofunsoteensct(lisesoarrk-ecde)ll, focal (minimal) 1a Page 1038 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-ASMEKNPOERMROITAOUTCNIOOLPNER4(F1OL8NU-EO0R2LO0IXTCTTEARNGPAETREGE(NAEPROA)TIO1Nh)RATS SPONSORS STIOY NBER: 6880.6 Individus)1 Anima)son2GProoosmseraantdi1oH1n1istosorpha.lgy Data sAx:v ser: W13708 DooEsAeTHhToYwPEe,: S1vacr ice-Schaculed SAOSS BSERIATIONS): SENERAL ho gross changes. HISTOMEPHOLOGIC.OBSERVATIONS): Net applicable THEEOLLONINGTISSUC(S)VEREWITHINNORMALLINITS: AREAL GLANDS igs Page 1039 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTVOOF-AGWEINPOERNROIATLTOWICOONLPE1R(O6FNL-EU0O2RL0OICTCTETRAVGPAETREGE(NAETROA)TIO1N4)WATS SPONSOR'S STUOY NBER: T-6289.6 Individual Anima) GAProeopasensnedraianxtdi1oH1n1istonorpholosy Data SAaitC WHER: W13710 oDuEsAtTHchTYoPwE:: SaIvcrifce-Schedaled BOSS ORSERVATION(S): BRIS): Swen, right. HISTOORPIOUGSICOBSTRATIONSS): chondropathy, suricular HsTousproLOGICopspRuATIONS: is): End of Record 13710 chondropathy. auricular (soderate) ies Page 1040 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTWOOF-GAEGNPNERROIATLTONICOONLPER4(F1OL6NUE-O0R2LO0ICTCTTEARNG7N6T%E.GE(NAEPRFAO)TIOINn) RATS SPONSOR'S STUDY MBER: T-6800.6 Individual Anima] sGFroeepasensnedriaaentdi1oH1n1istomorphelogy Dota SAe:wa wes: 13711 oDuEsAeTHrToYwP:E: SIvur ice-Schcled S058 SERUATIONSS): SEUEBAL: Wo gross charges HISTORRPHOLGSIC OBSERVATIONS): Not ppicasle isTomosproL051c oaseRvATIONS: AOREMAL GLANDS: End of Rocord- 13711 ypertrophy/vacustation, zona glomsraloss (minimal) = Page 1041 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTHOOF-SACMNPOERMROIATLTOMICOONLPE4R(1FOL8NU-EO0R2LO0IOTCTTEARNGPAETRE.GE(NPEFROA)TIOTNh)RATS SPONSOR'S STIOY NBER: T-6889.6 Individual ina] AGrpopsesndainxd1H11istonorpholosy Data Generation A sex: WrgER: W13716 DDoEsAeTHcThYoPwE:: SIavcri fice-Schedaled GROSS SERVATIONS): SEUEBALS No gross changes HISTORPHOLGSIC OBSERVATIONS): Not applicable HSToMRBrOLOGIC opsERvATIONS: AoRENAL Gunes: End of Record 13716 hypertrophy vacualation, zona glamsrulasa (minis) TTT ese Page 1042 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEU)DYTVOOF-GAEMNIPEORRMOAITTUOINCOOPNLER4(F1OL8NU-ER0RL2OI0OTCTTEARKGFAETRE GE(NAEPRFA)TIOINN) SATS SPONSOR'S STUOY WINGER: T-6099.6. Indivicun) Anima) sG7roGopesensnedraianstdi1Ho11nistomorphalasy Data SA ex: wre: W13717 oDoEsAeTHcToYwPE:. SIuvcrfice-Schedsled 8055 GRSERVATION(S): KIDHEYS: Right- pelvis, slight dilation HISTONRPHOLGSIC OBSERVATIONS): ahiynpaetraptliaosni,a.ppeelivviisc/papi lary epithelium, focal HISTORPHOLGSICOBSTRVATIONS: waowers: End of Record 13717 dPiytpaetraptiiaosnt,s.ppeeilvviisc/(paoipniieealr)yepithel im, focal (nile) 1s Page 1043 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEL)OYTOUFO-AGEmNPoERNROlATuTOnICOONLPE4(A1OP8WL-ER0I2LG0IETTTEARNGPAETR.GE(N7ER0A)TIO1N0)WATS SPONSOR'S STUOY WHGER: T-699.5 Individual neal sGFreooospmsarraaantdi1oW1n1istamorshology Data Asoxw:a wes: W13719 SsuEsNeTHcTaIoE:, Sa1vri ice-schuduted SHOSS OBSERVATIONS): SEMBAL o gross charges. HISTOMAPHOLOSIC OBSERVATIONS): Not appl scable THEEOLLOUINGTISSUR(S)VEREWITHINNon,LIMITS: AoRENAL cuwos of Record 197 " nse Page 1044 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTOWFO-AGWEINPOERNROIATUTOHICOONLPE4(R1OF8NL-EU0R2LO0IDTCTTEARVGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STUDY NMGER: T-6889.6 Individual Animal AGPrpSopesensnadriaaxntdi1oH1n1istamorphalogy Data sA ex: Wg: W13721 nDEoAsTeHcToYuPrE:, Sacrifice-Schedaled 8055OBSERVATIONS): GENERAL: Mo gross changes. HISTONRP101061C OBSERVATION(S): at. appl cable HISTOMRPHOLOGIC. OBSERVATIONS: APERpROiESoTAiAoLTmEiGsu:nes: einfreltarmorapthi.yon/,vaEccauhnoroloanntiticioun(i,ar11cz4oa)nan glfoomauruloasia n(ati)nins]) HEFOLLOUINGTISSUE(S) VEREWITHINNORMAL LINITS: CORUATING GUND prTuITARY SEMIAL VESICLES Testis End of Record 13721 rss Page 1045 ARGUS 418-020 REPROGDRIALCTI(OGNAVASGTEU)DYTOUFO-AGEMNPOERMROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(NAEPROA)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6809.6 Individual Anima) AGPFroeopesensnedraianxtdi1Ho11instomorphalosy Data MseAx:L weer: W13722 oDEsAeTHcToYvPEe.: Sucrfice-Schadslod R053 OBSERITIONS): SEAL ho gross changes. HISTOURPHOLOGICOBSERVATIONS): Nat applicable HISTONRPO\GGICOBSERVATIONS: PAERpORiSEToAAiLToEmGsL:ANDS: uaipintefairtTtacrtroiapotnhi,oynv,saclmuaoonnldoaneturic,otne,afro-czcooelnll(sg4l1af1om)cearlalo(smsini(mraold)arate) THE EOLLOMINGTISSUR(S)VEREWITHINhORMAL LINITS: CORSUATING GLAND Pinu soma vesteLes Testis End of Record 13722 1mi-se Page 1046 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DYTOVFO-AGWEINPOERNROIATUTOHICOONLPE4(R1OF8NL-EU0RL2OI0OTCTTEARNGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STUOY NABER: T-5299.6. Individual Anim) AGrpopGseesnndeiraxantdi1oH11nistomorphalosy Date sAexv:a wae: W13728 DoEoAsTeHoTwYP:E. Svacrifice-Schadsled 80SORSERATIONS): SEERAL: No gross changes. HISTOMEPHOLOGIC ORSERIATIONS): Not applicable HISTOOPH0.0GIC nstavaTIONS: AREAL GLANS: hvyapecrattrioophny,vaccourotleaxti(omni.nimzaoln)a glameruloss (soderate) `HEFOLLOUINGTISSUE(S)WCAGWITHINNORMAL LINITS: SCOHRTUAALTIVNEGSICGLLEASND eTvetstoinsoms PrTuITRY rRosTaTE Ed of Record 13725 es Page 1047 ARGUS 418-020 REPROODRULCTI(OGNAVASGTEU)DYTOHFO-ASEMNPIEROROMATITONICOOPNLER4(F1OLN8EU-R0RL2OI0OTCTETRAKGPAETREGE(NPEFROA)TIOTNh) RATS SPONSOR'S STUOY WINGER: T-6099.6. Individual Anima) AGrpopsesndainxd1H11istonorphalosy Data # Generation A sex: NER: W13729 DoEoAsTeHcToYuPrE:: Scheduled (Reduced Fertility) 80S GBSERVATION(S): KIDIEYS: Right- pelvis, shight dilation HISTORPIOLGSIC OBSERVATIONS): No microscopic change to correlate HISToMEPHOLOGIC OBSERVATIONS: Kaovers: No microscopic change to correlate THEEOLLOMINGTISSUE(S)VEREWITHINNORMALLINITS: SCOERNSNUAATIVNEGSICGLLEASND eTpetsosiomis wiovers rRosTaTE Ed of Record 13729 TTT i-se Page 1048 ARGUS 418-020 REPROODRIACLTI(OGNAVASGTEU)DYTHOFO-GAEMNPOERMROIATLTONICOONLPER(4OF1N3LE-U0O2RL0OIOTCTETRANGPAETREGE(NAEPROA)TIOTNh)RATS SPONSOR'S STIOY NBER: T-6889.6 Individual Anim) FAGrpeopasensnedriaaxntdi1o1Hn1istcmorphelosy Dota A 5 eR: W13731 oDoEsAeTHroTYvPeE:: vSarifico-Schdulod S055 QRSERUATIONS): SEUERAL Yo gross changes. HISTOMORPHILOGIC OBSERVATIONS): Not applicable HISTORRPIOLOGICOBSERVATIONS: APRROSETAATLE:Guns: hdiyinplfealrtatamrtaoitpoinho,yn,vgalcacunhcdrlaoatntaiirco,n(,foacza1o1lna(gslianmienrslu)lose (sf1d) THEFOLLOVINGTISSUE(S) VEREWITHINNORMALLIMITS: cSoTIspa cu ertotoms prrumRy SEHINAL VESICLES Edo ReordTTT ies Page 1049 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOUFO-AGMEINPOERMROIATLTOMICOOPNLE4R(1FO6LN-UE0O2RL0OIOTCTTEARNPGEART.EGE(NAEROA)TIO1Nh)RATSSPONSOR'S STUOY WINGER: T-6989.6 Individual nia) FAGroaopasansnadriaaxntdi1oW1n1istomorpholosy Data A sex: wre: W13732 DoEoAsTeHcToYuPrE:: Sacrifice-horibund 80S GRSERVATION(S): LTIUSERH: Aa)inaTtoebresal"palree,d.tan in color. HISTOORPIOUGGICOBSERVATIONS): nSeicrroopsniysd,egceennetrraitlioobnu,lamr utfoca, TESTIS HISTOMORPHOL0G1C BSERATIONS: uTevseti:s: End of Record 13732 Sniercoropantysd,egceennetrraitlioobnu,lamrul(tsiofdoecraalte)(marked) 11-60 Page 1050 ARGUS 418-020 REOERATL (ioGnAVSAGHEYTOVFD-AGEONTGSRHRATIIGONFE1(A8NP-EL1O5LR0IOTSTTERAN7A6T8EGE(N1ER0A)TIOIN)ATS srovsan'S Si WER -g085.6 Intivcia)duatAtnetaet FoeesrSoammnaidnHnhiestorid oa wkso wes: 13733 oSoEcTorI: Svcheduled (Rdicad arti) sss psn): CIDOB: Loft sui and acer Es; Right pews, stig tation. HISTORROLICCRSEITIONS): axSafreoalrtiaeotendE,sppAoemtsBstogntc calla, EPIOTOTHIS isIEOeservTion: rr avers: ext atad spematopentc cls (sinnal) Frraoptiiratrieo(n.aprelivdis)(sia) HEFOLLNINGTISSUES)VEREWITHINmL LIMITS: conuATivG Gto_ smosTaTe sou vesicles Tests End of Facor 979 EE a Page 1051 ARGUS 418-020 REPROORDAULCTI(OGNAIASGTEU)DYTVOOF-GAEWFNNERAIAIOTNIGONPES4(F1O6LNE-U0O2RL0OICTCTTEARNIPTEER.GE(NAEFRFAOT)IOINN) RATS SPONSOR'S STIOY NBER: T-6800.6 Individual Anima) AG#roGopesensnedarinadti1Ho11instororshalosy Data sAen:a eg: W13734 DooEsAeTHhoTYuPrE:. Sacrice-Scheduled 803QRSCRIATIONS): SEERA No gross changes. HISTOMRPHOLGSICOBSERVATIONS): Not applicable HISTOMRPHOLOSICOBSERVATIONS: PARORSETAATLE:GLAM: ivancfuloalmaattiioonn,,csourptpeuxra(tmiivnei,nalf)oce] (stnieal) HEFOLLOUINGTISSUE(S)VERE WITHINNORAAL LINITS: CTeOsUtiNsTING GUND evtooms PrrumRy Ed of Record 13734 Son vesicies ise Page 1052 ARGUS 418-020 REPROGDRIALCTI(OGNAVASGTEU)DYTOWFO-AGEMNPIEROROMATITOMICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(NAEPROA)TIOTNh)RATS SPONSOR'S STUY MBER: T-6809.6 Individus] Anima) GA#roGopesensnedraiantdi1Ho11nistomorphalaay Data sex:nL eR: W13735 oDEsAeTHrToYvPeE:: Sacrice-Schediled S058oBSERUATIONS): SEUEBALL No gross changes. HISTOORPHOLOGICOBSERUATION(S): tot apltcable HISTOORPHOL0G1C psERVATIONS: mosTATE: atropry, focal (m0) HEFOLLOUINGTISSUE(S)WEREWITHIN NORMAL LINITS: ASPmHToAL oVEuSaIwCsLES TCOEoSBTUSATING GLAND eptoroms prrumay Ed of Record 135 TTT ss Page 1053 ARGUS 418-020 REPRGOORIACLTI(OGNAVASGUES)YTWOOF-GAENMREROUATTNIOCNFE4R(1OP6NLE-O0O2LR0IOTCTLEARNGPNETREGE(NAERPA)TIOINn) RATS S70uSRS STUDY NAGER: T-5880.6 Individual Anima sGForapoaesmnsadriaaxxtdi1oM1n1atomorshology Data asatL wees: W133 sDuEsAeTHcTaYoPE:: vSoorifice-Schaduled SAOSS OBSERVATIONS): SEMEBAL No gross changes. HISTONORPHOLOGIC OBSERVATIONS): tot applicable HISTOAPIOLOGIC OpseRATION: PARROESTAALTEGuns: hTmoemrmtartoiphoyn/,uscchiroolnaiicon(.eiznoinmes}glomerloss (sederate) HEFOLLOMING TISSUE(S)WERE WITHINNORMAL LIMITS: Tcesotius nt swe evinioms Prue soa vestctes mes Page 1054 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTWOOF-GAERNPGERNAOIATLTOIMCOONLPER4(F1O6UNE-U0O2RL0OICTCTETRANI7TEER.GE(NAEPRFAOT)IOINn) RATS SPoNsoR'S STIOY NMG: 1-6889.6 Individual Aiea) AGFrepoapsnseenraadntdi1oH1n1istonorpholosy Data MsexA:L NBER: 13741 DOESAETHcThYoPrE:: Scheduled (Reduced Ferti1ity) S058OBSERUATIONS): EESPITmDEISO:WpIOEBiSl:aterBaillatseorfatlandsoft and flaccid. flaccid. HISTOMOBPHOLOG1C.OBSERVATIONS): SatRrotpsahptyai/rodneinasr,epnereErPataIteOitIpoOonIns,HsiLemScsulctTaifEnocT.alc. olonTESI s HISTOMORPHOL0G1CopseRvATIONS: eptotoms: Tesnis: exGhtiytpoaoltsaplteairtonenid,aspr(eemtraemraktetode)gsetnitsc cells (moderate) strophy/deseneration, multifocal (moderate) HEFOLLOUING TISSUES)VERE WITHINNORMALLINITS: CORSUATING GLAND FrosTATE soma vesicues End of Racord- 13741 or Tr ies Page 1055 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTUOOF-SAOMNKPEROROMATITOUICNOONLPER4(F1O8LNE-L0R2RL0OIOTCTETRAKGPAETREGE(NAEPRFA)TIOTNh) MATS SPONSOR'S STIOY NBER: T-6669.6 Individual Anime) sGProoopeaemsnrdaainetdi1oH1n1istamrpholosy ota A sex: ER: W13742 oDEsAeTHcToYvPeE:: Sacrifice-Schedsled S058opsERUATIONSS): SEERA Yo gross changes. HISTOMRPHOLOSIC OBSERVATIONS): ot appicable HISTORPHOLOGICOBSERVATIONS: AOREMAL GLANDS: hvyapceurotlraotpihony,uaccourstteaxti(omni,nizmoan)a glomerulosa (ai1d) HEFOLLOUING TISSUES) VERE WITHIN NORMAL LIMITS: SCOERHSIUAALTIVNEGSIGCLLAENSD Teepsinosioms prrurmaRy rosa Ed of Record 13782 nts Page 1056 ARGUS 418-020 REPROGDRAILCTI(OGNAVASGTEU)DYTOWFO-AGMEINROEOMRTIAUToNIcOoNPE4R(1OF8NL-EU0OL2RI0OTOTCETRAVPGEARTEGE(NAEPROA)TIOTNN)WATS SPONSOR'S STUOY WAGER: 1-699. Indivicus] Anima] GA#roGopesensnedraiantdi1oH1n1istomorpholosy Data Asax:L BER: W13743 oDoEsAeTHcToYvPeE:: Sacrice-Schedsled R053 QRSCRIATIONS): SENERALS No gross changes. HISTOMORPHOLOGIC ORSCRUATIONS): Not applicable HISTOMORPHOLOG1C SERVATIONS: PRAORSETAATLE:GuANDS: rPamratrtoipohyn/svaccuhorloamteionG, izonnaiglomeruloss (moderate) TH EOLLOMINGTISSUE(S)VEREVITHIN NORMALLIMITS: TCOeRsStUsLATING GLAND eproomis prrurmay EdofRecord Aas Sena vesicles 1s Page 1057 ARGUS 418-020 REPROODBULCTI(OGNAVASGTEU)DYTHOOF-GAEMNROENROIALTTINOCNPEA4(F1O6LNE-U0O2RL0OICTCTETRANGPAETREGE(NAEFRFAO)TIOINh) RATS SPONSOR'S STUOY NIGER: T-6809.6 Indivicus] Anima) sG?roGopesensnedraianxtdi1oH1n1istomorphalgy Data sAex:A WER: W13708 DoBoAsTeHgrToYvPeE:. vSacrifice-Schedsled 8055 GRSCRUATION(S): GENERALS No gross changes. HISTOMEPHOLOGIC.OBSERVATIONS): Not applicable HEFOLLOWINGTISSUE(S)WERE WITHIN ORUALLIMITS: PARORSETAATEGLANS ScoEnNsIuAALTIVNEGSICGLLEASND Teepsttoiisomas 0d of Recora- 13744 EE Frum TT---- nies Page 1058 ARGUS 418-020 REPRBOAOILTI(OGNAVASGTEI)OYTIOFO-AGEMIPOERNROIATLTONICOONLPE4(R1PO8LF-U0O2LR0IOTLTTEARKGPNETREGE(NPE7R0A)TIOINh)SATS sronsor'S STIoY WBGER: T-6089.6 Individual nea) AGFpripomesmnsadraianxtdi1oH1n1istomorshology Data SAaNIMAL BER: W13750 oDoEseNoTeE:, vScheduled (Reduced Fart) 055cosTRIATIONS): ESTES: tart tarse. HISTOMRPHOLOSICOBSERVATIONCS): No microscopic change to correlate, TESTIS HsTogsHOL0CoaseRvATION: srTaesstTiAsT:E: aNtorompihcyr,oscfoocpailc c(haainngeealt)o correlate HEFOLLOUINGTISSUE(S)VEREWITHINNORMALLIMITS: COUNTING GLO eriotomis soma vests Testis End of Record 13750 es Page 1059 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMXKPEORRVOAITTUOINCOONPLE4R(1OFN8LE-L0RL2RI0OTCTTEARKGPAETREGE(NAEPRFAOT)IOINN) TATS SPONSOR'S STUOY WNGER: 1-689. Individus] Anima) AG?roGopesensnedraiantdi1oH1n1istomorpholosy Data sAex:L or: 1F3602 oDEsAeTHcToYoPrE:. S1ucrFice-Schaduled 805s QRSERUATION(S): SEERA: No gross changes. HISTOMAPHOLOG1C.OBSERVATIONS): Not applcasle HISToMORPrOLOGICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTER: pUrreRuuns:e: we: pSrreaesstee)nncc.ee oopffarcgsorroIpvnoitrneagr/umatenetdrsa follicles BmGiacscitreofnpathiitogtnee.s,nTpo(immgadmneern(atatetedi)d)(sderate) THEFOLLOUINGTISSUE(S)VEREVITHIN NORMALLIMITS: AOREMAL GLANDS cervix onaies End of Record 13602 overs) 1mm Page 1060 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SAEM"NFOERMRoIAtITcIMcOoNlPER4(F1O8LNE-U0O2RL0OICTCTETRANIPAETREGE(NPEFROA)TIOTNh) RATS SPONSORS STIOY NBER: T-6880.6 Individual Anim GAorpGoeesnnsdeiraxantdi1oH11nistomorpholosy Dota DseAx:L MBER: 1;3804 nDoEsAeTHcaToYuPrE:. S1ucrFice-Haribund BOSS OBSERUATION(S): HEAD: Broken palate. HISTONRPHOLGGIC BSERVATION(S): pfernaocrtruhrea,ge,PAPUATLEATE HISTORRPHOUGGICOBSERVATIONS: PALATE: End of Record 13604 fhreamcotrurrheage (sarked) mn Page 1061 ARGUS 418-020 REPROGBRAILCTI(OGNAVASGTEL)OYTGUFO-AGE"NPVERROATITOICOONLPE4R(1OP8NL-EU0O2RL0OICTCTETRANOPAETREGE(NNEOR)ATIIOhNAATS = SPONSOR'S STUOY NUMBER: T-6809.6 Indivicusl+ Aniemaan) EG#reoRamnseSraantdiHoinstomorpholosyhd Data Asex:L eER: F13808 oDEsAeTHcaToYuPrE:. S1acrice-Scheduled ROSS OBSERVATION(S): SEMEBALS No gross changes. HISTONORPHOLGGIC BSERVATION(S): Not applicable HISTONORP/0L0GICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA: resus: Epparrceerssoeepnnhccaeepeoosff,cgroporiwpgiamnregan/taeTnduttre(anmldefroaltlei)cles HEFOLLOUING TISSUE(S) VERE WITHIN omuaL LIMITS: APITmUIeTARYcuavos ceVrivsiix owes End of Record 13808 ones) mn Page 1062 ARGUS 418-020 REPROODRULCTI(OGNAVSAGTEU)DY THOOF-SAEWNPOERMROIATLTOMICOONLPE1R(F6OLN-UE0O2RLO0ICTCTTEARNIPAETRE.GE(NPEFROA)TIOTNh) RATS SPONSOR'S STUY NBER: T-6800.6 Idtevicduhaall AnaAnimat) S#oGreoeaosnsearrnadtiionstoMmstoamrrpshhotostyosy atta sAona ees: 1V3611 DooEsAeTHsThYoPvEe.: S1cheduled (Reduced Ferti11ty) S055 BSERUATION(S): SEERA: No gross changes. HISTOORPHOLCSIC OBSERVATIONS): Not pple HISTOMRPHOLOGICOBSERUATIONS: OVARIAN FOLLICLESCORPORA LUTER: oVwiceisa:: PpSrraeetssaeenn)cc:ee oonfftfgcoroooruvpaiornriaaa/nalnuttreaal follicles mci ieation (at16) THEFOLLOUINGTISSUE(S)WEREVITHIN MORAL LINITS: cervix overs) ures End of Record 13811 " m7 : Page 1063 ARGUS 418-020 REPROORDACLTI(OGNAVASGTEU)DYTUOOF-AGEONPMERIROATLTONICOONLPE4R(O1FNL-EU0O2RL0OIOTCTETRANPGEARTEGE(NPE7R0A)TIOTNY)RATS SPONSOR'S STUOY NUMBER: T-6809.6 Individus) Anima) AG#rpeopasensnedraianxtdi1Ho11instonorphalosy Data sAex:C NER: F13812 oDEsAeTHcToYvEe:: S1acrice-Schedaled GROSSOBSERVATIONS): SEERA: No gross changes. HISTORIOUGICOBSTRATIONSS): Not applicable HISTONRPHOLOSIC OBSERVATIONS: OVARIANFOLLICLES CORPORA LUTEA wreRss: PpBurrceerssoeegnnhccaeegeoosff,cgroporiwpgiomnregan/taelnduttre(aamlodefroaltlei)cles HEFOLLOMING TISSUE(S)WERE WITHINNORMAL LIMITS: RARaEiA GLAS cervix owaies prrurmaRy LISSUE(S)MOTAVALUABLC FOREVALUATION: onoweris) 3 of Record 13012 1s Page 1064 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DY TOVFO-AGMEINPOERMROIATUTONICOOPNLE4R(1FO8LN-UE0OL2RI0OTOTCETRANPGEARTEGE(NFEROA)TIOINh) RATS SPONSOR'S STUOY NNGER: T-6009.6. Individual Anima AGFraoompamesenrdasintdi1oi1n1stmorphotosy Dota so AL sR: 1F3814 oDoEsAeTHhoTYuPrE:. Sa1 crice-Scheduled S058 oBSERUATIONS): SRLS): Swen, right HISTOMRPHOLOSIC OBSERVATIONS): chondropathy, auricular HISTORRPHOL001C opstavATION: 0s): chondropathy, auricular (soderate) 1s Page 1065 ARGUS 418-020 REPROODRIACLTI(OGNAVASGTEU)DYTWOOF-GAEMNPOERMROIATLTOWICOONLPER(4OF1N8LE-U0O2RL0OIOTCTETRANG7A6T%EGO(NPGFAOA)TIOTNh)RATS SPONSOR'S STO NBER: T-6000.6. Individual ra) oGFreopasmseeranantdi1o1Hn1istomorphalosy Date A six: wer: 1F3815 DoEuAsTeHrToYwPE:: S1acrifice-Schedsled S055 psERvATIONS): SERA: Yo gross changes HISTORPHOLGSIC OBSERVATIONS): Not ppcasle HsToRPIOL001CopsEavaTIOn: OVARIAN FOLLIGLES/CORPORA LUTER: wreaus: Ppparrceerssoeepnnhccaeegeoosff, cgrpooirvgpimonergna/taeTnduttre(aamldefroaltlei)cles `THEEOLLOUINGTISSUR(S)VERE THINNORMAL LIMITS: APIRTEUIATLARGYLANDS cVeiasviex onates End of Record 13015 overs) or 11-76 Page 1066 ARGUS 418-020 REPRGORDAILCTI(OGNAVASGTEU)DYTWOOF-GAEONPMERRIOATLTONICOONLPEA(4F1O6LR-U0O2RL0OICTCTETRAVGPAETREGE(NPE7R0A)TIOTNh)RATS SPONSORS STIOY NUMBER: T-6889.6 Individual nina sGroopseendained1H11istomorshology Data # Ganeration sA ex: Wg: v13816 DoEsAtTHcaTYoPuEr:: S1acri fce-Schedaled S058opsERUATIONSS): SEERA Yo gross changes. HISTORPHOLOSICOBSERVATION(S): ot applicable HISTORPHOLOGICOBSERVATIONS: AOVRAERIAALN GFLOALNLDISC:LES/CORPORA LUTEA: wrens: dpperrgeeessneeennrccaeetioooffn,Cgroorcwpysiotnrigac/,alnuttcreoaar)tefol(lsiicnliesasl) Pacropeges. pigmented (minimal) HEFOLLOUING TISSUES) VERE WITHIN NORMAL LIMITS: ceVaAvSiAx omaies overs) End of Rocord- 13816 Frum en Page 1067 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-ASMEiKIOEVRIAcUTNIOPNaEA(FOLN)UERRLOIOTCETRANGPAETRE GE(NrERrA)TIO[Nh) RATS SPONSOR'S STIOY NBER: T-6860.6 Individual Anima) AGrpGopesensnedraianxtdi1Ho11instomorphalosy Data A sex: wer: F13821 nDEoAsTeHcaToPuEr.: S1ucrfice-Schadslad 80S GRSCRUATIONS): SEUERAL: No gross changes. HISTOMRPHOLOGIC OBSERVATIONS): Not applicable HISTONRPHOLOGICOBsERvATIONS: AOVRAERIAALN GFLOALNLDISC:LES/oRPORA LUTER: oirweeRuss:: Tporpeesretnrcoephoyf/scaocrupoolraatiTount,sazona glamerulosa (sinisal) iPSrraeotsigeehn)ac.geeoisfn,trgorpooivdgaimnregin/otanendtr(aal116f)ollicles HEFOLLOWING TISSUES) WERE WITHIN NORMAL LINITS: cervix ovivier(s) PrrurTRY Astin Ed of Record 13821 - 1 Page 1068 ARGUS 418-020 REPCORALO(DSAVASGTEU)DYTOHFO-OGEMNREOERATNTOIO!NPE4(R1OP8VL-0O2LN0ISTETTERMGPAETREGO(NAGR)ATI1N8)RATS srousonS STUDY WAGER: T-3889.6 dividual Anes) sEregoeeserpaantdt1oW1n1stamorphalony sta asox:L wren: 1i3622 oSEsTeHcoTvIeE:, Sa1 rifce-Norttund GR0SSOBSERVATION(S): SENERAL No gross changes HISTOMORPHOLOS1C OBSERVATIONS: OUARIANFOLLICLES CoRPORn LUTER wreas: 'HISTOMORPHOLOGICOBSERVATIONS): ot apicable EpDrerecesrseoenpncmeegeoosff. cGoprriopgwomirenangt/eloduntre(aarldefroaltlei)cles `THEFOLLOWINGTISSUE(S) WEREWITHIN NORMALLIMITS: Ai E cLaos cTohmeitxa omsies of Record. 13022 overs) me Page 1069 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNIPEORRVOAITTUOINCOOPNLE4R(1FO8NU-EU0RL2OI0OTCTTEARIGPAETREGE(NPEFROA)TIOINN) RATS SPONSOR'S STUDY NNGER: T-6099.6. Individual Anima sGFrapoaesnsnedrassntdi1oi1n1stomorpholosy Dota SAxL eR: F13824 DooEsAeTHroTYvPeE:: __ 1Sacr ice-Sheduled S055 ASERUATION(S): SEUEBAL: No gross changes. HISTORRPHOLGSIC OBSERVATIONS): Not ppcable HsTomspioL061C OBSERVATIONS: CURRIAN FOLLICLESCORFORA LITER: ures: ppmrraeecssreeonnpccheeagooeff, cgorproipwgoimrneagn/tauendtter(saslodefroaltlei)cles THE FOLLOMINGTISSUE(S)VEREWITHINNORMALLINITS: APIRTEUIATLARGYLANDS ceVAnGiINxA omares overs) 11-80 Page 1070 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEI)OYTWOFO-mGEONRNEIROALTTnIOCNPE4(R1OP6VL-0R2LO0ICTTTAERNGPAETR.GO(NGAAA)TIO1N8)WATS SP0uSORS STUDY WAGER: T-6889.6 Individual nies] sGrooopesemsnedraianxtdi1oH11nistamorshology Data Asox:a wren: i13625 DoEsAeTHGaToYuPrE:: S1ocrifice-Schadulad SA0SS OosERUTIONS): EBS): Swollen, both HISTOMORPHOLOGICOBSERIATIONS): chondropathy, auricular sTougeroL0a1coasravaTins: aCUR)RI.RN FOLLICLESCORPORA LUTER: wrens: Bcprrreaesnserenoncpeeatoohffy.Gcorraepuvoririnacgu/lTaaunrteean(leurfkaeldl)cles macrophages, pgmented (sodeate) THEFOLLGUINGTISSUE(S)WERE WITHINNORWAL LINITS: PAmeTn,YGuns icotnan omates 84 of Rocare- 13025 oT overs) " TTT a Page 1071 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)OYTWOOF-GAEWNPOGRVROIATUTOINCOONPLER4(F1OL6NEL-R0RL2OI0DTCTETRAKGPAETREGE(NAEPRFAO)TIOTNh) AATS SPONSOR'S STUDY NBER: 1-6889.6 Individusl Anima] sG#roGopasensnedreianstdi1oH1n1istomorpholosy Data a sex: wees: 1F3028 oDEsAeTHcToYvPeE:: S1 acriice-Schedaled R055 GRSERVATION(S): SEERA Mo gross changes. HISTONRPHOLGGIC BSCRVATION(S): Not applable isTomsproL0GIe opscRuATIONS: OVARIAN FOLLICLES/CORPORA LITER: omraeraless: Spprraeetssieeennccbeeuroosffalceog)rrpouoirnsg/uanttersa) follicles macrophages, pigmented (sininal) IEOLLOMINGTISSUE(S)VEREWITHIN NORMALLIMITS: ARE suas cervix onowr(s) prrumRy LAISSUEA(S)MLOT UAFB OREVL ALATE ION: wei End of Record 13625 mee Page 1072 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEL)OYTGVFO-AGEMNPERIROATNTOICOONLPE4(A1OF8NL-EU0OL2RI0OTOTCETRNOPNETREGE(NPEFROA)TIOTNh)ATS SPONSOR'S STUDY MUMBER: T-6809.6 Individual Mma) AGFprepoaesnnsedraianxtdi1o1Hn1istonorphelosy Data AfyL nseR: 1F3836 oDoEsAeTHhoTYwPeE:. S11acrfce-Horibund GROSS OBSERVATIONS): DfXrRoOnUtTpIoEvS:: Swollen Misbs, left front leg, left HISTOMEPHOLOGIC OBSERVATIONS): fracture HISTONRPHOLOGICOBSERVATIONS: exons: fracture End of Record 1389 mies Page 1073 ARGUS 418-020 REPROGDRAULCTI(OGNAVASGTEU)DYTUOOF-AGMEINPOERNROIATLTOWICOONLPE1R(O6FNL-EU0O2RL0OIOTCTETRAVPGEHRTEGE(NPE7R0A)TIO1Nh)TATS SPONSOR'S STUOY WAGER: T-6289.6 Individual Anima] AGrpopsesndainxd1H11istonorphalosy Data # Generation sAeNxI:MAL WER: F13840 DoEsAeTHGToIwPE:. S1c1heduled (Reduced Fertility) 8085GBSRVATION(S): SEAEBAL: No gross changes. HISTONRPHOLGGICOBSERVATIONS): Not applicable HISTOORPI0\GGICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA: pPrreesseennccee ooff cgroorwpionraa/alnuttreaal follicles THEFOLLOMINGTISSUE(S)VERE WITHINNORMALLIMITS: ceVavGilixn ousaies overs) resus End of Record 13640 Crm ms Page 1074 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTUOOF-SAEMNPOERVROIATLTOIMCOONLPER4(F1O6LNE-U0O2RL0OICTCTETRANGPAETREGE(NPEFROA)TIOTNh) RATS SPONSOR'S STIOY MAGE: 1-6889.6 Individual Anim) sGFroeepasensnedrtaaentdi1o1Hn1istonorphlogy Date A Sex: wneR: 1V3851 oDoEsAeTHoTwYePE:. S1c1heduled (Reduced Fertility) S058 QRSERATIONS): SEMERAL No gross changes. HISTONRPHDLOSICOBSERVATION(S): hot applicable HISTORPHOLOGIC OBSERVATIONS: OVARIAN FOLLICLESCORPORA LUTER: wrens: pEfrFseetsseeennntccieeonoo,ffScuomreporgrrToanvianlrg/ukatenecdra)a) follicles THE EOLLOHINGTISSUE(S)VEREWITHINNORMALLIMITS: cevix onaies ovis) GINA Ed of Record 13851 ies Page 1075 ARGUS 418-020 REFROGRDALLETI(OGNAVASGTEL)OYTOVFO-ASEMNPOERNROATITOYICOOPNLE4R(1FO8NL-EU0OL2RI0OTOTCETRANPOENRTGE(NAEPRFA)TIOINh) ATS SPONSOR'S STUY MBER: T-6080.6 Individual Anima FAGrpeopasensnedriaaxntdi1o1Hin1stomorsholosy Data sA ex: Wr: F13856 oDEoAsTeHcTaYoPE:. Sa11crifice-Schadaled 80S GRSCRUATIONSS); RE): Swtten, right HISTOMEPHOLOGIC OBSCRUATIONS): chondropathy. auricular HISTOMORBHOLOGICCaSFRVATIONS: eas) End of Rocord- 13655 chondropathy, auricular (marked) mies Page 1076 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTWOFO-AGEMNPOERMROIATLTONICOONLPE4A(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STUOY NUMBER: T-6889.6 Indivicun) Anima) GAProGopasensnedraiantdi1Ho11instonorpholosy Data sAex:L Noe: F13852 oDEsAeTHcToYePE:: S1c11heduled (Reduced Ferti1ity) R055OBSCRIATION(S): RS): Swollen, both. HISTOMEPHOLOGIC.ORSERIATIONS): chondropathy. auricular HISTORPHOLOGICOBSERVATIONS: eaOVsA)RI.ANFOLLICLESCORPORA LUTER: ppcrrheeassneednnrccoeepaootffy,ogrroawueirnisgc/uallnautrtreaa(lrafkoeldl)icles TEFOLLONINGTISSUE(S) ARE ITH og LibTS: choanvae omares onus) End of Record nsmz ures TIT ter Page 1077 ARGUS 418-020 REFROORDAILCTI(OGNAVASGTEU)DYTVOOF-GAEMNKPEORRVOAITTUOINCOONFLER4(F1OLN8EL-R0RL2OI0OTCTETRANGPAETREGE(NAEPRFAOT)IOINN) RATS SPONSOR'S STUDY MIMBER: T-6899.6. Indivicus) Anima) sGroopsesndainxd1H11istonorphalosy Data PF eaneration sAx:A WER: F1386 oDuEsAtTHsrToYuPrE:, S11a1cr ice-Scheduled A055 OBSERVATIONS): BES: Traumatized corn. HISTORRPHOLOGICOBSERVATIONS):| ckaetraartaitcits, chronic. HISTORPHOLOGICOBSERVATIONS: eres: Karty, cont (strate) BdofRecords TBR mmm res Page 1078 ARGUS 418-020 REPROODRILCTI(OGNAVSAGTEU)DYTVOOF-SAEMXPIEROROHATITONICOOPNLER4(F1OLN8EU-R0RL2OI0OTCTETRAKGPAETRE GE(NAEPRF0A)TIOTNN) SATS SPONSOR'S STUDY WAGER: T-6899.6. MseAx:L weER: 1F3885 Indvividuamall G#GrGoesrnsaearnnadntdiHoinssMitarsholoyhd osa oDEsAeTHcToYwE:, S11a1crfice-Schedaled 8053 ORSCRATIONS): KIDIEYS Left- pelvis, marked dilation. LLSSUS(S)MOTAVALLABLCFOREVALATION: xiovers HISTONRPHOLGGICOBSCRVATION(S): Tissue not available ties Page 1079 ARGUS 418-020 REPROODRIALCTI(OSNAVASGTEU)DYTOWFO-AGEMNFOERVRoIATUToNICOoPNLER4(FO1LV-UE0R2RL0OIDTCTTEARKGPAETREGE(NPEFROA)TIOINN) TATS SPONSOR'S STUY NBER: T-6899.6. Individual Anima) AGFrpaopasemsnedraianxtdi1oH1n1istonorphalosy Dota Se nL eR: 1F3898 oDuEsAeTHrToYPwE:: __ 1Svucr ce-Scheculed 8053 ORSCRIATIONS): RS): Swollen, riche. HISTONORPHOLOGICOBSERVATIONS): chondropathy, auricular HISToMRPHOLOGICOBSERVATIONS: 0s): Ed of Record 13698 chondropathy. auricular (marked) 11-50 Page 1080 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTWOOF-SAEGNPHERROIATLTONICOONLPER4(R1O6LNE-U0O2RL0OICTCTETRANAPTEER.GE(NPEFROA)TIOINh) RATS SPONSORS STIOY NUMBER: T-6889.6 Individual Anima) aGFprepoaesnnsedraianxtdi1oW1nistomorphalosy Data Asx:L WER: 1;3900 oDoEsAeTHrToYwPE:. 1Svcheduled (Reduced Fert11ty) GROSS OBSERVATIONS): GENERALS Mo gross changes. HISTONORPHOLOGIC.OBSERVATIONS): Not applicable LALSSUVE(S)ANOTLLAFORBEVALLIATE ION: VQcAeUnARvRIiIAxENS FOLLICLES/CORFORA LUTE OuhrVeaIsNE) Ed of Record. 13900 ran Page 1081 ARGUS 418-020 REPROGDRUACLTI(CGHAVASGTEU)DYTOHFD-AGMEONPERMROIATLTOMICOONLPE4R(1FOL6NU-EO0R2LO0IOTCTTEARNGPAETRE.GE(NAEPROA)TIOINh)RATS SPONSOR'S STUOY NUMBER: T-6099.0 Individual Anima) sGFreiepasensraaratanetdi1oH1n1istcmorpha.tosy Dota Asex:a WER: F13901 oDEsAeTIoTwYeP:E: S1avcrifice-Schadaled LAG): Swollen, rion HISTOMORPHOLOSICOBSERATIONS: eas): End of Racord- 13001 chond apathy, auricular chondropathy. auricular (soderate) ns Page 1082 ARGUS 418-020 REPROORNACLTI(OGNAVASGTEU)DYTHOOF-GAEMNPOERVROIATLTOWICOONLPE1R(O6FNL-EU0O2RL0OICTCTETRAVIPAETREGE(NPEFROA)TIOTNh)RATS SPONSORS STUOY NUMBER: T-6889.6 Individual a) AGPFrpopeseasnndeairnxadti1o1H1nistcmorphelogy Data ASexL WNER: 1F3908 cDoEsAeTHGrToYuPpE:: __ 1Svacr ice-Schculed S053opsERUATIONSS): RLS): Swollen, right HISTORPHOLOSIC OBSERVATIONS): chondropathy, auricular HISTOORIO\GICOBSERVATIONS: 0s): Ed of Recora- 19908 chondropathy, auricular (a11d) 1 Page 1083 ARGUS 418-020 (sve) rScxciTion (ove LITTER, 78 GOEATIOn SroNSoR'S "PRSOTTUOOCYOLW4M1G6E-R0:206989.6 Individial Anes) aGFrpaopasensnedraianxtdi1oH1n1istamorsholosy Data SAoNtIMAL Wag: F13521 oDEsAeTHoTeYP:E: vSacr rce-Schadsled S055 OBSERVATIONS): SENERAL No gross changes. HISTOMORPHOLCEICOBSERVATIONS): Not applicable sToRmOL00CoastavATIONS: CUARIAN FOLLICLES/CORRORA LUTER: wees PPperrceersseeepnnbccaeegeoosff. cgorproipvgoimrneagn/taTenudttre(anslodfroaltlei)cles HEFOLLONINGTISSUES)VERE WITHINbolLIMITS: APHRTOTOARYunos cioaninn ous overs) rs Page 1084 ARGUS 418-020 REPROORDAULCTI(OGNAVSTEU)DY TOIFO-BGEGRINGOIRLATTNICOFE4R(1FO6LK-L0O2LR0IOTGTCETROOPNERT.EGO(NPEFROA)TIOINh) ATS SPONSOR'S STUDY MAGE: 1-6889.5 Indivichal Anfeal GsProeopseesnnriaaxntdi1oM1nistamorsholosy Data A55wa wees: 1i3522 sDEeATHgToYrPE:. Svacrice-Schedsled S055QRSERATIONS): SEMEL Yo gross changes. HISTOMAPHOLCSICOBSERATIONSS): tot apvcable HISTOMORPROLCEIC OpsERVATIONS: CUARIANFOLLICLES CORPORA LUTER: wrens: f pBrreesseenncee ooffe cgorropvotrnag/Tauttrea anl f]olcles HEFOLLOUINGTISSUE(S)VERE WITHINMORWALLINITS: PsioTUsToiRYcus VcenAinGx onaies End of Record 13922 aviocr(s) 119s Page 1085 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-AGEWNPOERVROIATUTONICOONLPE4R(1FO8NL-EU0OL2GI0OOTCTTEARKGPAETREGE(NPEFROA)TIOTNN) SATS SPONSOR'S STUOY NUMBER: 1-689. Individual Anim) AGprpoesnsdainxd11Hi1stomorshology Data Feaneration sex:AL eR: F13927 BooEsNeTHhoTYuPrE:: Sorifice-Scheduled 8053 QRSCRIATIONS): Rs): Swollen, right HISTONRPIOUGICOBSTRATION(S): choncropathy, auricular HISTONIO\GGICOBSERVATIONS: eas): End of Record 13627 chondropathy, auricular (marked) mess Page 1086 ARGUS 418-020 REPROODRIACLTI(OGNAVASGTEU)DYTUOOF-AGMEINPOERNROIATLTOWICOONLPE1R(O8FNL-EU0O2RL0OIOTCTETRAVGPAETREGE(NPE7R0A)TIOTNh)TTS SPONSOR'S STUOY MINBER: T-6099.6. Indivvicuat Antomanl) SFre0e3eseraaanndtdioBHnhistamrobotoaylay DatDat Asex:a wees: F13928 DooEsAeTHcrTYoPwE:: Svacrice-Schadulod R058 QRSERUATIONS): SEMERAL: No gross changes. HISTOMRPHOLOSIC OBSERVATIONS): Not applicable HISTONRPH0\0GICOBSERVATIONS: OVARIANFOLLICLES CORPORA LUTER: wreaus: Bpparrceerssoeepnnhccaeepeoosff,cgroporiwpgiomnregan/taeTnductre(asnli1df)ollicles distention, lone (mi1d) HE FOLLOUINGTISSUES)VEREWITHIN NolLINTS: ARENA GLAMIS oumaies onor(s) prrurTARY `LAISSVI(S)AMOTILAFORBEVALLUATEION: cVAeGvINxA End of Record 13620 sr Page 1087 ARGUS 418-020 REFROGROALLETI(oGnAVASG1E0)0TOVFO-AGONOOERTANTOIOLNPEA4(F1OLN6EI-O0RL2OI0OTCTETRANOPAETRE GE(NPEFROA)TIOINh) ATS srous0R'S STUOY WAGER: 1-68.65 ndivivciudlalAnalAnou! SSFheoaoema1re3aadtiMoMantactmmrsohroslahaoyloy OnData ASoi:L WBER: 1v3928 oDEsAeTHsTnYoPwE:: vScheduled (Raduced Fartiity) sa0ss pscmmTIONS): SEHEBAL: No gross changes. HISTORRPHOL001C OBSCRIATIONS): Not applicable HISIOMORPHOLCSICOBSERVATIONS: OVARIAN FOLLIGLES/GORPORA LUTER: ouTaeiaess: Eapbrrsesestneecn)ec;eofoifnctosfrraopowoviranarai/alanuntteraal follicles Gistention, Toman (moderate) HEFOLLOMINGTISSUE(S)VEREWITHIN NORMALLIMITS: cervix ovnoucr(s) Gin nd of facord- 13920 11-08 Page 1088 ARGUS 418-020 REFROODBILCTI(OGNAVSAGTEU)DYTHOOF-GREe"IKFEORANoAITTUoICKOoNLPE4R(1OF6NLE-U0D2LR0IOTCTTEARIGPAETREGE(NAEPRFAOT)IOTNN) SATS SPONSORS STIOY NBER: 6869.6 Individual Mma) FAGrpeopasensnedriaaxntdi1o1Hn1istonorphelogy Data sAex:C Wren: F13933 oDoEsAeTHcTaYoPE:: Sacriflce-Schedaled 80S QRSCRVATION(S): SENERALS Mo gross changes. HISTONRPHOLGGICOBSERWATION(S): Not applicable HISTOMORPHOLOGIC BSERATIONS: AOVRAERIAALN GFOLLALSIC:LES/cORPORA LUTER: ures dBPerrgaeessneeennrccaeetioooffn,cgroocrvypisentraia/ca,unticeroasrltexfol(lniicnliemsa) aScharnodp(rsa)g,ese,ndopmiegtmreinatle,d c(ymsit1idc) HEFOLLOUINGTISSUE(S) VEREWITHINNORMAL LINITS: ceVrivciixa owaies ovioer(s) End of Record- 13033 TT prruimaRy 11s Page 1089 ARGUS 418-020 REFROGROALLCTI(OGNAVASGTEL)OYTVOOF-SAEONPVERRIOATUTOYICOONPLER4(P1OLN8EU-O0RL2OI0OTCTTEARNOPAETREGE(N7ER0A)TIOIN) ATS SPONSOR'S STUOY NABER: T-6899.6. Individual Anima) AG#rpGopseesnnedarinaxdti1Ho11instonorpbolosy Data fAy WAGER: F139% wDBoTe: 1Sacri fle-Scheduled S058 OSERATIONS): SEMRAL: Yo gross changes. HISTORPHOLGSIC OBSERVATIONS): at applicable HISTORRPIO\GIC OBSERVATIONS: OVARIANFOLLICLES CORPORA LUTEA: wreaus: rpBrroeepssreennoccgeeeoosff,cgroporrwpaiamnreaan/taelnduttre(aamladefroaltlei)cles HEFOLLOWING TISSUES) VERE WITHINNORMALLIWITS: APHRTEUATLRYGLANS ceAavaix onaies End of Record 13654 onus) 1-100 Page 1090 ARGUS 418-020 REPRGORDAULCTI(OGNAVASGTEU)DYTHOOF-GAEMNPOERMROIATLTONICOONLPEA(4OF1N6LE-U0O2RL0OICTCTETRANGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STIOY NBER: T-6809.6 Individual Animal AGrpopsesndainxd1H11istonorpholosy Data # Generation A Sex: eR: F13935 DEATHtToVRe. S1acriFice-Schadaled 8058 RATIONS): SEUEBAL: No gross changes HISTOORPIOUGICOBSCRATIONSS): Not applicable HISTOMRPHOLOSIC oRSERUATIONS: OVARIANFOLLICLESCORPORA LUTER: remus: appcrrreessoeepnnhccaeegeoosff,cgroporiupgiomnregan/taeundtter(asnlinifnoalll)icles HEFOLLOUINGTISSUES)WERE WITHINNORMALLINITS: PAITRUTRYcus cAeRGviIx omaies End of Record 13am oT anoucr(s) Tr i-ton Page 1091 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SAEMNPKEROROVATITOINCOONPLER4(F1OLN8EL-D0GL2OI0OTCTETRANGPAETREGE(NAEPRFAOT)IOTNN) RATS SPONSOR'S STUDY NNER: T-6899.6. Individual Anima) sGPFroaopsemsnoaratanxtdi1oH1n1istororphalosy Data sA ex: NNER: F1353 sBoaencmp 1Sacri fice-Scheduled S055 QASERUTIONS): SEMERAL: No gross changes. HISTORRPHOLOSICOBSERVATIONS): ot applicable HISTONRPHOLOGICOBSERVATIONS: ceVAuRxIA:NFOLLICLESCORPORA LUTER wrens: pdirleasteantcieonof(csoardpeorartae)lutea Bresence of growing/antra follicles Sacrophages, pigmented (sarked) THEFOLLOUINGTISSUR(S)VEREWITHINNORMAL LIMITS: AVOARGEIMNAAL GLANDS owares anoucr(s) End of Record 13636 prrumRy nr Page 1092 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)BYTHOOF-SACWNRNEROIALTTNIOCNPER4(F1O6LNE-U0O2RL0OIOTCTETRAVAPTEER.GE(NPEFROA)TIOTNh) RATS sponscn'S STIOY MMGER 1-6069.6 Individual Anfeal GsFroeopasemsnadrataedti1oW1n1istomorshotogy Data . ASeNxI:MAL WE: F13542 oDEsAeTHoTwReE:. _ vSacrifice-Schedsled A055OBSERVATIONS): SENERAL No gross changes. HISTOMRPHOLOSICOBSERATION(S): hot applicable HISTOMORSHOL001C SCRIATIONS: OVARIAN FOLLICLES/CORFORA LUTER: wrens pRBarrceerssoeepnntccaeepeoosff,cgoprrioggwommreaan/talenudttre(aamldefroaltlei)cles HEFOLLOUINGTISSUES)WERE WITHINNORMALLINITS: APIRTEUAITLARGYLANS cahveiix onaies End of Record 13642 nous) 1-10 Page 1093 ARGUS 418-020 REPROODRILCTI(OGNAVASGTEU)DYTVOOF-GAEMNKREOoRVAItTUeINOlPNER4(F1O8LNE-L0R2GL0OIOTCTETRANGPAETREGE(NAEPRFA)TIOINh) ~ATS SPONSOR'S STIOY NIGER: T-6689.6 Individual nea) GAFreooaspnseeranantdi1oi1n1stonorsholosy Data AseNx:IL NER: 1F3063 nDEoAsTeHcTaHoE:E. Sucfice-Schadalad 8058OpSERMTIONS): SENERALS No gross changes. HISTOMRPHOLOGICOBSERVATIONS): Not applicable HISTORPHOLOGICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA: wrens: mBparrceerssoeepnnhccaeegeoosff, gcroporiupgiomrneaan/taelnduttre(eam)odefroaltlei)cles HEFOLLOVINGTISSUE(S)VEREWITHINNORMAL LINITS: APIRTEUIATLARGYLANDS cAesiin omares End of Record 13643 " Tr oviouer(s) TT ety Page 1094 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-AGMOINPOERMROIATUTONICOOPNLER4(F1OL8NU-ER0LR2O0IOTCETRANFGEARTEGE(NAEROA)TIOTNh)SATS = SPONSOR'S STUOY WAGER: T-6889.8 IndviivcaildualAAnnia! SG#hroGoeesnseoranandtiMHosnsttaomrosrhopthaoslosy Ousta Asex:L NER: v13904 DoEsAeTHcTaYoEE:, Sacrfice-Schadsled 805s GRSERIATIONSS): SEUEBAL: Wo gross changes. HISTOMRPHOLGGICOBSCRUATION(S): Not applcable HISTOMSPHOLOGICOBSERVATIONS: OVARIANFOLLICLES CORPORA LUTEA: wrens: pBrreesseennccee ooff cgorropwonraa/auntcreasl follicles EGaicsrtoepnttaigoens,, Tpoimgemnen(tmeidnim(amld)erate) HEFOLLOUINGTISSUE(S)WEREWITHINNORMAL LIMITS: APIRTEUIATLARGYLANDS ceVrAvGIiNxA outs End of Record 13944 overs) 110s Page 1095 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERVROIATUTONICOOPNLER4(F1OL8NU-EO0RL2OI0XTCTTEARKGPAETREGE(NAEPRFAO)TIOINN)RATS SPONSOR'S STUY NINGER: T-6299.6. Individual nim AGFraooapsnesanrdaaintdi1oW1n1istmorpholosy Data ASeNx:AL BER: F13646 SDEsAeTHone: vSacrifice-Scheduled R055 QESERIATIONS): 280): Swollen, HISTONRPHO\GGICOBSERVATIONS): chondropathy. auricular HISTOMORPHOLOGIC opSERIATIONS: exis) Ed of Record 13906 chondropathy. auricular (sodeate) 1-108 Page 1096 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 HISTOPATHOLOGY REPORT APPENDIX IV INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA F1 Generation KEY TO CORRELATION OF HISTOMORPHOLOGIC OBSERVATIONS Not applicable = Microscopic evaluation/correlation not appropriate or not required by protocol. Page 1097 ARGUS 418-020 REPRGOBRAULCTI(OGNAVASGTEL)OYTGWFO-AGENPNERROATITOICOONLPE4(R1OR8NL-EC0OL2RI0OT0TCETRMOENRTEGE(NE0RA)TIOINh)ATS SPONSOR'S STUOY NUMBER: T-6009.6 Individual nina] Grsooepsenadnid HIivstonorpholosy Data FGaneration sAex:L WrgER: W1003 woeTar S1acr ice-Schedsled 05S gsERuATIONSS): SEAEBAL: No gross changes. HISTONRPIOLGSIC OBSERVATIONS): Not applicable HIsToMsPIOLOSICopscRvATIONS: eprotoms: inf1tration, monanuclear-cell, focal (minis) TH FOLLOMINGTISSUE(S)VEREWITHIN noRHAL LIMITS: ASoERAeIuNAALL GVueaswtoesies CTEoSRTUIASTING Gur Frum prosTaTE End of Record 1003 wt Page 1098 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTOUFO-AGWEINPOERNROIATLTOMICOONLPE1(RO6FN-LEU0O2LR0IOTCTCETRAVPAETREGE(NAEFRPA0)TIOTNh) RATS SPONSOR'S STUOY WAGER: T-6889.6 Individual Animal GFrsiooGspesenneadrniadxtHiIioVnstomorsholasy Data MsexA:L eER: W1012 DsEoAeTHoTnHeE:: S1cheduled (Reduced Fertility) 80S ORSCRATIONSS); SEUERALS No gross changes. HISTOORPHOLGGICOBSERVATIONS): hot applicable HEFOLLOVINGTISSUE(S)VEREWITHINNoBALLIT: CTEOSUTINSTING GLK eptoioms PROSTATE 04ofRecord 1012 " SeHINAL VESICLES, TT we Page 1099 ARGUS 418-020 REPROODRULCTI(OGNAVSAGTEU)DYTUOOF-SAEMNFGERVROIATLTGIMCOONLPRRS(LOiUNeEORgOLeCICTTTEARNIAPTEER.GE(NAEFRFA)TIOINn) RATS SPONSOR'S STUDY NBER: T-6889.6 Individual Anim GFirApopsGeesnndeairnxadtiH1ovinstmorpholosy Date MS&AL BER: W1017 oDEATpH T:HE. S1aceice-Schaduled R053 ORSERITIONS): SEERA: No gross changes. HISTOMRPHOLOSIC OBSERVATIONS): ot applicable HISTOMgRPHOLOGIC SERVATIONS: AREAL GLANDS: vacuolation, cortex (minisal) HEFOLLOUING TISSUE(S) VERE WITHINNORMAL LINITS: SCOERAUALTIVNEGSIGCLLEASND Teepsttoitsonis pry PROSTATE End of Record 1017 ws Page 1100 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DYTHODF-GMEONiNCAIALTtNIONPeER(FNLE)LGLRIOTGTEETROGPARTEGE(NNEFROA)TIOINh) SATSSrouson'S STUDY MBGER: T-6880.6 Individual Anima GFrfGopespmsernaaintxsiW1ovsntomorshology Data AsNoIrMAL beER: 1018 oBEsNcTHce:THE: So1 cifice-oribund 05s oosTATIONs): IES: Coren apy, both eyes. HISTOMORSHOLOGICOBSERIATIONS): inflomation, chronica,)iris HISTOMAPHOLOSICOBSERATIONS: oes:ee End of Rocord- 1018 rIenfulraampmaattniyon,apciheronniecr,va(isr)is (s(osddeerraattee)) we Page 1101 ARGUS 418-020 REGROODRIALCTI(OGNAVASGTEU)DYTONFO-AGMEINPOERMEOIATLTONICOONLPE4A(1OF8VL-EU0O2RL0OIOTCETRANPGAETEGE(NAEFRPA)TIOTNh)BATS SPONSOR'S STUDY NNGER: T-6089.5 Individual Animal GFisrooGspesenneadrniadtiiIosvntomorshalosy Data Afyna wee: 1019 DsEAeTHon:WE. S1acrifice-Horibund R055 ORSERUATIONS): EYES:Corneal opacity, both ayes. HISTOMRPHOLOSICOBSERVATIONS): e inflae mation, chronaic,)iris HISTOMRPHOLOGICOBSERITIONS: eves: 03 of Record 1010 nienufrloapmamtahtyi,on,spcthirconniecr,ve(isr)i:s(n(ordoedreartaet)e) ws Page 1102 ARGUS 418-020 Akyva wer: REPROODRUALCTI(OGNAVASGTEL)OYTOVFD-AGE"RNPEVRROIATTONICOONLPE4R(1OP8NL-EU0O2RL0OICTCTETRANPOEARTEGE(NNEFROA)TIIOhNATS SPONSOR'S STUOY NBER: T-6099.6 Individual Anime GFlrsoosSpseonaadrniadstiHIoiVnstoeorphotosy ste W1020 sGENoTH r:THE: S1 ocrificeoribund EYES: Comes! opcity, both eyes. No microscopic change to correlate HISTORORPHOLOGIC OBSCRIATION: eres: No microscopt change to correlate HEFOLLOVINGTISSUE(S)VERE THINNOLLIkTS: eres Ed of Record 1020 FS ws Page 1103 ARGUS 418-020 REPRGRBOAILTI(OGNAVASGTEI)STIOFO-GAEWIPOGRNROIATLTONICOONLFE4(A1OP6NL-EU0O2LR0IOTCTTEARNGPNETREGE(NME1R0A)TIOINn) RATS sronsoR'S STUY WME: 1-6209.6 Tnividun) Ans) gFirAeoGsaspneaarnnastiHIosvntomorpialony Ota ASaxea we: u1022 DsEoAeTHcTmIePE:, S1ocrifice-Schaduled SA0ssOpsERMTIONS): HEAD: Lesion, Toft side, 1.0cn in diameter. HISTOMORPHOLOSICOBSERATIONCS): dara, ulcerative, SKIN (GAs LESION HISTORRPHOL001C opstavaTIoNs: SKIN (60s Lesion): darmtits, ulcerative (sodrste) End of Record 1022 - wr Page 1104 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOVFO-AGEMNPOERMROIATLTONICOONLPE4A(1OF6NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRRAO)TIOINh)RATS SPONSOR'S STUOY MMBER: T-6009.6 Individual Anima G#1rAooGspesenneadrniadxtHiIovintoorshology ata Asxn:a wees: W1024 DsEoAeTHoTmIePE:. S1pontanecus Death 805sGBSERUATION(S): AUG: ottled dar red, al) Tobes. HISTOMOEPHOLOGIC OBSERVATIONS): hemorrhage,mutifocal HISTORRPHOLO1C opstavATIONS: we: End of Record 1024 hemorrhage, motifacal (af1) TT " wes Page 1105 ARGUS 418-020 REPROODRIACLTI(OGNAVSAGTEU)DYTHOOF-SAEMNPOERVROIATLTOIWCOONLPER1(FO6LN-EU0O2RL0OICTCTETRAIAPTEER.GE(NAEFRPAO)TIOINn) RATS SPONSORS STUOY NUMBER: T-6889.6 Indivicus) Anime) Grsoogpsenadnid WIsvtomorshalasy Data FiGaneration MseAx:L BER: W1026 DEATHcorT:E. S1acefice-Schadaled S053opsERuATIONS): SES: Riga hteye enter HISTOHOREHOLOGICOBSERUATION(S): Satirorpohy:, Treetiantali.vifoycalboty HISTONRPHOL0S1C BSTRVATIONS: eAvResE:AL GLANDS: vSaetarrcoouppohhlyya,,tiorrnei,bsicmeotr,ftaefroyc(aalbiondi(myna1l1()dm)erked) THEEOLLOMINGTISSUE(S)VEREWITHINNORMALLIMITS: SCOORSUULATIVNEGSIGcLLAENsD Teesntison prTuITARY PROSTATE End of Record 1025 ws Page 1106 ARGUS 418-020 REPROODRIACLTI(OGNAVSAGTEU)DYTOWFO-AGMEINPOERMROIATLTOWICOONLPER(1OF5VL-EU0O2RL0OICTCTETRANG7A6T%EGO(NAGFAFA)TIOINh)RATS _SPONSOR'S STUOY NUMBER: T-6880.6. Individual Animal GFirsooGspesenneadrniadxtHiIiovnstonorphalosy Data MseAx:L NBER: x1034 DwEAoTHe:THRE: S1acrFice-Schedsled R055 ORSERATIONS): SEERA ho gross changes. HISTOMIRPHOLOGICOBSERVATIONS): Not applicable HEFOLLOWINGTISSUE(S)WERE WITHINNORMAL LIMITS: PARORSETAATEGLAS SCPOHRTUAALTIVNEGSICGLLEASND TEepsimnsions Ed of Record 10% prrumRy wo Page 1107 ARGUS 418-020 REPROGDRUALCTI(OGNAVASGTEL)OYTGVFD-AGEW"NPOERMROATITONICOONLPE4(A1OP8NL-EU0OL2RI0OTOTCETRINPOENRTGE(ANFEFR0A)TITOhNATS SPONSOR'S STUOY MINBER: 7-689. Indivicus! Animal GFirsooGspesenneadrniadxtiHIoivnstomorpholosy Data AeyL MBER: x1035 DwEAeTHaTE:: S1acrice-Schedaled 80S QRSCRVATION(S): SEERA Wo gross changes. HISTONRPHOLGGICOBSERVATIONS): Not applicable THEEOLLOHINGTISSUE(S)VEREWITHINNORMAL LIMITS: PARORSETAALTEGLAMIS SCOEoNRAUALTIVNEGSICGLLEASND Teepstrisom E03 of Record 10% prruimaRY wu Page 1108 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOHFO-ASMEKNPOERVROIATUTGNIEOOPNLER4(F1OLN8EU-D0RL2OI0XTCTETRANGPAETREGE(NAETRFA)TIOINh) RATS SPONSOR'S STUDY NBER: T-6889.6 Ta"ta tma1 6F1ir0oGsesnaaendnratiMotnHaimsrtosnhoroplhyelogy toData SAei:C NER: "1000 OwToHe:THE: S1cheduled (Reduced Fertility) R058 QRSCRIATIONS): SEMERAL: No gross changes. HISTOMEPHOLOGIC.ORSCRUATIONS): Not applicable HEFOLLOUINGTISSUE(S)VEREWITHIN NoRuAL LIMITS: CTeOsRtUiAsTING GLU epioioms rasTaTE End of Record 1040 SemaL Vesicles wz Page 1109 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTHOOF-SAOMNPOERMROIATLTOMICOONLPER1(FO6LN-UE0O2RLO0IOTCTTEARNGPAETRE.GE(NAEFRRAO)TIOINh)RATS sronsoR'S STL MGR: 1-6089.6 Asox:L NBER: 1087 Individualt AniAnimal GFrGiroGocossenaaarnadtiHoinstomorphatloayasy DaData oDEATpH TH:RE. 1Sacr ce-Schedsled TLR SENERALS Yo gross changes. 'MISTOMORPHOLOGIC OBSERVATION(S): Not applicable HISTOMRPHOL001C pseRvATIONS: ePRpOiSoTtAoTmEs:s: aI{ninfttFalrtaaamttaiitoiono,nn,:glascnoodnnuolntauerc,le(af1ro1-caac)lell(,nilfao)cal (ainsssl) THE EOLLOUINGTISSUE(S)VEREWITHIN MORALLIMIT: J unos COUNTING GLO prrumy som vesicues EndofRecorddg TTT wn Page 1110 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNIPEORRMOAITTUOIMCOONLPE4R(1FO8NU-EU0KL2RI0OOTCTTEARKGPAETREGE(NAEFRPA0)TIOTNN)RATS SPONSOR'S STUOY MBER: T-6889.6 Individust Anima) GFrsiooGepenennaadrniadxtiHIoivnstonorpholosy Osta sAeNx:AL wosER: W1048 DsEAeTHor:THE: S1acrifice-Scheduled 8085 CASTRATION): SEERA Yo gross changes. HISTONRPHILOSICOBSERVATIONS): Not applicable THEFOLLOUINGTISSUES)WERE WITAINNORMALLIMITS: PARORSETAATEGLAS SCOERMSIUAALTIVNEGSICGLLEASND Teepsitostoms E83 of Record 108 prrumaRy we Page 1111 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DY THODF-GAEMNPOERVROIATLTOIWCOONLPER4(F1OL8NUE-O0R2LO0ICTCTTEARNDPAETRE.GE(NAEFRFAO)TIOINN) RATS SPONSORS STUOY NBER: T-6889.6 Individual Animal rFsoioGppaeenneadrniadxtiHIoivnstonorpholasy Data kJiasc wees: i1051 oSsEeTHEcae: h1uerrico-soneatea ROSS ORSCRIATIONS): SEERA No gross changes. HISTOMRPHOLOGICOBSERVATIONS): Not applicable HISTOMAPrOLCSIC cosERMTIONS: TAeRsEtiAsL: GLANS: vaaicruooplhayt/idoeng,enecroarttieoxn,(mmiontimialfa)cal (minis) TEFOLLOUINGTISSUE(S)WEREWITHINNORAAL LIMITS: SCTOHUDNATLIVNEGSIGCLLAENSD eptoromis prrumar PROSTATE E03 of Record 1051 TT TTT ws Page 1112 ARGUS 418-020 REPROODRLACLTI(OGNAVSAGTEU)DYTHOOF-SAEMNPOERMROIATLTOIMGOONLPER4(F1OL8NUE-O0R2LO0ICTCTTEARNAPRETRE.GE(NAEFRRAO)TIOINh) RATSSPONSOR'S STIOY NUMBER: T-6809.6 Individual neal Grsogspsenadni H1s1tomorsholosy Data Fi Generation EAiL NR: 1052 SosHt IHcage: h1ioriico-screated ROSS OBSERVATIONS): SENERALS Mo gross changes. HISTONRPHOLGGICOBSERVATIONS): Not applicable HISTORRPHOLOGICOBSERVATIONS: AREAL GLANS: vacuolation, cortex (sinimal) HEFOLLOUING TISSUES) VERE WITHIN NORMAL LINITS: SCEOAMIGNUALLATVIENSGTeGLUENSD Teepsitoistoms prrumRy FRoSTATE End of Record 1032 TTT wis Page 1113 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTVOOF-GAEMNIPEORRNOAITTUOINCOOPNLER4(F1OL8NU-ER0RL2OI0OTCTTEARKGPAETREGE(NFEPROA)TIOINN) RATS SPONSOR'S STUOY NIGER: T-6209.6 Individual Anim GFiHroopsSeesnndaairnxadtiHIovinstmorpholosy Data Asox:L BER: W1054 DoEATeH T:HE. S1ucrFice-Schadaled R058 BSTRUATIONS): GENERALS No gross changes HISTOMEPHOLOGIC.OBSERUATIONS): het applicable HISTOMRPHOLOGICOBSERVATIONS: PROSTATE inflammation, chronic (minima) IHGFOLLOUINGTISSUES)VERE WITHINNORIALLIWITS: ASERNIENAAL cVEuSpICsLES CTeOsRtUiAsTING GLAND eptotomis Ed of Recore- 1054 prruimaRy war Page 1114 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTWOOF-GAEMNPOERMSOIATLTOINGOONLPEA4(F1OL8NUE-O0R2LO0ICTCTTEARNGPNETRE.GE(NAEFRRAO)TIOINh) RATS SPONSOR'S STIOY NUMBER: T-3800.6 Indivicus) Anima) GFirsooGspseennaednridatMi1oivnstosorphalgy Data Asinx a vee: W1083 DsEAoTH pTH:E. S11acr ce-Scheduled S055 aSERUATION(S): SEENo gross changes. HISTONRPHOLGSIC OBSERVATIONS): Not applicable THE EOULOMINGTISSUE(S)VEREWITHIN Noms,LTS: AREAL GLAS End of Record- 1063 CTT ws Page 1115 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTWOOF-AGWEINPOERNROIATLTOWICOONLPE1(RO8FN-LEU0O2LR0IOTCTCETRAIPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6009.6. Indivicus] Animal GFirsooGspesenneadrniadtiH1oivnstomorpholsy Data a5L wees: W1066 OsEoNeTHop:TIRE: S11cheduled (Reduced Frei) 8055 OBSERVATIONS): SEUEBAL: No gross charges HISTORRPHIGGICOBSERVATIONS): Not applicable TH EOLLGMINGTISSUE(S)VEREWITHIN noms,LIMITS: coi ao epioioms eRosTATE seaNAL VestcLEs, was Page 1116 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DY THOOF-SAEMNFOERNROIATLTGINCOONLPE4R(1OFN6LE-U0OL2RI0OTCTCETRAAPAETREGE(NAEFRRAOT)IOTNh) RATS SPONSOR'S STUDY NUMBER: T-6889.6 Indivicus) Animal GFirAooGspesenneadrniadtHiIiovnstomorpholosy Data fAyL NER: 1W077 cDEAoTHmpTHRE: S1cheduled (ReducedFert ity) 8083 GRSCRIATIONS): SEMERAL: Yo gross changes. HISTORRPHO\GSICOBSERVATIONS): Not sppticable HisTomsPrOLOGICopscRvATIONS: FRosTATE: inflammation, chronic (minima) TH EOLLOUINGTISSUE(S)VERE THINNORMALLIMITS: CORSULATING GLAND eproromis soma vesicues Tests End of Record 1077 wo Page 1117 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-AGEMFIKREOORWATITGNICOOPNLERS(F1OLeNEU-OcR2LO0IOTCTTEARNGPAETREGE(NAEFR90A)TIOINh) ~ATS SPONSOR'S STIOY NBER: T-6060.6 Individuat m1 GrSosospaand 1Wvstosorphalosy Data FI Generation ASexv:a wre: "1078 sDoTeHomg: S1a1cri fice-Schedsled 8Q0R5S3ERVATIONS): SEUERAL; No gross changes. HISTOMRPHOLOSIC OBSERVATIONS): Not applicable HISTOMRPHOLOSIC SERVATIONS: AREAL GLANS: End of Record 1078 vacuolation, cortex (sinima1) oT Tr -- wa Page 1118 ARGUS 418-020 REPROCDRAULCTI(OGNAVASGTEU)DYTDUFO-AGMEINPOERNROIATLTONICOONLPE4A(1OF8NL-EU0O2RL0OIOTCTETRANPGEARTEGE(NAEFRPA)TIIOhNRATS SPONSOR'S STUDY NUMBER: T-6889.6. Individual Ana) Gsroospsenadnid IHVistomorphelogy Data Fi Generation AsxL WER: W1082 sDEoAeTHcToWg:: 1S1cheduled (Reduced Fertility) GROSSOBSCRIATIONS): STEeRiEEpR:E aLoltit.,sPuaic.eia HISTOMORPHOLOGIC.OBSERVATIONS): NNoommiiccrroossccooppiicc cchhaannggee ttoo ccoorrrreellaattee,, ETEPSITDIISDWHIS HISTONORPHOLOGICOBSERVATIONS: eTepsttoins:oms: KNoo mmiiccrroossccooppiicc cchhaannggee ttoo ccoorrrreellaattee THE EOLLOMINGTISSUE(S)WOREVITHINNORMAL LIMITS: c5oma suo Epinions rRostare sou vestcLes wa Page 1119 ARGUS 418-020 REPROORDACLTI(OGNAVASGTEU)DYTUOOF-GAEMNFOERMROIATLToNIcOoNPE4A(1FOL8NU-EO0R2LO0ICTCTTEARNGPAETRE.GE(NAEFRRAO)TIOINh)RATS SPONSOR'S STUOY NIGER: T-6809.6 Individual Anima) GFrsiooGspseennaednridaxtHiIioVsntonorptalasy Data sAex:A WAGER: "1096 wBEATor S1acrifce-schedsled Sa05s opscRuATIONtS): SEMEBAL: ho gross changes. HISTORRPHOLGSIC O8STRUATIONS): Not applicable THEEOLLOUINGTISSUC(S)VEREWITHINNORMALLINITS: AREAL Guavos 0d of Record 109 was Page 1120 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTWOOF-GAEMNIPEORRMOAITGUTCNIOOLPNER4(F1OL8NU-ER0RL2OI0OTCTTEARNGPEART.EGE(NFEPROA)TIO1Nh)RATS SPONSOR'S STIOY NBER: T-6000.6 Individual Animal GFrsiooGepesenneadrniadxtHiIioVnstomorphalosy Data MseAx:L NBER: X1098 sDoEATHcToHgE:. S1a1cefice-Schadaled R053 ORSCRIATIONS): SENERAL: No gross changes. HISTOMORPHOLOSICOBSERVATIONS): Not applicable THEFOLLOVINGTISSUE(S)VEREWITHINNORMALLIMITS: AREAL GLANDS wa Page 1121 ARGUS 418-020 RGPRGOBRALLETL(OGNAVASGTEI)QYTGUFO-AGEWNPOERVROIATUTOYICOONLPE4R(1OP8NL-EO0O2RL0OICTCTETRAVOPNETREGE(NAEFRPA)TIOTNY)ATS SPONSOR'S STUY NUMBER: T-6855.6 Individual ma) FGArigoGpseesnnadarinaxdtiIHoYinstonorphelosy Data AaL HER: W1100 DoEsAeTHore:THE, S1u1crce-Scheduled GROSS ORSERIATIONS): SENERAL ho gross changes. HISTOMRPHOLOSIC OBSERVATIONS): ot apicasle HISTORPHOLOGIC OBSERVATIONS: AOREMAL GLANDS: vacuolation, cortex (ainisal) was Page 1122 ARGUS 418-020 REPROODRIACLTI(OGNAVASGTEU)DYOTVFO-AGWEONPNERROIATLTONICOONLPE4(R1FO6LE-U0R2LO0IITCTTEARNOPAETREGE(NAEFRPA0)TIOINN)RATS SPONSOR'S STUDY NHGER: T6589. Individual Animal GArpopsesnadnidx 1Hvistamorphalogy Dota Fi Generation ASoNxIMAL NBER: W1106 sDEAoTHp: S1a1crifice-Schadulod 05SOBSERATIONSS): SEMERALS to gross changes. HISTOMRPHOGGICOBSERVATION(S): Not applicable THE FOLLOUINGTISSUES)VERE WITHINNgRMALLIWITS: ADRENAL GLANDS End of Record 1108 was Page 1123 ARGUS 418-020 REPROORDAILTI(OGNAVSAGTELTWODF-GAEMIPNGRIIOATUTOKICOONPLE4S(1OTN5LE-U0RL2GI0ITCTTEARIGPAERT.EGE(NAEFRDA)TIOTNh) "ATS SPONSOR'S STUOY WAGER: T-6809.5 Individuol Anim GFrsaoapsnseanraantdtiH1osvntomorshology Data SAaxnea wees: 107 oBEsNeTHcTYPE:e: 1S1acrifice-Scheduled 05s oOSTRIATION(s): SEMBAL: No gross changes. HISTOMORPHOLOGIC OBSERITION(S): ot apcable HisTooRPIOLOGICopsERTIONS: AREAL Gua: End of facord- 1107 vacation, cortex (minima) TTT war Page 1124 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)OYTHOOF-SAEWNPOERVSOIATUTOIYCOONFLER4(F1OLN8EU-O0RL2OI0OTCTETRANOPNETREGE(NFERPA)TIOIN)ATS + SPONSOR'S STUOY MMGER: T-6899.6. Indivicus) Anima) GFrsiooGspesenneadrniadxtHiIiovnstonorpholosy Data sAex:a WrgER: W116 wOENeTHarTYE: S1acrifice-Scheduled 8058opsERATIONS): SEAL ho gross changes. HISTORPHOLOSIC OBSERVATIONS): Not applicable THEFOLLOMINGTISSUE(S)VEREWITHIN NORMAL LIMITS: AREAL GLANDS End of Recor- 1116 was Page 1125 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVOF-AGMEINPOERMROIATUTONICOOPNLER4(F1OL8NEL-R0RL2OI0OTCTETRANGPAETREGE(NFEPROA)TIOINh) RATS SPONSOR'S STIOY MAGE T-6889.6 Individual Anim) FGirHoospGseanndaairnxadtiH1oivnstomorphelosy Data Asex:a wreeR: 118 DsEAoTHe: S11acr ice-Schedulod 8055 GBSERUATIONS): SEERA: No gross changes. HISTOMRPHOLOSICOBSERVATIONS): Not applicable THEEOLLQUINGTISSUE(S)VEREWITHINsoma,LIMITS: AREAL GLANDS End of Record 1118 Tr CT was Page 1126 ARGUS 418-020 REPROGDRIALCTI(OGNAVASGTEU)DYTOUFO-AGEMNPOERVROIATLTONICOONLPE4A(1FO8KL-EU0O2RL0OIOTCTTEARNGPAETREGE(NAEPROA)TIOTNN)RATS SPONSOR'S SOY MBER: T-6899.6 Indivicus) Anima) Grsoospsenadnid HIivstonorpholosy Data Fi Generation fA ey WAGER: W1120 oDoEsAeTHcTaRoE:. S1a1cri fce-Schedsled S055opsERUATIONS): SERA: No gross changes. HISTONRPHOLOSIC OBSERVATIONS): hat. applicable HISTONREHOLOGICOBSERVATIONS: AOREUAL GLANDS: End of Recore- 1120 vacuolation, cortex (ainimal) ves Page 1127 ARGUS 418-020 REFROCRDALLCTI(OGNAVASGTEL)OYTVOOF-GAEMNROEROVAITTYIOCNPER4(P1O8LN-UE0O2RL0OIOTCTETRANOPAETREGE(N1ER0A)TIOINh) ATS SPONSOR'S STUOY NMGER: T-6089.6 Individual\ Anim) GHrAlooaspsrenaadntidioH1avntomorshroelloegy Data Asex.L wees: W123 DSEsAeTHor:THE. SIancnrice-Scheduled R055 OISERIATIONS): HEAD: Swoon snout HISTOMRPHOLOSICOBSERVATIONS): dfervaicattuiroen,wintahsaclalsluesptufmormation HISTORRPHOLOGICOBSERVATIONS: Heo End of Racor 1123 dfervaicattuiroen,wintahsaclalsleupstifmormation or oT wat Page 1128 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOWFO-AGMEINPOERMROIATLTOMICOONLPE4R(1OF8NL-EU0OL2SI0OTOTCETRANPGEART.EGE(NAEFRPA0)TIOINh)~ATS SPONSOR'S STUOY WAGER: T-6209.6 Individual Animal GFirsooGspesenneadrniadtiM1oivnstomorphalagy Data eMyL eR: W124 DsEAoTH oTE:. Snanceice-Schedsled R055 OUSERATIONS): LITVoERc:onLte,ftralantgeirnagl frIoobme-pintpaeninatreatso t0.o5ocnm.mrous HISTOMRPHOLOGICOBSERVATIONS): nPheyecpnreaortstoirpsoo,piheysf,tosc.haetepjaxmtttoricaeflnolcdualltaarr,y,dimffiustefocal HISTOORP0\0GICOBSERVATIONS: uve: End of Record 1124 r Penctroepra ooipehys.ts,s hepeaxttorcaa emlelduullalra,r(ys,dhmiefi)futsefo(cmaolder(astien)ine]) we Page 1129 ARGUS 418-020 REPROORDAILCTI(OGNAVSAGTEU)DYTHOOF-SAEMNIPEORRNOAITLTOMICOONLPE1R(6OFN-LEU0O2LR0IOTCTCETRAIPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S STUY NBER: T-6809.6 Individus) Anima) GFrsiooGspesenneadrniadxtiiIosVntomorphalosy Data SAex:C NER: "1125 sDEAtTHop:TRE. S1a11criice-Schadaled S055opsERATIONS): LSIiVzEeR:fLroofntpilantpeorianlt tToobe0-.1ctna.n aress (4) ranged in HISTORPHOUGSIC 0BSCRATIONSS): hSpnFritarmeapthiyo.n, hecphraotnoicce,lluFloacra,/dmiftfufsoecal HISTORRPHOLGSICOBSERVATIONS: Liver End of Record 1125 iPynpfelratmrmoasthiyo.n, hcehpreotnoicce,ifutoacra,l/maiiftfiufsoeca(lrod(enria1td)e) ws Page 1130 ARGUS 418-020 REPROORDALLCTI(OGNAVSAGTEU)DYTWOOF-SMENPGERROMATTOTICOONLPE4(A1OT6NLE-L0O2LR0IITTGEERTOPNETREGE(NNEFROA)TIOINn) WATS SPONSOR'S STUDY WAGER: T1-6889.6 Individual\ inal GFAriooGpsoesnnadarinaxtisIovtnomoranolosy Data SAexn:a ees: 1126 Scekomp: Smancri ice-Scheduled 8055GRSERIATIONS): HDDessi:co,nL,eFnIhtGeoHneE,d,Sirdateco,kp,, 0.r0di.cg9mhmt Insiniddid.aimaem2te.et0re;rx; 0lea.ss5itomonn,. cI2VapEni:ttpLaLoifotnttataott0o2rroniicInha315at6an, aaSoreoesm,eranmgingeanrg tofrom HISTORRPHOLONIC OOSERATIONS): Gdaerrmmaattiictiiss,, cuhlrcoenriact,iveS,KINSKI(NGRO(S6S05L5ESILOENS)ION) hTyopaemrtartopihoyn,., hecphatrohecopaetnlocle,lulfaolr,caarl, /dmitdfiiffuosecal HISTOHRPHOL01COBSCRIATIONS: uve: SKIN (68055 LESION: End of Record 1125 Gyiaprearnnttr1oosfh,y.lcdhreoannhe.paetotce(,iofdleiurctaei,ome)diifnftusee,. )(a(iron) dermatitis, ulcerative (moderate) west Page 1131 ARGUS 418-020 REPROGDRIALKTI(OGNAVASGTEU)DYTOVFD-AGWEINPOERNROIATUTONICOONLPE4(R1OF8NL-EU0R2LO0IOTCTTEARIGPAETREGE(NAERFA)TIO1NX)RATS SPONSOR'S STUOY MMBER: 1-689. Individusl Animal GFirsooGspesenneadrniadxtiHIoivnstomorpholosy Data as&L ser: W128 SDEoAeTHoTmIeE:, So11r1ifice-Schaduled A058 BSERUATIONSS): LIVER: Left lateral Tobe tan ares, 0.4 x 02cm. HISTONORPHOLOSICOBSERUATION(S): hypertrophy, hepatocellular, diffuse HISTORRpHOL001C oBsTRVATION: Lives: End of Recore- 112 pertrophy, bepatocelar, diffuse (sodarate) ws Page 1132 ARGUS 418-020 REPRGOO0AELT I(oGnAVASGLEA)YTOIFO-MGETNORRAMTOIOTNFE8(KOPN-UER5LIICTCTTERAN7A8TEGE(NAEFRGA)TIOTNh) ATS sronson'S ST WNGER: T-680.6 Individual Anim GroospGseeaardamtiR1ovinstomorology ts SA o a: W1129 wSeErTaHE S1itirice-schdiied 0sOmsERATIONS): HISTORICCRSERATIONS): GENERAL; Mo gross changes. Not applicable HE FOULINGTISSUES)VERE WITHINbow Libr: orem Gums Era of Racor 1150 wes Page 1133 ARGUS 418-020 REPROORDAILTI(OGNAVASGTEL)OY TOVFO-AGEMNPOERNROIATUTONICOOPNLE4A(1OP0NU-ER02LI0IGTETTEMROPNETRE.GE(N7ER0A)TIOTNh) "ATS SPOUSOR'S STUY NMGER: T-8889.6 Individual Anim 6FiA3pGpseenneadrniadxtiM1oivnstomorsnalosy Data sAo L woe: n1134 DsEAeTHce:THE. S11a1cr ice-Scheduled S058 OBSERVATIONS): SEMBAL ho gross changes. HISTOHRPHOLOG1C QRSERATIONS): tot ascatle HEFOLLOUINGTISSUES)WARE WITHINNo LIMITS: AoRewL sos End of Record 1134 [= Page 1134 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEL)OYTVOOF-SAEXMPEROROATNTOICOOPNLUEO4A(1ORR8N-EO00L2I0CTTTEIROPNERTGE(NAEFRPA)TIOINh) ATS SPONSOR'S STUOY MBER: T-6809.6. Indivicus) Anima) Grdoegpseanndd HIiVstonorphalosy Data FiGaneration sAeNx:AL NNER: W1136 SDEsAeTHoTeVR:, Siactrce-Scheduled GROSS OBSERVATIONS): HEAD:Swollen snout. HISTOMRPHOLOGIC OBSERVATIONS): nTfehrciarncoitstuiirsse,,witstouhoptphucraaltliusveformation HISTORPHOLOSIC OBSERVATIONS: Herd: nfFehrciarncoitstutirsae,, witstowhoptochraaltliuvsefo(ramialt)ion THE EOULOMINGTISSUE(S)VERE ITHINNORMALLIMITS: AREAL GLAS End of Record 1136 ess Page 1135 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOVFO-AGEMNROEMoRITAUToNIcOoPNER4(FO1LV-UE0O2RL0OIOTCTTEARNGEART.EGE(NAEFRPA)TIO1Nh)RATS SPONSOR'S STOO WNGER: T-6289.5 Individual Anim) FGIrAoospGseenndeairnxdatiHIovinstonorphelogy Dota Asx:L WER: W1142 oOoEsAeTHoTwRE:. S1c11heduled (ReducedFert 1ty) S055opsERUATIONIS): SEERA:Yo gross changes. HISTOMRPHOLOSICOBSERVATIONCS): Not applicable HISTONRP0\GGICOBSERVATIONS: FRosTATE: inflamation, chronic (ai1d) HEFOLLOUINGTISSUES)VEREWITHINbolLIMITS: CORSULATING GLAND epioomis son estes End of Record 1142 Tess - ws Page 1136 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DY TOWFO-AGEMPNIREOORMTAIOTNCIOOLNPE4R(1FO8NL-EU0O2LG0IOOTCTTEARNGPAETRE GE(NAEFRPA)TIO1Nh) RATS SPONSOR'S STIOY NBER: T-6800.6 Individual Animal GFAirpoGspesennaednridaxtHiIiovsntomorpholosy Data asax:L eee: W14 DsEoAeTHcTaHeE:. S1a1c1 eice-Schedsled S055opsERATIONS): SENEBAL: No gross changes. HISTORPHOLOSICOBSERVATIONS): Net applicable TEEOLLOUINGTISSUE(S) VCRE ITHIN NoRWAL LIMITS: Home sos ) Page 1137 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DYTWOOF-GAEWNRSERONAITTIIOCNFE4(R1OF8NLE-L0G2LR0IITTCECRTAPAETREGE(NNEFROA)TIOINN) 7ATS sponson'S STO MME: T-6609.6 Indditvivcuin)csAtniAnmts)) GFrGGroessraaantdiHoinstomorshologyogy otData asox:L vee: 154 sDEoAcTHoTYPE.ge S1u1crfice-Schadslad Sa0ssopsEmvTIONS): SEMRAL: No gross changes. HISTONORPHOLOGIC OBSERVATIONS): ot apcable HEFOLLOMINGTISSUG(S)VERE WITHINNORMALLIMITS: AREAL Gua End of facora- 1184 or wa Page 1138 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERVROIATLTONICOOPNLER4(F1OL5NU-EO0RL2OI0OTCTTEARNGPAETREGE(NFEPROA)TIOINN)RATS SPONSOR'S STUOY NABER: T-6299.6 Individual Anim] FGirAopepBneenndaairnxadtiW1ovsntmorphlosy Data AeNyAL wae: "1155 wDEAeTHerTHE. Smancr ice-Schadsled R053 ORSERIATIONS): LIME:Loft Tera Take 6 ta ares, ingin: HISTOMRPHOLOGICOBSERVATIONS): Pupertroshy. hepatocellular, diffuse HIsToMsPHOLOGIC ossERvATIONS: uve: End of Record 1155 hypertrophy, hepatocellular, diffuse (aid) " oT ves Page 1139 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SAEMNROEMROIALTTIMOCNPER4(F1OL8NUE-O0R2LO0ICTCTTEARNIPAETRE.GE(NAEFRPA)TIOTNh) RATS SPONSOR'S STIOY NBER: T-6889.6 Individual Anima GFrsiopaGesenneadrnsadtiH1oivnstamorpholosy Data MseAx:L ER: W1158 DsEoAtTHoe:THE. Sa11c1eifice-Schadaled R055 QRSCRIATIONS): SEAERAL: No gross changes. HISTOMEPHOLOGICOBSERVATIONS): Not appease TH 0LL0UINGTISSUE(S) VEREVITA NORHAL LIMITS: AOREMAL GLANDS End of Record 1150 TT ws Page 1140 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGEMNPOERVROIATUTONICOOPNLER4(F1OL8NU-EO0RL2OI0OTCTTEARNGPAETREGE(NFEPROA)TIOINN) 7ATS SPONSOR'S STUOY WAGER: T-6899.6. Individual Anima) GFirsooGspesenneadrniadxtHiIoivnstomorphalsy Data MseAx:L eR: 1"154 oDEoATHcap: S1a1c1rfice-Schedsled R055 OBSERVATIONS): SEERA Wo gross changes. HISTORRPHOLGSICOBSERVATIONS): Not pplicable THCFOLLOUINGTISSUES)WARE ITH Hog LIMITS: AREAL GLAS 4 of Record 1164 A ett Page 1141 ARGUS 418-020 REPROODBILCTI(OGNAVSAGTEU)DYTHOOF-SAEWNIPEORRMOAITLTOMICOONLPE4R(1OF8NL-EU0O2RL0OICTCTETRANGPNETREGE(NAEFRFA)TIOINh)RATS SPONSOR'S STLOY WAGER: T-6009.6 Individual Anima] GFirdoeGspesneeanrndadtHiIoivnstomorpholosy Data Asex:L weER: 1165 DsEoATHcanT:RE. S1a1c1 eice-Schadiled R055 QRSERATIONS): LoItoV-zEcRaunLto,ftralantgeirnagl inIosbei-zetafnroamrepaIsTIStIoRoCmTmoerous HISTOMRPHOLOGICOBSERUATION(S): hypertrophy, hepatocellular, diffuse HISTOMORPHOLOSICOBSERVATIONS: ves: End of Record 1165 Pypertrophy, hepatocellular, diffuse (moderate) 1s Page 1142 ARGUS 418-020 REPROODBILCTI(OGNAVSAGTEU)DYTWOOF-GAEOIPMERROIATLTONICOONLCR4R(1OU6NOE-R0O2LC0ICTTTAENREAPTEER.GE(NAEFRRAO)TIOTNh) RATS = SPONSOR'S STIOY NBER: T-6889.6 Individual na) GFArGopaspnsaearnnaddti1Ho1instonorphelosy Data sAex:A WER: W1167 sDEAtTHopTHE. S1c0heduled (Raduced Farti11ty) GR05S BSERUATION(S): SEERA Yo gross changes. HISTORRPHOLGSICOBSERVATION(S): at applicable HEFOLLOVING TISSUELS)VERE WITHINNORMAL LIMITS: CTeOsRtUsATING GUND eptoiomis PROSTATE End of Record 1167 SEAINAL VESICLES, vets Page 1143 ARGUS 418-020 REPROGDRAILCTI(OGNAVASGTEU)DYTOUFO-AGMEINPOERMROIATLTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRPA)TIOINh)RATS SPONSOR'S STUOY MMGER: 1-699. Individual Anima GFirAoospGseanndaairnxadtiHIoivnstcmorpholosy Dota A sex: wraeR: 175 DwEAToH eTHE. S1a0cri fice-Schedsled 80S QRSCRWATIONS): SEERA Mo gross changes. HISTORRPHOL00IC OBSTRIATIONS): hot applicable HEFOLLOUINGTISSUE(S)WEREWITHINNORMAL LIMITS: AREAL GLAS Ed of Record 1175 TT T-- war Page 1144 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOHFO-AGWEHNPOERVROIATVTONICOOPNLE4R(1OF8NL-EU0RL2RI0OTCTTEARNGPAETREGE(NAEFRFA0)TIOINN)RATS SPONSOR'S STUDY NIGER: T-6889.6. Individual nim) GFirAoosGpseenneadrniastiW1ovinstmorpholosy Dota vsax:a wer: W177 DwEATtH pTHE. S1a0crifice-Schedsled 8053 QRSCRIATION(S): SEAERALS No gross changes. HISTOMEPHOLOGICOBSERVATIONS): ot applicable HISTOORPH0L0SIC nsEnuATIONS: AREAL GLANS: vacuolation, cortex (sinima1) 04 of Record 1177 TT TTT -- = Page 1145 ARGUS 418-020 REFROGROALLCTI(OGNAVASGTEL)OYTOHFO-AENMPERAIOATTNOICOONPLER4(R1OLN8EU-O0RL2OI0OTCTETRANOPAETREGE(NE0RA)TIOIN) ATS SPONSOR'S STUDY MINBER: T-6899.6. Indivicua) Anima) Grsoospsenadnidx HIivstomorpholosy Data Fi Generation sAexD:A WAGER: W1160 wDEAeTHe:THE: S1a1crifice-Scheduled S055OBSERVATIONS): SEMEBAL: No gross changes. HISTONORPHOLOGICOBSERVATIONS):| hot. applicable HEFOLLOVINGTISSUE(S) WEREWITHINNORAAL LINITS: AREAL GLANDS End of Record 1180 wets Page 1146 ARGUS 418-020 REPROODRAULCTI(OGNAVSAGTEU)DYTWOOF-AGWEINPOERNROIATLTOWICOONLPE4(R1OF8NL-EU0O2LR0IOTCTCETRAIPAETREGE(NAEFRPA0)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6889.6 Individual Anima] Grsopspsenadnid IHVistonorpholosy Dota Fi Generation kAyL NER: V1182 SosEeTHE,cage: SIhveri ice-schadlad R055 OBSCRIATIONS): SENERAL: No gross changes. HISTONRPHOUGGICOBSERVATIONS): Not applicable HEFOLLQUINGTISSUE(S)VERE WITHINsomuAL LIMITS: AOREMAL GLANDS eso Page 1147 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DY TOWFO-AGMEINPOERMROIATUTONICOOPNLER4(F1OL8NU-EO0GL2OI0OTCTTEARKGEARTE GE(NAEPROA)TIOINh) 7ATS SPONSOR'S STUDY MUMBER: 1-689. Individual Anima] Grsoospsenadnidx HIivstomorpholosy Data Fi Generation sAex:A WAGER: W1189 sDEoAeTHcue SIavcri fice-Schedaled 8085 QESRATIONSS): SEMRAL: No gross changes. HISTORPHOLOSIC OBSERVATIONS): hot applicable HEFOLLOVINGTISSUES)VEREWITHINNORMALLIMITS: AREAL GLANDS End of Recor 1180 ws Page 1148 ARGUS 418-020 REPROODRLLCTI(OGNAVSAGTEU)DYTHOOF-SAEMIPKEROROVATITOUICNOONLPEA4(F1O6LNE-U0D2RL0OIOTCTETRANGPAETREGE(NAEFRPAOT)IOINh) RATSSPONSOR'S STIOY MBER: T-6869.6 Individual Anim GFirAopspnseanrdaainxtdiHIoivnstcmorphelosy Date A0L BER: W150 oSsEeITEchow: SIveririce-scheuied 8055 ORSERATIONS): LTrIauVnnEgaRirnoguLseffttrooTmactoaeurnpeti).ngoTiobnee,tmoed0i.a5nmloinbe-siztea,n taoroess HISTONRPIOLGGICOBSERATIONSS):. hn(eyocpFrelorastmirmsoa,pthiyos,nt,ighleceph-racotenoliclce,llufloacra,l /dmiftfusfoecal HISTONRPHOLGIC SERVATIONS: uve: Ed of Record 1190 inFeoncpfreloraaimtrmsoa,pthiyos.ni,nrgelcpehocrtcooenclielcl,l(umfltoancria.mla/ndm)iiftfiufsoeca(lmod(esriantien)al) wes Page 1149 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTHOOF-SAEMNPOERNROIATLTOINCOONLPE4R(1FO8LN-EU0O2RL0OICTCTETRANGPAETREGE(NAEFRFAO)TIOINh) RATS SPONSOR'S STUOY NBER: T-6889.6 Individusl Anima) GFsirooGspesenneadrniadtiH1oivnstomorpholay Data ASex:n wes: 191 ostear: S1tee ice-Scheduled 805 GESERVATION(S): AGLaEun;t rLaatnegrianlg lInobes:izetanfraormespsinBtoooInEmmteora0u1scmto HISTORPIO\GGICOBSERVATIONS): ypartroshy, hepatocellular, diffuse HISTORPHOLOGICOBSERVATIONS: uve: End of Record 1101 hypertrophy. hepatocellular, diffuse (soderate) Tr Tr ws Page 1150 ARGUS 418-020 REPROORDAILTI(OGNAVASGTEU)DYTONFO-AGEMNPOERVROIATLTONICOONLPE1(R8OF-LF0U2OL0RIOTTOECRTAPAETEGE(NAEFRPA0)TIOINh)RATS SPONSOR'S STUOY MBER: T-6299.6 Individual Anima] Grsoospsenadnidx HIivstonorptolosy Data Fi Generation sex:AL weer: W152 DcEAoTHmTIPE. e S1cheduled (Ruducad Forti ity) GROSS OBSCRIATION(): SEERA: No gross changes. HISTOMEPHOLOGICOBSERVATIONS): Not applicable HIsTOAproL061C opscRATIONS: PROSTATE: atrophy, foca (mininal) HEFOLLOUING TISSUES) WEREWITHINNORMAL LINITS: soo cos CORUATING GLAND eptotomis seaAL Vestas est Page 1151 ARGUS 418-020 REFROGBRLALCTI(OGNAVASGTEL)OYTOWFO-AGEWNPEROROVATTOIICOONLPE4S(1OT8NL-EU0GL2RI0OTCTCETRANPOEARTEGE(NNE7R0A)TIIONNATS SPONSOR'S STUDY MIMBER: T-6809.6 Individual Anima) GrAoospsenadnid HIivstomorpholosy Data Fi Generation Asex:L eER: 1193 SEoAsTe THEcage: ShIvorfice-schadiled 8058 QRSERITIONS): LIpiVnEpRo:inLtefttoT0a.te5rms.] Tobe- four tan areas. HISTOMRPHOLOGIC ORSCRUATIONS): hypartroohy. hepatocellular, diffuse HsTORRpHOL081C opsTRvATION: ves: Ed of Record 1199 Pypertrophy, hepatocellular, diffuse (moderate) ss Page 1152 ARGUS 418-020 REFROORDALLCTI(OGNAVASGTEL)OYTOVFO-AEMNPEORRMOATITONICOONLPE4R(1OP8NL-EU0OL2RI0OT0TCETRANPOENRTEGE(NAEFRPA)TIOINh)ATS SPONSOR'S STUDY MBER: T-6299.6 Individual Anima] GFirdoeGspesneeanrndadtHiIoivnstonorphalay Data sAexL NoER: W1194 DEATHoTmIReE. S1acrfice-Schedaled A053 oBSERUATIONS): SEERA Yo gross changes. HISTOMEPHOLOGIC.OBSERVATIONS): Not applicable HEFOLLOUING TISSUE(S)WERE WITHINNORMAL LIMITS: AREAL GLANS E83 of Record 1194 EE TTT ws Page 1153 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTVOOF-GAEMNpOREMORITAoLTcIMaOlN.PE(4RO1FN6LE-U0D2LR0IOTOTCETRANPAETREGE(NAEFRPAO)TIOTNh) RATS SPONSOR'S STUDY KNGER: T-6889.6 Indivicus] Anima] GrAoospsenadnidx HIiVstomorphalogy Data Fi Generation ISeMx:AL NBER: W1197 oDEsAeTHse:THE: SaIvcrifice-Scheduled SSSOBSERVATIONS): TALL: Tip missing 5.0cm from base. HISTOMRPHOI0SIC OBSERVATION(S): nperlasto/perkersosis HISTOMORPHOLOGICOBSERVATIONS: io End of Record 1197 ycpeerspslasta/myparkeratosts (moderate) west Page 1154 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNIFREOORVTAIOUTCNIOOLPNEA4(F1OL8NU-ER0GL2OI0OTCTTEARNGPAETREGE(N4E7R0A)TIO1Nh)RATS SPONSOR'S STIOY NBER: T-6880.6 Individual Anima) GFirAopspGseenndeairnxadti1Wovsntamorpholosy Data ASeMx:AL waER: 1198 OSEsAeTHcrToRwE:. SIvucr ce-Schedsled R055 SERUATION(S): SEUEBAL: No gross charges HISTORPHOLOSIC OBSERVATIONS): Not apple "THE E0LLOUINGTISSUE(S)VEREWITHIN NORMALLIMITS: AREAL GLANDS End of Record 115 Tr ss Page 1155 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEU)DYTOWFO-AGMEINPOERMROIATUTONICOONLPE4R(1OT8NL-EU0OL2RI0OTOTCETRANGPAETREGE(NAEFRPA)TIOINh)RATS SPONSOR'S STUOY NABER: T-6899.6. Individual Anima GrAoospsenadnid HIivstomorpholosy Date Fi Gearation Asx:L WER: W1200 oDEeATHcto:TRE: S1acr ice-Horbund A055 BSERUATION(S): GAWoSInTteRhOrIgeNagTsi:EoSnTsIttaoNmoAsLeTnhuR,mAeCcrToaursdiItanoctercsetoginintoe,ns.-rdeainrsgateetnIindoesdnisze frreogemitopenirn.fpiovientwltcoar0a.t1iconnsIpnindpioamientters.izseecionnd Tanws: sent HISTORRPHOLOSICOBSERVATIONS): u"plrecoresirit(oosnn)(i.st)i:sg,lganlfdaouncldeaslraraSrTemsOu,cCoKsSaT,OMSCTHOMCH GEdiiisstttaeernnctteiidoonna:,uicCcEolClyioaMnts'prectudes evaluntion, ILE `SeedreonanIynflumation, submucosa, CECH HISTORRPHOLGSICOBSERVATIONS: ceo coSiTueon:uc hs: ddiesmtae/nitnifolnem(amatrikoend,) submcosa (ni 16) dAuidlsvctaeenrncste)id.oun`tgo(llmayandrsukilesa)rpraercelsud(ersoceavraatleu)ation epSetrrroiostpiohonynist()is:s,asrlfeao)cnadluta(rmimnicmoatla).(nininel) AUTOLYSISPRECLUDES EVALUATION: new End of Record 1200 vss Page 1156 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOVFO-AGMEINPOERMROIATLTONICOONLPE4(R1OF8NL-EU0RL2OI0OTCTTEARKIPAETREGE(NAERPA)TIOINN)RATS SPONSOR'S STUOY MMGER: T-6809.6. Individual nim GFrAiopBspesennadarinaxdtiH1ovsntomorphalosy Data AeyC WER: 1205 DsTeHae: S1herfice-Scheduled ROSSOBSERATION(): LcISViozEmeRe:.rLoemftpiYamtpearian)t ltoobe0-.5tma,n atroesasrerarngeingtoin HISTOMEPHOLOGICOBSERVATIONS): nTeuEpreorsttreo,ohyf,ocahlejpmauttoecteflolcuallar, diffuse HISTORRPHOLOGIC OBSERVATIONS: uve nFeocpreoraitrao,phyf.ohcaapla/tmotciefloctealr,(noiilfau)se (moderate) 1-0 Page 1157 ARGUS 418-020 REFROORDALLETI(OGNAVASGTEL)OYTOVFD-AGEWNPOERMROIATUTONICOOPNLE4R(1FO8LN-UE0O2LR0IOT0TCETRANPOEARTEGE(NAEFRPA)TIOINN)AATS SPONSOR'S STUOY WHGER: 1-089. Individual Anima GFirSopsGsaennearntadtiWIoVantomorshology Data AsoNi:AL wae: 1206 oDEsAeTHcape. S11her ice-Schedsled 055opsERATIONs): LXITNovEiCRe:onnL:etftraTantgeirnag)1nlobSez-etafnroamreps,iotono mteer0ou8s HISTOMGRPHOLGGICCOSERATION(S): rerophy, bepstacalller, diffuse HisTotOe ouseRRUAPTIO0N: uve: End of Racor 1206 pertropty,beptosellular, diffuse (at1e) TT wa Page 1158 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNIEORHAITMIONPER(FOLVLEORLDIOTCTTEARMGPAETRE GE(NAEFRPAOT)IOTNh) RATS SPONSOR'SPRSOTTUODCYOLM4B1E8R-0:20T-6880.6 Individual Animal GrAoospsenadnidx HIiVstomorshology Data Fi Sonaration ISxM:AL NBER: 1W207 sotATcH ornScheduled (Reduced Fart11ity) `05S OBSERVATIONS): SEMERALS Ho gross changes. HISTOMORPHOLOGICOBSERVATION(S): Not applicable THE FOLLOVINGTISSUE(S)VERE WITHINNORMALLIWITS: CoAT slo evtonomis PROSTATE SOHAL VESICLES es Page 1159 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEL)OYTVOOF-GAENNPERIROATOLTCIOOPLNE4(A1OPN6UE-R0L2II0GTETTEMR OFAETR.GE(N4E7R0A)TIOINh) TATS SPONSOR'S STIOY WAGER: T-6089.6 Individual! Anim) GFrAloGosaspneranandtiHIosntomorshology NData AsaNAL aER: 1211 oBEsNeTHsme:THE: S1nrifice-Scheduled S055QBSTRATIONS): SEMEBAL: No gross changes. HISTOMRPHOLOGICOBSERVATIONS): ot spplicable HE0101 TISSUES)AREWITHINNOR LINITS: AREAL Guus End of Racord- 1211 " Er we Page 1160 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-GAEWNROEMAOIALTTINOCNDER4(F1O6LNE-U0O2RL0OICTCTETRANGPAETREGE(ANFERROA)TIIOhN-R)ATS SPONSOR'S STIOY NUMBER: T-6809.6 Individust Anima) GrAopspseanndd WIsvtosorphalosy Data Fi Generation ASei:L weER: "1212 oDEsAeTHcTaBoE:. S1uvcrFice-Schadslad 8053 ORSCRIATIONS): SEERA: No gross changes. HISTOMEPHOLOGIC.OBSERUATIONS): Not applicable THEFOLLOUINGTISSUE(S)WEREWITHINNORMAL LINITS: AREAL GLANDS est Page 1161 ARGUS 418-020 REPROODRUACLTI(OGNAVASGTEU)DYTWOOF-GAEMNPOERMROIATLTOINCOONLPER4(F1OL8NUE-O0R2LO0ICTCTTEARNEPAETRE.GE(NAEFRFA)TIOINh) RATS SPONSOR'S STIOY NUMBER: T-6889.6 Individual eal GFAriooGspesennaedrniatWiIiovsntomorsholosy Data asox:L wee: 1W217 DsEoAeTHcmeTHE. SIuvcrFice-Schadsled 8053 QRSCRIATIONS): SEAERAL: No gross changes. HISTOMEPHOLOGIC OBSERVATIONS): Not applicable HISTORPHOLOGIC OBSERVATIONS: AOREMAL GLANDS: End of Record 1217 vacuolation, cortex (minis) = Page 1162 ARGUS 418-020 REPROODLICTI(OGNAVASGTEU)DYTWOFO-AGWEINPOERNROIATLTOWICOONLPE4R(1OF8NL-EU0O2RL0OI0TCTETRANGPAETREGE(NAEFRPA)TIO1Nh)RATS SPONSOR'S STU WMGER: 1-699. Individual imal FGAirooGspesenneadrniadtis1o1tnomorphalosy Data MseAx:L weer: W1218 DsEAoTH pTYR:E. SuIvcrice-Schedsled `053opsERTIONs): A0U.E2R%: 0L.o2f0tm;Tactaaruad)ateIobTeo-beoneonetantananadrebnl.acOkdaerne.s, HISTOMORPHOLOSICOBSERVATIONS): Phhayeopmresortsto1rpeoo,piheysT,ts,hoeTpeaaxtstcoercahefnloaelcudslu]aarr,y,dimfiflutsiefocal HISTORRPHOLGGIC SERVATIONS: ves: Ed of Record 1216 rRReesrsastrotpoooiyaf.tescH,aelp/esxmttiortasimnteoidcouellrla.r(yd,s1iFmiehei of)eocoail e(ninioa Y ws Page 1163 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DY THOOF-SACMNIPERORONATITOLICWOONLPE4R(1OF6NLE-U0O2LR0IOTCTCETRAIPAETREGE(NAEFRFA)TIOTNh) RATS SPONSOR'S STIOY NBER: T-6889.6 Individual Anas] GFiAr"opGgpesneeanrndadti1Wo1sntomorphalosy Data Asexv:a WER: W1223 wDEeATaH p:THE: Sacrifice-Schedaled 805 GRSERUATION(S): L0TUo.E2cc:oaunLitne,fdtiraaTmnaetgteiernrag.l IInobsiez-e.tafnroamrepaI,TGOtIoRoEnutmoerous HISTONRPHOLGGICOBSERVATION(S): hypertrophy, hepatocellular, diffuse HISTORPHOLOSICOBSERVATIONS: Liver: End of Record 122 hypertrophy, hepatocellular, diffuse (eid) " esr Page 1164 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEWNPHERROOATNTONICOONLPE4R(1OF8NL-EU0OL2RI0OTITCETRANPGEARTEGE(NAEFRPA)TIOTNh)TATS SPONSOR'S STUOY NIMBER: 1-689. Individual eal rsoospsenadnisx Iivstomorshalogy Data Fi Generation a sex: wees: 1W224 DEATHtomeTHE. Sacr fce-Schedaled BOSS ORSERVATION(S): KIS: Right- pelvic dilation, s1ight HISTORPIO\GSICOBSERVATIONS): aitatation, pelvis HISTOMRPHOLOGICOpsERUATIONS: xioners: End of Record 1224 datation, paivis (sderate) ws Page 1165 ARGUS 418-020 REPROOILCTI(OGNAVSAGTEU)DYTUOOF-AGMEINPOErNRoIAtLToNIcOoNlPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRFA)TIOINh)RATS SPONSOR'S STUOY NUMBER: T-6809.6. Individual, Anima] GFirAooGspesenneadrniadtHiIoivnstomorphalasy Data MaAL ween: W1225 DsEoATHcnr:TYPE. SIuvcrice-Schedsled R055 QOSERUATIONS): SENERAL Ho gross changes. HISTOMRPHOLOGICOBSERVATIONS): ot apicable HisTomspuoL0GIcopseRvATIONS: AREAL GLa: End of Record 1225 vecuslation, cortex (aininsl) or Tr wes Page 1166 ARGUS 418-020 REPRROADILTI(OGNAVASGTEU)DYTOWFO-AGEMNPOERMROIATLTONICOONLPE4R(1FO8LV-U0OL2R0IOTOTCETRAV9G6A%TESO(UABFAPT)IOTNh)RAT_S SPONSOR'S STUOY NBER: 7-689. Individual Anima) Grsoospsenadnid HIiVstororphalosy Data FI Generation sAexN:A WER: W1229 oGEsNeTHcThEr:: 1Scrifice-Scheduled S055 QRSERUATIONS): SHLAESE): TSownollaerne,s,b2o.t0h x 1.5m, extends into the cco HISTOMRPHOLOGIC.OBSERVATIONS): Rcheocnrdoraotpsathy. auricular HISTONRPHOLOGICOBSERVATIONS: Sepsle)en:: End of Record 1220 Rcheocnrdornotpaa.t(hnye.rkeadu)ricular (marked) wr Page 1167 ARGUS 418-020 REPROODRIACLTI(OGNAVSAGTEU)DYTUODF-AGWEINPOERNROIATLTOWICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRPA)TIOINh)RATS SPONSOR'S STUY WAGER: T-6099.6 Individual Anima Grsoospsenadnidx WIsvtomorshology Data FI Generation ASexv:a wer: 1232 sDEoAeTHiTeHE:, S1acrific-Scheduled 8085 GRSERVATION(S): KIDIEYS: Right- pelvic dilation, slight HISTONRPHOLGSIC OBSERVATIONS): dilatation, pelvis HISTORRPHLOG1C seRvATIONS: xiowers: End of Record 1232 dilatation, pelvis (110) wn Page 1168 ARGUS 418-020 REPROORDAILCTI(OGNATASGTEU)DYTVOOF-GAEMNPOERVROIATNTOMICOOPNLE4R(1FO8NL-EU0GL2OI0OTCTTEARNOPAETREGE(NAEFPR0A)TIOINN)RATS SPONSOR'S STUOY NMGER: 1-3899.6 Individual Anima GFirAoosSpseenaadrniasxtiHIoivnstasirphalosy Data sax:AL eR: W1234 GooEsNeTHsTmHoEgE:: SIVorifice-Schaduled S055 OBSERVATIONS): Lr[Uaefng:inlTgaatnefrrarolmesp`Tsoibesotenodoanm1u0mT0eorb.oe7smsovesotcaonunatr.es 0.2m, HISTONORPHOLOGICOBSERVATIONS): RnheyaEpmremorstatrteoirphofyno,,cahtcejhmsrutotonecitcaf,loflcouacelorl,/mduilftfiufsoecal HISTOORPHOLOGIC OBSERVATIONS: Liver: End of Record 1234 nITeyncpFreiorastmtrasot,pihoyfn,o,chaaclph/armtouontciiecfl,olcfueot)cea.l(n/diailuefl)ftuifsoeca()sod(eariodt)e) wn Page 1169 ARGUS 418-020 REPRGORDAULCTI(OGNAVASGTEU)DYTWOOF-AGWE"INPOERNROIATLTONICOONLPE4(R1OF8NL-EU0O2LR0IITTCECRTAPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S TOY NABER: T-6809.6 Indivicus] Animal rFisoonGpseenneadrniadxtHiIiovsntomorphalosy Data a sex: wees: "1235 sDEoATHoqr:IVE: SIuvcrice-Schadsled A058OBSERVATIONS): LCITVaoEfuRtn:TarTtoaennrgaailrnegslsoi.nbema4ee:d.5ianfternoTonabpveientsposooirnmatnmgetironcgu0s.f5rcotmmo, pirpotnt 5 0 en HISTOMRPHOLOGICOBSERVATIONS): hypertrophy. hepatocellular, diffuse HISTORRPHOLOGIC ORSERVATIONS: Liver: End of Record 1235 Popertrophy, hepatocellular, diffuse (soderate) ws Page 1170 ARGUS 418-020 REPROGDOAULCTI(OGNAVASGTEL)OYTOIFO-AGEWIOOENRITAUTNICONPE4R(1FO8LK-U0O2RL0OICTCTETRANPGEARTEGE(NAEFRPA)TIOINh)ATS SPONSOR'S STUOY WAGER: T-6889.6 Individual nies) GFrAiopGspasennaadrinaxtiiIosVntomorsholosy Data Asowx:a we: "1238 BcoEeATcTmIeE:: S1vhrifice-Schaduled 5055QOSTRUATION): SEACH Ho gross changes. HISTOMORPHOL0GICOBSERVATIONS): tot applicable THEFOLLOUNGTISSUES)VERE WITHINbog LTS: AREAL sus Er TTT wr Page 1171 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-SAEMNIPEORRMOAITTUOIMCOOPNLER4(F1OL8NL-EK0RL2OI0OTCTTEARNGPAETREGE(NAEFRPAOT)IOTNN) RATS SPONSOR'S STUOY MBER: T-6889.6. Individual Anima) Grsoospsenadnidx HIivstonorpholosy Data Fi Generation sex:AL weER: W1240 sDEAoTHso:TE: SaIvcrifce-Schedaled 805s oBSCRATIONS): KIDNEYS: Right- pelvic dilation, sight. HISTOORPHOUGSIC OBSERVATIONS): mainnaetraatliiozna,tiopne,lvipselvis Pyperslasis,petvic/paptlary urotheliva HISTOMRPHOLOGICOBSERVATIONS: xiowers: End of Record 1240 dnFiyilpnaeetrrasatlliaiosznta,at.iopnep,levilpsevliv(icasi/dp()sainpriytmalu)rothelum (siniesl) wrs Page 1172 ARGUS 418-020 REPRCORDAKLTI(OGNAVASGTEU)DYTOUFO-AGMEINPOERNROIATUTONICOONLPE1A(O8TNL-EU0O2LR0IOTOTCETRANPGEARTEGE(NAEFRPA)TIIOhNRATS= SPONSOR'S STUOY MBER: T-6809.6 Individus) Anima) Grsoospeenadnidx HIiVstonorphalosy Data FiGanaration ASexv:a wren: W1200 oseaeTHour: Sacrifice-scheduled S055opsERUATIONSS): SENERAL Yo gross changes. HISTONORPHOLOSICOBSERUATION(S): Nat applicable HISTORRPHOLGSICOBSERVATIONS: AREAL GLANS: hypertraphy/vacualation, zona glemeruloss (s11d) HEFOLLOUINGTISSUE(S)VEREWITHINNORUAL LIMITS: CSEoMRIUNAALTIVNEGSIGCLLESK Teepsitoisioms Frum FRosTATE End of Record 1241 ws Page 1173 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEI)OYTWOFO-AGEMIROENORIATLTNOIO!NFE4(A1OP8NL-EU0O2LR0ILTTTEARNGPAETREGE(NAERFA)TIOINn)"ATS SPONSOR'S STUOY WAGER: 1-680. Individual Anima GFirsoo3GpsaenneadrniadxtiWIosVntomorshology Data foAsL woe: 1245 oCsEeNTaRoEe,: 1Sacriice-schadiled SH0SS OBSERVATIONS): HEAD: Leston, 0.2m in dianater. HISTOORPHLOGICGESERATIONS): dermatitis, chronic HISTOMORPHOLCSIC OBSERVATIONS: wean: nd of fncord- 1263 dermatitis, chronic (moderate) wr Page 1174 ARGUS 418-020 REPROODRAULCTI(OGNAVASGTEL)OYTOVFO-AGEWNFOERVROAITToNIcOoNPE4(R1OP8NL-EU0O2LR0ICTTTEARVOPAETREGE(NAEFRPA)TIOTNY)ATS SPONSOR'S STUOY NBER: 1-689. Indivicus] Animal Grsoospsenadnidx HIivstonorpholosy Data Fi Generation asex:L wees: W1204 sDEoAeTHcTgYP:E: S1acrice-Schedaled GROSS OBSERVATIONS): SENERAL: No gross changes. HISTONORPHOLOGIC ORSERUATIONS): hot applicable HISTOORPIOLOGIC RsERUATIONS: AREAL GLANDS: prvi VEIyayacptuelerelt)ar,toipohpnya,/rvseccoduristsletaxotrit(osin,ntzeon)a glamerulosa (siniesl) HEFOLLOVINGTISSUE(S) VEREWITHINNORMALLIMITS: CTOeRsUtLsATING GLAND Epinions rRostare Ed ofRecord zee SoC Vestas TT ws Page 1175 ARGUS 418-020 REPROORDAILCTI(OGNATASGTEU)DYTVOOF-GAEWNIPEORRVOAITTUGIHCOOPNLE4R(1FO8NL-EU0RL2OI0ITCTTEARIGPAETREGE(NAEFFROA)TIOINN)RATS SPONSOR'S STUOY WAGER: T-6899.6. Individual Anim GtrAropspasentadniidxoH1nvistomorpholosy Dota Asexv:a rer: W1250 DoEsAeTHone: Svaori fice-Schedsled 8083 GRSERUATION(S): TALL: Amutar constriction. HISTOORPHOLGGICOBSERVATIONS): Wo microscopic change to correlate HISTOMRPrOLOGICopstrvATIONS: oy No microscopic change to correlate `THEEOLLOUINGTISSUC(S)VEREWITHINNORMALLINITS: ni End of Record- 1260 CTT -------- ws Page 1176 ARGUS 418-020 REPROCDRAILCTI(OGNAVASGTEU)DYTVOFD-AGMEINPOERNROIATLTOMICOONLPE1R(O6FNL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S STUOY NUMBER: T-6889.6 Individual Anim) GrAopspsendainxd IWvstomorshology Data Fi Generation Sa o eR: W1251 sDEoAeTHcTYnE: r: S4acrice-Schedsled R053 OBSERATIONS): LrfIreEaaRms:,piLentfpotoo.lnnTutamteatrroosu)0s..3Totcobnecioanunnddti,ammeedrtiaeonrnginTgobien stiazne HISTONORPHOLOGICOBSERVATIONS): hypertrophy, hepatocellular, diffuse HISTONRPHOLOSICOBSERVATIONS: Liver: End of Record 1251 Pypertrophy. hepatocellular, diffuse (moderate) ws Page 1177 ARGUS 418-020 REPRGORAOLTI(OGNAVASGTEU)DYTHOOF-GAEWNFGERNROIATLTOINGOONLPCA4(F1O6LNE-U0O2RL0OICTCTETRAGAPTEER.GE(NFEPROA)TIOTNh) RATS SPONSORS TOY MBER: T-6889.6 Individual Anima) GrAoospeenadnidx HIiVstomarpholosy Data Fi Generation Asai:L weER: W1254 oDEsAeT TPEcog: Sacrifice:chadulad 8055GESERATIONS): SEUEBAL: No gross changes. HISTORRPHOLGSIC OBSERVATIONS): Notapp feable HISTORP0\G5ICOBSERVATIONS: PARROESTAALTEGLAM: ITynpFelratmrmaotpihoyn/,vaccuharloantiicon(,eiznoisnaal)glanerulose (nile) HEFOLLOUING TISSUES) WERE WITHINNORMAL LIMITS: CTEOSUTINSTING GLAND epiotomis Piru End of Record 1254 SoH vesicles wear Page 1178 ARGUS 418-020 REPROODRAILCTI(OGNAVASGTEU)DYTOWFD-AGMEINPOERMROIATUTOHICOONLPE1R(OF8NL-EU0O2LR0IOTXTCETRAKPGEARTEGE(NAEFRPA)TIOINh)TATS = SPONSOR'S STUDY NMGER: T-6899.65 Individual Anime) GFirAooGspseonnadrniadxtiiIosvntamorpholoay Osta Asex:L BER: W1256 sDEoAeTHoTrYR:E. S4aceice-Scheduled HOSSOBSERVATIONS): LIVER: Left laters) Tobe- tan ares, 0.8m. HISTOMRPHOLOGIC. OBSERVATIONS): Pupertrophy, hepatocellular, diffuse HISTONRPH0\GGIC SERVATIONS: uve: E04 of Recore- 1255 Pypertrophy. hepatocellular, diffuse (af10) wes Page 1179 ARGUS 418-020 REPROORNACLTI(OGNAVSAGTEU)DYTOAFO-AGWEONPERMEOIATLTONICOONLPE(4AO1FN8LE-U0O2LR0IOTCTCETRANPAETREGE(NAEFRFA)TIOTNh)RATS SPONSOR'S STIOY NUMBER: T-6880.6 Individual Aiea) GFrsiooGepasenanardnaidti1Ho1instonorphelosy Data feAtv wer: W1252 oDoEsAeTHcrToEw:: Svacrice-Scheduled GROSS OBSERVATIONS): LIpSVainEnpRae:rienTstosntaoprien0ap.so5,imn:mtetTdooifct0.l1laoctbneerafliveTobteantaarneassix TALL omar natrigtions of tail. HISTOMRPHOLOGIC OBSERVATION(S): + hypertrophy, hepatocellular, diffuse constriction. focal HISTOMRPHOLOGICOBSERVATIONS: huvee: Ed of Recore- 1282 rriircophy. heepeatnocellular, difuse (moderate) ess Page 1180 ARGUS 418-020 REPROGDBAULCTI(OGNAVASGTEI)OYTIGFO-AGEWIROENROIAUTTNIOCNPE4R(1FO0LV-G0O2RL0OIGTCTETRANOPENRT.EGE(NNE7R0A)TIOINh)AATS srousoR'S STUOY WMGER: T-6889.6 Idividunl Anmal GFrAieoGspasennaadrntadxtiWIoVsntomrpioloay Data sAo:L wee: W1263 sDEeATHGToYvPeE:: vSpontaneous death ssoosERUATION(s): SLES: Coren! apsity, both eyes. HISTOHRPHOLOGICGRSERATIONS): Yo microscopic chane to correlate HISTOMRPHOLCGIC cpseRMTIONS: eres: ho microscopic chang to correlate HE0LLINGTISSUE(S) EREWITHINNOLLIMITS: eres wa Page 1181 ARGUS 418-020 REPROODLCTI(OGNAVSAGTEU)DY THOOF-SAEWNIPEROROMATITOLICMOONLPE1R(O6FNL-EU0O2LR0IOTCTCETRAIPAETREGE(NAEFRPA)TIOTNh) RATS srousoR'S STLOY WAGER: T-6889.6 Individual inal rsoospeenadnisx WIivstamorshotosy Data Fi Generation A5L ser: 1264 GoEsReTHciToYuFrE:: Spontaneous death SassOpsERMTIONGS): E55 Comneal opacity, both eyes. HISTORPHOLOSICOBSERUATION(S): No microscoplc change to correlate HSTOMORBHOLOGIC sERvATIONS: eves: No microscopic change to correlate HEFOLLOUINGTISSUE(S) WEREWITHINNORWAL LIMITS: eres End of Record 1264 TT ws Page 1182 ARGUS 418-020 REPROODRULCTI(OGNAVSAGTEU)DY THOOF-SAENNPERROIATTOLICOONLFE4A(1OFN6LE-L0OL2RI0GTOTCETROGPAETREGE(NNEFROA)TIOINN) WATS SPONSOR'S STI MER: T-6880.8 Individual Anime) GFAirooGspesenneadrniadxtHiIiovnstomorpholosy sta sex:AL eR: 1W266 oDEsAeTHcToYuPrE:: Sacri fce-Schedsled O8R05S3ERATIONS): SEUERAL: No gross changes. HISTOORPIOUGSIC OBSERVATIONS): Not applicable HISTONORBHOLOGIC OBSERVATIONS: PaBRIOpTSUTIAmTTEa:Ycus: haSyopf)elratm.rmaotphhpoyanvr,sacsuiunoptlpeaurtrmieaodtnii,avezo(nsainoinlsolm)eruloss (n11d) TH FOLLOMINGTISSUE(S)VEREWITHIN NORMALLIMITS: CORUATING GL eproiomis soma vesicues Testis End of Record 1265 ws Page 1183 ARGUS 418-020 REFROOBRALLETI(OGNAVASGTEL)OYTGWFO-AGERNREVEOIATTNIOCNPE4R(1PO6LF-C0O2RL0OICTCETRANPOENTEGO(NAGFRPA)TIOINh)ATS SPONSOR'S STUOY WAGER: T6209. dividual Anna) GFrAiooGepasennaadrntasxtiWIosVntamorpraloay ta A8a wees: W1268 wDEeATHwTrYP:E: SacrFice-Schadalad sinsopsERATION(s); LICVoERE: Taannaeres, raSdzieofbomemtooormnero8us84tox HISTORPHOLOIC STRIATIONS): rpeetrrtorstoep,hyf.ocahtejpmauttoeceflolcuallar, diffuse HsToORPIOL001C opstavATION: uve: End of Record 1268 rRepceriorsas,sfhoycarlep/amotsiefloucatla,(su110s) e (sured) wer Page 1184 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEL)OYTHOOF-GME"NOFERRNoATIToIcOaNLFE4R(1OF8NLE-L0O2LR0IOTCTCETRVOPAETREGE(NNEFRPA)TIOTNh)AATS = SPONSOR'S STO NBER: T-6869.6 Individual Anima GFIrsosGpseneaprnastiW1oivnstomorsholosy Data 5AL eR: W1269 oDoEsAeTHhoTYuPrE:: Svacrice-Schedsled SA0SS OBSERVATIONS): SEAL ho gross changes. HISTOMRPHOLOGICOBSERVATIONS): ot applicable THE0LLouINGTISSUE(S)WEREWITHIN gman,LiwrTs: PRAORSETAALTEGLANDS CSEOHRIUNAALTIVNEGSICGLLEASD Teepsttosomis End of Record 1269 PrruimRy vss Page 1185 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNIPEORRMOAITTUOINCOOFNLER4(F1OL8NU-EO0RL2OI0XTCTTEARNGPAETREGE(NAEFRFA)TIOINN) RATS SPONSOR'S STUDY WAGER: T-6899.6. Individual Animal GrAoospsenadinx WIivstamorpholosy ata Fi Generation Asex:L NBER: W1270 oDEsAeTHcToYuPrE:: Sacrifice-Schadaled 805 GRSCRVATION(S): ALL: Amnatar constriction. HISTORRPHOLGGIC OBSCRUATIONS): No microscopic change to correlate HISTONRPIO\GGIC BSTRVATIONS: we No microscopic change to correlate THEEOLLOUINGTISSUC(S)VEREWITHINMORALLIMITS: i Ed of Rocore- 1270 vets Page 1186 ARGUS 418-020 REPROOBRLALCTI(OGNAVASGTEL)OYTGUFD-AGEMNPOERMROIATUTONICOONLPE4R(1OF8NL-EU0O2RL0OIOTCTETRANPOENRTEGE(NAEFRPA)TIOINh)ATS SPONSOR'S STUDY WINGER: T-6299.6. Individual Anim GFrAiopBepesennaadrniadxtiWIovantmorphalosy Date Sa o ves: W1271 oDuEsAeTHrToYwPE:, vSacr ice-Scheduled S058opsERuATIONS): SEMERAL: Yo gross changes. HISTORRPHOLGSIC OBSERVATIONS): Not applicable HISTOMORPHOLOSICOBSERVATIONS: PeROpStToArToE:ms: aItnrfoiplhtyr,atifoonc,almo(nnio1ndc)lear-cell, focal (aininal) HEFOLLOUINGTISSUES)WEREWITHINHo LTS: so wos COASUATING GLAND Piru SoMa VESICLES Edo Record dT 1v-s0 Page 1187 ARGUS 418-020 SAL (GAGE) io-SNEDATION (OK LITER FE SNCoTN) SPONSOR'SPRSOTTOUCYOLM4B1E8R-:020T-6889.6. Indivicus] Anima] GFirsooGspasennaadrniadtiHIoivnstomorpholosy Data akyL weer: 1273 oDEsAeTHcThYoPrE:: SaceFice-Schadaled 8055 QRSCRIATION(S): SEERA: No gross changes. HLSTOMEPHOLOGIC OBSERVATIONS): Not applicable HISTORPHOLOGICOBSERVATIONS: AOREUAL GLANDS: hvaycpueorltartoipohny,/vaccourstleaxti(ona,iznon)a glamerulosa (sinieal) TH FOLLOMINGTISSUE(S)VEREWITHINNORMAL LINITS: CTOeRsUtLsATING GLAND eptoroms osTATE SEMAL Vests comes: Prue 0Th0e1dpitbuoftcahrayinveads dvaasmagnoetd aatdeqnueactreopfsoyraenvdaltuhaetisoen.ction that ISSUES) NOT AVALLALE 08 EVALUATION prrurmaRy End of Record 1273 wor Page 1188 ARGUS 418-020 REPROGDOAULCTI(OGNAVASGTEI)OYTGUFO-AGEOIRNEOIRATUTNOIO!NPEdR(1FOaLV-U0O2RL0OICTCTETRANGPAETREGE(NNE7R0A)TIOINh)ATS sronsoR'S STUOY WAGER: 6889.6 Individual Anas) GFrAiooGsaspneaarnnadtiW1osntomorsholosy Data wsoa we: "1275 sDEeATHcTaPEo. Svacr co-Norsbund 8055ORSTRATIONS): LSISEVaEiERn:;t MTeSadenaiila?nngToinbe-sizteanfarroemasArtog0annumetroou0s16t8o. HISTORRPHOLOSIC OBSCRATIONS): hRSpieerrtetnrrsooshyT.ackhejpmatuotctelflouclaalr, diffuse HISTOMRRFHOLCSIC OBSERVATIONS: uve snueen: End of Record 1275 preorrysi,rma.orkee d tapatcs ce Tar, diffuse (110) TTT wo Page 1189 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTHOOF-SAEWHFOERMROIATLTOIMCOONPLESR(1OFNeUE-O0RL2OI0CTCTTEARNCPAETREGE(NAEFRFAO)TIOTNh) RATS SPONSOR'S STUDY NBER: T-6889.6 Individual Anira) Grsoospsenadnidx MIiVstomorphalasy Data Fi Generation AsoL waER: 1276. sSeEITge: vSuerrice-soneaies ROSS QBSERVATION(S): ER: ars~e. HISTORRPIOUGGIC OBSCRATIONSS): hDyFpermtertorphoys. chrohempaat.ocelHlular,o/mdisff1uaseeca! HISTOMORBHOLOGICOBSERVATIONS: ver: End of Record 1276 Iiynpfelratmrmoapthiyo.n,hecphraotnoicce,lluftoecra.l mduilftfiufsoeca(lmod(emraitne)e) ws Page 1190 ARGUS 418-020 REPROGDRAULCTI(OGNAVSAGTEI)OY TWOOF-GAENNPERRIOATLTOICOONLFE4(R1OF8NLE-L0O2LR0IOTTOECRTNPNETREGE(NNE7R0A)TIOINh) AATS SPONSOR'S STO NBER: T-6889.6 Individual 1 GrAoospsendainxd WIiVstomorpholosy Data Fi Generation AsexL BER: W1278 sDEoAeTHoTpYR:: 3Scheduled (Reduced Fert1ity) 8055 QRSCRIATIONS): SEERA: No gross changes. HISTORIOUIC 0BSTRATIONS): Not applicable HISTOMORPHOLOGIC OBSERVATIONS: eptotoms: Inf tration, mononuclear-cell, focal (minima) HE FOLLOMINGTISSUE(S)VERE ITHINNORMALLIMITS: CORULATING GUND PROSTATE soma vesicues Tesnis End of Rocord- 1278 west Page 1191 ARGUS 418-020 REPROODRIALCTI(OGNAVASGTEU)DYTOWFO-AGEMNPIEROROMATUTONICOOPNLE4R(FO1LN-UE0O2LR0IOTOTCETRANPGEARTEGE(NAEFRPA0T)IO1Nh) SATS SPONSOR'S STUOY WAGER: T-6089.6. Individual Anim GFirAoosepseernaadnitsiWIoivnstmorpholosy Dota SnoL ser: 1279 sDEAoTHrTH:E. S1aceice-Schedsled S055 OOSERUATIONS): LTIoVEcRo:unLtoft lateral Tobe- tan areas too numerous HISTORPHOLOSIC OBSERVATIONS): hypertrophy, hepatocellular, diffuse HISTOORP0I061COBSERVATIONS: ves; 0d of Record 1279 hypertrophy, hepatocellular, diffuse (moderate) ss Page 1192 ARGUS 418-020 REFRGGORALLCTI(OGNAVASGTEL)OYTOWFO-AGEMNPOERNROIATUTONICOONLPE4(A1O8RN-EU0OL2SI0TOT0ECRTPOENR.TGE(NNEFRPA)TIOINh)ATS SPONSOR'S STUOY MNGER: T-6899.6. Individual Anim) GAroospsenadnid HIvistmorphotosy Data Fi Generation Asex:a wees: W1283 sDEoAeTHoTHE:p: S1acrice-Schedsled R053 QRSCRUATIONS): LILpiEonRp:ouimnLetefrt1o0n.T0a.tte9aracx)o0a.un1dmr.maendgiianng oInbezs-etafnroamress HISTORRPIOLGGICOBSERVATIONS): hR ypertroe phy. p threpaatmoceo llularr.y,difmfeusee e) HISTOMRPIOLOGICOBSERVATIONS: uve: Ed of Record 1289 hFoepmasrttorpooptheys,ts,heepxattroacmeeldiuultlaarr.y.dimffiutsiefo(caalld)(nininal) vse Page 1193 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTOUFO-AENWPENRROIATLTOINCOONLPER4(F1O8LNE-U0O2RL0OICTCTETRANIPAETREGE(NAEFRRAOT)IOINN) RATS SPONSOR'S STIOY NBER: T-6889.6 Individual Anima) GrAopspsenadnidx IHVistomorphalosy Date Fi Generation Asax:L WHER: W1287 tDEAoTHe:THE. 1Sacri fce-Schadaled R053 QRSCRIATIONS): SEAERAL: No gross changes. HISTOMEPHOLOGIC.OBSERVATIONS): Not applicable HISTORPHOLOGICOBSERVATIONS: AEPRIEDAIOLMIGSu:ns: ITyrpfeTrrtarotpihoyn/,vacmuosnloantiicotne,srz-ocneal:glafmoerculo(sasin(ssiin)ieal) THEFOLLOVINGTISSUE(S)VEREWITHINNORMALLIMITS: coRiATIG GU prrumRr FRosTATE SoC vestcues wer Page 1194 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SACMHIPEROROMATITOLICMOONLPE4(R1OF8NUE-O0R2LO0ICTTCETRANPAETREGE(NAEFRFA)TIOINh) RATS SPoNsoR'S STIOY MAGER: 1-6669.6 Individual eal Gsroozpsenadni HIsVtamorsholosy Data FiGaneration sao:L wees: W1299 oDEoATHoTYnR g: S1acefice-Schadsled S055OBSERVATIONS): SEUEBAL: No gross changes. HISTOMRPHOLOSIC OBSERVATIONS): hot applicable HisTomspioL0G1coaseRuATIONS: AOREMAL GLANDS: ypertrophy/vacustation, zona glomerulose (mild) TH FOLLOUINGTISSUE(S)VEREWITHINNORMAL LINITS: SCOPGUALTATIVNEGSICGLEOS TeEpStToSioms prrumy osTaTE End of Record 1288 vse Page 1195 ARGUS 418-020 REPROORDACLTI(OGNAVASGTEU)DYTWOFO-AGEMNPOERMROIATLTOWICOONLPE4R(1OF8NL-EU0O2RL0OICTCTETRAVIPAETREGE(NAEFRPA)TIOTNH)RATS SPONSOR'S STUOY NIGER: 6889.6 Individual nim] GFirAopspGseenndeairnxadtiiIovsntomorphlosy Date Asex:L eR: W1293 sBeERT:cap: VSaorfce-scndiled R053 QRSCRIATIONS): LILoVa5nEeRnd;.reLsestraTnatgeirnag)InTobseizetopfrnoummeprionupsointto tcoount HISTOMIRPHOLOG1C.OBSERVATIONS): hypertrophy. hepatocellular, diffuse HISTOMORPHOLOGICOBSERVATIONS: uve: EL Iypertroshy. hepatocellular, diffuse (soderate) ss Page 1196 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTVOOF-GAEMNPOERMROIATUTONICOOPNLE4R(1FO8NL-EU0RL2OI0OTCTTEARNGPAETREGE(NAEFRPA)TIO1Nh)SATS SPONSOR'S STUOY WAGER: T-6289.6 Indivicus] Anima] GFirsooGspesenneadrniadxtHiIoivnstomorphalasy Data Asex:L BER: W1295 sDEAoTHnTYgR. : S1acriice-Schadaled R053 QRSCRIATIONS): LITVaERr;iLefItn Tsaitzeeraf]romTopbeifnoutr tofno 0a.n3downhite aress HISTOMEPIOLOGIC.ORSCRIATIONS): hypertrophy, hepatocelluler, diffuse HISTORRPHOLOGICOBSERVATIONS: uve E04 of Record: 1295 ypertrophy, hepatocellular, diffuse (soderate) 1-100 Page 1197 ARGUS 418-020 REPROODLUCTI(OGNAVSAGTEU)DYTHOOF-SACWNPOERMROIATLTOIMCOOPNLER4(F1ONU8EO-R0OL2CI0CTTTEARMEAPTEER.GE(NAEFRRAO)TIOTNh) RATS SPONSOR'S STUDY NIGER: T-6889.6 Individual Anim Grsopeesndainnd W1vistmorpholosy Data Fi Generation A S ser: 1F312 oDEsAeTHcapT:HE. So1cfice-Schedaled R055 OBSERUATIONS): SENERAL No gross changes. HISTOMRPHOLOGIC.OBSERVATIONS): hot applicable HISTORPHOLOSIC OBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTER pprreesseennccee ooff cgroorspionrga/alnuttreaal follicles HEFOLLOWINGTISSUES) WERE WITHIN NORMAL LINITS: APIRTEUIATLARYGLANS cToenmiisx Voniecs Ed of Record 1312 overs) Tr 01 Page 1198 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)OYTVOOF-GAEWNPOERNROIATLTOINCOONLPER4(F1O6LVE-U0O2RL0OICTCTETRANOPAETREGE(NAEFRFA0)TIOINN) RATS SPONSOR'S STUDY NHGER: T-6889.6 SABL WER: P1321 div"iin) ossinal GFrloGaGrosenaeanndrsatiMHosintsmtormsoholcyhd Onta DsEAoTHso:APE: |Sacrifice-Scheduled 8035 OBSERVATIONS): GENERAL: No gross changes. HISTONRPHOL0GIC OBSERVATION(S): Not applicable HISTO0GM1COOBRSERPVAHTIOONSI: (OVARIAN FOLLICLES/CORPORA LUTER: ures: pprreesseennccee ooff cgorropwoirnag/alnuttreasl follicles macrophages, pigmented (soderate) THEFOLLOVINGTISSUE(S) WEREWITHINNORMALLINITS: APIToUIETARLY as cViocIxA omares ovoucr(s) e102 Page 1199 ARGUS 418-020 REPROODRLALCTI(OGNAVASGTEU)DY TOWFO-AGMEINPOEOMRTIAUToNIcOoNPE4R(1OF5NL-EU0O2RL0OIOTCTETRANGPAETREGE(NAEFR7A0)TIO1Nh)RATS SPONSOR'S STUDY MGER: T-6080.6 Individus) Anima) GFAriooGspesennaedrniadtiWIosvntomorphalosy Data saoL eer: 1328 SosEeTcaHgeE: h1aririce-schouted A058 oBSERUATIONS): SEERA Yo gross changes. HISTOMRPHOLOGICOBSERUATION(S): Nat applicable MISTOMEPHOLOGICOBSERVATIONS: urOVeARI"AN FOLLICLES/CORPORA LUTEA: VAGINA: Brparecersnoegenhceaegeo1sf,cgorrpgeiagmrcenateidTautfeos ifeo(ronldaratceles mcification (ar1d) HEFOLLOWINGTISSUE(S)VEREWITHINMORAL LIMITS: APIRTEUIATLARGYLANDS cai omares End of Record 1328 onuer(s) 1-103 Page 1200 ARGUS 418-020 REPRGOBRLACLTI(OGNAVSAGTEL)OYTGWFO-AGENNPERIROATLTOICOONLPE4R(1OF8NL-EL0O2LR0IOTCTCETRNG7A6T%EGE(NNE7R0A)TIOINh) 7ATS SPONSOR'S STUOY NUMBER: T-6889.6 IndficviaildualAinieosa)l GFiroGmenaenrmasgtMiosntasmtomrrshsahtoytosyOaata A sex: WER: F1335 BsAToH r:TE. S1acrifice-Scheduled 80S GRSCRWATION(S): BRE): Swollen, both, HISTORRPHOLCSICOBSERUATION(S):| chondropathy, auricular HISTORPHOLOSICOBSERVATIONS: OeVsAR)IA:N FOLLICLES/CORPORA LUTEA: wrens: cpphrroeenssdeernnoccpeeatoohffy.gcroorawpuiorrnisgc/ualunattrersa(lssfrokeldl)icles Pacroghages. pigmented (roderate) HEFOLLOWINGTISSUE(S)VEREWITHINNORMAL LINITS: APIRTEUIATLARYGLAS cVaicii ouseies Ed of Record 1335 TT ovtoer(s) TT toe Page 1201 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-ASMEFKIREOOANTAIOTUCIHOOLNPER4(F1OL6NU-ER0RL2OI0OTCTTEARNGPAETREGE(NAEPROA)TIOINN)RATS SPONSOR'S STUDY NNGER: T-6680.5 Indica) Aneal rsoospsenadnis W1s1tomorsholosy Fi Generation Data sAai:L Wee: F1300 DsEAoTH m:THE. S1acrifice-Scheduled 8058 pSTRATIONS): SENEBAL: No gross ches. HISTORRPHOLOSICOBSERUATION(S): Not applicable HISTORRPHOUOGICOpsERuATIONS: OVARIANFOLLICLESCORPORA LUTER: wrens: ein: BPparrceerssoeepnnhccaeegeoosff,gcporirogpvmoternnagt/eladuntte(ramadefroaltlei)cles mGicsiteinctaitoin.onli(nmeundar(amtien)imal) HEFOLLOUINGTISSUE(S) WERE WITHINNORUAL LINITS: APITRUIETARGY LAS cevix owes end of Racord- 1340 " Tr ovibicr(s) Tr t-t0s Page 1202 ARGUS 418-020 REPROOBRALLCTI(OGNAVASGTEI)OYTAGFO-GAEMNPOERRNOATITONICOONLPE4R(1FO6LN-EI0O2RL0OIGTCTETRANOPAETREGE(NACFRFA)TIOINn) RATS SPONSOR'S STUDY MUMBER: T-6089.6 Individual\ oieal rFiAoospSseennadrianxtiiIosvntamorghalosy Data sAoNiI:MAL wae: F1301 DsEoAeTHoprT:EL Sa1 crice-Schaduled S805 ORSCRUATION(S): 286): Swollen, both HISTOMRPHOLOSICOBSERVATIONS): chondropathy, auricular HISTOMRPHOLOGICopscRvATIONS: 0s): End of Record 1341 chondropathy. auricular (sodeate) " 108 Page 1203 ARGUS 418-020 REPROODRULCTI(OGNAVASGTEU)DYTOHFO-AEMNPKEROROVATTIOINCOONFLE4R(1OFN8LE-U0RL2OI0OTCTTEARNGPAETREGE(NAEFRFOA)TIOINN) RATS SPONSOR'S STUOY WMGER: T-6899.6. Individual Anim GFsirooGspesenneadrniadxtiHIoiVnstomorpholosy Data AaL ER: 1F302 oDEsAeTHse:THE. Su| rFice-Schadsled R053 QRSCRIATIONS): RLS): Svallen, both. HISTOMEPHOLOSIC.OBSERVATIONS): chondropathy. auricular HSTOORPrOLOSICopsERuATIONS: BOuVsAR)I.ANFOLLICLES CORPORA LUTER: wresus: cpFhroeensdernsocpeatoohfFy,cr oaruproircaE uluatres(sarfkoedc)ies Gistention, Tumen (aiid) HEFOLLOUINGTISSUES)WERE ITNNolLIMITS: APIRTEUIATLARGYLANDS cVeArGvIiNxA omares End of Record 1342 avioer(s) weir Page 1204 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEU)DYTVOOF-GAEMINPOERVROIATUOTCNIOOLPNER4(F1OL8NEU-R0RL2OI0OTCTTEARNGFAETREGE(NAEFRPA)TIOINh) RATS SPONSOR'S STUDY NBER: T-6889.6 Individual Anim) FGIrAopepGseenndeairnxadtii1ovsntmorpholosy Dste Asex:L NBER: F1345 DsEAeTHor:THE. S1ace ice-Scheduled S058 BSERIATIONS): SENERALS Mo gross changes. HISTONRPHOUGSIC OBSERVATIONS): Not applicable HISTOMRPHOLOSICoBsERATIONS: OVARIANFOLLICLES CORPORA LUTEA wast: ppTrroeefssleeannmccaeetioooffn,gcroocrwhpiroonrngai/cal.nuttrefaao)calfol(lmiincilmeasl) aucifreation (minimal) THEFOLLOUINGTISSUE(S)VEREWITHIN NORMAL LIMITS: APIRTEUIATLARGYLANDS cerveisx ousaies End of Record 1345 " ovnoucr(s) 1-108 Page 1205 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)DYTWOOF-SAEINREoAIAtTLeIOlNPER4(F1O3LNE-U0O2RL0DICTCTETRAEAPTEER.GE(NAEFRFAOT)IOINn) RATS = SPONSOR'S STIOY NBER: T-6689.6 Individual ima] GArpopsesnadnidx 1H0istonorphelogy Data Fi Generation ASex:a wreR: F1353 DsEoAeTHge:THE, S1 acr ice-Schedsled 05s opsTRATIONS): SEMRAL: Yo gross changes. HISTONORPHOLOGICOBSERUATION(S): hot applicable HISTONP,0S1COBSERVATIONS: OVARIANFOLLICLES CORPORA LUTEA: wrens: Ppparrceerssoeepnnhccaeegeoosff,cgorproipgvomirenangt/euadtnet(rsmaarkfeodl)licles `THEEOLLOMINGTISSUE(S)WEREWITHINNORMALLINITS: PArTRUIOTRYLaws VcAoGmIiNxA ovate End ofRecord- 135 TT overs) ws Page 1206 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DY OTWFO-AGWEINPOERNROIATLTOWICOONLPE1R(FO6LN-UE0O2RLO0ICTCTTEARNIPAETRE.GE(NFEPROA)TIOTNh) RATS SPONSOR'S STUOY NUMBER: T-6809.6 Indivicun) Anima) Grsoospsenadnidx HIivstomorphalaay Data #1 Generation sAeL wee: F1355 DsEoAeTHoop:THE: _ Sa1 crice-Schedsled A055 OBSERVATIONS): SEERA ho gross changes. HISTOMRPHOLOGIC ORSERUATION(S): Not applicable HISTORRPHOL0G1COBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA: ves: appcrrreessoeepnnhccaeegeoosff, cgorpiroapwmoiernnagt/ealdn.uttre(aamlarkfeodl)licles HEFOLLOVINGTISSUE(S)WERE WITHINNORMALLIMITS: PAHRTEUATLRYGLAS ceAvaiax owes ovibucr(s) t-tto Page 1207 ARGUS 418-020 REPROORDAULCTI(OGNAVASGTEU)DYTOVFO-AGEWNPACRORONATITONICOOPNLER4(F1OL8NU-ER0RL2OI0XTCTTEARVGPAETREGE(NAEPROA)TIOINh)RATS SPONSOR'S STIOY NBER: T-6880.6 Individual Anima) GFAripoGepanerneadrniadxtii1o1sntomorphalosy Data Asex:L eer: 1F359 SEoAsTeTHE,cage: d1ariica-schduted 80s GesRATION): SEEBAL: No gross changes. HISTORPHOLOSICOBSERVATIONS): Not sppicasle HISTOMORPHOLOG1C OpSERMATIONS: OVARIANFOLLICLESCORPORA LUTER vraesats: EBpurrceorsoesgnehcsaegeoofsf,gcroopmivegirmnesgn/tleoduntte(rrmai16f)olicles =cification {arninat) TIE EOLLOHINGTISSUE(S)VEREWITHIN gous,LMITS: fPIoTUrITeARYGps cervix mares End of Record 1358 ovnoucr(s) Cr etn Page 1208 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEL)0YTOHFO-ASWEPGERNROAITTUOINCOONPLE4R(1OF6NLE-L0O2LR0IGTGTCETROGPAETREGE(NNEFROA)TIOINh) WATS SPONSOR'S STUDY NIGER: T-6088.6 Individual Anim GFiArpopsSesenadarinaxdtiHIoivnstomorpholosy Data A sai: WER: 19780 sDEoAeTHcTpHE:, S1ucrFice-Schadaled GROSS QOSERUATION(S): Sen soalt HISTOMRPHOLOGICOBSERVATIONS): atrophy HISTONRPH0L051COBSERVATIONS: seen: 4 oF Record 19780 atrophy (sare) wz Page 1209 ARGUS 418-020 REPROODRUALCTI(OGNAVASGTEL)OYTOWFO-AGEONFNERIROAUTTOYIcOoNPE4R(1FOL3WI-EO0RL2OI0CTCTTEARNOENRT.E.GE(NAEFRPA)TIOINh)AATS SPONSOR'S STUOY KNBR: T-6999.6 Individual Aasesl GrAopspsenadinx IiVatamorghotogy Data FiGenaration asoL ve: 1365 sSeETHEgr: S1p1ontaneous seth 805s opseRVATIONS) TAIL: Tip mvssins. HISTONRPHOLGGICOBSCRUATION(S): necrosis, focal HISTOMORPHOLOOICopsERMATIONS: Ls necrosts, focal (afl) End of Record 1365 - wus Page 1210 ARGUS 418-020 REPROODRLACLTI(OGNAVASGTEL)OYTHOOF-GMENOPERRNOATITOICOONLFE4R(1FO8LN-EI0O2RL0OIGTCTETRANOPAETREGE(NAEFRRAAO)TIO1Nh) 2ATS SPONSOR'S STUOY NUMBER: T-6809.6. Individual Animal GFsirooGspesennaednridaxtiiIosvntomorshalasy Data MEAyL WER: 1:973 SoEseTHEcage: o11 man oust S055 QISERATIONS): SLAdUSiGTsR:tOeDInotNriEsoSanTlINsAurLfTaRcAeC,T:riSgthotmaapcihcaalndToibnet,estines pressed white ares. 0.scn In alameter. HISTOMORPHOLO61C OBSCRIATIONS): denierscotrseoinsotinis(,osn);.fogcLallEanDdular moss. STOMACH arophages, Alves). focal HIsToMsprOL0GIC opseRvATIONS: Linneew: stomcH: End of Record 1373 dRe aicsrtoepnhtaigoens.(C saarlkvaedo)li focal (a Sroston(s). slandlar mocosa (ai1d) we Page 1211 ARGUS 418-020 REPROGDRUALCTI(OGNAVASGTEU)DYTHODF-ASWE"INPOERNROIATLTOWICOONLPE4(R1OF8NL-EU0O2LR0IOTTCECRTAPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S TOY NUMBER: T-6889.6 Individual Anima) GFirsooGspesenneadrniadxtHiIiovsntonorpbolosy Data a Sox: wees: 1F94 sDEAoTHmTHeE. S1ucr fice-Scheduled R055 QBSERVATION(S): TAIL: Alar constrictions of the tail. HISTOMAPHOLOSICOBSCRVATIONCS): No microscopic change to correlate HISTORRPHOL081C opstRvATION: lo No microscopic change to correlate THEEOLLOMINGTISSUE(S)VEREWITHINNORMALLIMITS: I Ed of Record 1374 Tr was Page 1212 ARGUS 418-020 REPROODRUALCTI(OGNAVSAGTEU)DY OTWFO-AGWEINPOERNROIATLTOWICOONLPE4R(1OF8NL-EU0O2LR0ICTCTTEARNI7T6E%.GE(NAEFRPA0)TIOINh) RATS SPONSOR'S STUDY NUMBER: T-6009.6. Individual Anima) GFirsooeepseernaadnitsiW1oivnstamorphology Data AsoMx:AL wer: F1407 wDEATaH e S1acrifice-Schediled R053 ORSCRIATIONS): TALL: Tp missin. HISTOMEPHOLOGIC OBSERVATIONS): inflammation, chronic HISTONRP0\G51C SERVATIONS: ms inflammation, chronic (minima) ene Page 1213 ARGUS 418-020 REPROOOLICTI(OGNAVSAGTEU)DYTHOOF-GAEWNPGERHROIATLTOINCOONLPCA4(F1OL8NUE-O0R2LO0ICTCTTEARNEPAETRE.GE(NAEFRFA)TIOINh) RATS SPONSOR'S TOY MBER: T-6860.6 Individual Anima] Grposps acnd 1Hvistomorphelogy Date FI Generation eay reer: F1015 wOATeHap S1acri fce-Schedsled ROSS ORSERVATION(S): H UE: r Loft Tatearal Tobe-amassTadhe,red to Taft HISTONRPIOUGSIC OBSERATIONS): Infarct. iver Tobe HISTONRPHOLOGICOBSERVATIONS: ver: End of Record 1415 infarct, Tiver Tobe er Page 1214 ARGUS 418-020 RCPROOBRALLETL(OGNAVASGTEI)G TNGFO-AGEWNPOERNROIATLTONICOONLFER(4F1O6LV-I0O2RL0OIGTCTETRANOPNETREGE(NAEFRFA)TIOINh) 7ATS sronson'S STIOY WME: 1-6009.6 Individual Anima) GFAirpopsGesannadainrxadti1Wosntomorshology Data ASora wore: 1428 sOEsRcTHop:THE: So11c1 ifice-schaduled Sa0ssonstmvTIONS): OME: Pelvic atetion, slight, bilateral. HIsToRRPHLSIC OBSERVATIONS): aitaation, pelvis HIsTomReroL001C opsemvTIONs: ones: Ed of Record 1428 anstation, pelvis (a16) wus Page 1215 ARGUS 418-020 REPROORDALLCTI(OGNAVASGTEU)DYTOVFO-AGMEPINROEOMRTIAOUTCNIOOLPNER4(F1OL8NU-EO0R2LO0IOTCTTEARNGPAETREGE(NFEPROA)TIOINh) RATS SPONSOR'S STIOY NBER: T-6869.6 Individual Anim FGirAopspGseenndeairnxadtii1ovsntomorphalosy Date Asx:A WER: 1495 sDEcAToH ne:THE. S1ucr ice-Scheduled 9085 GBSERUATIONS): EYES: Soft tissue surraunding eye swollen. HISTORPHILGGICOBSERUATION(S): abscess, pariccutar HISTOMORPHOLOGICOBSERVATIONS: eres: End of Record 1435 abscess, periccular nents Page 1216 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SAEW"NKFEORRNoAITToLICWOoNLPER4(F1O8LNE-U0O2RL0OICTCTETRANIPAETREGE(NAEFRFA)TIOINh) RATS SPONSOR'S STO MBER: T-6889.6 ndntdvtvicun) Antsosm) aFGrGroessraanntdiMonito stomp outa Asex:L NBER: 1;544 sDEAoTHpTH:E: Syacrice-Schedaled SA05S opsERUATIONS): SEAL Ho gross changes. HISTOMRPHOLOSIC OBSERVATIONS): Not app cable HISTOMRPHOLOSICOBSERVATIONS: OAVAdRImANFOGLLLIaC:LES CORPORA LITER uprreusn:e: Dproesseenctseesootaff,cgcrooomrvptiainrcga/lta,ntfrioacalftol(lemiicnliem)asl mCaactrioap)h:agepsa,rspdiigsmteanltiesd (moderate) TEFOLLOUINGTISSUE(S)VEREWITHINbog LTS: cevix ovsaies overs) et end of Record 150 wiz Page 1217 ARGUS 418-020 REPROODUULCTI(OGNAVASGTEU)DYTHOOF-GAOMNRKEOROVAITTUINOCNPER4(F1O8LNE-U0D2RL0OIOTCTTEARNGPAETREGE(NAEFRPAO)TIOINh)RATS SPONSOR'S STIOY NBER: T-6869.6 Individual ima) GFrAiopGspasennaadrniadxtiH1ovinstoorphalosy Date Asex:L BER: F1545 DoEoAsTeHTHEcage: Saorific-schdiled A058OpsERUATIONS): SEERA Yo gross changes. HISTOMEPHOLOGICOBSERVATIONS): Not applicable HIsTOMORPrOLcSIC CaseRATIONS: OVARIAN FOLLICLES/CORPORA LITER: wrens: pPprarecessreeonnpccreeaoooeffs gcrpooirwgpimenergna/taeTnduttre(anmlirfkeodl)licles THEFOLLOWINGTISSUE(S) VEREWITHINNORMALLIMITS: PAIRTOUIMTAARGYLANDS ceVvAiGx ousies ovioucr(s) iz Page 1218 ARGUS 418-020 REPROODRIACLTI(OGNAVSAGTEU)DY OTWFO-AGMEINFOERNROIATLTOWIcOoNPE4R(1OF8VL-EU0O2RL0OIOTCTETRANG7N6T%EGE(NAEFRFA)TIOINh) RATS sronsoR'S STUoY WMG: T1-6089.6 Individual AntAnimal cFiGrroGsoesnaenrdatHiiosntamorphottonyoay 0ata sAena wees: 1F 54 DoEsAeTHop:THE. Syaceice-Schedsled 8053oBsTRATIONS): RE: Swollen, rit. HISTORPHOLOSIC OBSERVATIONS): chondropathy., auricular HISTOMRPHOLOGIC OBSERVATIONS: sOVroARsInANFOLLICLESCORPORA LUTER: : crphraaensdenrnocspeat1ohfy,Gcroaerudrstiacaufllaaunrteaa(lmafrokeld)cles erenion:nin (eerote HEFOLLOUINGTISSUE(S)WERE WITHINNORMAL LIMITS: PAiTmUTeiRyGuavos ceARsviinx onaies End of Racor 1548 or or onus) " wiz Page 1219 ARGUS 418-020 REPROODRUACLTI(OGNAVSAGTEU)DY THOOF-GAEWNPOERMROIATLTOINCOONLPER4(F1OL6NUE-O0R2LO0ICTCTTEARNGPAETRE.GE(NAEFRPA)TIOTNh) RATS SPONSORS TOY NBER: T-6800.6 Individual An) FGirA"opspGseenndaairnxdatiHIovinstomorphalosy Data ASuva eR: 1;551 oDEsAeTHor:THE. Svacrice-Schedsled 05s opsgRwATIONS): TALL: Tip missing 11 cn from the base. HISTORPHOLOSIC OBSERVATIONS): riencfrlaanmtmsa,tiofno,calchronic HISTOMEPHOLOGICOBSERIATIONS: ES End of Record 1551 inencfrloaamtast,iofno,calchr(omnii1dc) (af1) A TTT ---- waz Page 1220 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTHOOF-SAEMNPOERMROIATLTOIMCOONPLER4(F1OL6NUE-O0R2LO0ICTCTTEARNEPAETRE.GE(NAEFRPAO)TIOTNh) RATS SPONSOR'S STIOY NIGER: T-6889.6 Individual Anim GFirAopspGseenndeairnxadtiH1ovinstmorpholosy Data SA o een: 1F552 sDEAoTHon:TE. S4acrFce-Schadaled R053 QRSCRIATIONS): GENERALS ho gross changes. HISTOMEPHOLOGIC OBSERVATIONS): Not applicable HISTONRPHOLOGICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA: urenus: ppRarrceerssoeepnnrccaeepeoosff, cgorpiroggvmaiernnagt/ealdnu.ttre(aamldefroaltlei)cles Gistention, lumen (moderate) HEFOLLOMINGTISSUE(S)VEREWITHINNORMAL LIMITS: APIRTEUIATLARGYLANDS ceArvGiIx onares End of Record 1552 avout) Tr ete Page 1221 ARGUS 418-020 REPROORDAILCTI(OGNAVASGTEU)DYTVOOF-GAEANFAREOORVTAIOTUCIYoOLFNE4R(1FO8NL-EU0R2LO0IOTCTTEARIGPAETREGE(NFEPROA)TIOINh)TATS SPONSOR'S STIOY NBER: T-6809.6 naividvuael tmAnimal 6F1iGr5oGsesnaeandrnatiMotHncimrssttoolcay oututs SAain:a wc: F1557 OwOArTHogrTHRE. Svacrifice-Scheduled 8055GRSERVATION(S): SEE: No gross changes. HISTORRPHILGGICOBSERUATION(S): Not applicable HISTOMORPHOL061CBRATION: OVARIAN FOLLICLES/CORPORA LUTER: urVAeGIsNA:: pRprarecessreeonnpccteeaeoosff, cgorproigegaimrneagn/taelnudttre(aaalllef)ollicles mci fication (nadarate) HEFOLLOVINGTISSUE(S)VEREWITHINNORMAL LINITS: APIRTEUIATLARGYLANDS cervix outs End of Record 1587 CT overs) or weizs Page 1222 ARGUS 418-020 REPROGDRUALCTI(OGNAVASGTEU)DYTOUFD-AGEWNPIERORONATITOHICOONLPE4(R1OF8NL-EU0R2LO0IOTCTTEARVGPAETREGE(NAEFRPA)TIIOXNRATS SPONSOR'S STUDY MINBER: T-6809.6 Individus] Anima] Grsoospsenadnidx HIivstomorpholosy Data Fi Generation sMexA:L eR: 1573 DoEsAeTHcan:TRE: Syacrifice-Scheduled R058 QRSCRIATIONS): SENERALS No gross changes. HISTOMEPHLOG1C OBSERUATIONS): Not applicable HISTOMEPHOL0G1CORSERUATIONS: OVARIANFOLLICLES/CORPORA LUTER: wrens: PRarrceerssoeepnnrccaeegeoosff,cgopripgromreanrtleudtre(arodefrosltlei)cles TH EOLLONINGTISSUE(S)VEREWITHINNORMALLIMITS: PArRTuETRYGLAS VceAaGnIiNxA onares 0d of Record 1573 onus) tweizs Page 1223 ARGUS 418-020 REPROODBULCTI(OGNAVSAGTEU)DYTHOOF-SAEWHKPEROROMATITOLICNOONLPER4(F1O6LNE-U0O2RL0OICTCTETRANAPTEER.GE(NAEFRFA)TIOINn) RATSSPONSOR'S TOY NBER: T-6889.6 Individual fea] rFisoosGpsaenneadrniasxtiWIosvntomorsnalosy Data vSex:a ser: F1579 DSEoAeTHce:THE, 3Sacrifice-schaduled 80S OBSERVATIONS): SEUERAL: No gross changes. HISTOMORPHOLGSICOBSERVATIONCS): Not applicable HISTORRPIO\GGIC SERVATIONS: OrVAeRsI.AN+ FOLLICLES/CORRORA LuTER: VAGINA: Baparcessreenpecheaeoosff,gcporirgepmdeontrteaad.fleuntei(anninfinodlcles mci hcation {oedarate) THEFOLLOMINGTISSUE(S)VEREWITHINYoRuAL LIMITS: APIRTEUIATLARGYLANDS cervix omares End of Record 1579 overs) wetzr Page 1224 ARGUS 418-020 REPROODRIACLTI(OGNAVSAGTEU)DYTWOOF-GAEWNFOERRONATITOIICOONPLE4(R1OFN8LE-U0OL2RI0OTTCECRTAPNETREGE(NNEFRFA0T)IOINh) RATS SPONSOR'S STUDY NNGER: T-6080.5 Individual Anim) Grfopspsenadnidx H1ivstomorpholosy Dota Fi Generation A sax: WHER: F1589 DsBAeTHor:THE. Sacrifice-Scheduled 8058 BSTRIATIONS): SENERAL: No gross changes. HISTONRPIOUGSIC OBSERVATIONS): Not applicable HISTOMPrOLOGICogsERvATIONS: OVARIAN FOLLIGLES/CORPORA LUTER: wrVeAauGs:: Bpparrceerssoeepnnhccaeegeoosff,gcrpooirugpimonerana/taelnduttre(eam)odefroaltlei)cles ification (arid) TEFOLLOUINGTISSUE(S)VERE THIN NoRuALLIMITS: APIRTEUIATLARGYLANDS cervix oussies End of Record 1580 overs) TT ez Page 1225 ARGUS 418-020 REPROORDAULCTI(OGNAVSAGTEU)DYTWOOF-GAEMNPOERMROIATLTOIMCOONLPER4(F1OL8NUE-O0R2LO0ICTCTTEARNGPAETRE.GE(NAEFRFA)TIOTNh) RATS SPONSOR'S STIOY NUMBER: 6889.6 Individual Anim) GFlrAoospGseenndeairnxadtiHIovinstcmorphology Data A5DL WrER: 1V593 oDEsAeTHcmp:THE. S4acrice-Schaduled S058 QOSERUATION(S): KIDNEYS: Right- pelvis moderate dflation. BCERTI nlaeaarh,ac1.0h rx at0e.r5m, one located at the ABIMARY BLADDER: Vs thickened. HISTORPHOLOGIC OBSCRUATIONSS): dGpihylesalttoeannteiipoohnnr,itpieslvis cFSyonapFtaiiratpmriasat,sitoapn,e,rmpcuihcroaossnatiicc HISTOMRPHOLOGICOBSERVATIONS: xiowers: OVARIANFOLLICLESCORPORA LUTER: {oRweaTrcehs:: wTReiha:y suse: dPFyrneealstoeanntecipeohnro,ifthpcaeolrvp(iomsroada(rumatdteeers)ate) dSpiryseststeeennt)ci:eon'oifnt(grmraaorokvueiadnr)gi/aanntral follicles cT{ynipFteurmtpmslaa,tsitoaBn,r.meucshcrolosnoaitc.(lmo(dmfeia1rraa)tiee)d Sacrophapes, pigmented (mderate) THE EOULOUINGTISSUC(S)VEREWITHINMORALLIMITS: AVOARGEIMNAAL GLANDS cenix onower(s) prrumRy End of Record 1599 mm------ iz Page 1226 ARGUS 418-020 REPROGDRAULCTI(OGNAVSAGTEU)DYTHODF-AGWEINPOERNROIATLTOWICOONLPER1(OF6NL-EU0O2RL0OICTCTETRANIPAETREGE(NAEFRPA)TIOTNh)RATS SPONSOR'S STIOY WAGER: T-688.6 TaiVinda)l orAnmimgFiGrorGsesnaeandnroationHistorMsamrstoly toto A 5 WER: 1;598 oDEsAeTHcTaHmE:. S1acrice-Scheduled S053oBSERUATIONSS): SEERA Yo gross changes. HISTONRPHOLOGIC OBSERVATIONS): hot applicable HISTORRPHO\GGICOBSERVATIONS: OVARIAN FOLLICLES/CORPORA LUTEA wreaus: Rpparrceerssoeepnnhccoeegeoosff,gcroporiwpoiomnregan/taelnduttre(aam)odefroaltlei)cles THEFOLLOUINGTISSUS(S)VEREWITHINNORMALLINITS; PArTRUIOTRYLaws ceVAnGiINxA ontes ovioucr(s) 30 Page 1227 ARGUS 418-020 ORAL (GAVAGE) TWO-GENERATION (ONE LITTER PER GENERATION) REPRODUCTION STUDY OF AMMONIUM PERFLUOROOCTANOATE (AFPO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 HISTOPATHOLOGY REPORT APPENDIX V INDIVIDUAL ANIMAL GROSS AND HISTOMORPHOLOGY DATA GROSS LESIONS - F1 and F2 Pups Page 1228 ARGUS 418-020 REOPRRAOLDU(CGTAVIAOGNES)TTUWDOY-GOEFNAEMRMAOTNIOINUM(OPNEERLFILTUTOERROPOECRTGAENNOEARTAETI(OANP)FO) IN RATS PROTOCOL 418-020 SPONSOR'S STUDY NUMBER: T-6889.6 APPENDIX V Individual Animal Gross and Histomorphology Data Gross Lesions - F1 and F2 Pups Dam #,Group#, Pup # GrossObservation(s) Histomorphologic Observations 5 13921, Group V, Pup #1 Mou0t3h%-0m.a1sesm#3, 02x Tissue not available 13946, Group |, Pup #10 KiGdanteeyd-,igmhot,deprealvties, Tissue not available : 1304, Group 1, Pup #1 Kidney- pelvis, diated, sight Dilatation, pelvis, moderate i 1383, Group I, Pup #6 Kidpneelyv:isr,igmho,dedriaattoen, Diataton, pelvis, moderate 1459, Group Ill, Pup #14 Kidney- bilateral, dilation, Dilatation, pelvis, mild k pelvis, moderate 1476, Group Il, Pup #3 Kiddnieayte:dr,igshit,ghptelvis, Dilatation, pelvis, mid 1623, Group IV, Pup #11 Taik bent Tissue not avaliable 1623, Group IV, Pup #3 Doimtededhetahdi;rdbarnaidn-lateral Eyeve-ntrriigchltens,tmparrekseendt Diataton, ventricular, marked Gonfirmed microscopically vit Page 1229 ARGUS 418-020 APPENDIX L HISTORICAL CONTROL DATA Page 1230 FEMALE FERTILITY GrCDER VAF/HIPSITuOsR[ICC1ACLDCBO(SNDT)RIOGLS DBARTVAAFIPIus] RATS SuMMARY 19952002 1091 TOTAL LITTERS ARGUS 418-020 OELVeRED LTTERS PPELRADNETLAVTEIROENDSUTTEISER AVERAGE MINMUM N . N wean 183 1a MAXIMUM = so wr #sTuDies cL. INANALYSIS = = PUPS FOUNDDEAD OR PRESUMEDCANNIBALIZED oa 1 n n % om oom 2m n ons 1s ~ wN am oom ow " oavs 1521 N N wom ook se a" VRBLTYMOEX ay4) % oem ook 000m " N vASLTYNOEX 7) % 10 see eon 0 ~ LACTATION NOEX wo seen seen teow " SURVIVINGPUPSILITTER ony 1 wen wz 120 181 Fy Page 1231 HISFTOERMIACLALECFEORNTTIRLOILTYDATA CHCDOBR VAFIPlus [Cr COBSD)IGS BR VAFIPIus) RATS. SummARY 1998.2002 1091 TOTALLITTERS ARGUS 418-020 #sTupies wc. AVERAGE MINIMUM MAXIMUM INANALYSIS oEuvERED LITERS ~ . @ ay 4 Preculing) wen me te 188 ays Poscaion) MEAN 87 7 100 a oay21 wea 11s 0 185 @ PURWEIGHTILITTER (GRAMS) ony? wen no 0s ne @ oay 14 wen mo nz us " oay21 Mea ws aut ws o Page 1232 ARGUS 418-020 DURATION OF GESTATION (CrCDBER VAFH/IPSITUOSR(ICrCiACLDCIOSNDT)RIOGLS BDRATVAAF/PIus] RATS 1997-2002 SummARY 1428 TOTAL LITTERS AVERAGE MINIMUM MAXIMUM #ISNTCUL.DiIEN S ANALYSIS oeuvEReD LITTERS 8 EY 5 OUoRaATrIsON OF GESTATION ven 228 27 22 5 Page 1233 SEXUAL MATURATION CHCDBBR VAF/HPIlSuTsOR(ICCrACLOCBO(SNDT)RIOGLS BDARTVAAFIPIus) RATS ARGUS 418-020 cooe: TDYRPAEFTOFFISNTAULDRY.EPORT MAL DATE: 1995-2000 SUMMARY 42 STUDIES INCLUDED IN ANALYSIS SEXUAL MATURATION AE RATS [] Preutl Separation (hv. doypostpartobusm) MEAN FEMALE RATS n V(ahgv.indaoyPaptoesnttpartum obs) MEAN AVERAGE MINIMUM MAXIMUM "61 8 a7 21 301 340 Page 1234 SEXUAL MATURATION CHCDBBR VAF/HPIISuTsOR(ICrCiACLDCBO(SNDT)RIOGLS DBARTVAAFIPIus) RATS ARGUS 418-020 cone: ORAFTFINALREPORTMALDATE: TYPEOFSTUDY. we we 51 or 100 2 BD) OJ215 OS1395 072085 072356 0GUSW6 08086 100996 Seq. Hamorized Hamonzed Seg. Repro.and Sep Wl Seg. Al Seo. Seg. Postal SEXUAL MATURATION aPErepRutAlTSSeparaton CE ====== Ovodeypospatmoss) MEAN 467 467 M7 41 489 ws 48 FEMALE RATS Nom = = = = = = Vagina Patent Gvg.dmpospamobs) MEAN 324 1 HM 22 Me ws Me Page 1235 ARGUS 418-020 HIS`TSOERXIUCAALLMCAOTNUTRRAOTLIODNATA (CHCDBBR VAF/PIus (CrCOB(SD)IGS BR VAF/Plus) RATS * cone ORAFT FINALREPORTMAILDATE: TYPEOFSTUDY. wm 28 2 102506 OVI4S7 012397 030857 Embryo Seg Pans Sep ll Fetal Dev. Postnatal ev. SEXUAL MATURATION ALE RATS Noe = proputa Separation (hg ayposparumate) MEAN 453 459 == 82 FEMALE RATS Now = = = V(AavgoinacaPyatpeonsttoarumcts) MEAN 20 317 nr se Page 1236 SEXUAL MATURATION CHCDBR VAF/HPIlSuTsOR(ICrCiACLOCBO(NSTDRIOGLS BDRATVAAF/PIus) RATS ARGUS 418-020 cove: 20 21 255 ms ws om = TOYRPAEFOTFFISNTAULDRYE:PORTWALDATE: SeOgAGWBSI? Pr0o6an2d8Po7st SOeBoA.IWSN7l SeOgW1WSN7 Se0g9.08UN7l Prs0nUdSP8o8st 03De1v08 Nota Natal Neurox SEXUALMATURATION ALE RATS Nz 1 2 2 2 = PraputalSeparaion vg cposparumate) MEAN 466 453 467 49 4s a7 wz FEMALE RATS FE = == = Vagina Patent (vodmpospatmas) MEW 20 m7 wi ws mo ws we Page 1237 HISSTEORXIUCAALLMCAOTNUTRRATOILODNATA CHCDBBR VAF/Plus (CiCDB(SD)IGS BR VAF/PIus) RATS ARGUS 418-020 cove: ORAFTFINALREPORTMALDATE: Ey OAGOSS 0s 06739 Ow31e0s 01u2s838 s05303SSS 03AZiGO TYPEOFSTUDY: Neurbohav. Dov. Comb.Pe Oral(Gavage) Dev.Neuro FulDers Gwktoxcty MutiGon. Dev. Newt. PeriPostRepro.and oso. SEXUALMATURATION APrLeEpuRtAelTSSeparation Nw Bl (Avg dayposparumots) MEAN 452 wr " 1 en = 1 az FEMALERATS Vagina Patent I = ws 5 (hv.daypostparatkusm) MEAN 316 21 22 sts 2s 20 Page 1238 ARGUS418-020 HISTFOERMIACLALE CFOENRTTIRLOILTYDATA CALCDBBR VAFIPls [CHLCDB(SD)GS BR VAF/PWse] RATS 102-202 summary 00 TorALRATS ssmuvies AVERAGE MIMUM MAXMUM INCLUDED esctre rOoBSERuVATIsONS ars EvaLuATED ~ . a om PrEposacE EsRoUS Creu eEESSsTTmRRoOOuUUsSSsSSTTTAAaGGcEEeSSsAATASoDOrAATsYSS MWMEEeANwN 233046 223046 233%00 2 ; SomosSTAGESNROS MEW 33 is 38 | MESASNTRNOUUSCYMCOLFEBCSOGMREPOLUERRTE Mew 37 as 3a s RAOTaSvWsIToHFD6EOSFTWROURSECONSEC. n 2 RAOTaSvWsIToHF E6SOTRRMUOSRE CONSE. ~ o o" weLaENnGETSHTGRROOUUSPCYeLe vow aa a ) PreevcoenAnBTATION ESTROUS MECAoNMNOUSUGYMOOLFEBCSOGMEPRLOERPTE Mew 32 a2 a 4 moussTAGESMDAYS Mew 34 2s tam estrous STAGES ZOOAYS MEAN smoussTcEs2IONS Mew so as sz 7 estRoussTAGESSONYS MEW 65 65 68 ' RAOTaSvWsIToHf 6ESOTRRMUOSR,E CONSEC " o [I ROAaTvSWsIToHF E6SOTRRHUOSRE CONSE. n o sm vparn eesTsRosuSeCveLE von a1 a a2 5 Page 1239 FEMALE FERTILITY CHCDBR HISTORICAL CONTROL VAF/Plus [Crt COB(SD)IGS DATA BR VAF/PIus] RATS ARGUS 418-020 1992-2002 summary 33 TOTALRATS #sTuies AVERAGE MINIMUM MAXIMUM INCLUDED RECOVERY PER. ESTROUS CYCLING ESTROUSSTAGEDSAZY0S MEAN 50 so so . [R"ADTASYWSIOTFHD6EOSRTMROUSRE CONSEC 0 ' RDAATYSSWOIFTHE6SOTRRUMSORE CONSEC. N o ' Page 1240 ARGUS 418-020 HISFTEORMIACLAEL CFOERNTTIRLOITLYDATA CH.CDBBR VAFIPIUS (CriCOB(SD)IGS BR VAF/Pus] RATS 1002.202 summary sus TOTALRATS ssTuvies AVERAGE MINMUM MAXIMUM WNCLUGED RATS IWCOMABITATION AS IN COMABITATION FarsTHAT ATED RAHTASTWIINGTOHACTOENSFIRMED. ] [a " ww Mew 28 as 2 we %" wa es wes om ~ ws oavs 14 oavss7 RAoaTvSUs 17ABYTFIRESTMDALE oavssie oavs 1521 RATavSMsATED BY SECOMNALDE oars 1521 FernUTY WoEX `copuLATION ox PREGNANCYRATE %n sox sow sem 1 6~ am em am . %n mon mon mee om %~ am om wx or %n zon om am 2 %n ae em me om %n am on an ow ~ % sme soe week wm I] owen maw me 7 RACTSoPmReErGTNoANnTIRATISN a wma eon wee wr Page 1241 ARGUS 418-020 APPENDIX M QUALITY ASSURANCE STATEMENT Page 1242 905soo hdA fom EIS esaTI0 Telefax: (215)443-8587 ARGUS 418-020 ~~ ARGUS RESEARCH Charles River Laboratories DiscoveryandDevelopSmerevincets QUALITY ASSURANCE STATEMENT Argus Protocol: 418-020 Sponsor's Study Number: T-6889.6 Study Director: Raymond G. York, Ph.D., DABT "The protocol, critical phases, raw data and final report were inspected by the Quality Assurance Unit (QAU), to assure conformance with: U.S. Environmental Protection Agency. Federal Insecticide, Fungicide and Rodenticide Act/Toxic Substances Control Act (FIFRA/TSCA); Good Laboratory Practice Standards; Final Rule. 40 CFR Part 160/Part 792. Organisation for Economic Co-operation and Development (1998). The Revised OECD Principles of Good Laboratory Practices [C(97)186/Final). `The undersigned indicate that the interim report is an accurate representation of the raw data. Data provided by the Sponsor or a subcontractor were not audited by the Argus Research Quality Assurance Unit. Page 1243 ARGUS 418-020 `The QAU inspection and report audit dates are listed below: Inspection Phase. Date(s) Findings Submitted to Study Inspection Date(s) __ Director Protocol TS Preparation TS Administration Natural Delivery! Litter Observations Blood Collection Male Sacrifice! Sperm Evaluations Dam/Liter Sacrifice Vaginal Patency Preputial Separation FI Natural Delivery/ Litter Observations Fl Blood Collection FI Male Sacrifice/ Sperm Evaluations FI Dam/Liter Sacrifice In-Life Data Formulations Data Necropsy Data 0607NOV00 16NOV 00 17NOV 00 15 FEB 01 02 MAR 01 02 MAR 01 08 MAR 01 13 MAR 01 23 MAR 01 21 JUN OI 03JUL OI 03JUL01 13 JUL01 1624 MAYOl 19-20 JUL 01 and. 23-26 JUL 01 1921 NOV 01, 26-30 NOV 01 and 01,03-04DECO1 10-17 DEC 01 06 AUG 01 17 DECOI 04-07 DEC 01 17-18 DEC 01 07NOV 00 20NOV 00 20NOV 00 26 FEB 01 12 MAR 01 12MAR 01 12 MAR 01 13 MAR 01 30 MAR 01 27JUN OL 03 JULOL 05JULOI 23JUL 01 24 MAY 01 273UL01 04 DEC 01 17DEC01 06 AUG 01 17DEC01 07 DEC OL 18DEC 01 Date(s) Findings Submitted to Management 07NOV 00 20NOV 00 20NOV 00 26 FEB 01 12MAR 01 12 MAR01 12MAR 01 13 MAR 01 30 MAR 01 27JUN OL 03 JULOI 05JUL OL 23JUL 01 24MAY 01 2730L01 04 DECOI 17 DEC01 06 AUG 01 17 DEC01 07DECO01 18 DEC 01 Page 1244 ARGUS 418-020 Inspection Phase Report Tables Report Text Revised Report Inspection Date(s) Date(s) Findings ~~ Date(s) Findings Submitted to Study Submitted to Director Management 30JUL 01 and 03 AUG 01 03 AUG 01 30 JUL O1 to 05 AUG 01 06 AUG 01 17-21 DEC01 06-09 AUG 01 21 DEC01 09 AUG 01 13-14 AUG 01 14 AUG 01 17,20,21,26 DEC 01 26 DEC 01 26-27 DEC 01 27 DEC01 27 DEC O01 25 MAR 02 27 DEC01 25 MAR 02 03 AUG 01 06 AUG 01 21 DEC01 09 AUG 01 14 AU0G1 26 DEC 01 27 DEC O01 27 DEC OI 25 MAR 02 Matthew Manager J. of Vaneman, Regulator yB.CSo.m pl iance Date CQuyanltihtiyaAMs.suKrealnscceh Associate/TeamDate Leader and Principal Auditor Page 1245