Document YrNq0NDD1yYmeRMg6qNLyj0QN

ARZI6-026F Te? e.| COVANCE. ocd Summary Report 104-Week Dietary Carcinogenicity Study with Narrow Range (98.1%) N-Ethyl Perfluorooctanesulfonamido Ethanol in Rats as % ron comessronnass 005113 SUMMARY REPOR-T WEEK 53 104-Week Dietary Carcinogenicity Study with Narrow Range (98.1%) N-Ethyl Perfluorooctanesulfonamido Ethanol in Rats `Timelines Covance 6329-212: In-life start date: January 26, 1998 `Week 53 completed: January 31, 1999 Covance 6329-228: In-life start date: April 6, 1998 `Week 53 completed: April 11, 1999 Introduction `The purposeofthese studies was to assess the carcinogenicityofthetest material, T-6316 (Narrow Range N-Ethyl Perfluooctanesulfonamido Ethanol, NEtFOSE), when administered in the diet to ratsforat least 104 weeks. This summary report includes information through Week 53 and contains current findings; it is not, however, the final report for the study. Covance Laboratories Inc., reserves the right of reviewof thesedata `before issuing the final report. Methods Male and female Cr:CD(SD)IGS BR rats were assigned to groups according to the following design. Grow. 2T(CLaowwo Ma"lNeo.ofAnimFaelmsale Covanez 6325212 & & D(ppmeNEaFOSlE) er 03 3 ((MMiidd)-High) 670 7600 1300 5 (High) 70 70 300 6 (Mid-High Recovery) 40 40 100 ADEE een Com vance e 63d 29228 meme ate m FCaw w 0 TE aeSo me TARPLemar a b TeTx-hp6er3ec1so6snietsrdo9als8a.pn1ip%mmanlo-sfetrNheEyclGeFipvOeesSdfElt.uhcerboaoscatlandeisetulofnolyn.amido ethanol (NEFOSE);dose levels are. 1 G0i11g Covance 6M32T9-l21e2l28 Food was providedadlibitum, except when animals were fasted. Water was provided ad libitum. The animals were observed twice daily (a.m. and p.m.) for mortality and `moribundity; findings were recorded as they were observed. At least once prior to treatment and weekly thereafter, each animal was removed from its cage and examined; abnormal findings or an indication of normal was recorded. Body weight data were recorded weekly for each animal for Weeks 1 through 17 and once every 4 weeks thereafter. Food consumption data were collected for each animal for Weeks 1 through 16 and once every 4 weeks thereafter. Bodyweights were also recorded for all animals in Groups 5 and 7 before sacrifice during Week 8. Clinical Pathology. Blood and urine samples were collected for hematology, clinical chemistry, urinalysis, and urine chemistry from five animals/sex/groupinGroups 1 and during Week 8. Blood and urine samples were collected for hematology, clinical chemistry, urinalysis, urine chemistry,and serum sampling from 10 animals/sex/group in Groups 1 throug4h during Weeks 14, 27, and 53. Blood and urine samples were collected for hematology, clinical chemistry, urinalysis, and urine chemistry from 10 animals/sex/group from animals in Groups 8 an9d during Weeks 14, 27, and 53. Animals were fasted overnight, and urine was collected chilled overnight (approximately 16 hours) before blood sampling. Blood was collected from ajugular vein. The anticoagulant was potassium EDTA for hematology tests. The samples for clinical chemistry and serum samples were collected without anticoagulant. The serum samples (that serum not used for clinical chemistry) were stored ina freezer set to maintain -60 to 80C,until shipped to the Sponsor for possible future analysis. When possible, a blood film was made for possible future examinationfromanimals sacrificed at unscheduled intervals. A blood film was also madeand held for possible future examination for animals at the scheduled sacrifice during Week 53. Serum Analyses. Blood samples were collected for serum analyses from fiveanimals/sex/groupin Groups 1through5, 8, and 9 during Week 4; five animals/sex/groupinGroups 1 and 5 during Week 8; five animals/sex/group in Groups 1 through 4, 8, and 9 during Week 14; and five animals/sex/group from Groups 1, 4,8, and 9 during Week 53. Animalswerefasted overnight. Blood (approximately 2 mL. during Weeks 4, 8, and 14, and approximatel3ymLduring Week 53) was collected from a jugular vein. Samples were collected without anticoagulant. Serumwas harvested, stored in a freezer, set to maintain -60 to -80C, until sent to the Sponsor for possible future analyses. 2 00C115 Covance 6I3M29T2611226218 Termination. During Week 4, five animals/sex/group in Groups 1 through 5, 8, and 9 were fasted overnight, bled for serum samples, anesthetized with sodium pentobarbital (Groups 1 through 5) or carbon dioxide (Groups 8 and 9), weighed, and exsanguinated. `The abdominal cavity of eachanimalwas opened, the liver was removed and weighed, and liver samples were collected. Animals were discardedafter iver collection. During Week 8, five animals/sex/group in Groups 1 and were fasted overnight, bled for clinical pathology and serum analyses, anesthetized with sodium pentobarbital, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observationswererecorded, selected organs were weighed, and selected tissues were collected and preserved. Additional liver samples were also collected. Adrenals, brain, eyes, kidneys, liver, `mesenteric lymph node, pancreas, spleen, testes, and ovarieswere processed and examined `microscopically. The remaining animals in Groups S and 7 were euthanatized with carbon dioxide and discarded without necropsy. During Week 14, five animals/sex/group in Groups 1 through 4 were fasted overnight, bled for clinical pathology and serum analyses, anesthetized with carbon dioxide, weighed, exsanguinated, and necropsied. At necropsy, macroscopic observationswererecorded, selected organs were weighed, and selected tissues were collected and preserved. Additional liver samples were also collected. Adrenals, brain, eyes, kidneys, liver, `mesenteric lymph node, pancreas, spleen, testes, and ovaries were processed and examined microscopically. Also during Week 14, five animals/sex/groupinGroups 8 and 9 were: fasted overnight, bled for clinical pathology and serum samples, anesthetized with carbon dioxide, weighed, and exsanguinated. The abdominal cavity ofeach animal was opened, the liver was removed and weighed, and liver samples were collected. Animals were. discarded after liver collection. During Week 53, five animals/sex from Group 1 and 10 animals/sex from Groups 4, 8, and 9 were fasted overnight, bled for clinical pathology andserumanalyses (as appropriate), anesthetized with carbon dioxide, weighed, exsanguinated, and necropsied. At necropsy, `macroscopic observations were recorded, selected organs were weighed, and selected tissues were collected and preserved. Additional liver samples were also collected. Tissues from each animal in Groups 1 and 4 were processed and examined `microscopically. Animalsthatdied ontestorweresacrificedatanunschineterdvaulwelreealdso necropsied, but organ weights were not recorded and liver samples were not collected. 3 003116 Covance 6I3M29T21623162218 Proliferation Cell Nuclear Antigen (PCNA) Evaluation. At the Week4 sacrifice for animals in Groups 1 through (five animals/sex/group), representative samplesofthe left lateral, right median, and right lateral lobesof theliverand any macroscopic lesionsofthe liver were collected and preserved in zinc formalin. At the Week 8 sacrifice for animals in Groups 1 and 5 (five animals/sex/group), representative samples of the lef lateral lobe of the liver and any macroscopic lesionsofthe iver were collected and preserved in zinc formalin. At the Week 14 sacrifice for aniimnGarolupss 1 through 4, 8, and 9 (five animals/sex/group), representative samples of the left lateral lobe of the liver and any `macroscopic lesionsofthe liver were collected and preserved in zinc formalin. Liver samples were embedded, and blocks were sent to Pathology Associates Intemational (PAI); PA will evaluate the samples (lef lateral lobe only) for PCNA. In addition, liver sections will be stainedwithhematoxylin and eosin and examined microscopically. Mitochondrial Analyses. At the Week 4 sacrificeforanimals in Groups 1 through 5 (five animals/sex/group),asample (approximately 1.5 g)ofthe liver was collected from selected animals. Samples were placed on wet ice and transferred to the Sponsor for `mitochondrial analysis `Palmitoyl-CoA (PCoA) Oxidase Analyses. At the Week 4 sacrifice for animals in Groups 1 through 5, 8, and 9 (five animals/sex/group), a sample (approximately S00 mg) ofthe right lateral lobeofthe liver was collected and flash-frozen in liquid nitrogen. At the Week 8 sacrifice for animals in Groups 1 and 5 (five animals/sex/group), a sample (approximately 500 mg)oftheright lateral lobeofthe liver was collected and flash-frozen in liquid nitrogen. At the Week 14 sacrifice for animals in Groups 1 through 4, 8, and 9 (five animals/sex/group), a sample (approximately 500 mg)ofthe right lateral lobe of the liver was collected and flash-frozien liquid nitrogen. The samples were stored in a freezer, set to maintain -60 to -80C, until analyzed by Covance for PCA oxidase: activity. Additional Liver Sample Collection. At the Week 4sacrifice for animals in Groups 1 through 5, 8, and 9 (five animals/sex/group), a portionofthe liver was stored in a freezer, set to maintain -60 to -80C,untilsent to the Sponsor for possible future analysis. At the Week sacrifice for animalsin Groups 1 and 5 (five animals/sex/group), a portionofthe liver was stored in a freezer, set to maintain -60 to -80C, until sent to the. Sponsor for possible future analysis.At the Week 14 sacrifice for animalsin Groups 1 through 4, 8, and 9 (five animals/sex/group), a portion of the liver was stored in a freezer, set to maintain -60 to -0C,untilsenttothe Sponsor for possible future analysis. 4 Goci1Y Results Survival. Adjusted survival data are summarizedin Tables 1 and 2. Covance 6M32T92112612128 Because of toxic effects seen for the body weights and food consumption at 300 ppm, the: animals in Groups 5 and 7 were sacrificed early (during Week 8). For the remaining `groups, survival after 53 weeks of treatment was 98.0%, 96.0%, 98.0%, 96.0%, 90.0%, 96.0%, and 96.0% for males in Groups 1,2, 3, 4, 6, 8, and 9, respectively, and 98.0%, 100%, 98.0%, 96.0%, 100%, 92.0%, and 96.0%forfemales in Groups 1,2,3, 4, 6, 8, and 9, respectively. Clinical Observations, Clinical observation data are summarizedinTables 3 and 4. There were no apparent test material-related observations noted through Week 53. Body Weights. Body weight and body weight change dataare summarizedin Tables 5 throughs. Animals given 100 or 300 ppm had significantly lower body weights compared to those of `animals given the controlmaterialstarting after the first weekoftreatment. Animals given 30 ppm had lower body weights compared to thoseofanimals given the control material starting after the first weekoftreatment; however, they were not generally significant until approximately Week 8. There were no toxicologically meaningful significant body weight differences for animals given 1 or 3 ppm. Animals given 300 ppm had significantly lower body weight changes compared to those of `animals given the control material starting with the first weekoftreatment. Animals given 100 ppm had numerous significantly lower body weight changes compared to those of animals given the control material, and the overall body weight change (Week 1-53) was significantly lower than thoseofanimals given the control material. Animals given 30 ppm had sporadic significantly lower body weight changes compared with thoseofanimals given the control material, and the overall body weight change (Week 1-53) was significantlylower than those of animals given the control material. Therewere no toxicologically meaningful significant body weight change differences for animals given 1 0r 3 ppm, andthe overallbody weight change (Week 1-53) was not significantly different than thoseofanimals given the control material. 5 003118 Covance 6M32T9-2112672128 Food Consumption. Food consumption data are summarized in Tables 9 and 10. Animals given 100 or 300 ppm had siguificantly lower food consumption compared to thoseofanimals given the control material starting with the first weekoftreatment. Males given 30 ppm had numerous significantly lower food consumption intervals compared to thoseofanimals giventhe controlmaterial starting with Week 3. There were no toxicologically meaningful significant differences for females given 30 ppm or for animals given 1 or 3 ppm. Test Material Consumption. Test material consumption data are summarized in `Tables 11 and 12. Animals were fed diets containing 0, 1, 3, 30, 100, and 300 ppm. The amountoftest `material consumed by animals on a mg/kgofbody weight/day basis was as follows. Target Dose Levels (ppm) 1 3 30 100 300 100 300 "Achieved Dose Levels - Range (mg/kg body weighvday) Males Females 0036-0103 0.049-0.108 0.108-0.259 0.147-0307 1126-2618 1454:3.070 3.847-8.124 5.686-10.166 16.058-25.408 19.568-28.712 3.841-8.873 5355-10.135 15.803-25.193 20.004-29.270 Clinical and Anatomic Pathology. Hematology, clinical chemistry, urinalysis, and urine chemistrydata are summarizedin Tables 13 through 42. Terminal body weights, absolute organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios are summarizedin Tables 43 through 49. Tncidencesofmacroscopic and microscopic observations are summarized in Tables 50 through 59. Incidenceof severity of selected microscopic observations is summarized in Tables 60 through 62. The Pathology Report contains a discussion of the data. 6 1 003119 Covance 6I3M29T-21162218 Dose Analyses. Results of the homogeneity, stability, and dose preparation analyses are. in Tables 63 through 68. Prestudy, several homogeneity analyses were conducted on eachofseveral mixes in an attempt to resolve issues related to the inherentvariabilityand lackofsufficient sepsitivity at low levels in the analytical method for measuring NE(FOSE. Mean valuesofthe homogeneity analyses for the mix done on January 15, 1998, ranged from 89.7-104%, 92.0-98.7%, 86.8-98.4%, and 94.0-96.7% of the theoretical concentrations for the diets containing 3, 30, 100, and 300 ppm NEtFOSE, respectively. Mean values of the `homogeneity analysesfor the mix done on March 30, 1998, ranged 91.3-106%ofthe. theoretical concentrations for the diet containing 1 ppm NEtFOSE. These results indicate: that the mixing procedure produced a homogeneous distribution ofthe test material in the dose preparations; although variability generally appeared slightly greater at the lower dietary concentrations. Prestudy, several stability analyses were conducted oneachof several mixes in an attempt to resolve issues related to the inherentvariability andlackofsufficient sensitivity at low levelsinthe analytical method for measuring NEtFOSE. Results of stabiliy analyses for themix conducted on October 15, 1997, of samples stored for 19 days at room temperature conditions indicated that the mean concentrations were 89.8 % and 87.5% of the initial concentrations of3 ppm and 300 ppm respectively. Results of stability analyses for themix conducted on October 15, 1997, of samples stored for 34 days at room temperature conditions indicated that the mean concentrationswere 90.4 % and 89.6% of the initial concentrations of3 ppm and 300 ppm respectively. Resultsof stability analyses for themix conducted on October 15, 1997,of samples stored for 8 weeks under frozen conditions indicated thatthemeanconcentrations were 89.2% and 95.3%ofthe initial concentrations o3f ppm and 300 ppm respectively. Resultsof stability analyses for the `mix conducted on June 5, 1998,of samples stored 32 days at room temperature conditions indicated that themean concentration was 77.9%ofthe initial concentration of 1 ppm. Results of stability analyses forthemix conducted on June 5, 1998,of samples stored at room temperature for 46 days conditions for indicated that the mean concentration was 93.4% of the initial concentration of 1 ppm. 7 60d3120 Covance 6I3M29T21621162218 `The mean concentrations of the dose preparation analyses for all levels ranged from 61.8%-134%ofthe theoretical concentrations (including the reassay and retention sample analyses, but excluding data that required reanalysis). Inherent variability and lack of sufficient sensitivity at low levelsinthe analytical method for measuring NE(FOSE resulted in homogeneity, stability, and routine analyses data that were in many cases outsideofthe standard limitsof+15%. These results will be reevaluated in conjunction `with the analytical results from the blood and liver level determinations when theyarc. provided by the Sponsor. 8 003221 PATHOLOGY REPORT Counce 6M3T2692311226218 SUMMARY `The purposeofthese studies was to assess the carcinogenicity of the test material, N-Ethyl Perfluorooctanesulfonamido Ethanol (NEXFOSE) when administered in the diet to rats for at least 104 weeks. Thetestmaterial was administeredat dose levels of 1, 3, 30, 100, and 300 ppm. Animals given 300 ppm were sacrificed during Week 8. This interim report discusses findings throthuefgirhst 53 weeksofthe study. Dietaryadministrationof NESFOSEwasassociatedwithmildlydecreasedredbloodcell count, hemoglobin, and hematocrit for females given 100 ppm; mildly lower glucose and `mildly higher urea nitrogen for males and females given 100 ppm (predominantly at `Weeks 14 and 27); moderately higher albumin and moderately lower globulin for males given 100 ppm (predominantly at Weeks 27 and 53); and moderately to markedly lower cholesterol for males given 30 or 100 ppm and females given 100 ppm. Administration of NE(FOSE at 1 or 3 ppm for approximately 52 weeks had no effects on clinical pathology test results. Ata dose level of 300 ppm for approximately 8 weeks, administration of NECFOSE was associated with many effects on clinical pathology results including lower red blood cell `count, hemoglobin, hematocrit, glucose, globulin, and cholesterol and higher urea nitrogen, albumin, total bilirubin (males only), aspartate aminotransferase (males only), alanine aminotransferase, and hepatic palmitoyl-CoA oxidase (also observed at Week 4). Mostoftheeffects were moderate to marked in magnitude. One male given 3 ppm,threemales given 100 ppm, and four males given 300 ppm died on testorweresacrificed moribund.Themalegiven 3 ppm was sacrificeddue to afracture: ofthe hard palate. The causeofdeath was undetermined for one male given 100 ppmand one male given 300 ppm. All ofthe other animalsthatdied or were sacrificed at unscheduled intervals had hepatocellular hypertrophy or hepatocellular necrosis due to treatment with the test material, or both. Hepatocellular necrosis was the causeof death for two males given 100 ppmandthreemalesgiven 300 ppm. 9 Gociz2 Covance 6M3T296211262218 At the Week 4 sacrifice, terminal body weights were lower for males given300 ppm, and absolute and relative liver weights were higher for males and females given 100 or 300 ppm. There were no gross findingsatthe Week 4 sacrifice, and tissues were not examined histologically. At the Week 8 sacrifice, five animals/sex given 0 or300 ppm were necropsied. Terminal body weights were lower and absolute and relative liver weights were significantly higher formales and females given 300 ppm. The only test material-related findings at necropsy were large livers for five males and two femalesgiven 300 ppmand mottlingofthe liver of one female given 300 ppm. Microscopically, test material-related findings were limited to the liver and consisted of hepatocellular hypertrophy, hepatocellular necrosis, and hemorrhage. At the Week 14 sacrifice,terminalbody weights were lower and absolute and relative liver weights were significantly higherformales and females given 100 ppm. There were no test material-related gross findings noted at necropsy. The only test material-related `microscopic finding was hepatocellular hypertrophy for males given 30 or 100 ppm and females given 100 ppm. At the Week 53 sacrifice, terminal body weights were lower and absolute andrelativeliver weights were sigaificantly higherformales and females given 100 ppm. There were no test material-related gross findings noted at necropsy. Test material-related findings were. limited to the liver and consisted of hepatocellular hypertrophy, vacuolation, necrosis, and bile stfaorsaniimasls given100ppm. 10 603423 METHODS Cove 3M29T:e21i262218 Nine groups of Cr:CD(SD)IGS BR rats were studied using the following study design. GT ow MtaleeetAuTT mesme GDemayNlEeOms)r w Cem wmCre ev an 320000m) @ 03 4 QvicHigh) i] 5 ((MHiigdhH)ighRecovery) 70 270 i300 7 (High Recovery) 40 m40em 300 8 (Control) 70 70 0 9 (Treated) 70 70 i a b TTrh-ee63sc1oe6nsitso59l8a.pm1om%amlno-fetNehcyElevSpeeErdfl.tuhoerboaoscatladneiseualnfoyn.amido ethanol (NEtFOSE); dose levels are During Week 8, blood and urine were collected for hematology,clinical chemistry, urinalysis, and urine chemistry tests from five animals/sex/group in Groups 1and 5. During Weeks 14, 27, and 53, blood and urine were collected for these tests from 10 animals/sex/group in Groups 1 through 4, 8, and 9. Blood smears weremadefor all `animals sacrificed at unscheduled intervals or during Week 53 (interim sacrifice). Necropsies were performed on five animals/sex in Groups 1 and sacrificed during `Week 8; five animals/sex in Groups 1 through 4 sacrificed during Week 14; and five animals/sexin Group 1 and 10 animals/sienx Groups 4, 8, and 9 sacrificed during `Week 53. At necropsy, macroscopic observations were recorded, organ weights were obtained (for sacrifices during Weeks 8, 14, and 53), and tissues were placed in fixative as. `specified by the protocol. At unscheduled necropsies for animals that died or were sacrificed because of poor health, macroscopic observations were recorded, and tissues were placed in fixative, but organ weights were not obtained. Microscopic examinations were done on selected tissuesfromanimals in Groups 1 through 5 necropsied during `Weeks 8 and 14. The tissues were adrenals, brain, eyes, kidneys, liver, mesenteric lymph node, pancreas, spleen, testes, and ovaries. Microscopic examinations were done on all collected tissues from animalisn Groups land 4 necropsied at the Week 53 interim sacrifice. H 003124 Covance 6I3M29T2e1321126218 In addition, microscopic examinations were done on tissues from animals that died or were sacrificed due to poor health. Five animals/sexinGroups 1 through 5 were sacrificed during Week 4, and five `animals/sienx Groups 1 through 4 were sacrificed during Week 14 for hepatocellular proliferation rate measurements and hepatic palmitoyl-CoA oxidase activity. At the Week 4collectionforanimals in Groups 1 through 5, samples of liver were collected for mitochondrial analysis. Five animals/seixn Groups 8 and 9 were sacrificed during Week 4 for hepatic palmitoyl-CoA oxidase activity and during Week 14 for hepatocellular proliferation rate measurements and hepatic palmitoyl-CoA oxidase activity. Statistically significant differences citedinthe Results and Discussion section are based on comparisons between the control and treated groups. RESULTS AND DISCUSSION Clinical Pathology `Week 4. Males and females given300ppmhad mildly, but statistically, higher hepatic palmitoyl-CoA oxidase activity consistent with peroxisomal proliferation. `Week 8. There were many statistically significant or otherwise notable differences for clinical pathology results between animals given the control material and animals given 300 ppm. Those differences considered to be effectsofthe test material were lower red blood cell count, hemoglobin, hematocrit, glucose, globulin, and cholesterol and higher urea nitrogen, albumin, total bilirubin (males only), aspartate aminotransferase (males only), alanine aminotransferase, and hepatic palmitoyl-CoA oxidase. With the exception of higher alanine aminotransferase for the females, these differences were statistically significant. The effects on the erythrocyte parameters, glucose, and globulin were consistent with poor health and failure to gain weight appropriately. Higher urea nitrogen `and albumin were most consistentwithmild dehydration and indicated the effects on other parameters (e.g., the erythrocyte parameters) would likely have been greater if the animals `were normovolemic. The effects on alanine aminotransferase, aspartate aminotransferase, and total bilirubin were indicativeof the hepatocellular degeneration and necrosis observed `microscopically. 2 CO3125 Covance 63292121228 - OOOO @ wTeia Other statistically significant differences were considered to be of uncertain relationship to `administration of the test material. Mildly lower platelet count was observed for males but not females. Absolute eosinophil count was statistically lower for both males and females, but the differences were extremely small as normal eosinophil count is very low. `Weeks 14, 27, and 53. There were several statistically significant or otherwise notable. differences for clinical pathology results between controland treated animals. Those differences considered to be effectsofthe test material were not always statistically significant but were generally consistent over time and exhibitedarelationship to dose. Several statistically significant differences that were inconsistent over time or did not affect the high-dose group were considered incidental. Administrationofthe test material was associated with decreased red blood cell count, `hemoglobin, and hematocrit for females given 100 ppm; lower glucose and higher urea nitrogen for males andfemalesgiven 100 ppm (predominantlyat Weeks 14 and 27); higher albumin and lower globulin for males given 100 ppm (predominantly at Weeks 27 and 53); and lower cholesterolformales given 30 or 100 ppm and females given 100 ppm. These effects were consistent with those observed at Week for animalsgiven300 ppm but were less prominent. `The effect of greatest magnitude wasthatfor cholesterol. At thehighest dose level, cholesterol was markedly decreased for the males. Theerythrocyteeffects and the effects on glucose and urea nitrogen wereverymild, and the serum protein effects were considered of moderate severity. Administrationofthe test materialt 1 or 3 ppm for approximately 52 weeks had no effect on clinical pathology test results. Anatomic Pathology Unscheduled Deaths. One Group 1 control male (Animal No. C90721) and one Group 1 control female (Animal No. C9179), two Group 2 males given 3 ppm (Animals Nos. C90806 and C90813), one Group 3 malegiven30 ppm (Animal No. C90878), one Group 3 female given 30 ppm (Animal No. C91282), two Group 4 males given 100 ppm (Animals Nos. C90945 and C90949), one Group 4 female given 100 ppm (Animal No. 91322), three Group 5 males given 300 ppm (Animal Nos. C90993, C91003, and 91029), four Group 6 males given 100 ppm (Animal Nos. C91045, C91046, C91049, 13 CociRe Covance 6M32T932112162128 and C91068), one Group 7 male given 300 ppm (Animal No. 91099), two Group control males (Animal Nos. C92198 and C92213), four Group 8 control females (Animal Nos. 92235, C92342, 92345, and C9234), two Group 9 males given 1 ppm (Animal Nos. 92273 and 92293) and two Group 9 females given 1 ppm (Animal Nos. C92403 and 92437) died on test or were sacrificed moribund. Animal No. C90721, a Group 1 control male, died due to a widespread malignant Iymphoma.Animal No. C90806, a Group 2 male given 3 ppm, was sacrificed because of a large subcutaneous undifferentiated sarcoma, and Animal No. C90813, a Group 2 male: give3n ppm, wassacrificedbecauseit had afractureofthehardpalate. Animal No. 91003, 2 Group 5 male given 300 ppm, andAnimal No. C91282, afemale given 30 ppm, were sacrificed moribund with pituitary adenomas. Animals Nos. C91045, 91046, and C91068, Group 6 males given100ppm, andAnimalNo. C91099, aGroup 7 `male given 300 ppm, were sacrificed or dieddueto hepatic necrosis. Animal No. C91049, a Group 6 male given 100 ppm, died with necrosisofthe musculature of the anus. Animal No. C91179, a Group 1 control female, was sacrificed because ofa large mammary fibroadenoma. The causeofdeath was undetermined for the other Group 1 to 7 animals. Histopathology was not done on the Group 8 and 9 animals. The macroscopic findings were typical of those observed in ratsin long term studies. Week 4 Sacrifice Organ Weights. Terminal body weights were lower for males given 300 ppm. Absolute and relative liver weights were higher formales and females given 100 or 300 ppm. There were no other test material-related changes for absolute organ weights, organ-to-body weight percentages or organ-to-brain weight ratios. Macroscopic Findings. There were no gross findings noted at necropsy. Week 8 Sacrifice Organ Weights. Terminal body weights were lower and absolute and relative liver `weights were significantly higher for males and females given 300 ppm. There were no other test material-related changes for absolute organ weights, organ-to-body weight percentages, or organ-to-brain weight ratios. 14 005s Covance 6329212228 eee SLL Macroscopic Findings. The only test material-related findings at necropsy were large livers for five males and two females given 300 ppm and mottlingofthe liver of one female given 300 ppm. There were no other test material-related gross findings noted at necropsy. Microscopic Findings. Test material-related findings were limited to the liver. The test `materialrelated hepatic findings were hepatocellular hypertrophy, hepatocellular necrosis, and hemorrhage. The incidence and severityofthe hepatic lesions are listed in `Text Table 1. `Text Table 1 Incidence and Severityof Test Material-Related Microscopic Findings Males Females N--_---EtylPefhorooctamesulforam(ippdmo) DNousmebeLreveexlamined 95 3050 05 3500 Liver `Hypertrophy Moderate 0 5 04 Moderately-severe 0 [J 0 1 Necrosis Minimal 0 1 0 0 Hemorrhage Moderate 0 2 [J 1 MMiondiemraatle [J0 30 00 01 `Week 14 Sacrifice Organ Weights. Terminal body weights were lower and absolute and relative liver weights were significantly higherformales and females given 100ppm. There were no other test material-related changes for absolute organ weights, organ-to-body weight `percentages, or organ-to-brain weight ratios. Macroscopic Findings. There were no test material-related gross findings noted at necropsy. 005125 Covance 6329212228 a wTeNel Microscopic Findings. The only test material-related finding was hepatocellular hypertrophy for males given 30 or 100 ppm and females given 100 ppm.Theincidence `and severity of the hepatocellular hypertrophy are listed in Text Table 2. Text Table 2 Incidence and SeverityofHepatocellular Hypertrophy DoseLevel Number examined Liver Hypertrophy Minimal Slight Moderate -- MN-Ea thyllPere fluos rooctan_es_u_lfFonoammidaol(eppsm) 05 35 305s 1050s 05 35 305 10s0 00 1 0 0 0 0 0 00 1 4 000 2 0 0 1 1 0 0 0 oo Week 53 Sacrifice Organ Weights. Terminal body weights were lower and absolute and relative liver `weights were significantlyhigherfor males and females given 100 ppm. There were no other test matecial-related changes for absolute organ weights, organ-to-body weight percentages, or organ-to-brain weight ratios. Macroscopic Findings. There were no test material-related gross findings noted at necropsy. Microscopic Findings. Hepatocellular hypertrophy and vacuolation of the liver were: observed only for animals given 100 ppm. `The incidence and severity of hepatocellular hypertrophy and vacuolation are listed in Text Table 3. Other test material-related hepatic findings were hepatocellular necrosis for one male and two females given 100 ppm and bilestasis for onemaanldtewo females given100 ppm. One female given 100 ppm had a hepatocellular adenoma. Hepatocellular adenomas are occasionally observed as an incidental finding in 1 year old rats. 16 02129 Covance6M32T9-261321126218 Text Table 3 Incidence and SeverityofHepatocellular Hypertrophy DNousmebLeerveexlamined Liver Vacuolation Minimal Sight Moderate Hypertrophy Minimal Sight Moderate ModeratelySevere --N---EthyMlaPelreflsuorooctan_es_ul_fFoneammidaol(eppsm) 05 30 300 11000 05 30 300 1100 000 3 000 2 000 3 000 0 000 3 000 0 000 0 000 0 000 3 000 3 00 0 2 000 4 00 0 5 000 0 n 603430 J-- } 2S . 8 & s.Nh = se ne See eee wae owe wie was wm wes o . se ee ee sees was wae we we was swe ses mmc of Majacad seve bcs e ite Eaa&e sno so Se Swe Se Se SG SE Se Se Swe Se Se Se . . ss ee se se se we we we wee wes wes wes we was we we we o =5< so F.Y - a . . se ee se ee se wie wie wae wes wis was ws wes wis we we se mary of Mifatad sev pata e a0 aoSs sho sho5 . . ss ee see se ve se ee se Cee ees < sho E a &a a5 Toe ene me wpe es ess ess ems 0 0 0 woe ws we wndo s awdonn we ws os arse ws oe are wo wm wm ede wwe wm wm we oo oo mse of Mutat sarvivt Ba oh a8= i3 fee eee ee ewe. we ns om de we es wre wm ese we ms we omy of fenced suviva usa 2 EA. & sh @ aw Cee one om oe eee wm we ed eee ee eee. we ems om ee om we . oe ee 2 sih a=& s3o 200 eee ae esse 4 ea we we om de we eds we em we em ok we ooo.oo...o - sho &s sh5o =3 se =; sw ss sus wm wm we eee eee ne ens we we ons mary of Maced survival Ba : &2 ,: BBs oe we me ene ws ens es ews we we ae we wae wns ene ene ens em ans vss ws oe maryofMassivitapsan g ,: &i 8 es en we ane ee am em oe am em we FA zg wo a miro Masiatas survival saa o e .: 2= vo we swe se swe se wee se we we swe we wo we we se ene we am om oe em em we &ge :, aao wo we se se se as seme ot cn ation Tp nor oEe a. Lb Emam F Bem .[EEE EEE iii  Encoun, && h4iwo coven =53 WRShmm ceoon. eyo Chicas canrvasions 11a e620 SEs eeoe e0 20 aaes 2 STRhieo,e IS5& [LT1EhE0 Cee ee oe PE PrEihtRti Es g go iEEm BRnE. [--- Eee. Cee fret f Pi ri i E[S:fAs E BEEEESr 8 EEmym f IP EREEi E EREERi E EEEE PPiidliii e E= =ES i ayy eeer Rar = m= P$P 3rs 3s3s8ss8oeese sss soso oe 2 f8 is s83ed &o TBEEdER gLso EBBsi E r Sctt irr oesd ss f IE EEi i EEi d EE gge EEige & Bie mm momar & Lx Epr as ston P SCil rE resE res: EE g mmm &5 i= 1s 2 EEeLlm SSf1ee8ns8osssesese PERI g 0 E mEEo. @&Eo arEETim r tPiistdd aEnEns Clee EEEEEE oES mTmhem &eB "Ea FE TT en c Ee8 Ee3 En8e 8EeE] Porras eae EIR o gE H B= a To orm I --- F iRiEs E PEPER os 1 0 0 0 0 o EEA eon nor ia E =E[reT -EH a ESEh Coie 0 oe e tEehEee REroes E s sess e&o BmEIEEEENN 5& Hhe mm LE If IRREEi EEEERRi EE]] P fiiE iiE id f133384 g9fEF 2 a EEiYe . &8 B=j IP 10Er8E0Ei38E0 ossE8e E 1RE 1 E E H o aw S mmae m n a2 EF3H] B = See 0 0 oe ee 000 ss P$3iso s l dded diodes ssw ot coors sis sgtsf EE Bil TT e B o gp e asm I1 IE3E E1 EEEiEEN colin og & a EeyE 88 ECrA [ t FE eReErE s o 0 1 08 0 0 0 egEe mE m H> emEmEe. Be $d sPorrosses PERE 2SfR adE E zF&E a Freu $ t1 o8 e8 d ceeraee ba J &eYS E EEEE.a E 8 EEE HE PPPihrdid fi z = >=& M = =H e ~N Da stowtarr 28d ssrsi8dd NE gcs m= == H &be E= E onset = i b Ps ig d d i Pes 2g Sa Sr= E EEE gm een = =a ss$Er8rEr1eE 10 ee sy tp oF BSe v am uff m=ooE. & @ E "Ha EGs afte By "EWeonuh he B3 E Gi kWa 2 moh. We Hs a" EP hw EF 8 se 5 ait . my treg FERRY mse of soy tan sen 1 &gSe BoEm. oa doa f," PE d5h dah5) . a2, . B oon. "aa.x. &a =H, He Hs an ptr SE FE oon=ooEg.o4Hs H 4 .W of &Eu 4 ND ome ot ge 1 &FE = Wm. EA kd: f "m4 4 & 4 5 "a Eo ee Ho He gd ama ot ot en 4 oe" BoE EL oH 04 % e00S" an pBx eoof,o5f, # O0f, 4o50 f d5h 4i., 8" Bm od 4 bh 4 4 sesot wn se Bod 4 4 4 A e oo 8 5 5. 5 ". 4 "4 & 4 BB C OB rr en I =o kN a Ha & Caw ol als BY a2 [RS -- =o, Be Ch. E < To= d o Eclu, aHe EH = no " & " o $ ON. CH. Ba Wa E gs s = onl oos moe E moa. Sh 0? ha od oo E a R @ CR, i a 8 sets otsare8 o EEE Ed Ev BmoowA # o. 44 84 BoA 4 4 4 ip epi on gS "mB m %% 50% 00%% 0%% 00%% 5OL 0O%03 Fi OUR O" 445 34 "0,% "0% O"L "0,% & "or " 5 5, , ", wo , mayo oy wt, or cn g o%, 4 4 4 2 g EE i, su. ow 5 5s . mey a ae ho eBn e "mw % 3 EH Ex& wn BBoLB5 O2L O5L %nL Bo owem.omooo8 0 B03 O I . i2 3 . CBC [RR ------ e BoE, 0 EH Eoovm 8 5 EC a nw 5 a 2, a, . i, EC 2, [ET ---- E& woBsOARx OoxE aB owoBwoo8d mEoozOE %a ahh w= h ahha oOsE a0%  Bol Lh I&& ump.B= w oa9 55hhP4l %. . @ ney oa 5 Pl . ~ woh i i i is "i4 e . ". i macy of 20d vane. couson es (1 <2 wma,B EC Hon iS=T 8= a3 . #"i . Bows & EFAI ow A #PAy #= a1 . "Go.h . maryo pat sata: che sata (0) - =H Be ds ds te "&& MT Eolw a aiBsa aBea ahle H3e S@o my of notva chan cst) e&2 woop.mh os Ba Hoa "Ba te moon, to te a ow # % 4 [ER Ee tm owen. #8 44 44 wu J ------ gS "SBwoA#84 &Ewan Wo s "4%. 8 amy 8 8 8EE8 E0% "4 wa maryo ety vat: cog Sata (6) &S ennB=e k,o8w a[RE.EB 5He | 2 =u. 5EHsc aTa =o. Be WL Bh e on 5 su zERBef. of 2, 2, o, ., - ol fs of lLf E gg "geBoodd,, Bf0d 4 8 & EEBool, E of, EdR C& ih C i PE 85a.a . && WOW. Ws Ns 0h wh 9BE LE TeeOEa.8 EU r EEs iu,n " = 2. . JTes x . $z&gG g" 4 4 4 4 4 [ER 2 Bwoool, Ef, : E mol, 4 4 4 &8 CI Bod,5 ofa, B E5 Ed : BOB B039.  Ei. E 0% m=eod,. 4Ba 8es f ee C # Hy C @ Poe df i$ a3 aff ale * seme fo esos tn & 8S tomBBeooodlB,, EooE ff.. ,E f3 h hEC he i@ macy of100 conmmpttia.o(5n1 p . XE RE ho &&& mtoodat. adE ah ai = i a3i mary of oot onnmpion Bata (4) &E| g B==OooB, aE"C,Be, awWWo,ee i5 8 om, af 8 8 macyo rest conmmpeton uc a1 oS wonoO, oe mae N8e N5L + m3ou. We. dh2 E won. a ao a 5 Q =m, Nuh Es sey of 1008 conmmtion psa. (1 &[g EE R =ue,o,"R ewa,Ea, = R& oan=oo,w ion, adM. ads mary of Tou Conmmtion Sata (6 - mos. dl 8, i E won. ao a a && mo. Hl H5 .W.: S a F E=w H, WwOR. BCdH. 8 PL ------ 22 Todma oBaae 5C0 B aowt twes "tm TooGaame Bfanamm "GwGemmn wBfiaamw & ano wm um & foe Tm le Gee Ba ha Bas [I -- 22 Fw =o te fmw oGam 8&[EE By Afe 9le "@4m . No ke fan Gm fw lEadw O L3e . ae ry fn rh Gmesion Bc ttn 2g LI ; EgE I mBootmw thmw Gimm 0 ia t(m ] C somo et crs nmin te. rir E wbBotane mie m weim mbe ig EE no BBeofanm welm melm3 0 weta3t @ Bohm hw im ta mary of est ceria ommeption Sa naharin) gSe 7 &&[PE Em a otamms Ye Bmaoofnae "fuame memw Bwem 2CmhaeouH= a GWere xnhaee Hdame HxAamn eal ow mow 2 " x mir of Tent saariad Conmmpticn usa taatder) ggS Fw moottmmoalmm Goomm O H& nowomw oom wGam "aGammee aGier . [SI a o . TEaHe O "aTa . a. cy of Tot Maeriah ommmption Sa mahal <S E * Fhoe ta a Taw a he iHM = Ee u fw Taame tiae LE " 5 Maate aow mae of Sst teria Common Baa (mh) Q won, ow 5 5 . &E on m on, ouown "mo"m . g&e =ooug um ol . Pa y . as mir of Tet wna ommmption Sa (mahal 5E w 7 B= Eaww e o Tfeer Guemm "fee B R oamoa m on mary of Tes Haarteh ommeption Bata maa) gQ wowmBeooaYnee 5Cha Ew on oa Ps aa Fog 8 o2 * = Ew u Gas luema [I 5 52 moun ; us he ta hes [ER -- &SEowonoBmie owte y te oim e 5 Bota haw - BOSH OU OI CER Uh hw e 55 & &8 B& e 358 Summary of clintoal eaatology Data. &8 B8 Sor of Cts sto - } BTR TR &E - BOER OH ouo%om 8 BOB OH OW th Mh i vn. maryo Client Nemssony baa -. #0 Ew &e fimog aaWoo aa I1W h R a H aF dwe wfe nr Ho bde let 8 we Ooo 5 a Bod Me Me te Lo & BmwOBeaOm mss es sCetsh omaYh owe es =8 ~ BOCROMH Ch Cth Uh &I &Sm= BOfMoAu Enof fdI Bh Ek Se th hh 4 om fe ms hf ae &&g BOOTRO%E OIE OR ou 8 e& 8J&d @ Pow ow &&5>S e& 8& Sey ten remo s BOBO Mh MR Uh Ch H g&B 100 BOHR HR WCh Ehe  BoM hoi op bb BB bh 5 EB&8 . B BOoS oHIE odbdoF oobF BBe ffo obe ko2 on g BOWE OW On OTE i 5E BOCEOE OY Hh EUh TRUh E 8 ow ame wae wee ss waa me Summary of Clinical Nematology Data. ) s BOMp Ch op ob = moe a onan ob a de om, Sh m,n ae &8 Fok oa ow od kod ob obo on e& 5a2 &e a5& &e 8 3 e&o BN&8 mary of cittens Heston oes ' eg mfwie a #f0 w oWo aTawh oumCaHs mreWwae wew 3 wMia @&a a- Wa dd wT <5& BimoosoWcw haa Wsn Wb a RdaeR oR owMd . a a9s o3wH. e wat Ne 0% 88 sms tmm-- &&4 Boe Ou YOR OPO OB 100 mBtO n Oowe oWw OmWn ea"mRn Bom g 2 BO oh Bd bp Be fe be be &8 BOWveO% Bh dh kB Bed Se bo &eo =8& S&s &=a c tn = e &aa e&2 HoB em fi 5&= eo om-oooog & LEN 1&3 - : BL mary ot chaten chemtacey usa e&o =B& g&s =SG e&o &ae &eo 884 g&5 4 e &&5 <&a za& e&oc &ia] %g woBGE oOlE de os ho 0% op ou 8g5 mary of Chateas hear usa & Pome Hho w Hwooop nfaeLs owMoewE aanea MGa WSC. ML 5@J s BOBOB OZ O% 0% oFEw oon a& @ mary of Clnten nmtacry aca 2 I a5& 8 Summary of Clinteal Chemistry Data } e& iFYi 358 &eg N - = i i 8 00 mw 3 o EL AA n< 8 e& &8& a8& e&c && && a8& s& 393 IS E=o EA Se 0k TA h Sh ho Be & se e8 mwooae aNki' TWwh 3i W i' bi' 1Be so gS EE A & Tew a 2 1, we 22, Ed ", 0g 00 $ ew am In . we sa 23, 2, " e Bobo 0% Row dB gge TeBw OMa Ene 3o, smp h 1 hEd .hb207 & 8 100 FoROoB ob WOR We aRHor g< BOW OE ROR OW OBB & 8 " Bowe Bowe EW WW ea3 @ &g EE & = &g& a e& "eBwokeomg " oad, 2R,h .%, 20g% d1, Eny a BoM be om Bow Wp g2- Boob [ FoLoOk ob ob I eh EI TA E ~ CEO OE LY TPT g BoE ode od 0% ow Wd ow && EOR OM bh BB 3 @ wae % 5, .s, 5.3. age 1, 3 BOB Be de Uh CE 5 LE e SJ2s Zg5o BOER bh RW & &e 385 - i oR de EW ww e&& 2& ry of chien ornate sea > mon Eh &e @a5 ryo chiens rtnaiate dca &e m i osPoW e d a@5 e& 5 il mOuohws Hy em ii er aJ] mw ma oum oe - mo Wk &1&e9 PwiWophawoowEmh eWw = ome oma ome sory fits rims g monOnBE oEwe aTR &&& ee&o 4&8 mary ot chatens einaiais own - . @ &&e Bi OoBmCaA neMmh Th 83 &g Boosns miwB 85 FRR ow ma oem "og g& g 8 & I$&8 &e BmoOunWEome g3 E aw Epa em ", Sey of Cnt mies 2g EE &4 WwwoORpeR E em kt a e& 538 e& <3 g&& 8 e&s 88I e2 & w H o wowsHe Bmm owou 83 &go FaoOoEBo0Bbo#2, EBD 88 e& &g8 &S &8a S Bf Hi a fESh | 3&& 2 ama of rianCmtoews 00 8@e& i B0Be. ogeheo@3 wow8 &e 88& &oc &S3 &e I83 e&c &g@e s& &2 e& &B Pini eked c g& & ae 8& & maryof organ wane bts &e w&ing m o orgy wig se a meet: HE SRE IRE UGE see Hd DHE ER LEN WE i i iEE el si a" ERWCal alae deme Bem bene fmm mba bees bem foe ee ele & mestm SHEE esINsE erNEeM f awewo RINe E MEs Nm B8 m moE w aCiEDa SfHeEa fSEeEw bIeMne TnUPeEwE uWlYEfaRn lINoEa bSaNsE maryof ors wah pia & ommemsEmoE oCfEHYr YMluRm bEs eYr F baBEmR EE en TBE wRhyIm: e b: or ;hem Ewan e SoTL eek beg EE iicew w C--hi----H--E--R ----S--ET----D--E"E Hmoe ----w--------CR--T --eMrNEaseNTESeerEeNs  EiB imge pe:he CRY EEE v MEE UI wesn ea eni: E RE SI s JEW HR Joe 5 eit gy TF REUTER agy DFE WF EE &i aan i Lor aor, 5 Cs CTT fTmUTTiEm mam eo d8rC8lm sbm Ebem | | cog summary of Organ WeighsData mend ) 8 & FBI Re wnamnaepe: C8ETEbmTTTharTTTbm aCnoceed:s ITIT fir sbw d3 m d3 aw B maryof orp tans bce . B BE emn om uHlYa [RMNmGm wie eee Gene Som a ow: & TE oBo weeS a meet 04 SHR SBE GSE i MRE wChRy lGeEm fBEoRm bEann o ToedE od bm hm Bm Too of bm hm hw & v3 BBOT osse dr btmm bhwa bmaew eTrOmO dy hDwm lTmm dtawr 8e m TmAeBeLmES ScafE trieishE bwas tabtaarst bw stits eTeoa oRREdr Jail osistaetssasissstissstasant as 0s Summary of organ Weight Data Covance 039-312 med - 2o EToEThr lTmm hTwm flmm eTTOE Bas Twoameg ofr bm E faT r C br eTm oaeSedT r sey of orn tan ea - 0B&e reme--sm------HO--M--E----M--E--ISNES A FaEe S CREtErRT i ErA TDI eWre T reCrER 8 aTmoaBneET fOCyRY IbeEnET HfeEn MfNmDs wessea wHE e gHYy ObeEe yfmm vben oSeTemwmERl wM y E tan fMeEsEs MbMeEm ewTWh aHgde fHaImM bSeEmR fEeNmD Bis vam TE CTT wee am EE : s movie: Chi SHE NEE DHE aewter WD SEN EN SER maryoforn tans uta ees monte: HE BC o mr em wie ee Sd SHE SE GEN em S MeS mCiHDa fEaRm IfaEmE fHaRm maryof Gro tanspcs G G Q e e mems m e aCrlyRoImMleeEm fEeemRm vtIeeBnm TmseTeeL w oCwmEdD elSeEmeR ml8wa8s nbNmaEn maryof orp wah sata PO Ca e mamiaEmE Een E aBlaDOEbT oRm dEeDE s fINaD eamm aeaEwE E mHbaDOIbNeEmE lNaNmR bMeRm oom for si oS mTshae hr Ydeeem Yheae fhawn TTeoia uw tm b;an bem 8OOwCdDLEeRm edrslm 3 my b5 w TOE wade I Gaur ssh d) m 5dma3 g 5 Taoaapdi TT hrT faTrTTdmTT an haToamteem dh dm TE TT BwTT dee macy of orp wane pata Sco meecm m aRly DlMms bSaHnE LMeEwR TmUPeRwE oRhD MfMaEe lBEoSa LJeRw & eWsEmaaBmEn E mls uT m baL w baw weTeE agBE da lw faT e Elem &eg reevmnoBe: oT ls ilS ua NfEeEw MLeEwNe TUmReIUsEtR uHlI, SfBeEn SlHaSa SLEa=Re a8 mary of Organ Weight Daca * - omToe e chr bm hhea hbmae TeTrool ah Thwa tlmm ldma 8 woes iaiFggr oEsTTbemTTThmTThm eTm oe ol dbe bmTTe baTTlum mirof orsvanbaeta c wkes aseaBtE oyBHlRuE fSEeNrTT IfuNeE eeesT eHeEE uHiDs MbE EeD JdeSnR bDaNn 84 amyoforo tee sta SS$o rmTmhEeang aElDs OlMaEs OfNaSe MbaRm UeaneEdE aW da o fam lBaEm Lan gE VS @ HE Yee tm ine BE dy Tm bm ban c emmmuarBiE EoBTyOE IEfaHT e T fDSeNwTBbNaRm eeanaweawHgWEe wUigRINbmEne BmEe bUas 88 So TemmNeGEwR nClEyD dOaHmHe GIeRn fIaEe UUnRReGEwR 0WD DH ae MSeD m S few vemmemh ls lam fame ae TURE ols fee lan joe 2 eit BE HRE HN HR sew HD OMME DNC JE &8g eyo organ wae saa mei - e& &A8 gSs ThE odakh B R egr gH & Ed ipeesnseestsasassssssnres --= ods hm b:ar lm wMie adiwoigmef sesessonBFse amenseBsasmnnsnnFDzamnegs ---- - men D2 &&=~ 4] mew HD EE BED JER a sem & a awyma nls TTT & os Hi TEwaEE mow aRla IlGem bEaMmTT b8a8w SummaryofOrganweight Bata wrmed L TToott 00 8g elEE ch lm im im - uo BG o e mem w aHlsDHfmDs uMwE tInNe TaUeTUeED aWlFs lLaNm fMaEmR bSa3m3 BB rrrazeetcressmasemecsereeerperes reese LSiPEREESERTSRCRR PRRTSSReE SSES  mE TTT emaEE &cs movie: BA UES NH DiNR oeeww HZ BBE DEN MR a& memmboagwd aClHsE EiRpEa HfEeD fSaEm UmWenEt aRsS reese estes seer nan PE a &a& a SBE ES Trenm Er Tbamea ibnany GBaBm T Tel e OW g aJ 8 dd Tm tm bpp Egg e ene h ew gHyE ogBNT iEm E Bhe8m HtuEm elme eaegBatE aly aa Sumofmorgaanwreigyht Bata reed : o meet ch bm dm bm Toad ah bw dm dm gw VE g0 TIHEREUde bam dfemm bfemn Toamerd dh dTme tbem lbmm macyof org igh pata wams boaBwE a lBE yD fEmNyET fSeEnNT bIeEsE eomeawy BE u3l2y fe em bem b:ae SummaryofOrganWeight Bata ; oeS mmee m 43 Tbeant bBmmn bbaum e Teenl U3 Tm beaen ldea mw bbaawm 8 wma Ten fam bmw ee Ten fen few maryofexp ane Bes &e be m y eBE oBlySEeDi m J bes IfmNmR eesn a eWwE E u2i bem sb:am vb;am a4 mr of re sth un 2 Toe el tr; lm lmm blm &8 aJTR wEayWh E a JNocd fi fm tm bm  5& eS agi maryof ors wanepts men : emmeMsSRo mHiZs fSamHe ItEaDm fLaAmN - eB OCHER DNB Ewe wy 8g EE EA mon WD HER ME oi iggy TY 5 ewer CHD B: E UNS m o orgy awan sta e WTE 0 em am Ta Ta a wePTes bee ea a &8 eDtOIE dC he ems hem-- aw PO OS shea hen. s fam ha &&EienoviensaBdTYfam=e m: e EbCo EuEn e ena m ewHsE wHha3SHGTE eZm Zbs HoIm Sb` EaBw Pp ---- E oamaagm EY o wees Ye 88 wens. HG hb cum 80 eeewww 953 HS ER SRE aomforpaenr esca c i i && meMwosm uClHaD dEaBgS bMaE bIEaRw ewWn e0ly BlaNsEs bIaEp bIaNs m i 8&- -- E TmEenESSdsT rtL hbtuE nhtttbe ahnt bk bagtmd e-- BaTdaReIeEisRt_ e idtarh,pe E ba mrtN es hswte esNid deems ory from i ce & w Troia ees ty weraotahta bm he rasgarntisis eHoTiedOiieEi sissosdsngbrs ahWsnoah errtapBaeaeetesgd:ems o SE + ft 4 ft SAAS RSVI AS gis hn gh eg SRe L SORt ETEE C&0 TmT enA or nClHaE SaHmE SbHaEm CtHeEm TsUeeEn e9lsDOBfBeRe GSeEnH fOaR mer of sr wi ce [2S[ &d e-- mdl- Ltt ater srt asta snst sents @ rar enegecncncntencanennee w Seud ensg oss s4ehs estsisis ses hme bur sigss f: m Bo seus iengerentgaenragenr &a mem 2] Rl East R treaat tints as mHie led riesd sn et aBtr me alft awm edl. emme wads wean: CA TTTTT TTTTTT TTT ny ae: Tae Te TT CT he : wmamewBweE gmmECiHaDTbME eSeE TbMuEnR bJeMeB wee s T wBE uHlyDMEbaE Nm fIam bLaim en wey aa a wes ee Ti mary of roan tan uta 8bf mmemenmE mRiaINleEs bMaEnR fUeEeS TeUNwEwL uSlH Summary of organ Weight Data ome ; & weamTewmeeweim3 HI ISS HRTT ME eaee eages o9yHTTT TTT & BS Bway i i i ERE ggp WEE im I! m Im2 "oaHdE dr iTmw ilmm iImm mw me o si retr es e bta tast iet Loire e terete ete assteetesee eect HE SEU SET NEN eet OB INE NE LEN IE 5 28 EEwTew rm ED mn B 5 EI Tn eeame HE EDEENE 2M macyotorp wanscea &Swei vea"m iB e dTY EeE oHE wHiRi3OyMuEgR mDMeE bOaNn E oI nTowmeeys Bar Ttm tm ihe eT kTaaEtET dTer Tahe am itm ae BE eegecrngprorogres Bede ire nejgn eete sfsog rons mon omy foro wt ce #E E a ETlois ieiiiie eiHpBirregirteasnsrgehrmeraprhearw ~ Lote st ieee eet rshstarhet wBToeodaeidicnes:edgrresgtreatesgtrieenngei:emn Said aiisseesatissereepEeeespse  mTeemrem H3 han i hm i bm eToe ews H5 dm i UGE 3 RE EY Salar resyptesegy satin ey oforn tan uta - & mMe om MB3a0 SHaRm SSaDm tUaNmE eeDOeRwN dBiEs tDeSnE SHuMmR SSeEnN BT rvemrsrreregrange Ee rnere args o E& WE waToP mmeaT wEm ERBa ItWame tOi aMmBe SSaBmR wi eme w eEwEed dWlFs itOeERxU t3amR ihem STE SU &Enmaeanyt cHi lsUEaa Sn huBUsS iha weeTs abalyi ,4 wt mm uE m Be ------------------_ Sse Trea ert army o rp aea BC & imSeadg lTraH iChmL faLihm nTeheeaemeas dHe oaeeuyTem aTH T `ammary of Organ Weight Data. PE - ggSE Ti ee2 r g hCh ees poaw g} I s H tmTlas Ga 8 agg A CE woah wigs i 8 mowJ:w Rd: wien gaz eth a HI SNE JES GE mary of organ etghe aca : &aEmameaB mWm Mi TaB ifSeRBm istSaHeE ishNa8e8 wash besa: mew d0s: gtam ishae itv am FJ 3&G wWeeImwdToeemTl sHEe a Mr eMeEresevsefe eSeaEmRer stfeUs asBm. TJieeIoaevmesegSdee9iesH nsEeAeR reTtStor soma of oe she a E wTeesmw @Ne igag CB hmm HER iH,R eeee e 9 Iler EITT i C ge mPedEWE DTI ly TTCCt TE 525 gE = 7 5 Tem am dram: iEerT haE haT ha eTeOe OEn R a Br hw e aetw tae cyof org weesaa &8Edm eo gBaEeMBaDitOGeEmD eSEwNs ibIaNm wede s ewBa E edEsINteEs itSEeR ibCaNwH `Summary of Organ weight Data SE ) e =m BEF Ur Elag DFS ur fmm demn GH en MEE dls em tme Sane SS MD EE MIE m wr 5Bs ve wn oo ere es OE 8 8EE5 8 8 3 3 8 sn FE CEOL D POE OLOM IIE iiE } Eo 2LEER 8 + ovooF ist ++ Le wm Si00 PR.XX SEo nrams oenmoe gEwe 4 sormza fr ot E TERE E R LE i ee gf S p Esme 8 on on mn > mE amc e 5 5 f eee am $8s1ss ss e&&s Eun & 100 S eo eE mE enE r Ei lb ie dt a gEne om S-----oanpoms,s5 rs:5 5o8f3 3s %gt% 88 wr mn 1s 0 0 0 8 00: Inca of Nacroscopic observations 4e NuaTrmRmincrooonwner &5 mom Rin @$ re sP ssere osyd WSBERGE 2 33 8 3IE8 ]8 ra ies 0 0 0 0 0 gS &&e aE mmE g@ ct I :PiI raI te IE EBLE & 28 wo rsconetasins we own rssasinsot $ ------sss os wemFpEa:memssf sff8 e4Ss E [Raa ma-- 4 E BERI esrE em Swom i sPaaoi tlaa ifyafa ee wE p n 3 nedunce of croscepie asercions & momrrrsgceaormemn ue R32B ou recs pen) rrmer nn en mEaRmIeN ees LsjHF3 OB co a ne PE a . ai ' e- som rusevir rss 8a& ormEwm --. renee TE RE CfEE3 E 8EEE83I % oe oo BREE S pammeme unos 3BEE RRSERINIR Lo ransvn, 10 16 16 16 $s$ae8E4aEda amroma 12 1 1g S S l omens sees nanspoe: 13 o19 w13 n10 2a aEonnprooon) HE PEeEEoR Ee I Incidence of sroscapie coanerations TRL INLE , oD oo cI riI ssG SSS B8 32 38 J G SOO GL ET) i m SE ERn ED dfoo J1o8%19 110 5 ow rou aaa a1 oo ze & wom a EEE Hey ) ag2& J ours neo 2 arm neo & oo br wen ve PEE oC nuspot ne: 1E0 E10 30 30 811 AE &S m A82 weno to woTansEpoNneE: +Lf5 3bt3 mTemEcoRmEes 8LL33bt3 gmmen g 3& m waewc & ovum EELE L33 pag]r1Leeee3.Sz o = we. namm AS 8 om orn ELE Lt ott mameI I3 I3 EI3 3 wEaPRcooEEm D313 3i &E& mr ton B5 vee wm Ct wUaEg 0ooC13 3 een mpm 8 33 EER won STITT : Eg mTTen R ESEE DDD 111 ETE 13 $Em msomenic 08) 8BRowE es cone, noon | J ESE L111 111g s$os85so8s 8os o81se ys GG oF g Emais B&o EE2 oRdoduld Eid  bei ei & aig marion, rem [-- ER BEioid BS ed3E aaldE ad aed  PER i 38 BE es 4g 4g Bodadodudodadadd iii iii & EgiTt B2&po [-- mememassr3 3tr3 i3 l3 l2 2id8 WDolodr0rd 0dor0dot0dr0o0r0r0 0d F EDI EhS aaCn O & b a errr JL 2 2 = pa wpmenpownEd: 3 10 3 10 | go EEee ha 1 8 EER. Pid] Emm wm IRR oN OR I &c maHEm cron B a w. some om mens ne RES $18 3 le S$118888 m wagese poe 3$e33 3 ig EE a oon e S C a8 easS STEN (0) nn wencom pa MMUSE REMED eee pSCe +e sk P 3 deR8R10 333 Tetducn of Micon Gurvtiens eed WIS osesrI reresserremN ereen tt ot 20 wih - AI &< ir Ror Hess wr mn 8 PEE Phat mma 5 is 3 1 ha &Emam-- mn 8Bom 0 waUeELoEeNsE L+LRe10 e51sB3 pee 3 3} | Emm E5 omErnom weg 1 1% weg $ Rten E e- n too > Bene Bem un NSE DRO oTnesEpRovRmaEn T 3 dgY3R30 PE ensame 8 8 4 AER 0) & roomoaes 0 &ComoES 60 enn RAL $d 3 1 opEavLa eAnN, 3L810 89 83 orn RCS Ll 8 8 ] aneot ets etn a HRT, creme, moaemin. & ITN 081 ooo pT S EE t Ig[J IRRn ,racronace, Hae Er 082388 d88 %3 I$I 8I 8 &8& Fon ean g Biaiiiafiadlal T1112 ]Do 83 eee SEiedie :Bo ofod d0d  8a RTRERTROIY, WERATOCELUAAR SElldididididiiid F208li4 i1 18 13 13 1813 $l didd g &&8 Er Sghiliidiairid 2sc -- &E& ==TOCUS,ALTEAEDNEPATOGELLULAR, BASOPMILIC. $21143.4044 ERF RREENERE] E | BLS & mmo, emma aa[J---- --1 01% 2$i3sit1i3 BSaihardeadss / per p-- . c --uarion, pecs "a 8 Bod of od 8 Sora os B Bo oi ss Bod a3l od of Covance 6329-212 . 3M T-6316.1 Table 63 Results of Homogeneity Analyses (ppm) Mixed 9/11/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOWL INRATS RANGE (98.1%) N-ETHYL Sample Location Replicate 3 teem _______ 30 100 300 Top 6.28 38.0 953 322 2 635 322 90.9 217 3 Mean 6.24 337 93.5 296 629 (210) 34.6(115) 93.2(93.2) 298 (99.3) Middle 1 2 3 Mean 517 33.9 5.65 34.1 5.89 349 5.57(186) 343(114) 102 143 96.8 114(114) 286 2m 266 274 (913) Bottom 1 2 3 Mean 6.61 5.24 537 574(191) 329 359 327 33.8(113) 109 108 99.4 105(105) 325 334 278 312(104) a Each value in parenthesis is the percent oftheoretical 03434 Covance 6329-212 . 3M T-6316.1 Table 63 (Continued) ResultsofHomogeneity Analyses (ppm) Mixed 9/29/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(58.1%) N-ETHYL T-6316 (ppm) Sample Location Replicate 3 Top 1 2 3 Mean 3.98 4.26 30.0 12.7 (423)" Middle 1 4.00 2 4.14 Me3an 34.0807(133) Bottom 1 23 `Mean 432 34.2908 4.17 (139) aEach value in parenthesis is the percent of theoretical Co3a3s Covance 6329-212 . 3MT-6316.1 `Table 63 (Continued) Resultsof Homogeneity Analyses (ppm) Mixed 10/15/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(38.1%) N-ETHYL T-6316 (ppm) Sample Location_ Replicate 3 Top 1 38 2 299 3 33 Mean 3.13 (104)" Middle 1 3s 2 31 3 332 Mean 332(111) Bottom 1 306 2 398 3 334 Mean 3.46(115) 2 Each value in parenthesis is the percent of theoretical. 0343 Covance 6329-212 . IMT-6316.1 `Table 63 (Continued) Resultsof Homogeneity Analyses (ppm) Mixed 11/7/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEISTYULSFTOUNDAYWMIIDTOHENTAHRARNOOWL IRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Sample Location Replicate 3 300 Top 1 2m 296 2 319 305 3 35 302 Mean 3.15(105) 301 (100) Middle 1367 2 251 3 28 Mean 3.00 (100) 304 300 297 300 (100) Bottom 1s 293 2 201 278 3 31 328 Mean 3.05(102) 300 (100) a Each value in parenthesis isthe percentoftheoretical. 03437 Covance 6329-212 . 3M T-6316.1 Table 63 (Continued) Results ofHomogeneity Analyses (ppm) Mixed 11/13/97 104-WEEK DIETAPREYRCFALRUCGIRNOOOGCETNAINCIETSYULSFTOUNDAYWMIIDTOHENTAHRARNOOLWIRNARNAGTES(08.199 N-ETHYL Sample Location _ Replicate 3 T-6316 (ppm) 300 Top 1 2.93 290 2 2.86 314 3 Mean 291 291 2.90 (96.7) 298 (99.3) Middle 1 2.65 2 2.90 3 2.87 Mean ~~ 281(93.7) 288 302 293 294 (98.0) Bottom 21 2m2.66 2284 3 3.40 308 Mean 297(99.0) 287(95.7) "a Each value in parenthesis is the percentoftheoretical. C03435 Covance 6329-212 . IMT-6316.1 Table 63 (Continued) ResultsofHomogeneity Analyses (ppm) Mixed 1/15/98 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYWMIIDTOHENTAHRARNOOWLIRNARNAGTES(98.1%) N-ETHYL Sample Location _Replicate 3 T6316 (ppm) 30 100 300 Top 1 289 318 894 275 2 254 219 93.7 278 3 263 290 992 204 Mean 269 (89.7) 296(987) 94.1 (94.1) 282(94.0) Middle 1 267 289 87.4 280 2 266 298 822 300 3 283 272 9038 289 Men 272(907) 28.6(953) 863(868) 290(%6.7) Bottom 1 30: 219 89.1 291 2 849 27.0 101 283 3 307 280 105 278 Mean 486(162) 27.6(920) 98.4(98.4) 284 (947) Bottom" 21 3.2638: - - - - - - 3319 - - . Mem 3130104) - - - a Each value in parenthesisi the percentoftheoretical b Reassay. 03439 Covance 6329-228 . 3M T-6316.1 `Table 64 `Results of Homogeneity Analyses (ppm) Mixed 3/30/98 104-WEEK DIETAPREYRFCALRUCGIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWINRATS RANGE (98.1%) N-ETHYL Sample Location Top T-6316 (ppm) Replicate 1 1 2 3 Mean 0.824 1.01 0.906 0913 (91.3) Middle 1 2 3 Mean 1.02 0.894 0.900 0.938 (93.8) `Bottom 1 2 3 `Mean 0.766 128 113 1.06 (106) `a Eachvaluein parenistthhepeerscenitosf `theoretical. o3440 Covance 6329-212 . IMT-6316.1 Table 65 ResultsofStability Analyses (ppm) Mixed 9/11/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYWMIIDTOHENTAHRARNOOWL IRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Storage Conditions Replicate "3 300 Initial 17s 27 2 47 292 Mem 6.14205) 282 (94.0) 19 days, room temperature 1. 2Mean - 215 207 211 (703) a Each value in parenthesis is the perceatof theoretical. 03441 . `Table 65 (Continued) `ResultsofStability Analyses (ppm) Mixed 9/29/97 Covance 6329-212 3M T-6316.1 104-WEEK DIETPAREYRFCLARUCOIRNOOOGCETNAINCEISTYULSFTOUNDAYMWIIDTOHENTAHRARNOOWL INRATS RANGE (98.1%) N-ETHYL Storage Conditions Replicate T-6316 (ppm) 3 Initial 1 2 Mean 4.00 4.47 4.24 (141) aEach valuein parenistthh epe ercsenitosf theoretical. CoG44z Covance 6329-212 . IMT-6316.1 `Table 65 (Continued) Resultsof Stability Analyses (ppm) Mixed 10/15/97 104-WEEKDIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYWMIIDTOHENTAHRARNOOWL IRNARNAGTES(38.1%) N-ETHYL T6316 (ppm) Storage Conditions Replicate 3 300 Inital 1 344 302 2 319 292 Mean 3.32(111) 297(99.0) 19 days, room temperature 1 28 250 2 31 270 Mean 298(993) 260(36.7) 34 days, room temperature 1 29% 266 2 309 266 Mean 3.00(100) 266 (88.7) 8 weeks, frozen 132 275 2 27 291 Mean 296(98.7) 283 (943) 2 Resultswere derived fromthesamplecollectedfrom the middleofthe dose preparations for homogeneity analysis. bEachvalue in parenthesis is the percentoftheoretical. Co3443 Covance 6329-212 . IMT-6316.1 Table 65 (Continued) ResultsofStability Analyses (ppm) Mixed 11/13/97 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Storage Conditions Replicate 3 300 5 days, room 1 temperature 2 7 days, animal 3 room conditions ~~ Mean 416 264 3a 258 300 267 3.53 (118)" 263 (87.7) a Eachvaluein parenthiesstihse percentoftheoretical. 03444 Covance 6329-228 . IMT-6316.1 Table 66 Results of Stability Analyses (ppm) Mixed 3/30/98 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(38.1%) N-ETHYL T-6316 (ppm) Interval Replicate "1 Initial" 110 2 08% 3 0900 Mean 0.938 (93.8)" 21 days, room 1 08% temperature. 2 0842 Mean 0367 (86.7) 32 days, room temperature 1139 2 120 Mean 130(130) 2 Results werederived fromthesample collected from the middleofthe dose preparations for homogeneity analysis bEachvalue in parenthesis isthepercent oftheoretical. Coia4s Covance 6329-228 . IMT-6316.1 `Table 66 (Continued) Results of Stability Analyses (ppm) Mixed 6/5/98 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(38.1%) N-ETHYL Interval T-6316 (ppm) Replicate 1 Initial 1 0966 2 13 Mean 1.05 (105)" 32days room 1 0828 temperature 2 0808 Mean 0818 (818) 46 days, room temperature 1106 2 0902 Mean 0.981 (98.1) b Each value in parenthesis is the percent oftheoretical co3a46 Covance 6329-212 . IMT-6316.1 Table 67 Results of Dose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL Week Replicate 03 T-6316 (pom) 30 100 300 13 1b 267 289 87.4 280 2b 266 298 822 300 3-28 272 903 289 Mean - 272(907F 286(953) 868(868) 290 (96.7) 47 1b ses 290 90.4 292 2b 310 27.0 975 301 Mean - 437(146) 28.0(933) 940(940) 297(99.0) 47 1 - 2.81 2-305 - - - - - Men - 293077) - - - 811 1b 4m 299 843 278 2b 345 28.1 86.5 262 Mean - 399(133) 290(967) 854(854) 270(90.0) 811 1 - 266 - 2-320 - - - - Mean - 293017) - - 12:15 1b 334 269 982 - 2b 267 356 99.1 - Mean - 301(10) 313(104) 98787) - a Results for the 3-, 30-, 100-, and 300-ppm levelswere derived from the sample collected from the middleofthe dose preparations for homogeneity analysis. b Below the limitof quantitation (<2.00 ppm). Each value in parenthesis is the percentoftheoretical. d Reassay. 03447 . Covance 6329-212 IM T-6316.1 `Table 67 (Continued) ResultsofDose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Week Replicate 03 30 100 300 16-19 1 oe 37 2 oe 304 393 315 872 9.0 - Mean - 341(114F 354(118) 90.1901) - 16-19" 1 - 2m 2-220 218 446 - - -. Men - 249830) 3201) - - 16-19 1 - 262 269 2-282 23 - - - . Mean - 257@857) 25.1@7) - M 2023 1 oe 261 2 oe 241 21.7 101 264 923 -- Mean - 251(8.7) 27.1(%03) 9670967) - 20-23* 1 - 215 - 2-247 - Men - 231(7.0) - - - - . - : 20-23 1 - 214 2-190 - - Mean - 202(673) - - - - : - - C Each value in parenthesis is the percentoftheoretical. d Reassay Below the limit ofquantitation (<0.5 ppm) f Retention. C0344g Covance 6329-212 . IMT-6316.1 Table 67 (Continued) Resultsof Dose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL Week Replicate 03 T6316 (pom) 30 100 300 2427 1 oe 26 24.1 833 - 2 oe 304 267 884 - Mean - 284947 254(847) 859(859) - 2427 1 -- 2. 253 240 - - - - Mean - - 47623 - : 24-27" 1- 2. 24 214 - - -- Mean - - 29(BO) - . 2831 1 oe 224 264 875 2 oe 23 284 86.0 -- Mean - 238(793) 27.4(913) 868(368) - 2831 1 - 320 2-260 - - Men - 2900967) - -- - - . 2831 1 - 320 - 2. 2m - Mean - 297(990) - - = - -- 3235 1 oe 29:2 2 e246 282 297 834 859 -- Mean - 269897) 290(967) 84747) - "c Each valueinpareathesis is the percentoftheoretical. d Reassay. e Below the limitofquantitation (<0.5 ppm) f Retention. o3449 Covance 6329-212 . IMT-6316.1 `Table 67 (Continued) ResultsofDose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL Week Replicate 03 T6316 (opm) 30 100 300 3639 1 oe 336 2 oe 258 249 914 27 872 M Mean - 297(990) 238(193) 893 (893) - 36-39 1 - 283 2. 25 23.0 - 28 - - - Mean - 252(840) 229(763) - - 36-39" 1 - 282 2-268 27.0 296 - - - - Mean - 275017) 283(943) - - 4043 1 oe 30 2 oe 526 289 955 283 99.5 - Mean - 414(138) 286(53) 9750975) - 40-43 1 - 2m 2-27 - - Mean - 272007) - - - - : - - 44-47 1 oe 397 293 844 - 2 oe 27 219 958 - Mean - 337(112) 286(953) 90.1(%01) - 44-47" 1 - 29 - 2-204 - Mean - 249830) - 64.0 - 596 - 618(618) - cEach value in parenthesis is the percentoftheoretical. d Reassay. e Belowthelimitofquantitation (<0.5 ppm). Retention. 03450 . Table 67 (Continued) Covance 6329-212 IMT-6316.1 ResultsofDose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCIETSYULSFTOUNDAYWMIIDTOHENTAHRARNOOWL IRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Week Replicate 03 30 100 300 44-47" 1 - 530 - 2. 27s - Mean - 403134 - 60.4 - 584 - 644(644) - 48-51 Toe 267 302 978 . 2 e259 290 94.7 . Mean - 263(877) 206(987) 963(963) - 52.53 oe 2 252 925 - 2 e345 240 976 - Mean - 334(11) 246(820) 95.1(951) - 52-53 21 - - 2201..40 -- -- Mean - 207(690 - - s52.53 ro. 190 - . 2 215 - - Mean - - 203677) - - 52.53 o- - 884 - 2 - 845 . Mean - - - 86.5(865) - `c Each value in parenthesis is the percent oftheoretical. d Reassay. e Below thelimitof quantitation (<0.5 ppm). f Retention. 8 Additional mix. 03451 Covance 6329-228 P 3M T-6316.1 Table 68 Resultsof Dose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL T-6316 (pom) Week Replicate 01 * 1b 1: 2b 08% 30-0900 Mean - 0938(938) 25 1b om 2b 0668 Mean - 0725(12.5) 25 1 - L12 2 - 1.04 Mean - 1.08 (108) 69 1 oss 148 2b 15 Mean - 151 (151) 69 1b 0.890 2b 08s8 Mean - 0874(87.4) a Resultsforthe 1 ppm levelwere derived from the sample collected from the middle ofthe dose preparations for homogeneity analysis. b Below the limitofquantitation (<0.5 ppm). Eachvaluein parenistthhepeercseaitosf the theoretical d Reassay. Cosas . `Table 68 (Continued) Covance 6329-228 3MT-6316.1 ResultsofDose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEISTYULSFTOUNDAYWMIIDTOHENTAHRARNOOWL IRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Week Replicate 0 1 10-13 1b 0966 2b LB Mean - 1.05 105) 14-17 1b 08% 2b 0870 Men - 0882882) 1821 1b 169 2b 107 Mem - 138 (138) 1821 1- 2- Mean - 03880 126 1.07 (107) 18210 1. 2. Mean - om 0704 0747(747) 225 1b 0798 2b 08% Mean - 0837(8.7) Below the himitof quantitation (<0.5 ppm). Eachvalue in parenthesis is thepercentof the theoretical. d Reassay. Retention, Cosas3 Covance 6329-228 . IMT-6316.1 `Table 68 (Continued) ResultsofDose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAINCEITSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Week Replicate 0 1 2629 1b 881 2b 188 Mem - 535(535)F 26.29" 1 - 0.730 2-076 Mean - 0758(758) 26.29" o-oo 2-096 Mean - 0919019) 3033 1b 105 2b 132 Mean - 119119) 30-33 1 - 0.951 2. 0955 Mean - 0953(953) 3437 1b 2b Mean - 1: 100 101 (101) Below the limit of quantitation (<0.5 ppm). Eachvaluein parenthesis is the percent of the theoretical. d Reassay. e Retention C3454 . `Table 68 (Continued) Covance 6329-228 IMT-6316.1 Resultsof Dose Preparation Analyses (ppm) 104-WEEK DIETAPREYRCFALRUCOIRNOOOGCETNAICNIETSYULSFTOUNDAYMWIIDTOHENTAHRARNOOLWIRNARNAGTES(98.1%) N-ETHYL T-6316 (ppm) Week Replicate 0 1 38-41 1b 08% 2b 16 Mean - 0.998 99.8)" 4245 1b oo 2b 0886 Mean - 0899(89.9) 4649 1b 2b Men - om 0705 0743 (743) 50-53 1b 089s 2b 2 Mean - 1.54 (154) 50-53 1 - 0916 2-094 Men - 0910(L0) Below the limit of quantitation (<0.5 ppm). Each valueinparenistthhepeerscenitosf the theoretical. d Reassay. 603455 . `Covance is an independent, publicly held company jor J 22 Be ca omcassonmonts mpoe Flin (0EA56 COVANCE> ShapingSolutions