Document 3NYY34e4MN4pvYBQ7BLDrygDE

} ACR EIDE AR22E-OH3F THO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS (RIKER Experiment No. 0281CRO012) Vou1ouFe4 Cowpucten DURING ApriL, 1981 - MAY, 1983 RIKER LABORATORIES, Inc. / 3M Company ST. Paul, MiwwesoTa 55144-1000 U.S.A. 00383 STUDY REPORT AMENDMENT NO. 1 EFFECTIVE DATE: NOVEMBER 2, 1987 Study Title: FTwlouorYoecahremOircaall (FDCie-t1)43 ToinxiRcaittsy/Oncogenicity Study of RIKER Experiment No.: 0281CR0012 The Table chemistry of Contents and the titles for individual clinical values for the males (Table 14; pages 66-70) and aRPfneredaamsaaodmlnoee:essch(enTTohmatiibssltecwrhaay1sn5g;Veaanbpotahcgiese.ntsadIvn7et3r-et7r7ep)nrtetsathtyoipuoolngdraorpFehaidtchae"lIcnhedirimvriioedreusaolntlhyta. . Approval: H C3 dSipiL naer o ke Study Director "foSirts 600384 THOSTYUEDAYR OOFRALFLU(ODIREOTC)HETNOIXCIACLITFYC/-1C4A3RCIINNOGRAETNSICITY (RIKER Experiment No. 0281CR0012) TAOFBCOL NTEE NTS PAGE(s) REPORT SUMMARY . . .. ....................... 1 INTRODUCTION . ote. 3 MATERIALS AND METHODS . . . .. .................. 4 RESULTS oii. 10 DISCUSSION . ove teeta. 18 CONCoL voUvoSteIONeSa. a. a. . 28 PRINCIPAL PERSONNEL LIST. . . ................... 2 SIGNATUREPAGE . . . . veo i iin. 27 REFERENCES . . . o.oo... .................. 28 REPORT TABLES . . .......................2.0.9 TABL1E - Analysisof FC-143 intheDiet . .......... 29 TABLE 2 - MSaulmeasryToLf MLeanLBLody WL eights- L 30 TABLE 3 - FSeummamlaersy of.M.ea.n.Bo.dy..We.ig.ht0s .- ........... =m TABLE 4 - SPeurKmialroygorfaneaBnodyFeeWdeigChotnsu-Mmpatlieosn . . ........ 34 TABLE 5 -PeSrumKairlyogorfanMBeaondyFeWeedigChotnsu-mpFteimaolnes . . ....... 36 TABLE 6 - MSaulmemsaryL of Mean AbsolutL eUFeUed ConsumpL tion - LL TABLE 7 - F Sumare y of m Mean a AbsLolLl utLeLFe eUedLCs oUnsump. tion . - L.L a TABLE 8 - MEisTtliimgartaendsPMeearnKFiC-l143oCgoPnresruamDpamtyion .In......... 4 00385 TABLE OF CONTENTS - Continued PAGE(s) TABLE 9 - Mortality Data ................... 4 TABLE 10 - Sumary of Clinical Signs ............. 4 TABLE 11 - Summary of Ophthalmologic Changes . . ....... 48 TABLE 12 - Mean and Individual Hemogram Values - Males . ... 50 TABLE 13 - Mean and Individual Hemogram Values - Females . .. 7 TABLE 14 - MMaetaensand LIndiLviduLal SeU run Chemistry VT alues - DLL. TABLE 15 -FeMemaanleasnd I.nd.iv.id.ua.l.S.er.un.C.h.em.istry1Va0lue0s -... n TABLE16 - UrinalVyasliuess ................. 78 TABLE 17 - WWIeeniidggihhvtti,sd,uaAlnMdeOanrOgragOnarngaWnTeoigRheBtlr,aaitniAvnedWeAiPgbehsrtocleunRttaetiTooMseaWnhAtolOergaBnody : OneYear. ..................... @& TABLE 18 - WIenidgihvtisd,ualHeOanrgaOnrgaWneigRhetl,atiAvned APebrscoelnutteTMoeaWnholOergaBnody WTewioghYte,ars"And LOorg.an..To BL rainLeign ht RL atio. s At.. 8 TABLE 19 - SFuimnmdairnygsof- MNaejooprlasMtiiccrosLceospioincs . .......... a TABLE 20 - SFiunmdmianrgysof- MNaojno-rNeMoipclraosstcicopiLcesions . . ....... 9 REPORT FIGURES . . ooo... 9386 FIGURE 1 - Mean Body Weights - Males ............. 9 FIGURE 2 - Mean Body Weights - Females ............ 9 FIGURE 3 - MKeialnogrFaemedeCaonnsuBmopdtyioWneigPhetr - Males . ........ 95 FIGURE 4 - MKeialnogrFaenedMeCaonnsuBmopdtyioWneigPhetr - Females . ....... 9% 00386 TCABLEOOFNTE-NConT tinuSed PAGE(s) APPENDIX . ITEH ITEM ITEM ITEM ITEM ITE ITEM ITEM ITEM ITEM oo 971223 A - Air Monitoring of Animal Rooms . . . . ....... 98 B - Diet Analytical Data Sheets . ........... 103 C - APcactheopltoagbylePRaarnagmeesterfsor . Cl.i.ni.ca.l ........... 11 D - HbyistDro.patRhoobleorgticG. EGxeaimli,natEixotnernaanld CPoantshuolltogayntReport Veterinary Pathologis.t . .. ........... 119 E - Biostatistical Analysis Procedures . . . ...... 407 F - SBoudmymarWyeigohftMeaannd BFeoeddy WJeairghWtesighatndDaItnadiv.id.u.al. An.im.a.l . 411 G - OOrp.hthSatlemphoesncopI.icBiEsvtanleura,tioEnxtearnndalDatCaonsbyu.ltant Veterinary Ophthalmologist . . . . ......... 1203 H - Copy of the Study Protocol with Amendments . . . . . 1206 - Quality Assurance Unit Statement . . ... ..... 1214 J - ACnhaelmyicsaels AonfalFyCs-e1s43ofinFDCi-e1t43 . an.d .St.a.bi.li.ty...... 125 00387 TWO YEAR ORAL (DIET) TOXICITY/ONCOGENICITY STUDY OF FLUOROCARBON FC-143 IN RATS (RIKER Experiment No. 0281CR0012) REPORT SUMMARY The purpose of this study was to assess the potential toxicity and oncogenicity of FC-143 (ammonium perfluoroalkyl carboxylate) mixed in the diet and fed to 50 rats per sex per group for two years. An interim sacrifice and evaluation was performed at one year on 15 additional rats per sex from the control and high-dose groups. A total of 360 Sprague-Dawley male and female rats were assigned to three experimental groups. The FC-143-treated groups were fed diets containing either 300 or 30 ppm of FC-143 for two years, while a control group received only untreated feed. In-1ife observations performed during the course of the study included: daily observations for abnormal signs; periodic physical examinations; body weight and feed consumption; ophthalmoscopic examinations; and clinical pathology including hematology, clinical chemistry and urinalysis. Macroscopic postmortem examinations were performed on all animals that died or were terminated prior to the end of the scheduled dosing. Selected organ weights were obtained from all of the rats necropsied at 1 year as well as from 15 rats/sex/group, randomly selected from the control and both FC-143-treated groups, at the termination of the study. Selected tissue specimens were harvested from each animal at necropsy, and preserved for future histopathologic examination. Microscopic evaluation was performed on all tissues saved from all of the control and high-dose rats, while a similar evaluation was performed on a modified list of tissues obtained from the low-dose animals. The major in-1ife findings associated with FC-143 administration consisted of: a dose-related decrease in mean body weight and a treatment-related n CC0388 increase in feed consumption per kilogram of mean body weight in males; and a slight treatment-related increase in the incidence of ataxia in the females. There was no increase in mortality in the high-dose treatment group when compared to similar values for the control population. FC-143 related hematologic changes in both treated groups consisted of a decrease in red blood cell counts, hemoglobin concentration and hematocrit values at various times throughout the study. Generally, these hematology parameters remained within the acceptable ranges for the rat. The primary FC-143 associated changes were found in the liver. These alterations were characterized by increased liver weights, hepatomegalocytosis with vacuolation of the cytoplasm, and some evidence of hepatocellular degeneration with occasional signs of necrosis. These liver changes were found early in the study and showed very little evidence of progression at the end of two years. < The incidence of almost all neoplasms in this study was relatively low, and the types and incidence of neoplasms were generally not different from those commonly found in geriatric Sprague-Dawley rats. Hepatocellular tunors were very slightly increased in the high-dose male rats. The other neoplasms in this study were associated with endocrine and/or endocrinesensitive organs. The increased incidence of mammary or testicular tumors in the high- and low-dose groups was not statistically significant and/or was similar to the spontaneous incidence reported for Sprague-Dawley rats. Under the conditions of this study and based on tumor incidence, types of tumors, time of tumor appearance, and the survival rate at two years, FC-143 1s not considered to be carcinogenic in the rat. 2. C0389 THO YEAR ORAL (DIET) TOXICITY - CARCINOGENICITY STUDY OF FLUOROCHENICAL FC-143 IN RATS INTRODUCTION This study was designed to evaluate the chronic toxicologic and carcinogenic potential of FC-143, an industrial grade of ammonium perfluoroalkyl carboxylate, in rats following oral administration in the diet for a period of two years. The study was sponsored by the Commercial Chemical Division of 3 Company and was performed by the Pathology and Toxicology Department of Riker Laboratories, Inc., 3M Company, St. Paul, Minnesota, U.S.A. The study and subsequent reporting was coordinated for the sponsor by the 3H Corporate Toxicology Services staff. The in-life or dosing May 5, portion of the study 1983. A copy of the began on April 21, study protocol with 1981, and was amendments is completed contained on in this report as Appendix Item H. : The study was FM-3324 and FC-143, designed using a to evaluate two separate fluorochemicals, comin set of control animals. This report will describe the results of the FC-143 treatment while the results relating to the FH-3924 study will be reported separately. The Operating study was conducted in Procedures (fe., SOPs) accordance with the Department's and in compliance with the Food Standard and Drug Administration's Good Laboratory Practice (GLP) regulations (21 CFR Part 58). Various phases Assurance Unit; their of the study statement is were inspected by the RIKER presented in Appendix Item I Quality of this report. The original signed protocol with amendments, list of study persomel, raw dita, study specimens, and other pertinent study samples/docunents will be maintained within the Pathology and Toxicology Department. archives currently located at 3M Center in St. Paul, Minnesota. 3. 00390 MATERIALS AND METHODS Test System: Three-hundred and sixty Sprague-Dawley rats [Crl:coBst CD(SD)BR, Charles River, Portage, MI], 39 to 41 days of age when treatment began, were divided by means of a table of random numbers into three groups. The control and high-dose groups each contained 65 males and 65 females, whereas the low-dose group contained 50 male and 50 female rats. The rats were housed in hanging stainless steel cages with wire mesh floors and fronts. The males were housed individually, but the females were housed two per cage. The control animals were housed in separate Toons fron those which received FC-143 in order to prevent a possible cross contamination by potential vaporization and/or sublimation of the test article which has a finite vapor pressure at room temperature. Air samples were taken from each of the animal treatment rooms four months after the initiation of the study in order to assay for the presence of airborne contaminants. The samples were analyzed by the Analytical Section of the 3M Central Research Laboratory and were found to be below detectable limits for the suspected fluorochemicals. In addition to the air monitoring, 30 untreated sentinel rats were placed in each of the two animal rooms. From each aninal room, 5 male and 5 female sentinel rats were euthanized during the first week of the study, and at 1 and 3 months after the start of the study. Plasma samples obtained from these rats were analyzed for organic fluorine and were found to contain less than one part per million (see Appendix Item A). Each animal room was temperature and humidity controlled with the lighting on a 12 hour light/dark cycle. Individual rats were uniquely identified by an aninal number on a cage card and on a tag affixed to their ear. Feed (Certified Purina Laboratory Chow, Ralston-Purina Co., St. Louis, M0) and tap water were provided ad libitun. Test Substance/Diet Preparation: FC-143 (Lot 37) was analyzed by the Comercial Chemicals Divisions (CCO) Analytical Laboratory prior to the start of the study, after approximately one year from the start of the study, and at the termination of the dosing period. No detectable changes were found in the test substance during this time (see CCD Analytical Reports Nos. 308, 348 and 413 in Appendix Item J). a 00391 The test substance was a white powder which was added (ie, stratified) directly into an appropriate quantity of untreated diet and mixed in a Hobart blender for approximately 20 minutes for each separate batch. Prior to initiating compound administration to any animals, the test substance/diet mixture was assayed. blended and stable for one to two. FC-143 was found to be weeks in the ground feed uniformly (see CCD Analytical Report No. 209 in Appendix Item J). Test study and article/diet mixtures representative samples were prepared fresh weekly of each were collected and during assayed the for test article content and homogeneity during the first month of the study and at 3 month intervals thereafter (see Appendix Item B). The results of these assays indicated that the level of FC-143 was generally within a few percent of that desired (Table 1). The diets in rats glass received either FC-143 treated jars 10.2 cm high x 8.9 cm in or control diameter. (ie, A 5.1 untreated) cm access hole were was cut renoved in and the stainless replaced with steel clean 1id. jars On a weekly basis the diet Jars containing fresh diet mixtures. Experimental Design: The study consisted of one control group and two treatment groups. hereinafter. The dosage levels and animal distribution are 11sted _ Treatment Dosage Levels GMraoluespSize&AnimalNuFmebmealress Groups (ppm) (An. Nos.) (An. Nos.) re ---- e ---------------------- 1- Control 0 65 (3516-3580) 65 (4576-4640) 5 - High 300 65 (3561-3645) 65 (4641-4705) 6- Low 30 50 (3646-3695) 50 (4706-4755) --ee------------ 5. G00392 An interin termination at one year involved 15 male and 15 female rats from both the control and high-dose groups. The remaining 50 animals per sex per group continued on study. In-Life Observations: All animals were observed daily throughout the two year dosing period. Weekly physical examinations included palpation for the presence of masses as well as observations for pharmacotoxic signs; mortality was recorded daily. During the study, moribund animals were closely monitored, and euthanized when in the judgement of the Study Director death appeared to be imminent in order to harvest non-autolysed tissue for subsequent histopathologic examination. Body weights and feed consumption were recorded once per week for the first six months, and then once every two weeks for the remainder of the study. Eye examinations using indirect ophthalmoscopy and/or slit lamp biomicroscopy were performed on the control and high-dose rats by the Staff Veterinarian prior to compound administration and at approximately one year. The eyes of the surviving control and high-dose animals were examined 2-3 weeks prior to the termination of the study by a consulting Veterinary Ophthalmologist (see Appendix Item G). Clinical pathology determinations included hematology, clinical (serum) chemistry and urinalysis. Tests were conducted on samples obtained from 15 rats per sex from each group at 3, 6, 12, 18 and 24 months; animals were randonly selected at each time interval. Hematologic tests included total red and white blood cell counts, hemoglobin, hematocrit, and a differential white blood cell count. Clinical chemistry parameters included total bilirubin, total protein, albumin, blood urea nitrogen (BUN), glucose, alkaline phosphatase (AP), creatine phosphokinase (CPK), aspartate aminotransferase (AST-formerly known as SGOT), alanine aminotransferase (ALT-formerly SGPT), and calcium. Urine tests included PH, specific gravity, albumin, glucose, bilirubin, occult blood and ketones. Blood samples were collected from the retrobulbar venous plexus of anesthetized rats which had been fasted overnight. Blood was generally collected from the right eye. Urine samples were obtained by placing each rat in an individual metabolism cage for 20-22 hours. The specific methods 6. 00393 used for hematology, clinical chemistry and urinalysis are outlined in Appendix C. The mean hematology and clinical chemistry values from the treated groups were compared to both the concurrent control group as well as normal ranges for these parameters obtained from historical control animal data generated in this laboratory (Appendix C). Metabolic Examination: Overnight (ie, about 24 hour) urine and fecal samples were collected at 2, 5, 11 and 23 months from five rats per sex per group for total organic fluoride analysis, and for the presence of FC-143. At the scheduled one and two year necropsies, samples of liver, blood, kidney, spleen, Tung and bone marrow (ie, from the femur) were saved from five rats/sex/group. After collection, all specimens were frozen pending subsequent analysis by the RIKER Drug Metabolism Department. Once these specimens are analyzed, a separate report regarding this experimental work will be prepared by the Drug Metabolism department. Postmortem Examinations: c Gross postmorten examinations were performed on all rats which died during the study and those which were terminated at the one year interin and two year necropsies. At necropsy, an examination was made of the external body surface and body orifices. The carcass was then opened and the contents of the abdomen, thorax and craniun were examined in sity and following removal from the body. Organ weights (ie, wet tissue) were obtained at the interim termination from both the control and high-dose groups, and from the control and both FC-143 treated groups at the two year necropsy. The weights of the adrenal glands, brain, testes, heart, kidneys, liver, spleen and uterus were recorded for 15 randomly selected rats/sex/group. Body weights were obtained just prior to necropsy from the same rats in order to calculate organ weights relative to whole body weights. Representative samples of the following tissues and organs from each rat were fixed in 10% neutral, buffered formalin for subsequent histologic processing: Aorta Adrenals (2) Brain (3 Sections including Liver (2 Sections) Lung (2 Sections) Lymph node (mesenteric) 7. 00394 frontal cortex and basal ganglia, parietal cortex and thalanus; cerebellum and pons) Eyes Gonads Ovaries (2) Testes/Epididynides (2) Heart Small Intestine (3 Sections) Large Intestine Kidneys (2 Sections) Mammary Gland (females) Pancreas Pituitary salivary Gland Spinal Cord/Bone Marrow (vertebrae) Spleen Stomach Thyroid/Parathyroid/Trachea/Esophagus Urinary Bladder Uterus or Prostate Any tissue masses (suspected tumors) Any gross lesion Light microscopic examination was performed on hematoxylin and eosin stained, paraffin-enbedded tissue sections from all tissues listed above, when available, and from all rats in the control (Group 1) and high-dese (Group 5) populations regardless of the cause of death. Microscopic exanination of tissues from the low-dose (Group 6) rats included the tissues listed above except: aorta, brain, eyes, small and large intestines, lymph node(s), and spinal cord/bone marrow. The histopathologic examination and evaluation of these tissues was performed by Dr. Robert G. Geil, consulting Veterinary Pathologist (see Appendix Item 0). Blostatistical Methods: The means and standard deviations for body weights, feed consumption, absolute organ weight, relative organ weight to whole body weight, organ weight to brain weight ratios and other laboratory data were determined separately for each sex and dose group. These data were analyzed using Bartlett's test for homogeneity of variance. If this test was not significant at alpha = 0.001, the data were further analyzed by comparing each treated group to the control group using a two-tailed Dunnett's test at the alpha = 0.05 significance level. The results of Dunnett's test have been indicated by asterisks on the mean tables. If Bartlett's test was significant at alpha = 0.001, the data were ranked and a two-tailed Dunnett's test was performed on the ranks. These results have been indicated by the pound sign (#) on the mean tables. 8. 20395 In addition, for each organ/lesion classification the sexes were analyzed separately using a two-tailed Fisher's Exact Test comparing each treated group to the controls. An alpha = 0.05 significance level with Bonferroni's adjustment for multiple comparisons was used within each organ/lesion/sex category. If the expected value of each cell was greater than 20, then Yates' corrected the sumnary tables indicates a Chi-Square significant test was used. An difference between asterisk on the controls and the treated group. are Internal presented RIKER memoranda within Appendix pertaining Item E. to these biostatistical procedures 9. C0395 RESULTS In-Life Findings: Body weight gains were depressed in excess of 10% in the FC-143 high-dose males compared to the control males through 66 weeks of the study. There was an approximate 21% decrease in the high-dose body weights by week 6. This difference was statistically significant from week 2 of the study until week 98 weights had gradually equalized. when the high-dose and control male Likewise in the low-dose male group, body a 5% decrease in body weights was observed at week 6, however, there was little additional decrease thereafter (Table 2, Figure 1 and Appendix F). The occurrence of a mild SOA virus outbreak at different times during the study may have had a sTight influence on the body weight data (see p. 12). Mean body weights were only very slightly decreased in the FC-143-treated females compared to the control female values through the first 18 months of the study. At 18 months, there was a gradual decrease in mean bady weights of high-dose females that reached a maximum of -11% at 92 weeks. The low-dose females also showed a decreased body weight, but the effect was not statistically significant and the change was of a much lower magnitude (Table 3, Figure 2 and Appendix F). Mean feed consumption, presented as grams of diet consumed per day per Kilogram of mean body weight, was increased in all of the FC-143-treated males throughout the study when compared to the male control feed consumption. This change was more pronounced fn the high dose group where there was roughly a 13% increase noted with sporadic values going as high as 29% during the two year test period. In the females the pattern was Tess consistent, but there was a trend toward lowered feed consumption in both FC-143-treated groups compared to the female control values (Tables 4 and 5 and Figures 3 and 4). Overall, these variations were related to the variation of body weight among groups. Actual mean feed consumption (without regard for body weight change) was slightly decreased in the high-dose males relative to control males, for the first year of the study. Feed consumption in low-dose males, while somewhat inconsistent, was slightly increased during this same period. 10. G0397 During the second year, the feed consumption of both FC-143-treated male groups Was reasonably stable and consunption was comparable to that of the control group. All of the treated female groups tended to consume less feed than the comparable controls throughout the study. The greatest decreases occurred fron 18 months to termination with the high- and Tow-dose groups being equally affected (Table 6 and 7 and Appendix F). The was tdeesttermairnteidcleatco3ncmeonnttrhatiionntermveaalssurewdithas apadrutpslipceartemialnlailoynsisin ptehrefordmieedt when aberrant values were detected. The mean deviations from the target concentration of the high- and low-dose FC-143 groups were less than 3% (Table 1). Actual test article consumption was determined for each 2 week period for each sex and each experinental group, and expressed as mg/kg/day. The mean test article consumption was estimated to be: males, 14.2 mg/kg/day; females 16.1 and 1.6 mg/kg/day for the high- and and 1.3 Tow-dose groups, respectively. Mean test article consumption values calculated at 2 week intervals for the entire study are presented in Table 8. Overall survival rates for the FC-143-treated rats were good during the full two years of the test period. There were fewer deaths recorded in the high-dose males and females than in the comparable control populations. At the end of 1 year, 15 rats/sex from the control and high-dose groups were terminated to fulfill the protocol requirement for the interim sacrifice. The final survival rate then based on 50 rats/sex/group at the end of 104 weeks was: males, 70%, 88% and 72%; and females, 50%, 58% and 48% for the control, high- and low-dose groups, respectively. The increased survival rate observed in the high-dose male rats compared to the control male rats, was statistically significant (p < 0.05). Monthly mortality data are presented in Table 9. A summary of the most commonly seen clinical signs is contained in Table 10. The only clinical sign that occurred more frequently in the test article-treated groups was a dose-related increase in ataxia reported for the FC-143- treated females. While the ataxia was most commonly associated n C0398 with morbid animals and was seen in the control males and females, only the treated females showed an increase in the incidence of this clinical sign; 2, 15 and 9 cases in the control, high- and low-dose groups, respectively. The incidences of all other clinical signs in the FC-143-treated groups were generally less than or equal to the incidence of the same signs in the control group. Rats administered the test article experienced a suspected outbreak of sialodacryoadenitis (SDA) viral infection between the first and second months of the study. Clinical signs included swollen submandibular salivary glands and occasional ocular manifestations. The submandibular swelling was resolved within 10 days, and the incidence of ocular changes was extremely low. Similarly, the control animals had comparable symptoms during the sixteenth month of the study. Thirteen males and 13 females in the control group demonstrated signs of this condition which lasted for about 16 days from the time of onset. One male and 3 females developed ocular opacities during this period. The incidence of palpable tissue masses in FC-143-treated groups was comparable to that of the control group. There were more animals with masses in the male controls than in the male treated groups; that is, 19, 10 and 7 animals in the control, high- and low-dose groups, respectively. Likewise, when the number of palpable masses which regressed or resolved before the termination of the experimental period were evaluated, there were still fewer masses found in the FC-143-treated animals than in the control group (Table 10). The results of the final ophthalmoscopic examinations were negative relative to any FC-143 treatment-related effects. Changes that were observed included a random distribution of cataracts believed to be normal geriatric changes of the lens and some cases of chronic uveitis and superficial keratitis which were also considered to be within normal limits for aging populations of rats (Table 11 and Appendix 6). Many of the rats found to have ocular lesions were identified as rats which were used to obtain blood samples via the retrobulbar venous plexus. 12. 000399 males, the changes were of a lesser magnitude and in some cases, were Red blood cell counts, hemoglobin and hematocrit values were minimally decreased in the high-dose male rats compared to control values, from 3 through 18 months. Statistically significant (p = <0.05) decreases were seen at various times in the following parameters: erythrocytes at 6, 12 and 18 months; hemoglobin, 3 and 18 months; and hematocrit at 3, 12 and 18 months. While some of these parameters were also altered in the low-dose increased as well as decreased (Table 12). The female high-dose erythrocyte counts and hematocrits were slightly decreased at 3 months, but were slightly increased at 6 months compared to control values. At 12 months there was a statistically significant decrease in erythrocyte count, hemoglobin, and hematocrit (Table 13). Mean leucocyte counts were increased in both male treatment groups compared to control values, through the first year of the study. These changes were due to increases in absolute counts of lymphocytes at 3 and 6 months, ind in neutrophils at 12 months. Statistically significant increases were observed: in lymphocyte counts at 3 months in the high- and low-dose groups, and at 6 and 18 months in the low-dose group; and in neutrophil counts at 12 months in both groups (Table 12). Similar changes were not . seen in the FC-143-treated females with the exception of a slight increase in neutrophils and a slight decrease in lymphocytes seen in the low-dose group at 18 months (Table 13). alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Clinical chemistry findings at 3 months included slight increases in alkaline phosphatase (AP), as well as a moderate decrease in creatine phosphokinase (CPK) in both FC-143- treated male groups. From 6 until 18 months, the high- and low-dose male ALT, AST and AP values were increased above the concurrent control values, whereas these values in the high-dose group were still elevated at 24 months. Albumin values remained very slightly elevated in the high-dose males until the end of the study. Similar changes in clinical chemistry were not observed in the FC-143-treated female groups (Tables 14 and 15). I 000400 Urinary findings included increases in incidence and severity of albumin and occult blood in all of the male and female control and FC-143-treated groups at 12, 18, and 24 months. These findings were more pronounced in the males than in the females at the termination of the study. Other than an occasional incident of slight ketonuria in both control and FC-143-treated animals, there were no other remarkable urinary findings (Table 16). Postmorten Findings: The Consulting Pathologist's complete report is Tocated in Appendix D. The gross pathology findings seen at the 1 year interim sacrifice were unremarkable with the possible exception of a single high-dose male having small testes and 3/15 high-dose females with mammary masses compared to an incidence of 1/15 in control female rats. Possible FC-143-related gross findings seen in male and female high-dose rats which were either found dead, euthanized in extremis, or euthanizedtat the termination of the study, included Tiver and testicular observations in the males and only a very slight increase in the incidence of mammary masses in the low-dose females. The liver findings seen in the males consisted of a slight increase in the incidence of liver masses, nodules and raised lesions, mottled livers and yellow or pale liver foci. While small testes were observed grossly in the control males as well as in both treated groups, testicular masses were found in 6/50 high-dose and 1/50 Tow-dose rats, but not in any of the controls. Mammary masses reported at necropsy in 1 high-dose and 2 low-dose males were found microscopically to be non-mammary lesions. Mammary masses were observed in 27/50, 26/50 and 37/50 of the control, high- and low-dose female rats, respectively. Ho remarkable FC-143-related liver changes were seen grossly in the female rats. Other gross pathologic findings were typical of findings in aging rats of this strain (Appendix D). Organ weights presented as either absolute or relative (ratio of organ/body weight or organ/brain weight) values are contained in Tables 17 and 18. At the 1 year interim sacrifice where the only groups examined were the high-dose and controls (n = 15/sex/group), there was no change in male body weight (absolute) but a statistically significant (p = <0.05) increase in 1a. 000401 relative liver and kidney weights (vs. body weight) for the FC-143-treated males only. At the terminal necropsy, slight increases in relative (organ vs. body weight) liver weights were noted for both the males and females of both dose groups, but the increases were not statistically significant. STight increases in relative kidney weights were observed in both the male and female rats in the high-dose group; however, only in the females was this finding statistically significant. Complete details of the histopathologic Findings are contained in Appendix D and a summary of the major neoplastic and non-neoplastic microscopic changes found after 2 years of continuous oral administration of FC-143 are listed in Tables 19 and 20. Histopathologic evaluation of the tissues from the animals necropsied at 1 year indicated the major FC-143 effects were confined to the liver. Diffuse hepatomegalocytosis (12/15 animals), hepatocellular necrosis (6415 animals), and portal mononuclear cell infiltration (13/15 animals) were seen in the high-dose males while incidences in the control group were 0/15, 0/15 and 7/15, respectively. Testicular tubular atrophy with marked aspermatogenesis was found in 2/15 high-dose males but was absent in the control males. The only remarkable change seen in the high-dose females was minimal to mild hepatocellular vacuolation; the incidence for this Finding was 11/15 at the high dose and 5/15 in the control group. The majority of neoplasms observed after 2 years of dosing with FC-143, involved either the liver or one of several endocrine or endocrine-related organs (Table 19). Hepatocellular carcinomas were found in 6%, 10%, and 2% of the males from the control, high, and low-dose groups, respectively. For the females, hepatocellular carcinomas were found only in the high-dose group with an incidence of 2%. The organ with the highest incidence of tunors was the pituitary gland where the incidences of adenomas in the males was 35%, 28% and 36%, and in the females at 71%, 71% and 83% for the control, high- and Tow-dose groups, respectively. Mammary gland adenocarcinomas were present in both control and treated females at an incidence of 15%, 11% and 31% for the control, high- and 15. 600402 Tow-dose groups, respectively. In a similar comparison, fibroadenomas were seen in 22%, 48% and 42% of the female rats at the end of the study. Mammary gland adenomas (7%) and carcinomas (2%), were seen only in the fenale controls, while increase in testicular one high-dose female Leydig cell adenomas had was a lymphangiosarcoma. An statistically significant (p = <0.05) in the high-dose males. The incidence for this lesion was 0%, 14% and 4% in the control, high- and low-dose groups, respectively. There were minor variations in the tumor incidence patterns in the adrenals (pheochromocytomas) and thyroids which represent deviations in two commonly occurring spontaneous C-cell adenomas of the tunors of this strain thyroid in male rats, of rat. appeared Only the to show incidence of a slight dose dependent increase; namely, O%, 9% and 4% for the control, high- and Tow-dose groups, respectively. However, C-cell carcinomas were seen only in the controls at an incidence of 5%. Non-neoplastic changes adrenals, heart, liver, were found at the termination of lung, pancreas, ovaries, salivary the study glands, in the spleen, testes, thyroids and uterus (Table 20). As noted in the 1 year interim histopathologic evaluation, the liver FC-143 treatment-related effects, and was the primary organ associated with there was a remarkable consistency in the type of findings observed in the males after the second full year of test article administration. Megalocytosis, cystoid degeneration, and portal mononuclear cell infiltration were the major dose-related changes seen in both male and female test article-treated groups. Megalocytosis was found at an incidence of 0%, 80% and 12% in the males, and 0%, 16% and 24 in the respectively. females Hepatic fron the control, high- and low-dose groups, cystoid degeneration, a condition characterized by areas of multilocular microcysts in the liver parenchyma, was more commonly seen in male rats with a control incidence of 8%, whereas the high- and Tow-dose of this males had lesion in incidences of 56% and 14%, respectively. The incidence females was 2% in both of the FC-143-treated groups. Hepatocellular necrosis was equally distributed between the control and FC-143-treated proliferation groups. The incidence of hepatic parenchymal of hyperplastic nodules, a localized cells, was slightly increased in the high dose groups with an incidence of 6% in the males and 2% in the females as compared to 0% and 2% in the control males and females, respectively. 16. 600403 No hyperplastic nodules were found in the low-dose group. The incidences of other hepatic changes such as basophilic hepatocyte alteration and/or chronic inflammatory changes consisting of portal mononuclear cell infiltration were slightly increased in the high-dose males, but only against a high incidence of similar changes in the control group. Pulmonary changes that may be associated with the administration of FC-143 in the high-dose males, consisted of an increase in the incidence of alveolar macrophages (62%) and hemorrhage (44%) compared to control incidences of 20%. However, the incidence of chromic interstitial pneunonia and perivascular mononuclear infiltration was greatly reduced in the high-dose males when compared to the male controls. Pulmonary vascular mineralization was observed commonly in both control and test article-treated male and female rats; however, the FC-143-treated females displayed an increase that was inversely related to the dose. The incidence of chronic sialadenitis, an inflammatory change of the salivary gland and often associated in rats with an antemortem viral infection, was increased in both the high- and low-dose males. Hemosiderin, an iron rich pignent, was found in greater concentrations in the spleens of both high-dose males and females, but in greatly reduced amounts in the low-dose males and females as compared to controls. Two changes observed in the gonads of both sexes, appeared to be related to the administration of FC-143. Vascular mineralization of the testes occurred in 18% of the high-dose males and 6% of the low-dose males, but was was not seen in the controls. only slightly increased in The the incidence high-dose of testicular tubular atrophy (22%) and low-dose (20%) males compared to the control males (14%). In the test article-treated females, there was a dose-related, statistically significant increase in tubular hyperplasia of the ovarian stroma. Tubular hyperplasia is considered to be a diffuse, non-neoplastic increase in stromal tubular elements which is usually bilateral and associated with decreased or absent follicular development. The incidence 0600404 of this groups, change was O%, 32% respectively. Cystic and 14% in the control, high- and low-dose glands of the uterine endometrium were found at a higher incidence in the low-dose females controls (14%) and high-dose females (10%). (24%) when compared to the eOntdheemricnodni-sneeaospelsastaincd/olresgieonrsiat(rTiacblech2a0n)gesarefoucnodmmoinnlythiasssosctriaaitnedofwitrhat.eithTheer ofrollwoewrienguscuhaalnlgyesdecwreeraesecdonsbiedleorwedtheequciovnoccuarlrenttestincairdteincclee-irnelactonetdroflinrdaitnsg.s Adrenal changes incidences were are commonly seen in inconsistently either aging rats higher or of this strain lower than the and the control values. The very slightly incidence of only in the sinusoidal ectasia (dilatation) high-dose males (32%) compared was increased to the control males (224), while equally affected (82 the and control 86%). and The FC-143-treated females were almost incidence of chranic myocarditis was reduced in an increased above apparent dose-related the control incidence fashion in in the high- the and females while being low-dose males. The incidence of thyroid C-cell hyperplasia was dose fenales, while only the low-dose males slightly increased in the showed a similar change. high The incidence of acinar atrophy of the treated males, while being the pancreas was very slightly increased slightly depressed below control values in in the high-dose female. 18. 00405 DISCUSSION The purposes of this study was to define the long term toxicity and oncogenicity profile of FC-143, an anionic fluorochemical surfactant belonging to the chemical class of amoniun perfluoroalkyl carboxylates. The study was successfully completed with sufficient numbers of animals surviving in all of the experimental groups. The survival rates for the high-dose male and female rats were actually higher than those of the control rats after 24 months of the test. The general health of a rat exposed to the experimental conditions of a 2 year feeding study may be examined at the beginning of the test by evaluating body weight gains and feed consumption compared to the study control aninal population. Body weight gains of the FC-143-treated males decreased as early as the second week of the study, stabilized after 6 weeks, but remained slightly depressed in the high-dose males by at Teast 10% through 66 weeks. The treated females did not demonstrate any real decrease in body weight until rather obvious sex difference `the 18th month, so in this parameter. there appeared The body weight to be a changes did not appear to be associated with the palatability of the diet admix since feed consumed on a body weight basis was actually increased. Further, since there was a modest dose-related effect seen in the male FC-143-treated rats, it appears that these body weight changes could be associated with a direct test article effect. The concentration of the test article in the diet was within a 3% range of the proposed levels of 300 and 30 ppm for the full 2 years of the study. The average daily dose of FC-143 for the same time period and for both sexes combined, was estinated to be 15 and 1.5 mg/kg/day. Both in-life and postmortem results confirmed the systemic absorption of the test article and the 300 ppm dosage level appeared to adequately comply with the concept of a maximum tolerated dose for a Tong tern study in this strain of rat. The only clinical sign seen during the study which was associated with a test article effect was ataxia. The incidence of ataxia was increased in a dose related manner in the females, but not in the treated males. A cobzes background incidence of this finding was seen in the male and female control population. During the early course of the study, a decrease in red blood cell paraneters was observed in the high-dose males. While these hematologic values were often decreased below the control male measurements at a statistically significant level (p < 0.05), generally the decreased values were still within the acceptable ranges for these parameters in the rat. The elevation of serum alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase activities only in test article-treated male rats, suggested that FC-143 affected hepatocytes. These changes were seen from 3 to 18 months in both of the male FC-143-treatment groups, but only in the high-dose males at 24 months. These findings were substantiated by organ weight changes and histopathology observed at the 1 and 2 year sacrifices. : Changes in the character of the urine specimens were similar in both control and treated rats examined during the course of the study. These findings were considered to be associated with the slowly developing degenerative changes of naturally occurring chronic renal disease commonly found in rats of this strain. The liver was the primary target organ affected as seen by an increase in relative organ weights, gross findings at necropsy, and histopathologic alterations. These changes seen at the 1 year necropsy showed remarkably Tittle progression 1 year later. The FC-143-treated males were more obviously affected than the females. The sex differences seen in this study were consistent with earlier pharmacokinetic studies using carbon-14 labeled ammonium perfluorooctanoate, in which the females during 24 hours had excreted essentially 100% of an intravenous dose in the urine while the males excreted only 20%. Radioactive tissue residues were not detectable after 17 days in the females, while at 36 days, male rats had 2.8% of the carbon-14 in the liver, 1.1% in plasma, and lower but still detectable anounts in other organs.! Similar results were reported by Hanhijarvi, et at 20. 600407 Hepatonegalocytosis and hepatocellular vacuolation are characteristic of increased metabolic activity in the rat. Following chronic hepatic stimulation, evidence of cystoid degeneration and, occasionally, hepatocellular necrosis may also be observed. Since the liver in the rat rarely repairs parenchymal cell loss with fibrosis or scar tissue, the most common finding is hepatocellular hyperplasia. In this study, the incidence of hyperplastic nodules was increased very slightly in the high-dose group, but the incidence was not significantly different from controls. It is also important to note that no proliferative hepatic lesions (i.e. neither hyperplasia nor neoplasia) were seen in any of the high-dose ratsreceiving FC-143 for 1 year. The observed hepatomegalocytosis was similar to that reported by Pastoor et al orally to male rats at a in which perfluorooctanoic acid higher dosage (50 mg/kg/day).2 was It administered was proposed that the hepatocytic enlargement was due to proliferation of smooth, endoplasmic reticulum, mitochondria, and peroxisomes. The only hepatic neoplasms found in this study were hepatocellular carcinomas. The incidence of this tumor was 6%, 10% and 2% in the control, high- and low-dose male rats, respectively. Only one high-dose female was found to have this Tiver tumor. The incidence of hepatocellular carcinomas - in high-dose males was not significantly greater than that of the control males and was tunor. Based comparable with the reported on these findings, FC-13 was spontaneous incidence not considered to be a of this hepatic carcinogen in the rat. The other neoplasms observed in this study originated from endocrine and/or endocrine sensitive organs; namely, the adrenal gland, mammary gland, pituitary gland, testes, and thyroid gland. The incidence for each of these tumors are presented in Table 19. The incidence of mammary gland adenocarcinomas was 15%, 11% and 31% for the control, high- and low-dose female groups, respectively. While mammary gland carcinomas and adenomas were found only in the controls, there was an increased incidence of fibroadenomas in the high-dose (48%, statistically significant: p < 0.05), and the low-dose (42%) compared to controls (22%). It should also be noted that 2/13 of the high-dose females necropsied at 1 2a. 000408 year were similarly found to affected. have fibroadenomas, while 0/15 of the controls were Although the incidence of fibroadenomas in high-dose females was significantly greater than that for the control females, the incidence addition, was when similar to that reported for untreated aging rats. the incidences for benign mammary gland tumors (adenoma In and Fibroadenona) are combined, the tumor no Tonger statistically significant. incidence in the high-dose group is Leydig cel] adenomas tissue), were found at (i.e. benign an incidence tumors of 0%, of 14% the and testicular interstitial 4% in the control, high- and low-dose groups, respectively. The high-dose incidence for this lesion was statistically significant control group was unusually (p < 0.05) low (0%). because the incidence in the In addition, the spontaneous incidence reported for this neoplasm in this strain of rat was 7.4% for rats 24 to 29 months Based on another set of of age and was 14.6% Sprague-Dawley two at 30 to 38 months of age'. year study data compiled by Hazleton Laboratories, tumors was 28.7.5 the spontaneous incidence of interstitial cell The remaining evaluation of non-neoplastic findings reported from all of the animals originally scheduled the for histopathologic the 2 year phase of The the study organs in were mostly geriatric which these lesions lesions comon to this were found included: strain adrenal, of rat. heart, Kidney, lung, testes, ovary, thyroid, urinary bladder deviations from control values seen in FC-143-treated and uterus. groups were Specific addressed in be the results section of this report; however, the following changes considered incidental or equivocal test article-related effects. may The incidence of nodular hyperplasia of the adrenal cortex was increased (not statistically the sane finding in significant) the controls in the high-dose males (18%) compared to (4%), while the high-dose females showed a much lower incidence (2%). Increases in the incidences of adrenal gland sinusoidal extasia (dilatation) were reported in the high- (32%) and low- (26%) dose males compared to male controls (22%) while the incidences in 2. 000409 all test article-treated females were equal to control values. It should be noted that adrenal lesions are commonly seen in old rats. Thyroid C-cell hyperplasia was seen in the control males and FC-143-treated groups with an incidence of 10% and 7% for the low-dose males and the shitgaht-idsotsiecalfleymalseisg,nifriecsapnetctiavnedly.wereThelowienrcidtehnacnes twheererenpootrtdeodse-srpeolnattaendeouosr incidence of this lesion. Cinhrotnhieclomwy-odcoasredit(i3s6%)(iannfdlatmhaetihoing)h-dwoasse s(e3e4n%)atmaalesslicgohmtplayrehdigthoertheinccoindternocle (28%) group. The female incidence for this lesion was 32%, 20% and 10% in the control, high- and low-dose groups, respectively. Inflammation of the heart is common in old rats. The lack of a true dose-related effect in either sex suggests that this finding is probably not a treatment related phenomenon. Chronic renal histopathologic `changes, commonly observed in aging rats, were not meaningfully altered by FC-143 treatment. None of these changes were apparently severe enough to produce pathologic lesions over a 2 year period. Therefore, none of these findings are considered to be directly related to treatment. Lung changes which were seen more commonly in FC-143-treated rats than in controls. included an increase in alveolar macrophages, pulmonary hemorrhage (agonal) and vascular mineralization. The first two lesions were seen predominantly in the high-dose males where the incidences were statistically significant (p < 0.05). Control males on the other hand, had higher incidences of interstitial pneumonia and pulmonary perivascular mononuclear cell infiltration. Pulmonary changes are common in aging rats? Other than the possibility that an increase in the alveolar macrophages may be associated with FC-143 administration, all of the pulmonary changes were not considered related to test article treatment. Chronic sialadenitis or inflamation of the salivary glands was significantly (p < 0.05) increased in the test article-treated males, but 2. 600410 not in the test article-treated females. These changes were attributed to outbreaks of sialodacryoadenitis viral infections which occurred in both the control and FC-143 animal rooms, but at different time periods and apparently with different levels of intensity. The incidence of splenic hemosiderosis, depositions of iron-containing pignent in the sinusoids of the spleen, was increased above control levels by approximately 12% in only the high-dose males. However, the incidence in high-dose males was not significantly greater than the control incidence. The incidence of this lesion in FC-143 treated females was significantly lower than the incidence of splenic hemosiderosis in control females. A statistically significant, dose-related increase in the incidences of ovarian (stromal) tubular hyperplasia was found in low and high-dose groups. The interpretation of these changes in the absence of any observable progressive pathologic lesion after 2 years of treatment, must be considered as equivocally related to FC-143 treatment. 2. 600411 conclusions. The results obtained under the conditions of this study when FC-143 was administered in the diet of male and female rats at concentrations of 300 and 30 ppm for 2 years may be summarized as follows: 1. FC-143-related changes were found more commonly in males than in females of each of the two treatment groups. This finding supports earlier pharmacokinetic studies that demonstrated a increased FC-143 retention by treated males compared to treated female rats. 2. The major dose-related findings were observed in the liver and consisted of megalocytosis and cystoid degeneration with only a eminnziymmael acptriovliitfieersa.tive response and related elevations of serum 3. Other non-neoplastic' findings reported in this study were not considered primary test article-related effects, but rather were related to spontaneous changes occurring in aging rats. 4. Based on the incidence, types of tumors, time of tumor appearance, malignancy patterns of tumors and survival rate after 2 years, FC-143 is not considered to be carcinogenic in the rat. 2. 00412 PRINCRIIPKAELR EPXEPRESROINMNEELNTIKNOV.OL0V2E8D1CWRIOT0H12THE- TCWOONDUYCETARANODRALREP(ODRIETTI)NG OF `TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHENICAL FC-143 IN RATS NAME S.1. Bistner, D.V.H. M.T. Case, D.V.H., Ph.D. R.G. Geil, D.V.M. R.M. Hawkinson, Ph.D. J.D. Henderson, D.V.H., H.S. HK. Hopp, A.A.S. C.D. King, D.V.M., Ph.D. C.E. Ludemann, B.S., M.T. L.A. Marschke S.E. McCarville, B.S., M.S. W.C. McCormick, III, B.S. JR. Nelson, H.T. 6.C. Pecore S.L. Westmark, A.A.S. L.0. Wiseth -_-- : POSITION/FUNCTION ExVteertnearlinaCroynsOuplhttahnat/lmologist Manager, Safety Evaluation ExtVeertnearlinaCroynsuPlattahnotl/ogist Supervisor, Statistical Services ManMaegdeirc,ineLaabnodratPoartyhoAlnoigmyal SenSitoudryLAasbsoirsattaonrty Technician/ ExtReerpnoarlt CProenpsaurlattainotn/Draft SeCnliionricMaeldicPaalthoTleocghynoDleotgeirsmti,nations AdRveapnocretd TSyepcirnegtary/ Advanced Biostatistician ToRxeipcroelsoegnyStpateicviealainsdt/PSrpoojnescotr Coordinator HiSsltiodteechPnroelpaorgaitsito/nMicroscope Supervisor, Laboratory Animal Care Laboratory Technician SeAnsisoirstLeadboWriatthoryStTuedychnDaitcaian/ 2. 00413 SIGNATURE PAGE TWO YEAR ORAL (DIET) TOXICITY/CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS RIKER Experiment No. 0281CRO012 From the Pathology and Toxicology Department RIKERSt.LabPoarula,torMiiense,soItnac./U3.SH.AC.ompany Study Director: ahs fonard J. SWinski, B.A. Senior Toxicologist G//r ate Report Reviewed By: Uae. Jams L. Allen, Ph.D. Diplomate, A.B.T. Research Toxicologist g-at-F? Date Report. Approved By: Ela 775L Edward E. Erickson, Ph.D. Laboratory Manager 8-29-27 Date 27. 600414 REFERENCES 1. FTJooCth-an1ls4o3n-C,arbJC.o.Dn.-1R4iEkxetirnentMLaalbaeonrdaatnRodoruitFeeesm,aolfIenEcRx.ac,trsetStAi.fontePraaunlda, STMiinsgslu5ee510DI1Vi,sDtorIsinebtuertonifaoln of Drug Metabolism Report, 1-20, January 30, 1980. 2. PEBanislotacorhogeremm,iecnaTtl..P.C,haTrhLeaeec,tTeorxK.iiPsc.otliocagsnidsotfG,ilPl5ei(re1fs)l,:u1o5rP5.o,Jo.cMtaarnMcooharpthe1o9l8-o5.gIincdaulcedandLiver 3. AAngvee-rA,ssoMc.Ri.a,tedCohLeens,ionBs.J.i,n BLaartrtuiaedra-,ReaCr.Pe.d MaandleFSosptrearg,ue-SD.Ja.nley Comparison Between Hap: (SD) and Crl: COBS CD (SD) Stocks. RaEtxsp:er. A Aging Res., 8(1)Part 1:3-24, Spring, 1982. 4. PERraKetjs,eaanna,dndJSW.w0ei.is,ssbuMPrieeccegk.emra,n,CJa.JnH.c.Ce.r, "RSeCpsaoseneatyra,cnheAo.3uE3s.:,2T7u6Gm8or-ri2ss7w7oi3ln,d,SNopDv.rePa.mg,bueerW-,eDiasw1bl9ue7r3yg.er, 5. HFaezblreutaorny 1L7a,bor1a9t84o.ries, Vienna, VA. Historical Control Data, page 16, 6. HDEiaxfpnfrhe.irjeaBnricvoeil',. iMnHe.,dP.eOrpf1hl7au1uo:g5r,0c-o5cR5t.,Ha.no1aa9t8n2ed. ESixncgreert,ionL. inThteheSeRaxt-.RelaPtreacd. Soc. 2. 600415 Table 1 Two Year OroaflPl(uDoireto)caTrobxoinciFCt-y14-3OnicnogReantsicity Study (+ AAbnoavley/tBiecallowAnDaelsyisriesd CoofncFeCn-t1r4a3t%ion) ASptpurdoyxiMomnatthe 0 (mnttian) 1 . 7 10 " n 16 1 22 20 RCeCpDorAtnaNluystbiecrasl 213 229 250 289 319 328 360 366 84 395 404 30 romptewn pm 3 + 0.60 +o. + 5.00 +n 2 acon BERN - 23 + 2.60 + 2.00 + 3.00 +o. - tov + Lov -2 0.00 - 67 we +7 +a vn +30 +10.00 _------ Mean Deviation for the Study -_-- Sse +19 2 Commercial Chemicals Division (CCD) 2 Ithnicsordroescatgevalleuveeslgviavsenreaatnatlhyizsedleavfeltedruneewtodeitnescttrourmevnatsmiinfsutnacltlieodn.: Excluding from mean deviation the percentages over + 208 acceptable limit. 29. 00416 Table 2 TO Year OorfalFlu(oDrioetc)arbToonxicFiCt-1y4-3OnciongReantiscity Study Susmary of Mean Body Weights (g) + % Difference from Control Maes --- MHseoteukay MCMeooanantrWoWeEl.. MM3ee0aa0npWpWtem. u8DADifff.. Me3Wa0eannpwpWWme..wuis prire.. o 2 165.3 270.9 1621-19 2343-135 167.0 2710 + 1.0 10.0 .6 339306..70 23078.66 7-1271.20 3.5 369.4 sie - 5.4 150 442596..22 3338201-1611777 a44015--3a2le 2 1 475.5 493.2 3980-1603 4128-163 ase 475.4 3.7 3.6 1168 550125..39 44235604--115544 487.9 438.5 - 3.0 - 3.3 2202 20 552462..83 4a4s7.e4 --11550019 ssiie o2a. 550.4 4642 -15.7 526.3 - aug 2286 30 556671..50 448745..90 1-154.l36 ss3e.z9 -oa3.. 576.3 497.2 -13.7 sse.6 - 3.1 332 36 558802..69 55015.17 8-1-122129 5s6761..43 -- 22..40 591.0 S142 -1300 s7sl4 - 206 3w8 a2 650989..44 55325.02 8-1-12240 sseeaas - 2.6 2.6 612.9 560.9 -11.7 600.5 - 2.0 a as 661293..85 555502..80 --1111.51 6e1l20..14 11..88 Py 50 662369..12 s56568.175 --1110.83 662178..19 - 11..19 52 638.6 570.1 -107 63.6 -o.8 -_-- 30. 600417 Table 2 (concluded) Two Year OorfalFlu(oDrioetc)arbToonxicFiCt-1y4-3onciongeRnaitcsity Study Summary of Mean Body Weights (3) + \ Difference from Control Les _--_-- HMoesteukdy se ss6e 602 6664 768 72 776 78 8820 84 8868 5902 %9 19080 110020 MMCeeoaanntWroWeEl.. MM3ee0aa0npWpWetm.. vDDiifff.. 666514..63 SS783716 <-11719 668.0 673.2 S873 590.8 -1200 -12.2 667644..45 5599.832-1-120.02 650.8 656.6 598.2 604.5 - 8.1 - 7.3 666518..93 660088..25 -- 87..16 666607..87 6`06015..14 --97.63 668.8 670.6 604.6 611.8 -9.6 -8.8 666638..11 661107..05 --78.060 667785..96 661147..74 --89ll65 668960..00 662241..68 --99.54 667702..35 662271..60 --78.35 667715..17 662215..25 --76..28 666452..09 661239..34 --54.s5 Me3e0aanpnpwwme..wiprice.. eedasi.4 21..39 es2.7 6s6.8 - 2.3 - 2.4 66s558..73 0.2.98 662.5 6s6.5 + 1.8 + 1.5 6e6s64.d2 ++ o00..96 666s39..82 -- 00..62 661.7 ee9.2 1.1 - 0.2 66662..93 +- 00..96 666544..57 -- 31..66 6e6s22..49 - 4.0 4m eess03.40 -- 32..67 e66500.70 -- 21..74 665604..80 + 0.3 1.4 _-- 31. 00418 Table 3 Two Year OorfalFlu(oDrioetc)arTboonxic#iCt-y1-4O3nciongRenaitcsity Study Summary of Mean Body Weights (3) + A Difference from Control FEMALES eSteuka.y MCoenatnroWtl. 3M0e0anppWem. 8 Diff. M3e0anppWme. 3 puff. 2 113589.022 116378.03 +T0s.0 tmz teeo - 0.7 +43 6 22089.75 223173.84 +-20051 221.479 1+2a06 108 226596..29 22564363--0252 22605.338--12.29 112s 2270990.57 a28264--11.9 2218520.58 1- 24.4 116 239016..88 228959..44 --22.24 2859-20 298.0 - 2.3 20 22 316 31901 3076-13 C3146 - 1.4 3041 3009 - 2.4 2.9 22 332270.53 33226025--0o064 16.6 32.6 - 1.8 1a 320 333338..73 33366 -0so6l 333390..04 -+o1.0 32 34 335405..75 3352a.8 +-00l64 3a5l3s5 -+o0.2 3368 335859..53 33672..13 ++0058 358.0 3634 + 0.7 +1. Pay 3a63z.2 a3662.0 +s0o0l8s a36s7.s5 ++1132 a 46 380.1 385.7 380.4 385.9 +01 40.0 382.0 38.7 +05 + 1.0 Py 50 39928..36 339991.63 +"0022 339959..87 ++0o.. 52 406.1 406.1 +000 406.2 +00 -_-- 32. 600419 Table 3 (concluded) Two Year OorfalFlu(oDrioetc)arbToonxicFiC-t1y4-3onciongReantiscity Study Summary of Mean Body Weights (3) + \ Difference from Control PeALES --_-- MHSeteukkay MoCMooanantnrWoWetl..MeM3ea0a0nnpWpWeEm.. \%DIDifff.. MM3ee0aanppwWmee. wuos pputreee,, 54 5566 44149.01 4a21S2 0vo6ls 41020.76 -so0u. 420.9 426.4 +13 4273 sis 60 652 442263..66 44237.s0 1+028 a430s.0 4+a 15 426.1 436.0 +19 amis saz 66 7608 442247..95 4433535.50 ++2153 awess. s4s an 431.4 291-05 als +28 72 776 44365..52 443a2e.68 0- 046 4a6d3e.l3e ++331 455.2 447.4 = 1.7 assis 43.0 078 82 446744..89 484.0 445527..70 461.8 --32ll86 - a6 aarmsie 485.7 s4o1.a + 0.4 8864 3 449824..78 44558726--75060 44796..73 - atilg 499.1 456.6 - 8.5 e343. 9502 9 550102..65 44555.918--9117.0 4a8s6s..32 -a5n1 505.7 451.0 -108 492.0 - 2.7 9%8 100 550006..09 446684..05 --86l.44 55050.543-401.. 501.2 464.2 -7.4 505.6 +0. 110020 550032..60 445602..38 --180.13 s50o3n.e3 1-0o..f0 _-- 3. 600420 Table 4 Two Year OorfalFlu(oDrieotc)arTbooxnicFiCt-1y4-3OnciongRenaitcsity Study S(3ummofarydieotf cMoenasnumFeododpCeorndsauys)pt+ion% DPiefrfeKrielnocgerafmroBmodCyonWterioglht mazes -_-- study MHeoek MeMCeoaanntrWoWelt..MeM3ea0a0nnpWpWeim.. %%DADiffff.. MM3ee0aanpwpmWee..wusipiere.. 21 . 18052..20 9986..86 -+13336 180.308 -1o.28 76.4 8el0 +00 77.0 sols 56 10 s69i.s4 760.076 -+alas 664112-s1a1z 53.7 63.0 w7.3 S74 +6 112 16 5501..77 SS89051 seieslis 551335 e+13l2 8.0 55.2 slo 93 +27 18 2220 466..89 s52a.s6 s12e.z4 4a879 +e4l3s aes sis isle 23 es 2 226 a570 052..20 ssiizee 446s3 ++2025 as 4.3 wz as sao 30 3324 4a229 497.72 va02 aa7o +e2las as 46.5 a2 4208 +24 36 38 38.4 0.7 4426s0 4w1037i 4329..27 ++33007 90s als ail als +s a2 aPs 39.3 38.9 wo 436 wz wz 43 4005 es salt 39.0 426 +92 39.7 +1 a 5520 3389.005 aa32 aaziz |me4 0e2333 3605 a wz 1-0 -_-- 2. Co421 Table (concluded) To Year oOfralFlu(oDrioetc)arbToonxicFiCt-1y4-3OnciongRenaitcsity Study S(5ummofarydieotf MceoannsuFmoeoddpCeorndsauym),pt+ion% DPiefrfeKrielnocgeramfrBoomdCyonWterioglht MALES -_-- MHseoteuka.y MMCeoeanantrWoWeel..MeM3e0aa0npWpWeem.. wDADifff.. MMe3e0aannppWWme..wsipiere.. 5564 3367..60 a422.2 ssaelne 73s63-+1396 058 62 36s.i1e 4400.67 wwya 73753 ++3s 59 370 +30 31 ah 6660 3 3316030 0082 w20z07 336s4 +a0n3s 32.9 365 +1009 35 +1 7702 7 3332..06 3377.75 asaslee 3340s ++s1i2s 344 39 w0l2 367 +67 776 80 36a016 91972 s+a5s7 36459 - oaulss 346 39.4 413s 68 v6 s8e2 3635..36 3368s7 e+1 s2 33643-3+3 8868 50 3384081 8360-5+10200 3340-5vo2ls 34s 36:3 +a 47 ols 952 9% 33850.s1 w37s.3 e+6s3 33608 soo Cal 37.1 "0 eal as et 1900 102 376..37 8319 ++348 737..43 +o +1 3800 383 vel 72 vel 104 3s EX ws ato _-- 3. 600422 _--_-- HHSoeteuekdy 21 46 5 1120 1 1168 20 222 26 3280 32 3364 "308 "a2 P3y 5502 --_-- Table s To Year OorfalFlu(oDriostc)arTboonxicFiCt-1y4-3OnciongReantiscity Study Summary of (g Of diet Mean Pood Consumption consumed per day). + % DPeirffeKrielnocgeramfroBmodCyonWterioglht FEMALES Control 300 ppm MoMeaannWWee.. MeMeaannWWee.. WD% ADAffff.. 19087..80 1960.616-25.02 9871..02 ssils 1+5o08 7401 72.6 [XEN] 72.5 -o0.1 70.2 64.2 7602..04 +-30.31 5647..32 5662..39 -+12.26 63.4 58.6 61s -300 61.2 +a 59.5 57.0 58.0 - 2.5 56.2 1.4 6519..77 5587..14 -- s3.s8 58.4 52.9 se. - 309 514-28 56.7 56.8 5542..27 --7a.n2 58.4 54.2 sie 53.6 1s - 1.1 4584..57 5510..88 -+s437 49.2 51.4 50.3 +22 4s. -12.3 48.3 4.3 so. 30 pra MMeeannwWee..wptDeifrf.. 19063.01 -- 32..77 8832..68 1+42..02 734-00 6793.57 +-01.27 643 +1 5684..86 ++20.58 65.5 +303 6613..22 ++270.9 5587..30 10.0 Tiss 5559..70 4-16.2 557.10 5-+2075 543-4 503-139 5532..99 1- 2s.4 s52i.e1 ++573. 4500.0 o-2s.7 36. 600423 : Table 5 (concluded) Vo Year OorfalFlu(oDrioetc)arTbooxnicFiCt-1y4-3OnciongeRnaitcsity Study S(u5smoafzydleoft cMeoannsuFmoedodpeCronsdauym)pt+ion% PDiefrfeKrielnocgeramfrBoomdCyonWterioglh FEMALES _-- HMSoteeudkky s564 s08 62 6646 870 772 76 378 : 8842 836 50 9542 9986 110002 104 MCMeeoaanntWroWeel..MeM3e0aa0npWpWeem. \D\ IDfAfff.. s8i.1s a8.a4 o-a6n0 4469:.36 a9is2-+0 28 a1 4 4.5 41 <a - als 4a1s0 m4/3s 3a70 446513 a ar 2 els 88.s3 a4ss8-5s2z 4454017 aaos 2 -ol2 aalso 239.508 - aalls 4454.33 F 2.E3N .6T6 a6s..19 aasse 1 - al 1642..94 aaiss eeaadl ar8s 44402 s+i6e0 a2se s406.29 ++28274 MM3ee0anpnWmWee..wpa ipeirre.. 3 an a-aals 476.3 sToalloe as a0 als al 1 3986-o3 ni 4a08-2o0i0l 4ase -oelen a87s C-ioslise 38020 -12a0n2i 77.72 aalnse 835s caiteas 32777 Sansnh a4l2es +a2l.s 4a623 v+a3l _--_-- 37. 00424 zebies vo Year OorfalFlu(oDzheotc)arTbooxnicFiCt-y1-4O3nciongRenaitceity Study Su(sas/acsayt/doafy)Ma+an%FoDoifdfCeornesncuemptfiroonm C-oAnbtsroollute wazes re---------------------------------------------------- SMtoeasckky mecMeoaannntwrWroe.. Me3M0ea0ann'WpWem.. Mvoiifr.. Wem30emawnpptwme.. opiiree.. 21 : 22.02 sls 2107.7 22 "N1se. 2E2.e9 Zalo 503 vl3o.l2 Tole o. 10 267014 20200ss pried alo rTasls 22620.36 Ii i JCoilst 18 1i2 1s 225001s 201 220s als Ctaasz aslis las ad Cloals foo I 2 22071 203 22.05a 27 IIiseo 3asls las 20s TIi ile tis 2py 2s 2200ss 203 2n0l1 nl 1lC3aa;as a224u03d2 lIiil: Lolo 320 3 2p0ys 203 2l2s 20s lli as 2a0d5 Ia 20s TToall Tos 338 22074 224s1 200 als lSaisz aalls la 20s L`oil Tals pwH" " 22011 203 22000s ls lCoila aad7s 18s 203 vLaalls Lolo S54o28 22244.3s4 pr224e4.t2 T-Co0.ko8 ad222yl4.s1 T ILoz sl r ---- e-------------------------- 38. 00425 _-- MHaSotsoukkdy. s564 s0e 6624 686 7 7720 76 780 82 8864 3 5920 99 19080 110028 _--_-- Table 6 Two Year OorfalFlu(oDrieotc)arTbooxnicFiCt-y1-4O3nciongRenaitcsity Study Su(m3m/azrayt/doafy)Me+anvFDoiofdfeCroennscuemptfiroonm C-onAtbrsoollute MALES MMCeeoaannntrWoWeEl.. 220.22 2234018 2204.26 2210366 216 2212.77 248 22430.52 2401 227378 2306 22440011 2625.011 2254.26 2273 MeM3e0aa0npWpWeem.. 22402.04 2234.009 2262.000 222..41 2209 2222.88 22430.07 22240041 2233.08s 20.3 222.72 2254..09 2230048 224021 D\ iDfifff. -+oos. +-o 0 -"1960.15 ++2330 +60 v+o50l1s -pp 20 -+370 +F0o0e0 -1s4508 -37 -- o2s7 --3323 ++639 MeM3e0aannppwmWre.. 23.3 2244055 2244..35 227 22420313 2200 224022 2240.5 25240016 22327s7 22130060 22.9 2244.35 22440767 224..47 wbusipeicre.. -3.7 +1127 ++ 2ol9s +0.2 ++230212 +15 ++666 --is27 ++4620 -- o4l6s -- 4allss - 5.0 -- 624 -+ 02.000 T2e4l 39. 600426 Table 7 Vo Year OorfalFlu(oDrioetc)arTboonxicFCi-t1y4-3onciongReantiscity Study Su(mam/acrayt/doafy)Me+anAFDoiofdfeCroennscuemptfiroonm C-oAnbtsroollute FEALES -_-- MsWeeteeukdk.y MoCMoeanantrWoWel.. MeM3e0aa0nnpWWpeEm.. Nu%DDIifff.. MM3ee0aanppwWmre.. wpipeurre.. 21 117..50 1173..05 +T0o0o 1173..3 -+ 1olss 55 21901034 11790.52 SSoalls 1810905 "tiileo 19.0 1911 `ols 18.6 - 20 1120 11990.65 11990.31 "- l2 s 1199..22 -- 210s0 1160 18 1168..76 16170.18 "- a33s 1168..84 S+ iohl 19.7 18.8 - 4s 1903 - 200 2202 2 1189..78 1918.129 -`2al7s 1199.069 "+olas 19.3 18.7 -30 195 +100 2E6Y 30 20180.67 19180.33 S- 2603 11980.34 -- 613s 20.2 jr - ao 2000 -1o 3324 36 2108..52 2002 11981.31 1904 -Za2l2s 1198..22 Sao 2004 --s1lso +10 38 a 2201.24 2001 1189..91 2000 "-1060s 1189..57 ols 1919 1-2037 Silo a6" py 21080.78 1199.076 1903 19.7 +-sal3 2200.036 +201 2005 -+8160 +62 s502 12090056 1189.60 o12l.2 2109.50 -- o2s4 -_-- 40. 0004277 _-- MsWeteeudky s5e4 s08 62 6660 678 772 776 80 882a 8868 9902 9 9986 101020 104 _-- Table 7 To Year OorfalFlu(oDrioetc)arTbooxnicFiC-t1y4-3OnciongeRnaitcsity Study Su(mam/raarty/doafy)Me+an%PoDoifdfeCroennscuemptfiroonm C-onAtbrsoollute FEMALES MeCMoeanantnrWoWele.. 21190.69 2191050 2200.16 17. 11990:92 2191.67 202025.0 217 2211031 2212068 2233001s 22130s7 2203.048 21.6 209 MMe3e0aa0nnpWpWetm.. 2109..04 2210030 22000.10 117.02 1189.051 202.0504 2109.39 1198..02 1179..83 2200.006 221006 22000.70 2158 22. AADDiiffff.. -- s2es ++ 0a0l0t TSo2l0 --1628 --730 -- s6l8s -- 260s -13e.l7s 1l7e.e9 -1E0r.e8d --a927 1-110sl 000 Tole WM3ee0anpnpwwee.. 1199.058 2109.058 119905.4 1177..77 11980.92 20200.68 21080.63 11980:02 1818.001 1189..70 21190000 221000s9 203 27 wpa ipeire. -- 28.30 +- 2s. --3sils a-778 -+1al0s -- salss +150057 1-103..87 2-107.l40 11970s1 -r1i1les 1v037 +85 +38 a. 00428 _-- SWteeukdy -_-- 1 42 68 1120 14 1168 20 222 226 3302 3346 38 042 4464 48 5502 -_-- TABLE 8 Estinated Mean FC-143 (mg/kg Body Weight) Consumption Per Day Hale 300ponFenale 29.6 29.0 3209.50 25.2 20.3 25 243 1281::92 2212.58 1177..59 1281:16 1516..86 1168..99 16.4 1506 1188.34 1145:.86 1176..94 141.465 1177.24 131:492 1615.48 1213::88 1615::38 113322 1165.51 11320:1 8 1155..25 13.0 13.0 1153:51 12:3 145 Male 30pon Female 32.16 32.19 2:3 18 2:5 25 1179 22..22 11.56 22..10 1145 1198 1145 12..09 1.4 14 18 17 1133 11.88 13 13 17 18 1132 1167 1132 1165 1.2 12 16 18 1122 1155 11 14 42, 00429 -_-- WSeteukdy --- 54 5568 6620 64 6686 7720 776 78 882 8 888 9902 9 99%8 110020 104 FE TABLE 8 (Continued) Estinated Mean FC-143 (mg/kg Body Weight) Consumption Per Day Male 300 pon Female Male 30pom Female 1122:.47 141.41.5 1212::22 114483 121.1 114308 1211:.20 1121:.49 111:.32 1132::29 1174 1133:.88 11189 113332 1111060 1121:98 119.69 121.77 110..29 1133.27 1212:.01 182 133 174 113332 1 115 1315::33 1111 11.44 1111 1144 1.110 13 13 11.10 11.22 11.10 1132 i11 1133 1111 1123 11.10 1122 1110 1111 11.10 1122 11 11 13 11 1111 1132 1111 1134 -- 43. 00430 BoIID eT ER Ig " ee oe = _ P FEai 3DEspy ecoe=ee J o HHo - Il - oe = ae. 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Liver Hepatocellular Carcinoma MaAmdmeanroycaGrlcainndoma Adenoma Carcinoma Fibroadenoma Lymphangiosarcoma Pituitary Adenoma Testes/Epididynis Leydig Cell Adenoma Thyroid C-cell Adenoma C-cell Carcinoma NEOPLASTICLESIons MleControlfse8mle Wal5e0 HighFem50ale Mal50e ou Fa5m0 e 4 4 8 0 8 0 0 0 0 2 2 0 6 0 - 15 - 7 2 - 22 - 0 10 2 -1 - 0 - 0 - 48 - 2 2 0 -a - 0 - 0 - 42 - 0 35 7 28 3 36 83 0 - 14% - 4 - [3 2 9 0 5 0 0 0 4 0 0 0 1 = 50 rats/sex/group were at risk, % values derived from actual tissues examined * = Significantly different ( = 0.05) from controls 91. 600478 TABLE20 Two Year Oral Fl(uDoierto)carTbooxniciFtCy-14-3OnicnogReantsicity Study of Sumary of Major Microscopic Findings - Percent Incidence at 2 Years NON-NEOPLASTIC LESIONS Oraan/Lesion WaCloentrolFsemale n=l 50 50 Adrenal NSionduusloairdaHlypeErcptlaassisia 242 80 HeMayrotcarditis, Chronic 2 32 LiCvyesrtoid Degeneration 8 0 HHyeppeartpolcaesltliuclarNodAlutl.e Basophil. 04 126 Megalocytosis Portal Mononuclear 0 7 0 38 NecroCseilsl Infil. 6 . 10 LuAnlgveolar Macrophages 20 2 HePmeroirvrahsa.geMono. Infil. 4220 228 VPnaesucnuolnaira,MinIenrtearlsitziattiiaoln 382 4144 Testis/Epididynis TVausbcuullaarrAtMrionpehryalization 1 0 -- ovary CyTusbtular Hyperplasia -- 130 Thyroid UteCr-CuesTl Hyperplasia 2 0 PanCcyrsetaisc Glands - 14 SaAlciivnaarry GAltarnodphy 13 12 SplSeieanladenitis, Chronic 2 2 Hemosiderosis 32 50 FaleHigh Female 50 50 1328 82 34 20 1526% 42 806+ 164% 96+ 38 10 4 62+ 44 38 38 9144% 5228 1 18 1282% -- -- 312 2 7 - 10 2 9 Ed 5 a" 2+ Male ou Female 50 50 22 86 36 10% 162 182 120 02 64 22 10 12 32 28 20 2 866 7a6% 10% 6 206 -- - 18 14+ 13 2 -2 20 12 27 2 86 1 = 50 rats/sex/group were at risk, % values derived from actual tissues examined * = Significantly different ( = 0.05) from controls 92. 600479 g ii :|qie 8h! HAY gE RQ g So 1 31 i 2 (sunuB) juBiom Apogwen +3 : : 1 : LyiJ | 8 ;g 3 1 g 31& (swnuB) juBjom Apog Uden iis ks} . : 1 : ii ed ys . s R . i +S. 5 BS \ 1s i 2 i i g& 2 Foor _J : 8 3 3 (AoR/im ApoqBx/B)uojydunsuc pooy : bi 2 . 23 A 8 : i 2 Lf : Z : s F 's < / : 5i pr 3 L 2 (op/mApo 81/8)uoydursuospoo } THO YEAR ORAL (DIET) TOXICITY / CARCINOGENICITY STUDY OF FLUOROCHEMICAL FC-143 IN RATS APPENDIX ITEMS 97 00484 Interna Caxespondence ei appenaix teen a SaDE. GS riersR on I 220-2, 502 ei FJ. AK. oSuegg, -W2E0-E28-e02ee <M. for S. T. 3. CASE =~ SORENSON -RIMKEEDRICLAALB,ORAINTDO.RIEHYSG.- 218-35 SERV. - 20-28-02 se duane 27, 1981 Swe: Alr Monitoring, Project 89002107 -_-- 00000000 3M Summary mr4o1onoimtmooursnieidntgoriiwnansgfluhtaoosroecvbhaeelenuniactcaeolndpusoctsutsdeiidbelsei.naitrThhbreoerenpeuarnptfomosaneltaotifrneoasntocnmse.nt . Tahney, savmerpele berleoswultdseteicncdaisciacteamtohuanttsf:luorochemical exposures, if eran 3ATnLodTonsFsoa-um1sp0el3di.nginw"mateshe sctotuwndodyucyteheaasdr 1 baienneinmtahlein' ftpherreoedgeirnegannsismtausldiyncteorfeAasFbmaieignteatl, SwATKerorCeoemas lssboiayclmaiptcmleeeaadsnzs"ew)olenorfetsoapcmeipotollfhilenergcthteetidumbpaeinisnin:gmeaerlasWcihrtawhciokftsho.ntemheeTteahxscacenevopoeltnrieaolmneed.kticrso.espaartmoirmpaelsnets A"flusosouraa:int a"oiTrrhess'tapemeaprdltyeodrsstlasotacem"aptlecedodndntaeiraieronJtshu.edgecdoonrepairreseensthaatuisvtemoofce ihe Tehveeryflo30w mriantueteosf tthherousgahmopulse ptuhmepssawmapslincghecpkeerdioadpproximately aCTAhecmencetrrreisadcalaimntpalReteIsisnoednauwrsectrahrseiaaaLlnanbaolIHryynazgdteiuodesrntyeib,iyaAlstshToHehriytsgAainsealinlaoetbnyo:iLrcaaatbloorryaSteochrtayisonbryuothfthethe 3 00485 9g BEST COPY AUAILRBLE Appendix Trem a WT. case a Aoguse 27, 108 PTltrohieetnetintsstea.ismatplleOfnblyuroterahsioiuscvlhtbesobmrainsiceinasdl,misec,aainttseifisitsahnajytuu,ndigaeiwidkererbleotyrh.nabe:eloccwroonsdcseenttecrcoatntatibaolmneisnatoifon Please call of there are any questions. soNsie'O0r 4sAgee 00486 99 APPENDIX ITEM A nr cam lsPraaomspeilcetncusscaiasao-a3sion fost suspic Mumber CLI Description C0o0p .ot ricoonn:trol teem, cci81-23 CC8l-2l CCLe1-25 wiz C912 Same as above RRDoi-oo3mn3.2.donsePaHmF-pu3lc9ek2r.4,indotsoep of FeDf3lz3eo2..rToamstaamhhpelrierrsaahmtomvee Robfoammi..onSSraomotplaleesrT,acohnd.omteop pseimoe eaeRe scArTsaempaie,wee. a Time 921235 922-1225 926-1236 1055-123 asm meme rogue 27, 1901 Compound wersse re-1a3 w-3924 me1924 concentration, mg/a' Coon Lo.001 <o.003 Lo.025 ran Loar ree < 0.002 SMPLING METHOO, F-121902"4 TSaKpCtsaigleirca+ agaetlhasnacmtp.ling tubes. AALYTICN. WETHD: FPOH-L39324 =C agGaasrtivcaheteiosmaattioognt,aghdyu,s celhercmtsrsoonrceapphtyu,resdieetceicrteonr.capture marron regs. aaaozes. 00487 tou Internal Correspondence ) APPENDIX ITEM A BL. sibtaekt Fo 3. D. Johnson Sout we ioAcnttaholbyTsewiros7,Yoefa1Pr9l8Ta5somxaStSuadmyp-lneastafro(mRiSkeenrtiSntaaldyRaNet.s 0H3o8u1s0eRd00i1n2)Reva -_-- = sICeonhltalivenecatieadtrtaaastcsheddaisnctrRhiiebkeeodrn.eStpuOadngyeJuNpolr.yotOo133c6,o1lC1R9aO8tO1tI,aZc.hfmoerntThtyespfeo.arssetshmeisuuensmepvreoerfe(see BaCathctakaacihcbeaydl)sDr.vfeoVrre8a/nt2ar0la/yn3as1tt.aerozAfeLdLortsogaamVn.pilcePsoftlnvueaorpreeianqleaescseTha(evaen.Seovsn)teitissnancvtoemmpmeerrscoinett SF1ilniu'ioStr7oiGnn.eNoptraFebrasosemkntth3i6ts3h,3a1t,ivtapsc5a3nI.nbteercfoenrcilnugdveidthhatthisshsoereedyv.as Pareesasbrcmorremeare aRemraesace0p.h idobeiaiiat Riker Laboratories, Inc. 00488 101 Lo -_-- . Appendix teen a Internal Correspondence cer MviTb.. CGaesiettien wRi.iE.. obbeearlson -- Ron. Prokop. | ~ 3 % V. Pothapragads From J.D. Johnson - Steet owe wAintahlysTiwso July 1s, Yo1efsaarlPlaTsomxaSStaumdypleRsatsfro(mRiSkeerntiSntauldyRaNot.s 0H3o8u1sedCRin001R2o)o.m Faonratlyysipsl.asmaThessameplseasmplfersomisneclnucdienal5 IR 3864, and IR 3865) and 5 female mraaltes a(rIeR s3u86b1m,ittIeRd38f6o3r, fIlnuor3i8n63e, (IR 4921, IR 4922, IR 4923, IR 4924, oaSttnhaderrtTeRdt.h49i2c5Tt)hyerwpehliacsahmraeves5rumecpaltsesascotfwiofrieecacehdcoslbelexefocrtfeerdodmoasttihne3gbcodwanasytsroiluntitrteoiroamt,eddo.sfirnogmThe the room in which study Fats are feceiving FC-143, and from the room in which study rats are receiving FM-3924. The nuabecs for these rats are as follows: 5 male Control Room (IR 3866, IR 1867, IR 3868, IR 3869, IR 3870) 5 female Control Room (IR 4926, IR 4927, IR 4928, IR 4929, IR 4930) 5 male FC-143 Room (IR 3876, IR 3877, IR 3878, IR 2879, IR 3880) 5 female FC-143 Room (IR 4936, IR 4937, IR 3838, IR 3839, IR 3840) 5 male FM-3924 oom (IR 3886, IR 3867, IR 1888, Ix 3889, In 3830) S female FH-3924 Room (IR 4346, IR 4947, IR 4948, In 4549, IR 4350) Ptlheeasreesguelttsbavciklltloeauds wtiothspetchiefidcatsa.nalyIstismayofbetothaantalyisnitseropfrettiastsiuoen. of 5. aSuchree - 00489 102  ; | || | || Appendix Ttem 8 CCD ANALYTICAL REPORT #213 CERES fom P. J. Colbert - 236-28 Sons SLC Analysis of "into Ground Lab CFh4o-w3.524(Ri(k1e-r299S5tCuodCy) #0F2C8-11C4R3O0(I12-)2998C0C) Blended 3 owe April 29, 1981 Reference: RCeoqmumeesrtcsial#17C0h7e9m,ica1l7s080A,nal1y7t0i9c6al Laboratory MCeotmhmoedrci#a'ls GC3h0e-n0ic4a8l1s. A6n3a1l-0y4t8i1cal Laboratory Chdg,e samaplloensg woifthF-f3o9u2r4bl(aWn.kR. GrEoLuFnOdSE)LabbleCnhdowedsaimnptloesG,rounwegre{ab rseacmepilveeddpefrreomruL.n iJ.n tSriibpilnisckaiteo.n 4-T2h0e-8r1esuflotrsanaarglysis. All Compound Theoretical ppm Aucgt/ugalFH-p3p9n2 Blank for concenthqte PU(-b3l9e2n4dedCo4n-c1e7n-t8r1a)te 200 FH-392 Top Sample 100 Mid Sample J00 Bottop Sample 10 F-39024 Sample 30 Mid sample 30 Botton Sample 30 FM-3924 Top Sample 10 Mid Sample Lo Botton Sample 10 26 ot 105 oo 105 p< m 29 3207 \25 n s\& EV | 00490 103 AppENDIX 179M 8 LC.EOJ.Anasliybtiincsakli Report #213 -_-- APpargiel 229, 1981 Compouad Theoretical opm (vAac/tg)ual eepzoen7E _J Blank for 100 ppm Tem 0 o Blank for 30 ppm Tevel 0 Blank for 10 ppa-tevel 0 0 evel of ethanol in FH<3926 Concentrate (blended 4-179) was also checked and found to be Tess than 1 ppm (ug/g). ~ SbilxanksamGprloeusndofLabFCC-h1o4w3 sbalmepnldeesd wienrteo GrreocuenidvedLabfroCmhowL,. aJ.lonSgibiwnistkhi two oTnhe4/r2e0s/u8l1tsfaorre:analysis. All samples were run in triplicate. Conpound FC-143 Top Sample Theoretical ppa 300 (Aucgt/uga)lFe-p1pm43 326 Hid Sample 300 82 Bottom Sample 300 w Blank for 300 ppm Tevel 0 0 FC-143 Top Sample 30 2 Mid sample 0 23 Botton Sample 30 28 . Blank for 30 ppm evel 0 io sBeetcauofsesatwmopleosf wtehreethrreeceeiv3e0dppfnromlevLe.l J.saSmipbliensskwieroenl4ow/,37/a8n1other! , 1) for analysis. The results are: 00491 gy APPENDIX rTMB CL.CDJ.Ansailybtiincsakli Report #213 APpargil3e 29, 1981 Compound Th-eoretical pom FC-143 Top Sample 30 Hid Sample 30 Botton Sample 0 IQ Modi Blank for 30 ppm Tevel 2 LIs/msao fords7 ; cc: MT. Case - 21y8-2 WEC.GC!L MLcaCmoprrmeicchkt -- 221280--32-02 R2I0AD.. PLraoZkeorpte--23263-62-811 V. Pothapragada - 236-34 {Aucgt/uqa)l Fppemore3 a a 0-1 0 CC 04922 gs ApeEDIx 17en 8 Internal Correspondence dei 3ME0TG0.. LLCaaastpeerretcent VW.oPCothMacpCroargmaidcak LR0D 0A:. WPirnotkeorp 221231668--123 22306--2364-02 223366--2288 CAonmaglryetiiaclal ChReenpiocrtals Teas TL. J. Sibinskt 218-33 Fem PL J. Colbert 236-28 Sect GLCIntAonalGyrsoiusndofLabFMC-3h9o2w4(R(iTk-e2r999StuCdoyC) #F0C2-8114R300(1T2-)2998 Coc) Blended SRLr ee -- Jun-- eB15H, 1981----e------ LSeibx AT sCsahamompwplleesssamwpoleferseF,Cr-wu1en4r3einblreetnrcdieepildviecdianttfeor.oGmrToL.huendJ.reLsaSubirbtiCsnhsokwsi,re.aonlon5g215w.i8t1h ftowou obnleamnsksiGsr'ound sample Theoretical ppn 19A/cgtuaFle-1p4p3m Blank for 300 ppm :0 0 FC-143 Top Mid 300 300 , 203 oi 1 ws Botton 300 Ee Nass Blank for 30 ppm 0 0 FC-143 Top Mid 30 2 3 a es ( a Botton 2 "=\ gg ATuhgeusntext17,set198o1f.Ground Lab Chow Samples will be submitted for analysis on PaC:da 00493 106 nanaGtr [r-- Comercio) Chemicals Analytical Report #250 LO Stbtnskt - 208303 fom b. 3. Colbert - 236-28 Sweet GCLhCowAn(aRliykseirsStoufdyFC-f1042381C(RTO-021929)3CoC) Blended into Ground Lab RL, -- 00(ie0 RAReufgeuorset0 nc2em0:, 1C99O 8o1merci0 al chem@ icals A0 nalyticO a LasoO ratory OV Request #17449, and CCD Method 631-0481 1x samples of FC-143 blended fnto Ground Lab Chow, along with Ton Th pie: The robin aes two Blank Ground Lab Chow samples, were received from La. Sibinski on August 17, 1981, for analysis. All samples were Sample Theoretical ppm Actual ppm ug/g FC-143 Stank foBrot3t0o0nppm 30 8o : FC-143 Top 300 Mid 300 308 - r 310 +7 Sotton 5 Hid 30 Blank for 30 ppm 0 FC-143 Top 30 rime Bk 0. (otoitF-- dr WT. Case - 218-2 E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1L VI . Fothaprageds - 33638 W. C. McCormick - 220-2E-02 L. D. Winter- 236-28 R. M. Payfer - 236-28 G. W. Kirsch - 236-3A 0 3208 232%% 00494 107 Internal Correspondence ApeENDIX TEM B ACNOAMLMYETRICCIAALL CHEMICALS REPORT 0289 Le J. SIBINSKI = 218-3-3 Fom R. M. PAYFER - 236-28 Swear GLC ANALYSIS OF FC-143 (T-2998 CoC)BLENDED INTO GROUND, ------ carLeAB CNHoONvWovee(mmRbbIeeKrrER3300S,,TUDt1Y9o8b1#- y2081R0012) 3M 000000000000 References: CReoqmumeesrtcia#l177C7h9emicals Analytical Laboratory Stiwxo bslaamnpklesgrooufndFCl-a1b43chbolwendseadmplienst,o gwerroeundrecleaibvecdhowf,romaloL.ng J.with rSuinbinisnkitrionpliNcoavteembewrith16,the19f81ollfoowrinagnarleyssuilst.s: ALL samples were Sample Theoretical PPM uAgc/tgualFC-P1P4M3 BPPlMankFC-f1or43 30T0op o300 BMoitdtdolme 300 300 2108 a 310 323 FBCl-an1k43foTrop30 PPM 030 29 BoMitdtdolme 3300 2383 RMP/he Ror pAw L de: MG.TW.. KCaisresch- - 23286-2-38 JE..DG.. LLaaZmeprrteecht- 2-362-118-3 WV.. CP.othMacpCroargmaicdka--23262-03-42-02 LR..AD.. WPirnotkeorp -- 223366--2288 (2 conies) 600495 108 APPENDIX 172M 8 --- InternalCorrespondence de MT. Case - 212 2 GE..GW.. LKaimrpsrcehch:- -`262. -3 WVJ..IDC.,PotMLhacaZCpeorrratmgeiacdk-a Z3-22-223-62-63-402 L.D. Winter - 236-23 To. L. J. SIBINSKI - 218-3-3 . ACNOAMLMYETRICCIAALL CRHEEPMOIRCTAL4S319 From R. M. PAYFER - 236-28 Suoject: Owe. GLC ANALYSIS MARCH 5, 1982 LOFAB F CC-H1OW43 (R(ITK-E2R9 9 8STUCDoYC) #2B0L8E1NDECRD 0I0N1T2O) GROUND Reference: Commercial Chemicals Analytical Laboratory Request #13069 Six samples of FC-143 blended into ground lab chow, along with two blank ground lab chow samples, were received from L. J. Sibinski on February with the 15, 1982. following These samples results: were analyzed in triplicate for FC-143 HEk Sample Blank for 300 PPM 300 PPM Top 300 PPM Middle 300 PPM Botton Blank for 30 PPM 30 PPM Top 30 PPM Middle 30 PPM Bottom Theoretical PPM 0 300 300 300 0 30 30 30 Actua) PPM ug/g FC-143 4 o re, (16s. rb "7Tas Te Ss Zl 0 } 27 33 #4: if 2% Ca LLIN 2 RMP:df wh24 C0496 gg Internal Correspondence ApvENDIX 17eM 8 ToL. Jd. SIBINSKI- 218-33 + ACNOAMLMYETRICCIAALL RCEHPEOMRITCAL#S328 Fon R. M. PAYFER - 236-28 Souee GGLRCOUNRDEALNAABLYCSHIOSW O(FRIKFECR-14S3TUD(YT-249209881COCCR)O01B2L)ENDED INTO SME -- 0M0 Mearcchh3,1,i198g 2 000 Reference: Comnerctal CHemfcals Analytical Laboratory Request #18100 8bT,lharne1ke982gs.armopulnTedhsesleoafbsacFmhCpo-lw1e4s3sawbmpellreeen,daendwaelriyenzteordegcreinoiuvnetddripfllaribocmacthLe.ow,fJ.oralSFoinCbg-i1ns4wk3iitwhiotnohneMtahrech following results: (77 sample Theoretical PPM Actual PPM ug/g FC-143 B3l0a0nkPPMforTop300 PPH 3000 2780 ot 330000 PPPPMM MBiodsdtloen 303000 2283 :. 0 RMP/ne ac: MGTW.. KCaisresch- +21283-62-34 3E0.0G0. LLaamZperretceht- 2-362-118-3 WV.CCP.othWaepCorramgiacdka -- 222306--23-02 LL 0. Winter- 236-28 00497 |p A e Wo gle Jo SIBINSKI = 218-3-3 Taam GLC ANALYSIS OF FC-143 (T-2998 Coc) BLENDED INTO GROUND m . e Che Grou" 1kinm Srupv oses chooLs) e A3RK a May 28, 1982 L Six samples of FC-143 blended into ground lab chow, along with two Liank ground 1ab chow samples, were received from L. J. Sibinski on May 17, Ll A 30 PPM Top 30 30 PPM Middle 30 30 PPM Bottom 30 dc: M. T. Case - 218-2 G. W. Kirsch - 236-GB E. G. Lamprecht - 218-3 W. C. McCormick - 220-2-D2 V. Pothapragada - 236-G8 L. D. Winter - 236-28 31 33 * 33 - 004998 "ni osmors sms To From L. J. SIBINSKI = 218-3-3 R. M. PAYFER - 236-28 comercia rpnicns ANALTYICAL REPORT #366 we 000 e AM Suoject Date GLC ANALYSIS OF FC-143 (T-2998 Coc) BLENDED INTO GROUND LAB CHOW (RIKER STUDY #0281CRO012) Sept. 13, 1982 Reference: Commercial Chemicals Analytical Laboratory Request #18609 sa Six samples of FC-143 blended fnto ground lab chow, ground lab chow samples, were received from L. J. f19o8l2l.owinTgherseesulstasm:ples were analyzed in triplicate along with two blank Sibinski on Aug. 16, for FC-143 with the Sample Theoretical PPM ug/g FC-143 Blank for 300 PPM 300 PPM Top 300 PPM Middle fae fer 300 PPM Bottom Blank for 30 PPM Lule 30 PPM Middle 30 PPM Bot RMP/hc. 0 300 300 3300 0 30 30 0 300 319 ' EH304 0 35 29.5 + dc: M. T. Case - 218-2 G. W. Kirsch - 236-GB E. G. Lamprecht - 218-3 J. D. LaZerte - 236-1 W. C. McCormick - 220-2E-D2 C0499 12 ara Gorespensence Em ne dL. Shin = 21003 wm B. %. Korean = 2308 vComeercieal CShoemaicmaless Sov GLC Analysis of FC-143 (T2998 Col) Blended nto Ground ove becamer 5, 1902 Reference: SCoomaerrcsiaalgCerarmicals Analytical Laboratory SSRSaiixcaanTmsoaaimrrpTolue3n,sdo11f918320F.Gc-h1o4eor3snebs.ealmepnSldsaeneassdl;meimnwneetroweargerreocusanetdauimy1siaebsfcrhoiomnw,LS.IaRl1onogdiemwikthtvoon _ Decrotical gem ef--_e-- t BR ne B3l0a0nkppmforTop300 ppm Jon oom Boreem Frigg 3BZ0zA050 33S0oLpoooonm Bhooaprtoen 0%% BB32s30 aee E~O~ BB 5e ley t 3 oGmlaenn cer EMpTG. a CCoosmepi -ac2t18l 2aves FbR EBroiemmanaweggatse s= een } Yr 000s00 1 13 Internal Correspondence 2ESTOOPY AVALABLE ApeeroIX TEM 8 CAnoamleyrtciicaall CRehpeomritcal#s395 To wki0. SIBINSKI T2183 fom G. W. KIRSCH - 236-28 Sect ove GMLACRCHANA7,LYS1I9S83 OF ROFDCE-N1T43 CH(OTW-29(9R8IKCEoRC)STUBDLYEND#E0D281I-NCTROO0G1R2O)UND 3M TT Reference: ComercTal ThenteaTs Amy EieaT Taboratery Request PII Sg16ir,xouns1da98m3pT.laebs TcohhfeosweFC-ss1aam4mpp3lleebssl',enwdeweredereiannrtaeolcyezgiervdoeudnidnfrltaarmbipLcl.hiocwaJ,.te aSlfioodrnignsFkCwii-t1h4o3ntwwFioetbhrbulaatrnhyk following results: sample S30a0nkppmforTop300 ppm 330000 ppopnm BMoidtdtloen B3l0anpkomfToorp30 pon 3300 ppppmm MBiodtdtloen Theoretical pon 000 303000 100 330 Avac/taua)Foprpems Loar0 3823 2 0 , a 0 3 aik/ne nh de: MEDTG.l CLaasmepre-ch2t1s8-2- 218-3 300. LaZerte - 236-1 RWL. WC.. MPcaCyofremric<k 23-6.22280-2 NL.L 0HL Wpienatreirson- 2-3262-32-65 000501 4 BEST COPY AVA ABLE InternalCorrespondence AppmvoIX r7ew 8 . lo PL. J. SIBINSKI - 218-3 fom GW. KIRSCH - 236-28 CAonmamleyrtciicaall CRehpeomritcal#sd0 Suoect GLC ANALYSIS OF FRCO-D1E4N3T C(HTO-W299(8RIKCoECR) SBTLUDEYNDE#D028I1N-TOCR0G0R1O2U)ND 3N oe py 2, 1983 Reference: Commercial Chemicals Analytical Laboratory Request #19333 Six samples of FC-143 blended into ground rat chov, along with two blank gf1r5o8ol3ul.nowdinrg`aNt11recsh`uSolawtmsp:lseasmplweesr,e waenraelyrzeecdeiviend tfrriopmliLc.atJe. SfiobrinsFkCi-14o3n Awpircihl t1h3,e Actual ppm Sample Theoretical ppm ug/g FC-143 B3l0a0nkppmforTop300 ppm 3000 300 ppm Middle 300 300 ppm Bottom 300 Blank for 30 ppm 0 30 ppm Top 30 30 ppm Middle 30 30 ppm Bottom 30 260 =Y.0y 33m 328 0 38. 34: - 32 auk/ne Bithn dei MT. Case - 218-2 J. D. LaZerte - 236-1 W. C. McCormick = 220-2 RM. Payfer - 236-28 W. H. Pearlson - 223-6SE L. D. Winter - 236-28 000502 115 Appendix stem Tvo Year Oral (Diet) Toxtcci-t1y4-3OnicnogReantiscity Study of Florocarben Nora RangesatfRoirkeHremLtaobloorgaitocriaensd, BlIonocd.ChSte.miFsatsrsy, Vam0lues of Rats Erythrocytes Hemoglobin Hematocrit Mean Corpuscular Volume (MCV) Mean Corpuscular Hemoglobin (NCH) MeCaonncCeonrtpruastciuolnar (HMeCHmCo)globin r-- Neutrophils 2-228 Lysphocytes 65-35% Monocytes 0-su Eoutnophils 0-6 8100 Ures Nitrogen (RN) G1ucons Total Bilsruntn Tota Protein Atbuatn aterm Alanine Amtnotransterase (ALT) Aspartate Amtnotransterase (AST) Alkaline Phosphatase Creatine Phosphokinase (cK) 5,000,000-8,000,000 cells/eu =m 117 5/0 26-520 57-77 microns? 18-24 picograss 20-300 ,000-15,000 cetts/cu am 500-4,000 celia/cu mm 5,000-14,000 cetls/cu ma 0-500 cotia/en aa 0-500 cotte/cu am 10-30 ag/a1 120-160 3/1 0.1-1.0 mg/a1 5.5075 gra 3.55.5 oa 10.2-12.5 mg/a1 10-40 International Unitas 20:60 International Units/2 50-200 Intemational Untea1 50-150 Intarnationai Untea/s 00503 116 Appendix Teen Methods Used for Hematology On Blesdings at 3 and Months Parssaters Unies Methods Homtolagy Total Erythrocytes & Leukocytes Hemoglobin Hemtocete Differential cells/cubic mm ssa packed calls +100 wee CCoouulltteerr ECloeucnttreorniMcosdel FN RIenmsotgrluombeinntoamteitoens,LabMoordae1tor2i31e,s NMoidcerlohneamatocrit Centrifuge, Intemational Squipsent Co. Microscope s11de 00504 117 APPENDIX ITEM METHODS USED F12O,R H1E8MAATNODLO2G4YHODNETTHESRMINATIONS FOR METHODS USED F3OR,6C,LIN1I2,CAL18CHANEDMIS24TRYMONDTEHTSERMINATIONS FOR HePmaaratmoeltoeorys ErLyetukhorcoyctyetses HeHmeomagtloocbriint Differential Chemistry Tot8a0l0dBilUirreuabiNni,troGgleuncose AAllbkuanliinn,e TPohtoaslphaPtraosteein AST, ALT, CP Urinalysis Specific Gravity PH,aGnlduAcloKbsueemt,ionn,eGsccBu1l1tiruBbliono,d nits gcc/eedllll]ss((11003/mmm3)) #/100 WBC Methods and Techniques CUllAatynraalAldyoazgmeisrc, 80D0iviHseimoantoloofgy Secton, Dickinson& Co. Microscope slide mg/dl 9I/n1ternational! Units/1 TRroatvoecnhoeln L36ab1o1raataorieIsnc,. ~ TS Meter, A0 Instrument Co. ABnielsilaCbosmtpiaxny 00505 |g APPENDIX 1TEH PATHOLOGY REPORT OF RATS RECEIVING FLUOROCHEMICAL FC-143 IN DIET FOR TWO YEARS 00506 |g BEST COPY Avues : ABLE weraons Gross patholo ALL rats which vere secrificed at the 1 year interim or the 2 year terainal sacrifice or which died or vere sacrificed in extrents during the course of study vere necropsied. At necropsy, an exemination vas made of the externsl body surface and body orifices. The carcass was then opened and the contents of the abdone, thorax and cranium were examined in situ and after removal frm the carcass. Representative tissues and organs from each rat vere fized in 10% buffered neutcl formalin for subsequent histologic processing. At the 1 and 2 yenr sacrifices, wot veights vere obtained on adrenals, brain, testes, heart.- kidneys, liver, spleen and uterus from 15 randonly selected rate/sex/grosp. Body weights were obtained prior to necropsy from the same rata for calevlation of relative organ weights. Histovathology Microscopie examination vas made of hematoxylin and eosin stained parafin tlarse sections of the following tissues and organs, where available, from ll rats fron the control group (0 ppm) and the 300 ppm group which vere sacrificed at 13nd 2 years or which died or were sacrificed in extremis during the coutee of study. aaodrrteanals (2) Lliuvnegr (2(2 sescetcitoinosn)s) brain fr(3ontsaelctcioorntsexinacnldudibnasgal ganglia, parietal cortex aIsymampharynodgelan(dmes(efnetmearliecs)) pancreas ianndd ptohnesi)smus: cerebellum SPaileiaviacrayrygland epveenrds ovaries (2) SSppilneaeln cord/bone marros (vertebrae) Stomach hear Cestes/epididynides (2) small fntescine (3 sections) utrhiynroairdy/bplaadrdaerthyrotd/creascophheaagu/s uterus or prostate dlarrgoe sint(e2stsiencetions) aannyy ottihsesruermoassesesles(isounsspected tusors) Microscopic examination of tissues fron the 10 pp group included all che above listed tissues except sorta, brain, eyes, small and large intestine, Lyaph node an spinal cord/bone marrow. o281CR0012 (FC-143) 00507 120 ress . Gross Pathology fron There vere no gross findings the 390 ppm group which vere suggestive sacrificed of at a compound the | year effect in incerta. any rats At the 2 dyuerairngtectnhienaclourssaecroifficsetudaynd (TnS/Dr0aSt)s,vhpiocshs-idbileedcoormpovuenrde sacrificed inextrenis related lentons included an tncreased tnctdence tncreased tnctdence sf of masses, nodules or raised yellow or pale liver foct or lesions lesions in the and an liver, an {ncressed PtnPctdgernoucpe.ofTmhoetretlevdereivneorsfiannddingtsestsiucgugleasrtivmeassoefsaincommaploeundFatesffefcrtomintheTS/3D000S female xats from the 300 of 20 pra groups or in male rats fron the 30 pp group. this Other gross pathologic findings strain. These fncluded mammary vere typical of Findings in ageing masses, pituitary foci and masses, fats of ulcers on the hind footpads, Organ weights pale livers and pale, picted and enlarged kidneys. There were statistically significant (p 0.05) variscions in absolute and relative weights (orgenthody or organsbrain velght ratios) of a number of aonrgafnnsczo0ss300ntphpegrLoiuvpermbaoldeyrwaetsighstacrriaftiioc,ed thatesethevar1 iayteioornsinwteerrien.not Ecxocespetidnfroerd tortcologieally significant. The increase in liveribody veight ratlo correlated 6h compound related morphologic weight and the Liver:brain veight liver Tatio changes. in these The recs mean also sbalute liver vere increased but not 4 statistically significant variations tn organ vetghts in 300 degree. There vers mn pps females sacrificed statistically at the 1 year significant incerta. rats Noe of the several sacrificed st the 2 stacisescally significant yeas termination occurred orgen weight variations in in target organs of shoved a dose response; none was considered toxicologically significant. Histopathology Compound related microscope changes vere observed in the liver of male Fats sale fron the 300 ppm group and fezale TS/00S rats at at the 1 year incerta sacrifice and boch the 300 and 30 ppm levels. in liver of The principal compound tncrease related tn size Liver change vas segalocyosis. of liver parenchymal cells due which was charactertred to increased eytoplasaie by an volume. The The increased cytoplass coarser cytoplassic us of a finely organelles vere granular "ground glass" appescance. relatively decreased and were displaced ozatcaootz (re-143) - ccosos to the cell membrane. The nucleus:cytoplasm ratio was decreased by the increase in cytoplasm in affected cells. In affected livers. most or all lobules were involved and the centrilobular cells were more severely affected. At the 1 year interin, megalocytosis occurred to a minimal to moderate degree in 12/15 males fron the 300 ppm group. No females were affected at the | year interim. In TS/D0S rats, megalocytosis to a minimal to moderate degree occurred in 40/50 males at the 300 ppm level and to a minimal to mild degree in 8/50 females at the same level. At the 30 ppm level in TS/DOS rats, megalocytosis to a mimimal degree occurred in 6/50 males and in 1/50 females. In more markedly involved livers, the megalocytic hepatocytes were frequently vacuolated with multinle small spherical cytoplasmic vacuoles which in life probably contained lipid. ~ Livers which had appreciable involvement with megalocytosis and cytoplasmic vacuolation also commonly had focal areas of necrosis. This association of hepatocyte vacuolation and necrosis with megalocytosis suggests that the progression of lesions is megalocytosis to fatty degeneration to necrosis. Incidence of hyperplastic nodules was also increased at 300 ppm, indicating regeneration also occurred. The association of hepatocyte vacuolation and focal necrosis with megalocytosis vas more clear-cit at the 1 year interin than in TS/DOS rats because of the normally higher background incidence of the former in older rats. Cystoid degeneration, characterized by areas of multilocular microcysts in the liver parenchyma, also was increased in male TS/DOS rats from the 300 ppm group. Incidence of this lesion was 4/50, 25/50 and 7/50 in the 0, 300 and 30 ppm males, respectively. The increased incidence of cystoid degeneration, megalocytosis and portal mononuclear cell infiltration in the 300 ppm dosage group was statistically significant at the 5% level in male rats. In females fron the 300 ppm level, only the increased incidence of megalocytosis was statistically significant. Occurrence of these histomorphologic changes in the liver correlates with elevation of alkaline phosphatase, aspartate aminotransferase and alanine aminotransferase levels observed in male rats. The markedly reduced incidence and severity of histomorphologic liver changes in females parallels the absence of alterations in liver specific serum biochemical values in females. There was no direct or indirect compound effect in tissues other than liver at the 1 year interim sacrifice. In TS/DOS rats, changes which vere considered secondarily compound related, probably through to FC-143 altered liver metabolism of endogenous steroids, were observed in the adrenals, ovaries and 0261CRO012 (FC-143) -3- 00509 122 testes. In the adrenals, an increased incidence of nodular hyperplasia of the cortex occurred in males at the 300 ppm level. Incidence of this finding {n sales was 2/49, 9/50 and 1/50 in 0, 300 and 30 ppm males, respectively. The increased incidence of nodular hyperplasia in males at the 300 ppm level vas not statistically significant, however. In females, tubular hyperplasia of the ovarian stroma occurred in 0/48, 15/47 and 7/50 rats from the 0, 300 and 30 ppm groups, respectively. This incidence was statistically significant at both the 300 and 30 ppm levels. Tubular hyperplasia of the stroma was a non-neoplastic diffuse increase in tubular elements of the ovarian stroma which vas usually bilateral and associated with absent or markedly reduced follicular development. In male rats, there was a statistically significant, compound related occurrence of benign Leydig cell tumors of the testes at the 300 ppm level. Incidence of Leydig cell tumors was 0/49, 7/50 and 2/50 at the 0, 300 and 30 ppm levels, respectively. Although occurence of 2 Leydig cell tumors at 30 ppm is also suggestive of a compound effect, these neoplasms are not uncommon in untreated rats, although none were found in control rats from this study. The occurence of Leydig cell tumors correlated with the observations of testicular masses at necropsy. Testes uhich contained Leydig cell tumors were usually totally aspernic. Mineralization of vessels within the testes occurred in 0/49, 9/50 and 3/50 rats from the 0, 300 and 30 ppm groups respectively. The increased incidence of testicular vascular mineralization at 300 ppm was statistically significant. In female rats, there vas a statistically significant increased incidence in mammary fibroadenomas at the 300 ppo level. Incidence of this tunor was 10/46, 21/44 and 19/45 at the 0, 300 and 30 ppm levels, respectively. An increased incidence of focal accumulations of foamy alveolar macrophages occurred in the lungs of males from the 300 and 30 ppm groups. The incidence Of this finding vas 10/50, 31/50 and 16/50 at the 0, 300 and 30 ppm levels respecitively. The increased incidence of alveolar macrophages at 300 ppm was statistically significant. In females, the incidence of 14/50, 19/50 and 10/50 at the 0, 300 and 30 ppm levels did not have a statistically significant increase in treated animals. Other microscopic lesions in tissues from FC-143 treated rats were typical of naturally occurring inflammatory, degenerative and neoplastic lesions in an ageing population of Charles River CD rats. Commonly occurring inflammatory lesions included chronic nonsuppurative myocarditis, vith associated myocardial fibrosis, mononuclear inflammatory cell infiltrate into the portal 0281CRO012 (FC-143) 4 3C00055:10 55 triads of the liver vhich was frequently associated with portal bile duct proliferation and perivascular ononuclest inflammatory cell infiltrate and suleifocal chronic interstitial pneunonis in the lung. A high incidence of chronic sialadenitis occurred in male rats fron the 300 and 30 ppm groups sacrificed at termination. The appearance of the salivary glands in these animals vas typical of glands in the recovery stages of dacryostaladenitis, a common, highly contagious disease of laboratory rats. Its pecullar incidence in this study was attributed to the housing arrangement. Both affected groups vere housed in the same roon and the unaffected groups were housed in other rooms. Although the incidence of sialadenitis in male rats from the 300 and 30 pcpommpogurnodupsrewlaatsedstastiinsceticitallwyassiegxnpilfaiicnaanbtl,e tbyhistheinchroeuassiengwaasrrannogtemceonnts.iderOetdher ~ statistically significant variations in incidence of non-neoplastic lesions which were not considered of toxicological significance included decreased chronic myocarditis in females fron the 30 ppm group, increased lung hemorrhage ia males from the 300 ppm group, decreased perivascular mononuclear cell infiltrate in the lung in males from the 300 ppm group and in males and females from the 30 ppa group and decreased splenic hemosiderosis in females from the 300 ppm group and in males and females fron the 30 ppm group. Some of the more comonly occurring degenerative lesions in this study included adrenal cortical vacuolation and sinusoidal ectasia, focal mineralization in large pulsonary artery branches in the lung, focal acinar atrophy in the pancreas and chronic progressive nephropathy. Pituitary adenomas were the most common neoplasm in male and female rats. Overall, the health of the rats in this study vas excellent, vith organs free of lesions of comon infectious diseases vhich would have had an impact upon survival or the validity of the study. us TDoibpelrotmatG.e, GAenile,ticDaVnNC.ollege of Veterinary Pathologists Barefo fic 0281CR0012 (FC-143) -5- 00511 124 BEST COPY AAFLRE3E8C2A%Y TABLE OF CONTENTS Table2TScumrboeMrascrcooscpoipicc TInncciiddeennccee ffoorr NFaelmeasjes= =1 Y1eaYrearInIcnetreiraim.o.vrssoserosinriri.?]Pace 35 MMNaaoccnre-oonssecaooopppiiiacesiIIcnncciiIddneecnniccdeeencffeoarrfMoFraeTmMeaaslletesess:=esr|ossYriesasrrieoIrsnmitsserrsieimmr.sostrsmoisrsirirseiiisiitisdnsiet8ss?l 7 5 NNNooannnooonnneeeoooppplllaaassstttiiiccc TIInnnccciiidddeeennnccceee Neoplastic Incidence for MfffaooolrrresFMFeaa--mm1siae1 elssFeesav+rrse1sIsYsnseriaresrsrioTioemnrer.eseorsioronrmsormormsrirsrrsssssoirisiooi1bntss5otes2sssi0 1T1o 12 NNNeeeoooppplllaaassstttiiiccc IIInnnccciiidddeeennnccceee fffooorrrFMFeaemlmaealsle.esss.=.rr1esYeesasrreirIeonrtseoormsissnr.ss.riooiorosroiierosoiiis23si3s66ii6s3e37s0s AEppeendTiMxiemnbegr le 2 Single TTaabbuullaatteedd AAnniionaall RReepopratr=te1 rYeearrsTonntseerrimouseeeieseseesirssI2er9ar.]gse210 5 Tistue Taventory - 1 Year mnrerim ool II osieI sotos ozs1cR0012 (FG-143) 0512 125 Feet La Your 0a) ap A TonStosbas omer -- Sd 9 2s + 02 Yor Tata towe1r rs dears ARE Scie seas -- Grote pisAin-- ts testom . Ls \ vIer.pid . piers esto es wyr 2 rs ue : : Sae s i: siepwoae : \ sre IaneLrEet : ToteTE s l Ae T [ST coos1z 126 FEE Tn ea ora Taoensrtoemeossrpasese STerpt nbnBRaEsSTGoCsOePuYTArVinL one 2 ree hres GEMAZ Spates oe storf-- wrt vs A sonyny No visible lesions. srHrsses a orsremsn) epnogre anyA i siryt-- sai "GLeincese,incet eyrpreoitso sn 2wi toss + 3Le ; : fa . : : ai : . :; : vs : . onsSwo 1 Rci 3 00 * tetas "tty" esate tars aes 2 000511 127 Fel: To TmeaaicvrreoerslcLoTaneoesrtsneieovsrgato-ennscsceoIptnonr.icwah3ryhesStuyBEinShTasCOPY rae Meer: TZ species: Rt stesrescristion Grow1 Grow 5 trou6p iYo nviasistearTeessts .I : be omcttprcroner jd \Lo Pitctuarvantaregreaiad rernermmaterred fYsfson [OsoEm rete rTraorenenelnCatrigrmeaadr"nncae 2 1 1 1 Toshate fives ' ung -eNnelrarmggedt"a/ormhagic Teston 1 2i \ wftriattesrach nut \i ordcoRnneisnorslaietdiaetmidioenTs"estToentons : 1 : accion : roseienyla(rsgnetda"rst) : 1 aP Saan,sinsoeotI ny of food p-- ia i semai[nengrtencstaned . : : \ LsaorgneereoInTsnartiireoeasntssei/t,nueelrceedrdaetnieodnspeers patches \ 1 2 peinaornses, resseed peers patches :: RYRTAoHLte:PL3 E . Tes: GGGrroruopom1 FrCOoNATdRSsOL 0300pp5mmm * includes "possivly" [PR 000515 128 F113: To YMuarcroosncoEpoiTconIenrcidencoe afomrr Mcalaes!BSEsStTinUaOtPs Y Ai 3LE Sb taTyore3 Sra. weer: SESE Spe: tot rseee[ n -- ps wns Guns sorota }. ni paloe/pdaSle loT vese"ss,vm 105 : 3J1 E 3 senorensns corgeton Po ,- L oeetsn }[ET i J po p :\ Leenrpseeobnteiryn ceatemr eron re a: wrpiveedenslarea aiaens wise \ FR : } wnhLarrkersi,gaonme,dites soi : pninee Sars :: 4 : 3 ienwglrepsms, tee aiatation T}: os : wpi a ee Hag ih SHAT SH oe: Tatpr ticetah ns . os rsosinon Pod . omawreions Le . foTToopns1 oBan Bpgomn mine we -- , Warssphe Sttern ign & coos1s 129 Foie Tn ve Macroscopeese w ty 0 ic Incidence for MaleBs EST CO one reser: sc spt: -gin srciop n ms bons ips Gos Precio ehinflamed area" 1: 2: itpTPoeye : :Po soe umwe cour . RS ee . . ---- Co nsF sEol R e. e -- Wee tee ees 5 coocry 130 wg ee ee BESTCOPY fg Ter Lysordaries, Tn. 1 14 - FC-162: Tuo Year Ora) Toxicity-Oncogenicity Study in Rats brogees Naver: GEIRKIE Sectes: hat sirsesrtpston Grant Grows Grp6 Be[r-- srrassryvos/entararestied Taston Karenrrmariars Toston aaenstigreeaatied Toston ws oh jToiorettaacion Lyjonts (srancntal) entorses : 2 n=FI ss ! : : F:E 1i i : SotSoeorhnsel.saCsriygDgepdua"rtrasee)sfitrieosn sree StomiTneetermattotioantssearrsesstpornsadesnd so ITntoetnets erasion/icersied oupesening 1 :: :1 : : Ler ssioane pCraiiatrstecs"i/etnaordultee/srtaotns/emdtelesfioont . Sure Testonyettomish Teston enlarged" : : C : 03 Le 2 1 2 Ties: : GGGrreouenpyt51 rFCOeNaTaRnsOL B33 opppm * includes "possibly" Wacrssenp Tntence Pager 6 00513 131 oe tase te resBEST COPY AVAILABLE EE :, enlarged" pare" 1 1 i swollen foot. Grou1p CONTROL 0ppa : 1 *includes "possivly" 132 00519 - F434 Te Ye 1 Tproopseenee Sl 3 Non-Neoplastic Incidence for Males rset mers GAZ pte: Or Ye eriAn . Tissuve/ owe Adrenne aaltpeimptm tviste care -SaLooksta, cote oSpdan seott ets ots wcoimA pirn -- o pPElE--y ---- wreedrst vs WapripStln, crate saris --fiThsmsn m its rnoowrneste eniy woDeeierpes 2 est, see it tn 3a 09.vn Group 1 Group S TraFREsPp:FP oole15) hPP o oaogb dPho oIhE ddF Phh oEwddbb dEhFFIIE db wo:5ah FPP i oE o d aP yo halh3 PTo oaon PPpTI oooo 0 +e coms ern tr ee 3 cooszo '33 on-HecplRaiskteirc LaIvnacriadteonrcseesf,orIMnae.les 3(continued) py Prasest thasFoCr-s32Q:2TUuCo KYeZar OSrpaalcTeosx:icRaity-Oncogenicity Study in Rats = Ona Year Inte TasYtean,AAS"48) TissaSnisssnestss edition e wapn1 Grom KidnePyyei(sceoinss,iauseess)s .1 1 aaitnat :1 :| LargeinItntsesniionmest 1iaits (5 nim Liverenatudicsss (m3n om1 . iHenpaitecsyosratlteTrianttison, azsolased 27 3a aaiintiant 13 '3 [TSnatan 5 21 Hegstogaynzeosis 53 jt1 ninteian 7> incronisirste 33 z3 sniitnes) o8 :: pigasass,taKiunpfer cell :> 1: ForcalaiSiidte dacs proliferation 35 :1 aiEnninal :1 31 Porsalipnonroanuclear cell infiltrate ;1 x Lung nite (s3m om> uAsiivneisntarnosrazaropihsigtes: 31 25 Mesteacsiasdis :: 5. Hesarraaaigee :i 35 owoidleerste $ 1: Hyperpilaasia, septal eal 31 .o TGirtoleusp: 1 CONTROL 2 gon - Grove 3 FC-153 302 pm 00+ Tota) Examines Wierascopic Tneiancs page: 0 134 00521 . . - JoneHesptastic nctdence for aes (contiSvEihAeTs WMame OE Aner,an iE Project tmaFsCro:143G:EETICoROYIeZar OSrpsa)ctTeosu:RtiekReayrtsLacboorgaetonrties1y, SInec.u 3144 Ras - ne Your IntarTicoe:5 TissieSrhamosis/ Todtrier Nwoowto1 oGruwp l5 [rert-- wsesta snanacler infilirase - : ) Prestpaai,eainsrssizia, ehvanic 5: :: : 3 Wasaoaairemoinreratizacion ::; ::: . eon tateIi(mesemseric) wtents rorat Traits (33 oh; 3 pi praseSiiirei :5 :i amar GiSanite E5 E]: Messrmaenri moras 11ates (3 naw3 etrotssa,refeas i1 |> Stecttrie echronic |i 33 p--ini ros Tatts Gih oim Kirasieire :3 :: PascreMantieasriaaz,e ehesnic 5i : : 3 fa rnin sara iaiss (7 nom5 Pat[iranpp-- G3o o1m ProCstpyastrtei -- brastaitnitieo,n chante SottiairayinGrennodre itis salMitIanitnesmtainra ists nii omi2 .3 3T a1n ia [iI i TGireoesn: 1 coo, 3 pp Gra FOr: 30pm 0 + Tort Examines J ---- 00522 135 Non-NeaplRaiskteirc LiIvnocriadteonrcteesf,or IMnac.les 34(continued) FC-143: Tuo Year Oral Toxicity-Oncogentcity Study in Rats = One Year InteriTnavte: 5 Project Number: O2SICRO0IZ Species: Rat TissuDeisagnosis/ Hod tier cGrroew me1 eGreowns5 SpinWaithCionrgnorma] Mafts C1 1 C1155) SpleeWnithin normal Mats C1155) (115) Henosfadielrdosis oo 11 Stomach Within norma iaits C11 C1155) - TestWiist/hEipnignioarmmias linits (11s5) (11s) Tubulemaartkreodphy, spermatogenesis 2o 22 ThyrWoittehin norma iaits c1m (1 1 Trachea 15) (15) UrinWairtyhiBnladndoerrma limits (1155) (1 15 Within normal 1aits 15 13 TiGtrtoiueps: 1 CONTROL 0 pp : Group 5 FC-163 300 ppm 0) = Tota Examined Wicroscopte Incidence Page: 11 600523 136 NonF-ileeprtaLsatviocratIonrctteast,nceIncfeor Fonetes FCr163: Teo Yur Gra)Tote onopenie3 Sy In ats = Gn Year Inerin broject Naber: GERICROIZ Species: hat HsuShasnosts/ ier iwows1 SGra0s 25 AdrenCIaolrIian eepene-- ration W1os:) i1(15) Simsarhhanees scasta, orten :: 35 3 3 rorta pi Sieh noes) 1inies G: ao2 i3 - SoniHtarmroerors 1iates ais a1m sna itnin normal Tints G3 sm1 Esoipunsi norma Tintts G3s o5m te within norma imics Kiros aWn aBmn | : Funcppatenrakaeitsts i: :: heart rs esti nora 1imics si oe: 21 Nostaraeitnriga,n chrome ramssprative i1 o| xianey we (9o om3 Wpientinhseort t1aies ` S: i i Chronimcodperroagtreessive nephropathy i3 o3 ant he 3i 03 [oate a i3 0: roeveadte o3 o: Hyperplatseia, pelvic epttnelivn Minera zation o1: o!o ite : 3 GGrroowusp 51 FC-O1N3T30R0p0OmoLm 0 =Tota Exemined Wiroscopic Tctdence Page: 12 coosz2a 137 F165 Tuo YeuNoGnr-MaopTtoaMusateesiicro-Lnniesctoodrepanetcnoettlefso,r FSferhemeaulesIn(Rcaotnsti-nueOde) Yer Inkrie Project Number: GEBICROIZ Species: Rat Tate6: Tissues Gow 1 Grom 5 otter Xierav(iconmtnienruaetzstion . \ fhriet |s '1 Frepnnhe,oehsrontc o5 3} LarNgetetiInnntstrtootnasn atts Gio} Gio} . werrVeennitnurreorasitiematiieosn, violated T :: Tfo Neps"oehrtee vicstacion |: io Shirei :3 | Porathpare duet proiferation :: :i Poratnimneairoomnetaar cel nfilirate :|i ::: wnssRteecnitnorsomrraopmTiaegietss GeB| om:: Wesrehmsee u} i; weete 5: ;: PPenretmvoanshieaae,tarinseorvsotmicslieaa,r cfhirlotnircate 1ii ooo Vacatenener tation 1i o: Lyon Nodeh(emesenteric) Ga| om| Yeamnrrnrargoema Tits i3 Ai [--Wi--nnw--amnoeadr init GiH5 om| Concronere ? 1 . TGerosws: 1CONTRpOnL Grow 3 Feu143 300 vm 0 = Tota amined Wierosopic Tntdence pag: 13 cooszs 138 Forts: To YearloOnrsaelsTtosiusttteoihcry-LIOinnvccoierapaeetnaocnretrefsso,yr FSItneucm.diyesodnn(Rcaotnstin-uends) Year Inserts Project Naor: GESICKO12 Spectes: Rat Tone2s TissStanesis/ Taito teses2tors,ieron - Sencisintsorveanic oursFrente sare tictss Pacoeast rPanrrasticre, tranic rarsiyrotei ptrintrinn nora sora ates 111s SatriinnGa1ro 1inics sinavenin sar 1iaics solstIanntesstianr tinics SyodhteEnoresar 1inics scFitna roast tiatzs Nemrduraneits ssemieanin arms Vites Thyr[oid Hp ---- Tracihens i ora miss urteCrheats Sstiaornise Inflatdieonr,echante B ow 1 t sw HE no ii :: Gia: oie: Gai om. i| i5 Ei E): Gi: aopo; Gia oim I : ): Gih oim GIho cim GIHn oim || :: Gi eoi Lani d3n Gia oim da. ohi :3 i: :: :: BESTCOPPYYA AVAAILIALBA]BLE . TGireowss: 1 coat. on - Crom 3 Feri we 0 = Totat Examined Wiersscope Incidence 73g: 14 ccosze 139 C11 Te TerrreeuTsoeweeermImetepnateretosr Femtes St fenton ats Oe eb Iain rast Nr: SHE Speen fat Toes sony [I Wr --_i -- on t3e7 oum| orihe omnpstate, siste 3'J :;: wyGj one ow-- n m5: oh3 . tpaJoo n core .:: :;} rso resee e sion :3: ;}: wenaprtya srs :;: '.; on Yorn - Group FC-143 300 ppm 1 Tout Gennes Weroeste Inctence page: 15 ceoszy 140 NoRni-xteeroplLaasbtoircatoIrniceisd,encIenc.for Males FC-142: Tuo Year Oral Toxicity-Oncogenteity Study in Rats, Project umber: 020ICR0IZ Species: Rat Taste: 7 Tissues DiagnoHsoids/iier Gop 1 Grp 5 Gra 6 r0rsoeresncs owms enscs e0e0aseeneSeKnCs ArenWai)thin norma limits Cies u0m30 C6o)z eonz (105) (315s) Corticaalodedresgteen.cration oo o3 00 oooo 2 22 Cortical vacuolation 7 uz ou es amiinlimal 02 12 30 som 1s 3s mmoadrskreadte 3oe 0oz 00 :02 01 00 Medullanriyniecaelll hyperplasia : 63 01 62 03 30 nile 141 oa 53 Hodulereodheyrpaetreplasia, cortex o122 01 33 00 31 aininal oo 1 0 0 9 amoidderate 55 11 00 711 03 01 Sinusotds! stasis, cortex : i070 ows soe mniilneal o2 z3 900 om2 0a 1os ooderate zz 0 3 1 2 nora earked (E5 30oc C0em1 (0oo0 Hithin norma Timits Box 5 a 0 0 Mineranliilzeation 1108 932 00 2a 00 tecrosmiosderate 1198 63 00 02 00 sone Arritis, synovitis; Joints ta ta2 ca0 cn1 c0on1 moderate 3 0 1 92 1 Bone Haramnarked (10503)2 (3820 (N9 l 00 BrainWithin norma] Mats C158302) (0as @ (0on0 AWoistcnefsnsnormal Mats 1 o0m 0os @oo 90 00 aid 10 0 0 0 0 Hemorrhmaodgeerate 11 00 00 00 00 0 . TrGreoeusp: 1 CONTROL 9 pp. GGrroouupp 5 FFCC--114433 33000ppppm 0) = Total Examined D$0A5C=e UPrnostcohceodluleSdchDeedautlhe(ds)Sacrifice(s) 141 Microscopic Incidence Page: 16 CLOET8 Hon-NeoplRaiskteircLaIbnocriadteonrcieesf,orIancl.es (continued) FC-183: Tuo Year Oral Toxicity-Oncogenteity Stuy in Rats Project Nucoer: 0231CRO12 Species: Rat Table: 7 Tissues DiagnoNsoidsi/fier Gop 1 Grow 5 Grow sDersererrsecrs e0e0eserrsemcs Deorsmaereseiece EsophWaigtuhsin norma limits G5HWumCsoc oa (n3o2 ere Hithin norma 1Haits C2RWow C4awoa (a1 0 9 CKoetraartaicttis, acute oo o0 91 00 13 02 nares Keratitis, chronic oo2 01 01 09 91 y wild oo 0 0 1 Phthatsmodbeurlbatte o 02 09 11 900 00 Retinamlarakterdophy oe 01 09 11 00 01 amairdked 55 01 02 01 00 03 HeartWithin norma) Vinfts C168) (3m0 6(6) (32) (196 0(316) Endocardiis, chronic oo 0 2 9 1 Myocarrdairakledfibrosis 3oozo0 01 01s1 Myacaaridiltsis, chronic nonsuppurative sizw 00 ow1 1sosm peaend) 72 00 15s 0tow1 Kidney moderate C1o6O (3)1 (69 (40) (101) (3:00) Within normal limits <0 1 2 3 2 Cacutumsnie) oo 11 01 90 00 10 nile 0 10 0 Chroniactnpirnoaglressive nephropathy. w1 okoe 31 ow9 92 om2 afte 5 16 0 zm 3 2 moderate 2m 1s 2 7 ost marked 213 3 01 1oz 12 13 moderate 51 01 10 Hydronenpahkroesdis 112oz 00 01 00 00 ate 10 0 1 0 0 moderate oz o o 0 0 Titles: - GGrroouupp 15 CFCO-N1T8R3OL3000ppppm Group 6 FC-143 30 pp 0()05== TUontsaclhedEuxleemdinDedeaths) SACe Protocol Scheduled Sacrificals) 142 Wicroscoptc Incidence Page: 17 000529 Non-NeoplRaiskteirc Latvnocriacteonrcieesf,orIKnec.les34(continuee) Progect ser: 0221F0C0-11243: STpeeocieYse:arRaOtral Toxdeity-Oncogenicity Study in Rats Tobie: 7 TissuDei/agnosts/ Hosier naGraaeppeneze1, nGenraoewpaser5n sGemrgoewneeien Tos me bs se 00s ac XidneWype(rcsolnatsiinsu.ed)pelvic epfenelivn 50 03 0a naoidterate oooo 00 o1z 00 90 Hineras1izeation oo0 00 11 0ooo3 napnrossotdserate 1100 o0o 00 00 oooo . Papiilsaoreyranetcsrasts PIosoooo 00 00 oooo pelvicamiinniearnalization Los1 o0a a1 06s1 caoeerate o1o2 00 2o 3oza protesnarrteessorption droplets c o0 00 00 11 90 pretiaetist,eacute 0 00 00 90 11 20 Pyetonipt)ritis, acute 1ec 00 00 o3 01 2oo aaedienerate 109 0ov 2o1 00 00 Vacustastiinoni,)conv. tub. epithet 00 00 o0o 11 00 LargewitIhnitnestnionree Maits CW10o3m0 Coeamow (D1C0 LiverNosatocasts C1o0s30 Cootoe (1000360 WCiytshtionidnodromgaelner1aitaiiotns o2 04 01 ow0 12 sos aainiidma o0 21 91 om2 02 Nesatmaopdofeersast,e extramedullary 5o 01 00 33 10 0a Hepatocyate alteration, basopnilic co2 00 o5os 0101 aaintia oo o1 05 21 02 01 Hepatomcoydteeraatleteration, vacuolated 1s1 o0 om3 01m9 maoidearate o1z7 00 8oz 01s1 TGitrroews: 1 CONTROL 0 pe GGrrooww 65 FFCC--11643 2300pppmm 00)05+= TUontsac)hedEuxlaemdineDdeata(s) Sica protocol Seheanied Sacrificels) 143 WicroBgeaaOt LEce page: 13 Nan-teoplRaiskteire.LaIpnocriadteonrcieesf,orIMnac.les (continue) Project Number: O1CRFO0OILZ:STpeucoieTse:arRaOtra)Tastes Oncogenic Study fn fats Tote: 7 TissuDeisagnosis os er sGtaoswmasto1n sGesrgoiwbesrs5e nGarrgorworsses ws se os se 00s LiverHep(aetmotciyntaeedv)acuslation 5 wz ow os 2 aaineiaat seo n1 o11oe 92 1oa amorsieersate :zo0 5110 39 oao Wypersotoaestraa.texuptfer cell oe 00 90 09 00 11 HeWgypaelrostcaysttiscs mate seo ooz0 om3 0os0 anmda 30 0oz oomw 29 4 . Noronuoelreaartceell fafil tration oooo 00 +0 00 01 ecrostasit z 0z0 23 02 31 aeiiinde) T o0ro0 1 0 21 Pores!Soiclerestdeuct proliferation saor 1 ou1s1 ow aJinda osao 91 ow1 0sow portalmosdoenraantueclenr cell fnffitrate 1To0x 5soa2 01 ow0s aantiea aTn2 0soa2 01 x Lungwitain norms Tims 19e0o 301 C0502 (11 932 Alveolaarintmacrophages s 12s:0 o20 s0 owoo mdaeilreate o 21 o3zs 06 82 Aestectmaasrtcsos as 00 910 90 o1 oo com maerate o3os 03 9zo1 aa amoidgerate 11ss 00 99 00 o0o Fibrosiasrtes 1T0oo0 01 o0 oo0 Siocaerate 102 90 01 00 0 TGireousp: 1 COUMIOL 2 ppm GGrroouvpe 58 FFCC--114433 330 p3mpm 000)S:= TUontsaclhedEuxlaemdinbeedstn(s) SKC Protacon ScheduledSacr ice(s) 144 Wierosconte Incidence Page: 19 G00531 KontesKaisacriLunseotraaetnocrieesf,orTatens ORSTOANY AVAR ARIE broecs Humars GRIFCorEte: SpTeecsieYs:eofaOrsalTostp-Bicogetcisy sty in foes re Hasse wom 1 ma 5 was other ww me wm fprWaoir--onn:-- o Lodo -- rnTiooewresrs Pc [EEooahhos : dharpeareriah, aries Sobona : . fo"rat torolos Dl2s sPerritburshogtnaaabiaa nyonrenmpeirngfilasattse FSfI oeuos ; o7oa waiei! P PaR esLo:o3ud roormooictaierrssmttaaerit, ate 5S3 3o0us0o1fa oa1t.d PremaTnhtse imarstiziat, aranic PTuooao10 h1dd TVoavmaiSdaaorersismtaerattzision op Pnhtl oossssoa8s iarein BSoEao4oeoa8 ao8a LonvitonsTonrvoerrseatnetioriy3s (BmSomNm aeEh CRaRn Cwrrametnoontrste SSPSLosSenh 85 pmrie PPeros00 o5 e Stmsoaraita ectasta sA oo ods vamaWryiGnlanmdam atts Chcemecencdn endey vesSnotsearryteriiteiss CogHcrheEecadiyn (npaedh - Troawes 1 CoOpLm GGrroos F1162 0o0p7m 005.- TUnostcndaimiicenerdent) Sen bree semanes cricaty 145 Wiroscopte. Inctdaize pass: 20 00532 Non-NeaplRaiskteircLaIbnocriadteonrcieesf,orIMnac.les (continued) FE-143: Two Year Oral Toxicity-Oncogencity Study fn Rats Project Number: G2BICRO0IZ Species: Rat Table: 7 Tissues DiagnoHsoidsi)tier PancrWeiatshin norma limits Aeinar atrophy aaifndieal moderate ried Hyperpaliasdia, acinar cell eoderate Hyperpaliaseia, islet cell moderate Polyarmtierntitiss meaordkeerdate Parathyroid PituiWtiatrhyin normal Vinits Within normal limits cyst Hyperplaaislia prostWaitthein normal tints Een Prostamtoidteirsa,teacute nmiinliemal mmoadrekreadte Salivary Gang WSittahliandenniortmiasl, aVicauittes mmoadrekreadte Stalagemniintiiss], chronic amiodlerate Gop 1 Grow 5 Grow 6 e0e0osmnaseecn eDoos nssc eDmoseneseace (Bmoa 6os a2 (1w2v03 oa 2 oom 1s oooz 09 61 01 1 11 2 oo 2 1 oo 01 912 30 02 66 00 51 13 00 11 5oz0 01 33 11 11 oz 1 3 5 2 5eo4 00 02 00 31 oz2 00 o2 20 02 Coe CR (Nz C1s 906 3 sC9 cxe (137) (30 73 om 3 ow zz oz 0oooz 10 2 oz oo 0 1 (wEo w sC8 Ca (u13x3 10 0 oo 0 0 130s 0130 20 91 oooz 00 91 10 a0 1 13110 11 10 o0o Cry Cs ca (10 (3 o uooox1 00 a1 00 0 01 o0 01 6o 11 00 1o 00 o0m o o0 o0o 07 00 1 TGitrroeusp: 1 CONTROL 0 pp GGrroouupp FFCC--114633 33000pppp.m D()0== TUontsaclhedEuxlaemdinDedeaths) SACe Protocol Scheduled Sacrifice(s) 146 Microscopic Incidence Page: 21 600533 Mon-tieopRliaksteirc LaIbnocriadteonrcieesf,orIancl.es3(continued) FC-143: Two Year Oral Toxfetty-Oncopenteity Study fn Rats. Project Number: G2310R0012 Species: Rat Table: 7 TissDuieasgnosis) Modifier eGnoper1 eGrmoupma5 eGemreoewneeen6s os sc 00s sc Dos sa SalivSatraylagGelnaintdis(,cocnhtrionnuiedc) sin marked 0 Cacn 97 coca os nea APoosdcaedsesrsatitis, ulcerative 30s9 00 01 21 20 marked 30s 0 1 2 2 - cer marked 1100 00 22 01 91 Saal)WitIhnitnestnionrema Timizs CBlow Cosamow (1no0 Polyartmoedreirtaitse 2 0 32 0 0 o 1 0 2 0 Spina) Cormdarted C1s5o 32)1 (08a2 0 (0 a spreWithin normal Viafts B (16) (30 5s 2 (6) (8) 00 (10 (3) WAtirtohpihnynorma Hiaits so w9 11 ox0 8oo3 Fibrosmiosderate o 1 10 99 20 90 Weaatompoodleersaits,e extramedullary, fncressed 3 01 13 10 a1 o0 sionderate 20 01 00 o 10 00 Hens dmearraksetds s1u0 03 wa oe1 00 Necrosaisi. e 5s om1 30 w0 f0 0oo eoterate Polyarterieis 1 0 92 o 0o 00 01 Stoasch moderate C1o6 (o3 (09 oo 01 (10) (3) Within normal sits eens n3 o0ms0 o0e on0 o0 moidrekreadte 20 00 00 19 0 0 0 0 Gastritiisd, acute 5oo2 11 09 00 93 eermarked 10 0 0 3 0 10 oo 3 0 - TGortoeusp: 1 CONTROL 0 pp GGrroouupp 65 FFC--1143330300ppp.p 0) = Total Examined 0$0A5C=e UPrnostcohceodluleSdchDeedautlhe(ds)Sacrifice(s) 147 Microscopic Incidence Page: 22 00534 Non-NeoplRaiskteirc LaIsnocriadteonrcfeesf.or IMnac.les 3(continued) FE-163: Tuo Year Oral Toxictty-Oncogentetty Study in Rats Project Wusber: SZICRIIZ Species: Rat Tae: 7 TissuDelagnosts/ Hodifter TestiWsitehpiindindoyrmmails 19mis GLeryaoniugloncaei,l shpyepresratpilcasia nooidleerate Minernaililzaation Polyartneirliasis mmaordekreadte Tuitaeiadtrophy, aspirmatogenests maoadrekreadte Vascalaprinmineralization Thymus moderate Hesarrnhaargieed ThyrWoiitdhin normal nits Cystnicotleloid Follicumloadrerahtyeperstasta, cystic Hypernpalraskiead, C cell noidetrate Trach1etaioobranchial cyst UrinWairtyhiBnladnodremral 1inits WCailtchuilnusnoncal fates Cystitmiosd,eraactuete Cystiewtisn,iecarlontc mGrroepereee1s mGmreeoewmenn5s eGaromw es6 os sc os SC 005 SC CBO o(3wCsoeom (170 (o3n o ooo5 so 1 10 11 9 05 20 21 01 o1o 11 00 22 00 0 . 11os 00 20 o1o s2 5oo 31 00 a2 a1 21 sToe101 1ow 3ss0 1 12 11 0s 3 11aa 2os0 0es7 33 0 Cusnoeo (n0 en2 Cu0 ca0 o o0 0 11 90 09 (n2o(3 s (9o(m@ (1on2o (3) oo 11 11 13 00 1 oo 11 00 11 10 01 2 01 09 21 11 s1 oi 01 00 01 21 23 (19I) E(3E8) (8) (aER(13R) (]3) (BROxW C6OEoe (110 (3ox) oR3 0os ow0 o1 un0 1100 00 00 00 00 00 00 00 11 00 . TiGtrloeusp: 1 CONTROL 9 po GGrroouupp 65 FFCC--111432 33030pppomm 000)5+= UTontsac)heEdxualmeidneDdeath(s) SACs Protocol Scheduled Sacrifices) 148 Microscopic Incidence Page: 23 G00535 Non-tieopRaiskteirc LaIdnocriadteonrcteesf,or Iancl.es M(continued) *FE-163: Tuo Year Oral Toxteity-Oncogenteity Stay in Rats Project limber: 023ICRIIZ Species: Rat Tate: 7 TissDuieasgnosts/ Hodiier [Gobpua1 Grow 5 Grow 5 os sc 00s Ss 00s Sac UrinaErpyftnBallaidadnerhy(pceornptliansuiead,) papillary nil Epitnelianlnahy)perplasia, siople aild Hemorrhaangiemal marked 02 99 o2c 10 10 5: 15 51 31 30 3 21 12 19 100 00 11 00 00 ' 10 02 00 Ties: GGrroouupp 15FCC-O16N3T3R00pOppLmpa Group FC.143 30 ppm 0) = Tots! Examined DSA0C=e UPrnostcohceodlulSecdheDedautlhe(ds)Sacrificels) 149 Microscopic Incdsnce Page: 2 00536 = Mon-RHikeearplaLsatbiocratIonrciiedse,nceIncf.or Fels FC-143: Tao Year Ora] Toxieity-Oncogenteity Study in fats Tove: 8 Project Wunder: Q2SICRIZ Species: Rat TssDei/agnasis/ Host er AcronNni)thin normal nits Corticraoldeartartaephy Corticaalfl doganeration nmaordeeeraate Corticaaligvacustation Henatoproofdeesrtsst,e oxtramullary anoidelrate Henos{dfeorrskiesd. aig Hedanlary cell nyperatasta miodderate Necrosis msaordceerdate todutamrodheyrpaetreplasia, cortex Stnusofidna)aelctasia, cortex amfodderate marked RortaWithin normal iaits Mineraa)izlation SoneWHiatrhirnownormal nits BrainWithin normal mits EsophWaigtuhsin norma mses tGrrouep es1 eGroeup e5 eGercoiweein Ds sic 00s sac bos SK m2 m0 (amzm (28s)o (20 2 02 11 o2z 09 20 2s 1 0 a a rososo aa3122 oz 1 0 0 9 23:1 11 3oz a1a 12100 01 31 01 3100 90 a2 , 90 21 oo 0 o' 1 0 o2 o0 09 50 11 0 12oz 21 00 00 22 35s 00 01 00 o3 oo0 12 00 90 00 00 00 5 30 00 11 11 22 BSon10os 511ou 92 54 96 7 3 s5s s0s 34m1 15 m tvaorwa (peoaw maeoa 22 02 090 00 00 00 (a2335 (aasno(ot 0 (nmosw (aadow 0aL 0 Cs oa Csaoss (2om3 (2oz) TiGtrloeusp: 1 CONTROL 3 ppm Group FC-133 300 pon Group 6 FC-103 30 pp D0)0s~= TUontsaclhedEuxlaendtnDeseaths) SAC Protocol ScheduledSacrifice(s) 150 Microscopic Incidence Page: 25 G00537 BESTCOPYMARABLE cnais sRerBmvrou Group FC-193 20 ppm SAC Protocol ScheduledSacrifice(s) 151 Microscopic Incidence Page: 26 00538 > NoncheoplaRsitkiecr LIinbcoirdaetnacrefefso,r Females (continued) Inc. 30 FC-143: Tuo Year Oral Toxtetty-Oneagenicity Study fn Rats, Project Number: 92310R0I2 Spacis: Rat Tavie: 3 TissuDeisagnosts/ Modifier Group 1 Grp 5 Gra mwesmmensecne e0mseiesncs e0e0mseenesekne Kianey (continued) Pelvicnmairnkeerds ization e112 Pigassta,iniceoanlv. tub. epithelivn 5 o5 20 11 a0 2 Polyarmsoedreirtaitse 2 00 20 04 00 21 wininel Protein resorption droplets oooo 01 o0 o1o 11 nile narted o o0 13 0oo 21 01 Petitnsi,l acute 25 00 21 032 22 00 Pyelonmzopdaerriaitse, acute 519 01 00 00 o0o vacuolmaotdieorna,teconv. tub. epfthetun 1100 00 90 00 99 Large Intemsotdienreate Cot A(EmE im oy Within noma Nematodiasis linfts 2112 wv6 22 90 00 Liver Within norma Viaits (s1c0e (aoe (en (279 (27 Atrophmyoderate o5 o8 02 23 11 32 : cystoidandiemgaelneration oo0 02 1 1 13 20 aie Hesatopotests, extramedullary 35 00 01 20 15 23 aniindinal 3oo0 60 00 23 11 Hepatomcoydteeraatleteration, basophilic 1 0 10 02 05 0a ominna] 0os 9 0 1 1 sa 0 3 Hepatocmyotdeeraatleteration, eosinophilic 122 92 990 9ao0 ila moderate 132 09 oao 00 09 Hepatomciyntiemaallteration, vacuolated 2ooom 21 1s 3 01 nile zu 1 + 0 a iGtrioeusp: 1 COITROL ppm . GGrroouupp 55 FFC--1163320300pppmp 000)5+= TUontsac)hedEuxlaemdineDdeath(s) SACs Protocol Scheduled Sacrifice(s) 152 Nicroscoptc Incidence Page: 27 00539 BEST COPY AVAILABLE sorseomusec mmctaemce rr remit ccominue 163 Ts ear 6 Toerpcapnttcy Sse In acs reset wr: SIE Species: at Te: 5 tosses wr 1 Gow 5 Gon odtsier ww ww a nere(rceonstiantterstion, cotates Wastwweiieencastles EEbThowiA nhiros ReorgeiToeniecs es sSdoooesloe11roo375dde . HEiwiecnei, cress sSPooopoo eov 16onso do Rosreohenrs1 nftration sCLoooooos1sso oodooos eerstwweiaett PsPoa1o2n8dsos so16 oo ganftro,eratpeter cen iSLoso0o10so 26a o2t yhhpee p---- sP s oosoipw e s saods oresSemorrrostnecior cl afierce I sTehoooeos ao aRatiosiars sTeoosoooodowhoofsooe:d . wsTeumiweiceuns C1LEooEoomeoomoooo0csmog [ iRsaciensr art -- vite 2 $Tss5 ossSw2a% RgY isienrnce PTsooredo0 hhogoa ed Neteihies SSeooo 00o 11 s . oGGrrropo 5$17c271o3Bmpmoomn 2S005E-= TUpoetramlascEnxesSsienvessersesd)cits) 153 Weroscntc ncasns se: 2: 00540 Non-NeoplaRsitkiecr LIanbcoirdaetnocretefso,r FIenca.sles3(continued) FC-143: Tuo Year Oral Toxfctty-Oncogenteity Study in Rats. Project lumser: 2281080012 Spectes: Rat Taste: 3 Tissues DiagnoNsoidsiier rGeopnee1 eGroew e5 eGeareaeneens 20s sc 00s SC 00s Sac Lung (continued) . edemanite oo o0 00 a0 11 09 Granvaioinsg 2 0i 01 co oz 9 1 Hemorrhmaagretes 96 05s 50 ow1 09 0oe amiingimal oo 0 0 0 1 a 3s 5 5 0 - moderate marked 5 o1r 1 o0a a1 21 Hyperplialseia, septa cell o 90 00 o0 0oo 11 perivasicnunlaar mononuclear infiltrate a9 59 a2 1 3 s+ 5 0 apiodderste o 71 20 o5 0o 02 pigaanmtoderate o 11 00 o 00 00 Preusanta, acute exudative ane 10 2 50 00 10 10 Preumomnotdae,ratfeo.reign body 10 0 0 0 0 00 10 Preusomnaira,kedinterstitial, chronic [OE 0E0E0 1 0 amiineimal 0 11 00 +03 1 5 0 3 marked Vascular aineralization ooows1 oowo ao 80 maifnidmal ooow o5s Wo on71 a soderate oo 0 1 0 0 LymphHyptieordpelasta, reactive (Ootoa Co0 ta0 n1en1 soderste. oo 0 0 1 1 LymphWitNhoidne n(omremsaelnt1eHriaci)ts (oBze (w2o)u Caolo HeGaroarnvrihoamgae 2oo1 00 21 09 00 nila 10 0 0 0 mmoadrekreadte o1o0 0oo 11 02 00 TGirtoleusp: 1 CONTROL 0 pp GGrroouupp 55 FFCC--114333 33090pppon 0) = Total Examined S0A0C5s PUrnostcohceodluleSdchDeedautlhe(ds)Sacrifice(s) 154 Wicroscoptc Incidence Page: 20 G00541 Mon-NeaplaRsitkiecr LIanbcoirdaetnocredefso,r FIenen.sles (continued) FC-143: Tuo Year Oral Toxiefty-Oncogentcity Study in Rats Project Nusber: G281CRO0IZ Species: Rat Taste: 8 TissDuieasgnosis/ Modifier eGonp n1 l GroupL5 C GroupL6 00s SAC 005 SC 005 SAC Lyoph Node (csenteric) (continued) . Piguen`tm,inbnrsotw 5 00 00 51s 00 00 afte soderste 5 00 o0o 22 23 00 Strusomioddaelraetcetasta 1100 00 o1z 00 90 Mamary Glmaanreked tcaot (m0 ca1 (29 (a0) . Within norsa) Fibrosis Miaits as oo 7 01 a 0 Ganactnoicleale 5s o0 02 11 70 02 Lobulamrodheyrpaetreplasia 3 1922 01 20 9 ovaryWithin norma Viefts (av) v(2) (1o8m) (2ow) (2z)o(u20) Tousntular hyperplasia . o3e 30 07 8os 022 77 maondeerate o ooo5 25 00 1 Pancreas marked 60 C20 (25) 1 (19) (25) 03 (22) (20) AWciitnhianr antorropmhylimits 2os1 152 ow2 1.3 ow2 amiinigaal oz1 02 11 11 01 mmoadreireadte 3 o0 o0 01 01 Edoesmta 55 01 01 02 93 00 moderate Hyperplasia, islet cell 50 o 0 91 91 00 10 itd Pancreatitis, chronte oce o9 10 01 00 01 Polyarmtoedreirtaitse oo 1 0 0 2 oo 0 0 0 1 Parathyrotmainimal CH C08 C0900 (1050181 Within noma aits 50s ue 1s ous TGitrroeusp: 1 CONTROL 0 pp Group Group 5 6 FFCC--114833 33000ppopnm () = Total Examined SDA0CSe= PUrnostcohceodluleSdcheDedautlhe(dsS)acrifice(s) 155 Microscopic Incdence Page: 30 00542 Non-tieoplRaistkiecr LIanbcoirdaetnocreiefso,r IFnecm.ales3(continued) FC-143: Tuo Year Oral Toxieity-Oncogenicity Study in Rats Project Naber: 020ICRN1Z Species: Rat Tavie: 3 TissuDeisagnosis/ Hod fier rGermoemreen1s rGemrnoreen5s sGoromwmes6 205 SC 005 SAC 005 SAC PituWiittahriyn nomol Timits tas) tz7 ta1n (27 (203) (20) Heomsotrrhage 1o0o 3co0 00 01 Necrosirsaked 1100 50 09 00 09 moderate 19 0 oo 0 9 SaliWviatrhyinGlannodrma Timits QBooCw2 (1sso(w28 (22 (2on0 . Staladenniilteis, chronic 100 0oz0 00 11 Sein moderate Ca1t0 Ca0 cooz 30 coca Within norma] Visits 0 02 22 Acanthnosiids oo 11 00 29 00 00 Pododeearrtkietdis, ulcerative 9 10 00 oo 1 9 0 0 cer 20 02 00 msoadrekreadte 1100 00 00 02 00 SmalWitIhnitnesntionmea Tatts C2202285 (1uv9 (o2w (D0 CD0 Edemaaie oe 0 11 9o2o 0oo a3 Sranutosa oo 0 1 90 0 cer marked o 00 09 00 11 09 SpinWaithCionrnorma] Mates C3s 23 (aand (o0 l 00 Malacia 1 oo 9 Speen moderate C251) (025) (a0) (290) (20oo) (20) HWeimtahtionpontoersmias,Memxfttrsamedullary, increased 7un2 o2r o#1 1 nosw efodaerate 11 11 100sa22 oarked 20 01 21 Hemostmdienriomsatls 1o B o7s1 21 0 ail moderate +8 013 16 13 01 01 TGortoeusp: 1 CONTROL pp . GGrroouupp 6 FFCC--114833 33000ppppmm 0 = Tota) Examines 0$045C=e UPrnostcohceodluleSdchDedeualtehds)Sacrifice(s) 156 Microscoptc Incidence Page: 31 00543 Mon-NeaplaRsitkiecr LIanbcoirdaetnocrefefso,r FIencs.ales3(continued) FC-183: Tuo Year Ora)Toxty-Oncogentcity Study in Rats Project Number: J231R0012 Species: Rat Tavte: 5 TissDuieasgnosis/ Hoc fier eGaostpeasns1 sGorvoeumprest5r SeGersorwpisie6s 0s sc 00s Sc 00s Sac SpleeHnes(ocsoindtienrusesd) Stomach sarked (2o02o5) (2000 0 (20) 10 (29) (20) WEidtehnisn norma Vines 2o %oz13 oow B9 ow9 moderate Hemorrhage o 2 oz 0 0 0 10 9 0 1 oo amiodlerate 100 0oo0 o1o 20 Mineralization aid 1100 20 00 09 00 Hecrosatis d 2100 00 0 0 1 1 0 0 eersoderste 1100 00 00 0os 09 Thyrote aig C2 (20) (105 (26) 2 (2) 0 (22) FWiotlhliinculnaorrmhaypeTripmliatssia, cystic 210ow o9u oz0 2oooa Hyperplaaisliea, cell 10o 10 o0z 13 90 ile ltinsbranchial cyst 21 01 2oz o1o 01 TrachWeiathin normal Mafts C2n9)o(s28) (200 ow (28) 5 (20) (2) a2 UrinWairtyhiBnladnsoerrma limits (2v)o(2x5) (1o6s) (2o6x) (22) (2o2z) CaElpcituhleulsa1 hyperplasia, papillary 1100 00 00 o0 o0 Epitnealuar)iedhyperplasia, simple 17 00 00 01 20 00 meoidleerate 6100 00 51 02 00 Hypertarioplhy o9 ooo 00 11 00 00 uterus Within norma Tinits (2a9 (2u5v) (1o9v) (2o0a) (2v6)o(u23) eysticingilaanadls 2 o 0s o1 4 1 15 00 nid moderate 61 21 12 01 a1 oa 2 TGirtoleusp: 1 CONTROL 0 pp . GGrroouupp 5 FFCG--116633 33000papm.p D0)0Sw= UTontsaclheEdxualmeidneDdeatn(s) 157 SACe Protocol Scheduled Sacrifice(s) Microscopic Incidence Page: 32 G00544 Non-hesplaRsitkiecr LIinbcairdaetnacreiefro,r FIenmceales0(continued) broject lumber: GEAICAFED-O1I623:SpTeocoieYse:arRaOtralToxty-Oncopenityc Study in Rats Tate&: Tissues eattier UteruCsyst(iccongtiannuaesd) yaroscearrtaes Ayperstaarstiea, endmesrial maarite Gop 1 Grow 5 Grow 6 ws se oe Se 00s SK ooc 31 01 00 03 oo1 01 00 ooo o1 oa 0 0 0 1 TGiGrtrrooeusp:1CFOCNAT1R6O3L300p3 epn Group 6 FCA 30 pm 005. TUontsacheEdxiatmeidneDdeaths) SKC protacel Scheduled Sacrifices) 158 Microscopic Inctdence Pag: 23 00545 RNiekoeprlasLtaibcoraItnocriideesn,ceInfco.r M3ales FC-143: Tuo Year Oral Toxieity-Oncogenteity Study in Rats - One Year Interia Project Number: 0281CR0012 Species: Rat Tave: 9 Tissues Diagnosis/ Modifier sinKeratoacanthons mGeopres1 raGareorwamene 0 tn 1 Tittes: GGrroouupp 51 CONTROL ppa FC-143 300 pp 0) = Tota) Examined 159 Wicroscoptc Incidence Page: 3t 00546 NReiokpelarstLiacvorIantcoirdteensc,e fIonrc.Fea3rles FC-143: Tuo Year Oral Toxictty-Oncogenicity SWy in Rats - One Year Interin Project Nmber: 0281CR001Z Species: Rat Tavte: 10 TissuDeisagnosits/ Mod Fier MamaFriybroGaldaenndons PituAidteanryoos SGrtowat1 i (15o) (151) aGrraonwrse5r (uw 2 0 TGirtoleusp: 1 CONTROL 0 gpa Group 5 FC-143 300 ppm (0 = Total Examined 160 Microscopic Incidence Page: 35 G00547 RFEYSTOOPY MARABLE,IABLE,,..,. SESEREIS Riker Laboratories, Inc. 31 Adrenal 9 (38) (6) (an) (18) ( 36) = Group 6 FC-143 20 pp Bede hed odd SACs Protocol Scheduled Sacrifice(s) 161 00548 NeoplasRtiikcerILnacbiodreantcoerifeosr,MaIlnecs. (3continued) FC-143: Two Year Oral Toiefty-Oncogentity Study in Rats Praject Nuber: G2810R0012 Species: Rat Tavle: 11 TissDueisagosts/ Hodiier eGrroepereer1s eGrrmoewerse5s sGevrroewvssees Ds SC 0s sc 00s SAC SkiKner(actoonsticnaunetdh)oa: 12 0 1 2 a PLaippialsiaoracsons 1o s1 28 0a 20 00 Saal)HesIanltyesstpihnoereticular neoplasa present CE nn E CaE e (] no SoftHeTmioslsyumepsho(raebtdiomceunl)ar neoplasn present 1c 1 0 0 9 Caco cata (an - SofFtidTrisosnuses (thorax) (ascoa caoo cn0 ca2 rn1 Wistiocytoma, malignint 0 01 0 SotHeeemnangiosarcana C18) (310 (80) (a0o) (10o) (30) StomaHcehnolymproraticular neoplasn present 11 1 0 1 0 C18 0 C6 Can (1m (36) HAedneonloycmaprhcoirneotniscolar neoplase present 1 00 02 01 00 0 TestiLse/yEdpiicciedlalisadenam C18) (3oo C6) Ca1n (100) (32) TymaHseaolyaphoreticalar nesplasa present (n1e9a cu1 e0 Cu1e9 Thyroid cel adenoma Crmooncex (10 0m2 Fcolelinculcaarrciandoennsams 5s 2 2 0 0 0 50 32 01 UrinHaerymolBylmapdhdoerreticular neoplasa present (1C0w Co1 ta0 (masm o HensMlaylmipghnoarnett.icTuylcaoronSsy,stolnympIfhocayftfieccted] tTReInITnira nnTeogo Malignant Leukeata, m1yemlpohtodms, histiocytic 3 01 21 00 01 00 TGireousp: 1 CONTROL 0 pp GGrroouwp 65FFCC.-114633 33000pppmp 0) = Total Examined DS0ASC= UPrnostcohceodluleSdchDeedautlhe(ds)Sacrifice(s) 162 Microscopic Inctdence Page: 37 00549 NReiokplearstLiacborIantcoirdteensc,e fInocr.Fees FC-183: Two Year Oral Toxfesty-Oncogentcity Study fn Rats. Project tuber: 0231R0012 Species: Rat Table: 12 Tissues DiagnoHsoidsi/tier Grow 1 Grow 5 Grow eorsrmensecns m00senscea00smSeac Acrennt (2 (2) (200 (29) (2) (20 CAdaerncoimnao,s,cocrotritciacles) o5 o9 00 01 31 01 Preochrosacytons, benign o2 00 0 PHheeaogclhyrmopmhaazrysttoincsu,laraslniegonpalnastm present a2 00 01 90 o2 o0 AortaHenolyephorsticular neoplasm present Ca2nc 0 (we0 Co0 t . BoneHMeasrorloywmanoresicalar neoplasm present (2zs (o2 (a0n (2o) o(oC 0 Brain 011godendroghfoma, benign Ca5) (31 (a0n 0 (o2 C 09) EsopHheangoulsymphoreticular neoplasa present Cm1csa Co0: (28 (20) ee Hemolymohoresicilar neoplasa present (1 26 (105 (29 C0an0 Harderian Sand Adenocarcinoma Co0 to2 (9ao0 (n1 en0 Heart (2 (2) (an (2) (2) (2) KidneHyenolymparsticular neoplasn present C281) (32) (a0n (29oo) (23) (203) Hecolymphoreticular neoplasm present 3 0 0 2 9 oo LargeHeaIonltyeostpinnoereticular neoplasn present Ca1m0a (m5 emoo Co5 la9 Liver C25 (28) (a) (29) (28) (20) HHeempaaltyoocpehlalrueltaircazlaarrcinnoenosplasm present o5 00 a1 19 o1 o0 LungHenlyephoreticalar neoplasn present C285 (20) (an1(920) (261) (200) LyHmneotildeymp(hmoerseetnitecrailca)r neoplasm present (B3 ea)0 (m0 em0 ooo oa) LyshHentiooldyemp(htohrocrtaciiccu)lar neoplas present Co5 co3 (a8 ca3 n1eo3 Mammary Gland (20a (me (2 (2) Addeenncocearcinoma th1 29 a3 e0 f0 Cercinons 31 2 0 9 0 LyFnipbhraonadgeinoosnaarcoss iooo4 51 o3w c0 om0 Heoolymanareticular nesplasa present 29 00 00 Titles: GGrroouupp 51 FCOCN-T1R4O3L3330ppppm Grow 6 C173 32 pp 000== TUnostcehedEuxlaemdinDeadath(s) SAC Protocol Scheduled Sacrifice(s) 163 Microscopic Incidence Page: 35 00550 Vase Teton for Fete fentinnt SREESLYTDOLPOYY RAvVaAnRARE reso no veRiekerrsLaborraiteorriess,ceInnc.er3yi str tn tts rae Neer: SBTRNZ Spctes fot oer 2 ong i2 ----i " toa s, mtgm ourTYamtrons eet to, satan [iwese. Toe ett spss eioTnr eme pe. sonfroorntes woLaaeeiens iwoom n m sma Te2 restree wm re. Wiroeomenerrecoiar mm ret J vireSse . meseson stem pe. Sratoreo betSa rematiot e rett a croamn w me Tm osoae or 1 wn 5 ow 6 [rr (aPtoe3 (ea8 tpa3 ea1cr3a CpPrdasopyme Aci amy (3EeEh3 h1omEh1o1m pp pe ey (D3Bhe3p3hopm3%(phyo3 JPFaEhppdade adyh (E FMeem T eremm ChnTEeigh ((ShBDeDB mmCemnm hBeoey (hp2 oipd oo(hpReEhnP m(peepemn Chp2irbmgecpd5 eeph0 eghbeooyd C(3Ahh hh41Dood3 Gch20h6r oPpohospee ss c1oagse CBP5E.4rO CoN4.Cv0G on0.s1 t Prracialaly C Tur a +EcomR2p 4. Te nTHtiecgaense erties) 161 00551 IndividSuuaalsarMiazcerdoscSoinpgilceanTdabuNliactreadscMopiincdObRseeprovrattions FC: Too Year Oral TeRnickietry-Ltabnocroagteonrcieist,y SIntcu.dy in Rats - One Year Intern Table: 1 SFoaitnea:l WNeoesbkesr: $3I)RI1S1Y6ear teSerxi:aMaSlaecrifiGcreoups (1) CONTROL 0pp Macroscopic Bsernations: Micro[scropeic Diservations: LLyuanpgh Node (esenteric) PPaarnactrheyarsoid Saal Intestine Thyreid o v:isible Lesions. ""DWiarsocnailcarpraoignreersasliivzeatimosnh,voapnaitmhayl, ald Nhoitneaxanaitnreodp,hy,aisasiilndg N~boittheixnanniooreada,l aLiisnsiitnsg Feutr thin protocol susber Hot enaine, missing The fallouing tissues were found to be within mors lit: UBrraiinna,rySBpliandadlerC,ordA,ortBao,neTeNsatrirosw/,EpiSdpildemeani,s,LiPvreors,taHteea,rt,RamSetaornyschG,lanLda,rgePitIunitteasrtyi,ne,Adreml, Trachea, Escahagas, Salivary Gland, Eye. fnisal aber: IRIS Sex Male Groups (1) CONTRIL 0 pp Fate: Meeks 59) 1 Year Interia Sacrifice Nacroscopic servations: Micro[scoipic Bhservations: LuPnagrathyroid Thyroid Xo visible Lesions, ~"Cvaarsacnuilcarprwoignreersasliizvaetimopnh,roapialtdhy, sinieal Naott eexxaanniinneedd,, waiissssiinngg The following tissues vere found to be within normal Linits: LBarragine, InStpeisrtailneC,ordU,rinBaornye BMlaardrdoewr,, Sfpolretean,, TLeisvteri,s/EHpeiadritd,yaSitso,uscPhr,ostSawtael,l Intestine, Nassary lan, Pituitary, Adrenal, Trachea, Esophagus, Lywph Made aesenteric), Pancreas, Salivary Elan, Ere. ial Nesber: R350 Sex: Male Group: (1) CONTROL 0 pa Fate: (ets 3) 1 Year Interia Sacrifice Macroscopic Observations: Nicrosrcoepilc Ohservations: Kidney Xo visible Lesions. "Swiintursaotideal ectasia, cortes, bilateral, ~Caronic progressive nephropathy, minimal SPpreocjieecst:MRaasther: 02818012 Suarized STAR Page: 1 165 00552 SInudaisvairdiuzaeld NSaicnrgolsecoTpbiuclaatneddMidcnriaoaslcopRiepcorbts.tr(vcoanttiionnusnd) F43: Too Year ral ToRrickietry-LGinocroagteonriceist,y SItnucd.y 3in0 Rats ~ One Year Interin Tate: 1 Ffraitnea:l (asebker:$B3-315Y2e0ar InSteexr:iaMaSlaecrifiGcerog: (1) CONTROL 0 pon NicrLoiscvoepric servations (continued): LuLnyagsh Mode aesenteric) PFiatruaitthayrrayid Hseipnaitnaaclyte alteration, vacuolated, focal, H"ioatscaelxaarinseidn,erwaliisziantgion, sininal ""NNoott eeaxanniinneedd,, insotsiinngplane of section The following tissues were foun to be within normal limits: BUrraiinna,rySpBliamglderC,ordR,ortBao,ne TMeasrtriosw/,EaiSdpildeeyna,is,HeaPrrto,staStteo,ascThh,yrSceiadl,] TrIanctheesst,ineE,xcpLhaarggees,IntPeasntcirneea,s, Salivary Bland, ye. Ffantien:al(Meaksheer:3R)112Y2ear IntSeenr:iaMSaalcerificGeroup: (1) CONTROL 0 pp Nacroscopic Observations: MicroLsicvoepric hservations: [re LLuinvegr ThPyarraotihdyroid "Light (pale) tan in color, "~PDoarrtoanlic spornoognrcelsesaivrecnelelphrionpfaitlhtyr,atea,inianianlisal "hHaeswcoarlrahragea,inewrsailtiizfaotciaoln,, swiilld "PNeortiveaxsacsailnaerd,soaviosnsuicnlgear infiltrate, ald "Hot esasined, missing The following Brain, Spiral Ctoirsds,ueosnweerKeafroou,n Stpolebeen,wiHtehairnt,noSrtmoaasclh,itSe:al] Intestine, Large Intestine, EUsrcipnhaargyisB,laLdydseprh, NAoodreta,esTeenstteirsi/cE)pi,ciPdaanicsr,easP,roSsataltiev,aryNaGbalaarny, GElyaen.d, Pituitary, Arenal, Traches, dFaitae:l (Neosibser:$138-31Y52e7ar InSteexr:iMaSluecificGeroup: 1) CONTROL 0 gpa Macroscopic Observations: Microscopic Diservations: Liver Lung Xo visible lesions, "PPoorrttaall bsimloenudccletarprcoellilferiantfiiolnt,rataei,ldwild "Hesorrhage, witifocal, aild The folloning Brain, Spinal tCiosrsd,uesBoweereMafroounn,d Stpolebeen,witKhiidnneyn,orHmeaartl,iStt:onsch, Small Intestine, PSrpoejceicets:NoRsatter: 0281080012 Suanarized STAR Page: 2 166 00553 ISnudmiavriidzuaeld SaicnrgolsecoTpaibclaatneddMiMcirnosacopRiecpoOrtbse(rcvoanttiionnused) FL-143: Tao Year Oral ToiRickietry-LGanbcoorgaetnoirciiest,y SItnuc,dy 3in1 Rats = One Year Interin Table: 1 dial Nosber: 18-3527 Sex: Male Groups (11 CONR0IppL Fate: Geis $3) 1Yeu teria Sacrifice Wicroscopic Bsarvations (continued): LTahregefoIlnltoewsitnignet,isUsruiessarwyereBlafdoduenrd, to be within normal Lists Aorta, Testis/Epididyais, (continund): Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophags, Lys ode (aesenteric), Pancreas, Salivary Glund, Ere. AFantiem:alMKeoeskbser:53I)B-1ISYIeSar InSteexr:isMSaalcerificGeroup: {11 CONTROL 0 gpa RacrNosecsoepnitcarsyervations: WicroLsacnogpic servations: Resentary PTahryartohiydraid "hrea of fat mcrosis, 21 3x 0.5 ca "Alveolar sacraphages, ARellectasis, focal, wmilidtifocal, ail "Necrosis, fat, marked Steatitis, chronic, oderate "lNaott eexxaasniinneedd,, aaiissssiinngg The falloning tissues were found to be within normal linits: BLraarigne, ISnptiensatlinCeo,rdU,rinBaorvye MBalrardodwe,r,Lihvoerrt,s, KiTdeosetyi,s/KEpeiadri,yaSitso,macPhr,ostSaetael,l Intestine, Pituitary, Mreml, Traches, Esophagus, Lysgh Node (esesteric), Pancreas, Salivary Glan, Eve, Spleen. AFantie:l tNeossbtesr: $(3RI1SYKeSar InSteexr:inMaSluecrifiGcreoup: (1) CONTROL 0pou Nacroscopic Bhssrvations: Nicroscopic Observations: KiLtivoeery Lung Ho visible Lesions, ~"CPiorrotnalicapornoegnruecslesairveceelslhriongfaitlhtyr,atea,iniaaiall Psoirtnalibile dct proliferation, focal, "Sascalar ineralization, aininal TBhreainf,allSopuiinnagl tCiosrsd,uesBonweereHarfroouwn,d to be within normal lit: Spleen, Heart, Stonsch, Swall Intestine, Large Intestine, UTrriancahersy,BlEasdodpebra,gasA,ortLa,ysTesNtoties/E(pneisdeindtyearsi,c),ProPsatnactree,as,PitSuailtiavrayr,y ABdlraennda,l,EyeT.hyroid, Parathyroid, PSrpoejceicets:Naastber: 0281080012 Sunarized STAR Page: 3 167 00554 SInudsiavairdiuzaeld aScinrgolsecoTpaibculaantdedMiacirsoaslcopRiepcorOtb.se(rcvoanttiionnused) Riker Liboratories, Inc. 30 FE-I43: Tuo Year Oral Tosicity-Dacogenicity Study in Rats = One Year Interia Table: 1 - Ffantien:al GMeaeskhser:$3R) S1 SYer IntSeexr:iaMSaalcerificGerow: (1) CONTROL 0 gpa Macroscopic servations: Nicroscopic Bhservations: Harenal Liver LSutnognsch Ho visible Lesions. "Nootdeurlaatrehyperplasia, cortes, wilateral, "PPoorrttaall sbiolveondculcetarprcoellilferiantfiiolntr,ataei,ldwild sHielpeatocyte alteration, vacslated, sultifacal, "perivascular sonomclear infiltrate, aild at esanined, wissing The following tissues vere found to be within narmal Jinits: Ubrrianian,rySBpliandadlerC,ordd,ortBao,neTMeasrtriosw/,EpSipdleieyni,s,KidPnreoys,tathee,artP,ituSietaalry,InTtheysrtoiinde,, PLaurragtehyIrnotieds,tinTer,aches, Esoahagus, Lh Node (aeseteric), Pancreas, Salivary Gland, Eye. dFaetien:al(Nboeaebtser:55I)R-31 55Ye0ar IntSeeriaMSaalcerificGeeoups (1) CINTROL 0 pou NacroKsicdonpeiyc Observations: Nicroscopic Dbservations: Heart Kidney LLiuvnegr Pancreas "Bilateral hydronephrosis "Mayiolcarditis, chronic nonsspprative, focal, "HCyatlrcaunleussh,ropseilsv,icbilateral, soderate "Fosrctaallarasnmoinnuecrlaelairzatcieolln,inafiilldtrate, ail ~hPcainncarreataittriosp,hy,chfroocnailc,, dfoocdaelr,ateale The following tissuts were found to be within normal Linits: BUrraiinna,rySpBilnaadlderC,ordA,ortBao,neTMeasrtriosn/,EpiSdpiledepsa,is,StoPwraocsht,ateS,walPlituIintteasrtyi,neA,dreLnaarlg,e Intestine, Thyroid, Parathyroid, Traches, Esophagus, Lys ode (aeseneric), Salivary Gland, Eye. SPpreocjieecst:aRsatter: 0281CR012 Suirized STH Page: 4 168 G00S55 SInudainvairdiuzaeld NSaicnrgolsecoTpaibclaatneddMifcarimoaslcopRiepcorDtb.se(rcvoanttiionnused) Riker Laboratories, Inc. 3 FL-I43: Too Year Oral Tosicity-Dncogenicity Study in Rats = One Yeur InteriTaable: 1 mFaitnea:l (Nbaesbtesr:S3I1R1ISYour InSteer:inMaSlaecrificGreoups ( 1) CONTROLO pon WacrosLcivoepric Observations: Nicroscopic Ghservations: Liver Lung Pal>e tan "PPoorrttaall sbiolneodnucctlrprcoellilferiantfiiolnt,ratael,ewild "PHoeesuosrornhiaag,e,inwtietrisftoictailal,, ichlronic, focal, ail Hyperplasia, septal cell, focal, mile The following tissues were foun to be within normal limits: Brain, Spinal Cord, Bone Maron, Spleen, Kidner, Meart, Stonsch, Seal] Intestine, TLhayrrgoeidI,ntPeastrianteh,yraUirdi,narTryacBhleaad,derE,sopfhoargtuas,, TLeysatgihs/NEopdedid(syeasse,ntePrriocs)t,ateP;ancPrietausi,tarSya,livraernyalli,nd, Ere. mFaitnea:l (Nbaeebtesr:55I)RI1SSY9ear InSteexr:inaSlaecrificeeowpt ( 1) CONTRIL 0 pp Macroscopic Dservations: Microscopic Bbservations: idney Liver Lung 40 visible lesions. "Pye, acute, bilateral, aininal wMielpahtietniasl,, iintderstitial, chronic, focal, "portal snonuclear cell infiltrate, ald "PHoerstcarlrhabgiel,e dmuicttifporcoalli,feraaltidon, wild TBhreainf,ollSopwiiranlg tCiosrds,uesBoweereMarfroounn,d tSoplebeen,witHheianrt,norSstaolmacLhi,nitSsw:all Intestine, Large Intestine, Urinary Traches, BlEasstdpehra,gesA,ortLay,ghTesNotdies/E(psiecsiedtyenrsi,c),ProPsatnactree,as,PitSuailtiavrayr,y AEdlraennda,l,EyeT.hyroid, Parathyroid, daioal Nosbers 1R-IS6 Sex: Male Group: (1) CONTROL 0 gpa Fate: Weeks $9) 1 Yeu teria Scrifice Nacroscopic Dservations: Nicroscopic Ohservations: Kidney Pancreas Parathyroid Ho visible lesions. "Chronic progressive mphronathy, ald "RPeuicmraerataittriosp,hy,chfroocnailc,, afolcdal, ald "Not exanined, not in plane of section SPrpoejceicets:MaRsahter: 02810012 Suanarized STAR Pag: 169 00556 Sumarized Single Tabulated niaal Report. (continued) Individual NaRcikreorscoLpiibcoraatnodriMeisc,rosIcnocp.ic 3O0bservations FC-13: Teo Year Oral Tonicity-Gncogenicity Stady in fats - One Year InteriTnale: 1 BFaitnea:l WNeueskbesr: S310R-I156Y8ear InSteexr:isMaSlaecrificGreoups 1) CONTROL 0 pps Microscopic Observations (continued): TBrhaeinf,ollSpoiwnianlg Ctoirsds,aesBonweerMearfroourn,d Stpolebeen,wiLtihvienr,noHremaarlt,LiLnuintgs,: Stomach, Saal Intestine, TLhayrrgoeieI,ntTersatcihneea,, UErsionpahrayguBsl,addLeyra,ghANoortdae, (Taeesstenitse/rEipci]d,idySaailsi,varPyrosGtlaatned,, EPyiet.uitary, Arenal, AFoaitae:al (Mhuesette=r: $3I)R-S1SYTe0ar InSteex:riMaSlaecrificGeroup: ( 1) CONTROL O gpa Macroscopic servations: Nicroscapic Observations: Lhuenrg.ent Parathyroid Ho visible lesions. "~CPorretaiscoanli,vaciunatleartsitoint,ialm,ltcihfroocnailc,, afiolcdal, Kseisnoirnrlhage, saltifocal, aild "hot exasined, not in plane of section The folloving tissues were found to be within normal linits: BLraarigne, Spisal Cord, Bone Intestine, Urinary Marrow, Bladder, Spleen, Aorta, Liver, Kidney, Heart, Stowach, Swall Intestine, Testis/Epididyais, Prostate, Pituitary, Thyroid, Trachea, Esophagus, Lh ode (sesenteric), Pancreas, Salivary Gland, Eve. Ffaotei:l (Mboeaebter:$3I)R-I1 STYeSar IntSeerx:iaMaSlacerificreaupt (1) CONTROL 0 ppm MacroSsocfotpicTisOsbuseesrva(tlieog)ns: WicroKsicdonpeiyc Observations: Lng. Pituitary "Swollen Left hind foot at the hack joint. ~Ohvonic progressive nephropathy, sinisal "Vascular wineralization, ininal AHlevseoorlrahrages,acrfoopchaal,gesa,ilmultifocal, aild "Oyst, pars distalis BThreainf,allSopsiinnagl tissues were found Cord, Bone Marrow, to be within normal Linits: Spleen, Liver, Heart, Stomach, Small Intestine, LPaarrgaethyIrnotiees,tinTer,achUersi,narEysopBhlaadgduesr,, Lyfsorgtha,NoTdeest(isse/sEepnitdeirdiyce)i,s,PaPnrcorsetaast,e,SaAldirveanrayl,GlaTnhdy,roiEdy,e. PSrpoejceiecst:MaRsatter: 028100012 Suaarized STAR Page: 6 170 CG00557 Susearized Individual MSaicnrgolsecoTpaibcalaantdedMidcorinoaslcopRiepcorste.rv(caotnitionnused) F143: Too Year Oral TonRickietry-LObnocroagteanriiceist,y SItnucd,y i3n0 Rats = One Year Interia Table: 1 fFnaitnea:l WMeaeshkesr: $R3 81Y0ear teSersi:aMaSlaecrifiGcreoup: (1) CONTROL 0 pp Macroscopic servations: MicrKoisdconpeiyc Observations: BKoindeneMyarron Lung Pancreas PaSrpaintahlyrCooirdd "Bar-k cystic lesion, 0.4 ca ha., eit. d"oChtaneixcaniporeodg,reasissisviengneshrogathy, ile "OAlsvte,olacrortaiaccarlo,phwaielsa,temrualltifocal, aild Poeasonia, ald interstitial, chronic, sultifecal, ""HPoatncreeaastiinteids,, chronic, focal, not in plane of ail section "hot exanined, aissing The following tissues were found to be within normal Limits: Tbersaitni,sEpSiplgeiedny,assL,iverP,rosHteaatret,, PSittoumiatcahr,y,SmaAldlrenIanlt,estTinhey, ,LargTeracIhnetse,stEisnoe,phaUgruisn,ary Bladder, Aorta, Lyaph Node (nesenteric), Salivary Bland, Eye. Ffantien:al(Weasstheer:9RA1SYTear ntSeerni:sFSeiwarlieficGeroup: (1) CONTR0OgpLa Nacroscopic Bhservations: Microscopic hservations: KLiydonsheyNode (eseateric) Parathyroid Ho visible Lesions. "Hpaetlviecxassiinneedr,aliaziastsiionsg, aininal "Not exanined, not in plane of section BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueosnweerNearfroouwn,d Stpolebeen,wiLtihvienr,soHeraart,LiLutng:, Stonsch, Sua] Intestine, TLhiyrrgoeidI,ntTersatcihnees,,UrEisonpahrayguBsl,adPdearn,creAaosr,ta,SalUitvearursy,GOlvaanr,y,ErMea.seary Gland, Pituitary, Adrenal, fninal Maher: B-4582 Sex: Female Group: ( 1) CONTRIL 0 pon Fate: Gels $3) 1 Year Inter Sirifice Macroscopic Dservations: MicrKosecsoepnitcarhysarvations: [HY idhey "fellow sotular aass, 11 0.5 ca. "Msyiorcianradlitis, chronic moasippurative, focal, "Calculus, pelvic, wilateral PSrpoejceicets:aRtaetr: 0281080012 Sunsarized STR Page: 7 171 600558 Suamarized Single Tabuated pina Report (continued) Indivieual MaRcirkoesrcoLpiibcoraatndoriMeisc,rosncco.pic3O1bservations FE-143: Tuo Year Oral Tonicity-Oncogenicity Study in Rats - Gne Your InteriTaable: 1 Fmaitnea:l WNeaesskesr: $3I)R-41SYRe2ar laSteexr:iaFeSmaaclreifiGcreoup: ( 1) CONTROL 0 pon NicrosLcaorpgiec Isnetersvtaitneions (continued): Lung hesentary PaUrriantahryyroBildadder theres "lPonteuaeosnainai,nedi,ntemrisstsiitnigal, conic, sultifacal, Haeislodrrhage, local areas, ald "NPeecrriovsaissc,ulafart,sonnoodslcalre,arsoidnefrialttreate, ail "SNtoetateixtainsi,nedc,hronnoitc,insopldaenaeteof section h"Haytpeerspalnaisniead,, gmliasnsdiunlgar epithlie, aild Netaplasia, `seancus, glandular, 4il BTrhaeinf,olSlpoiwnianlg Ctoirsds,uesBonweerMearfroouw,n to be within normal Linits: Spleen, Liver, Stousch, Swall Intestine, arta, Dury, PWaasscaraerays,GlaSnadl,ivaPriytuiBtlaarnyd,, EAyree.nal, Thyroid, Trachea, Escphagus, Lysgh Node (aesenteric), minal Masher: IR-ES Sex: Female Group: (1) CONTROL 0ppm Fate: Weeks $3) 1Year Iteria Scrifice Macroscopic servations: Microscopic servations: Mrenal Kidney LLuinvegr Parathyroid 4a visible lesions. "Sinusaidal ectasia, cortes, focal, unilateral, "Paeillvic sineralization, ainiml F"Woarstcaullaraonsainnuecrlaelairzatcieol]n,inifliltrate, aininal "HNoetsorerxhaangien,ed,mlntoitfoicnalp,lawnieldof section The following tissurs were found tobewithin normal Tinits: UBrriainna,rySBpliraadlderC,ordA,ortBao,eUtMearrurso,w,OvSaprlye,en,RasHseaarryt,GlSatnodn,schP,ituSiwtaalrly,InTtheysrtoiinde,, TLraragceheI,ntEessotpihnae,gus, Lyaph Node (oesenteric), Pancreas, Salivary Glan, Ere. PSrpoejceicets:NoRsabter: 0281080012 Suanirized STAR Page: 8 172 G00559 Sovmiadiaueld BSionglseoTnat1a4sRnrieaslcnRstpBaecvottiinoannt) FC103: To Tew GalToxkicetry-Lirecrastgacriietny, Sotea,y in Rats - One Yor Iter Tai:1 nFaatels eNnre: 51015t8er ISteexrFSewmrlieficGeap: (1) CONTR. 0 gon WcroScianic uration: WcrosbcreiectShsarations: rent itn tensr Spiunma Cort afirLosi, mack. Swiinvsas acts, crt, wilatea, --Cpoertriacialsitne,grpaitnieona,itwhielltie,rl1, 6ald CCapltc,uluase,teliavyi,c, awililatral HSeapaastrahcayge,vfaicaftei,ons,osrltteifocs, wild oSotwoiwdaernodui,s,iwsislng SThaeinf,llBoonsengRatriosns,uesHewrtr,e fStuonrdcht,o bSeuwsithIinntesstoinmea, HLairngetsIntestine, rinry Badr, hort, Utyesr,NoGtrru,sasRtavearriy),ElaFnadc,rePsit,stSatryi,varTyhSoann,,FEarya,thySrisni.d, Trche, Esphges, fFiantael tahbeeter: 3()0155ter InSteesrnFSoacwriliceers (1) CONTROL 0 pon NcrPaistoupitcarByrvtions: Worosrciasic aration: FaNraswtoiSidang Slightly mlarge FPaorrttall sbiloendictaprcollleraitnfiiolnt,ratiel,ewild oStietranaind, sat in sane of sction rTaheinf,olSlioinnag Ctoirsts,asJeswrearoeun,n ytoebne,wiKthiinnes,oHrar,LitLnegs, Stoich, Sal Itetine, EUrragheagnest,stLiunh, Riondear(yaBsltasetrer),,forPtass,rehae,resS,aliDvuarryy,SPhiatdu,itarrey., dro, Tyron, Trache, Srpoejceicest:hRaabte: QZIEROL2 Sanrized STH Pugs 9 173 G00560 SInudmimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMidcnriaoaslcopRiecporster(vcaotnitionnused) Riker Liborataries, Inc, 3% F143: Too Year ral Toicity-Oncogenicity Study in Rats ~ One Year InteriTaable: 1 Fmaitnea:l ONeaincbesr:$3B1 91Y0ear laSteesr:iaFeSmaaclreifirceow: (1) CONTROL 0pp Macroscopic Ghservations: Microscopic Observations: Lung b.o visible Lesions. "Hessrrhage, local areas, sodeate BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonweerNearfroouwn,d SLpolebeen,wiLtihvienr,norKmiadlneyL,isHtesa:rt, Stonach, Swall Intestine, TLhuyrrgoeidI,ntPeasrtaitnhey,roUirdi,naTrryacBhleaad,derE,sopAhoargtuas,,ULtyesrupsh,heOdveary(,sesNeanstwearriyc)G,lanPda,ncrPeiatsu,itaSrayl,ivaArryenSalla,nt, Eve. fninal Nasder: IR-4601 Sex: Female Group ( 1) CONTRIL 0pp Fate: Gel $3) 1 Year Intern Sacrifice Macrosicdohpeyic Bssrvations: Hdronshrosis, wilateral . Microscopic servations: ieney "Hdromshrosis, wilateral, soterate Liver "HCealpcautloucsy,tewvialcastleartailo,n,ailsdultifocal, winisal Lung "Hesorrhage, witifocal, 416 TBhreainf,ollSopiwnianlg tCiosrds,uesBweereMarfroouwn,d tSoplebeen,witHheianrt,norSmtaolusclhi,nitSsw:all Intestine, Large Intestine, UTrriancaheray,BEasgedoehra,gusA,ortLay,ghUteNroudse, (Oaveasreyt,erRiacs)s,aryPaGnlcarneda,s,PiStauliitvaarryy, GAlarnedn,alE,ye.Thyroid, Parathyroid, Fnaitnea:] (aeseblesr:$3I)R-1A6Y08eu teSrexi:aFSeamcarlieficGerow ( 1) CONTROL 0 ppm Macroscopic Osarvations: Nicrosecroapisc servations: Liver LLuynsggh Node (aeseteric) [i "Left horn cystic looking lesion, 1 x 0.6 ca. ""HHeewpoartrohcaygtee,vawciwtoilfaotciaoln,, awliltdifocal, sininal h"Oaytstiecxangilnaendd,s,aifsoscialn,g marked TBhreainf,ollSopwiinanlg tCiosrds,uesBowneereMarfroouwn,d to be within norsal lisits: Spleen, Kidney, Heart, Stonach, Suall Intestine, LPaarrgaethyIrnotieds,tinTer,acUhersi,narEysopBhlaadgduesr,,Pfaonrctrae,as,DuSrayl,ivaarsyeaGrlyandG,lanEdy,e.Pituitary, Adrenal, Thyroid, PSrpoejceicets:esRatter: 02100012 Suanarized STAR Page: 10 174 G00561 uSbavnsrdieane aSrsaescaTpue lideRdciroenstsoprteracttiioonns) F105 Teo Yor tralTonie-rnCoorpsasrinonity, SToo,d in Rts Gor Yeu trie Tae 1 iFitle eseer S51 10Tor IoSearnFSorailicreo {11 NRL 7m [HIeat -- Stigtly whos [Aeores ---- Simnly mld trnryve ntstioe "rSiinsnsitlects, corte, ale Siva arituges, mitt, sig P[aarra aFatreeinntiinne,, ortot0,hofealof isedction es SMrtpsrlapshisai,nssuens,ls$hiitnherl,o,ilMs16 The felon ties ie found 0 be within sew Tints LBUroaihrn, bSepaeiniaelrsC,aortdfr,oirBtco,,neOMSartrrraowr,oynSapnlretyen,,LaELvdievy.er,iKaidnrey,, HeTarat,iSttomracha, oSealsl hInatesitine, Fiintel eeses59 1 TTDer InSaeriFSeureifiGcre |) EON 8 on Wcrotseasc Osrations E------ WerosHeesic Ovrntions: upthtati, wilatoral, sried Gane rreben,stweiihoatt,inssdme uWnsit Basie aSeveaage,,mlstisisancy, aid CBhrerisnf,laoSewisinintngeCi,osrf,oertbso,nwerUeateorounws,,tOStpyole,been,wSiLtshiivene,slHnaedle,,iPnSitttousui:ktcahr,y,SWarlenIsn,teTstoirn,d, Fiathrid, raion, Fanaa, Lh Mote (irst, Pret, Suv hn. uPtae tRaeveers50 3 1 Tor stSeerxnFSouarlificSe p | 1) CARL 0 pn [ Sir -- Wrosroepc Otion: Hair ow, be, eh, fae. awriteical tsertio, focal, wilaterl, PSaigees haatr: OIRO Suanarized STH Page: 11 175 00562 ISnudniuvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMiMcironsacogRiecporOtb.se(rcvoanttiionnused) FL-143: Tuo Year Oral TosRiickietry-LDaabcoorgaetnoirciietsy, SItncu,dy 3in Rats = One Year Interin Taste: | mFaitnea:l eNalbser:$I3R-41Y62e9ar InSeerxi:nFeSmuaclieficreow: ( 1) CONTRIL 0 gon Nicrosfcoorptisc Oservations (continued): LiLavregre Intestine Parathyroid "dHaetsiteoxdainianseids, aissing <Fartal bile duct proliferation, ail "Hot exanined, not in plane of section The following Brain, Spiral tissues were found Cord, Bove Marrow, Stpolebeen,wiKtihdinneyn,orhmaelartL,inLiutnsg:, Stomach, Suall Intestine, LUyroisnharyNodBelad(daeers,etUetreircu)s,, PDarncyr,easN,amSsaalriyvalrayndG,lanPdi,tuEiytea,ry,SkiTnh.yroid, Triches, Esophagas, Fnaitnea:] Gaebeeksr:513R-4163Y0ear InSteexr:nFeSmaaclreificGeroups ( 1) CONTRIL 0 pon Macroscopic Bservations: HicroLsicvoepric Observations: possibly slightly pale in colar. . LHiivdenrey ""CHaelpcautloucsy,tepeallvtiecr,atiwoinl,atvearcawlo,latseadd,eramtietifecal, Lung haelsodrrhage, mitifocal, wild PTahryarteihdyroid ""hNaott exsnined, canines, aissing aissing The falloning Brain, Spinal tCiosrds,uesBowneereMarfroouwn,d Stpolebeen,witHheianrt,norSmtaolwsclhi,sitSsw:all Intestine, Large Intestine, ULryianpahryMoBdlead(dneers,esAtoerrtiac,l,UtPearnucsr,easO,varSya,liRvaaarmyarlyanGdl,andE,ve.Pituitary, Adrenal, Trache, Esophagus, nFaitnea:] WNeaebkesr:$3I)R-4163Y1our InSteeyr:iFeSmaaclreificreowps ( 1) CONTRIL 0 ppm Macroscopic Observations: NierKoistcoopeiyc Dservations: LuLynagph Mode (aesesteric) Parathyroid Urinary Bladder Ho visible Lesions. ""pHeelsvoircrhasgien,eralloiczaaltiaorne,as,sinaiinladl ""HHaott eexxaanniioneedd,, aniostsiinngplane of section hat exanined, missing BTrhaeinf,olSlpoiwmianlg Ctoirsds,ueBsonweerMearfroouwn,d to be within normal Linits: Spleen, Liver, Heart, Stoaach, Suall Intestine, SPpreocjieecst:NRaabter: 028100012 Suuaarized STAR Page: 12 176 00563 ISnudainvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMimcirnoaslcopRiecposrter(vcaotnitionnused) FL-143: To Yar Oral TorRiickeirty-LGaabcoorgateonriiceist,y SItnuc.dy 3in% Rats = One Year Inari Table: 1 dFoaitnea:l Waebeekrs: 3I1R-4163Y1ear teSerxi:aFeSmuaclreifiGcreoups (1) CONTR0pIoLn The fNoilclroawsicnogpitcisBshaseesrvwaetrieonfsouncdonttoibnueedw)i:thin normal linits (continued: LEasrogpehagIunst,estPiannec,reaAso,rtaS,aliUtvearruys,laOnvea,ry,EreN.amsary Gland, Pituitary, fdrenal, Thyroid, Traches, FAartiem:a] GNeoesktser:$31)8-41 63Ye2ar IntSeexr:iaFeSmuaclieficGeroup: ( 1) CONTRIL 0 pon MacrPoistcuopiitcarOybservations: Nanwary Gland Nicrohsacroepniacl servations: idney LLuinvegr Nanna Gland duary Pituitary "Shsiugrhfatcley.enlarged with dark red forus on "Suall dark spherical ass, red fluid, left i1.n2guicnnald.ia., containing "Saiinludsoidal ectasia, cortes, focal, unilateral, ""CHherpoantioccytperogvraceusosliavteionne,phrmolptaitfhoyt,ala,ilwild "Hesorrhage, mitifocal, ail "GCahlraocntiocceilneflasation and hesorrhage in cysts. ""Chyesrto,nswailateral The following tissues were found to be within normal Linits: BUrraiinna,rySpBilnaadlderC,ordA,ortBao,neUNtaerrruosw,, TShpylreoeind,, HPeaarratt,hySrtooimda,chT,racShaeasl,l EIsnotpehstaignaes,, Lurge Intestine, Lyssh Node (sesenteric), Pancreas, Salivary Gland, Eye. iFantae:l (ohneebte=r: 9I)R41HY0er InSteerxiaFeSnuaclreifiGceeoups | 1) CONTROL 0pou Macroscopic Observations: NicrLoisvcoepric Bservations: PLaurnagthyroid Ho visible Lesions. ""HHeespoartrohcaygtee,vaiclwdslation, sutidocal, aininal "hat exanined, not in plane of section The following Brain, Spiml Ctoirsds,urBsoveereMarfroounn,t Stpolebeen,wiKtihdinneyn,ormHaelartl,inSittso:nch, Saal] Intestine, TLhuyrrgoeidI,ntTersatcihneea,, UErsionpahrayguBsl,adLeyra,phfNoortdae, (Uateesreunst,ariDcu)r,y,PanMcarseeaasr,y GSllainvda,ryPiltuaintda,ry,EyeA.drenal, SPpreocjieecst:Naastber: 0281080012 Susuarized STAR Pag: 13 177 00564 IndividSuuaslaarRiazcerdoscSoipnigcleanTdabMliactreodscoipnicalObsReersvoarttions F143: Too Year Oral ToiRickietry-LOanbcoorgaetnoirciiest,y SItnucd,y i3n1 Rats = One Year Intern Tale: | inal Fate: WNeoestkesr: 9R) T1 SYear InSteerxiaMaSlaecrifiGceeoups (51 FO-1A3 00 pon NacrLosicvoepric servations: Ricrfoascrotpsic Oservations: KiLitvoeery Lung Parathyroid Hle Hot- eanined, wissing : ""PCohrrtoanlicspornoognrcelsesairvecemlel.priongfaitlhtyra,tea,ldail Portal bile duct proliferation, aild NNeecgraolsaicsy,tosfiosc,al,sodaenriamtael ~Vascalar Hlveslar awaicnreorpahlaigzeast,ionw,iltaiiflodcal, ail lot exasine, not in plane of section BThreainf,allSopniinnagl Ctoirsds,uesonweereHarfroouwn,d to be within normal lit: Spleen, Heart, Stousch, Swall Intestine, Large Intestine, ULryiansahryNoBdleadadeesre,stTaersitci)s,/EPpanicdrieyaass,,SaPlriosvtaartye,GlPaint,uitEarrey., Adrenal, Thyroid, Traches, Esophagus, Ffantiee:al (aebiesr:3 IR1-3Y5o80ur IntSeer:inMSaalcerificreow (5) FE-143 300 pou Macroscopic Gservations: Nicroscopic Ghsarvations: KLiidvneery Lung Spleen ba visible lesions. ""pCorhtaalsspmroongurcelsesairvecnelelshrionpfaitlhtyr,atea,iniwnialld NNeecgraolsoicsy,tosmilst,idwoicladl, ald ""Hveawsocsuildaerrowsiinse,raaliizlation, ald BTrhaeinf,olSlpoinrianlg Ctoirsds,ueBsonweerMearfroouwn,d to be within sors lit: Heart, Stonach, Saall Intestine, Large Intestine, UTrraicnhaersy, BElsatdpdhearg,esA,ortLay,gThesNtoides/E(psiedsiednptueirsi,c),PrPoasntcartees,s,PiStuailtiavrayr,y GMlranedm,l,byeT.hyroid, Parathyroic, SPpreocjieecst:NRaabter: 0281080012 Summarized STAR Pag: 14 178 00565 Suamarized Single Tabulated nial Report (continued) Individual BaRcirkoerscoLpaibcoraatndoriMeisc,rosIcnoc.pic3O0iservations FE-143: Too Year ral Toicity-Dncogenicity Study in Rats ~ Oe Year Inerin Tale: 1 AFoatuea:d (Neoskbeees$I3RI1YSeHar InSteerxinMaSlcerificBeeaupt (5) FC-143 00 pon Macroscopic Bhservations: Microfsocrotpsic Dservations: Liver PLaurnagthyroid Thyroid "bo visible Lesions, "Nat examined, aissing eNretgaallocystoonsainsu,claeialrcell infiltrate, ail l"Waatscaelxaarninseidm,ermailsisziantgion, sild "Not exanined, aissing The falloning Brain, Spinal tCiosrds,uesBonweereMarfroouwn,d tSoplebeen,witKhiidnneyn,orhme]artl,iniSttso:asch, Swill Intestine, Large Intestine, Esophagus, Lysgh UNroidnear(yseBsleandtdeerri,c),TesPatnicsr/eEapsi,diSdaylaisv,arPyrolsatnadt,e, EPpei.tuitary, Arenal, Trachea, Fdantien:alMMeaeskhser:9[)R31 9Y2ear InSteexr:iaMSaalcerificBerow (5)FC-143300pon MacrPoistcoupiitcarsyervations: Nicro[scoipic hservations: Liver Lung Parathyraid Urinary Bladder "Saall dark red mass, 0.3 cn dia. ""CPhorrotnalic spornoognrueclsesairve cnelelphrionpfaitlhtyr,atea,inisaianliaal HPiegsuaetnatc,yteipvfaecruolcaetlilo,n,misltuitdiodcoacla,l,braoiwl, aild "Vascular wineralization, aild lAaltveoelxaarninmeadc,ropnhoatgeisn, pallanteifoofcasle,ctaiolnd "Not esanined, aissing BTrhaeinf,allSpoiurianlg tCoirsds,ueBsoweerMearfroouwn,d to be within normal init: Spleen, heart, Stonsch, Seal] Intestine, Large Intestine, LHyoargtha,MoTdeestinse/sEepsitdeirdiyca)i,s,PaPnrcorsetaast,e,SaPliitvuairtyaryS,lanrge,nEayle,. Thyroid, Tracke, Esophagus, oFaitel: Geesetkesr: $3I1R1IYSear InSeexr:tMaSluecrifiGcreoup: { 5) FO-145 300 pa Macroscopic servations: Nicroscopic Observations: Heart Ho visible Lesions. "Mwyiotciafrodciatlis,,scihnrionnlic sonsuppurative, PSrpoejceicets:uRsabter: 0281080012 Sunearized STAR Page: 1500566 179 TSRainvrdiieals RSiTnEglseETiacalaatdedriaol oReprmt cimtiennt F143: Ton Year 0a ToicbieyL-aaGscteorpiceeistn,y Sott,d i3n Rats - ne eur Intern Tole: 1 fFitae eWakseer: 5I9 R1 EYer aStecieaSlueriicreos (5 F143 50 pn Ncrosicnpiec Buarations (continues ler OFovretrailc sroegnrsetsseinvecsolpialttr,atie nwlie wcarsuloso,tenasl,itaarnliyl snat LuFPnuags.trrsy i oaAlttveomelaairinnwesac,,ropsohkiagneisng, smhualnteiffocasla,tiwoinld BThaeinf,olSowyinng CiosrstesJowereurfunn Stopbee,wiSthoinwsa,raul]Liintbss:tine, Lure Itetine, LriyoeryhtBeadeear,tehror)t,, TPuersest, iSlsiv,errEosnt,ie,ErW.ren, Told Troe, Esphs, iFunel tNhoeets5311 10ewe IlSeeassaSluerifcGerou 5 F-18 30 3n [---- Ho visible Leics. Wcrosrcpnic aration hort . artocnhoen,wainsei,ngteal, ide rlievers T"Fhurrtnalisproogrmesisivte seernohsIab,atwhildalg Tcergossosc,renasl,bewietn,d ile rs cMaalry wsinreriaiz,atonm,iatide, wild nratayoid Hoetsrehxasgies,tacal iwnesl,asaloef section Slay Bld St vasoe, msing he flloing tsses wre md to be withis som ints: Brain, Spinal Cord, Bone Narrow, Spleen, Stomach, Seal] Intestine, Large Intestine, UUrivnaryhtBeladedesr,aTteseti,s/EpPiudirdeynsi,s, EPer.ostate, Pituitary, Adrenal, Thyroid, Trachea, Esophagus, fFo--ck_a--br: asco Sorin STR pug: 16 180 00567 STnonirviizdueld RSaicnrgolsecoTpbiuclantdedMincaraos]copRieeporOtse(ncaotnitionnused) F-403: To Yer Oral ToiriacrityG-bnrcoagterniciet,y SItncu,y i8n Rats - Ow Yur nti Tae:1 iFantaedl teesrte:$1363161e3ur InSaerxiMaSlaecrificGerogs (9) F-10100 po Racfrorsceopc Buration: Karey HcrasTceopc Dervtion: Goer LPoagrstoid TestiEsdignis HSaulleltadnercaelsoer,d ares, 0.2 co ia, right one. HToerttialatornacyl,eafoccaall, ainniimlatlate, wile aNsecalloayrtenaiinse,ramliiantiimon, ald oTatbleeassetdra,p,sassienrpaltasnegmoefssse,ctiwoinlateral, aries rTaheinf,olSlpoian Ctoirs,snsfoeereMaroround, Stoobwe,wiKthoianya,rHmeartL,itSteo:nch, Sell Intestine, LEasrpghegeIsnt,esLtiynen, iNodve a(esBltaeddresr),,forFtaer,ePsro,staStle,vrPiytuGitaanrdy,, Are, Troi, Triches, iFanea:l Gobeeer: 556) 01 7Tear ItSeexrMaSliecrifcreua (9) F105 500 go RcrSetcaanpc aration: Hcrusictoepsc Bervtion: hfro siLonh Note arsnteric) "caenr,ates sete in the dorsal ares, 15 co nPeeriattiinsa,ticoint,, salntiiloactar,a,coarltidcal S"Higvaelloacrrosucisr,shaaiesm,emitifecal, ile Sahrwsetrohracguet,rsoinninsl BhUareiinnaf,roylSlBpoliaanslgterCt,oirstsh,uoerBsto,wnrTeNeatroriuosnn,aiStdsydlbneesa,wsi,HtheiPanrto,sstoaStroewa,scPLhii,aitiSsta:aly,InMtreestniln,e, TLhroigd,IntPeasrtaitnev,oid, Trachea, Esophagus, acres, Salivary lan, Ey. sPrpoijeecst:Naabter: EzbCROL2 Saurised SH Page: 17 181 00568 Suauarized Single Tabulated Mim) Report (continund) Individual MaRcirkoesrcoLpaibcoraatnodriMeisc,rosIcnocp.ic3O%bservations FO-143: Tuo Year Oral Tosicity-Dacogenicity Stady in Rats - One Year Interia Table: | fFaitnea:l ONhaeblesr:$3I)R-3162Y0ear InSet:iMaSluerificGerow: ( 5) FC-143 300 pp Macroscopic Oservations: Nicroscopic Observations: Khiodrnteay Liver Parathyroid Xo visible Lesions, Hot exanioed, aissing ""PCohrrtoanlicaopnroongarcelsesairvecenlelphrionpfaitlhtyr,ates,insi1alal NHeespaaltooccyyttoesivsa,cusoliantiiaoln, multifocal, simisal "Hot exanined, mot in plane of section The following Brain, Spinal tCiosrds,uesBonweereNarfroouwn,d Stoplebeen,witHheianrt,norLmuanlg, LiSntiotmsa:ch, Sell Intestine, Large Intestine, ULryianpahryNoBdlead(dueers,eTnetesrtiics),EpPiadnicdryeaaiss,,SParloisvtaartye,laPnit,uitEarrey., Adrenal, Thyroid, Trachea, Esophagus, Fiatae:lGaebekesr:$3R31 2Year InStexe:rMSaluecificGeeaupt (5) FC-143300poe Macroscopic Observations: ETeestis "Ocular opacity, bilateral, "Let testis sual. Nicroscopic Ghsarvations: KiEdeney "Cataract, bilateral "Chan progressive neshropathy, wile - Liver "Fortal aonenuclear cell infiltrate, sininal PWiegguaelnotc,ytKousipsf,eracienlils,albrom, animal Lung "Vascular aineralization, siniml Pirenuacnia, interstitial, chronic, seltifocal, PLayraapthhyNroodied aeseateric) ""HHoetnorexrahsaigoee,d,ailnodt in plane of section PrTeossttiastEepididais "Tautbuleexaantirnoepdh,y,aissspienrgmatogenesis, unilateral, wrked TBrhaeinf,olSlpoiwnianlg Ctoirsds,eeBsonweerMearfroouwn,d to be within normal linits: Spleen, Heart, Stomach, Seal] Intestine, Large Intestine, SUarliinvaarryyBllaadndde.r, Aorta, Pituitary, Adrenal, Thyroid, Traches, Esophagas, Pancreas, PSrpoejceicets:uRsabter: 0281080012 Sunrized STAR Pages 18 182 00569 dSuisvnirdiuzaeld RSaicnrgelsecoTpaibclaatdedhicraans]opficoretre(actonitoinnused) FES: Toe Yer Oral ToHiictietyo-rnacteonrciietsy, SItcd,y 3in% Rats One Your Intern Tale: 1 Ffiotea:l GNeaekbser5R1312Y6er InSterciaMSaulcerificreegs (5) FOALS 00 on Nacrosepic Oserations: Wicroasdcpriecs Osarations: Lr PLaoragthyroid PHrtousittaitrey So- visible Lesions, "FOorrotnailc wperaagcrelsesinve cnalglhrnafpiaitrya,tes,iniinlael ARlevaeluacrtoasiscr,oswhiangisn,lsltifocal, ale lHoott eearsiinne,, irasti1ngplane of section Fsroisntat)itis, craic, focal, interstitial, STahinf,olSlpoiwnailn Gtairsds,uesBownerMearfreonn,d Stpolebeen,wiHtehianr,soSrtaonei,witSsa:l Intestin, Large Intestine, iLensahryodBeai(re,stheorrtsa,, TPeusctrie/sEsp,idSibdiavsar,yrEelaanld,,ETe.hro, Traces, Exphages, fFaotiesl (Nsottee: 510)8316T2ear InSterctiaaSlaecrifioceus: (5) F103 30 pa RcrasLicvpeic Oaarations: HeroGseioric aeration: Pawraagthyroid "Sightly pale tan in color, F"ohretcarlrnwgree,sclloceaalraereaals,inwfiilletrate, asin] ol exsine, mt in plane f section BTrhaeinf,olSlpwiinnag Ctoirsds,uesBonseerMearornond, Stpolebeen,wiKtihdinneyn,orHmeaarti,niStto:aseh, Sal] Intestine, TLhurgoeieI,ntTersatcihneea,, UErisncairaygsB,atLiyrg,hfRoortdee, Taeessteinst/epici)d,iyPuaissc,resPsr,ostSaatlei,varPyitGuliatnadr,y,EeMr.enil, fFaotie:l MNeaebkesr: S5I0 R1 SYer InSterxiaKaSluecrificoeus (51 F143 30 pe Ncrsscpic atrations: WirLoisveesric servations: uLnygs ode (asenteric) e visible lesion, "Meretraolns,oamnictilfeonclc,ellwiilenfiltrate nies oHetsseerxaagien,e,1Hcissrnegs, ssterate SPrpoijeecst:Naabter: BICRIOIZ Sunnrized STR age: 19 183 C00570 ISnodminvriidzuaels miancgrloescoTpoibclaatnedRiMcnirgaaslcopRiecpoTrtowr(vcaottiinounnsd) FEE: To Yer Bal ToHiictitey-LOinveorsaptneirciiets,y SItcu,y 3in0 ats = One Yer Intern Tale: 1 fFaotoel GNeatbser $8 1 1 eur ntSeeicnMaSlaecrificreag: (5) E003 00 an WicroHsictoupiictiuryarations cantioued: PUrroisntaartyeBader oHott eexxssiinnee,, aaiisssiongg ot mrnine, sissing TBrhainf,olSlpoiwnian tCiasrs,uesBowneereNafrreouwd, tSolebee,witKhiicnoys,orHeartl,iwiStos:ws, Sell Intestine, LFiacrreesIsn,tesStailniev,arhyoltaa,n,TeEsrtei,sEpididass, Arenal, Thre, Farathyrid, Traces, Esaphges, Ffaotea!l sNkabserS6H 31 6eur ToStee:sMSaluecrifcre a (5) FS 00 an Naroscopic servations: Ncrosictpeirc Osarvtions: LiLvregr Intestine PaLryatshyNroodied (senteric) Myrsid o visible Lesions, "Serwastnoedisgsriesressive epropaty, sinionl egalacytois, aild oott erxusninees, aiissssiinngg "ot exaioe, nissig TBhaeinf,olSopwiinnagl Gtoirsds,uesBownereMarfreonwd, tSoplbeeen,witHheirnt,orLaulg,LiSmtitos:w, Seal Intestine, Urinary Blader, fSoarltiav,aTreysSthianEd,piErdei.as, Prasate, Pituitary, rem, Trche, Esophagus, Fares, IFraiee:l ewsatteer:5R9I1EeSu loSetctiaSlaecrificGerow: (51 F163 30 pp Racroscpic Gnerations: Weroshcuorptic Oserations: Xiidvorey Lng ke visible Lesions. "hocarial Gbrass, focal, wnimal sWorcianrlitis, chronic sensative focal, o"hrrtaanlicspsreomgrcelsseinvecnaelpriaapraitlrya,tea,ldwild Mcergaalsosc,ytowilst,ifsuocdaelr,ataeld sPcraeluasrs,siinnrtearlsitaittiiasl,, wdirlndic, sltifocal, aPelrdivascalar snaeclea inflate, wild SPpreocjieecst: MRaasther: ZBICROLZ Suanrized STH Page: 20 184 000571 ISnudaiwvaiidzuaeld MSiicnrgolsecoTpaibculaantdedWiMcaroaslcopRiepcor(ts.er(vcoanttiionnused) FES: Tao Yar tal TaRviikceirtyL-aDbnocraapteoirciiest,y SIntc.d 3in Rats - One Yur Ineria Table: | mFiatnea:l Gbeeirs: 53I)A1AYTear InSteexrnMaSlaecrifiececu (5) FO-143 300pp WicroPsacroaitchyrOosiedrvations (continued): ot canine, nat in plane of section BTrhaeinf,olSlpoinnianlg Ctoirsds,ueBsonweerMearfroounn,d Stpolebeen,wiStthoiwnacnho,rSaaln]itInst:estine, Large Intestine, UEsroisnhaargyesB,ladLdyearg,h hRoordta,neTseestteirsi/calid,idPraanrcsr,easP,rosStaaltiev,aryPiGtuliatna,ry,yeA.renal, Thyroid, Triches, nFaitne:a fKloeebtesr:$31)B-A164Y2ear InSetxe:rFeSmuaclreifiGcreoups (5) FC-143 300 pon NacrasEceopic Gservations: Nicrastceorpeisc Gservations: Ere tiLturngeey Intestine LiRnurearthyroid theres "Bhortohghhyo,rnrsiegntlaerrgee.d, Filled vith clear fluid, "FAurnoapphhyt,hawliiltaitse,rawli,latwaerrkaeld, warked ~HCehnrtaonbciapsriosgressive nephropathy, wild "SHoetpatesxcanyitneedv,icssoltatiinonp,lanmeiltoiffosceaclt,ionaild yEdxrdooenttrrait,s,sotcehrraatneic, aile rThaeif,olSlopwiinnag Ctoirsds,uesBoveereNarfroonwd, tSolebee,wiHtehairnt,norLumnagl,LSitmoimtasc:h, Small Intestine Urinary Blader, Lfyoorptah,oDduery(,ssReanntseirriyc)G,lanPda,ncrPeiatsu,itaSrayl,ivairryelnaln,d.Thyroid, Trach, Escphages, mFaitnea:l tKeobkesr: $3I)-14Y5ear InSteexr:nFeSmaaclreificGeroups (5) FC-143 300 ppn Racroscopic servations: NicrKaisdconpeiyc Observations: PLairvaetrhyroid Ho visible lesions. ""CHherpaantioccytperogvrieusasliavteionne,phsrlptaitfhoyc,alw,ildaild "Not exanined, not in plan of section TBhaeinf,alSlpoivnianlg tCoirsds,ueBsonweerNearfroouwn,d Stpolebeen,wiHtheianr,soLrumnlg,lSintiotmsc:h, Small Intestine, Lage Intestine, VEsroipnhaargyusB,laLdydeegrh, ANoordtea,(aWeesernutse,ricD)u,ryP,ancNraesass,arSaSllainvda,ryPBiltaunidt,aryE,ye.Arenal, Thyroid, Traches, SPpreocjieecst:hhaabter: az8ICROOL2 Suanarized STAR age: 20 185 G00572 SInudairviidzueald aScirngolsecoTpaibcalaantdedBiAcnrinoaslcopRiecpoOrtsse(rcvoanttiionnused) FL-143: Tao Year Oral ToRniikcearty-LOanbcoorgateonriiceist,y STtoucd.y 3in0 Rats - ne Year Interin Table: 1 Fmaitnea:l GNeaebkesr:$3IR-1 SY5ear IntSeerx:iaFSeamcarlieficGeroup (5)FC-143300 pou Macroscopic Observations: Nicroscopic Gservations: foLrivtesr LPuintgsitary ho visible lesions. "hHaetpaetxoacnyitneedv,acmuioslsaitnigon, multifocal, ail ""NHoetsarerxhaangien,ed,locaailssairnegas, wild TBhreainf,allSopniinanlg tCiorsds,uesBonweereHafroruonwd, bo be within normal Lists: Spleen, Kicoey, Heart, Stoaach, Seal Intestine, LTarragceheaI,nteEssteianhea,gesU,rinyarhy BlNaodddeer(,aeUsteetreurs,ic)O,varPya,ncNraeaasw,arySaGlliavnadr,y AGlraennda,l,EreT.hyroid, Parathyroid, fninal Nusber: IRS Sex:Female row { 5) FC-143 300 pp Fate: Weekes $3 1 Year Interin Sacrifice Wacrascopic Ghservations: Nicrosictonpeiyc Observations: Liver LLyunogsh Node (aesnteric) a visible lesions. "Chan progressive nephropathy, wile "HWeipnaetroaclyitzeativoanc,uolsautlitoinf,ocamlu,lticfoorctailc,al,ailadld "Hesorrhage, witifocal, wild "Hot easined, wissing The following tissues were found to be within normal lit: BUrraiinna,rySpBliamdlderC,ordA,orBtao,neUNtaerrruosw,,OSvpalreye,n,NaHmeaarrty, BSltaondn,schP,ituSeiatla]ry,InMtersetnianle,, LTahrygreoidI,ntePsatrianteh,yroid, Trachea, Esophagus, Pancreas, Salivary land, Eye. nFaitnea:] GNeaebesr:531)-01 6Y4ear InSteex:rnFeSmuaclreiicreoupt ( 5)FU-143300 goa Macroscopic Dservations: Wasary land "Sabcutaneous ass, 3.5 co ia. Lei inguinal MicroLsicvoepric Observations: Nasaary Gland Hepatocyte vacuolation, waitifocal, wild "Fibroamon TBhreainf,ollSopwiinanlg tCiorsds,uesBoweereMafroruonwd, tSpolebeen,witKhiidnneys,ersHaelartL,iniLtusn:g, Stonsch, wall Intestine, Large Intestine, Urinary Bladder, forts, Uterus, Dury, Pituitary, Adreml, Thyroie, SPpreocjieecst:MRaasther: 0281030012 Suanarized STR Page: 2 186 00573 ISnudainvairdiuzaeld aSicnrgolsecToapbculaatneddMiicorsos]copRiecporOtbse(rcvoanttiionunesd) FE-143: Tao Year Brad Toiictietry-LGanbcoorpaetnoirciietsy, SItnuc.dy 3in1 Rats = One Yer Interin Tle: | nFiatees:] eKeusr: 5I9)R-A1G6Y4ear InStee:rnFeSmaaclreificGeroup (5) FC-143 300 pp ThefoFliLcorvoisncgoitcisOshuseesrvwarteionfsoun(dconttoinbueedw)i:thin normal Tints (continued): Parathyroid, Trache, Esophagus, Linh Node (asenterc), Pancreas, Salivary Shand, Eye. fFaotie:l bMeaesthesr: $43)6186Year InStee:rFeSwaaclreifiGceroup (51 FCS300on Macroscopic Observations: NicraLsicvoeric Osernations: "ho visible lesions. FPorotratla aboilmeondacclteaprcoellilferiantfiiolnt,ratael,ewild BTrhaeinf,ollSpoivnianlg tCairsds,uefsonseeraerrfoouwn,d Stpolebeen,wiKtihdionwyn,ormHaelarti,niLtisn:g, Stomach, Seal Intestine, ' TLhayrrgoeidI,ntPeasrtaitnhey,raUirdi,narTyracBhleaad,deEr,spfhoargtias,,ULtearuhs,NoOdueary(,nesNeanntnearriyc)S,hanPda,ncrPeiatsu,itaSrayl,ivahriyrelnaln,d, Ere. fFaitnea:l OKhoerbieer:3A)G1EYSear ISteexr:inFeSmuaclreificGerow: {51FE-143300 pp Nacrascopc Ooservations: NicrLoisvceoric Ohsernations: Muanguna Shand visible lesions. H"Heeptaotrorchyatge,vwaacutlaftoicoanl,, awaltdifocal, ald Hot exanined, aissing BTrhaeinf,olSlopniimnlg Ctoirsds,uesBowneerMeadroonw,d tSpolebeen,wiKtihdinneyn,orHme]rtl,inSittosu:sch, Sal) Intestine, PLairragtehyIrnotieds,tinTer,achUerai,narEysapBhlaagdedse,r, Lyhoorgtha,NodUeter(uase,seDntuerryi,c),PiPtaunictraerays,, ASraelniavla,ryTGhlyarnodi,d,Ere. mFaitnea:l GKhasebeer: S5R04617Y]ear teSerxi:aFSeumclreificGeroup: ( 5) FC-143 300 pon NacroNsacosiecrQGslearnndtions: NicraKsicdonpecy Obserations: "Susbhcouutladnere,ous mass, co i, behind leit eClavlilcusa,imrpeallviizca,tiaoinl, wild SPrpoejceicetstMuhsatter: GZBICRO012 Sunnrized STAR Pg: 23 187 00574 SIundsiavriidzuaeld SRaicnrgolsecoTpaibculaantdedMipcirnosacopRiecpoOrbtse(rCvoanttiionnuse.d) FC-143: Too Year Oral TorRiickeirty-LSanbcoorgateonriiceist,y SItnucd,y i3n1 Rats = One Year Interia Tale: 1 fFnaitnea:l (Nbaeebtesr:SO1)8-4167Y1our InSteexr:inFeSmaaclreificBeroup ( 5) FC-143 300 pou Nicroscopic servations (continued): LLiinvger PNaarsaatahryyroGiladnd ""HHeiapiartrehcaygtee,vamclutsilfaotciaoln,, aelitleifocal, minimal F"Niobtraeaxtaennicnaesd, not in plase of section Trhaeinf,ollSopwiinnagl Ctoirsds,uesBowneereNarfroouwn,d tSoplbeeen,witHheianrt,norSmtaolnacLhi,nitSsw:all Intestine, Large Intestine, ULryisnaahryNodBlead(deesre,ntfeorritac,),ePraenscr,easO,rySa,liPviatruyitGalrayn,d,AdEryee.nal, Thyroid, Trachea, Esophagus, AFantieo:al WNeaebkesr:3R)-4162Y8ear IntSeexr:iaFSeamcarlieficGeroups ( 51 FO-14530 pp Macroscopic Gsermations: Nicrfoosrcotpsic Ghservations: LEasorpgheaguIsntestine LPianrgathyroid Xo visible Lesions, a"Htot eexaasniinneedd,, amiissssiinngg "hat exanioed, aissing ""HHaetaorerxhsaaignee,d,santoitfoicnalp,lanaeilof section BTrhaeinf,olSlpoiwrianlg tCoirsds,ueosnweerMearfroouwn,d SLpolebeen,wiLtihvienr,norKmiadloeyl,inHietasr:t, Stousch, Sul Intestine, Urinary Blader, Uterus, brary, Nawaary Gland, Pituitary, Adrenal, Thyroid, Trache, Lyaph Node neseateric), Pancreas, Salivary Sian, Eye. AFnaitnea:l (Neskbeer:$3R)417Ye6ar InSteer:iaFeSmaaclreifiGcreoups [ 5) FL-I4S 00 pou MacrosNcaospeiacryOGblsaenrdvations: Ni[erosicopic Observations: Heart Kidney Liver "Toaoreassu,bcu1t5ane0odus2aassdeisa.in oLetfht siindgeuinal Silk cyst, right side cyst filled with rust colored Fluid. "Sinusoidal ectasia, cortex, wild "aMyloecarditis, ironic nonssparative, focal, "Calculus, pelvic Hepatocyte vacuolation, multifocal, wild SPpreocjieecst:sRtaetr: 0281080012 Sunrized STAR Pages 24 188 : C00575 : rival Sussarized aSivonsgelceaLTnaibsrulsnaateerdeenAn,rieahsle,Rteporrta(tcoinotinnused) F155 To Yor BalToco-uogehfy Sod in Rts On Yer triTeoei 1 oFriets eYiotr51) 71 sYu ItSeersasnFuireicGroup 3 F-10530 pn PtE on -------- Try Sant p Sinta--cls -------- Soweottevt oed ith chic inlaptary recent sine TIRE ik cE Shaeinf,llSoyinng CtoisrstueTsoaereofrend Stpolebeen,wiSthoinussarSlelLliItn:sti, Lire ntstin, IWineryekBeakaersftrei Wreesn,,GuSyuiFrarStl,rTEoreey, Parad rch sabe rFetl lNeies 5R1EYu IoSeantnFSereeeGo) E183 0 0 [iAnaey-- Baer wet ty [ Faas-- Gir P-- arad eer inary Baste wes tBiahsteeerneetld dwctlhalawititinne0oafndwccbeonfttians.ininfgilgerdenwiisthh Sahlacr nr the 1 of on Sllatcesinmrtihedtricsre.p with sre xSoicriaeennis,,insaaterratl,scotwiioens JaPeotieetis,noi,,caw,iigwn ehatesof section TJ iana ---- SBpluitntiao,puerriepsen, sia, its, itd rCsiitrs,echrome hfe rte hreefeSlpoann Ctrsys,esBoeeerfoo,d StopbeewitLhiivneryrewrt,itLnsg:, Storch, Sul tation, LPragrie oSalnivarKyohrtt,,OtEey. aia, renal, Tras Trion gh Ne eeneric, PSaignetsaabt s BGR Swine STE ug: 25 189 0576 dSuiavairdiuaanld MSienrgsleeaTiacul0tedPicraolsspiceBtuscaosnttiioonnd) FEA: Too Tew Gal TrRiyit-eOcoargatmoirciietsy, SItnca,y in ats = Gn Ter Intern Tae: 1 nFaate]s eNensebrs513 19er ISteen:reSwicerifcge t (9) F100 360 on WcroEceapc Buratisns: LGearn Kote arenteric) Wcrosraepinc Brnations: be Lirnge LPrashtoNiotee arsneric) Thoid iTaglhet tnane iantcroptvei:d. Sesorrhgic SSitnruosoyi,calaatcetrsa,lcworrtie,t wild pPuaepthoaalaivtasc,atcioonn,c,wuwlitlisftoecras,l,wilrdied hHewsaorrirhagge,, laorcaildwes, aie oYotdwapapsonsti,, siatnsinetlasneseocftiosnection The along issues see found to be within ara Lite LBErurapgihena,gIeSstp,eintaFilannC,correids,n,aBorSnayeliBvMaaarrryeowS,,onSdfp,olretesn,, WKiedsnsey,, OHeyar,t, MStoonsatcyh,ShSamnadl,l PInitetsttiane,, Trachea, FTaiteadn eNsaweers5I3 1GEear InStenetreSermifiecer (51 F185 90 pon Ncrascopc Dervations: lo visible lesion. NrosTaisnic Dsrvtions: etrrhge, Loca ares, rte Lh Note arene Ja essai, ising Th folloing tissus wre foun to be within sora Lints: BLTrhrayirgno,idI,nStpeiPsntaailnteC,horedU,r,inBaornTyeraNBclaearsdr,doewr,E,xSpfpholraetegsne,,,eLPisvaesrc,,esKiO,drnyeSy,,uWMieaarret,sSaSSdtho,asnaecr,h,ePiStmuailtlarIyn,teKstiienen,, iFatae}ntsieer:S311 81 1ear InStaesrFSeumarlieficGeap (5 F143 300 gon Wcroscaic aration: Wcroasraeiacl uration: LUrrge ntestine o visible lesion, SNienmsstooifcianlsisecasa, corte, wild Sepatocye vacation, wltifoca, aild SFpracc:eart : 2CROL2 Sancizd STR Fuge: 20 190 00577 ISnuinvirdeudl RSaicnrgelsecoTpaiuclaantddRihciroaaslopRiecpoOrtomrCncoanttiiovnusrd) FEU: Tao Yar Ural TosHiikceirtyL-iDsnocraagteeiiceist,y STca,d i3n% Rts = One Year Interin Tae: | SFiotien GNeabtesr:$I9R1AeEur TnSteercinFeSwaaclreifiGcreoups (8 FCS 30 po Nicros[ca4pic Bsarvations (continued: "Herrhge, Tal areas, seteate BThienf,ollSoowuinlg oKries,sasBowneeraerfroenn,d Stpolebeen,wiKtihdinneyn,orHmeaarl,isSttso:nch, Sul ntestine, UErcianhaarygsB,asLiieg,h fNaordtes,(aWeasreesst,riDca,yP,uscRroessasr,ySSalainvda,ryPiGltaunad,ryE,e.Tyroid, Parathyroid, Trach, Ffiatea!] eNsatbeerS3I1 1TYour atSaerciFeSmuarlieficSeow: (5) F143 30 pn Nacroscpic Wervations: NicroHsecarpeics Oservations: Liver ny rsd o visible Lesions, "Csoirtteical degeneration, focal, wilateral, oHretpaatlocystnesvaicclsaalnaticoanl, imnlftiilftercaatle,, w#i1l1d4 "esocrarilarges,intrailifzaati,se,i1l1e4 ot exsaine, sat in plane of section SThaeinf,ollSouwtianlg Gtairsds,uesBowoereMarfroounn,d tSoplbeeen,wiKthiidnoyn,orHmartL,isStos:nic, Sul] Intestine, LTirrceheI,nteEsxtipnae,tsi,naLryayphBlNaedeir,esofotretrs,icO)a,rsPa,ncOrveaarsy,,SaNlavniayy SGhlaann,, FEirea.itary, Parathyrsd, SPpreocjieecst:NRaahtr: a28cRO12 Somurized STH Page: 27 191 ceesvs Surnarized Single Tabulated Mim) Apart Individual RaictreorscoLpiibcoraatnedriMeusc,rosIcnco.pic30Oservaticns FELT: Too Tear Oral Toxicity-Docogenicity Study in fats Table: 2 AFeaitnea:l (NWaebeiesr:1016)0-3T5e1r8ainal Sex Male Sacrifice Group ( 1) CONTROL 0 ppm Nacrassckoipnic Bhservations: Mierohsicroesriacl Observations: Haart Vitney Liver Long Parathyreid FiSteairitary Threid "hiftosaetdpati.nflassed lesion on right rear "CRoerttailclaalryacceulsltahtyipoenr,plawsiilat,idomclatli,fowcialld, wile "Mlyosccaalrdairteiass,, wraetneriactenonsprative, "DFherlavniiccspirnoegrraelsisziavteicnn,hriongaitnhly, ainisat "Portal ononuclear cell iniltrate, wininat "Ploarstcaollarbilaeineurcatlizpartoiloinf,eramtiaamn,i a:1d Parleesaania, iterstitial, chronic, wiltifscal, "Pteortiveansacvailnaer,aomnisosnicnlgear iniltrate, ssderate t"Peoedrodoenraatitis, cerativ, hineleg, marked Not eanires, missing BTrhaeinf,otSlpoiwriarls Gtoirsts,ueBsoeereMarfroouwn,d tSpolebeen,wiStthoiwnacnho,rmSaaalliniItnst:estine, Large Intestine, itary Hlagaee, Arta, Testis/Epiiapas, Prostate, Traches, Esophages, Lye Note tneseterscl, Pancreas, Salivary Shand, Ere. frist Nabors IRS19 Sex ale Graugt (13 CONTEC 0 pn Fate: (Weeks 106) Tersinal Sacrifice Macroscopic servations: FicrosHcraepniacl Bservations: HEesaorpthagus Liievneery 4a visible lesions. "SCionrutsiaciadlalvaeccotlaastiiao,n,corstuetsi,domciallt,ifeacialle, nile "lMayteceaxraimtiinse,d,rwainsisicngnosswrative, ~Cwhirtainfioccaplr,ograessive eparopathy, ald "PFoorrttaall baiolneenducclteaprrocleilfleriantfiiolnt,rataei,idwild sHielptatocyte alteratien, vacsolated, wtifocsl, SPpreocjieecst: Nfaastber: 0281080012 Suarized STH Page: 20 192 CO5'79 Sfarnriiates iSingale TlilatedpniaaamiBssgri(ottiinme RAS To YeoueGrraLoTerossortes,anrp. c Say i ats rae 2 Fite eh 10) Terns Sutice pp Wcosoasmic Oration ction: iFecveirrtwioamtciioenn, wiinlletrate, strate wFaens, artis,! ots mics Hhaei,fStivm Ctri,seHowereaafunnd Stopebee,wiSthoinwvarul]Linttstine Luge Intestin, UUoiedEekiintFrort,e, TPreesedSitassyrBstrte,oet. tn, Trove Foatests, Triches iFbl eNter 0BrEiceSein Nwareensoo 1) ENR 0 ParSons Geeations Sliiwe WeraPaEns Graton: Koirtets i. os - SPirnityoie Sis ton 4F0a3e ind fsa wcwratd, | Ei "Fartlicaalyscaaalltipoens,tesa,l aseis,siwi,le itd sDicvaarnedprfoitrieesn,rstsriaoa,l 6trite Sierntacere waitin, colon, Saiicaa,ieerrastitaittiioan,, owinec, eal arse, [iere ---- FTibrrosois, plea, le raetnens,,wiwcswnativs, bse, wrk Piereiemi reaioritag iy Frew simian, arise he felloin tsses were md to be within renal ints: TeBPsraatiiinrs,sES,psindSairliaaCorsryd,rhBeostneteM,aErrer.Howu, tSesal,l Tarte Intestine, Tracie Eps gh Large Intestine, Urinary HBleaedde(r,sAnoratar, l f-- inp-- Swain ST age: 29 . 193 cces30 SIunninvriidezaeld SaicnrgolescTpaiuclaatnedNficarolscoRpeiscorOtbsCecrovnattiinounest) FLA: Tos YeirteBralLiToorstiocriiteys-,GcaTgoecn.ici1ty Stay in fats tle 2 fFaoea:l eNkoee:953)5S3ac5rificeSd ein Mearleentrou (1) CTRL 0 pn NacroSsoctpicTiOsssueersut(itohanrsa:n) stone Piroscraesailc Bservations: teiunrty Live ng frosate sn stony "F.ass, 10% 9x cn in Lait ailla smolvieg wTsittlethoarnadcircib,unisttye,nticnogllaipnstisng Ie Lug. "WPIaTssedsonfattaons wfiatthty.posible lceration in arta, "CSoirtsicsail ]waceacetlaastii,on,carmtietsi,fofauls,ew,ildwild ""WCyocnaicraplrofgirbersossiivse,sweihtriaftahcyl,, wwiillee "oForrttaall sbiolwendculctenprcoellilfersantfiiolnr,atwei,leitd ~Haespeaatlzrcteaiavletearlaitaiotni,c,vawsialldaec, ai hAelcearlrahrgew,acfreaglha,pesm,1Ewild "Friborsoastairtcso,n,actuhtoer,axscparative, awrked weerlatdieffecorlelnatgieastef,orhmiagthiolny.cellular vith cer, wares Trhaeind,olSlpaarls tCiosrs,uesBweereNafrard, tSpbleen,witShaianlnoIrnataelstiLnnei,tsL:arge Intestine, Urinary Blaser, Lfeyrtea, aTceest(saErpeinctiereiyci)s,, PPaintcuriatsar,y,SaTlhiyvraoriyd,ShPanadr,athEyyreo.id, Trach, Escphges, Ffartien:leNotsteer:1081) 5Te0rina SSuecifMiaclee Grout (1) CONTROL 0 0 WrFaisisiteursyervations: Niroshceorneinct Wernations: iday ULarrge Intestine "sul red lesion. ""RCerdaatnlearyprcaerlessbiyvpersnlaespioap,atmlyt,ifsoocdarl,atewild HPeenlviitciaaisnesr,aliczoaltoinon, ail "hFeorattaaleystsemoaelctleeraartiocne,llvianufliltterdat,e,soadlelrdate Portal bile dct proliferation, aild sPpreocjieecst:Naabter: ZBICROIZ Sawrived SW Pe 0 Go0c1R9g4 Summarized Individual RSaicnrgolsecoTpaibculaantdedMifcnriaoaslcopRiepcorDti.se(rcaotniinosnesd) FE-IA3: Too YeaRrikOerralLaTboorsaitcoirtiye-sD,acoTgeec.nici3ty Study in Rats Table: 2 final Fate: OMakndeer:1081)53Te5r0minal SSaecxriMfailcee Grow ( 1) CONTROL 0 pon KicrosLcrognic Observatiars (ccatinaed): LPyaarsahthNyordoeid(esenteric) PTihtwuriatiadry :Vascular wineralizatios, wile ""Nhoott eexxasnaiinneedd,, aniostsiinngplane of section -Fboilelniocnuslar hyperplasia, cystic, unilateral, woLdaerrgaetecystic lesion occapying auch of te thyroid lobe. The fallouing tissues were found to be within sors limits: Grain, Berka, STpeisntails/CEosridd,icGyoanse,MaPrrrooswt,ateSp,leTerna,cheHse,artE,soSpthoangsucsh,, PSaunaclrleasI,nteSsatliinvea,ryUriiansaer,y BElyaed.der, Ail Nowbers 1R-3S25 Sect Male Grasp (1) CONTROL O pan Fate: (beets 106) Terainal Sacrifice Macroscopic Bservations: ne Liver Microsrceonpiacl hservations: tee Heart LKiivdenrey Lung Parathyraie SpTleesetins/Epidiemis "Joints of right forelind and right hndlinh "hasiuslelenp.ale circular lesion, 2 ca dia, in wedial lobe. ""Caorrtthirciatlis,vacsuyanloavtiitoins,} ljoocianlts,arefaosr,elewgo,derate "hHiynsdclaergd,itissa,rkecthronic roasuppurative, Local areas, wild "Chronic progressive nepraputhy, moderate "hPaorrttaall obnileenedculcetarprcoellilfernadtiilotnr,ataei,ldmild HeLpaartgoe,celplouolralry cdairfcfienroennstiated, anaplastic, ienfailltraitnivleu.ng.Adenoid areas, Maltiple turer "Wveatsacsutlaatricainneeorpallaiszeation, aild "Not exanioed, not in plane of section ""HTeuabsusliedeartorsoipsh,y,wialsdpermatogenesis, aild BThreainf,ollSopwiimnlg Ctoirsds,uesBoenereNarfroouen,d tSotobaescwh,ithSienal]norImnatlestliinnei,ts:Large Intestine, Urinary Bladder, PSrpoejceiecst:eRsatter: 0281CR0012 Summarized STAR Page: 31 195 G00582 SInudmimvairdiuzaeld aScirngolsecoTpaibculaatndedMiMcrriansaclonRiecpoOrtbse(rcvoanttiionnused) FLAT: Tuo TeaRrikOerralLaTboorriactoirtiye-sD,rcoIgnecn.icity Study in Rats Table: 2 AFantie:l Moeaetkesr:106()R3Te5r2ainal SSaecxrifFiaclee Group? (1) CONTRI, 0pon The fFailclrsawsicnaypitcissBuhesservwaetrieonfsouncdonttoinbueedw)i:thin ners .Lins (continued): fSoarltisv,arPyroSsltaantte,,ErPeituitary, Thyroid, Trackes, Esophagus, Lyssh hate (aesenteric], Pancreas, FAaotien:alWNeeevkesr:1061!6-T3e5r2ainal SSaeccrtifWiaclee Grau: (1) CONTROL gps Fasroscopic Bhservations: Microscopic Oervations: Li[vrere Lung Ho visible Lesions. "Earonic progressive eshropathy, wile "PFoorrttaall baiolneenduucclteaprrocleilf!eriantfiiclat,ratmel,ewile HCerssattooicdytdeegaelnteerraattiioonn,, fvocaaclw,lawtielde, aild "vascular aiseralization, wil The following rain, Spiral tissues ware foun Cord, Bone Marron, to be within normal limits: Spiess, Heat, Stowach, Suall Intestine, Large Intestine, UTrriancaheray,BlEassgttearg,usf,ortLa,hTesctiesEs{aiedsieznytaeirsi,c),ProPsatnactree,as,PitSuailtiavrayr,y SAldarnedn,al,yeT.hyroid, Parathyroid, frisal Fate: (NHeaeblesr:108B) IToEran SSieccrifailcee Gro { 1) CONTROLO gon Nacrescepic Qservations: HicroVsicanpeiyc Diservations: Khiidrneenayl Liver Lng Pituitary Htronirosis "Cortical vacwlation, focal, ald ~HCyhrreanniecghprroosgirse,ssuinvielanteesrharlo,patahoyd,erastoederate "PFoorrttaall baiplneanduucclteaprrocleilfleriantfiiolnt,ratwei,ldwild "HHoagsacuzloacryteainvearcawlliaztaitoino,n,mmeitlidfacal, silg Presssnia, interstitial, chronic, aultifecal, "hayipledrplasia, focal, pars distalis, wild BTrhaeinf,olSlpoiwrianlg Ctoirsds,ueBsoneereMarfroouwn,d to be within normal Linits: Spleen, Heart, Stoasch, Seal] Intestine, Large Intestine, Urinary Bladder, hort, Testis/Epiticyais, Prostate, Thyroid, Parathyroid, Traches, Esophagus, PSrpoegceiecst:NuRsabter: 028100012 Suanaeized STAR Page: 32 196 00583 SIannirtiizaels RSiTtEeETPaCb1ldaWorneaslcoensrtBercaettiionnnst) F-13 Ta teairarraUsToaoterier,egInec.ncy Say in Rats Tale 2 SFietel eWsaes10I 0) Teraiml SSectifailcee Gros 1) COREL 0 30 The fWaalrlsosuotpitcisBssesrnttrieo1n6(dctontibneues)i:thin som Tits tind): Ly hoe esterscly pres, Saliva Gln, Ee SFuuen wNhoete30I) SgificedSeien HeatlrenisGroat (1) CONTROL 0 po WrSaarp Bertions: Lr Hereoriacl Gserations: Kilidvoetry ws fPraosstatte a Shisry Sse iney Beer recasteofsdebramca,titsiisd,thaouni .Los, so aiosee. sale ane, 11 a a, i 10 Dera ""tCrrotniiaclrvogcroelsastiivoen,petwoisafthay,, sallg FHoeratthcesllalnartcaarccinealnsimitate, vite Tdriassecslainpa,ter, fairly wil aSsecol,arsasileeaini,ntisoinw,itseil oott raasioen,, asaitsiinnglan of section cate,usbickn,,smioinnsg, wried "teal hperlasa, sil, eft, 616 The ottoning sss wre fond to be within ara Lit KFBoraractiern,,esTS,epsitniEasel.aCourd,dBion,e MPartruorwa,rySp,leeTnr,oHiea,rt,TrSatcohmea,ch,EsSaeablglesIntiesthine,RodLeargeesIenttesetirner, TFaataeleNeaseer:1001) T5erisl SScurtifailcse rp 11 CONTROL 0 gon Hrosic Gharations: Heraonitc Oharations: LGivienrg o visie Lesions. sacnairmtailtis, oronic norsmrativ, foal, oTForrtnl sporongerelsesirvecsalsinpfil,tratweilewild FCoarttieabisleegndecattiporno,liffeorcaatli,ont,ed1r1a6te Heastort alteration, vcwlate, ald SPorcoijoest: Maatbe: Q20ER012 Sanrizd STR Pigs 35 197 00584 SInudmimvairdiuzaeld RSaicnrgolsecoTpaibculaantdedMidcarinoaslcopRiecortO.bse(rcvoanttiionnused) FEAT: Too TeaRrikOerralLaTboorsaitcoirtiye-sD,ncoIgnecn,ici3ty Study 1a Rats Table: 2 Arisa] aber: R530 Sex: Male row ( 1) CONTROL 0 gon Fate: Wek 108 Terminal Sacrifice Micros[co4pic Diservations (continued): Spies "pSearsicbarloanrchwiianleraIlyiszpahteiiodn,hypaielrlisia, wild "hesosiderasis, ails The following tissues were font to be within rormal Limits: Bforratien,,TeSspitniasl ECsoirtdi,ovBaiosn, FParrorsotwa,teS,toPeaicthu,itaSreya,llArIentneaslt,ineT,hyrLoairdg,e PIanrtaetshtyirnoei,d,UrTirnaacrhyeaB,laseer, Ssgghagis, Lyn Kode taeseatersc), Pancreas, Salivary Gland, Eye. Ffantien:al WNeoeakbsert1081)6-T3e5r3m1inal SSaecxrifailcee Seoups | 1) COVIRDL 0 gpa Macroscapic Observations: Micro[sco0pic Observations: Liver Lang Xo visible Lesions. ""CHherpoantioccyptreogvraecsusoilavteioane,prcmuplattihfyo,calw,ildaild Portal sonaclear cell infiltrate, wininal "Fvrasecsunliara,wiinnetnearlsitziattiiaoln,, cwhirlodnic, local areas, trate The fallosisg Grain, Spiral Ctoirses,aesonweerMearfroouwn,d Stpolebeen,wiKtheianr,noSrtsoanlsclhi,nStw:all Intestine, Large Intestine, Urinary Traches, BEasodprha,gusR,otya,hTeNsotdies/E(pniedsiednytaeirsi,c),PrPoasntcarteea,s,PiStauliitvaarryy, BMldarnedm,l,EreT.hyroid, Parathyaic, final Nasber: R352 Sex: Male Grogs ( 1) CONTROL 0 pon Fate: (eek 108) Terminal Sacrifice MacroPsictoupiitcarDyservations: NicroKsicdonpiecy Bservations: HEeraert Kidney Liver Lng ""RFaliusiedfrieldleadscsy,st,0.41 aco ddiiaa.., in right Kidney h"Heytsicnaarldiaaltrofpihbyr,osifso,calf,ocwali,lewild "CChyrsotn,iccoprrtiocgarle,ssiavrekendephropathy, soderate "pPoorrttaall sboinlaemudcuicetarprcoellilferiantfiiolnt,ratwei,ldald "Pvraesscauclnaira,siimnetaelrisztaittiioaln,, wild chan, mltifocal, pHesmorrhage, local areas, wild Perivascailr sonoma infiltrate, ail PSrpoejceicets:NaRsabter: 0281080012 Sumvarized STIR Page: 34 198 C00585 ISnudainviirdiuzaeld RSaicnrgolsecoTpaivcalaantdedMiAcnrimoaslcoskiecpOtbse(rcvoanttiionnused) Riker Liboratories, Ine. 30 FEAIA3: Tuo Year ral Toncity-Dicogencity Study in Rats Table: 2 AFraitaes:] (Mhoeaebhe=r:10I6)RITSeTr2ainal SSaectriWfailcee Groups (1) CONTRDL 0 pon Bicrescapic hservations (continued): PLiytausihtaNroyde aesenteric) Sivan 3 hHeewraroeshage, wile "Hevssiderosis, wild The faliauing tissues were fone to be within normal Limits: RBorratian,, TSepsitnails/ECaoircdi,dyfaoinse, MParrorsotna,teS,toAmdarcehn,alS,eaTlhlyrIonitde,stPianre,athLyarrogied,InTtresatcihnee,, EUsroipnnairgyusS,laFdasnecrr,ess, Salivary Bland. Ffaitnea:lNMeossthser:10R6ISTTe3ra) SSaecx:rifMiaclee Grow: ( 1) CONTROL 4 gp Nacroscopic Bservations: MicrSopslcoepeinc Gsarvations: Ere Heart tidney Liver Lng Spsrioesetnate "Fale circular depressed area, 0.4 ca ia. No diagnosis, inadequate section "wMiyotciafredciatli,s,wiclhdronic nonswpurative, "Exranic progressive nepropathy, eile "PHoerstaatlocyatneonvuacclselaarticoenll, iwnidlitliidroactael,, 4e1i2lde vPaoseawlonaira,aiinnetrearlsitziattiiaoln,, cwihlid c, sultifocal, Pselrgivascalar sovonclear infiltrate, wild ""HPersossstiadteirtaissi,s,acawtiel,d supprative, aild Fitrasis, local areas, soderate BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueBsonveerMearfroounn,d Sttoombaechw,itSheianl]norImnatlestLiinnei,ts:Large Intestine, Urinary Blader, Lhyuerstsh,NoTdeestiase/sEepnitdeireiyca)i,s,PaPnictrueiatsa,ry,SalAidvraernyal,GlaTnhdy.roid, Parathyroid, Trachea, Esophagus, Ffraitnea:l (Measihser:105I)RSIacSrificeSdei:n eKaslteranisGroups ( 1) CONTRIL 0 pp NacrosTchyoupuisc Dservations: Piscreas ""EHnalsasrigveedbeige colored mass, 7.5% 3 ca in area of pancreas comletely asruerarsouonfdirnigghstpleaennd alenidtadlhateerrianlg to postericr SPpreocjieecst:NaRnatber: 0281020012 Suanarized STS Page: 3% 199 00586 ISnadwriitsueld rSiiegeRlrceoLTpsbcoualtaaantreiredso,sncalpoci.Rtes3es0ter(vcanttiiountst) F101 To Yer GalTenbyDect Stat in Rats Tle: 2 eFaatel tNhaisser191) S0ucrificedSen1t FealreesGrunt (1) CONTROL 0p Fcrossic Guration (cntined: jpiacses eatin) tTirate HiSreeems Bsrtions: sieey Lwivger Loh Kate arsntericl faFaratehsyrot FistuultirIyntestine tSoeuecnh Testa Eididyis Tes iTnraoriyd Bhdter ailverwldobsesi.tes. TFailghetwittehstyiesllsouwils.h circular lesicn 03 x Ganetr 1 right marion Le "CWoertaicralyvccellaltpiorn,aiifafsel,aacotearraetse, rsioariteragressive osbrpathy, sere Hlaipogctyepvhaoasnt,ioMns,tidcifoftuisce, wrked SWevloirgrninagte,Iydhifofsuss,e, Nwisrtkiesdetic Hlenirgrhtae,Iyap1hons, bisticetic KlotirgatnoeI,ghwoinssi,ngMstiseytic l"iirognase, histicrtic l"Riliggntst yInogtmon,s, NMssttiiocrottiicc "rTiuelde strsh, sseratapenss, silat, iWglteilne sIenctgieonns,ofhitstuircrtfircon tic anc otsdiaintninea, aariessi.ng hig Ions, Mstisrtic rThaeif,llSopiinoag Ctaisrs,uesBowereMarfroounn,d htoerbe,wTitrhaicness,oErxactiansts,:Salivary Sand, Ev, Large neste, hort, Prostate. SPpreocjieecst:WRaavtes G2GRO1Z Sunrized ST Page: 36 200 00587 TSudainvairsiiaaelg BSiengrlesoTbnulnteedMiicreosscopRiecgeOrsercvoanttiionunesd) FUT: Tao YukreOrralLaTbooriactiotriye-sr,eongce,nic3t0y Stdy in Rats Tale: 2 fFaotaesl hNeoene1065) T%erinal SSaecriMfailcee rags 1) CONTROL @ pn Rcrospzoense servations: Nicrosrcaepnict Dissruations: KLiidrneey Intestine Liver Lg sun Suciases,lesion, 15 eb a, apes te be "CSoirtsicsail ]vaseacltatsi,on,Carftoeasl,, fiotald, aerate "Aerwastnoetiapsrioag,rescsoilvoen sepapaty, aininsl Faoirdta bile duct praiferation, mltifeal, FHorataltoananvcalcoealarticoenll, imnlftiilftroaatle,, wsiolidns "Piercivaalsclsai"nedaolniaantciloenn, i1n1f6late, il "riasteediaLnetsiioonnfran back BTrhinf,atSlpoinnialc Ctoirsds,isBonweeraerfroewn,d Staylboew,wiethairnl,noSrtmoanlicihn,iSte:al) Intestine, horta, LTeosthishiedi(owtsesr,teiPrco)s,tatPea,cPeistu,itaSruy,vaTyreGdl,an,FaEreat,hyUoriidn,ryTrScahtei,e.Estas, fFaotiesl aWskose 101)13F5ou5n esdSec Male rou C1) CONTROL 0 pe RcrasLciovpeic Oserations: RLoyasrsotGesteCraadaeln)ial) "SeernyspIieya notes enlarge hatttacehes,to ofveeryt,saesf, 4inxgi3n5alx 1.5 HiroFsieuciitcarsyervations: Htoert Live tng FiLcryesNsote (anenteric) Parathyreis Hesarriagic mss, 0.7 co fis, oatlisganidI,tgwhiosmi,ngNisticoytic STeaslaitgsnortteLvyashcoantsi,onhi,stiicfcfrutiec, awrked lHeingrehhtge,Lylpohcoanls,arehaiss,tissoedteircate oHott eerrmniinee,, wwiisssiinngg Not erwin, wising PSrpoejceicets:MaRaster: ZBICROIZ Sunrized STAR Page: 37 201 CG0588 ISnudsimvairdiuzaeld RSaicnrgelsecoTpaibculaantdedMifcoriaoaslcopRiepcorDtb.se(rcvoanttiionnused) Riker Laboratories, Inc. FEAT: Too Year Gal Tovicity-Oncogenicity Study in Ruts Tale: 2 fFnaitsea:l GMeaedkesr:79R)1F5ou7nd DeadSea: Male Grow: (1) CONTROL 0 pon Nieroscepic servations (continued): PiSthiunitary splers Thyroid ""Mbaileirgoumst Iyshon, histiscytic MIpasspshofnrao.n iTnhgeurienalwasareeaxtewnassivaealingeucarnotsis ie "Hetwacnesi,derosis, aild "Not exaninet, missing BTrhaessf,alSlpoinnianlg tCoirsds,seBsoweerMearfroouwn,d Ktiedabeey,witSthoimnacnho,rmaSelalL]inIntt:estine, Large Intestine, Urinary Satter, orta, Testis/Epiticyais, Prostate, teem, Traches, Esophagus, Salivary Elase. foiaal bert IRIE Sect Male Group: (1) CONRL 0 pon Fate: heeks 106) Terairal Sacrifice NacrPoistcuopiitcarOybservations: LiSpvleeren Microhsocroepniacl Dservations: LKiivdenery Ling PLayreasthhyNroodied tnsateric) PSrpolsetenate Urinary Bladder "Suall hesorrhagic ares, 0.2 co 6a. ""Ewnallatrigpelde pale foci, all lobes. ""tCehrrtoinciacl pvraocguroelsastiivoen,nefsohcraolp,athayi,lile "Maligeant Iyeshosa, histiocytic "Avlavsecsullaarr smaicerroaplhiangaetsi,oni,lemild Naliguant Iysghona, histiocytic "PHeeraiovrarshcaaglea,rissooinnuclear infiltrate, ail "PHrootsteaxtaistiinse,d, ancoutte,iaspulpapnueratofives,ectmiaornked "maligunt Iyspbon, histiocytic "Epithelial hyperplasia, simple, diffuse, wild The following tissues were found to be within normal linits: Brain, Sim Cord, bone Narrow, Heart, Stonach, Seal] Intestine, Large Intestine, horta, Testis Epitidyais, Pituitary, Thyroid, Trackes, Esophagus, Pancreas, Salivary Bland, Eye. SPpreocjieecst:MaRantder: 028108012 Suarized STAR Page: 36 202 G0589 SIunmcmivairdiuzaeld NSiicnrgelsecaTpaibculaatneddMinciraoslcopRiecporOtbse(rcvoanttiionnused) FW: Te YeaRrikaerlLaTbooriactiotryi-eOsn,caIgnecn.icity Stay in Rats Table: 2 final Fate: (Mhoansdtoer:10I6)R3T5e3r9ninal SSeaxc:riMfailcee Grow (1) CONTROL 0 ppm Facroscosic Bhaervations: Micros[c2opic Qservations: LLiavregre Intestine Long PPiatruaitthayrrysic TShpylreoeind ko visible lesions. "NOehnraatnoitcispsriosg,rescsoilvoen neshrogathy, nile "FHoergtaatlocaystmeonviacclseoalraticoelnl, minuflitlitfroactael,, wmiilled "FVrasecwuclnaira,aiinnetrearlsitziattiiaoln,, sild chronic, multifocal, Pseirtievascalar woonaclear infiltrate, ald ""DNyostt,expaamrisnedd,istnaoltisin plane of section "~UHietwoissibdrearnceshiisd,l weirlsdt bTrhaeinf,olSlpoinnianlg Gtoirses,ueBsonweerMearfroouwn,d Hteoarbte, wSittohmianchn,orSmaulaLiInntte:stine, Urinary Bladder, Rorta, TestisfEsidierais, Prostate, Adrenal, Trache, Escphags, Lyaph Rode (nesenteric), Pancreas, Salivary Bland, Be. Ariaal Naber: RISO Sex Wale Greust (1) CINRDL 0 gpa Fate: beets 44) Fount Dead Macroscopic Observations: Microscopic Dbservations: LiovneerMarron ry pSrpoinsatlateCort Thyroid Urinary Bladder Xo visible lesions. ""NFootrtaelnansioneend,clweiasrsincgel) infiltrate, wild "Pvoarstcaullarbilwenednuacltizpartoiloinf,erawtiilodn, wild Eiveslar aacrophages, oil Kheatt eexxasnaiinneesd,, maiissssiinngg "Ultiecbranchial cyst "Not exanined, aissing BTrhaeinf,olSlpolweienng, tKiisdsnueeys, vHeeraertf,ounSdtomtaochb,e SwmiatlhlinInntoersntailneL,inLiatsr:ge Intestine, Aorta, PTaensctriesa/sE,piSdaildiyvaairsy, BPliatnudi,tarvye,.Adrenal, Parathyroid, Triches, Esophagus, Lymph ode (aesenteric), PSrpoejceicets:MaRsahter: 281CR002 Suanirized STR Page: 39 203 G00590 ISnadnirviiszueals rSietse oTnblantedAiirnasltpRicpOteetaaitinonts) F143: Ton eaRriGealLTaossrcsatriBe, sfcm. t Sty ie ats Tie: 2 iFaaten tNhaibesr:1065 ) Terra SSueriFWiaclee Gross (1) CONTROL 0 gon NaroSsanpc sation: Wcrorcemiac Serations: Livgerrey Lay sireose TeisntairsyEiSdhaigotenris Faied Lesion an 166 re ft, CSairmsiociadalelsaettiao,n,forftoceasl,, niilsal "FoGrrtaailcsraognreistaivcseleirmieli.atea, iaise "FasocratlarBlmenedacltizeatailoenr,tailogn, itd Faiaetes ntrsttia, Gesc, wltifcal, SPeeriavarsc,lardisffousoen, ewrakefdiltrate, nile oottedewaasstnit,i,issihnrgine, Nidies, wiried aJott sseiinnss, iAsiisnign aToien,olSloiu]e tairs,snsFoeereMarcrodn, StopeSeen,witHheirnt,sSrtwoncLhi,itSse:al Intestine, Lure Intestine, Sritlv,wyFtSaltanatr,y,freT,rost, Faathrid, Traoen, Expat, Lh Rods ean), Pres, Fiatnesl evnasees108I) TRewial SScercifailcee ro 1 CONHOL O pn NaroTsesotpics pBeirvdtieons: "oth testes smal. Moroasnsec Garvitions: "Ovic regressive sgpromaty, sorte fLorg ZHnasptaatlooytessveaaclaitatiioonn,,sauntimoacls, a6 PaLocrsNsate arsnteric) SHpeserprtaaaiga,,sIisnlientlcell, woteate Tati Eiditmis "wniilee strap, sserstspnens, bilateral, Toit oFtolpmaarsteoint,i,iaslieng rhaeinf,olSlpoailn toirsds,nsBoanreFaorouen, tSoslbeer,witHheirnt,soSroawiLhi,nitSsu:l! Intestin, Lrg Intestine, Wpiintshylade, Korth, Prostte, Fiustary, Kien, Prahyrei, Tichs, Suivwry San, 6, Psrpossse:Maabte: 2010802 Saurized STA Fags 40 204 00591 SIunmdmivairdiuzaeld RSaicnrgolsecoTpaibclaatndeeWigcnrinoaslcopRiecpoOrbtse(rcvoanttiionnused) FELT: Too TeaRrikOerralLaTboorxaitcoirtiye-sD,ncoIgnecn.ici0ty Study in Rats Table: 2 AFraatne:a] (Nhaeebtesr:106R)3T5er0uinal SSaecxriafilcee Group (1) CONTROL 0 33m Racrsscapic servations: PiKtiuenietyary MicrosTceosptiics/EOgsiedrivdahtaiiosns: Harensl igrey LLiinvger Pancreas Parathyrois PSiptlueitnary Testis/Epidieyais ""HBeestehrrehnalgaircgedl,esipoanl,e 0n.t7 pcnittGiead.. "Left testis suall. "CSoirntsiscoaildalvaceucotlaastiiao,n,comrattei,foacnaste,rastceterate ""Chherpoantioccyptreogvraecsussilvaetionne,hraelgtaitdhoyc,alm,ark4e1d1d "vAalsvceuollaarr wmiancerreaglhiazgaets,iona,wl "PAoilmyaarrteartirtoiast,y,soadledrate "Not exanined, not in plane of section "kHieaecsniderosis, il "Twurbkuelde atrophy, asperaatogenesis, wailateral, Pelyirteritis, irked The following brain, Spinal tists were found Gord, Bone Marrow, Sttoosbaechw,itShienllsaIrnmtlestliinnei,ts:Large Intestine, Urinary Bladder, HHuorrtta,, Prostate, Thyroid, Traches, Essphaqus, Lymph Made (nesenteric), Salivary Bland, Eye, FAartien:al ONlaebker:108I) BFIouSnd Sex Dead Male Groups ( 1) CONTRIL 0 gpa Macrsohsiconpic Observations: MicrLosicvoepric Observations: hired HeEarre t Xidoey Lung PPiatnucirteaarsy "Circular lesions, 2.5 ca dia. on both hind "slfiagahtptaltys.ple "SCionrutsiociadlalvceucstlaastai,on,corsatlet,ifsaectale,ratseoferate ""ANyootcaerxgainailnedf,ibrwoississi,nglocal areas, aild ""VCahsrcounliacrpariomgrreaslsiizvaetinoenh,rcwgialtdhy, ail "Ahlevienoalraratrmoapchryo,phasgoedse,rataeld "bern PSpreocgieecst:Nfoastter: 0201080012 Suanarized STA Pages 41 205 00592 Sraenriisoees StiingowlesTLsialwaat1aerdiWenrsaalssef,s8thetsattionis RA5 To Yur Ba Toiapi Sayi ats nae 2 ovat aves 150 Se tes (1 GOR 6 0 BES: Fate: (Meek= 104) Found Dead T COPY AV,ILA - rSeshteent,itiasw,dwicking, Nett, Siem Aenean re. sre, vhei,feSlpoan CtosrstesFoeeeNaetrodn vSo sbe tShhianwnrrELneti, ure nein, Usohyveietaaelsthiatb,iitesetnht haiha Mash i a Se wie Gr 0 EN, jpo i apss, 0 ta woeeen "SSsLiensusecimtetalrraeetinasotsna, e oetre, wdeate fur, rity [. ChCinre Peet E eis y5 taitnen ei hn te, iE je Srotia ewosoeosGo, ptrraatiea,, isaae Hwraeiti Suieam saint wie Haw Son sic, tere FSCeeitasa eTeaeto,i eEHeotmereson,e,esSfthaedntsoceThotstiS,unlrsatetitnenei,terTsrsiosI,ntSesatipn,a,rina Blase, i ete omental aero, Sear Bah, Fe. FFitt eaibe101) T0rin SSeretee Gr (0) COUR 6 an [r---- Werosraesc Gseations: Ho visible sions. Sartical vaalatsn, wits, sig Fo Species: aRbatr: CEN Summarized STH Fage: 42 206 00593 ISnofvrideuas} TSiOtReITCatnadsWiionstloneipcoretracttiionnasd) . F-13 Tao TeirbGeraLiTerotacriesr,egInec,ncy Sad in Rats Tae:2 SFiitel tNheees1085) 0T8ras SSuurtifailcee Gros (1) CORR 0 pe Hersictpeirc Brations (cntined: toe ss PLreihyeetied anne) Ttrietii i;rri prgpesie seep, wie FVeersaatleosteewreilaetiecne,l sieitrlc,, ullee wHra,tt vcslate: Lite tne srs of svellaar csreonpluignst,iss,nwle HPerirvaa,tewelnclose, 16 JGatt,usarisn,sstaalisie plane of section Leah crciron rThaeif,olSoiwinntg Ciosrds,esBoaeearfroowu,n Stpolebeen,wihthairn,naSrtawahLi,nitSsu:a) ntti, Lure Itetin, SrtiinrlGaldne,,Erho.rt, Testarpicias, rotate, riche, Esphages, Press, FBiiteatahnbkse80T) SSacrificesSein tMlreentrat (1) COR 0 po miroFGsocuearrc yBratios: HSetvrirhggipcaless, 141 0.8 ch. Hearrst trations: rpp------ ner Hweipttiaeyatle,iwcsieltion, tifa, wild Lag uAualla wsireirsaltasti,ons,iwnlad fairtaitosie SHeeoenra, ising SiTrreis ASeewsnidiresiss,iwsiilneg rThaeif,olSlpoiwnialg Ctoirsds,ueTsoweeraerfroouwn,d Fteiobee,wiSthtionurr,erSealL]iintst:ti, Lure Intestin, iLnharykdBead(eer,stKeorrt,, TPeuscrteia:, iSusl,iPGroissta,te,ErMe ee, Trach, Seas, SpPercoijeest:sRaetr: BICEOI2 suwvstiazpgee:s6 207 00594 ISnudainvairdiuzaeld BSaicnrgolsecoTpaibclaatnedMifcariaoaslcopRiecsorDti.se(rcvoanttiionnesed) FT YeaRrikOerralLaTborxaitcotryi-eBso,coIgnecn,ici3ty Study in Rats Table: 2 fFaitnea:l GNeoeskdesr:108I)RTSer2minal SSeacxraMfailcee Grow: C1) CONTROL pe Macroscopic Bservations: MicrSopsicocpeirc Observations: herenal vidoe; Liver Lung PPaunrcartehaysraid PPriotsutiattaery Spleen "Circular raises lesion, 1.2 co dha. "ePerdtuilclaalryvacceullslahtyipoenr,slawsiitai,folzoacla,l aarledas, "wEhtreornaitceprogressive oetregathy, ssterate "PFoorrttaall sbielneucdlicetarproclelilferiadtiilotnr,ataei,ldwild "lascular wineralization, il Farledusonia, interstitial, civonic, wultiiocal, "hhaitneaxaaaitnreasp,hy,notwilidn plane of section "~bhrdaesstoantaitis, acste, swpuative, eile "Heungiosircons TBhreainf,ollSopniirnagl tLiosrds,uesBowneereNarfroouwn,d tHoeabrte,wiStthoimnachn,ormSaalal)linIinttse:stine, Large Intestine, Urinary ladder, forts, Testis/Epidicyais, Thyraid, Trachea, Escabagus, Lh Node (asseteric), Salivary Blane, Bre. foinal Watters 1RISET Sect Wale Groupt (1) CONTRO 0 pas Fate: haeis 88) Found Dead Racreascroepailc servations: MicroHsecorpeicl Observations: HeErret LLiadrngeey Intestine Liver LLyasnsgh Node (aeseteric) "Left enlarges by a 1 ca dia. mas. "Simsoidal ectasia, corte, wild "NFohtecceharnoinncecdy,tonasi,ssibnegnign, wnilateral "ocarditis, chronic nensuppurative, "Cwhirteinfioccaplr,ogrweislsdive neshropathy, ail "Not exanioed, wissing "PPoorrttaall bsoinloenudculcetarprcoellilferiantfiiolnt,ratsec,herwaitlee HNeecpraotsoicsy,tesvuatciudoolcaatlio,n,wisldutifocal, sile ""Nvoatsceuxlaanrinweidn,eraailsisziantgion, aild SPpreocjieecst: Mfaastter: 0281020012 Suanarized STH Pages 4 208 C00595 Summarized Single Tabolated Mrinal heport (continued) Inividual NaRcikreorscoLpaibcoraatnodriWeisc,rosIcnoc.pic Observations FE-IA3: Tug Year Oral Tosicity-Dacsgencity Study in fats Table: 2 fFraiteen:d WMaesehler: 88R)ISFoSu3nt DeaSdex: Male Grow: (1) CONTROL 0 gpa WicrasFcaoncpriecasservations (continued): PSiatluiivtaarryyGland Sul? Intestine "NEiytst,sapnairnsesd,istwailsissing N"heott eexaassiinneedd,, mwiissssiinngg BTrhaeinf,olSlpoiwrianlg Ctoirsds,ueBsoweerearfroouwn,d Stpolebeen,wiStthoiwnacnho,rmaUlrinLairmyitBsl:adder, Aorta,TestisEgicityess, prostate, Tyrese, Parathyroid, Trachea, Sscpnages. Misa! Matar: (BIS Sext Male Groups (1) CONTROL 0gaa Fate: sie 108) Terminal Sacrifice Nacrascepic servations: Kicroscapic Doservations: LViivtenrey Lung PPraorsattahtyeroic Ho visible Lesions. ""CPharrotnalic sporcongurcelsesairve cnele]pheicnpfaitlhtyr,atem,odewrialete Portal Bile duct proliferation, wile "AHlevpeaotloacrytaecralotpehraagteiso,n,slvtaicsdoolcaatle,d,soafielrdate Perivascalar aomonclear infiltrate, ssderate PVarsecsusloanria,winienrtaelrisztaittiioanl,, ichtrdonic, sultifocal, "soetraextaenired, not in plane of section "prostatitis, cate, sugprative, soierate BTrhaeinf,olSlpoiwnianlg Ctoirsds,aesBorweerNearfroouwn,t StpoleBeen,wiHtehairnt,serSmtaolsacLhi,nitSse:al} Intestine, Large Intestine, LUyrsisnharyNodSeaddaeers,tntReertiac,l,TPeasntcirse/aEsp,idiSdaylaiivsa,ryPEiltaunidt,aryE,ye.rel, Thyroid, Traches, Esophages, Aoinal aber: IR-ISSS Sect Male Graugt (1) CONRDL 0 pou Fate: Werks 100 Sacrificed in extremis RacrKaiscdoopeiyc hservations: Urinary Bladder NicroAsrcoepailc Observations: ""PEanllea,rgeedn,lar{g1eudi;d afilleledh,ybraelnlepharpapseiasr.s Nesorrugic. "Cortical vacwlation, local areas, ssferate SPpreocgieecst:NReastter: O2BICR012 Suanarized STA Page: 45 209 G00596 Suauarized Single Tabulated final Report (continued) Individual RaRcirkoesrcoLpiibceraatnoriMeisc,rosIcnocp.ic3Observations FEIT: Too Year Deal Tonicity-Dacogemcity Study in Fats Table: 2 rina] Mander: IR5SS Sex: Male Group? ( 1) CONTROL 0 gpa Fate: Geers 102) Sacrificed in extranis Nicrasscoorptiac servations (continued): heart vitney Liver tung Rarathyraid prostate Swall Intestine StSopnlesecnh Wrinary Hatder "H.inralination, sild "Mwyiatciafrodciatlis,, ac1h1ronic norsspprative, "PNaeppihlrloasriys,netcarbousliasr,, swooddeerraattee HTyubrsolneesshedoisliast,edwwi1th low, bascphilic "poerptiatlhelbiiulme,duscctattperroelidfearianteiroanl,izeadildtubules. "Hpeassactualcayrteaivnaecrsaolliaztaitoino,n,slatiilefocal, sild HHelsvoersrlhaarges,acrfoopchaal,gesa,ilail "hat exasined, not in plane of section "Epdroesnt,atiinttise,rsiatciuttiea,l,suspoptuerartaitvee, ail "FHeivtehrinthsaonraaplrotloicnoiltsner "~EHetnecns,idesrsobsaissc,oswli,leacdeate "EHpeiwtohrerlhiaagle,bpaerripelsasia, single, citfuse, nile Cystitis, acute, woderate BTrhaeinf,olSlpoiwrianlg Ctoirsds,urBsonveereNarfroouw,n Ltaorgbee wInittehsitninneo,rmaTlestLiinsi/tEsp:idieais, Pituitary, Thyroid, Tract, Escobages, Lys hate nesentericl, Pancreas, Salivary lane, Eve. final Koster: 16-3556 Sext Male Group (1) CONTRI 0 pan Fate: (beets 106) Terminal Sacrifice Pacrowsacreepniacl servations: PicrHosacorpeicl Observations: itoey Liver "Right enlarged by mass, 2x 1 cu. "CaLirrcgienonme,cpcloarstei,caalo,stwliylnaetcerroatlic. Cells fsohaemeyt,s.polHyihgehdraailtoatircraancgteiviitny,cordMsulatnidple "ChLeiangaicsetparsotgarseesss.ive nepopathy, aild "FPoorrttaall aboinlaenuuccltearprcoellilferiantdiiolntr,ataei,ldald PSrpoejceicets:NoRsabter: 0281080012 Suanarized STAR Pages 46 210 00597 ISnudainvairdiuzaeld MSaicnrgolsecoTpaibculaatededMiicraotscopRiecsorOtb.se(rcvoanttiionnused) Riker Laboratories, Inc. 30 FEAT: Too Year Dra! Tovicity-Dacogeicity Study in Rats Table: 2 rina] Nasser: R356 Sec Male Grow: (1) CONTRCL ppe Fate: Geet 108) Terainl Sacrifice Microscopic Oserations (continued): Leg Paratryreis : "Paiolkuanni, interstitial, chronic, altifecal, FPeetraisvtaastciuclarnesspelnaosneaclear indltrate, ald "Vhoatscuelxaarnivweidn,eranloitzaitniopnl,anea12of section The following tissues were found to be within ncrtal Limits: BUrraiinna,rySBpliandadlerC,oreA,ortBao,neTeMasrtriosn/,EpSipcliedenni,s,HeParrto,staStteo,nicPhi,tuiStmaarlyl, ITnhtyersotiidn,e,TrLaacrhgees,InEtseospthiangeu,s, Lye Noce (snterscl, Pancras, Salivary Slane, Ere. final Nobert IBIS Sect fale Groups (1) CONTROL 0 gaa Fate: Wesie 108) Terminal Sacrifice Macroscopic Observations: Wcrosictonpeiyc Diserations: Liver Lung Thyroid Xo visible lesions. "Chronic progressive neshropathy, nile "HPeorptaatlocystoenoanlctleeraartiocne,ll vaicnsillattreaez,e,aialldd "Pbraesucsuslnaira,miinnetrearlsitziattiiaoln,, achlronic, multifocal, "aHylpderplasia, cell, wild Trhaeinf,allSopniinnagl Ctoirsds,uesBowreereMarfroouwn,d tSoplbeeen,witHheianrt,norSmtaolnacLhi,nsSw:all Intestine, Large Intestine, Urinary Blaceer, Aorta, Testis/Epididyas, Prostate, Pituitary, Adrenal, Farathyoid, Trachea, Escahages, yh Node Ineseteric), Pancreas, Salivary Gland, Eye. fnisal Naber: R352 Sex Male Gros: (1) CONTREL pou Fate: Weeks 108 Teraimal Sacrifice MacrPoistcuopiitcarDyservations: MicroAscropeicl Bservations: Hither Liver "Raised ass, 0.9 ca tia, ""SDirnounsiocidaplroegcrteasssiiav,e cnoerptreox,pawtiyl,d aild ~Ctaylsctuoliuds,depgeelnveirca,tiowni,ninfaelcal, sini] PSrpoejceicets:NaRsaster: 028108012 sunrizes sti pgs 1 211 00598 SInudniavriidauaeld rSinaglesTpasalaatnedHiicmoaslcoapisOtbsecrovnattiioonnst) -143: To YuirkrealLToooractaortiye-sn,cqIennc,icity Stay i ts ne: 2 nFaatea tahbeetr1061) 3Tr5ina SSeureifTiaclee rat (1) CORD, 0g [I Parsthr-- ord -- Ftuitiy Ko. t naioe, sat in shane of ection Sharon, Spleen. -Hesosiderosis, wild ETreinf,olSlpoiinnalg otrids,ssSownreNoorounn, Hteabret,wuitnhi,n sStoomrach,LiSnwiatlsls tein, Large Intestine, UinharyHokBelatatmeer,nteforritce, TeFsaticsres,utSirvias,rPSroasnta,te,EeT. roi Traces Estas, Fianaasl Gaabeelr359 S0uriiceSeicn FtarleoisGroups C1) CONTROL 6 go RacreHscaansc Barvtions: wy SiGnie ode Genial [ELivre -- rn pGer LSuyls NIneteestairnsenteric) FoGcarlaccei,ruisstriaberdenaarkeawegsg,horreal c(e0si2raelrshe)ignheereLit(e1r.a2lctsdeish, of ript "hrratrhedsisudaet amtotttrliicnhg,n.al abe red Jaatpratgieceand rea nates enlarged. ate, pers nls, "rshcaeg,e,itdsltifocsl, ssdrste Tahitigganstt tIoonns,, bNsattiisooerttiicc WNeccrrornaigse,Hodcifuasrei,s,waurireedd NHietwrirnhrae,nsiLniisntls Few tha protec] reser Spleen ried -Hesstopciesis, extramedellary, increased, SThieafnolGlaordi,ngTtoiesshursrosnr,eKiodoue, tHoerbet,wiStthienncsh,orLairLeiniItnstsestine, Urinary Mader, ort, FTeasrtiess/E,piadildytnaisr, ian, Ee. Prostate, Pituitary, Adrenal, Thyroid, Parathyroid, Trachea, Esophagus, PSrpeocpieets:aRbaetr: QZIER012 Sonvrions ST Fuge: 8 212 00599 ISnudaiwvairdiuzaeld BSaicnrgolsecoTpaibclaatneddMifcariaoaslcopRiecporOtb.se(rcvoanttiionnused) Riker Liboratories, Inc. 0 FEAT: Too Year Oral Tonicity-Dacsgencity Study in Rats Table: 2 fninal Mosbers R356 Ses: Male Brow: (1) CONTROL 0 gpa Fate: eels 108) Terminal Sacrifice PasrosScoofsticTusBsausersva(tlieogn!s: Nidney Picrahsecroepniacl servations: tone nSaoenseey Narron LiLviregre Intestine Lung FFiutnuaitthayrryoie SSpplieneanl Gort Testis/Epidiyais Thrsie "Risguhltleann.d Left Rindpan an right forepan "Hight Lidoey polyerstic. "tPaerstuilclaalryvacceulsllahtyipoenr,plawsailat,ifamciatli,feacialld, nile "bfeotrherlietgi,s,masrvkoevitisi joints, hindles, H"Cohtroneiacsipnreotg,resissisviengnephrogathy, wild Pelvic ineralization, ails "GNyesuta,toctoiratsiicsa,l,cowlionlateral, wirkes "Portal snonuclear cell infiltrate, wild "HPeorritavlascbaillaerdsucotnopnrcolleiafreraitniiolni,raatiel,d aild Vascular ireralizatior, ald Psrlegssonia, interstitial, cbranic, witifoaal, NHoetacreexhaangien,ed,Locaailssianrges, soferate "benons ""Hheotncseixdaenrionseids,, aaisisling "FToulbyualreteartirtoipsh,y,wasrpteersmatogenesis, soderate at exavined, wissing TBhreainf,atlHoeanritn,g tSitsosnsacehs,weSraealfouInndteLsotinbee,wiUtrhiinnarsyoBrlaaddeLri,sthso:rta, Prostate, Traches, Esophagus, Lyon Node (esntersc), Pancreas, Salivary Gland, Eye. Aeinal Noster: 10-352 Sect Male Grasp: (1) CONTROL 0 pas Fate: (Meeks 106) Terainal Sacrifice Macrsostcionpic Observations: MicrosScpolpeiecn Dservations: Arenal "Raised slcerated inflamed Lesion, right rear "Sefvoeoratlp.pale foci. "Mwaottuelraartehyperplasia, cortes, ailateral, PSrpoejceicets:MaRsatter: 0281080012 Suanarized STR Pages 49 213 GG0600 SInudmiavairdiuzaeld MSaicnrgolsecoTpaibclaatneddMiAcrrisoas)copRiecpoOrbtse(rcvoanttiionnused) Riker Laboratories, Tc. 30 FEAIA3: Too Year Oral Toricity-Dacogemcity Study in hats Table: 2 AFraitaess] (Nuaaaebresr:106()R3Te5r2aisal SSaecsrifailcee Groups (1) CONTRIL 0 pra Wicrascapic servations continued): Heart iene LiLvaregre Intestine Lang PPairtautihtyarroyid SSaeliinvary Bland | "Awylotciafrotciatlis,,wcihlrdonic somsupurative, "Chronic progressive nephropathy, aild ""PHoerutaatlodisaosnisc,lecaolroncell infiltrate, wile hParsecsulnaira,wiinnetnearlsitziattiiaoln,, wchirlodnic, wild hPoetrievsaasaciunleadr, mnoontoniunclpelaarneinoffilstercattei,onwild "adenoma l"Faatdeteesarvaianteidt,is,wisaslicnegrative, biadles, wirked BThreainf,atlSopniinnagl Ctoirsds,sesfoweereMarfroouwn,d tSoplbeeen,witShtionnicrho,rmaSlull]iniItnst:estine, Urinary Blader, hurts, TestisEsicidyais, Prostate, Thyroid, Trachea, Esophagus, Lyaph Node aesenteric), Pancras, Eve. frinal Naabert R563 Ses: Male Grow: (1) CONTROL 0 gpm Fate: (eke 108) Terniml Sacrifice MacrosTchoypraizc Dservations: Sin MicrosAcroepniacl Gservations: brain Hurt LHiivdenrey Lung Pancreas PPirtousittaatrey M"taoses,sid1e7e1nla1r4geda,, 1d3ors0a.l8 caar.es. "CSoirntuiscoaildalvaceucstlaastiiao,n,corwtietsi,fomcailn, iwil "astrocytons, beng Fcuegrleyusd,efinTeodrolescieolnlsinspbiansaellataer.ea of "wHyiotciarfdoilti,s,wiclhdronic nonspurative, ""HCeisraatnaiccytperoaglrteesrsaitvieonn,egbharsooppahtihlyi,c,sasdoedreartaete Portal sonauclear cell infiltrate, aild HNeecpraotsoicsy,telaolctaelraatrieoans,, vaaocdurcaltateet, soderate "vascular sinealization, aild "Phecriinvaarscaatlraorphys,onaoanrckleedar infiltrate, ail -"pbrmosotantitis, acste, swpurative, saderate PSrpoejceicets:Mafsahter: 0281080012 suri spe 0 214 600601 ISnutmimvairtiuzaels MSaicnrgolsecoTpaibcalaatndedMinciroaslcopRiecpoOrtbse(rcvoanttiionnused) Riker Laboratories, Ine. 3 FE-143: Tuo Year al Toicaty-Dncsgenicity Stuy in Rats Table: 2 AFnaitne:al hNeaeblesr:10I6)RTIerSainal SSaecxriafilcee Groups ( 1) CONTRIL 0 pp Microssckoipnic Observations (continued): Thyrsid :"Heratoacantion, back cell carcinons TSphieraflolCloorwdi,ngBuinsesuMearsrowwe,reSpfloeuennd, tSotobmeacwhi,thiSneanlormIanltesltiinniet,s:Lirge Intestine, Urinary laeer, Berta, Testis/Epididais, Parathyroid, Trachea, Esophagus, Lyssh Node (aesenteric), Salivary Slant, Ere. Ffartiee:al WMeaebkesrt1085)35Te5r0minal SSaecr:rifailcee row: ( 1) CONTREL 0 pon Macroscopic Dservations: MicrosVcaotpriecr Bservations: Herenal fone Marron Heart Fitney Liver LuFnurgcreas Parathyroid Pituitary SspailniavlarCyorBdland TestisEpidiais "Pale area in cortex of on Kidney. "Cortical vacselation, mltidocal, aild Hsaeddeurlaltaery cell hyperglasia, wlio, lt. exanine, missing "Wwyistciafrodciatlis,,aclheronic nonssguTative, Mscardial fibrosis, matidocal, eile "CDyisrta,nicuniplraotgerreasls,ivesodneerpahtreopathy, acterate rLiepaid ofchaanlgteiliancusluarrroucnydsitnsg ipnarceonrctheyrsaw,ith "HPeoprtaatlocyBtielevadcuucotlaptrioolni,femrualttiiofno,cawli,ldwild Portal aonencclear cell infiltrate, ail Vascular wineralization, ai1 ""Nhoott eexxaanaiinneedd,, aniostsiinngplane of section Heenan hloott eesxaanniinneed,, wwiissssiinngg "Aineralization, focal, aie Tbhreainf,ollSopwlienegn,tiSstsounecsh,werSemaflolunIdntteostibnee,witLhairngesoIrnutaelstilniem,itsU:rinary Basder, Aorta, Prostate, Thyreld, Trachea, Esophages, Lys Node (aesenteric), Eye. SPpreocjieecst:Nfaabter: 0201030012 sunrized st Per 51 215 00602 ISrodniriidzule RSiangTlGeRTabRula1t8edNirriaalsRpesOtse(acaonttoinnused) F103: To eairaGralLnTeorvaetyar-idesc,apInnci.cit8y Sty ie ats Tae 2 iFiee tNnoene 8305F6a5me beeSe Rae Gross (1) COREL po [TSiny -- Folrinseer Oharations: thone EPypes siLnnry Intestine ter prg g -- FuFsartersat FiPrtausiattiy SiSislivry Slt SSiuml Intestine TDyoronis wrinwy Bhdter ir}ge us, 757 ca, sroal wen, oh eatt ewavnie,, iaissiinngg aJotduingrirsi,s iisnisntgete sition "Yoondacgspirsog,resisninsgestvs asetcti,on ald Sersasttoc,rtwvlitcisalnatlisenstriifa, ile "scala simalintion 118 oott wvaassnet,, swiissiinngg ooJottt ewaaannnneee,, waaiiisseiiinnnggg JLoitpowurainoinn, aising Tcheolsrssetdlwamnrsswlsencocmlsle.d fTheLaregee,e of Saeuttstseopseixestusi,desistrsasercalalrye, lincceesrtt,ain, Kseiteanion, aissing JNoott vxauriinees,, aaiissiinngg rThei,feSlionn tCiosrs,esEeweeearfroouwn, Btoebve,wiStthoinics,eTaenstLaiiti:enis. Foaitee(aebiesr108T) TEorwinal SSuecxiffiaclee Gruss (1) CONR0OpoLn RaFrietusitiByaration: Herosmaiacl Baarations: tity "Sal ark Lesion. iTtohionf rpuorupreTsientts ron prograsive spat, ald SPpreocjieest: MRaabte: 0ZCROL2 suri sige 8 216 00503 SInodmiavriidzuealt MSicnrgelsecToaisclaantetMcforiaasalcsRiecporster(vcaotntiionnuses) FES: Tes eufrieOrralLisTeornactaotrys-ef,hcongcn,ici3t0y Study in Rats Tle: 2 fFaotae:l tKhheer,1066)3T5e6rinal SSaec:riTfailcee rai (1) CONTROL an RicrLoisceapric Diservations (continued): ng FFaarnactrheyarsesd Sen PFoorrttaall abielneoaacclteaprcoellilferiantfiiolnt,ra1te4itd "Fiearsciaaasrclnaeralsioznaotnicolne,a wiinldflate i1 oeltyiretxeanriinteids,,nsai1e0tpelane of section heosiderosis, wild TShaeinf,llSoniinnag tCiosrs,esFownereKrfoonnd tLougbee iItntheisntineer,mailnaLiriytsB:atr, forte, Testis/idideis, PSraasltitTee,stFiinsgi,taHr,arT,hyrEoried,,ETsrapchnesa,.Lys hod aesntericl Salivary Shand, Stomch, Ffaoti:lhdeoeers1061)83Te5r6inal SSaecxr:iflicee Bro: (1) CONTL 0 pn Ncrosicipnic Oserations: MicrosScpolpeiecn Oservations: Hiren Ldioveerr ay sun Senn Ranifslaeneseatpllleosnison, perighmtssreoan Bfuocksstr.aised "To pat foci. LeTrotliacarl hassecrllaatsiioan,,cmolrteirfofaoclal,wilidle DPoirotanle apsroorgraeeslsairvecnele}shienpialtihrya,tes,odarialtde sAclavlears aaiceraplhiangaetsi,onw,inainladl "Fpearpiivlalsocnasl,arbasckonncclear infiltrate, sinioal MFeerdoodseirsa,stiltoicsa,l aulrceesr,atiwveh,erhiedles, siked Trhaeif,olpoiwtianlg tGeirsds,uesBowneereMafrreonnd, taortbe,wiStahiwnar,oSrealinIintt:estin, Lire Intestin, UEsrcipnh'ayusB,laLdyerg,h fNaotrea,lnTseessttiesr/iEcp)i,eiPoannicsr,easP,rosStaaltiev,arPyitSuhiatda,ry,EreT.hyroid, Parathyroid, Trachea, SPrpoegceicets:Kaastbr: a2CE12 : Sevnrized STR age: 55 217 00604 ISnuaiwvairdiuzaeld RSaicnrgolsecoTpaibclaatneddKiicmraoslcopRiecporOtb.se(rcvoanttiionncsed) FLAIAT: Tuo YeahrikeOrralLaTbornactoirtiye-sD,acoIngce.nci3ty Study in Rats Table: 2 Aoiaal Fate: Master: IRIS Weeks 108 Terminal SSaecxrifMiaclee Groups (1) CONTRIL 0 gpa Macrescopic Dserations: MicroNsicdonpeiyc Diservations: adrenal Heart Kidney Liver tang PiTtesutiitsa/rEypidierais "Bi.laterally enlarge ale, pitts. "CSoirstuiscsailtalvaeccstlaastiiao,n,corftocearl,, wsiilninal "MAeydauclalratriytisce,llcoWnpeircplnaosnisas,ppmuaattiidvoez,al, wile ~wOhirtainfieccaplr,ogwrielsdsive ntshropathy, aarked "pHoerptaatlocystneonvaacclaooalraticoelnl, isnsfhitlitdroactael,, waiilled ~Pfearsicvualsacralwairnesraolnioznactliaoanr, winiflidltrate, aile "Hpyapleyraprltaesriitai,s,fowcaadl,eraptaers distalis, nile TBhreainf,olSlpoiwnianlg Ctoirsds,uesRonweerMearfroouwn,t Stpolebeen,wiStthoimnacnho,rmaSlmallliniItnst:estin, Lirge Intestine, LUyrsignharyNodBelad(dnesre,ntfeorritcah,,PPraonsctraetaes,,TShaylriovida,ryPGalraantdh,yraEyied., Trachea, Esophagas, foinal Nasber: (RIS Sex Male Groupt 1) CONTROL 0 gpa Fate: heels 108 Terminal Sacrifice RacrLasicvoepric servations: Kidney MicroRsecsoepincterOybservations: sirenal heart Kidney Liver Lang PNaerscarnetaesry PiPtauriatthayrryoid ""Phiallee, pitted, enlurgec. "Mesesteric vessels thickened ""CAoyratciacratlitivsa,cactrionoinc, nfooncsalp,raatiinivnea,l "wDiotniifoccaplr,ogwriesnsiiivle nshroathy, marked "PPoorrttaall bsiclmeondculcetarprceellilferinaftiilotnr,ataei,lwild "Hveapsactueleayrtesianecnaaslliaztaitoino,n,wlmitliedocal, ald Perivascalar sonsnclear infiltrate, sinisal ""FFaallpyaarrtteerriittisss,, awrrkkeedd ""hlaatt eexxaanmiinneedd,, sniostsiinngplane of section SPpreocjieecst: NRuastber: 028180012 Summarized STAR Page: $4 218 G0060S TSnriiiame RSksoeerwaTLinslri4teorRebsr,eisaTcc.sser3tB8 eeattiioeusds RAE Ta Yor ra Toby capcity Sud a ats ne: 2 rFkd eawie108B) ITLorin SSeerilicee Geo (1) CORO 0 RcroSsalpciRntseestaitneios contre Site FSaeratmasrairtnss,, twieery, wrist Testes Fovataite, rte TrhaeircaSsie,SlToaanteCtnrssyEssaBsnreesR,rfroLdnuptoobsobdehe,iatLsiusegtereeniaecls,tniSinbt,sv:UrryinalriydB,akEerr, fort, Prastate, Fiitte taekee108T) TrEinaSSrifilcee feo: (1) ONL an Rroxcic Onrations: He visile esos. Keroistaeirc Bertin: pi vFaatacl mregaresnsivecrllepneeata,t,inalid Ffeerpatlsbtieeveceettapriaoi,feamtiiotni,fcwlidid Fpwaryseras SSupaerpetlaasssr,mniieattrceepl,,lew1iioefrsteection frat at eaie, wssies rrihaeiefrtSiipooirns,CirysF,oerBt,nwrTeNsafriars,tlsptslddoie,ew,iHtarhtes,etarwtlem,l tiniiettia:nn,, iaree,neTsoei,, Traces, Eps, gh Rot arsenic, Sutry Sand, re Foti earbieer166T) TTeSriel SSreiflcee eo 1) COMBO 0 on RKroossPctroieecssBeeraattiionn:: reat Urinteey teste Sul circa pale ws, 0.5 cn ia GPaetcihraolmsscrattoniso, nb,ermg,iswtial,tewdld erSepeutntcoedrireerei,teecrsalteoions, pvciatlt,eliwie pppaarsatsbalessulaestrlaattpiieoocnni,f,rbashtiiitolfnis,ca1l,,dwsild6 Frat nce cel nlite, a6 SFpoiees: aabtr: zc sarsiipgen5050602619 ISnudniwvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMifcerioaslcopRiepcorDtb.se(rcvoanttiionnuse.d) Riker Liboratories, Inc. 30 FL-143: Tao Year ral Toncity-Gncsgenicity Study in Fats Table: 2 SFaoteu:l (Keosskheer:10B6ITSerTaiml SSecxr:ifMiaclee Group: (1) CONTROL 0 as Wierascopic servations (continued): [= Pancreas Farathyroie "vPaesrciavlaasrcalwairnersaolnioznactlieona,r siinlfiltrate, wild "hcinar atrophy, aerate "NIosltetexacenlilneda,bennoontsin plane of section The following tissues were found te be within normal Linits: Bforratisn,, STpeisntails/EC5oirgei,yBaoinse, NParrorsowt,ateS,plPeietnu,itHaerayr,t,ThSytrooniadc,h,TeSawcahlels,InEtsecsathiangea,s,Urinary Blatter, Lyosh Node tesentersc), Salivary Eland, Eve. final Naber: 16-3 Sex: tale east (1) COMA 0 gpa Fate: Geeks 9) Sacrificed in extremss Macroscopic Diservations: Sin HeTahrortax tintersal) KLiidvneery HicrosTceosptiics/hEapeirdviayteiiosns: airesal farts Heart ideey Liver Lang PLuyracgrheaNsode (asenteric) Parathyroid "Ulccierrcautleasr rwihgihtte asnudbulteainttohiunsgafsoss,tpats; Fi1l.l8edcawditihd,Fluiind,right inguinal area. ""SSlliigghhttllyy ppaallee and flaccid. "Pale and pitted; 1.5 co cyst in right Kicaey. "Testes sual] "Cortical vacuolation, wltidocal, aild "HUencirfoosirss,inltoicmaall anreecsr,osimsodweirtahtereactive cellular indiltrate. "wAiyslctairfdiotli,s,wcihdronic nessugparative, "Ovonic progressive neprgathy, aarked "OPyusrtt,alwiwlnaotneurcalle,irrcieelldinfiltrate, wile Portal bile duct proliferation, wild "eFnreuaatoneia, interstitial, chvenic, iffuse, Perivascular senonuclear infiltrate, ald Edens, local areas, marked wohtc.inaerxaantirnoep,hy,miwsislidng "Not exasined, not in plane of section PSrpoejceicets:MaRsahter: 028100012 Susaarized STAR Page: 56 220 00607 SInudnirviidzueald MSaicnrgolsecoTpaibcalaantdetMincironsacopRiecpo(rster(vcaonttiionnused) FE-143: Too YeaRrikGerrabLaTboorsaitcoirtiye-sO,ncaIgnecn.ici3t%y Study in ats Taste: 2 Ffaitnea:l eMalbsers9(9RSIacTrificeSdexi:n MeaxlterenisGroup: 1) CONTROL 0 pp MicroPsictoupiictaDrsytrvations (continued): pSraolsitvaatrey Slant Shin Testis Epidiyais : "Cyst, pars internedia ""pNrotosteaxtaintiinse,d,acauitses,insguppritive, acderate "PFoidborgeor,uatsiutbicsa,tanuelocsesr,atiivneg,uinhailndles, wirked "Tubule atroghy, aspermatogensis, Bilateral, wderate The following tissues ware foun to be with sora lints: UBrraiinna,rySpBilnaadlderC,ordT,hyBrooinee,MaTrrraocwh,es,SlEseo,phaSgtuoss,acEhy,e.Seal Intestine, Large Intestine, FAaitnea:lMKeaetkesr:9)R3S7ac6rificedSecitn etaxlterenisGroup: (1) CONTROL 0 pn NacrSaiscaonpic servations: Ratoner. internal) Nicroisctorpeiyc Bssrvations: FaLruangthyraid Sle urinary Bladder "paist "Large aarseoaunatroofundgagseniintaglastprapoiilnltae.stinal tract; no food in stomach. ""pHeelwvrirchasgien,eradliifzfautsieo,n,maarikled ""NHoetnoseixdaesirnaesdi,s,nowtilein plane of section "Not exatines, issing The fallouies tissues were foun to be within normal Linits: BTreasitni,s/ESppiindailcyaCiosr,d, PBroonsetaNtaer,roPwi,tuLiitvaerry,, heart, Stoaach, Swall Intestioe, Large Arenal, Thyroid, Traches, Estphagis, Intestine, forts, Lyash Node aesesteric), Pancreas, Salivary Slane, Epe. fnital Masher: R357 Ser Male Grow ( 1) CONTRGL 0 ppe Fate: Olek 108) Terminal Sacrifice Macroscopic servations: MicroFsicdonpeiyc Bhservations: Liver Ho visible lesions. ""Cphorrotnailc spornosgurcelsesaivre cmeleltriongfaitlhtyr,atea,stewrialtee PHoerptaatlocbyitleevdauccutslraotiloinf,ermalttiiofno,cawli,ldaild GHyesptaotiodcydteegeanletreartaitoino,n,mlvtaicedoolcaatle,d,aialidld PSrpoejceicest:Mafsahter: 0281080012 Sunearized STAR Page: 57 221 G00608 SIunaduivairdiuzaeld MSaicnrgolsecoTpaibculaanteedMipcriosocopRiecpoBrthae(rcvoanttiionnused) FL-143: Tao YeaRrikaerlLaTbooriactiotryi-eDsn,coIgnecn.ici3t%y Stuy in Rats Table: 2 Fraitnea:] WMeasldsers108B)35Te7r7minal SSeunr:ifMiaclee Grow (1) CONTROL O pn MicrosLcanogpic Dservations (continued): rePsaenscrteearsy SSwoallolnIntestine Thyroid "va.scular ainealization, wild ""rFaallpyaarrtteerriittiiss,, rwatrteed ""HFeaulcysiirdtearrcistiiss,, smeisledntery, soderate "Cyst, colloid, wile The follonizg rain, Spiral tissues were found Care, Bone Marron, to be Heart, wSittohmianchn,ormLaalrgeLiIinttse:stine, Urinary Bladder, Rorta, LTyeaspthisNEogtiedineasienst,erPirco)s,tatSea,livPairtyuitSalraynd,, hEivree.nal, Parathyroid, Trachea, Esophagus, Ffantiea:al(Nheasbke=r:1081)8-T3e5r7w8inal SSaecxrifMiaclee Graupt (1) CONTROL 0gga Wacroscopic Bservations: Pituitary tin Nicroscapic Ghservations: [2 Liver Lrg Pituitary prostate Salivary Gland skin ""RHaeinsseedrhaugliccerawatsesd, i0n.f7lacnaaeddiae.si, 1.5 ce dia, Left hint footpat. "HCrharonneeshprroosgirse,ssiwvielanteesrtarlo,matshoyf,erwaitled Calculi present in ureter of hydronghratic "facrtrael .sonanuclear cell infiltrate, wil "WPaosrtcaallarbilweinedruactlizpartoiloinf,erastiilodn, mild Hesorrhage, local areas, soderte ""pbreoesmtoamtaitis, acute, suppurative, aederate "SViearlyageasiintiissa,l lceosnioinc,,onsliynionnael duct affected. "Potogaraatitis, wcerative, hindleg, wrked The following Brain, Spinal tissues were found Cord, Bone Marrow, tSoplbeeen,witHheianrt,noSrtoauaclhi, tS:wall Intestine, Large Intestine, ULryiangahryNotBeladadeesre,ntaerrtiac,),TePsatcirse/aEsp,idiEevyea.is, Adrenal, Thyroid, Parathyroid, Traches, Escphagis, PSrpoejceicets:Nafsabter: 0281020012 Surized STR Page: 8 222 C00609 STarnivriiazle TSnoskleenTaslaanetriessloRneseBta(raattisn) F-3 Teo tovr eOralLkTroatcres,conc Say in Rats nae: 2 rFietet lNeea 8T) SYariicedSe0r PHOeat-- ar sus Nrasianirc Berations: Hw[iis tSar Sut Ttstioe TSshteiesitianis inteensGra (0) CON 8 0 Hii atus, aor ple 20a6 haniss.ss in right aert Auasn:ee clinically a right sie wis So heist ei. C"peenraclpereedscivoelsfarstiohn,, amlreied Poorntaal lahntotCearccirhomtat, ile rSetravsianienssaoanpranIoVsSt,onWild SSSeiernmTaoonmro right site. sFiutritraneaotiftsshe oSensseitartsrtosso,n,Hailsdpermteess, wiliterl, Fwireets, itd arThiiensf,eol,SlpwiitnnagnGiotsrdsyeTsFhorweeerteerfoTonr,sibrtoetb,eExwpSitathtaisnc,hargLmhgeLeitietes:iWnRR,EFUrCiHv,ayTBaartee), Bra, Sir it, Fiinet eawnee25TSTuifcetSe1r FroeesGr 0) EOL 6 on [rTeer -- Lyny ode Gronchiat) SShones WcrsLtoic YOokeervstitoensr:ic GNSieoveenrron SSiolreents sted elie ci Spuea erthpeatchyadareesstone.mcs, SSaiinntt bstaanin,, cIogrtree,riwicld aHloeirglinntipoenn, sc,ortiIcnalp,earltec Fsrpgcet:aabter: GBEROIZ A -- "9 cobio SInudniavairdiuzaeld MSaicnrgolsecoTpaibclaatneddWifcnrinoaslcopRiecporDthse(rcvoanttiionnased) Riker Liboratories, Inc. 3 FE-1A3: Tuo Year Oral Toxicity-Oncsgenicity Study in Rats Table: 2 Fnaitnea:] GMeaslhser:29A)5S7ac6rificedSeni:n FeextmrleenisGrow ( 1) CONTROL 0gps HierosLciovperic Diserations (continued: Lung LFayrcsraaNsode tasseteric) SSpailniavlaryGorStlant SStsoimvaecnh Urinary Mattar : "Nalignant Iyshona, Iyshocytic "Hteaaloirgrrhaangte,ygmhlotnidao,cayle,ghwoiclydtic ""HHaalliiggunaanstt yIsyspphhoonsaa,, IIyygpheoccyyttiicc ""HhaotligensaanatineIdy,ghsoinsas,ingIymtocytic ""thiacteirgrant Iyghona, yeghocitic "Epithelial hyperplasia, sisple, diffuse, wile The folioeing tissues were found Le be within norma Lis: TBeraacihne,s,HeaTrhty,reiSdu,l!ParIattehsytriocied,, ELsacrpgheagIenst,esEtrien.e, Aorta, Uterus, Dury, Maney lane, Pituitary, AFraitaes:! eNcatbesr: 99()RAFoTuTnt Sex Dead Female russ (1) CONT0RpOpL Facroscopic Bservatiors: PNiatauwiatrayryEland Microscopic Observations: Kiadrneenyal Liver PLaysaapahryNodSelanaeesesteric) Pituitary Spleen eras ""Hteaslotrielhoabgailcarasnass,e,0.485cax d3i.a5. 1 2 ca, in right wile, ""Spienluvsiocidaailneercatlaisziaat,ionc,ortae1r1, soderte "NPeoprhtraolsisso,votnacbluelaarr,caelrlkeinfiltrate, eld Portal bile duct proliferation, aiid "NHeetsatroacsyitneedv,acuioslsaitniogn, mltifocal, ai1d "~LHoebneolrarrhaghey,perwpalrakseisa "NHeecnroossiidse,rosaiast,eraitlee "Dystic glands, soderate The fellonieg Brain, Spinal Ctairsts,uesonweerMearfroouwn,d Hteorbte, wLituhxi,n Sntoormmaaclh,LiSnwiatlsl: Intestine, Large Intestine, Urinary Bladder, Aorta, Ory, Traches, Thyroid, Parathyroid, Esophagus, Pancreas, Salivary slant, Fre. PSrpoejceicets:Nofsatter: 0281080012 Susnarized STAR Page: 40 224 00611 Suamarized Indhvideal RSaicnrgalsecoTpaibclaatneddMiicnraoslcopRiepcorOtb.se(rcvoanttiionnuesd) FL-LA3: Too YeaRrikDeeralLaTboorsaitcoartiye-sD,acIongce,mci3t%y Study in Rats Tate: 2 Ffantien:al GWeaedkesrs80I)R-SAaScTr9ificedSeni:n tFermaelesGroup: (1) CONTROL 0gpa Nacroscopic Deervations: PiSteuinitary StLiovnecr h Titney Wicroshceorepniacl servations: forte Heart icney LLuinvger LFyaargahthyNroadiee (asenteric) Pituitary Stn Sstpolmeaench ""RRaaiisseedd wtuhsisc,ke0n.e5d co dia. Lesion with scat an right "ssliitgeh.tly pale "~FSlcuazedehaFtilrleesdecnyesdt in edt isney. ""SHiinvuesroaildiazlatieocnt,asiwai,ticfoorctaels,, wlildd "Mwyiotciafrodciatlis,, scohdreornaitce mossgparative, "PHeelpvhircosssi,nentaulbiuzlaatrion, wrked EHyspte,rplcaosritai,calp,elvaiocdeerpaittehelium, diiuse, wild ""vHaespcautloacrytweinvearcauloilzaattiioonn,,wwuilltdifocal, wild Co"tlat eexaanmiinneed,, nmoitssiinngplane of secticn "hdmoea UlSckeirn, Lweiscikoendfron sice. ""MHienneorsaildiezraotsiiosn,, wmiulcdosal, ald BTrhaeinf,olSlpoiwnianlg Ctoirsds,urBsownereFarfroouwn,d Stmoalble wInittehsitninsea,raaLlargLeinIinttse:stine, Urinary Bladder, Uterus, Dury, Kaanry laze, Traches, Thyraie, Esephages, Pancreas, Salivary Slane, Eve. Sainal Naber: 1R-4580 Sex: Female Group: (1) CONTROL 0 aa Fate: (Meeks 52) Sacrificed in extrenis MacrPoistcoupiitcarOybservations: NicroAscroepiacl servations: horta ELsyoapshhagNeoste (esenteric) FPaasraaatrhyyrSoliadnt "Enlarged urk red mass, 0.5 ca ia. "HSoitnuseoxiadnailnete,ctawsiisas,ingcorter, il "lloatt eesxaanniinneed,, amiissssiinngg ""NSoatlacetxoacsienleed, not in plane of section SPrpoejceicets:MaRsahter: 028160032 Suarized ST Page: 61 225 00612 ISnucsinvairdiuzaeld NSaicnrgolsecoTpaibclaatnedMiMcariomslcopRiecetO.bse(rcvoanttiionnused) FL-IAT: Too YeaRrikeDrralLiTboorractietryi-eDsa,coTgneen,ici3ty Study in fats Table: 2 AFraitmea:] NMeasdtesr: 512)R-4S5a8c0ridicedSexi:n FeexmtarleemisSroups (1) CONTR0pOpLm Microscopic Dhservations continued): PSiptlueeintary ""Hbedwecnsaimdaerosis, azerate The falloning tissues were found to be within normal linits: Brain, Large ISnptiensatlineG,ordU,rinBaornye KEalrarcowe,r,LiUvteerr,us,FiOdueic,y, BeTarratc,heaL,urgT,yrSotiodn,schP,anScuraelals, ISnatelsitvianrey, Glare, Ere, final Mather: 1-421 Sex Fenale Graust (1 CONT0RpOoLn Fate: fhasis BS: Sacrificed in extrenis PacroRsaenswpaircyGGslearnvdations: SpLliveeern Nicro#sacroepniacl Oservations: Liver Lng PNaarsaetahryyroSildant Spleen "Ulcerated ass, 6x 6 x 3 co behing right "pSehsosuilbdleyr,slightly pale and soller "Enlarged ""SFionrutsaolidaaolnevsuctcalseiaar, cceollrteixnfiltrate, ail Hepatocyte vacuolation, witidaal, wild HHeesgaattoopcoyiteesiasl,teerxattrioanm,etablalsaorpyh,iliaci,laild ~Firaescsuslnaira,wiinnetrearlsitziattiiaoln,, cwhirlodnic, wiltifosal, "abilmdscarcison ""HHoetuateoxpaaiineesdt,s, noetxtirnanpeldalnlearoyf, seicntcirzenased, irked The following Brain, Spinal tissues ere found Cord, Bone Maron, Ktiodnbeey,wiHtehairnt,noSrtmoaulaclhi,nitSse:all Intestine, Large Intestine, LUyroisnharNyodBelag(deesre,ntAeorritcal,, UPtaenrcurse,asD,urSya,livPairtyuiGtlaarnyd,,TEryaec.hes, Thyroid, Esophagus, nFaitnea:] MNeaebkesr:105I)R-4TSe8r3ainal SSeaxc:riFfeimcaele Group: (1) CONR0CpoLe Wacrascopic Bhservations: Ere Maanary Gland "Extensive post bleeding inflamation of right "Fiorea.nodular mass, 6x 5x 3c, leit inguinal. SPpreocjieecst: Naastber: 0281080012 Suwrized st Pug: 2 226 G00613 ISnunimviirdiuzaeld RSaicnrgolsecoTpaibculaantdedMifcraoslcopRiepcorOtb.se(rcvoanttiiovunese) FE-143: Tuo YeaBritOerralLaTbooriactiotryi-esD,nceIngce.nci3t%y Study in Rats Table: 2 BFaitges:) WNeaeskbesrt105I)R-ATSeErSminal SSeaxc:riFfeimcaele Sroust (1) CONTR0pOoLn Nicrascepic servations (continued): bEieresal Kioney Liver Lung oRaunrnyary Gland Parathyroid Siler eras ""SPiansuessohitdhaallaietcitsa,siaw,ilcaotretreas,i,masrikrekded "PCehlrvoincicaipareorgarleisdsaitvieons,heaolpdathy, aininal "HNeepcartosoicsy,tefvuaaaclu,olawtiilodn, sltifotal, aild "PAelrvievsatsacralmacrrcsaohoanguecsl,eairtdinfiltrate, wild "FTiubbruolaasrenaodennsoma, wnilateral ""HNeoutateoxpaoaiienseids,,noetxtrinaspeldaanlearoyf, seicntcrieoanses, "Ewyisrtriacteglands, arkes Trhaeinf,ollSopwiinnagl Gtoirsds,uesBoanereKefroounn,d tHoeabrte,wiStthoimnachn,ormSaelallinIinttse:stine, Large Intestine, PUarnicnraerays,BlaSdadleirv,arSyorltaan,t,Pituitary, Trathes, Thyroid, Escphagus, Lyaph Note (aesenteric), inal Kosher: 1G-0580 Sex Fenale Groups (1 CONTR0OgLpa Fate: (beers 105) Terainal Sacrifice NacrosEcreopic Observations: Paiatrueintaalry FicroHsicroepniacl Bhservations: Ee Heart LKiivdenrey Lung Purathyroid "Slight atrophy with corneal opacity, right "Enelea.rged Left atrenal enlarged. ""SiPnuhsoiidablulbesc,tassioad,ercaotreter "Wwyistciafrodciatlis,,wiclhdronic nonsugpurative, ""PDohratrailcbpirloegrdeuscstivperonleisfherroantaitohny,, wwiillde Hepatocyte vacclation, sltidocal, eile "sPirleesacnia, interstitial, chronic, saltifocsl, Perivascalar sononclear infiltrate, eile lHoetsoerxrahmaignee,d,loncoatl ianrepasl,anewiolfd section SPpreocjieecst: uRbaetr: 0281680012 sunrized st Page: 3 227 00614 Sriaonugs vSigce sTlt4esbtasBsrBactntoivnnt FEA: Ta Yuivae LToorstirgcooep, ii Ste in Rts Tie2 rFiae NMeaers16B 5 Traiss al Suriofcee es {1 GRRL 0 [ Stnryep tServoinaswrais, wa hHeayflSorua Ctoirts,tsBneeRatfonn, ttobch,witShienl]prInatesLtiint,asUrge ntsin, Winry Bld, Fraeryineris,yGuoSvaenny El re Tess Eins Lh hfe. BRAC FCiitsn tNhaeebe15TTEonal SSeurFeue Gras |) COMI on heTasinBeatin: Ase at as, 0.3 ca i Ga ik re 05405 ch ok hors sr Kontriercn aration: we Saivvnaoracetma cporoters,twi,g ie FoPtreadil sbisleemrsaicttoranci,fler1sf4tiilotnr,atmei,cie wbsy ASHtepavtwoacyantee,alttemroatgiton,ovaecuorlateed,,eiwleeil JFaoirsn SJSiioveowvnasnirtwy,skmb18epsls of sctisn [= rte hots, mies hreiefolSlpniinee tCares,esBowererfoonnd oSpbrewitwhitn,ortaoThaStul Intestin, Large intestine, rSiitynBBaenr, rfeort, Man Gan, rahe, Tra, Shae, Lr Rode weet rFuel: tYheser,15BETrTial SSeuiFsee ro {11 ENR, 0 WrwaapryaSeorkation: Sul moda ws, 3x2 ch, nll Dre a $1853 th, trot rn Hee Species:NRaabte: caBcR2 suri sarge 228 600615 dSuioriaued RSianrgelsecTniacstnedWnrioaslcoRicsOsecrnattiionnnsd) FCS Too teRreBealLaTroatraaiyes,capotr,i Stay in ats Tate2 Fainteh hweatrs109T) ETeTrisal SSein tFiela Gat (1 CORO. 0 on Weresceasnc Barnations (cotinnd: rt Po. Fuarma Slant SFlrbsatroyeiStlant SSiire tena Si:nsaital scasia, corte, ried yasatrieti,s,atlreonic nnssativ, "Freonniiccariiatreassaitviens,srssuatlhy, alg oSenpltsyatpseractaaasaatin, alifca, arin o"hte veasnoae,taeisiinngple of section FSeiwbsriodri,rossitsi,otwiinleecs WFituheintrhnorraLtinaitsuber aThien,fotSlpoiinen]g tCoirsds,aeFsoeereMaraooun, Ltoigb,e Swtiothmicnh,soSneaall LIinttees:tine Large Intestine, Fraiimree,hioee.r, drt Ory, Pitty, riches, Thold, Esohaes, Lys dae steric, Foiitee hNaabher109S) TEeraisal SSceritFiecmele rons (1) CORD. 0 [re------ Werscrniect Braticns: Lidineery fwyr -- FaPaantchryerasaid Hester -- "Sorotuiscaoltlacswotlaaitni,on,Galtoecsal, asrieans,deterate "rDurroanilc wregmresasive cslelpreohaItthyr,tea,niamalld "espatsloatesianletaelraitaitoino,n,vaacladte, wild koiknaananre,s,aisfionagl init "JHoatrorna,ne, ne 10 han of section hHeaio,llSoniimg tCiosrds,uesBowreererfoounnt tSsoabek,withhainr,orSatlowLi,ncSse:ll ntstine, ire Ttetin, : iSalnivyaryBSlaadne,, EKe.et Wars Dury, Mery lad, Traces, Thoid, xomaes, rSoaccih:eaetr: 2BCROL2 29 SaanarizedSTA a"ge:45 cooFes16 ISnudmimvairdiuzaeld MSaicnrgolsecoTpaibculaantdedMidcrrinoaslcopRiecporOtbse(rcvoanttiionnused) F143: Tao YeaRritOerralLaTbooriactiotryi-eOsn,coIgnecn.ici3t0y Study in Rats Tale: 2 Aeiaal Noster: 104592 Se: Female Groups ( 1) CONT0RpLpLu Fate: Gerke 89) Found Dead NacrasPciotpuiictarByhservations: Microhsicroepniacl Diservations: Yidrey Lilvuser KLaynswsahryNoSdheanGdasenteric) Parathyroid PSiptlueietnary "E-nlarged, 0.931 a. ""SDihnruasnoiicdaplroegcrteasssiiav,e cnoerptveosg,atahsyt,eraetienieal "~Haesgcautlaacrytewivnaecruaolliaztaitoino,n,uwlitliddocal, ald Perivascalar sosonclear infiltrate, wild ""LKoobtuleaaraihnrepde,rplaaissisai,ngsoderate "Not exanined, not in plase of section -"hHdeewrso:ndaerosis, wile TBhreainf,ollSopwiirnagl tCiosrds,uesonweereMarfroouwn,d tHoearbte,wiStthoianachn,ormSawlalllinIinttse:stine, Large Intestine, Urivary Blagder, Aorta, Uterus, Diary, Trachea, Thyroid, Esophagus, Pancreas, Salivary Eline, Ere. . frital Naabert I-55 Sex: Female rou: ( 1) CONTRDL 0 gpm Fate: eek 105) Terminal Sacrifice Macroscopic Qservatians: Hiceosscreepriacl servations: Liver Ptaurnagthyroid "Ke visible Lesions, ""Shienpuastcsicdyatle eaclttaesriaat,iesc,ortvecsi,lawatrekde,d wild "WVeapsactuelcayrteaianlrtaelriaztaitoino,n,bassohplhdilic, aild "lot exasined, not in plane of section BTrhaeinf,olSlpoiwnianlg Ctoirsds,ueSsovnerKearfroouw,n Stpolebees,wiKthiinnen,ormHaelartL,inSittosn:ich, Seall Intestine, TLhiyrrgoeidI,ntEessotpihnae,gusU,riLnayrysBNloadteher(,sefsoerntesr,icU)t,ersPsa,ncrOeuarsy,,SaNlaimvaarryy Bllaanndd,, EPyiet.uitary, Traches, Species: Rat Project Noster: 02000012 Suanarizec STAY Pages 66 230 00617 ISnusimvaireiuzaeld RSaicnrgolsecoTpaibclaatneddMiAcmrionsacopRiecgtO.bse(rcvoanttiionnused) FU-143: Tuo YeairteOrralLiTsooriactiotryi-eDsa,csIgnecn.ici3t8y Study in Rats Table: 2 Ffraitees:] GMeasihser:7R0 5Fo9und Sex: Dea Feaale Group: (1) CONTROL 0 pon Nacroscopic Oservations: trey RIPE Kidney appears slightly enlargecs einary Bladder "EnFlialrlgeedd,wit4h.5y5el2lcowaiwiFlillylefsluwict.h large, are Pituitary "Hecsaalrrlhia,gic wiss, 0.93 0.6 co Wicrowsacraepniacl hsarvations: "sinusoidal ectasia, Cortes, soderate feria Ntehte cofanpianire,prewsiesnsting titney "Ppyterloonneegpbhrroistiiss,, bacialtaet,erbaill,ataecrtaelr,ateacderate Neghrosis, tabular, bilateral, asterate Lievner ""hHaespcaatloacrytewinaelrtaelriaztaitoino,n,vawziulsdlatet, ail + Lysit Node (mesenteric) dur ""NHoitthienxaanionremda,l Liisssiitnsg Farcreas tne Not eoxfaspianierd,preasiesnsting Farathyrait "Ket exanined, not in plane of section Pituitary -biencea SSapalte?enIntestine ""NHoetnsseixdaenirnoesdi,s,siwsosdienrgate inary Hatder <isithelial perslasia, papillary, ditfuse, Gwialrekueldes The following Brain, Spinal tissues were found Cord, Bone arrow, to be Heart, wSittohniinchs,orLaargeLiIsnttse:stine, Uterus, Kammary Slang, Trachea, Thyroid, Esophagss, Salivary Gland, Ere. Ffantien:al (Meaeshker:105R)ATSerSsinal SSaecx:rifFiecmeale Group ( 1) CONTRLL 0 ppm MacrPoistcuopiitcarOyservations: Manna Shand Parcreas Nicroscopic servations: harenal ""HSeusalolrrhlaagbiuclaarsss,s,0.82.c7axdi1a..5x 18 ch, leit "Swuaillllal.obular mss, x 0.7 ca, in ares of pancreas, "Sinusoidal ectasia, cortes, soderate SPpreocjieecst:Nfaastber: 0281080012 Sanriveg s pge: 9 231 00618 STeoneisn cSiigwne Lltaet1seM,ieroweg8atiione FEA To You BkTorcoBape Sty bn ite ie:2 iFre s BTLein SitFeete ot 1) GOL BEST COPY AVAILABLE wfeioro Bowing E or wrm a--s t--e_--wid [Soofnisopeungisirwibeieg,ehwe Yor Gt bem -- TCeoiivaiel,yswWee1eshwehossatiinm of i! rere pty ec, rhEeainnis5nBgeHEsoiosmsTraeonst S0oibysthRiEtno,sirSnlihoLisStfttBmetonE, rsSSiresinBr Trbin Foe hr 8) sieA n es pp ssHficbtarti nTon 0ELE0 et [Jooi Eririns $s4eroet toees irity [cfeveaam-- Poulin tortie tion, fa, ttre feCortneerpcpoelnegnh,si,oToolwnwite,yi,stiee wn awiawalenwsisaiaeoftwirsyofs1eteedi iy i Cstatcreaoeoarwseestsh, aie owe Se lan itm, ute fHrope or: 2 Swvizss u 232 00619 ISanrneae rSiegcleonTaeelantdedWMeinsesratrcattiinonnt FetA3: Too teHriGealLTaorrincaOictea,pmoti,cty Study in ats nae:2 FGrueen tNeoknseT6H S5idedSein FmoutlsrGroat (1) CORD. 0 go Hrestopric Bsrations ction): LYueryteShanadnsanric) fPiessiotriayit SSiietu att ine Bate vec merase, ai--oe-- oFitvassatnreon, aising afitvevsind, ne in alae cf section Soetsoeiatrsoei,s, aitsrinig e "italia haerslasia, sie, 6a, silt EThreifnitSoneilng CtoirsksyasFowereMrorunss etorebe, wSittohimnacshorSalLiItntee:stine, Lrg Inkestin, Urs, ry, Then, hss, Esp, Paces, Be, Fiiaten eNoees10S) TTerie SSaeritFiecmsle rugs |) ENTE. 0 pon HMaacrrosHTeceeospeei:nc: BDhasreravtatiioonns:: itor L wns tLrys Nate aseteric FFuarcsrturssi Sieerems - Right adrenal entre. SNiendsasliartylceeltap,wcsort,e, wfhaelt, ile aYerwine asmreoarneaesiivomn iK1e6s, diel aProtratall bdilreodmcteracleileraitiilont,rtwieleaie lBevrsveascamlcrrosstaingsi, aileindiltate, wile iloaGragsste,ini,nmsittatteenssection J"oottnine, net in hae of section iSatcissarrumts,iwsites Fear tha procs user STaheina,lSopinnga Ctairs,sesBowweeFrrfons, BteorSte,wSittheinnchm,arSeaalLIitetstioe, Lire Intestine Laiesi Bate, forts, Naas Sis, Pte ay, Traces, hres, Espasn, Selvary Sas, FSrpeocgieets:RaRabter: (ERLE Sanrize ST ge8 41 6de0 ISunnrtzait SNicitrloeecaLapalcaarttaoedrsiMeiisc,raolsIcnoe,peicrterattiionnes) FA Teo ter Oral Tec Bcogencity Say in Rats Tae2 fFrted eVers10I5) TTerisal SSucrtifeicwee Gru 1) COVE 0 30 HesHseuneyBarations: reel iLe,k s07ena ase.stly whe. Rehseein Duration: Sinan ects, contr, wrieg bewarit y"sicgersietiirsg,hieornan,icbesgvssgratne witifeal, ld ens DFirecmsparroagrlessastiiveons,sbwrlopay, aerate ver epapietesscttse,vepaellvticieo,iihwelltiiet,zall,elwilwdes, ws uPseariivltstelsairartewaelnaitcaotlnieo,nn,sfwgiildhtra,te,v.616k FBariyrs hrahysit HTeiarasrtorgo,m state et aie, te in plane of section Hietrtsin | "Hoteioc shuts, sorte SrTehti,fnelSCoountssyEiStsastRn,rrrwae,aehsefhe,esT,htosSitbden,swiE,tnhgiShnaslru]se,taeLisigthieto,:deLu(reesIattrit],,Sarliivoarry lBand,er,Ey. iFinatl tdhnakrst100I) SFoSur tedSut Fels Gro 1) COT 0 an WcrsacgcicyBisnradtions: Sttarns inwey Vader Hersftepic Brations: forrttes Eoepes "HSpeearstiviinstsrieml.ss, 133 25 a, in ohcehseeofdmalleassteudsscLeEaxton,a, ith AeaeHiosnarsatbsniuati0newsllt.ar cares Sliinagsnieal Lcnagtsoan,, icesrttisc,htriiced oaltigwuitndJ,eins,ingNisiaatic Psrpocjtest:eart: ECRSI2 sanrsiestes 0 234 00621 Summarized Single Tabulated foinal Report. (continued) Individual MaRcirkoesrcoLpiibcoraatnodriMeisc,rosIcnoc.pic Observations FO-143: Too Year Oral Tosicity-Ducogenicity Study in Rats Table: 2 nFaitnea:] hMeasshser:1021)B-0F5o9u9nd TendSex: Female row ( 1) CONTROL 0 poe NicrosHceeaartic servations (continued: ines Large Intestine Liver Ly FLaynansahryNoEdleantdaesesteric) DuParncyreas PPairtaeitthayrryoid SStploeneinch Thyrsie Leinary Badeer terse "M. ears, chranic nensuzpurative, "wlailtiigdnoaccatl,Tyswgihlodns, histiocytic HPyeplevripclaasiinae,rapleilzvaitcione,itahielldiun, local areas, Naelsehrasis, tabular, wild "Haliguant "malignant yIeyspghoonna,, hhiissttiiooccyyttiicc Necrosis, local areas, marked "HMeaaloirgruhuasgte,Iywsshlotniaf,ocahli,stwiiolceytic ""MNaalliiggnnaanntt IIyyspghhoosnas,, hhiissttiiooccyyttiicc ""HNaalliigguuaanntt IIyysspghhoosnas,, hhiissttiiooccyyttiicc ""hhdeetroemxsanined, not in plane of section "~hHeecaroossiidse,rssaicsc,asaali,lsoderate "Malignant yshons, Nistiscytic maEsliitgheulnitalIhyypearp,lasidai,stisoiclytei,c diffuse, eld "waliguant yushona, histiocytic TBhreainf,ollSopwiirnagl tSiosrts,uesBownerearfroouwn,d tSoulble wIinttheisntinneo,rmaTlraclhienai,ts:Salivary Gland. frinal Mester: ADD Sex: Fenale Grow ( 1) CONTROL 0 ppm Fate: tases 9) Found bag . WacrosFcaopaicssGelravnadtions: "Subcataneous cystic mass, 4x 3.5 x 2a, in wruelgtiiolnoboaflatrhrwoaasts,su5b1cu4taxneo2ucsa, in right Liver "tgaplelaras,wottled Microhsicroepsiacl Observations: Necrosis, wilateral, marked Ere Heart ""MNyootcaerxdaintiinse,d,crwiasnsiicngronsuppurative, witifocal, wile Species: Rat Project Nasber: 0281030012 Surized SR Page: 1 235 00622 ISnudainvairdiuzaeld MSaicsrgolsecoTpaibculaantdedMiMcariomslcopRiecporOtb.se(rcvoanttiionnused) | FEIT: Teo YeaRrikOerralLaTbooxriactoirtiye-sD,acaIgnecn.ici3t0y Study in fats Table: 2 fFoaitnea:l HMeasteesr:991)5-4F6o0u0nd DeadSex: Fenale row: ( 1) CONTR@pOeL PicraKsicdanpeiyc Ohservations (continued): Ler HLarsgaary Slant P[ur5athyrois PSiptlueeintary . "tronic progressive ephrogathy, ail MPeeglhvriocsissi,nrtaalbilzaart,iona,cdewrialtde "Portal Portal bmiolneonduucclteaprrocleilfleriantfiiolnt,ratwei,ld soderate HHeezpaatteoccyyttee avlatceuroaltaitoino,n,eomslitniofpehciallic,, wsilaecerate "vTaeslciurlgairectwaisniesr,aliwzialtdion, il "Adenous, papillary "OLyosbtu,larunihlyapteerrpallasia "Not exasined, not in plane of secticn "-Hbeiaecrscimdserosis, wild bTrhaeinf,alSipzinniaslg Gtoirsds,ueBsoweereNarfroouwn,d Sttconbaechw,ithSeiant)reIantlestLiinet, :Large Intestine, Urinary Blaser, forts, Uherus, Trachea, Thyroid, Esophages, Lymph ode (sesenteric), Pancreas, Salivary Slane. Ffaetiea:albKeaetresr:1051!6-T4e6r0s2inal SSoarctrifFiecneale Groups (1) CONTROL 0pp PacroBsceopic Bhservations: Paidtrueinatlary Wicrabsictohpeiyc servations: adrenal HeEarre t [2 LLuinvger PPiatruaitthayrryoid ""Rtaoirsreeds aapspse,ars1 cclaouiday,. "Right adrenal enlarged. "Fale and pitted. "SCiormtsiociaglaldeegcetnaesriaat,ionc,ortdeisf,iusmea,rkeadrke ""AHyoocdairadgintoissi,s,chirnoandiecqunaotaesispepcutriaotnive, "Cwhlrtoinfioccaplr,ogrweislsdive nephropathy, marked EPseltv,iccaoirnteiraallization, wild ""HHeespoartrohcaygtee,alltocearlatiaorne,as,bassoopdheialtiec, eile -"bhdotenceuxsanined, not in plane of section PSpreocjieecst:NReastter: 021CR012 Sunred STE Pus 72 Gob.3 SInudsimvairdiezaeld MSaicnrgolsecoTpaibclaatnedMifcoriaoaslcepRiepcerDti.se(rcvoanttiionnuses) FEIT: Tao YeaRrikeOrralLaTboonriactoirtiye-sD,icolgnec,rici3ty Study in Rats Table: 2 nFaitnea:] tNeosatbesrt1051)0-4T6e0r2ainal SSeaxc:riFfeimcaele rowpt (1) CONTROL 0 ppm Wicrascopic Ghservations (continued): Spleen Uterss Heussiderosis, aild "HFiotnheirn tnhoarneaplrotLoicsoilts nuster BTrhaeinf,olSlpoiwrianlg Ctoirsds,ueBsonweerKeafrooun,d tStoombaechw,itShwianllsorIenatlestLiinmei,ts:Large Intestine, Urinary Elader, Sfaolritsv,aryGuSilrayn,t.Faneiry lant, Trachea, Thyroid, Esophagus, Lysph Note (aesenteric), Pancreas, Ffantien:al (Meoesitear:1051)-6Te3r3ainal SSaecu:rifFiecmeale ros ( 1) CONTROL 0 ppm Macroscopic Oservations: Liver "Circular raised lesion, 0.6 cb ia., leit ein "haLraeterLaolssloebne.forelints. Microshcaorpeniacl Diserations: "Sinusoidal ectasia, cortes, aodrate Heart "MCyosrctaircailtidse,gecnherroantiicon,nondisfvlpuusrea,tiavnec,erite witifoal, ald - rLiicvheers ""fPoerltvailc aienneersaulcilzeaatriocnel,] ailndfiltrate, ail HPeoprtaatlocybtielealdtuecrtatpiroonl,ifveraartciloant,ed#,ilail MLarsgtary Slant ""Spaelraicvtaaszceullear ssnomcliar iniitrate, wild Purattyroid "Not eanined, sot in plane of section Pittisnitary ~hbcdaesntchuoasis, wild Slee "Henosiderasis, wild The following Brain, Spinal tissues were found Cord, Bone Marrow, to be within norual linits: Stomach, Seal Intestine, Large Intestine, Urinary Blader, SAaolritav,aryUteSrlaunst,, DEurrey., Trachea, Thyroid, Esophagus, Lymsh Mode (esenteric), Pancreas, PSrpoejceicets:Mafsahter: 0281080012 Sariaed STIR Pages 73 237 00624 ISunwtrinzle RSiTngElReCTEbCua1teddrfersacRoeseBter(actonitoinnasn) Fe14: To YeirerOrLaelTrosxoicriiteysr,ccIgnne,icity Stay ie Rats Tie2 aFaneh tehrees151 ) Tran SSaecerifFicoe wler C1) CONTR. 0 pon nos[ias Buration: Weroshroirtoennc Shurations: KSahriege Ltiag Intestine eiit aren wasn. S"tait mnasinea,ctmas,ncortes, ried JiPaltruivaeaanopeeraa,tgaesstsiiionenga,ro5s4sthy, ile Fdsooatrtan]ooibpnielee,adccsatlasltiiinofse,rattiionc,ew,ild a1 Ptraryy ce Hers "JHeyp,errpalwianistelidcs,onoendtulein sla of section WTiothtintnheorrmoTtiateuae ETFhraeinsf,slSo1enses, CtoiPsrstutesBsewreMaTrfrroaooune,nn,ptolTebosel,idtH,ehryt,shoLnuaNgla,eLSitnatossne:et,ariSmca)l,l PInatnecsrtaisn,e,SUeilniavrryy H1a2cse,r, oe Fiiwe eNsatsee7)IESuErifcetSei:n aFtoeesrua {1 EONRL 0 po haroGcaariecy uration: ws Wcroceainc aration: hort iter ar wn SRitsit gpipciattlsob coneliate and sonst eanrlaerngeed:peonsiss, tokr, ass, NVeecarrotsesp,seasec,l sairrean,ststflenayt,emltifcsl, Sariceartits, oor asprtive, Rwiitigfeocl,Iorondsr,te Imphctic Dirvoniesrmerparleisasaitvieonn,vrsosmmtahly, tse HRepiiagcarepaocatlsit,iorn,csriirecn, sdeate "Wsalciagmrnt sIoeornalsi,stiIonp,ac1t0ic Lrg circasribet as mith exensing FSprco:Naatber EBERLE Sumrized STARPa"geeTs 70 e0203682s ISnucainvairdiuzaeld BSaicnrgolsecoTpaibculaantgedMiacrloscopRiocrO?bse(rcvoanttiionnused) Riker Lboratories, Tne. 3 FEAT: Tuo Year Oral Tosicity-Dacogencity Study in Rats Taste: 7 Fnaitnea:] GNeaeakbesr: 71)R-0S6a0c5rificeSdexi:n FeesmtarleenisGroups ( 1) CONTROL 0 p50 WicrosBcaorpyic Observations continued): PaPritautihtyarroyid SpSleoeinn Cort inary Hadder "Gu.st, unilateral -"bheatenoeuxsauined, not in plane of section ""HMeasloasciiad,erolsoicsa,l wairleeas, aterate "Epithelial hyperplasia, sisple, diffuse, wterate The following tissues ere found tobewithin normal limits: BTrraaicnh,ea,BonTehyraorirdo,w,EsSotpohmaagcuhs,, SLyeaaplh INnotdeest(ianees,enLtaerrgiec),IntPeasntcirneea,s,AoSratlai,vaUrtyerBulsa,nd,Naavwea.ry Gland, foinal Musbert R006 Se: Female Groups (1) CONTROL 0 po Fate: heats 105) Terminal Sacrifice NacrosRcaonpwiacry BGhlsaenrdvations: Pituitary Uerss Nicrohsecroepniacl Bsarvations: Heart titney Liver Lrg NLyasaahryNoSdlean(tmesenteric) PBaurraythyroid PiUttauristsary ""SEanaltahrgewdu;ss,cir1c.4ulacro ddairak,Leesfiton,lat0e.r4alcaardeiaa., "hahrakr.fluid Filled lesion, 0.5 1 0.8 ch, right "SCionrutsiociadlaldeegcetearsaitai,onc,orbtiel,atewrialld, soderate Pheochronccytons, benigr, wailateral "wAyistciafrdoiatli,s,wirloeric nesigpative, "Caranic progressive seprathy, wild "PHeelsvaitcacayitneervaalciozlaattiioonn,,amludltifocal, wild Hepatocyte alteration, vacuolated, aild "FSicgaetetnetr,edstseuraaltlefoci of ark brow piguent-laden aacroptages iti alveli. ""bHgeennocrcrhaargcei,nonwsild "lhaatt eexsaaneiinneedd,, swoitssiinngplane of section "hyaidreanne:tra, warked TBrhaeinf,olSlpoiwrianlg Ctoirsds,ueBsonweerNearfroouwn,t Stpolebeen,wiStthoisnacnho,rmaSlwalLlisiItnst:estine, Large Intestine, SPpreocjieecst: NRuastber: 0281020012 Swarizee Stik Page: 15 239 00626 [Sanrriionts aSolleiTnilaedatmaailnfgstM(nmti) RAE To Yevu eraLiTraotaorciena, on. cun its ie2 Fk: tet 109 Terai S Surey pps, he eWlerisseopsc iseentwiroenfs uconotienueid:n somal nts Cento ives chr srt Traoen Tas, Soman Pores, alors a, Ee. iFi v fNeetes 0BSTmifSeinn Fmoier,es ro | 1) GN an PareSseiicTiBsestooen): Lo at SGien Wrerset Srtions Jente arom bpeoi Gierr py [-- rPSranswtyrroGiidt SSiiewb Sse Sones woyrsis SertonistrsLie sk trctors es, osibly "ahrss willy, hstic, aeteic ct sotsetlny slihtyIphle,ate Taitonly elie, "lgirgahntt Itheonns,, IItheeccrttiicc SJoaia gon meg ns, Ina ghatic Sauibsanhnat Ipeen,, aInnarteiticc lHilgingnatt LLioptnon,, LItnebiprttiicc eowsenr, ect rrr id frWiins-- ion, nhatic eraiinneyacieesof eti bsy omeitrwees lCgannnote wIroens,ariInlhyantiecin, Toativnationrsaank,10Lphonre tofcaction Slaimciantoea,mesti,gIntec Sgriaent,hnobela,swree ialngptt LIioonn,, Ippeacctyilce hien,fenloan Ctoortn,esWte,e efoulnd Itnotebsetiinte,isLisreertasltines,: tinry Mads, Pituitary, SHoipnesNnabter: acini sawing 0 c264006)27 Fes ev a Se St is roi2 hi po in sti, cr, wi inher i ae He rae Te Std SAMA Se nat, arn, sr, FEE: cnn sone rs 1 los ISnutmimvairdiezaeld WSaicnrgolsecoTpaibculaantdedMifcnriaoaslcopRiepcorOtb.se(rcvoanttiionnused) Riker Laboratories, Inc. 0 FLAT: Too Year Oral Toxicity-Dacogenicity Study is fats Table: 2 nFaitnea:] (Measkheer:1058)-6Te1r1ainal Sex: Feuale Sacrifice Grow ( 1) CONTROL 0 pps MacrosNcaopsicuDGslearnvdations: Micrawsacreepniacl Bservations: Liver tong Faneary Slane PPairtautihtyarroyid "Lirge lobular mass, 1017515 cn "SCionrutsiaciadlaldesgcetnaesriaat,ionc,ortleosc,alaarrkeesd, asterate "HHeepsaattooccyyttee vaalctuesrlaattiioonn,,omsiitniodpoaclailc,,aim1ild "AHlevseoorlrahragem,acrmoisthiafgoecsa,l,mulatiilfocal, eile ""NFoitbreoxaadseinnoends, not in plane of section "bin Ihe following Brain, Spinal tissues were found Cord, Kone Warron, Stpolebeen,witKhiidnneyn,ormHaelartL,iiSttso:uach, Seal) Intestine, Large Lyesh INnotdeesteisnsea,ntUerriinca)r,y BPlaandcdreera,s,AoSratlai,vaWryerSclsa,ne,DuEryye,. Trachea, Thyroid, Esophagus, fninal Nusder: 14612 Sex: Female reap ( 1) COTRIL 0 pon Fate: Oieke 105) Tersinal Sacrifice MacrPoistcsopiitcarOyiservations: Nasnary Bland Microscopic Dservations: HEirreenal LiLvunegr Hanaary Bland PiPtauraitthayrryoid teres "Raised mass, 0.1 "hass, 3 ca dia, aLedtdiaa.rilai 4 dia, right witli Taba2e, righ side, ""SHionudsioaigdnaolsise,ctaisniaad,eqcuoartteexs,ecstoidoenrate ""HHeepsaotrorchaygtee,vadciufofluastei,onn,rkmeudltifocal, ail Hlveslar macrophages, wil "FGiablriasstdoecreolnes FTiuborotuusmoornsspresent. ""bldatenceaxsanine, not ir plane of section ~Fbeiutehrinthsaosraparlotloicnei!tsnusber The following Brain, Spiml tissars were found Cord, Bone Maron, Stpolebees,wiFtihdinneys,orHmeaulrtL,inSittso:uch, Sull Intestine, SPpreocgieecst:Mfaastter: 0281080012 Sunwarized ST Page: 18242 C00629 SIundmiavriidzuaeld MSaicnrgolsecoTpaibculaantdedMiAcnrinoaslcopRiecporDtise(rcvoanttiinounesd) Riker Laboratories, Inc, 30 FEAT: Too Year Oral Tonicity-Dacogenicity Study in Rats Table: 2 nFiatnea:] (Mbaeedtesr:1051)0-0T6e1r2ainal SSeaxc:riFfeimcaele rou ( 1) CONTR0pOoLn The Wicrascapic Observations continued): following tissoes were found to be within normal Fists (continued): LLaargee INnotdeestaiensee,ctUerriinca)r,y PBlaardcdreera,s,arStalai,vaDryurSyi,anT.eaches, Thyroid, Escpagss, dFaetiem:l eNantsert91)6-S0a1c3ridizecSeaitn FexetmraelneisGrasp (1) CONTR0pOeL PacraPsictoupiitzarOyeeations: Hastiry Sand Liver Microscopic Bservations: harenal Eisdurpehaygas LLiavregre Intestine Lung FFiarratehsyroEileand Fitaitary Ssien terirnasry Bladder ""Shoanses,nta1t0e5nl8a1rg5edca, inguinal area surface ulcerated. "Hgpears pale HeSinnsutsoopiodiaelsiesc,tamsitar,asceodrutelra,rya,i1wild oCotrtiecxaalnivnaec,slaaitsisoinn,g focal, aiid eWdivsiercplmaisniear,alpiezlavtiicone,piwtihledliu, local areas, Naoitldnanined, aissing "hNeepcartossicsy,tewvailctuisfloactailo,n,wiplderiportal, wild Hesatapoiesis, extrasedullary, at "PHreesacarernhiaag,e,inwtielrtsitfietciaall,, wcihlrdonic, multifocal, "Laalbeelar peplasia + "Not exanined, not in plane of section ""Hheesraotnopsoiesis, extranedllary, increases, "Ewpsietrhaeltieal hyperplasia, simple, diffuse, wild "FHeivtehrinthnaonrmap!rotLoicnoiltsauser The following Sriin, Spinal tissues were found Gord, Bone Marrow, to be within rormal Lisits: Heart, Stowach, Swall Intestine, Aorta, Dury, Trachea, Thyrale, Lash Node (aesenteric), Pancreas, Salivary Glan, Eye. PSrpoegceicets:NaRsabter: 0281080012 Susmarized STAR Page: 79 243 00630 ISnudmimvairdiuzaeld MSaicnrgolsecoTsasbculaantdedMidcnrionsaclopfiecgoOrbtse(rcvoanttiionnused) FAA3: Too YeaRrikreralLaTbooriactiotryi-eDsn,caIgnecn.ici3ty Stay in Rats Table: 2 Ffraitsea:l Guesibeer:105I)R-T6e1r8minal SSeaxc:riFfeimcaele Grow ( 1) CONTROL 0 gpa hasroscopic hservations: Ntarnewraarsy Gland Microhsicroegniacl Diservations: Tigney LiPavnewrary Share FiPrasnctrheyarsond Fituitary Spinal Gord Thsyirvaeid teres ""HLiasrsgeingepleartiinneeasls careerav;icaplossaisbsl,e a2lcka cdyisat.. ""SFienluvsiocidaailnercatlaisziaat,ionc,oratien,ieaaloferate HCehpraotnoiccytpreogvraecsusoilavteionne,phrmolgtaitfheyz,ala,ilsil ""Abceinnsacraractirnoosnhys, ald "~hhateneoxmasnined, not in plane of section ""hHoewdsiageuroossiiss,,inialdeequate section ""UpTlohtliiysapsswraasncthhiealaasesrstat cervix noted at necropsy. BTrhaeinf,otBloonneingFartriosws,aesHeawrrt,e Lfuonugn,d tStoonbaechw,itSheianl]noIrnmtaestiintes, :Large Intestioe, Urinary Blader, forts, Duary, Trachea, Esophages, Luh Node (vesenteric), Salivary Gland, Eye. Fnaitnea:]ONeosstteer:1051)0-T0e6r1a5inal SSaecx:rifFiecmeale rowpt (1) CONTR3I3L0 Macroscopic Observations: Microscopic Observations: Hfeorretael Fidney Liver Lung PNaaraantahryyroGildand SpUleeressn "ko visible lesions. N"Soitnuseoxiadnailnede,ctaissitai,ngCortes, arked "pelvic "Portal abiinleeradluicztatpiroonl,ifesriantiimoln, sil Hepatocyte Hesatazyte alteration, alteration, vacuolated, basophilic, waiilled "PBrlevesoolnaira,maicnrtoeprhsatgietsi,ali,lechronic, aild ""HGoattascxtaoncienleed, not in plane of section ""HHietnhoisnidenrorossails,Liilnte. Fewer than protocol aber PSrpoejceicets:aRbaetr: 0281CR0012 suri srg 244 00631 me Eom Species:Rat soni GORA ISnudniwvairdiuzaeld aScinrgolsecoTpaibculaatngedMiMcariomslcopRiecptD.ise(rcvoanttiionnased) FL-A43: Tuo YeaRrikeOrralLiTbooxriactiotriye-sD,acoIgnecn.ici3ty Study in Rats - Taste: 7 AFeaitnea:l WNeaeakbesr: 731)8-0S6a1c7rificedSexi:n Feexntarleesisrout ( 1) CONTROL 0 pon MacrosBcuoapriyc Bservations: WicrLasicvoepric servations: herenal Liver LuPnagseary Slant Bury Parathyroid Pituitary "Heuorrhagic "Pale left Lmastesr,allaobedigau.r,k left rec. ovary. "Sinusoidal ectasia, cortes, wile "pnoertaolf epaniornspcrleesaerntcel} infiltrate, wile NMeacsrsosiivse,nedcirffoussies,ofnaornieedlobe with compensatery increase in sitoses in another "valseceu.lar wineralization, wild "Net examined, aissing "LLeairogwerownesll differentiated nesplass, wostly "tantecrsoxtaisci,vedp,ronboatblyinaprliasnees orfonsecatnioonviduct. "hot exaeined, wissing The following Brain, Spinal tissues were fou Cord, Bone Marrow, tSoslbeeea,thKiidnaeyn,ormHaelartl,imiSttso:nsch, Sul Intestine, LLyuersge IKnotdeestfianees,ntUerriinca)r,y BPlaandcdreera,s,RoSratlai,varWyerGulsa,nd,TraEcyhee.a, Thyroid, Estphages, Ffaitnea:leNealsesr:931)F-S4a6c1r8ificedSeixn eFsetmraelmeisGroup (1) CIVI0RpCaLu PacrPoistcsosiitcarsyervations: Nanwary Gland Microhsicroepniacl Observations: Esophagus KLiidvneery Lung PWaaraantahryyroSihdand Pituitary ""RLaairsgeedumlcsesr,ate1d.4aass,ia1.01 7x 9 ca, right axillary area. ""SKiontuseoxiadnailnede,ctawsiisas,incgorte, wild ""ppoerltvailc waionneernaalcilzeaatriocne,llaiinnifmialltrate, site "vBalsvceusllaarr awiamcrroaplhiazgaetsi,onw,ildaild "Pheortiveaxsacnailnaerd,soaniosnssicnglear ndiltrate, nile "Not exanined, not in plane of section -bienams Psrpoejceicets:Nefsatter: 0281080012 suring spe 2 246 00633 Species: Rat sane sr 5 0B ISnudainvairdiuzaeld PSaicnrgolsecoTpaibcalaatndedMIMriansacoRiecerOtbse(rcvoanttiionnuse.d) FE-H43: Too YeaRrikeOrralLiToorxaitcoirtiye-sD,acsTgoecn.icity Study in Rats Table: 2 AFoaitnea:l (aebseter: 601)0-F0o61u3nd DeaSdex: Female Groups ( 1) CONTRIL 0 pon The fNoilclroowsicngopitcisBsauessrvwaetrieonfsoun(dconttoinbueedw)i:thin normal limits continued]: Traches, Thyraie, Purcress. Ffiotrem:alfNhasetkesrt91)0S6a2c1rificedSeixn eFxetnrselnessGecupt | 11 CONTROL 0pp Pacrescopic servations: PHiatsuaiatrayryBlane ALdirveenral Microscopic hservations: hareal EsFoaprrtages idoey Liver Lung Paanary Slant FiPtauriatthayrryoid Spies ""SSluibgchuttlayneeonulsaruglecderated ass, $x 4x 15 ch, in right axilla. ""sdlgirgehatrlsy wetntliaerdg.ed. "CSoirntuiscoaildalvaceucstlaastiiao,n,cofrotcearl,, mwairlkded ""NWoytscaerataiitnies,t,chwriosnsiicngnonsugperative, "wDihtainfiocaplr,agrielssive nephropathy, eil NPeeglhvriocsissi,netraabluilzaart,iona,cdearialtde "Hpeorptaatlocyotneonvcalceaatriocnel,l pienrfiigletrrtaatle,, wisiaal aiid "PAelrvievoatasrcelmaarcrompohoangcesl,eaBrilienfiltrate, wile FHiebvraararthearges,hslocal areas, nile "GNaoltacetaancienleed, not in plane of section h"heernoatnospciesis, extrasedallary, increase, wild BTrhaeinf,olSlopwiimnlg Ctoirsds,uesFonweerMearfroounn,d Sttooabsechw,itSheianl]norImnatlestliinmei,ts:Large Intestine, Urinary Bladder, Horta, Uterus, Dury, Trachea, Thyroid, Lysph Mode aesenteric), Pancreas, Salivary Gland, Eye. PSrpoejceicets:MaRsatter: 02810012 Sunrizee si page 00 248 00635 ISnudninvairdiuzaeld BSiancgrlaescoTpaibculaantedMifcariaoastcopRiepcorOtb.se(rcvoanttiionnused) FE-143: Too YeaRrikOerralLaTbooruaitcoirtiye-sD,ecoIgnec.nici3ty Study in Rats Table: 2 fFnaitnea:l (absesbtesr: 421)-6Fo2u2nd DeadSex: Female ros ( 1) CONTROL 0 pon Racrascspic Bhservations: Shin Naawary Bland Kitney Fitutrguitary Wicroscopic Observations: hhiorresnaal Kidney Liver LMuanagnary lant Parathyroid PiStiunitary "SLaosss coinrcLuelfatr lLaetseiroanl osnidbea.ck; slight hair "Hadsisa,,2Laeftain,guinrailghtaraean,ilary ares 1.5 cu "Rabiisendessareaap,pe0a.-7s CF0lufida,filloent.surface of right ""SDlairkghtrleyd wgoetltalteidnous ass. "lSoitnusecxiagsailsede,stawsiisas,ingcortex, irked "CPherlovniiccipnrroaglrieszsaitvieonn,episroodgeartahtye, acterate Haylpgerplasia, pelvic eitheliue local areas, ""hHelpvaetsetcayrtemavcarcoupshlaagteiso,n,ilpeeriportal, soterate ""SNaoltacetxaacaeiloeed, not in plane of section N"oictesu,anifoaceadl,, woidsesriaotge The following Brain, Spiral tGiosrds,uesBonwereFarfroown, tSoplbeeen,witHheianrs,rerSataolniclhi,mitSsu:all Intestine, Large Intestine, Urinary Bagdsr, Werus, Dury, Trachea, Thyroid, Escphages, Lyssh Node (mesenteric), Pancreas, Salivary Bland, Ere. fninal Nasber: B-4623 Sex: Female Group ( 1) CONTREL 0 gpa Fate: haste 96) Sacrificed in extrenis NacroEsrceopic Observations: Nasnary Slant herons] Wicroscopic Bservations: MeEsrtepnhaagles Kifdeney Liver ""pNaalctiitlyo,burliagrhtmsasy,e. 111 12x 3 a, right igapneiallra.enlarged ""HSoitnuseoaidraelde,ctaissisai,ngcortex, arked ""GPaetlavriaccta,imwriallaitzeartailcs, aisinal "PHoerstaatlocsytoenoaalctleeraartiocne,ll viancfsillattreadt,e, aaiilldd SPrpoejceicets:Nuastser: 0210R0012 sani srg ss 249 C00636 Species: Rat sans sr Got SInudmiavriidzuaeld aScirngolsecoTpaibcalaatnetWiMcnrinoaslcopRiecpoOrbtse(rCvoanttiionnused) Fiber Laboratories, Inc, 30 F143: To Year ral Toxicity-Dncagenicity Study in Rats Table: 2 AFoaitaea:l (beekre:100()E4S6a2c8rificeSdecitn FeexmtarleenisGroups (1) CINR0OpoLu WicrosPcaorpaitchyrsoeirdvations (continced): PSiptlueeintary Ht3 examined, net in plane of section ""Hheseantcompaoiesis, mtrasedallary, increised, woierate BTrhaeunf,alSipoieniarlg Gtoirsds,uesBonweerMearfroouwn,d HLeoarbte, wSittohrianchs,orSmalal]LisIinttse:stine, Lurge Intestine, USarliinvaarryyBlBalganeer,,Bydeo.rta, Uterus, Trachea, Thyroid, Esophagus, Lysph Note nesenteric), Pancreas, frisal Noser: 16-4625 Sex Fenale Soups | 1) ENR 0 pp Fate: Washes 100) Sacrificed in extremis MacrPoistasogiitcarDyiserations: hFiraennael Slang Nicrosizdorpeicy Dservations: sarenal oEseophages Heart KLiidvnerey LPuanngaary land PiPtuuriatthayrryeic Spleen "Enlarged due to raised was, 1.2 co dia, ""BCaytshtiacppaeaasrs,en2lacrogeddi.a., leit milla, "Soneehit pitted "Sinusoidal ectasia, cortex, mrked Cortical degeneration, local areas, wild K"Nootdieaxgannoisniesd,, ainiasdseiqnugate section "wWiystciafredciatli,s,wiclhdronic nonsupgarative, ""pCoratanlcsopnreongurcelsesairvecenlglhrionpdaitihtyr,atem,arakeldd Hepatocyte vacsolation, multifocal, minisal F"Hieburoarartheangoea,slocal ares, sodrate ""Nbotinesanined, not in plane of section "Hencsiderssis, wild The following tissues were found to be within normal linits: RBerratian,, eSprianasl,GDorudr,y,BoTnreacMhaersr,ow,ThySrtooiada,ch,LymSpmhallMadIente(snteisneen,terLiacr)g,e PIanntcersetaisn,e,SaUlriivnaarryy lBalarcdd.er, SPpreocjieecst: NRuastber: 0281630012 Suwrized sti Page: 7 251 00638 ISnucaiwvairdiuzaeld RSaicnrgolsecoTpaibculaantgedMiicraoslcopRiecgrtO.bse(rcvoanttiionnused) FE-IA3: Tao YeaRrikeOrralLaTboorsaitcoirtiye-sD,coJgoecn.ici3ty Study in Rats Table: 2 nina] aber: 10-4626 Sex: Fenale roup ( 1) CONTROL psn Fate: (Meets 105) Terainal Sacrifice NacrPaistcoipiitcarhyservations: Wierohsecroepniacl Daservations: Kidney Liver LPinagrathyroid PiStpsaniatlarCyort Spleen . "Hiised wuss, 0.9 ca ia. "Phescheonceyton, benign, wiateral "PEehlrvaincicaipnreorgarteiszsaitvieonn,essoopdaertahtye, doerate ""VHaesscautloacrytaeinvearoallaiztaitoino,n, wltifocal, tc wild ""Nbeitmoenxsasined, not ia plan of section ""HNeotusseindaenriaoseids,, wiissing : BTrhaeinf,olBloonweinMgartriosns,ueHseawretr,e Sftoounnadcht,o SbeaawlitIhnitnesntoirnmea,l Lluirsgiets:Intestine, Urinwry Bladder, hota, Utara, Ovrs, Kamnary Slant, Trachea, Thyroid, Escohages, Lyssh Node (asseneric), Pancreas, Salivary Bland, Eye. Arial Nasser: 15-0827 Sex Fenale Graust (1) CONTROL 0pan Fate: theses 115) Terainal Sacrifice RasrFoistcaopiitcarDyhservations: Nassary Bland Mierohsicreesniacl Diservations: Heart Kidney Liver Lung Hannay Gland tary "pass, 11 0b cn "Fairreaasmslso,bul5a.r52mas4sx, 7316ca1,5ricgxh,t lateral Left axilla, "NSeidnuslsliadrayl ceesllashiyap,erpcloarstiea,, smoldteifrotceal, ait "Mwyaolctairfdoictails,, wcihlreonic noospurative, "Cironic progressive aepbropathy, ssterate "PFoarrttaall baiglreesduccltearprocleillferwaetfiioint,ratses,deraaitle "HVeapsactuolcarytewiavletrearlaiztaitoinz,n,balssepiilic, senate AFlevreicvtaasrcalmaarcrosgosnaoguecs,leanrileinfiltrate, aile "tNeesrgclcausracianroinses in several places in 3 Fibrsatencea. "GTrusbtu,labrilaadteenroamla, anilateral SPpreocjieecst:MRaantder: C281CR0012 Semwarized STAR Page: 88 252 00639 Sainvriitaunld RsrreescoTplcat4esdMdcirsacifeosta(ttiinse) FE To YeSuoGiaLrTseasrtiyes, sTpe,icy Say a ats ies 2 aFta: eWtaers10I9) TTTari] SSeet rFeewer 1) CONTR. 0 pn WarePsariecssOration cntind: Hjitateiy sisss JTaaleteacweillneaytoomtsin sie of sxction FSiebrron, siesanens "Tytic shane, wile hrreiiof,naSBiinante,tGarR,mteB,oseeTeMaaftrostn,, 0TSprebeeed,,witShEoicnnpesa,ogmsS),ulyi]nethIsnt:Nesateineu,esLeungeercnht,stSineel,va 10s, fe Fiintel haehe165T) Tsrae SSacerifFiceee feo |) ONO0 pn RcrosFcrraitc Oerntions: Hany lat Hcrssrpeisc Darvticn: GGomessis jit [wirs a fatsittieesst uSsesl 1se.a2l0,ia1,5 cn din, rigt ill Sossitle ik ont. Setienansinta,ctsusi,gcores, aerate S"paevtail sbieleadseopno,l fevristaiso, wild pHattoss avletselrsattiioonn,,vmicistltse,,a5ld4 "ucstrlsittin, B16 RSetslo,igpahpilclaeryla seals ying sacst at0 nsienael,Lir8e 1g1laicteacoorFs,section fren hBerif,alSliinlg tCoars,esBoweereFaroend, Spebek,witbhuinr,suStlowacihn,tsSu:l] Intestine, urge testi, USrailniavrayryBlatne,, Ehre.t, War, Dy, Trichet, yrs, Lh Node aeartari) acres, srcaeentRatte: IZ sanriee sti ge 02056340 SIunaduivairdiuzaeld HSaicnrgolsecoTpaibculaantdedMifcnrionaslcopRiecpoOrtbse(rcvoanttiionnused) F143: Tao YeaRrikreralLaTboerxaitcoirtiye-sO,ncaIgnecn.icity Study ie Rats Table: 2 rina] Fate: ealbeer: 83I)-S3a5crificeSexi: Feexmtarleesisros (1)CONTR0OpoLn PacrosLciveepric Bheervations: RSalaenesry Bland Misroscosic Diservations: horenat faEsrctphsages ney LiLavnegr Nanny Eland PaSrataitvhayrryoiBldane Spleen v"Setriyghptillye enlarges "Lawrigteh ssuebccruottainceoaursesa,ssc,on&taxini1n0g3 2.5 ca, dark aroun fluid, ventral bdo. "HSeinrautsocpiotiaelsiesc,taseixat,racsoerdtlelsa,ryH,ilcdortical, wild hat exanines, aissing N~Dohtraneixcanipnreodg,rewsissisviengnephropathy, minieal Vicualation, cow. Lub. epithe, asserate ""vhaespcautloacryteaivmaecauloilzaattiioonn,,cewnitlrdilobular, sirked Hesorrhage, multifocal, ald ~HWoemlnlacdairfcfienroennntiated, dctular pattern, aress of soderate aitetic activity, large areas of "hneetcreoxsaimsi.ned, not in plane of section ""hHeetnaetxosrnciineesdi,s,miessstirnagsedullary, increased, sserate The following Brain, Spinal Lissces were found Gord, Bone Marrow, to be Heart, wSittohsianchm,orSaaal]limIinttse:stine, Large Intestine, Urinary Blazer, Uterus, Guiry, Pituitary, Trachea, Thyroid, Lut oe (sesenteric), Pancreas, fe. AFantiem:albMaastiecr:105()B-T4e6r2a4inal SSaecctrifFiecseale Gross: (1) CONTR0pOnL MacrPoistcoupiitcarDyservations: Nasnary land Nicroscopic servations: AEsroepatalges Heart M"aLosbsu,lar07mass,di8a3. 63 4 a, right axillat Tabular mass, 9373 3.5 ca, left inguinal. "Sinusoidal ectasia, cortes, soderite ""Mhyostcaerxaintiinse,t,Eariosnsiicrgnossipprative, witifocal, wild PSrpoejceicets:NaRsabter: 0281080012 suwrizeg shag: 0 254 C00641 ISnucnievairdiszaeld SNaicnrgolseceTpaibcslaanteedMiicmraoslcopRiescorOtb.se(rcvoanttiiovnasee) FEAT: Too YeaRrikOerralLaTboosriactoirtiye-sD,ncoIgneen,icity Stuy in Rats Table: 2 rina] Masher: I-46 Sent Feuale Grows ( 1) CONTROL 0gpa Fate: Meeks 105) Terminal Scrifice Hicrasicanpeicy Bservations (continued): Liver Ling Rann Shand PiFtaruaitthayrryaie Steer | "Pelvic sinsralization, animal "PPoorrttaall Bsielneudculcetarprocleillferiadtiilotnr,atwei,iwild HHeepaattoaccyyttee aalltteerraattiioonn,, bvaascussttialtiect,, awcidleerate "Hheapsacutloacrytewianletrearlaitziaotni,or,eowsiilndophilic, ald Perivascular smonuclear indiltrate, wil FHiebsroarsrtheargeo,nsmultifocal, ai1 FBiobtrhouadaesnsoens were fibroadencas, reas of necrosis ane cystic areas in ters. b"heatsoexsanined, not in plane of section "Henatopaiesis, estrasedullary, increased, Hseistoesiderasis, wile The following tissues were foun to be within sormal Limits: rain, forts, SUpeirnaasl,CoOrvda,ry,SoTnracFhaerar,ow,ThySrtooinda,ch,yaSapal]odIente(sateisneen,terLiacrsg,e PIanntcersetainse,, SUarliinvaarryy GBllaansdt,er,Ere. Seieal Noster: 16-435 Sect Fesale Group: (1) CONTROL 0 pe Fate: Waeia 8) Found Dead FacresScuelp!ic IGntoeesrtaitneions: "lejunun appears inflansed with reddish Fluid: ilecn appears inflamed near Narwary Gland Nicrohsicrsepniacl Dservations: BEseomhagus Kidney Mass, 7x15 1 2 ca, mtilobelar and uTlicgehrtatbeedi,geTiignhtcolianrg,eiasaplh;eriacsasl,, 2 ce din., in deft acilla, "HSeinmastooipgoailesiesc,taseixa,trcaomretel,lyw,ilecortical, erate hlaatt eexxaamniinneed,, wwiissssiinngg "PCehlrvoincicsipnreorgarleiszsaitvieonn,epshirnoipnaatlhy, wild SPpreocjieecst:Mfaasther: 028100012 Sunarizes STH pice: 1 255 0064 nSaiwmriuzle MSaicnrgolsecoTpaikclaitnedcnraasclopRieepOtse(rcvoanttcinnsant : FEA: Teo teatraGralGbToeraactGarciaeps,enInicc, it3%y Sot in hts Tate: 2 Faoens Gseeer906) FGoun BeatSee Fenle russ (1) CONREL 0 pon Parfosicatpic Berations ctinat): ws Hany ace PFaaristthroit Ssiiievnary lant Droit eHpeamttoocspieeivsa,cawttiroaeni,ctdiaffruys,e,aiwdild atastelscsinveiatlyi,atiinocnr,essti,strate sNaearsteatc neslas stemecnaricsinsomecs. oJott nraaniaonn,, 5ai5ssi1n8glan of secon oStenwsanees,,aeisxirnagmalary, increase, fwrriit---- UaThiienefa,oytlSEpoiainsnagtlrCt,oirsdAs,rntsBs,oenrWeMaarareosun,n,DtHroeyrb,te,TwriSattchohinenca,hs,oirSsaehalLNioIidntetse:s(tsineer,eLrucr)e, IPnatsecsrteianse., Fiatee: eNnaseer1056 1 Teaial SSaeceriFfiectee rca (1) CONTROL 0 pn RaresHapaiceBSsheurnattions: tr Wcrosraeinct Goerations: Xsiodierety LGegre tetine Lg FpaHacarruaertsyyseGedls Fituitiy HSalsiitn igrhattedalrlks geepnr,s0. tocbbeiwin, cIrtt, ates lab. "aSritincaaliaacceltatsi,on,Corftoceasl,, iitlde yDsicroanritciaslrafriebsrsosiivse, awtpifeecsal,, aitte aSHewsasosttitasisav,litcecaroaalltoaintoino,n, vwatciafetcea,l,willd amsaaltatinaelrtaelaitzaitoino,n,ba1s6ic, wile -ALvaeblsatrabwaecgrtaagns, ald eJeitnrwasatireidg,hy,ro11i6n pane of section Hanon sPpreocjieecst:Raavter: C2ICROL2 Sunsricet ST Pe: 2 256 00643 ISnudsimvairdiszaeld MSaicnrgolsecoTpaibcalaatndedMiicnraoslcopRiepcorOtb.se(rcvoanttiionunesd) FE-143: Too YeaRrikeOrralLeTroastiocriitye-sD,acTorgee.nci3ty Study in fats Tate: 2 BFoarteea:l (Mbueaebtesr:105I)-T6er3ainal SSeaxc:riFfeimcaele rout (1) CONTR03O3L0 FicrssSclaepeic Observations (contin): Henosiderosis, ale Tbhreainf,atlSopniinnagl Gtairsds,uesonweereMafrroonwd, tSotobreachw,ithSianallnorImnatlestLinniet,s:Urinary Bladder, Aorta, Uterds, Dury, Trachea, Thyreid, Esophagus, Lah Note (aesenteric), Salivary Bland, ye. Ffraitsea:l eNaeber:82R)ASSacTrificeSd ein eFesmtarleesiseeuss (1) CONTR 0pan Macroscopic Observations: FiLtrsgitary MicrLosicvoepric Qservatiors: KEiedney Liver Leng PiRtauaniatrayryBland StSoprleesen ""RFeedcatleneadreaassso,f c1ocnasodliiad.ation in atericr part of right and left lon. possibly pile ""tpaerlavtiictiisn,ercaaltieza,timoanr,kedald Hineralization, cortical, aild "HCehpraotnoiccytperovgirceusssliavteionne,shpreorpiaptohryt,ala,iladceite "wPraerursactaeia, ate endative, local ares, Hescerhage, wltidocal, ile ""Shaelnaccteesele ""OHyesatciscidegrlacnsdiss,, sooddeerraattee The fatloning rain, Spina! tissans ware four Cord, Bont Marron, ta be Beart, wSittohmianchn,arsSawlllLinIinttse:stine, Large Intestine, Urinary Bader, Rorta, Lyssh Note aesantericl, OPaarnyc,reaTsr,acSheaal,ivaRriyrerEalla,nd.Thyroid, Parathyroid, Esophagus, final Naber: 10-4638 Sex Female Groups ( 1) CONR0CggLa Fate: (Hest 105) Tersinal Sacrifice MacrPoistcoupiitcarhyservations: Microscopic Dservations: hEisroeprhaalgis "Hass, 0.5 cu dia. ""SNiontuseoxiadsailnede,ctaissisai,ngcorter, wild PSrpoejceicets:asatter: 0281080012 Samrized STi Page: 55 257 00644 eSobnirbiuzle SMianrgelsecTosac twnerdraiasl Rpesester(vactoinotnisn Fez Too erieBralLsTeeaitocrtiye-sc,apIenci.city Std in ats Tale: 2 aFiateh haeres101) T0erie SSersifFiecmele eps (0) CORO. 0 gon [I ---- Kilgivneery Hwyak Ghne Pitausittryy tSeolroswe C"Vhoersorsnttioccbppiereogvrdcecistsliivrteieonlne,pahrtmolipatotihnfy,cliw,tidldsete J"ostaslaasinnei,nenailisaitnion ald Jot vaio, tet in sls of section JSoentsigtrsos,is,i4n1a6taute section Tyetic slant, sire TShaeine,llSnaindg tarssesFowoerMearfroounn,t iva Bate, Forte Tacos, hTLooorrbtse,icw,Sittrheinncshe,rKmSoaehlaliensItnstset:setirnie,,LPisrcereInut,estSianlei,vary last, Er, Gury. Fiatae:neNeakar591SHacrificedSeaisn termesesr: (1) CONTR. 0 pon WcrSoiscnapc ration: [rlear Aa-- ner tLgre Intestine Rwsaa Ghat SiSainlty she teres iSdsttiergmalpasleects aie, 1833 ch, "Cehtriecncwpireorglriesnstiivoesr, a1t6h, ald Jeaurstoltiasmieo, leconloncel infitrate, le SFietwrrortieargoen,saltos, 16 SoHtewsmiadesrioes,s, swiseizg MFieahritoharglreistssur SPhaietiunif,toalrSlypo,iinsTagraCtnoissrs,duaesbiwwrrdeMa,orruTosnroHtioe,rbte,FewSirtaohtinhnriscrtot,SsaaEalrLitIsatesn:e,eL,i(rAinse sEsetrii,eB,etsS, wSues,, be. FSrpient:hfuate: ZEROS Swiss ge % 258 00645 IntividSuuaatmarMiazcereosScionpigcle aTnaebaMliaetreotscRoriinc dChRseeravartions FEA10: Tee YeRaarbeDrealLitTcoeiaccietryi-eDs,aceIgnec.ricity Stuy in fats tie 1 BFaetne:a nbeeerrst06()ETTRerEwinat SSaectrifMiaclee Bemus (5) FOALAT 30 par PacrFsistcoasiitcarBysernatices: His[rcoscesi]c aerativns: Viteey Lover . ws fgiltaeitary put raised wags, 05 ca ia. P"Crherasnaitcrpsreogornenss,ivedenriegpserathy, eile "Porsal wnsclear call Hegatosyte vasiclatia, andre, seitifscil, wilt iid MReegsaaltcaccyittoesiasl,teraartiioanl, vasslates, ails "Hlaassscrarlhaargem,aearcatilfionrtailo,,soate2rate ""hheenesnoecaaress, wild < ceil atencna TGhreatef,olSipoisrea;l tCiasrsdu,esSowneensFarfroouwn,d KHoearbte,tShtionnschn,ormSawlilllimIinttse:stine, Larse Intestine, wLiuntasnyNoBdeat(omres,entdeortiac,),TePsastcirnaiaGsi,ciSdalyiavsa,ryPrSohsatsa,te,EyeP.arathyroid, Track, Escptags, Fraitsee:! tNheasbkesrt108I) RTeIrmial SSaecxrifailcee rapt (5) FLAIGS 300 gon McrSosicsnsic Oiserations: PiKitdunietyary sTiersetniss)/Epdionis PicroAsrcoepniacl Ghservations: fe Heart LKiivden:ey LPuanrgathyroid Pituitary SSahliinvary Blant ""UHlecseorrartheadgicasLse,sio2n.,8 x0.26icae.,Gad.orsal. Fale ""TLeesfttesatsreunaall, ebnillaartgeerda,l.0.7 ca dia. was. "RPehtesicnhaeonactcryotpohnys,,dbiefnfiugsne,, wiirlkaetderal "Mwyietciafredsiatlis,,wiclhdronic orsugpurative, ""CPhorrotnalic eonroangurcelsesairvecnelelphrionpfaitlhtyr,atem,adearialtde Cystaid degeneration, focal, mild N"poatscualmairneedin,eraailsisziantgion, nile "bienons N"teatratexoasnciannetdh,onsa,issbianckg Species: fat Project Neaber: 0281080012 Snvizes st pge: 35 259 00646 ISnuainvairdiuzseld RSaicnrgolsecoTpaibculantdedMifcaroislcepRiocgD.ose(rcvoanttiinnuse.d) FE-I43: Tao YeafrakOerralLaTboorsaitcoirtiye-sG,acelgnec.nici3t%y Study in fats Table: 2 BFaetie:l hNeasbheer06S) ITeErinal Ser: Wale Sacrifice Geass (5) FLAG 0 pon Wicrosclcesinc Baarvations (continued: TestisEsitiermis Thyraia ""Tbuebuuslsieteartarsoiphsy,, waislpderaatogenests, Bilateral, "Kwoitleesanined, wissing TBhreainf,ollSopwiinnagl t(iosnds.arsBawneereParfrocuwn,d tSotobmeachw,ithSianalnorInmtaestliinmei,ts:Large Intestine, Urinary Blattsr, forte, Prostate, Track, Esoshags, Lah Node (sesentericl, Fascress. fFaitnea:l lMuoerediosr:06)13TeSrainal SSaecxrifhailcee Grout (5) FOALS S00 gon hacresLcivaepric servations: Wierasbcaerepniscl Gservations: Lsinveers Leng Testis Eritityais "FaLlaeterraaliseLdobemsiss0e.s6, ca1.3Gicao.ieai,t right lateral lake. ""SCihnruosnoiicdaplroegcrteasssiiav,e aCoerptresp,atahoyd,erawtield "HWeepgaatloocceyltlousliasr, caairlcirons Portal soronaclear cell inilirate, eile HCeyssattooicdytdeegeanleterraattiiocna,, fveacawll,atweild, wild "AVlavsecsullaarr amaicnreorpahlaigzeast,ionw,lsile "VLaasyctuilgarcelalineardaelriozma,tiowni,la#t1e2r6al The follonieg Brain, Spiral tissues sere found Crd, fone Harrow, to be within nareal linits: Splees, Heart, Stowach, Small Intestine, Large Intestine, Urinary Bacder, Aorta, Prostate, Pituitary, Thyreid, Parathyroid, Trachea, Esophagss, Lyosn Kode (nsantericl, Pancreas, Salivary Shand, Ere. Soinal Noster: IRIE Sex vale Braupt 5) FEAAGS 0 pin Fate: tele 108 Terminal Sacrifice MacrLoasncogpic Ohservations: WicroKsicdonpeiyc Ghservations: "Raised pale lesion, 0.5 ca dia., let lave. "Chronic progressive aeprogathy, wild SPpreocjieecst:Nhaaster: 0281880012 sami spe 8 260 00647 SIonndniavriiduzaeld SMiamcprloescToapbiaclaatneesMfinciraoaslcoRpeipcorOtbse(rcvoanttiinounesd) FLALA3: Tuo YeRairkerralLabToornaitcoirtiye-sS,ucIongc.rici3%ty Study in fats Table: 2 Ffaitnea:l eRsaatbee:108T ETeSrmin! SSaecdriMfailcee row: (5) FC-1D 300 pin MicrosLciovperic Disrvations (contisd): Ling fancreas -"Fortal asnamuclear coll infiltrate, wild WCaytsiigoeiadntdeIgeynseprhaotsi,on,Iymtlotciydtoiccal, mild MHeegpaaitozceyyttoesiasl,teirantiaonl, bascamlic, saterate ~Faisbcraslsaisr, wpilneerwaalli,zatsioodne,ritaeil wHiycpienraprlaastirao,phya,cinwairlecell, wild rThaeinf,elSlpainnianlg Ctoirses,cesonweerNearfroouwr,d Stpolebees,wiHtheianr,sorSstaolnsclhi,nitSsw:all Intestine, Large Intestine, Tirniachreys, EEastsephra,gisd,ortya,hTeNsotties/EUpeistaitoyeariisc,),PrSoasltiavtea,ryPSiltauniet,aryE,ye.Arenal, Thyra, Parathyeid, fFnaitae:al (Keossibezr:108I)RTIerSminal SSaectriMfailcee Bracst (5) FO-L45 0 sp WacrLaiscvoepric Ghservations: PizresTceasptiics BOpuisgeirdviateiiosns: airenal Hiedarrtey Liver FLuirngcress TSaelsitviasr/yEpiBdliddyais ""pSoaslseibmliess,pal|ecfeocdiia.00 on ove. "CSoirntuisccaildalvcscatlaastiiao,n,cofrotcearl,, Baiiild ""HCyhcrcoanridcitpirso,grSesrsoinviec nnaoghrrsogpgautrhayt,ivweo,eraaitle "fGayrsttaolidsdneognecaelreanteionc,ellwiitnidfiolctsrla,te,ssasieirdate ~Fveaqsaclaalzayrtowsiinse,raalilzdation, wild ""ASciianlaargeraittroissh,y,chroodneirca,teaderate "TWuibraelrealiaztartopihoyn,, atsabpuelraara,towgielndsis, soderite Leydig cell ato, bilateral STyhleesfno,llSowtionngcht,isSssuels: wIenrteesftoiunned, tLoirbgeewIinttheisntisneer,salUriLnianriyts:Bladder, orta, Prostate, Pituisary, LByreasint,NoSdpeinailnesCeonrtte,riocn),e EMvaer.row, Thyroid, Parathyroid, Traches, Esophagss, PSrpoejceicest:Mafsahter: 0281080012 Sunrise srg 9 261 00648 ISnuaimvairdiuzaeld RSaicnrgolseceTpaibculaantdecMiicraoslcopRiepcorOtb.se(rcvoanttiionunesd) FL-AAT: Tuo YeaRrikerralLaTboornactiotryi-eDsa,csTgneem,ici3t0y Stuy in Rats Table: 2 BFoaiteea:l (Noesrtser:10R8ITSerEsinal SSeacctriMfailcee Beousi (5) FEA143 300gp MacrosEceopic servations: Wicrascepic Chsarvations: fkieerensl rLiievesrey Lary Fpaarncsrheyarsoid PiSatluiivtaarryyBlane : Spleen ."Hipopyon, righ eve. ""SPiantuhssoiisdablulbeic,taswiiat,atcoerrtae,r, maairnkiem:al CLeastiaornactc,haraancdtecroirzneesalbyvarsceetliamrlizaatitoen ,wich "Ccaorlalnaipcseproofgrtehsesigvleadnee.sropathy, wild "PCorrsttaolidsedvegoemniecriaetaionc,almailntfiidlctcraalt,e,mil6eitd HNeepsaatlooccyyttaesiasl,teraaitniionns,t bscazilic, ainial "Avavseccullaarr smaicnreoaplmiazgaetsi,oni,lewile "HFyepreirvpalsacsuilaa,r issnloentaccieolalr, sinofdielrtartaete, sininat ""HDoytst,xapnairnsedd,istnoatlisin plane of section "SiTaoltaagraantietirse,accthirvoenihcy,pesropdlearsaitaeof inclutes "HLeynacsshidenrodces.is, wild The felloning Brain, Spinal tissues sere found Cord, ne Kurrow, Htoeabre,wiStthoimnachm,erSwaallLimIinttse:stine, Large Intestine, Urinary Badcer, Arta,TestisEpididpais, Lys Kode (usenteric). Prostate, Thyroid, Trachea, scabs, Fnaitcea:lGNeoeakbsert191)0-S3a5c9r0ificesSeixn eWxatlreenisbreust 5) FO-1E3 30 gon Nazrascapic Observations: LTihveess lLyaasnh Node (esenteric) LSyasaglh NIondteestGibndeoninal) LiadrngeeyIntestine inary Bladder Penis ""EEnnllaarrggeedd,, 1br.o3wx/y1e.l5loxn0.a3ticon,gd.ark red. A"aEnrlkaerdgleyd waged, 8x 21 1 ca ""hPeepyaetri'cs Lpyaatpc.hensedeenslaregneladrgaendd. recdered. ""PSelyiegrh'ts dpialtacthaetsionwloafrgreednalandpelrveisse,ntB,ilateral. "bistended with urive. "Swollen PSrpoejceicets:Mafsahter: 0281020012 Somnrizes st Pge: 0 262 00649 ISnudainvairdiuzaeld RSiicnrgolsecaTpaibcalaantdedMidcnriuoaslcopRiecposrter(vcactniionness) FO-143: Teo YeaRrikOerralLiTboorvaitcoirtiye-sO,acIongce.nic0ty Study ie fats Taste: 2 fFraitne:al (Nhaabereer? 119)83S5a9c0rificedSein Meaxlterenisrospt Ricraasocroepniaclhsernations continued!: frfoanen Marron HIigney Liver wg Loop Note abeseinal) FLayarpahthNyootiee aesesteric PSiutlu]itaIrnytestine SpTlheyemse Tryraid inary Raster (5) FC-I4T 00 gon ". Haligeant Iyshons, Iystocytic m"aNaltiiggnuaanntt LIyynsghhoonnaa,, IIynsnborctytiicc ""NHaalliiggnnaanntt LIyysshsenas,, IIppmmpcrcyyttiicc "rFaalriegxncahnytasysaglheosssat,coImylgehotceyltyicreplaces by diffuse nosslastic cell infiltrate. "Hteaalairgruhaangte,Iylsohccaals,areIaysp,hoacsycteircate "HEaxltiegnnsiisvteInyesohpolnaas,tichisitnivcoelyvseincznt of hesatiz note. "Malignant Iysghons, Iyphocytic "HHootdeixaagnnionseids,, wiinsasdienqguate secticn ""HHaalliiggrraasrtt IIyysghhoonnas,, yIsptpaoccyyttiicc ""rhaatligenxaanntineyds,ghwoinsas,inigstiocytic "rEapliitghnealnitalIhpyspeorspi,asiLay,mphsoicmyptliec, diffsse, aild The following tissses Heart, Stonch, Large vere fount Intestse, to be forts, wTietshtiics/nEoprimtaileyLaiinsi,ts:Prostate, Traches, Esohagas, Farcreas, Salivary Bland, Spiml Coe. Ffaitnea:leNeuakber:108163T5e9r0ainal SSaecxrifMiaclee Sesipt (15) FEALAT 00 gor Mcrcscopic Oiserations: Mieroscspic Oosernatioss: hEesropehaalges LiKivdenrey Lung ke visible lesions. N"Soinudsioaigdnaolsise,ctaisniaad,eqcuoartteers,ecwtiilodn ""Dphorrotnalic wpornoognrcelsesairve cnelelphrianpdaitlhiyr,itew,iniweialld CHyesptaotiodcydteegnalatreartaitoino,n,sboaesrsagtheilic, soterate "Nveagsacluolcayrtomsi:nse,rasliiznaitmilon, aild AHlevsecorlrahrages,acrloogchaalgeasr,esa,ldsoderate PSrpoegceicets:Naistser: 028180012 Suanarized STAR Page: 99 263 C00650 SIorinneas aSBrlieeecLTaai.rstlmaardtieerMso,awloatsnrOttr(actsnitoinnses) F-14: Too eur Bal Tacit Gcoricity Sty in ats Tate 2 fFitae tveets10TTLern SSroiflicee rugs 9 F10 30 0 [HIit ---------- -- UTHhrieiien,ietSnaiidnmge,tCsosArerstEaveerTeierafoornusysittosianSnen,si,tPiursro,eteSmt,ncTLhirytaeSnstsLPaInrtaetsteisnse,, iTrreotT,tatio, Une Nee esate, Press, Savery Se Fo. Fate thar 164 Tosca rIifAe PE PfRia -- Huis al Lesion, 0.6 8 ta. interior Hcrosic Barntizst Cute ise. Laeny J Sensis, mow---- | FCoortthedsatrmaittiocnelailnftilatrrate,neld NsWstslaactdeeilfaaelrarencctuertscii,vvoitntye, lwakpsatneri,sin, - wn [- oAscctaar assierrbaalsgast,ion1,8#16 A exit, 6 i Ble of section jet Teall swans Th Felling Sees aie od 0 be within corm its wBUraahine, kSepBianaasleeC,rortdf,rorBita,,ne TeFRarEerAoewp,eiFSpdlSerein,sayHearrSota,tkaStsteossraeci.ht,aiSteaarlyl, InKtresetnin,e, TLraartgoees,IntEestsineo, Fioel hteohrs108I1 TTeHrasa SSeucriailcee Grou 3 F010 30 30 [tr er ---- pale fc traps, Hersrteonn uration: Sinaia aca, ores, ase rt rstiittie,,wceonlic smsspritive tos Desc pregesive seventh, ile P--rop_et --ar: gBcE012 Swnrices ST Pages 160 264 00651 Sfanrricie Stfsakteer TLeiustrrataerefs,alI,srt continue) Fe Te Yur alTactSeog Say i ts nan 2 vFale eneesr1081 Trial SSrniflcee Gr 8 F109 [roEE -------- eStoocntesevnattiiorn,ileeffse, were sWlastratysta,vsattoenr,nmalate, sderice Cosel tlt aged sith Fiely ws JPaattths Tersios itinis eSvgrapinuitlanar, ensosiiinaopth.il,ic, "grout glass chose, siden, wp ie ------ eXoeensos, ak hoe of sect: SSpieretessnwaticzoaltsiawni,s sie Ehreine,lSiomnai CtoovenyesFewerre fro,us Stoytbaen,wiSthtinuo,rmSalintTst:stin, ire Ttetine, SUtrySStiidr,sTFeite, Fons, rave Espns Lah i esr Fares, Siiv aNa10BTEeil SSnrifiHciee Fro 5 FEI 0 rosaews GSrinadton: WeHrhooration prorehrm Goes pSierrweis,a3w1a2s,30118 8my7rigs ath, SIeisentaaindc,aswi,ycartes, wild eeilivsoewa,ieitaitoen, swiildd lw fe. SttiitrySat FTHyaoptreratplaivsoiera,endpateileviwpceceflpeitrhfieiloilnurn,a,twdeii,ffuisee, wild Sycreaidreaenrraattioinsonmitaiiaealy mie SWievaenl repute, ale Shatssmietnisc,eat8e,mwrirpte95 snr glist wSsawrenngtaltye oeWe ssivee,ovafenweed reset on a tite SFcaieen amwte: ascsnz Sunrizes SH Fuge; 01 265 00652 ISnudnivriiduzael SRicnrgleeRaTpbcuaitaeRncraaslconRieesOtrv(actonitoinustt) FCA: Teo teirteGralLsToroatiartieOsc,apInec,ict3%y Study ie ats Tae:2 Ffiaerl teaer1085 ) Tesial SSecwifailcee rant (9) FES 300 [I prec -- sien Heetvoseidaesraes,i, waiisding rShieent,ihHeleriitstsSias,vmieorse,swtSareteex,feTnhedrset1lidn,bge,AwrListrthiginrenrde,smtiTnrgLi,ciatr,:iaErsypnMast,herL,efhortosd,e (esteicl, face, re, Fbiaern aNiaear19T) Terina SSeeccifmiaclee Groat (9) F100 po RarGaeresy aration: Woresroenac! Banation: rt [i Live wg TeisttiasrEyionis Hale, enlarge an tte, Bilateral. "CHorteicasl sclelaltpeer,psmiit,idsfceacla,l,ainliel Hwsictarikatcils,,srioesie nvserative "Ovsat,necoprrtiocgarle,ssiwveesreath, airked "Haerattascmteovnotlietiosenl, miniftiilftreaatle,, wiillee HHseaaocrytesa,lterwaitlidon, icles, n1 "Hsecralrye,wneIaelcailzaatrieoans,, wirlkees FSeotlnrotnrsitis, wderate rhaeinf,otSlpoiinrag Gtoirsds,ueBsoweerMearfroand, Stolobee,wiSttehncsho,rSemalLliiItnst:estine, Lage tein, LinharyNeEildaeerse,ntdeortiacl,,PProasntcartaes,, TSralaiiva,ryPEaarsa,thEae., Trachea, Esse, iFsear! eNnoer:106113T5r9eva SSeanctriafilcee rapt (9 F147 380 on Racroscspic Ssteations: Nrasezrstic Bsevations: Ho visile leis. bncridtiets,,wcilrdic sonpuratioe, Fspreoceice:Maadter: zB0KO12 Sonwined SH Fuge: 12 266 00653 Sonnarized Individual MSaicnrgolsecoTpaibculaantdedWidcarioasactosRiecpoOrtbse(rcvoanttiinounesd) FI-143: Too YeaRrikOerralLaTboorractiotryi-eSsn,caIpnecn.ici1ty Study in Rats Table: 2 Ffraitnea:l GMaesbler:1081)05Te9r7minal SSaecriMfailcee Brow (5) FC-LAT 300 pp Microscopic Diservations (continued): Fitrey Liver Lrg Funcraas Prostate -"Ohranic presressive seshromathy, wile FPoorrttaall bsiolneanduucciteaprrocleilfleriantfiiolnt,ratee1,l6ail NHeegzaaltooccysttoesiasl,tesraitnicia!, vacate, aile h"Weasicarlaratrwoipnheyr,alwiizladtion, aild "prostatitis, acute, suppurative, sivieal The folloeieg rate, Spinal tissues were found Cord, one Marrow, Stpolebeen,witShtionsacnho,rmaSleaLliiItnst:estine, Large Intestine, Urinary Bagder, Essphages, Lyssh ANoordtea,(nTeessattiesr/iEcp)i,diSgaylaisv,arPyitausitea,ry,EvAe.renal, Thyroid, Parathyroic, Traches, frsnal Nosder: 19-3599 Sex Male rout () FL-LAS 00 pou Fate: Wears 108 Terainal Sacrifice Macroscopic servations: Wierhoiseconpeiyc Bservations: itney ver Lung Sativary Gland len "yroneshrosis, right kidney. "CPherlovniiccspirnoegrraeliszsaitvieonn,esharielaathy, wild Hapseerrpaltaesia, pelvic epithelive, miltiiecal, "Portal Portal sboilneomdculcetarprcaellilderiantiiloinr,ataei,ld6116 ERyesgtaolrodcytdaesgiesn,erawtiiloen, multifocal, wile "Pirasecsaolnaira,miinnetrearlsitziattiiaoln,, cshirlodnic, maltidecal, Aallvdestar nacrophages, nile "SHieasloardrehnaigtei,s,Loccahlronairce,as,sodsedreartaete "Henasiderosis, ald BTrhaeinf,olSlpoiwrianlg Ctoirsds,ueBsonweerMearfroouwn,d Hteoarbte,wSittohmianchn,ormSawlallLinIinttse:stine, Large Intestine, TUrraicnhaersy,BElsasdpdhearg,esR,otLa,hTeNsotdies/E(saietsiedtyeuriisc,),PrPosatnactrea,s,PiEtruei.tary, frenal, Thyraie, Parathyroid, SPpreocjieecst: MRaastter: 028108012 Sanarized 5TH Pages 165 267 00654 ISnutaimvairtiuzaeld NSaicnrgolsecoTpaibcuaatnedMimcarioms)copRiecporOtb.se(rcvoanttiionnuse.d) Riker Laboratorses, Tne. 30 FL-443: Tag Year Oral Toncity-Dacogenicity Study in Rats Tle: 2 AFaate!: Gbeaebkasr:108()3T0er0ainal SSaecxrifMiaclee Seoupt (5) FEAIAT 00 pon MacrosLcivoepric servations: Microscopic hservaticss: Sbeorneenatlarron Heart vitney Liver try FiLtiatsttaNroyde (mserteric) sSsplienoanl Cart Testis/Epididnis "nottled ""CNoorttiecxaalninveadc,wlaitsisoinn,g nile Mysaolctairfdoictails,, aelenon nonsippative, ""Dphorratnailc apnreosgurecslseiaveceelplroiandtihltyr,atew,ileaid Portal bile duct proliferation, aiid FGeygsatlozciytdoesgiesn,erawtoidoenr,acefocal, wild "AViavsecsullaarr maaicnreorpahlaigzeast,ioni,leile Hencrrhage, local ares, saterate ""NHeetaczerahnaignee,d,nwiismsing Lo H"eNoetoseixdaenrianseids,,aaiislsding "lascular wineralization, ld The following tissaes Brain, Stonszt, Saal] were doin Intestine, to be Large wIinttheisntinrea,rmaUlrinliamriytsB:laster, fort, Prostate, Thrcid, Parathyroid, Trachea, Esophagus, Pancreas, Salivary Gard Eye. Arinal Naser: 103001 Sec bale eoupt ( 5) FEALAS 00 gon Fate: heei= 196) Tereimal Sacrifice Racrescepic Ohservations: Liver Lyash Node aasesteric) Stomach Microhsecroepniacl Dservations: Heart Kidhey Liver "Nottlet; yeilow raised lesions, 0.7 ard 0.9 "Enclbardghead. pasterior castate lobes. "Enlarged gastric rugae "Cortical vacuslation, altidocal, soderate Wwaictairftaictails,,wicnrionaailc novssprative, ""PCoarrtaanlicwporoongcrelsesairvecenlelphironpfaitlhtyr,atew,ildwild CNeyssattoaicdytdeegealnteerraattiioonn,, mvualtwisfloactaeld,, swoidledrate RHeepgaatleoscyytteosiasl,teraasttieorna,tebasophilic, seterate SPpreocjieecst:MRaasther: 02810012 sommrizes st ge: 1 268 C008SS5 ISnudainvairdiuzaeld RSaicnrgelsecoTpbiaclaatnedMidcnrionsalcopRiescorOtb.se(rcvoanttiionnused) FL-L43: Too YeaRrikOerralLaTboorsaitcoirtiye-sD,acIongce.nci3ty Study in Rats Table: 2 fFrastnea:l (Nbaeasbtesrt106R) TTeLrainal SSaecriMfailcee rowpt (5) FE-1AD 300 ge NierosLcegpic servations (continued): Lys Vote nesesteric! Ffiatrucirteasrsy Stomach .~ascular sineralizaticn, wild Hesorrhage, local ares, wartet "HHeeanasnrghiaogsea,rcwoinld "hCyisnt,apaartsredghiys,taleiosderate "HEoxetneancsairvceinoinnfsiltration inte sebescosa ard wwistcoutliacriisn.dex.WellProdbiafbfleyrenptairaiteetsa,l high cel? erigia. Tumor cells in lymphatics, The following tissues were fuse to be within normal tinits: Brain, farts, Spiral Testis Cord, oe Epididyeis, FaPrrrooswt,ateS,pleTehny,roiSdw,ellPaIrnattehsytrianiee,, LTarragceheaI,nteEsstcipnhea,gesU,rinSaarlyivlarayddleirn,c, Ere. final Noster? IRI02 Se Male Brow (5) FEIT 300 pp Fate: heeh= 108) Terisal Sacrifice Macroscopic Dservations: Microhsosraepsiacl Dasrvations: Heart Kidrey Liver tung Lyaph Node (esesteric) Purcreas SpTleseteins Epididais Thyrsic Ho visible Lesions. "hMaetsuallalraryhycpeelrlplahsyipae,rplcaasriteas,, ffooccaall,, wwiilldd "Wwyietciafrdoiatli,s,scihlronic nonsugpurative, "Chronic progressive nephropathy, wile "Wpeogrtaallacymtoonsoinsu,clesairniacaelll infiltrate, aild "AWlavsecsallaarr mmcirmsrgahlaigzeast,ioni,le#ild "Heaorrnage, ile ""IHselneotsidceelrlosiasd,enownisld "Vascular aimralizaticn, 114 "C cell adeno BThreainf,allSopniimnlg tCoirsds,uesBowneereMarfroouen,d tSotobnescwh,ithSiwnallnorImnatlestLiinnei,ts:Large Intestine, Urinary Bladder, forts, Prostate, Pituitary, Parathyroid, Traches, Esophagus, Salivary Bland, Eve. SPpreocjieecst:MRaasther: 02108012 Somnarized 5148 Page: 105 269 00556 BEST COPY AVALABLE oe Laan ee pr wo SunaSr74iPazgees1d06 270 C00657 ISnutainviirdiszaeld RSaicnrgalsecoTpaibclaatneedMiMcraoslcopRiepcorDtb.se(rcvotnitainnsu.ne) FLAT: Too YeaRrikeOrralLaTboorraitaotryi-eDsa,coTgneen,ici3t0y Study ie Rats Table: 2 AFoaitnea:l MNeaebkesr:1661!03T6e0r5ainal SSaecxrifMailcee rows: ( 5) FE-143 300 pou Ficrescapic servations continued): The fotlouing tissaes were Fouad to be within normal Hits: Bfroaritna,, SPprionsatlateC,ordP,itBuoirtearyFa,rrAodwr,enaSlt,oaaTchh,roS,aalPaIrnattehsytrionied,, LTarragcehesI,nteEsstoipnhea,gssU,rinary Blagder, Lyoss Note ausecteric), Pancreas, ye. foiual Musbert [306 Sex Male Brow (5) FEAT 300 gpa Fate: heers 106) Tersinal Sacrifice Pacrsscopic servations: NicrosHcroepniacl Gservations: Kite Liver LPuarragthyroid spieen ka visible Lesions. ""hCahtualrair hpyrpaegrrgelsassiivae,nceasrrtoepsa,thfyo,calw,ivleds ePrrtelaolnepahcrniatniusc,leaarcutcee,ll1iilndiiltrate, wile "Nieassaclaolsayrtowsiiesr,alsiiznaitaiaoln, wl ""NHoetncesxiadneirnsesdi,s,rowtilin plane of sectior. The following tissses wre foun to be withic rermal Limits: Urraiinna,rySBpliartadlerG,orsf,ortBao,neTPeasrtrias,iEHpecairtd,isS,tornaecsht,atSee,alPitIunitteasrtyi,ne,ThyLriorigde, ITnrtaecshteian,e,Escshages, Lys Node taserteric), Pancreas, Salivary Bland, Eye. foinal Noabert IR3607 Sex ale oust | 5) FLA1AS 300 gon Fate: teers 105) Terminal Sacrifice MacroPsictoupiitcarOybservations: Microhsicroepniacl Dservations: Kigaey LLiunvger Pancreas "Henorrhagic ass, 11 0.7 ca, "CPoerstcihcralonvcayctuoanlsa,tiobne,niganu,tiufnoiclaalt,eraslcterate "LFarrealnoincesphrriotgirse,ssiavceutea,ehrsocfaeartahtye, wile Hrserglasia, pelvic epithelian, diffuse, aild ""phoarstcaullarwownicnelraalairzatceiloln,iniflieltrate, wild "Hhicviensalrarataraecgrhyo,phawsielsd, il Hyperplasia, islet cell, moderate SPpreocjieecst:Naantber: 0281080012 Suanarized STA Page: 107 271 00658 COPY AVAIL ABLE iSanario nSoeeecTtoaatesobidmst8BCorni BE Re: a Yur Ba Tosi copay te is Rts 2 v FlwSe Sei ent (9 [ar-- ne ---- "rtne oSrhaaetn SHronami,ie snw,i nti, win Eetr nae pEnereope)s, sui, ts vos i Eins moeeshOaorpTbet,,UBncWrSla Msotiv,ELnr ttn, ht PCrean leeaaSe eis an 9 70 on aerpagiioncc tOeiti:on hed tae eon, Lf in Gt, pat tom aer sa -- ieseviitail, ae or eottinMteaasnyaanetsi hat, wiewie - oiotni,etitn,wueeit ui wo ihFeaeaitwsnredeoenansiAto,, ositee Trtans pfrarn ion ipIetreeeSnenaGsesowrrre onttStbedestbhire rndthit sull ety n, Le sie rat ke ns, Poses Si Sts ept--irs onan Suanized Sit Pages1008 0625792 ISnudainvairdiuzaeld MSaicnrgolsecoTpaibclaatneedMiAcnriomsalcopRiecporOtb.se(rcvoanttiiosnasnt) FO-443: Tue YeaRrikeOrralLiTeorraitcoirtiye-sD,ncIongce.nci3t0y Study in fats Table: 2 AFnaitaea:l (NWaedekesr:108[)36Te0r9ainal SSaecxrifailcee oust (9) FLAIAS 00 poe Nacrascopic hservations: Microscopic Oaservations: [seirteeal Live Lrg FLayrcsreaNsode Caesenteric) Parathyroid Testis/Epididrais Ne visible Lesions. ""NCoidvuolnairc Wppreogrrpelsassiivae, nctorrotegsa,thfyo,calm,iniweialld "PFeorrttaall sBoinloenudcilcetarprcoellilfernadtiilotnr,atwei,lewild ~Pveassaclealcayrtawsiinse,ranliilzeation, wild "HSeisnoursrohiadagle,elcotcaaslia,araeisi,d saferats "hPcoilnyaarrteartirtoipshy,, waxotdeerraattee "~KLeetyteixyancienleld,bympeetrsl56aspila,anefoocfal,secmtiiloen The folloning rics, Spiral tissues were fund Gore, oe Marrow, tSplbeeen,witHheiant,naSrtoasacThi,ntSsc:ll Intestine, Large Intestine, Urinary Siadder, Aorta, Prastate, Fitoitary, Thyroid, Trachea, Escphages, Salivary Bland, Ere. SFraitneasl ebsortdser:1061)83T6e1r0ninal SSaecriMfailcee Groups ( 5) FE-LAT 300 pou Mcrosczsic Diserations: LiTvesetris/Epitidyais Microsbcaorpesiacl Riseraticas: LViivgenre: Lang TFeasstcirseaEspicionis F"Teenstpeasleapfpaecair. sonesat sual. "~PChhercosnhirconpsrcoygtroensss,ivbeenniegpnr,oguantihlya,termaille "FHoerptaatlocayotneenvuacclweoalraticeolnl, imnldtiildtorcaatle,, nile auld CRyesstaeliodcytdoesgiesn,eraatiinoina,almltidocal, wild ~Parsecuaalcanria,wiinnetrearlsitziattiiaoln,, cwhirlodnic, mltifocal, Paelrdivascalar sonoaclear infiltrate, wicinal "AHceisncarrrhaagter,ophlyo,calwiladreas, soderite "Hineralization, Tubule atrophy, tsapbeurlmaart,og1en4esis, bilateral, wirkes PSpreocjieecst:uRsaetr: Q2810R0012 Suarized STH Fuge: 19 273) C00660 TSarriios StfioiernnTLevirlittrRivgaalToe,fs0tBrCeonetnin FE: To tar Bl ToySopris Sey in fts ie2 TFers tWhones08BTira Sw ilfceh Gr (5 E10 0 PR Tae-------- tFeaatiwtomnpstaia, sic, wlan, te fhreant, Stina StoratsBnwrehofnun,d S1ebo,irtti,coSromn]icL,ieSsel] ntetioe, Lore tein, UaeyvaBtawiessBitrt,, eSsotver,y iPtR, GBe Fates, rahe Exit uCtrr tveres10BTtrail rSwiilte rn (5 F163 0 [rToR -- Foanalne ftoicnaaeon,al Isis, 07 ca [rrme -- SCoriticacl vaechtai,,caftoeca,l,ielrin wrte cAitrlanityee,1m1w0 iigrestive ites - FA eairan erannce,col wn--milte--, ile Geeaentdcsredt paiwcimtto,sn,,imtWcoilaengsh,,aiaaellde WrTallasaacsoremssiofessiinie col hitnss, May 1 rGalage, virsa--s, --arse--cotral isd Filed Prroiss fevroa,roaies orate et wind, sing Sinn nt iEnvtietne,sireet,staorinsee of ect rsa tSotpevosiilsti,ci, hWeasSpeaastcicstkhhlaen.by ornitnNaabter: ccRALE Saneize soe60100662174 Saabnorideed ASinTleETRbla1teddrieatseprttrattiionnuse RARE To erikae LkToorsraryes,coee,ct Stay in fats na 2 rFabs toweer100T ) TeraS i SurMlie Gr (8 FT WerescoosNc Gsention contin: Jet nang, ising nhHaeiynf, iScieisrtCri,Kseetosew,rTeersoftensngd dtSoioabeeks,w,itShtironensrithemS,eliP]tiaIttna:trens,tin, puhrgdeete(setri,ic, re. FFotnt tatnee 5BFEd De Se mle Grog 9) F180 Retsea Gsetins: PTor wa ---- tGooeon ws Torraess tTiiaaltermsTnbe,45s1ta4r0eTtoe wen cf Gat Ton. Crorotebailainn,afc,dison FFaraarha abiemuteprcatisfreefici,laeidas JWilbfleet, testa pte, iLcagesreenrlofieartaens wwiit fue Ehiian,bwurer,,aiwwriiee, atte oleesaat,esAwAe C Hi he aioe tses re ot 0 be within srs Listed FSLriaairnn,ysSpSiGnaaadlti,Ceorrdfe,o,rBtLo,neTheMsatroirstoew, vScplieetnr s, ,Heaorvt,atSeto,sacFhk,itSeaarlyl, rato Intestine, LargreiIontnestiSnet,ates Fwitle eNeaks106I) TIras SSeacrBelee reg (5 FG 0m Weesiss Owdriatoimosns: Werasanpeiyc Gratin: lw ERR ---------- rBaernale wparaemrietsievre cslspieintattea,idwile Eait eration, stl Howl SFaesse:Naatsr: amcson2 Semriet si pe 11 275 00662 ISnudeinvairdiuzaeld RSiancgrloescTpaisculaantdedMinciraoaslcopRiecporDtitr(vcoanttiiannused: BEST COPY AVAIi ABLE FAIA Too YeairteOrralLaTboornaitcoirtiye-sO,ncoIgnecn.ici3t0y Stuy in Rats Tale 2 fFartiee:d tKhuebeert106I7 RTeArwinal SSaeccriMfailcee Bros: (5) FOLKD 300 pa HicraLscaopc Oservations (continued): pSreoestnate Testissidiynis ".discal sreralization, wild Hives scrophages, ail ""Hteatwsseciadneirnsesds,, swiislsding Twotnelraeteatropny, aspereatogenesis, wilaterl, Leys cell adesocs, unilateral rTaheinf,olSlpoiwnianlg Gtoirses,ueGsenweerMearfroounn,d Hteoarbte, wSitthoinnen,oSramllLinIinttse:stine, Large Intestine, ULryianparoytBela(sueers,teAtoeritcah,, PPiatnucirteaarsy,, SMarleisvarly, lTahynrdo,id,freP.arathyroid, Trachea, Escphass, fFartien:l GKhabeeers106I)RST6e1rSminal SSaec:riMfailcee Group (51 FE-L4T 300 pp RacroPsictouiictarsyervations: WicrosTceosptisc/Espeidriaaniis t Khienreenyt Liver lg FFiatruattahryeyit Salivary Sand sToelsetis/Epidionis Hiagshs,t 0t.e8stcias Gsiuaa,l, ""SCihrnosnoiicdaplroegcrteasssiiav,e cneoprhtreo,patwhiyl,e exdeate oCrytsatolntwrdorgmeurcalteiaonc,ellmintdiifloicrailt,e,wi#lidc "Nhesaasleacnytossntesr,alsiinnaitniioln, ails HHeesezsrirahragem,calhocaag:esar,easa,ilwild "-hHaetereoxmanined, nak in ple of sectien SaElxatdenesiitviesh,ypcehrrpalsaisci,a maanrdkeadetilasia of duct "reercistihceelriscsni,s, wild "iTrakbelde atrophy, aspermatogeesis, unilateral, BTrhaeinf,olSopniinanlg Ctoirsds,ueBsanweerFearfroonw,d Kteoarbte, wSittohwiinchn,orSmm)allLimIinttse:stine, Large Intestine, PUarnincarrays,BlEaydee.r, Aorta, Prostate, Thyreid, Trachea, Exsphaqus, Lysh Node wesentric), SPrpoejceicets:aabter: GZBICROO12 swan 18 Pa: 1 276 ~00663 BEST COPY UAL { Svunrai nSiangloecTbcslaitdedcnraadspsrGt crstinust VP Tl.F403: Teo teRrikGeralLaTboroatsorties,caIgnnc.ict3y tad in ats Tae 2 iFateeh WVeorteer 2h1 iFusnd BeaSe Nae Gross (5) FG 300 po Wr[sschaichBarations: Rcriooiec asrations: lve "tare, 05 co tia. "FOorrtaailcsperongriesosirvecseolvaiamtihtya,tew,iiaeaile HCeiattaoytdergansesaltaiotno,n,almittaicfeec,al,siwdnt Necross, altel, sorte Lung sFulratets SSaitein lane "dVsaerscrlulheargesmcinrdesritailugiszeas,t,iomna,rleewile hpiemresnis, sin cll, sorte SJeoutciedarrssei,s, aKiislieng rTaheinf,eSlroan Ciosrs,esRowneeMarfruone, Hteerbte,wSitthaicnhe,eSnel]LiItntee:stine, Lure Intestine, EUupnhagisE,idyeerh, Yfoodrote,esToesttiesrict),tEsr., Prostate, fires, Troi, Partha, Traces, Fblern wNeonses100F) TErenal SSuerifKiaclee Grogs (91 F010 500 pe . Warslsivaeirc aration: Worersoaiac, Baration: tLitry TM HoCpenatrtsesalolbee,sale rset is, 1a da, "raSairntnuiscioaildarliocrsceealsnasitvsioe,n,gcarmhtietrsi,fpuic,alle, iilted TaForttaulrseonsccleleasiocra,l winlftiilsteraatle,, siilmeul SWecalrociyeiorfiosc,l,sianrii]el HTsraatboeccuellalralpiatcearr,cirsony tue cells --sskaulatredsn,ertaleirastieont,otmiilce activity. Hear mrepages, 416 BTrhaeinf,llSounnmg oirses,aBse weeNavoasns, Stgoibeen,wiHtehiant,seErtwiacih,stSs:ul Intestine, Lrge Intestin, SFpreocyieecst:Naabter: zBEROL2 Swnarizes ST Pages 12 277 00664 Suanarizes Single Tablated tinal Report (continued) Inthvitaal MaFcirtoesrcoLpiiscoraatndoriMeisc,rosIcnocp.ic3O0bservations FL-LAT: Too Year Oral Toxicity-Dacogencity Study in Rats Tale: 2 nFiatnea:] (NMaeedtesr:1016)03T6e1r8inal SSeacxriafilcee rout (5) FE-143 00 pou The fFeilclroansiczogpitcishssueesrvwaetrieonfsouncdonttoinbueedw)i:thin normal Jisits (continued): Urinary Blagder, Esuphasus, Lyesh dNoordtea,aeTseesnttiesr/iEcp)i,diPdaynacsr,easP,rosStaaltiev,arPyitBuliatsa,ry,EyeT.hyroid, Parathyroid, Trackea, SFaotiea:al dKeaetresr:106B)T6Te1r9ainal SSaeccrtifMiaclee Braap: 9) FC-143 0 par MacrLoisvceepric Dserations: "Raised lesions, 21 1.5 ca, wediar doses. Kidney inary Hagder "Hytraneshrosi, 1eit kidaey. "Histened inte atdonen, Hllec with cark . colored Fluid. Wicroasecreonpsitc Baer ations: "Sinusoidal ectasia, corter, wild Kidney "CNhortosnliacr phryopgerrepslsasiivae,nschorrtoepra,thfyo,calw,iniancaleite Hytroneshrosis, bilateral, ail Liver "fCaorsttaolidaedneogneunceireaatrionc,ellmlitniffiolatarla,te,wiwliele Fegalacytosis, wild HPeopoartloycedlilfuflearrenctairactiend,onadmoid and tradecular fe scpoalttaerrnsa,inewreadleiaztaetiomni,totwiicld activity. Salivary Eland NHoetsorerxhaangier,ed,lecwailssairnegas, moderate wriry Bladder "EHpeirtohrerlhiaagle,hyfpoecragll,asaiiam,iaasliuple, diffuse, ald TBrhaeinf,olSlpoiwnianlg Ctoirsds,uesBonweerMearfroouwn,d Stpolebeen,wiHtehairnt,narSetaolniclhi,sitSsw:all Intestine, Lurge Intestine, Gorka, Testis/Epidinis, Prostate, Pitcitary, Thyraie, Parathyroid, Trachea, Esophagus, Lyap Mode nesenteric), Pancreas, Eye. deial Mober: 103621 Sex Male Beaupt (5) FLA145 00 gan Fate: Meeks 106) Terainal Sacrifice Wacrascopic servations: FicroKsicdonpeiyc Bsarvations: ko visible lesions. ~Dhranic progressive nephropathy, wininal SPpreocjieecst:Mafsather: 0281K0012 Samwariced STi ges 114 278 00665 oSanndrizg rSoigsehesLT:bel1ntaeBo,eranTees.Be Gcradtie)n Re To tur Ba Toscy Stay be ats aie2 rFait tohret1BETLrial SSuiitaceh ron (9 F650 [fvEa ----"rpaatacsrpsmrsoticecsallaliiitotc,,a4wits fwsries AiWliymrieea,,maiwtin0op,inesoef ection SSioonns Bt TSieixkiatne,s aavloen, seas FrThreiaefsniSlHmaeiirrytdi,KersRkonwerTeTakfrroanu,niBtiibel,wSitthoHinwa,ovraSm,al]FTianttee:at,iKoLuwreaITnssetn,, Toes Emi, gh Ne neater), Paras, Ev, TFitos tNhsaee10I8 ETSria SSuerifaicee rot (9 F020 [---- Rosse Barats a5 sil lin. pa ites ScSetnialsilewayeitetnis,n,acofereesrl,,asw,hldeled tir SeKanettaar,sewswiiafnteo,cni,twiwiddnte, ad os AeFcestriin,ssr,aaoraii,, awlvdai, aif, Le ee antricl fBivrt w)re, ie SrHoartaiytne bse SArehesiathnaantnee,, saaatrse,eissawgiadn, etre Testis/Epididysis. "Vascular mineralization, wild VhreiaafylSlBonoia)giratritsKyeisrJotnwerTeBarrareon,s tSooiobson,twibt,hitn sTrrSaclesw,iiEscg:ulel ,etertei,nF,rLeueresTate rcoitns:Nfrt: CCRALE Sei51z0 raege s55 279 00666 ISnucnhwvairdsuzale MSCinTgOlReCOTpiibculaantgedMiicnraoslcopRiecsoDrtbse(rcvoanttiionnused) Hiker Laboratories, Inc. 3 FEA: To Year Dra Toxcity-Dicogenicity Sty in Rats Tales 2 final Naater? 16-3620 Se Male row (5) FE-14T 300 gpa Fate: (Mest 901 Sacrificed in extrenis MacroPsictoupiitcarDyiservations: "Heaarrhagic mass, 13 0.5 ca. KLiidvneery ""SPloisgshitbllyy penallaerged and pittec. MicrTosecsotpiisc/Espeirdviattriniosns: "Both testes appear somewiat sll. areal "CBoerttuilclaalryvacceulallahtyipoenr,alamsiitai,demclatli,fcas:altg, eile sidney <Chrnic progressive negrmathy, woderate Liver "HFeoprtaatlocyatoenovnaacculaelaarticoenl,l pienrfiiplotrrtaatle,, aasiltdeite Lng VParsecwuolnaira,aiinnetrearlsitziattiiaoln,, #114 cironic, wltifocal, Hwiivledslar sacrshages, wwtidocal, ild FFirtausittaatrey "Fbrioesntcantaitis, acute, sgpurative, mrie . TSeistteissEididais "Hescsiderosis, wild "Tubule atrophy, spermatogenesis, bilateral, wried The following tissaes were found to be within normal Liits: rUraiinna,rySpBilnaadlerC,ordo,rtBao,neTMhawroriodw,, HPeaarratt,hyrSotiodn,achT,raScheeaal, IEnstcepshtaignues,, LLayrgghe INnotdeestniensee,nteric), Farcreas, Salivary Shad, Eye. Pfaitnearl(Nheoeirs:27B) ESuSerificedSein eMxatlreenisGrow (9) FCAT 00 pon FacreSosfctopTiOsbsseesrvaoteicotn)s: MicrSopslcoepeinc Bservations: Liver Lrg "Large sltinodular was, 9x 8x bc, in oLfestsanmecmkyasnldantdhrooratsraebgiivorn.y sPohsasdibloryigin, Mass contained several cystic ares "Stohsaitblwyeresliiglhltelcy weintlhargaeudr. fii "FNoerctraolsisw,ovfrouccall,eailcdell infiltrate, wile Negalocytosis, ainiaal "Tnhertaassbtuastic neoplase Lsiarlgievatrhyrogslbaunsd ctoonrta.inineglttiuptlore csealallsl fron aetastass of salivary tus throughout lung. SPpreocjieecst: sftuetr: 0281080012 surizes 518 puges 1s 280 00667 SInudainvairdiuzaeld WSaicnrgalsecoTpaibculaantdedMidcnrinoaslcopfiocrtD.ose(rcvoanttiionnused) Riker Laboratories, Inc. FE-U43: Too Year Oral Tosicity-Dacogenicity Study in Rats Table: 2 fFraitnea:l eNeskse:rt 210)83S6a2c5rificedSexiin MeatlreensGrow (5) FC-143 300 pp MicrosScaolpiivcaryDiBslearsattions (continue: Spleen "tHairgchilnyonacellular, amplastic tor. fevers to ohfavsealairviasreyn gilnanpdarottiisdsueglaarnodundducts.ass.Seal ric "wHoetueartaotpeoiesis, extramedullary, increased, BTrhaeinf,olSloowiimnlg Ctoirsds,uesBoneereNarfroowu, Ktiodnbeey,wiHtehairnt,sorSmtaolnscLhi,niStwsi:ll Intestine, Large Intestine, TUrraicthaeray, Hsaogadhearg,asA,erLtay, sTeKsotdies/(Gapsisceindtmeirssc,),PrPoasntcarteei,s,PiEtruei.tary, hrenal, Thyroid, Parathyric, AFraitne:al (Nbaebetesr:1061) 3Te8reinal SSeacctrifMiaclee Groups (51 FEA143 300 poe Razrascapic Observations: Microscopic Dserations: HYairgenreayl Liver Lung Parathyroid Spleen Xo visible Lesions. "~CCohrrtainciacl pvraocguroelsastiivoen,aufgohcraolp,athoyd,ersaotseerate "Portal aenonuclear cell intiltrate, ald GPyosrttoalid bdielgeendeurcattiporno,lifmealrtaitfioocna,l,wialidle "KVeagsacluolcarytomsniesr,aliiziatmicn, soferate FHlovsecsrlrahragem,acrLoopchaalgeasr,ess,ilsederate ""HHoetscesriatneirnoesdi,s,aowtildin plane of section TBhreainf,ollSopwiirnagl Stoirsts,uesBowveerearfroonw,d tHoeabrte,wiStthoinnachn,ormSaalalLimIinttse:stine, Large Intestine, Urinary Bladder, Aorta, Testis/Epiidyss, Prostate, Pituitary, Thyroid, Trache, Escprages, gh Node (aesnteric), Pascress, Salivary Eland, Eye. SPpreocgieecst:tfeatr: 02180012 Sonnrizet 51 puge: 17 281 C00668 SInutaimvaireiuzaeld MSaicnrgolsecoTpaibclaatneddMiMcironsacopRiecpoOrtbse(rcvoanttiionnused) Riker Laboratories, Inc. 3% FE-IA3: Tuo Year Oral Toicity-Dacogenicity Stuey in Rats Table: 2 Arial Nonbert IRI Sex Wale Beoust (5) FL-I4S 00 poe Fate: (eke 108 Ternnal Sacrifice Macroscopic Bservations: FieroHsecaorst:c Osrvations: idney Liver ng ThSaylaiivaery Gland "He visible Lesions. Mawcitairfdeintails,, wcihlreonic nonsuppurative, "Direnic progressive neproathy, wile "Ppeosrtaallecynteorsaisc,lewairlecell ndilirate, ald "Aplavsecsallaarr aacirseorpahlaigzeast,ionw,ileail Heacrrhage, local areas, erate "SUialltaidsernaintidsi,alchcryosntic, arket The following tissues were found to be within sormal Linits: BUrraiinna,rySpBilnaadlderC,ordA,orotan,eTeasrtrioswE,piSpliedepra,s,StoPvraocsht,ateSu,alPlituIintteasrtyi,neA,drLeunragle, IPnatreastthiynreo,id, Trach, Esephasus, Lysh Node (nesenteric), Pancreas, Ere. Aninal Maabert 163630 Sex Kale Groups | 5) FL-1AD 300 poe Fates Wests 106) Terninal Sacrifice Macrascopic Oiservations: Wicrohsicroepniacl Bservations: heart Liver tury PiTteustiitsaErpyigidais ko visible lesions. ""SAiynoucsaoriddiaall efcitbarsoisai,s,colrotcearl, awrielasd, aild WIyoeccaalrdairteiass,, cwhirlodnic noasupperative, FCayrsttsa]idsodnecgneuncelreaatrionc,ellmuitnifdiolctarlat,e,wialidl "Haesgcaallocayrtoasiimse,raaliiznaitnilon, wild ""lsactaelxaarnineeism,ermailsisziantgion, sild The following tissues were found to be within normal Linits: UBrrianiae,rySBplinaadlderC,ordA,ortBao,nePrMoasrtraotwe,, STphlyereani,e,KidPnaerya,thySrtooinda,ch,TraScwhaelal, IEnstoegshtaignees,,Large Intestine, Lyash Node aeserteric), Pasreas, Salivary Glan, Eye. SPrpoejceicets:NuRsabter: 081CR012 Suanarized ST Pages 18 282 00569 ISnudainvairdiuzaeld BSCiPngOlSeCOTpaidculaantdedMidcarioslcopRiecporOtb.se(rcvoanttiionunesd) FL-IA3: Tuo YeaRrikeOrralLaTboorxactiotryi-eDsa,csIgnce.mci3t0y Study in Rats Table: 2 AFoartaea:l (Neaembtesrt10R6ITEeSrminal SSaecxriMfailcee Beoupt (5) FEAI4S 300 gon Wacrascopic Beermations: Microscopic hservations: Sarena! LKiivdenrey Lg Salivary Blast spieee .Xe visible Lesions. "NFoadtuellalraryypecerlsllahsyipae,rplcaosriteas,, ffooccaall,, wwiisilaeal ""DPhorratnalicasgrmoegnrcecslseairvecpelelshriongfaitlhtyr,atea,lleail Portal bile dict proliferation, aiid PHeegpaaltaoccyyttoesivsa,csaliantiimoln, local ares, wile "Avlavsecoullaarr nwaicnerroaplaigzeast,ionw,ildsoderate "HSeisaolrartheangiet,is,Loccahlronairce,as,aurskcedderate Tshleirdee,weornelytuoonesencatsioinnsvolofvedg.land on the Hesssiderasis, wile The follauizg tissues were found to be within noraal lints: Urraiinna,rySBpliandadlerC,ordA,ortBao,neTeMasrtriosw/,EpHiecairoty,isS,toPnracoks,tatSe,ulPitIunitteasrtyi,ne,ThyLraarigee, IPnatreastthiynre,oid, Trachea, Esoatagus, Lyi ede mesenteric, Pancreas, Ere. risa! Nasbert 3632 Se: Male Browpt (5) FC-IAD 300 pp Fate: Weeks 108) Terairal Sacrifice PacroLsicvoepric Ghsermations: RicrTosecsotpiisc OEspedrivtayteiiosns: [re Liver . Lung Pancreas ""FPoaulepamlaes,foc1i5, cn dia, "Chronic progressive nephrapathy, moderate "HPeorptaatlocystoenavuaccloelaarticoenl,l milntfiildtorraatle,, awiilldd HPeessaatlaoccyytteosiasl,teraaitlidon, basophilic, mild Single subcapsular area of buscphilic aalttierpalteionc,ytoMploaustaiconevaNcaulolesof. th cells have "ascular wneralization, ail AHlevseasrlrahrages,acrfeoschaalg,esa,ilail "Hyperplasia, islet cell, soderate PSrpoejceicets:Muastter: 0281080012 Sawarizee ST4E Pages 19 283 C00670 Suanarized Single Tabulated faiaal Report. (continund) Individeal WRCirkoesrcoLpaibcoraantdoriMeisc,roIknocp.ic Diservations. FOLATE Tuo Year Oral Toxicity-Dncogenicity Study in Rats Table: 2 fFraitnea:l (Naenbker:1085)36Te3r2minal SSaec:riMfailcee rowp (5) FC-LAT 360 pp MisrosTcessgtiics/EDsiisteirdvyaatisosns fcontind): "Twaibrukleeg atrashy, aspernatosenesis, wilateral, Leydig cell adenom, unilateral The fallonirg tissues were fwd to be within norma Limits: BUrraiirna,rySpBiarsadlerG,ordB,arFtae,ePMraorsrtoant,e,SpPlieteuni,tarHye,artA,dreSntaola,schT,hySrwoaildl, PIanrtaetshtiynreo,id,LarTgreachIenat,estEisrse,pges, Luagh Note assenterich, Salivary Slant, Eve. Arial Kathe: 16333 Sect Male Graupt {51 FOALS 0 pan Fate: (beets 108) Terainal Sacrifice PacraEsrceosic servations: sidney Wicressecroepniacl Bservations: HEeeart Kidney Liver Lung Thyroid "Bpcity, right eye. "Bilaterally pale an pitted. "SSiunnugsloiiodnaelsrcantaasia, corte, wile Large, well differentiated tur arising in sfiebdeurlslaanogf Loaergeglgaunrd.glioCnomcpeolslesd. of nerve heratitis, chronic, soderate "MTyosccaardairteiss,, cahielsdaic onsugurative, ~Drheranoifcppariorgrpersessievnet nesheopathy, earved "Fortal aonanuclear cell infiltrate, ail GPyosrttoaild bdielgeendeurcattiporno,lifaelrtaitdioocna,l,aiwiidld HHeegsaaltooccyyttoesiasl,tecradteiroant,evacate, aild "AVlavsecoullaarr amaicnreorpahalgieast,ini,lwild HFeearosrvrahsacguel,arlosceaclouacrleeasa,r maifliltrate, mivieal "Eysty colloid BTrhaeinf,ollSopuiinnagl tCiosrds,uesEowneereMarfroonwe, Stoplbeeer,witShtionwscrhe,raaSlualllistInst:estine, Large Intestine, ULryisnaahryodBelad(daeers,ntAeorritac,),TePsatnicsreEapsi,diSoalpiavsa,ryPrGolsatnadt.e, Pituitary, Parathyroid, Trachea, Escphages, PSrpoejceicets:NuRsabter: 0281080012 Suanarized ST Pages 120 284 00671 BESTCOPY AVA Fev SE 2 C00872 Sormarizes Single abulated Arinat Fert (continued) Indivitual WaFcirboesrcoLpiiocraatnadriMecsr,osIsreeg.ic Dbservatians BEST COPY AVAILABLE ree: Teo vou art Tnscity-trasmicty sey ie ats Tate: 2 frinal Norters RE Sed Male Grom (8) FCI Tot gan Fate: tsi 15 Toren Sazrfice The fWaiiclrsoesiczespitcisssueersvawteireonfsoun(tctoetBieztahis aol Liits (continues UCrpinearyheEsieasleeeers,teiteortiac, TePsatnicsreaGsi,tiEdrae.is, Prostate, Thyretd, Farathiesie, Trachea, Escphazs, Broned Merten BE Sen Male Bros | 6) FILE 0 gor Fated tae 08 Tesi Satritice mpEnec Ration: Tesuis Britis FicrasEcvoesic Gserntiaes: Heart iLicvteery tung LPaynscsrheaNsote taster) Testis Epigiyais "SuLcilslse,r satirnal joints, bilateral bing "Bath testes appear small. "hetheitis, syovitiss joints, bites, treat "Msyisncianarlditis, Sronic nonsperativ, fecal, ~"Dphorretnailc wpornoagnrcelsesairvecenlelhroinpfaitlttyr,atem,inimmialld PCoyrsttaalidbidleegednuecrtatiporno,tiifeorcaatli,onw,imaiimladl "Nveassacluolcayrtoisniesr,alsiiznaitniaoln, wild Aiveslar sacroghages, 126 ""Pborlayraarltoenrsi,tiwss,ltsifootcuarla,tesoderate "Tubule atrophy, spermatogenesis, Bilateral, wParlkyeatrteritis, soderate Vascular aineralization, ile BTrhaeinf,otSipoinniarls Ctoirsds,cesBowoarMearfroounn,d tSpolebeen,wiStthoiwnacnho,rmaSelalL]imiItnst:estine, Large Intestine, Urinary Bladder, Aorta, Prostate, Pituitary, Afreral, Thyroid, Parathyroid, Trache, Escphagus, Salivary Bland, Eye. PSreocjieecst:ufsaetr: 0281080012 . Sunrined ST Pues 2 286 00873 CA otpBk iTte a St 1 ts Individual Macroscopic and Microscopic Observations PET Pr i ae i a FO ch ay geeeisat: nz Fr. PO -- i Te ie smi py Tn Swit 10 n0i 62 : ISnudsiwvairdiuzaeld SMaicnrgolsecoTpaibculaanttedMifcnrinoaslcopRiecporOtbse(rcvoanttiioonusech FE-143: Tuo YeRairkeOrralLboTroaxitcoartiye-sG,ncoIngce.nici30ty Study in Rats Table: 2 FAraitnea:l GNeaibesr:108R)3T6er9minal SSaecriMfailcee Brow (5) FC-LAS JE pp MicrosFcaorpcircesCsoservations (continuetts Furathyrais PSiitlueeintary lot ena. nine, missing "hat exanined, not in plane of section "~Hhenesrsoimdaeresis, wild The follosing tissues were found to be within normal Limits: Brain, Spinal Cord, Bone Yarron, Heart, Stomach, Swall Intestine, Large Intestine, LUyraisvharKyosBeagndeesre,ntBeorrstcal,,TeSsatliivsa/rEypildaincey,us,EveP.rostate, Thyroid, Traches, Escahagas, final Noner: 63600 Set Male rowpt (5) FE-14S 300 pon Fate: beeie 72) Sacrificed in extrens Facrssccpic Diservations: Syfiaecceaner tisternal) MicroEscroepic Observations: soareenal Litivteorey Lung Sphere Stonsch ~"FGoassstirboliyntesswtailnlaelr ttrhanctsofrraoanl.stoaach to cecon Hidgihsttenadpeedswliitghhtlguys.atrophied "hraetraaltairtish,ypearcpaltaes,iaa,rkceodrtex, focal, minimal uLelscieornatiinon.right eye. Extensive corneal ""PGoartteaallusw,onopenlcvlieca,ewcielldl infiltrate, aild "VRaesgcaulloacrytoasiinse,ralwiizniamtailos, ale "HHlevseccsliadreramascirso,phwaigleds, ile Brophy, woterate "Gastritis, acate, iffuse, nile The following tissues were found to be within normal Limits: fBorrakisn,, TSepisntails/CBopridd,idBaoise,MParrorsotwa,teH,eaPrti,tuiSttaarly, ITnhtyersetiidc,e,FaLruartgheyrIanitce,stTirnaec,heUar,inEarsyosBblaagcst,er, Lyogt Kode tesenteric), Pancreas, Salivary Bland. PSrpoejceicets:Nuastber: 028108012 soared 57 pige: 1 288 C00875 Saudnirdeuadl MSicnrgolsecsTibcaaatnetNCirnoaslceRiecporOto.se(rcoenttiionnused) F143 Too YeairbreaLTeorsactaoriOe,caTpce,icty Std io Rats nate2 fFarteast tNhosee:108H) ATLein SSuatriiaclee Geos (51 F160 30 on [Ifri ---- [Haoon: ---- bert Ktieern wy tSaseenrs Testis pidinis "Yellonsh foci, 0.5c dis, sedan Lobe, "THhedeurlelasyec,elcohynpiecrplsasiam, lsocal,wes, aii BJrianviiceaprgehreislsive sheath, werase Syoertaisdeeenracteionc,elwlitniffirtarli,t,H6E1: [Hperrshsmti o-- le Csrrecsmersartiisone,oftnaoumrsai?vearscihotnectwiet,h Fort rSueaapshptirce,s,viceulllatsedi,n rtale are "eaersrdiage,wneorcalai,satwiielre, itd iSenwsaidaartornopsh,y,iwttderte eri cll ston, lateral Trrird,algoniirnag tCiosrs,ueshowwerevafrruonn, tSotobnechw,ithSinlroInwtestliinniet,s:Lire Intestine, Urinary Flac, ESitiaviyBaShtanid,s EFnt.iiary, Trad, Pirithole, rachen, ESamaes, Loh Kde este, Fiitve tNhaebter000Terainal SSuerifiMclee Gon (5 FC 10 5 [line-- r -- WarNeeesn aeration: hort tLiivtery sTeo.s wetted wali ale wes ic mic ~Neretliasl paeerlaastiioan,, cforatle,, iftads, wile ewiittiisaalg, aw ie era rFaratacl eprrogerecsstivesnllpadrit,raei, naiid Pioaratacyboilsesa,ctsiranfaaration, iid WEpierrleaosftinccretehae slightly ore ussilic crtoptasi any are coated, SPraojceoct:uastr: OLEH Sunizet STH Pages 125 39 y codes SInodainvairdiuzaelg RSaicnrgolseceTpaibculaantdedMidcnriaoaslcopRiecporhtear(vcoanttiionnused) FEAIA3: Tuo YeaRrikOerralLaTbooriactiotryi-esD,acoIgnce.nci3t%y Study in Rats Table: 2 AFvataea:l WNeabeekr:106I) RTeSrninal SSaecxrifMiaclee eaupt (5) FE-IA3 300 gon Microscopic servations (continued): Lung TSeasltiivsarEypiBcliudnntais "Ailavsecsallaarr awsicnreerpahlaigzeast,ion1, il ""HSaisaclaaldaerritiinsa,raclhirzoamtei,o,aasroiteedrate TBhreainf,olSlpoiwnianlg Ctoirsds,eesbonweerMearfroounn,d Stpolebeen,wiStthoinnacnho,rsaSlaalL?isiItnst:estine Large Intestine, LUyreischaryKodBeac(deesre,rtAeorritcal,, FPraonsctraetaes,, PEivteu.itary, Thyroid, Farathyroid, Trachea, Esopmaqus, fnisal Naber: 16-3605 Sex: ale oust { 5) FLA1AT 300 gon Fate: Geeks 108 Terainl Sacrifice MacroTsecsotpiiscEDpiisdeirdvyaatiisons: Hieroscopic Bservations: fHoritreed TiEescnpehyagis Liver Lung Farcress Parathyroid SSoafltivTairsysuBelsunt(thoras) TSepslteiesnEpididais UTrriancahreys Bladder "Fale ass, 13 cn a, let testis. ""Nroedtualsatratyipcenrepolgalsaisae, corter, aaltidocal, wild ""MCehtraasntiactipcrongercepslsaisvee phropathy, wile "Fartal aononaclesr cell indictrate, aininal NPeogratlalocybtiolseisd,ucstinpriomlliferation, aisimal "Pvraesacsuslnaira,aiinnetrearlsitziattiiaoln,, c#iolnic, sltifocal, Ewlivleeslar acrophages, wile "Hhecsinoarrrhaagter,ophfyo,calw,ildile "herons ""HSiisatliaodeeyntiotniss,, mcahlriognnica,ntsoderate Diffuse infiltrate of istiseytic cells in wiatetiisaasctilneaaltetigsisaunts. ceNllosd.eratIenfniulstbrearteof extends into muscle around bane. ""HLeencvsiideceriolsisa,denaclwsd, anilateral ""EMpeittahsetlaitailc hnyepsegrlpalsaesia, single, diffuse, wininal PSrpoejceicets:NuRsabter: 0281080012 sunvrizee si piges 1 290 C0067? dSoimvairdiuaaels RSianrgelseopTiiuclantdesWieoaslcoiBcgOsacrsattiinoest) FAS: To YeaRrikGeralLaTooraitcoirtiye-sG,cafponc.ici0ty Stuy in Rts Tae2 iFate: ehoimsers1080 ) Terinal SSeucrifWiaclee Grogs (9) FE-LS 300 pn Fresca rations contin); rThaeif, Sopinna GsarsdsEnwereRrorua,n tbsarbe,wiStthoianchs,oSruatlLimtietss:tin, Lage testis, Prostate, Ftattars, Tred, gh Roce estteric, Ent Fiateas tNheerees7)ASLcrificeSe1r eFexmtarleemGran (9) F160 gn RarHaenasry BSalaanttiors: Herreensal hsrations: Gsatraegyes ver wg Hbuarayr Sind Salivary Sane "Lnggeuimmilltainlopelrainessbtewsetan,es ws, Left 1sw0fa7c3e 3i.n5sicdae, eHpasstsiculwciehrataeidiyon oe oral fluid preset. SNietmsesrianliee,awsis,ingcorte, mies "pDorroanliciplreegdeuscstivperlnigfehrraptaitohny,, wa1sin Hseepitsncte alteration, vcselted, foal, uverlair,wcrlsocbaalgrse,asm,itailfeocl, ale oFitbraxsienoen,s aissivs et wane, ising "BHaeiea, nSpiina tCiorsde,esBowneereNafroruonwd, tSpeBee,witHheianr,srStlonscLhi,itSs:ul etestine Large Intestine, tUetaryNeBeataer,sefnoritcs,,WPeuncar,easP,itsEcea.ry, Trachea, Thai, Parathyroid, Ffatiesa eNwoneber795)-S0cr5iticedSein aFetmaelesrou (5) FCL6S S0 pe NarFoistcuoiitcrysernationst NicroEsscpphiacgeserations: LKiivdehtry Hewrrhgic uss, 0.8 cb dia. Heltvimcaisinnee,rliwziastsiionng, ald Heatscyte vicaslation, diffuse, wild SPpreocisees: Nhaabter: 2CHOIZ swnrize stage 1 291 00678